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Avacopan for the Treatment of ANCA-Associated Vasculitis.

The C5a receptor inhibitor avacopan is being studied for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. In this randomized, controlled trial, we assigned patients with ANCA-associated vasculitis in a 1:1 ratio to receive oral avacopan at a dose of 30 mg twice daily or oral prednisone on a tapering schedule. All the patients received either cyclophosphamide (followed by azathioprine) or rituximab. The first primary end point was remission, defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 (on a scale from 0 to 63, with higher scores indicating greater disease activity) at week 26 and no glucocorticoid use in the previous 4 weeks. The second primary end point was sustained remission, defined as remission at both weeks 26 and 52. Both end points were tested for noninferiority (by a margin of 20 percentage points) and for superiority. A total of 331 patients underwent randomization; 166 were assigned to receive avacopan, and 165 were assigned to receive prednisone. The mean BVAS at baseline was 16 in both groups. Remission at week 26 (the first primary end point) was observed in 120 of 166 patients (72.3%) receiving avacopan and in 115 of 164 patients (70.1%) receiving prednisone (estimated common difference, 3.4 percentage points; 95% confidence interval [CI], -6.0 to 12.8; P<0.001 for noninferiority; P = 0.24 for superiority). Sustained remission at week 52 (the second primary end point) was observed in 109 of 166 patients (65.7%) receiving avacopan and in 90 of 164 patients (54.9%) receiving prednisone (estimated common difference, 12.5 percentage points; 95% CI, 2.6 to 22.3; P<0.001 for noninferiority; P = 0.007 for superiority). Serious adverse events (excluding worsening vasculitis) occurred in 37.3% of the patients receiving avacopan and in 39.0% of those receiving prednisone. In this trial involving patients with ANCA-associated vasculitis, avacopan was noninferior but not superior to prednisone taper with respect to remission at week 26 and was superior to prednisone taper with respect to sustained remission at week 52. All the patients received cyclophosphamide or rituximab. The safety and clinical effects of avacopan beyond 52 weeks were not addressed in the trial. (Funded by ChemoCentryx; ADVOCATE ClinicalTrials.gov number, NCT02994927.).

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Risk of colorectal cancer in patients prescribed statins, nonsteroidal anti-inflammatory drugs, and cyclooxygenase-2 inhibitors: nested case-control study.

Several studies suggest that statins prevent some cancers, with one study finding a 47% reduction in colorectal cancer risk after >or=5 years of regular use. A nested case-control study was conducted within 454 general practices in the United Kingdom using the QRESEARCH database. Cases with colorectal cancer were diagnosed between 1995 and 2005. The effects of statins, nonsteroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitors, and aspirin on colorectal cancer were estimated with conditional logistic regression adjusted for morbidity, smoking status, body mass index, and socioeconomic status. We analyzed 5686 cases and 24,982 matched controls with >or=4 years of records. The adjusted odds ratio for colorectal cancer associated with any statin prescription was 0.93 (95% confidence interval: 0.83-1.04), with no trend in duration of use or number of prescriptions. For any nonsteroidal anti-inflammatory drug prescription the adjusted odds ratio was 0.94 (95% confidence interval: 0.88-1.00), with a significant decrease in risk with increasing number of prescriptions and an adjusted odds ratio of 0.76 (0.60-0.95) for >or=25 prescriptions. Prolonged use of cyclooxygenase-2 inhibitors was minimal, but for those receiving >or=25 prescriptions the adjusted odds ratio was 0.34 (0.14-0.85). Results were similar in the subset of participants with >or=8 years of records; the adjusted odds ratio for >or=61 months of statin prescriptions was 1.00 (0.67-1.48). In this large population-based case-control study prolonged use of nonsteroidal anti-inflammatory drug and cyclooxygenase-2 inhibitor was associated with a reduced colorectal cancer risk, but prolonged statin use was not.

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Health benefits of an adverse events reporting system for chronic pain patients using long-term opioids.

Safety data from long-term opioid therapy in the real world has been poorly studied in chronic non-cancer pain (CNCP). The aim was to design a pharmacovigilance data recording system and assess whether participation in this recording system improves pain management, enhancing patient's health status. A pharmacovigilance data recording system was conducted during 24 months. Data were self-reported by patients (pain, adverse events [AEs] and healthcare resources use) and physicians (morphine equivalent daily dose [MEDD] prescribed and suspected adverse drug reaction [ADRs]). Outcomes from patients with (case) or without (controls) suspected ADRs and cases follow-up were also compared with Spanish Pharmacovigilance System data. A total of 753 patients were recruited in 897 visits. Fentanyl and tramadol were the most prescribed opioids, 89% with concomitant drugs, pregabalin being the one with the most potential drug interactions. Cases presented significantly higher pain intensity (VAS 67 ± 26 vs 59 ± 30 mm, P < 0.05), number of AEs (8 ± 6 vs 5 ± 3 AEs/patient, P < 0.01), polypharmacy related to pain (65% vs 34%, P < 0.01) and MEDD (139 ± 130 vs 106 ± 99 mg/d, P < 0.01) than controls. Furthermore, cases presented significant higher changes in pharmacological pain therapy due to pain, unplanned emergency visits and hospital admission than controls. Physicians notified 168 suspected ADRs mostly related to neurological or psychiatric events and 8% of them were previously unknown. This data recording system provided important information to achieve a better control of CNCP pharmacological pain therapy, improving patient's health status and reducing costs to the Health System.

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A 5-year prospective assessment of the risk associated with individual benzodiazepines and doses in new elderly users.

To determine the risk of injury associated with the new use of individual benzodiazepines and dosage regimens in the elderly. Prospective database cohort study with 5 years of follow-up. Quebec, Canada. Two hundred fifty-three thousand two hundred forty-four persons aged 65 and older who were nonusers of benzodiazepines in the year before follow-up. Population-based hospitalization and prescription and medical services claims databases were used to compare the risk of injury during periods of benzodiazepine use with those of nonuse. Periods of use were measured for 10 insured benzodiazepines by drug and dose as time-dependent covariates. Injury was defined as the first occurrence of a nonvertebral fracture, soft-tissue injury, or accident-related hospital admission. Patient age, sex, previous injury history, concomitant medication use, and comorbidity were measured as fixed and time-dependent confounders. Cox proportional hazards models were used to estimate the risk of injury with benzodiazepine use and to determine the extent to which patient characteristics, differences in dosage, or in the effect of increasing dosage for individual drugs explained differences between drugs. More than one-quarter (27.6%) of 253,244 elderly were dispensed at least one prescription for a benzodiazepine, and 17.7% of elderly were treated for at least one injury during follow-up, of which fractures were the most common. Patient characteristics, systematic differences in the risk of injury in elderly prescribed different benzodiazepines, and differences in dosage prescribed for individual drugs confounded the risk of injury with benzodiazepine use. The risk of injury with increasing dosage varied by drug from a hazard ratio of 0.92 (95% confidence interval (CI)=0.60, 1.42) for alprazolam to 2.20 (95% CI=1.39, 3.47) for flurazepam per 1 standardized adult dose increase. The risk of injury varied by benzodiazepine, independent of half-life, as did the risk associated with increasing dosage for individual products. Higher doses of oxazepam, flurazepam, and chlordiazepoxide are associated with the greatest risk of injury in the elderly.

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Effect of pharmacological treatment for urinary incontinence in the elderly and frail elderly: A systematic review.

The prevalence and severity of urinary incontinence (UI) increase with age and comorbidity. The benefits of pharmacotherapy for UI in the elderly are questionable. The aim of the present study was to systematically review the efficacy of pharmacological treatment for UI in the elderly and frail elderly. We searched PubMed, EMBASE, Cochrane library and Cinahl databases through October 2013 to identify prospective controlled trials that evaluated pharmacological treatment for UI in persons aged ≥65 years. Elderly persons living in nursing homes were regarded as frail elderly. Outcomes were urinary leakage, quality of life and adverse events. We screened 1038 abstracts and assessed 309 full-text articles. We identified 13 trials of high or moderate quality; 11 evaluated anticholinergic drugs and two evaluated duloxetine. Oxybutynin, the only drug studied in the frail elderly population, had no effect on urinary leakage or quality of life in elderly with urgency UI (UUI). Seven trials evaluated the effects of darifenacin, fesoterodine, solifenacin, tolterodine or trospium. Urinary leakage decreased (standard mean difference: -0.24, 95% confidence interval -0.32-0.15), corresponding to a reduction of half a leakage per 24 h. Common side-effects of treatment were dry mouth and constipation. Data were insufficient for evaluation of the effect on quality of life or cognition. The evidence was insufficient to evaluate the effects of duloxetine. No eligible studies on mirabegron and estrogen were found. Anticholinergics have a small, but significant, effect on urinary leakage in older adults with UUI. Treatment with drugs for UUI in the frail elderly is not evidence based.

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Treatment pattern of familial hypercholesterolemia in Slovakia: Targets, treatment and obstacles in common practice.

Maximal doses of potent statins are the cornerstone of treatment of familial hypercholesterolemia (FH). Despite this, a substantial proportion of FH patients are either under-treated or not treated at all. The aim of this work was to evaluate, in a retrospective study, the treatment of FH patients, the proportion of FH patients reaching low-density lipoprotein cholesterol (LDL-C) goals, and reasons for not reaching LDL-C goals, in 8 lipid clinics in Slovakia dealing with FH patients. 201 heterozygous FH patients (50.8 ± 14.9 years, 55% females) who attended the lipid clinics at least three times were included in the study. At the first visit, 31.3% of patients were treated with statins and the most common dose was 20 mg of atorvastatin, rosuvastatin and simvastatin. At the third visit, 78.1% of patients were treated with statins and 24.4% with ezetimibe. The majority of patients were treated with atorvastatin (75.8%) and rosuvastatin (18.5%) and 31.3% of all patients were treated with atorvastatin 80 mg or rosuvastatin 40 mg with/without ezetimibe. However, only 11.9% of patients with the LDL-C goal level <2.5 mmol/l and 6.9% with the goal <1.8 mmol/l reached the level. Reasons for not reaching the goal levels were evaluated by physicians in each patient. Insufficient LDL-C lowering effect of treatment, side-effects of therapy and non-compliance of patients were responsible for 46%, 18% and 30% of cases, respectively. Referral of FH patients to lipid clinics in Slovakia leads to improvement in the treatment; however, almost 22% of the patients are still without statin treatment and the majority of patients do not reach the LDL-C goal level.

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Utility of routine left ventricular ejection fraction measurement before anthracycline-based chemotherapy in patients with diffuse large B-cell lymphoma.

Despite the lack of evidence, routine left ventricular ejection fraction (LVEF) measurement in diffuse large B-cell lymphoma (DLBCL) before anthracycline-based chemotherapy (ABC) is recommended by practice guidelines and required in DLBCL trials in the United States. We determined the frequency of the following in 197 consecutive patients with newly diagnosed DLBCL treated at our institution: one, LVEF measurement before ABC; two, finding of asymptomatic LV dysfunction (ALVD); and three, modification in treatment strategy as a result of LVEF measurement. The median age was 71 years, and 54% of patients were men. LVEF was measured in 128 patients (65%) pretreatment, including in 15 with prior congestive heart failure (CHF). The reasons for not measuring LVEF were: clinically low risk for ALVD (n = 32), medical frailty (n = 15), palliative care (n = 3), ABC not standard therapy (n = 12), and prior CHF (n = 7). Among patients without prior CHF who had LVEF assessed (n = 113), ALVD was detected in four (4%), with LVEF ranging from 41% to 48%. Four patients were not treated despite normal LVEF because of comorbidities and anticipated toxicities. In contrast, all four patients with ALVD received ABC. No patient had a modification in treatment strategy as a result of LVEF measurement. After a median follow-up of 60 months, among those who remained alive, CHF developed in 15% versus 6% of patients receiving ABC who did and did not have LVEF measured, respectively (P = .246). Our findings challenge the utility of routine LVEF measurement in patients with DLBCL before ABC. Potential cost savings to our health care system could be substantial.

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The ECHELON-2 Trial: 5-year results of a randomized, phase III study of brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma.

For patients with peripheral T-cell lymphoma (PTCL), outcomes using frontline treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like therapy are typically poor. The ECHELON-2 study demonstrated that brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) exhibited statistically superior progression-free survival (PFS) per independent central review and improvements in overall survival versus CHOP for the frontline treatment of patients with systemic anaplastic large cell lymphoma or other CD30-positive PTCL. ECHELON-2 is a double-blind, double-dummy, randomized, placebo-controlled, active-comparator phase III study. We present an exploratory update of the ECHELON-2 study, including an analysis of 5-year PFS per investigator in the intent-to-treat analysis group. A total of 452 patients were randomized (1 : 1) to six or eight cycles of A+CHP (N = 226) or CHOP (N = 226). At median follow-up of 47.6 months, 5-year PFS rates were 51.4% [95% confidence interval (CI): 42.8% to 59.4%] with A+CHP versus 43.0% (95% CI: 35.8% to 50.0%) with CHOP (hazard ratio = 0.70; 95% CI: 0.53-0.91), and 5-year overall survival (OS) rates were 70.1% (95% CI: 63.3% to 75.9%) with A+CHP versus 61.0% (95% CI: 54.0% to 67.3%) with CHOP (hazard ratio = 0.72; 95% CI: 0.53-0.99). Both PFS and OS were generally consistent across key subgroups. Peripheral neuropathy was resolved or improved in 72% (84/117) of patients in the A+CHP arm and 78% (97/124) in the CHOP arm. Among patients who relapsed and subsequently received brentuximab vedotin, the objective response rate was 59% with brentuximab vedotin retreatment after A+CHP and 50% with subsequent brentuximab vedotin after CHOP. In this 5-year update of ECHELON-2, frontline treatment of patients with PTCL with A+CHP continues to provide clinically meaningful improvement in PFS and OS versus CHOP, with a manageable safety profile, including continued resolution or improvement of peripheral neuropathy.

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Efficacy of Tolvaptan in Patients with Volume Overload after Cardiac Surgery.

The vasopressin type 2 receptor antagonist tolvaptan (TLV) has recently become available for treating congestion. However, there is no evidence confirming the efficacy of TLV for patients with volume overload after cardiac surgery. Here, we retrospectively studied the efficacy of TLV in patients with volume overload after cardiac surgery. We enrolled a total of 39 patients who had volume overload after cardiac surgery and who were treated with our protocol of body fluid management. The primary endpoint of this study was to evaluate the hospitalization period, while the secondary endpoints were to estimate adverse events such as hypotension, electrolyte abnormality, presence or absence of renal dysfunction and liver damage, and the incidence of atrial fibrillation (AF). The hospitalization period of the T (TLV) and C (furosemide and spironolactone) groups was 12.3 ± 2.6 days and 14.7 ± 4.4 days, respectively (P = .044), the mean urine volume was 2761.5 ± 850.3 mL/day and 2205.2 ± 598.5 mL/day, respectively (P = .024), and the incidence of postoperative AF after diuretics administration was 2/19 (11%) and 9/17 (52%), respectively. TLV successfully and rapidly improved organ congestion without causing hemodynamic abnormalities (hypotension, arrhythmia development), electrolyte abnormality, liver damage or renal dysfunction, thus significantly reducing the period of hospitalization.

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Effect of the cyclooxygenase-2 inhibitor celecoxib on bronchial responsiveness and cough reflex sensitivity in asthmatics.

Cyclooxygenase (COX), an essential enzyme in the pathway of prostaglandin formation from arachidonic acid, exists in two isoforms. Cyclooxygenase-1 (COX-1) is expressed under normal physiologic conditions, whereas COX-2, the inducible isoform, is associated with inflammation. Recent studies have linked COX-2 induction to the asthmatic inflammatory response, but potentially beneficial results, such as enhanced production of antiinflammatory and bronchoprotective substances, may also occur. The aim of the present study was to investigate the effect of selective COX-2 inhibition on bronchial responsiveness and cough reflex sensitivity. Eight adult subjects with stable asthma underwent spirometry, bronchoprovocation challenge with methacholine, and cough challenge testing with capsaicin, before and after a 7 day course of the COX-2 inhibitor celecoxib (200 mg orally, twice daily) and placebo, in a randomized, double-blind, crossover fashion. No significant changes in pulmonary function, bronchial responsiveness, or cough reflex sensitivity were induced by celecoxib. It appears, therefore, that 1 week of therapy with celecoxib does not significantly affect basal airway tone, nor the afferent airway receptors controlling bronchoconstriction and cough. However, the results of this trial cannot be extrapolated to subjects with severe asthma, or those suffering an asthmatic exacerbation. In such conditions of enhanced inflammatory response, the role of selective COX-2 inhibition remains to be elucidated.

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Response of panic disorder to fixed doses of alprazolam or imipramine.

This paper reports the results of a double-blind comparison of fixed daily doses of 6 mg of alprazolam, 2 mg of alprazolam, 225 mg of imipramine, and placebo for 8 weeks in 81 patients who met DSM-III criteria for panic disorder with or without agoraphobia. Final scores on eight clinical measures were analyzed from all patients who entered the study and from the subset who completed at least 4 weeks of treatment. Eighty-six percent of the high-dose alprazolam patients completed the study. Only 50% of the imipramine patients completed 8 weeks of treatment, apparently because of activation early in treatment and slow onset of therapeutic effects. This study confirmed the therapeutic effectiveness and safety of alprazolam, especially at the higher dose, in panic disorder. It also confirmed the therapeutic effectiveness of imipramine among patients who tolerated the drug. It suggested the usefulness of a flexible, individual approach to dose escalation with imipramine. Methodologically the study underscored the importance of using multiple approaches to the analysis of clinical data from therapeutic trials of psychotropic agents with complex effects that may contribute to patients' premature termination.

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Design and rationale for the Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial.

P2Y12 receptor antagonist therapy is recommended in addition to ASA for up to 1 year after acute coronary syndrome to reduce ischemic events. In contrast, the benefit of long-term dual antiplatelet therapy beyond 1 year remains unclear. Ticagrelor is a potent, reversibly binding P2Y12 receptor-antagonist that has been shown to be superior to clopidogrel in patients with acute coronary syndromes for up to 1 year. PEGASUS-TIMI 54 is a randomized, double-blind, placebo-controlled, multinational clinical trial designed to evaluate the efficacy and safety of ticagrelor in addition to aspirin (75-150 mg) for the prevention of major adverse cardiovascular events in patients with a history of myocardial infarction and risk factors. Patients with a history of spontaneous myocardial infarction within 1 to 3 years are randomized in a 1:1:1 fashion to ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, or matching placebo, all with low dose ASA, until the end of the study. The primary endpoint is a composite of cardiovascular death, myocardial infarction, or stroke. Recruitment began in October 2010 and completed in April 2013 with a sample size of over 21,000 patients. The trial is planned to continue until the latest of either 1,360 adjudicated primary end points are accrued or the last patient randomized has been followed for at least 12 months. PEGASUS-TIMI 54 is investigating whether the addition of intensive antiplatelet therapy with ticagrelor to low-dose aspirin reduces major adverse cardiovascular events in high-risk patients with a history of myocardial infarction.

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[Prospective study of the new oral anticoagulants in private practice: cautious optimism].

The new direct oral anticoagulants (DOA) such as dabigatran, rivaroxaban or apixaban are an evolution in the management of patients requiring curative anticoagulation. However, behind the simplicity of prescribing and monitoring, several questions remain about their daily use. The aim of this prospective study was to measure the feelings of general practitioners (GP), angiologists (AP) and cardiologists (CP), potential prescribers of this new anticoagulant family. Between December 2012 and May 2013, a questionnaire including five open questions and 11 questions using a positioning on an analogic visual scale (AVS 0 to 10) was subjected to GP, AP and CP in Alsace. Responses from 224 physicians (150 GP, 35 AP and 39 CP) were collected. Thus, 83% of GP, 83% of AP and 100% of CP were prescribers of DOA. However, among these prescribing doctors, the feeling was not the same and the trend of prescription was lower in GP (2.0 [1.1-3.2] AVS units) than in AP (3.1 [2.0-5.6]) and in CP (5.0 [1.2-8.7]) (P<0.0001 in multivariate analysis). The female doctors tended to prescribe DOA in younger patients than male doctors (respectively 66.1 [52.5-76.7] vs. 75.0 [65.7-81.0] years; P=0.004). The DOA were more considered as progress by AP and CP (respectively 7.8 [5.3-9.0] and 7.9 [7.0-8.7] AVSu) than by GP (6.1 [4.8-8.2] AVSu; P=0.02 in multivariate analysis). The answer about the eventual replacement of vitamin K antagonists by the DOA was very mixed whatever the practitioner group (5.1 [3.0-7.8] AVSu; P=0.139). The ease to use and the lack of biological monitoring were the main arguments leading to the prescription but the attitude of practitioners was very balanced by the lack of experience on the bleeding risk and the lack of available antidote. If the DOA are considered as an improvement for the physicians, the enthusiasm remains cautious whatever the type of practiced medicine. The results of clinical trials and the clinical experience should better appreciate the ongoing change in the field of anticoagulation.

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[Change in the spectrum of lipids and apoproteins A1 and B as affected by hypothiazide and pratsiol in patients with hypertension].

A comparative study of changes in plasma lipids, apo-A1 and apo-B under the effect of 2-week, 2-month and 6-month treatments with hydrochlorothiazide and pratsiol was conducted in 48 patients with arterial hypertension. Hydrochlorothiazide caused a significant increase in total cholesterol (CH), LDL cholesterol, apo-A1 and apo-B, and a decrease in cholesterol load of HDL particles as compared to placebo effects. Increased levels of HDL cholesterol were only noted in the early days of hydrochlorothiazide treatment. Pratsiol therapy produced a significant reduction of total triglycerides (TG), VLDL cholesterol, the cholesterol atherogenic coefficient, the apo-B/apo-A1 ratio, and increased HDL cholesterol. The activity of post-heparin lipoprotein lipase was not basically affected by hydrochlorothiazide, while pratsiol evoked a significant increase in its activity. The pratsiol-associated TG decrease was more pronounced in patients with elevated TG baseline, and the rise in HDL cholesterol, in those with initial hypo-alphacholesterolemia. Therefore unlike hydrochlorothiazide, pratsiol is associated with a favorable antiatherogenic trend of changes in the lipoprotein spectrum.

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Mirtazapine is more effective than trazodone: a double-blind controlled study in hospitalized patients with major depression.

Two hundred hospitalized patients with DSM-III diagnosis of moderate to severe major depressive episode were randomized to receive mirtazapine or trazodone for 6 weeks in a double-blind trial. The dosages were 24-72 mg/day for mirtazapine and 150-450 mg/day for trazodone. The improvement on all depression rating scales used was generally greater for mirtazapine, with statistically significant differences over trazodone in the Hamilton Psychiatric Rating Scale for Depression total score and two subscores (the Bech melancholia factor and retardation factor), the Brief Psychiatric Rating Scale total score, the General Psychiatric Impression Global Assessment Scale, the Beck score and responder rates. Mirtazapine was well tolerated, while the trazodone-treated patients experienced somnolence more frequently, particularly during the first 2 weeks of treatment. Furthermore, postural symptoms were a clinical problem in 6% of the trazodone-treated patients. In this trial, mirtazapine showed significant clinical advantages over trazodone in terms of overall efficacy and tolerability.

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Investigation on the efficacy of meloxicam in sows with mastitis-metritis-agalactia syndrome.

The efficacy of meloxicam in the treatment of sows with mastitis-metritis-agalactia syndrome was investigated in comparison with flunixin. Basic therapy comprised administration of an antibiotic and oxytocin. A total of 200 sows and litters were examined in a double-blind clinical study with observations up to 8 days after the first treatment. The primary parameter, the clinical index score on day 2, consisting of rectal temperature, feed intake, general demeanour, respiratory rate, vaginal discharge, degree of inflammation of mammary glands, milk flow and nursing behaviour, revealed a significant (P < or = 0.05) non-inferiority of meloxicam in comparison with flunixin implying equal efficacy of both drugs. No significant differences were noted in the distribution of clinical efficacy scores within both groups at each day of examination. The differences in litter weight and daily weight gain per piglet were not significant between the two test groups. The mortality rates until day 8 of the study were without significant difference between groups. In piglets of diseased litters, however, the mortality rate was 50% lower in the meloxicam group in comparison with the reference group, this difference reaching statistical significance (P < or = 0.05).

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Changes in anxiety sensitivity with pharmacotherapy for panic disorder.

Fear of anxiety symptoms (anxiety sensitivity) has been implicated in the etiology and maintenance of panic disorder, and has been shown to improve with cognitive-behavioral treatment. The impact of pharmacotherapy on anxiety sensitivity is less clear. We administered the Anxiety Sensitivity Index (ASI) during a 12-week randomized controlled trial investigating the relative efficacy of paroxetine, paroxetine plus sustained clonazepam, and paroxetine plus brief clonazepam for patients with panic disorder. We found a mean reduction in ASI scores of 9.6 points, which correlated with symptomatic improvement, and did not differ significantly between groups. Our data provides further evidence that pharmacotherapy leads to significant acute reductions in fears of anxiety symptoms in patients with panic disorder, albeit at levels that may be somewhat less than the changes associated with CBT. Implications of these findings are discussed relative to optimizing pharmacologic treatment of panic disorder.

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An understated danger: Antimicrobial resistance in aquaculture and pet fish in Switzerland, a retrospective study from 2000 to 2017.

Aquaculture is a rapidly growing field of food production. However, morbidity and mortality are higher in aquaculture species than in domestic animals. Bacterial diseases are a leading cause of farmed fish morbidity and are often treated with antimicrobials. Since most Swiss fish farms release effluents directly into surface water without treatment and since aquaculture fish are consumed by humans, antimicrobial resistance (AMR) and multi-resistance in aquaculture fish are important for environmental and public health. In this study, AMR tests for 14 antimicrobials were performed on 1,448 isolates from 1,134 diagnostic laboratory submissions from farmed and ornamental fish submissions for the period from 2000 to 2017. Amoxicillin, gentamycin and norfloxacin had the lowest proportion of resistant samples. However, AMR was highly variable over time. Resistance proportions were higher in: (a) ornamental fish compared with farmed fish, (b) fish from recirculation systems compared with those from other farming systems and (c) isolates originating from skin compared with those originating from inner organs. Multiple resistances were common. The results of this study provide useful data for Swiss fish veterinarians and some interesting hypotheses about risk factors for AMR in aquaculture and pet fish in Switzerland. However, further research is needed to define risk factors.

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Effects of methylphenidate on appetite and growth in children diagnosed with attention deficit and hyperactivity disorder.

The purpose of this study was to determine the levels of leptin, ghrelin, and nesfatin-1 to elucidate the causes of poor appetite and growth retardation in patients receiving methylphenidate therapy for attention deficit hyperactivity disorder. The study was performed on 89 male subjects; 48 patients and 41 healthy controls, aged 7-14 years. Following treatment, patients' leptin levels increased and ghrelin levels decreased while no significant change was found in nesfatin-1 levels. Of the 48 patients, 34 developed lack of appetite. In patients who developed lack of appetite, body weight SDS, body mass index (BMI), and BMI SDS were statistically significantly reduced; moreover, height SDS was reduced, though not to a statistically significant extent. This study attempted to elucidate the mechanisms that mediate the association between methylphenidate and appetite and growth, for which no studies have yet to be published.

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Sertraline for Preventing Mood Disorders Following Traumatic Brain Injury: A Randomized Clinical Trial.

Prevention is more effective than treatment to decrease the burden of significant medical conditions such as depressive disorders, a major cause of disability worldwide. Traumatic brain injury (TBI) is a candidate for selective strategies to prevent depression given the incidence, prevalence, and functional effect of depression that occurs after TBI. To assess the efficacy of sertraline treatment in preventing depressive disorders following TBI. A double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted at a university hospital from July 3, 2008, to September 17, 2012, with 24 weeks of follow-up. A consecutive sample of 534 patients aged 18 to 85 years, hospitalized for mild, moderate, or severe TBI, was eligible for the study. Ninety-four patients consented to participate and were randomized (46 to placebo and 48 to sertraline), of whom 79 (84%) completed the study. Intention-to-treat data analysis was conducted from July 1, 2014, to December 31, 2015. Placebo or sertraline, 100 mg/d, for 24 weeks or until development of a mood disorder. Time to onset of depressive disorders, as defined by the DSM-IV, associated with TBI. Of the 94 patients in the study (38 female and 56 male; 92 white), the number needed to treat to prevent depression after TBI at 24 weeks was 5.9 (95% CI, 3.1-71.1; χ2 = 4.6; P = .03) for sertraline treatment vs placebo. The influence of sertraline in the course of neuropsychological variables was not detected. The intervention was well tolerated, and adverse effects were mild in both the sertraline and placebo groups. Sertraline appears to be efficacious to prevent the onset of depressive disorders following TBI. Future studies should replicate these findings in a large sample of patients with TBI and depict their long-term physical, cognitive, behavioral, and functional outcomes. clinicaltrials.gov Identifier: NCT00704379.

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[AT1 angiotensin receptor inhibition as a new therapeutic possibility].

The octapeptide hormone, angiotensin II, binds to two major subtypes of cell surface receptors: the AT1 and the AT2 angiotensin receptors. The important physiological and pathophysiological effects of angiotensin II on cardiovascular regulation and salt-water balance are mediated by the AT1 receptor subtype. As a consequence of the outstanding clinical success of angiotensin-converting enzyme inhibitors, the appearance of AT1 receptor inhibitors in the therapy of hypertension and other cardiovascular diseases was preceded with great expectations. The available experimental and clinical data indicate that the first AT1 receptor inhibitor, losartan, has the same therapeutic potential as angiotensin-converting enzyme inhibitors, but it does not evoke the angiotensin-independent side-effects of ACE inhibitors, such as dry cough or angioedema. The physiological importance and the biochemical, molecular biological and pharmacological properties of AT1 and AT2 receptors are reviewed in this paper, and a summary of the available clinical data is presented.

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Maternal exposure to amoxicillin and the risk of oral clefts.

Prior studies have suggested an increased risk of oral clefts after exposure to amoxicillin in early pregnancy, but findings have been inconsistent. Among participants in the Slone Epidemiology Center Birth Defects Study from 1994 to 2008, we identified 877 infants with cleft lip with/without cleft palate and 471 with cleft palate alone. Controls included 6952 nonmalformed infants. Mothers were interviewed about demographic, reproductive and medical factors, and details of medication use. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) associated with use of amoxicillin in the first trimester using conditional logistic regression and adjusting for known risk factors for oral clefts, as well as for infections, fever, and concomitant treatments. In the control group, 2.1% of women had used amoxicillin in the first trimester. Maternal use of amoxicillin was associated with an increased risk of cleft lip with/without cleft palate (adjusted OR = 2.0 [95% confidence interval = 1.0-4.1]), with an OR of 4.3 (1.4-13.0) for third-gestational-month use. Risks were not elevated for use of other penicillins or cephalosporins. For cleft palate, the OR for first-trimester amoxicillin was 1.0 (0.4-2.3) with an OR of 7.1 (1.4-36) for third-gestational month use. Amoxicillin use in early pregnancy may be associated with an increased risk of oral clefts.

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Resolution of gastritis induced by Helicobacter pylori 4-5 weeks after successful eradication of infection using a triple therapy regimen of pantoprazole, amoxycillin and clarithromycin for one week.

This open-label study was designed to determine the extent of histological resolution of gastritis induced by Helicobacter pylori infection 4-5 weeks after successful eradication of the infection. Eradication was achieved using a triple therapy regimen consisting of a twice daily dose of pantoprazole 40 mg, clarithromycin 500 mg, and amoxicillin 1,000 mg taken for 1 week only. No other medications were given thereafter. Four biopsies were processed for histological examination of each patient, two from the antral and two from the corporeal mucosa, first at the start of the study and then again 4 weeks after cessation of the medication trial. Scoring for H. pylori colonization and the severity of gastritis was determined for each patient according to the Sydney system. 53 of 57 patients in this study had their H. pylori infection successfully eradicated by the regimen mentioned and could be histologically evaluated. According to the severity of gastritis in the antral mucosa, patients were studied in 3 groups: mild, moderate and severe gastritis. 17 of 19 cases with mild gastritis showed complete resolution of the inflammation, with residual inflammatory changes persisting in 2 cases only. 22 of the 26 cases with moderate gastritis showed almost complete recovery except for minor residual inflammatory changes as judged by irregularity of intracytoplasmic mucine storage. Persistent residual inflammatory changes in the lamina propria were detected in 4 cases. Of the 8 cases with severe gastritis 5 showed subsidence of the inflammatory changes, but the mucosa in these cases revealed some scarring, distortion of the glandular epithelium and atrophy. In 3 cases residual inflammation persisted. One-week therapy with a twice daily dose of pantoprazole 40 mg, clarithromycin 500 mg and amoxicillin 1,000 mg, used to eradicate H. pylori causing active inflammation of the gastric mucosa, has led to subsidence of the acute inflammatory changes in all the cases with residual inflammation persisting in 17%. Severe gastritis may cause irreparable damage to the gastric mucosa. The density of H. pylori colonization does not appear to be related to the severity of gastritis, nor to the successful eradication achieved.

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Rosuvastatin Is Effective to Decrease CD8 T-Cell Activation Only in HIV-Infected Patients With High Residual T-Cell Activation Under Antiretroviral Therapy.

The aim of the trial was to evaluate in patients under antiretroviral therapy (ART) the effect of rosuvastatin on cellular and soluble markers of immune activation/inflammation, as well as to identify patients who better benefit from statin administration. IMEA-043-CESAR was a phase II open-label pilot trial that enrolled patients under suppressive ART and CD4 <500/mm. Patients received rosuvastatin (20 mg/d) for 12 weeks. The primary outcome was the variation at week 12 (W12) in the proportion of CD38HLA-DRCD8 T lymphocytes. Secondary outcomes included evolution of other markers of T-cell activation and of inflammatory biomarkers between baseline, W12, and W24. Fifty patients were enrolled; end points were available for 43 patients. When considering all patients, the proportion of CD38HLA-DRCD8 T cells did not significantly decline throughout the follow-up. However, the proportion of CD38CD8T cells significantly decreased at W12 [median percentage change of -22.2% (-32.3; +1.4)]. Principal component analysis allowed identification of 3 groups of patients based on their baseline activation/inflammation profiles, 1 group with elevated levels of CD8 T-cell activation, and a small group with high levels of systemic inflammation and low levels of T-cell activation. Half of the patients exhibited relatively low levels of inflammation and activation. The proportion of activated CD8 T cells significantly decreased only in the particular group of patients with high baseline CD8 T-cell activation. This study shows that combining rosuvastatin with effective ART can result in a sustained decrease in CD8 T-cell activation and highlights the importance of identifying patients who can benefit from specific immunotherapeutic strategies.

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Effects of amlodipine on steady-state digoxin concentrations and renal digoxin clearance.

The effect of oral amlodipine on steady-state digoxin concentrations and renal clearance was studied in 21 healthy male subjects. After 2-week digitalization (digoxin, 0.375 mg/day), they were randomized in a single-blind crossover protocol to receive either placebo or amlodipine (5 mg/day) in combination with digoxin for the following two 2-week periods. Mean (+/- SD) digoxin concentrations of 0.64 +/- 0.19 ng/ml after 2-week digoxin monotherapy and 0.61 +/- 0.23 ng/ml during placebo were not altered by amlodipine (0.60 +/- 0.18 mg/ml). Renal digoxin clearance was 202 +/- 44 ml/min on placebo and 207 +/- 55 ml/min during amlodipine coadministration. No change in pharmacologic effect of digoxin was noted during amlodipine coadministration, nor was blood pressure or heart rate changed. These data indicate that oral amlodipine does not significantly influence steady-state digoxin concentrations in healthy subjects.

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Gender differences in the treatment of non-ST-segment elevation myocardial infarction.

Women are at greater risk for worse outcomes associated with acute coronary syndrome (ACS) than are men. One explanation may be that they tend to be treated less aggressively than men even when more aggressive treatment is warranted. The purpose of this analysis was to assess this issue. We used the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation (CRUSADE) Quality Improvement Initiative registry, an observational data collection that began in November 2001, with retrospective data collection from January 2001 to December 2006. A total of 32,888 subjects met the inclusion/exclusion criteria for our study, based on strong biochemical evidence of myocardial infarction and acute onset of typical cardiac chest pain. We stratified subjects into 16 cells for coronary intervention, based on 4 age groups and 4 cardiac catheterization findings (insignificant, 1-vessel disease, 2-vessel disease, 3-vessel disease). We also stratified subjects into 20 cells for medical treatment, based on 4 age groups and 5 medical treatments. In each cell we compared the rate of coronary intervention (coronary artery bypass grafting or percutaneous coronary intervention) or medical treatment (glycoprotein IIb/IIIa inhibitors, aspirin, clopidogrel, beta-blocker, and statins) for men vs women. Men demonstrated significantly higher rates (P < 0.05) of coronary intervention in 7 of the 16 cells and 9 of the 20 medical treatment cells, compared to no cells in which women had statistically higher rates than men. These findings suggest that men are more likely than women to receive coronary intervention and to be medically treated when presenting with evidence of non-ST-segment myocardial infarction, controlled for age, cardiac catheterization findings, and biochemical evidence of myocardial infarction.

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Successful withdrawal of steroids in pediatric renal transplant recipients receiving cyclosporine A and mycophenolate mofetil treatment: results after four years.

Despite their numerous systemic side effects, glucocorticoids (steroids) still form a cornerstone in immunosuppressive regimens in pediatric renal transplant recipients. The addition of mycophenolate mofetil (MMF) to a cyclosporine A (CsA)-based immunosuppressive regimen after renal transplantation may allow steroid withdrawal and amelioration or avoidance of steroid-specific side effects. In a retrospective case-control study, covering a mean follow-up period of 46 +/- 2.3 months and 40 patients aged 11.4 +/- 4.9 years, we analyzed the safety and efficacy of steroid withdrawal in pediatric renal transplant recipients receiving CsA micoroemulsion, MMF, and low-dose prednisone treatment. : Steroid withdrawal in all 20 pediatric renal transplant recipients receiving CsA and MMF was successful and not associated with an acute rejection episode; graft function remained stable. At baseline, the degree of growth retardation was comparable between the groups (mean height standard deviation scores [SDSs] -1.60 +/- 0.30 [withdrawal group] and -1.32 +/- 0.39 [case-control group]). After steroid withdrawal, prepubertal patients exhibited a significant catch-up growth with a mean height gain of 1.47 +/- 0.32 SDS, whereas height SDS did not improve in patients receiving steroids. Growth was also improved in pubertal patients who stopped taking steroids. Standardized body mass index in patients who stopped taking steroids decreased significantly by 49% from 0.87 +/- 0.31 SDS to 0.45 +/- 0.30 SDS. After steroid withdrawal, mean arterial blood pressure SDS decreased significantly by 45%. Moreover, the need for antihypertensive medication declined significantly in patients who stopped taking steroids. The white blood cell counts and hemoglobin levels were comparable between the groups. : This study suggests that steroids can be safely and successfully withdrawn in selected pediatric renal transplant recipients receiving immunosuppressive maintenance therapy consisting of CsA and MMF.

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Positron emission tomography/computed tomography findings during therapy predict outcome in patients with diffuse large B-cell lymphoma treated with chemotherapy alone but not in those who receive consolidation radiation.

To assess the value of mid-therapy positron emission tomography (PET) findings for predicting survival and disease progression in patients with diffuse large B-cell lymphoma, considering type of therapy (chemotherapy with or without radiation therapy). We retrospectively evaluated 294 patients with histologically confirmed diffuse large B-cell lymphoma with respect to age, sex, disease stage, International Prognostic Index score, mid-therapy PET findings (positive or negative), and disease status after therapy and at last follow-up. Overall survival (OS) and progression-free survival (PFS) were compared according to mid-therapy PET findings. Of the 294 patients, 163 (55%) were male, 144 (49%) were age >61 years, 110 (37%) had stage I or II disease, 219 (74%) had International Prognostic Index score ≤2, 216 (73%) received ≥6 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, and 88 (30%) received consolidation radiation therapy. Five-year PFS and OS rates were associated with mid-therapy PET status: PFS was 78% for those with PET-negative (PET-) disease versus 63% for PET-positive (PET+) disease (P=.024), and OS was 82% for PET- versus 62% for PET+ (P<.002). These associations held true for patients who received chemotherapy only (PFS 71% for PET- vs 52% PET+ [P=.012], OS 78% for PET- and 51% for PET+ [P=.0055]) but not for those who received consolidation radiation therapy (PFS 84% PET- vs 81% PET+ [P=.88]; OS 90% PET- vs 81% PET+ [P=.39]). Mid-therapy PET can predict patient outcome, but the use of consolidation radiation therapy may negate the significance of mid-therapy findings.

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The effect of preoperative clopidogrel on bleeding after coronary artery bypass surgery.

Clopidogrel treatment is associated with a reduction in thrombotic complications in coronary stent placement, improved outcome after acute coronary syndromes, and decreased mortality in patients with coronary artery disease. The purpose of this study was to analyze the effect of preoperative clopidogrel exposure on bleeding complications, blood transfusions requirements, and reoperations in patients undergoing coronary artery bypass grafting (CABG). This study included 320 patients from a single institution that underwent an isolated CABG who were discharged between July 2003 and June 2004. The cohort of 320 patients was classified into 3 groups. The control group consisted of 255 patients that did not receive clopidogrel or stopped clopidogrel 7 days before surgery but were treated with aspirin instead. Clopidogrel I consisted of 25 patients that were taking clopidogrel within 3 days of surgery, and Clopidogrel II consisted of 40 patients that were taking clopidogrel 4 to 7 days before surgery. Patients were compared based on preoperative data (age, gender, use of clopidogrel, preoperative hemoglobin, and ejection fraction), intraoperative data (cross-clamp time), postoperative data (chest tube output, rate of reoperation, units of transfused blood, length of stay in the intensive care unit, and length of intubation). There were no significant differences among the 3 groups concerning age, sex, ejection fraction, or preoperative hemoglobin. There were no differences in length of intensive care unit stay and length of intubation among the 3 groups of patients. Patients in the clopidogrel I group had more units of blood transfused than either the control or the Clopidogrel II group (p=0.027). There is also a trend toward more chest tube output in clopidogrel I group compared with the control group. Fifteen patients (4.6%) of the total group required reoperation secondary to bleeding: 2 (8.0%) in the Clopidogrel I group, 2 (5%) in the clopidogrel II group, and 11 (4.3%) in the control group (p=0.41). This study demonstrated that clopidogrel within 3 days preoperatively increases the requirement for blood transfusion in patients undergoing CABG. Waiting more than 3 days after the last dose of clopidogrel decreases blood transfusion requirements. There is also a trend toward more postoperative bleeding for those patients that took clopidogrel within 3 days before their CABG. The reoperation rate of patients that took clopidogrel within 3 days of their procedure required almost twice as many reoperations as the patients that did not take clopidogrel.

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The effect of zolpidem and zopiclone on memory.

The effect of 10 mg of zolpidem (ZLP) on memory function was evaluated in healthy male adults using word recall test, passage recall test, and Sternberg's memory scanning task. This study was carried out as a double-blind cross-over study with 7.5 mg of zopiclone (ZPC) and a placebo. No difference was noted between the active drugs and placebo in the number of words recalled from the word list presented before administration. No evidence of retrograde amnesia was suggested. However, encoding ability was slightly affected as indicated by a decrease in the number of words recalled from the list presented after administration. Slight impairment of a delayed recall was noted for both of the active drugs, but the effect disappeared the next morning. In the memory scanning task, ZLP prolonged a non-specific component of reaction time 1.5 h after administration, but the effect disappeared after 12.5 h. ZPC did not prolong the reaction time. The two active drugs showed no specific effects on either memory scanning or response-selection stage in short-term memory at any time. The findings suggest that residual effects did not reach clinical significance at the standard dosage, although the active drugs slightly affected encoding ability and retention soon after administration.

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[Usefulness of fenspiride in the treatment of acute otitis media in children].

Acute otitis media is very general disease and concerns every child practically. The shortening the time of treatment as well as quick decrease of symptoms, and mainly the pain have large meaning in treatment of this disease. Combined treatment of fenspiride and typical treatment of otitis media permits as our investigations show on quicker and observed at children's larger number decrease of symptoms in children with acute otitis media. The aim of the study was to observe effectiveness of combined treatment with antibiotic and fenspiride in children with acute otitis media. The study comprised 40 children (mean age 8.2 years). The diagnosis of acute otitis media based on medical history data, otolaryngological examination and audiometry (tone and impedance). Children with GERD, hypersensitivity to amoxicillin and fenspiride as well as hypertrophy of adenoid were excluded from the study. Children were divided in two equal groups randomly. All children received amoxicillin in dose 80 mg/kg/day in three partite doses (Amotaks, Polfa Tarchomin Poland) as well as oxymethazolin 0.05% nasal drops 3 x day 1-2 drops (0.05% Nasivin, Merck Germany). In children from second group fenspiride was applied in dose 2 ml/kg/day in three divided doses (Eurespal, Servier Francja) additionally. Treatment was provided by 10 days. During the treatment parents made record of recession in 10 point scale, estimating following parameters: the pain of ear, bother, raised the temperature of body, loss of appetite, vomiting, diarrhea, otorrhea and crying. After end of treatment control otolaryngological and audiological examinations were performed. In studied children symptoms were similar, and the pain of ear was in both groups main suffering. Vomiting and diarrhea the most seldom were observed. In children with acute otitis media treated additionally with fenspiride statistically significant (p<0.01) quicker recession of clinical symptoms was observed. Statistically significant (p<0.01) reduction was observed of such symptoms as the pain of ear, bother, raised of body temperature as well as crying in children treated additionally with fenspiride in comparison to children treated only with antibiotic. Earlier return of hearing and state of middle ear was observed in children from group II than in children from group I (p<0.01). We observed also statistically significant (p<0.01) improvement of hearing estimated in tonal audiometry and impedance in this group. The undesirable symptoms during the treatment were not mentioned. Our study show that combined treatment with fenspiride and antibiotic in the treatment of acute otitis media in children causes quicker reduction of symptoms as well as improvement in audiological parameters (tone and impedance).

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Mucosal healing effect of mesalazine granules in naproxen-induced small bowel enteropathy.

To investigate the effect of mesalazine granules on small intestinal injury induced by naproxen using capsule endoscopy (CE). This was a single center, non-randomized, open-label, uncontrolled pilot study, using the PillCam SB CE system with RAPID 5 software. The Lewis Index Score (LIS) for small bowel injury was investigated to evaluate the severity of mucosal injury. Arthropathy patients with at least one month history of daily naproxen use of 1000 mg and proton pump inhibitor co-therapy were screened. Patients with a minimum LIS of 135 were eligible to enter the 4-wk treatment phase of the study. During this treatment period, 3 × 1000 mg/d mesalazine granules were added to ongoing therapies of 1000 mg/d naproxen and 20 mg/d omeprazole. At the end of the 4-wk combined treatment period, a second small bowel CE was performed to re-evaluate the enteropathy according to the LIS results. The primary objective of this study was to assess the mucosal changes after 4 wk of mesalazine treatment. A total of 18 patients (16 females), ranging in age from 46 to 78 years (mean age 60.3 years) were screened, all had been taking 1000 mg/d naproxen for at least one month. Eight patients were excluded from the mesalazine therapeutic phase of the study for the following reasons: the screening CE showed normal small bowel mucosa or only insignificant damages (LIS < 135) in five patients, the screening esophagogastroduodenoscopy revealed gastric ulcer in one patient, capsule technical failure and incomplete CE due to poor small bowel cleanliness in two patients. Ten patients (9 female, mean age 56.2 years) whose initial LIS reached mild and moderate-to-severe enteropathy grades (between 135 and 790 and ≥ 790) entered the 4-wk therapeutic phase and a repeat CE was performed. When comparing the change in LIS from baseline to end of treatment in all patients, a marked decrease was seen (mean LIS: 1236.4 ± 821.9 vs 925.2 ± 543.4, P = 0.271). Moreover, a significant difference between pre- and post-treatment mean total LIS was detected in 7 patients who had moderate-to-severe enteropathy gradings at the inclusion CE (mean LIS: 1615 ± 672 vs 1064 ± 424, P = 0.033). According to the small bowel CE evaluation mesalazine granules significantly attenuated mucosal injuries in patients with moderate-to-severe enteropathies induced by naproxen.

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Comparison of immunological parameters in patients with pemphigus vulgaris following rituximab and IVIG therapy.

Information on certain immunological parameters in patients with pemphigus vulgaris (PV) treated with rituximab (RTX) and intravenous immunoglobulin (IVIG) therapy is limited. Comparing immunological parameters in patients who achieved long-term clinical remission (LTR) with those who relapsed. Retrospective analysis of 19 patients treated at a single centre using the same protocol. Comparisons were made between patients who went into LTR and those who relapsed following completion of the protocol. Treatments prior to IVIG and RTX included prednisone with or without an immunosuppressive agent. The immunological parameters measured included peripheral blood B cells (CD19+), serum quantitative immunoglobulin levels, and levels of antibodies to desmogleins (Dsg) 1 and 3. Eleven patients achieved LTR. Eight patients developed 15 relapses. The mean follow-up time for the LTR group was 29·6±11·2months, and for the relapse group, 40·0±7·0 months. There were no significant differences in times to B-cell depletion, repopulation, or recovery to pretreatment levels between the patients who achieved LTR and those who relapsed. Recurrences usually occurred after B-cell repopulation. Repeated treatments did not influence the time to B-cell repopulation. IgM levels were decreased after therapy and remained decreased. A consistent increase in anti-Dsg1 antibody levels occurred at the time of relapse in patients with mucocutaneous disease. The majority of patients treated with rituximab and IVIG therapy achieved LTR. Retreatment of relapses can induce LTR. Decreased serum IgM levels persisted following treatment. Increases in anti-Dsg1 antibodies during therapy in patients with mucocutaneous disease suggests a close follow-up for a potential relapse is required.

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Statin therapy and its association with long-term survival after colon cancer surgery.

The current study aimed to address the clinical equipoise regarding the association of ongoing statin therapy at time of surgery with long-term postoperative mortality rates after elective, curative, surgical resections of colon cancer by analyzing data from a large validated national register. All adults with stage I to III colon cancer who underwent elective surgery with curative intent between January 2007 and October 2016 were retrieved from the Swedish Colorectal Cancer Register, a prospectively collected national register. Patients were identified as having ongoing statin therapy if they filled a prescription within 12 months pre- and postoperatively. Study outcomes included 5-year all-cause and cancer-specific postoperative mortality. To reduce the impact of confounding from covariates owing to nonrandomization, the inverse probability of treatment weighting method was used. Subsequently, Cox proportional hazards models were fitted to the weighted cohorts. In total, 19,118 patients underwent elective surgery for colon cancer in the specified period, of whom 31% (5,896) had ongoing statin therapy. Despite being older, having a higher preoperative risk, and having more comorbidities, patients with statin therapy had a higher postoperative survival. After inverse probability of treatment weighting, patients with statin therapy displayed a significantly lower mortality risk up to 5 years after surgery for both all-cause (hazard ratio 0.68, 95% confidence interval 0.63-0.74, P < .001) and cancer-specific mortality (hazard ratio 0.76, 95% confidence interval 0.66-0.89, P < .001). The results of this study indicate that statin therapy is associated with a sustained reduction in all-cause and cancer-specific mortality up to 5 years after elective colon cancer surgery. The findings warrant validation in future prospective clinical trials.

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Budesonide/Formoterol Anti-Inflammatory Reliever and Maintenance or Fluticasone Propionate/Salmeterol Plus As-Needed, Short-Acting β₂ Agonist: Real-World Effectiveness in pAtients without Optimally Controlled asThma (REACT) Study.

In the prospective, observational, 16-week REACT study conducted between October 21, 2008 and May 12, 2011, we compared the real-world effectiveness of anti-inflammatory reliever and maintenance therapy with budesonide/formoterol (Symbicort^® Turbuhaler) and maintenance therapy with fixed-dose fluticasone/salmeterol (Seretide^®) plus as-needed, short-acting β₂ agonists (SABAs) in Taiwanese patients with inadequate asthma control. Asthma control was assessed using the five-item Asthma Control Questionnaire (ACQ-5) and standardized pulmonary function testing. Assessments were performed at baseline and at weeks 4-5 and 12-16. Overall, we enrolled 842 patients at 11 clinics, 723 of whom were included in analyses (budesonide/formoterol, 563.3±1.3 μg/d, n=551; fluticasone/salmeterol, 1013.8±1.4 μg/d, n=172). At baseline, 72.5% and 27.5% of all patients had "partly" and "uncontrolled" asthma, respectively. Mean±SD ACQ-5 scores were 1.54±1.06 and 1.46±1.28 in the budesonide/formoterol and fluticasone/salmeterol groups, respectively. ACQ-5 scores significantly improved from baseline (ie, decreased) in both groups at weeks 4 and 16. ACQ-5 difference scores were significantly lower in the budesonide/formoterol group (-0.91±1.11) than the fluticasone/salmeterol group (-0.69±1.27) at the end of the study (p=0.027). Peak expiratory flow rate significantly improved from baseline in the budesonide/formoterol but not the fluticasone/salmeterol group at the end of the study. Severe exacerbation rates and medical resource utilization were comparable between the budesonide/formoterol and fluticasone/salmeterol groups. Collectively, results indicate the real-world effectiveness of budesonide/formoterol anti-inflammatory reliever and maintenance therapy is better than fixed-dose fluticasone/salmeterol plus as-needed SABA. ClinicalTrials.gov registration number: NCT00784953.

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Pharmacoutilization of antihypertensive drugs: a model of analysis.

To identify clinical and economic indicators of pharmacoutilization of antihypertensive drugs. 4614 subjects receiving a first prescription for amlodipine, atenolol, fosinopril, indapamide, or losartan were included in the study. All prescriptions filled during the study period from January 1, 1997 to December 31, 1998 were considered. A retrospective analysis was carried out on information recorded in the drug database. The percentage of patients continuing, discontinuing, and switching the initial treatment, duration of treatment, and doses used were calculated together with total costs. A large proportion of patients (65.1%) discontinued the treatment. From the analysis of the mean daily dose taken by patients who continued the treatment, it was found that many subjects took a drug dosage which was below the therapeutic dose range, whereas the administration of doses above the therapeutic range occurred only occasionally. Continuation of treatment accounted for 48.1% of total costs, switching accounted for 20.8%, and discontinuation represented 31.1% of total expenditures. With adequate markers, helpful data can be collected for monitoring the quality of antihypertensive drug prescriptions and the rational usage of resources in the general practice setting.

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Comparison of effects of quinapril and metoprolol on glycaemic control, serum lipids, blood pressure, albuminuria and quality of life in non-insulin-dependent diabetes mellitus patients with hypertension. Swedish Quinapril Group.

To compare the long-term effects of the angiotensin-converting enzyme (ACE)-inhibitor quinapril and the cardioselective beta-adrenergic blocking agent metoprolol on glycaemic control, with glycosylated haemoglobin (HbA1c) as the principal variable, in non-insulin-dependent diabetes mellitus (NIDDM) patients with hypertension. A randomized, double-blind, double-dummy, multicentre study during 6 months preceded by a 4 week wash-out and a 3 week run-in placebo period. Quinapril (20 mg) and metoprolol (100 mg, conventional tablets) were given once daily. No change was made in the treatment of diabetes (diet and hypoglycaemic agents). Seventy-two patients fulfilling the criteria were randomized and entered the double-blind period. Twelve patients did not complete the study. Sixty patients, 26 on quinapril and 34 on metoprolol, were available for the final analysis. The effect was assessed by changes in HbA1c, the fasting serum glucose and the post-load serum glucose, C-peptide and insulin levels during the oral glucose tolerance test. In the quinapril group, the fasting serum glucose, oral glucose tolerance and the C-peptide and insulin responses, determined as the incremental area under the curves (AUC), showed no change, but the mean HbA1c level increased from 6.2 +/- 1.1% to 6.5 +/- 1.3% (P < 0.05). In the metoprolol group, the rise in the mean level of HbA1c, from 6.3 +/- 1.0% to 6.8 +/- 1.3% (P < 0.01), tended to be more marked than after quinapril, although there was no significant difference between the increments. The mean fasting serum glucose showed an increase from 9.1 +/- 1.9 mM to 10.1 +/- 2.8 mM (P < 0.01) which correlated significantly with the duration of diabetes (P < 0.01) and the increase in fasting serum triglycerides (P < 0.001). Moreover, in the metoprolol group we found significant decreases in the oral glucose tolerance as well as C-peptide and insulin responses to the glucose load. Treatment with quinapril for 6 months appears to have advantages over metoprolol in NIDDM patients with hypertension. Although treatment with quinapril or metoprolol over 6 months was concomitant with a rise in the HbA1c, increased fasting blood glucose, decreased oral glucose tolerance and decreased C-peptide and insulin responses to a glucose challenge were observed only in patients treated with metoprolol.

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Cyclophosphamide or azathioprine in lupus glomerulonephritis. A controlled trial: results at 28 months.

Thirty-eight patients with diffuse glomerulonephritis of systemic lupus erythematosus were randomly assigned to add cyclophosphamide, azathioprine, or nothing to low-dose corticosteroid treatment and have been followed for a mean of 21/3 years thereafter. Of the 11 patients with unfavorable outcomes (8 deaths and 2 beginning hemodialyses), 2 occurred on cyclophosphamide, 4 on azathioprine, and 5 on prednisone only. Deaths due to infection occurred on the cytotoxics, while deaths ascribed to central nervous system lupus erythematosus occurred exclusively on prednisone only. Gradual deterioration of renal function was observed in all three groups, most frequently on prednisone only. Undesirable events, some due to drugs, were observed. At the time of reporting, the cytotoxic agents seemed to add marginally to the control of the disease; other treatment schedules should be evaluated.

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Small airway bronchodilator response to different doses of salbutamol in 7-year-old children.

The Global Initiative for Asthma (GINA) guidelines do not specify a bronchodilator range for bronchodilator response (BDR) testing and simply recommend a salbutamol dose of 200 to 400 μg. We determined the oscillometric BDR results of children given low-dose (2 puffs, 200 μg) and standard-dose (4 puffs, 400 μg) salbutamol to compare the small airway responses of healthy controls (defined using criteria based on the guidelines developed at the American Thoracic Society) and exclusion subjects (defined as any child that did not meet the inclusion criteria for healthy controls). The oscillometric reactance of small airways is significantly associated with the dose of salbutamol used for BDR testing in exclusion children. We suggest use of the standard-dose of salbutamol for oscillometric BDR testing.

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A healthy lifestyle index is associated with reduced risk of colorectal adenomatous polyps among non-users of non-steroidal anti-inflammatory drugs.

In a Columbia, South Carolina-based case-control study, we developed a healthy lifestyle index from five modifiable lifestyle factors (smoking, alcohol intake, physical activity, diet, and body mass index), and examined the association between this lifestyle index and the risk of colorectal adenomatous polyps (adenoma). Participants were recruited from a local endoscopy center and completed questionnaires related to lifestyle behaviors prior to colonoscopy. We scored responses on each of five lifestyle factors as unhealthy (0 point) or healthy (1 point) based on current evidence and recommendations. We added the five scores to produce a combined lifestyle index for each participant ranging from 0 (least healthy) to 5 (healthiest), which was dichotomized into unhealthy (0-2) and healthy (3-5) lifestyle scores. We used logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) for adenoma with adjustment for multiple covariates. We identified 47 adenoma cases and 91 controls. In the main analyses, there was a statistically nonsignificant inverse association between the dichotomous (OR 0.54; 95% CI 0.22, 1.29) and continuous (OR 0.75; 95% CI 0.51, 1.10) lifestyle index and adenoma. Odds of adenoma were significantly modified by the use of non-steroidal anti-inflammatory drugs (NSAIDs) (p(interaction) = 0.04). For participants who reported no use of NSAIDs, those in the healthy lifestyle category had a 72% lower odds of adenoma as compared to those in the unhealthy category (OR 0.28; 95% CI 0.08, 0.98), whereas a one-unit increase in the index significantly reduced odds of adenoma by 53% (OR 0.47; 95% CI 0.26, 0.88). Although these findings should be interpreted cautiously given our small sample size, our results suggest that higher scores from this index are associated with reduced odds of adenomas, especially in non-users of NSAIDs. Lifestyle interventions are required to test this approach as a strategy to prevent colorectal adenomatous polyps.

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Quality-of-life issues for end-stage renal disease patients.

Given the importance of making comparisons regarding quality-of-life issues for end-stage renal disease (ESRD) patients, the research presented here first compares 766 patients who experienced one of the following therapies for at least 1 year: (1) center hemodialysis, (2) continuous ambulatory peritoneal dialysis (CAPD), or (3) successful transplantation (one cohort of patients from the 1970s, a second cohort from 1980 to 1984). Second, since the most recent transplant group was randomized to two alternative immunosuppressive drug regimens, we compared the quality of life of the patients on cyclosporine/prednisone therapy (N = 51) and the patients on a conventional immunosuppressive therapy (antilymphocyte globulin/prednisone/azathioprine; N = 40). Patients had to be age 19 to 56 years and nondiabetic to be included in this research. Data were collected with survey questionnaires containing measures of physical, emotional, and social well-being, vocational rehabilitation, sexual adjustment, and marital and family adjustment. Case mix or background differences were controlled as much as possible using an analysis of covariance (ANCOVA) and comparison of adjusted means. Our results show that the successful transplant patients scored higher than both dialysis groups (P less than 0.05 for nine of 11 measures) on almost all variables, demonstrating a higher quality of life. The effect of a failed transplant on quality of life was also examined. In terms of the recent transplant patients, the cyclosporine group scored consistently higher on all physical, emotional, and social well-being measures (excluding males' vocational rehabilitation), although differences are not always significant.(ABSTRACT TRUNCATED AT 250 WORDS)

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[Survey and treatment strategy of antidepressant-resistant depression].

The present study investigated the phenomenology and treatment of antidepressant-resistant depressions (ARD). To be classified a nonresponder, a patient had to have been treated adequately with two tricyclic (or tetracyclic) antidepressants (i.e., a minimum of the equivalent of 150 mg of imipramine for 4 weeks). The 34 depressed patients (25 unipolar patients and 9 bipolar patients) failed to respond to these antidepressant trials. Seventy-two % of the unipolar patients were in their first depression episodes, but 89% of the bipolar patients had 2 or more previous affective episodes. The mean duration of the current episode of depressions was 3.8 years. In 5 unipolar patients, the duration of the current depression episode was 10 years or more. The addition of lithium, bromocriptine or levothyroxine treatment to tricyclic or tetracyclic antidepressants were effective in the treatment of ARD. Levothyroxine were more effective in the treatment of the bipolar patients than the unipolar patients. Safrazine, a monoamine oxidase inhibitor, and electroconvulsive therapy were also effective in the treatment of ARD, but had the drawbacks of the high incidence of moderate or severe adverse reactions and high relapse rates, respectively. We propose a step-wise approach to the treatment of ARD, which mainly includes the pharmacotherapy and can be used in Japan.

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Influence of serum cholesterol level and statin treatment on prostate cancer aggressiveness.

Both cholesterol levels and the use of statins have been described to influence the development and prognosis of prostate cancer (PC). In this retrospective, cross-sectional analysis of consecutive cases from a tertiary referral center we evaluated an association between hypercholesterolemia (≥5.0mmol/l), the use of statins, and advanced/aggressive PC in 767 men with histologically confirmed, clinically localized PC awaiting radical prostatectomy. We found that patients with HCE (n=287, 37.4%) had a significantly higher incidence of poorly differentiated PC (Gleason score ≥7b, 81.1% vs. 4.9%), advanced local tumor stage (≥pT3, 57.7% vs. 22.2%), and nodal involvement (19.8% vs. 1.6%). Multivariate logistic regression analysis identified hypercholesterolemia as a risk factor for aggressive and/or advanced PC (OR 2.01, p<0.001) whereas statin intake showed an odds ratio of 0.49 (p=0.005) indicating a negative association with high-risk PC. Despite a limited number of patients using statins (~9.5%), adjusted and weighed multivariate logistic regression models revealed that preoperative hypercholesterolemia is associated with a diagnosis of high-risk PC which is negatively influenced by statin intake.

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Omeprazole preferentially inhibits the metabolism of (+)-(S)-citalopram in healthy volunteers.

Citalopram (CITA) pharmacokinetics are enantioselective in healthy volunteers and the metabolism of (+)-(S)-CITA to (+)-(S)-DCITA is dependent on CYP2C19. Omeprazole is a potent CYP2C19 inhibitor. This study indicates that omeprazole induces a loss of enantioselectivity in the CITA pharmacokinetics because of the selective inhibition of (+)-(S)-CITA metabolism. The study assessed the influence of omeprazole on the kinetic disposition of the (+)-(S)-citalopram (CITA) and (-)-(R)-CITA enantiomers in healthy volunteers. In a cross-over study, healthy volunteers (n = 9) phenotyped as extensive metabolizers of CYP2C19 and CYP2D6 and with an oral midazolam clearance ranging from 10.9 to 149.3 ml min(-1) kg(-1) received a single dose of racemic CITA (20 mg orally) in combination or not with omeprazole (20 mg day(-1) for 18 days). Serial blood samples were collected up to 240 h after CITA administration. CITA and demethylcitalopram (DCITA) enantiomers were analyzed by LC-MS/MS using a Chiralcel OD-R column. The kinetic disposition of CITA was enantioselective in the absence of treatment with omeprazole, with the observation of a greater proportion of plasma (-)-(R)-CITA [AUC S:R ratio of 0.53 (95% CI 0.41, 0.66) for CITA and 1.08 (95% CI 0.80, 1.76) for DCITA] than (+)-(S)-CITA. Racemic CITA administration to healthy volunteers in combination with omeprazole showed a loss of enantioselectivity in CITA pharmacokinetics with an increase of approximately 120% in plasma (+)-(S)-CITA concentrations [AUC S:R ratio of 0.95 (95% CI 0.72, 1.10) for CITA and 0.95 (95% CI 0.44, 1.72) for DCITA]. The administration of multiple doses of omeprazole preferentially inhibited (+)-(S)-CITA metabolism in healthy volunteers. Although omeprazole increased plasma concentrations of (+)-(S)-CITA by approximately 120%, it is difficult to evaluate the clinical outcome because the range of plasma CITA concentrations related to maximum efficacy and minimum risk of adverse effects has not been established.

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Stop of proton-pump inhibitor treatment in patients with liver cirrhosis (STOPPIT): study protocol for a prospective, multicentre, controlled, randomized, double-blind trial.

Proton-pump inhibitors (PPI) are liberally prescribed in patients with liver cirrhosis. Observational studies link PPI therapy in cirrhotic patients with an increased risk for infectious complications, hepatic encephalopathy and an increased risk for hospitalization and mortality. However, patients with liver cirrhosis are also considered to be at risk for peptic ulcer bleeding. The STOPPIT trial evaluates if discontinuation of a pre-existing PPI treatment delays a composite endpoint of re-hospitalization and/or death in patients (recently) hospitalized with liver cirrhosis compared to patients on continued PPI medication. The STOPPIT-trial is a prospective, multicentre, randomized, double-blinded, placebo-controlled, parallel-group trial. In total, 476 patients with complicated liver cirrhosis who already receive long-term PPI therapy without evidence-based indication are 1:1 randomized to receive either esomeprazole 20 mg (control group) or placebo (intervention group) for 360 days. Patients with an indication for PPI therapy (such as a recent diagnosis of peptic ulcers, severe reflux esophagitis, severe hemorrhagic gastritis, recent endoscopic therapy for oesophageal varices) are excluded. The primary composite endpoint is the time-to re-hospitalization and/or death. Secondary endpoints include rates of re-hospitalization, mortality, occurrence of infections, hepatic decompensation and acute-on-chronic liver failure. The safety endpoint is defined as manifestation of an evidence-based indication for PPI re-therapy. The impact of PPI continuation or discontinuation on the intestinal microbiota will be studied. The recruitment will take place at 18 study sites throughout Germany. Recruitment has started in April 2021. The STOPPIT trial is the first clinical trial to study the effects of PPI withdrawal on relevant outcome variables in patients with complicated liver cirrhosis. If the hypothesis that PPI withdrawal improves clinical outcomes of cirrhosis patients is confirmed, this would argue for a strong restriction of the currently liberal prescription practice of PPIs in this population. If, on the other hand, the trial demonstrates an increased risk of gastrointestinal bleeding events in patients after PPI withdrawal, this could create a rationale for a more liberal, prophylactic PPI treatment in patients with liver cirrhosis. EU clinical trials register EudraCT 2019-005008-16 (registered December 27, 2019). gov NCT04448028 (registered June 25, 2020). German Clinical Trials Register DRKS00021290 (registered March 10, 2021).

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Clinical and epidemiological characteristics of adult patients hospitalized for erysipelas and cellulitis.

The purpose of this investigation was to analyze the clinical and epidemiological aspects of all cases of erysipelas and infectious cellulitis admitted to a tertiary hospital during a period of five years. All patients admitted with the main diagnosis of erysipelas or cellulitis to the Department of Dermatology of the author's institution from January 2005 to May 2010 were included. Seventy patients were identified and their medical records were retrospectively reviewed so as to record the epidemiological and clinical data. Univariate and multivariable analyses were performed to analyze variables that predicted longer length of stay. The frequency of cellulitis in the lower limbs was higher in men and patients older than 65 years. Moderate/severe cellulitis in patients with basal comorbidity followed by a poor response to oral antibiotic therapy for 48 h were the most common reasons for admission. At arrival, four patients had abscessed areas. Fourteen patients developed local complications and 18 cases developed general in-hospital complications. Most patients improved or were healed with intravenous amoxicillin-clavulanate 1 g-200 mg/8 h. Intravenous amoxicillin-clavulanate 1 g-200 mg/8 h may be a good choice for empiric treatment in our setting. The development of in-hospital complications and the need for changing empiric antibiotic therapy were significant and independent variables associated with longer length of stay.

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Assessing medication adherence simultaneously by electronic monitoring and pill count in patients with mild-to-moderate hypertension.

Poor adherence to antihypertensive medication is one of the major problems in the treatment of hypertension. Electronic monitoring is currently considered to be the gold standard for assessing adherence, but it may trigger patients to open the pill bottle without taking medication or to take out more than prescribed. In adjunct to electronic monitoring, pill count could be a valuable tool for exploring adherence patterns, and their effects on blood pressure reduction. Among a total of 228 patients with mild-to-moderate hypertension, adherence to treatment was measured by means of both the Medication Event Monitoring System (MEMS) and pill count. Patients were followed-up for seven visits over a period of 1 year. At each visit to the physician's office, patient's adherence was assessed by both methods. Adherence is defined as the percentage of days with correct dosing; median adherence according to MEMS was lower than median adherence according to pill count (91.6 vs. 96.1; P < 0.001). Both methods agreed in defining patients as adherent in 107 (47%) and nonadherent in 33 (14%) patients. Thirty-one (14%) patients were adherent only by MEMS and 59 (25%) patients only by pill count. At the end of the study, patients in the four categories reached comparable blood pressure values and reductions. Pill count could be a useful adjunct to electronic monitoring in assessing adherence patterns. Although deviant intake behavior occurred frequently, the effect on achieved blood pressure and blood pressure reduction was not remarkable.

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High-dose corticosteroids improve the prognosis of Bell's palsy compared with low-dose corticosteroids: A propensity score analysis.

The aim of this study was to evaluate the effectiveness of high-dose corticosteroid (120mg prednisolone equivalent daily) in Bell's palsy compared with low-dose corticosteroid (60mg PSL equivalent). A single-center retrospective observational study was performed. We included adult Bell's palsy patients who were treated within 7days after disease onset. We compared high- and low-dose corticosteroid for the non-recovery rate at 6 months after disease onset using inverse probability-weighted propensity score analysis (IPW-PS). A total of 368 Bell's palsy patients (281 in the high-dose and 87 in the low-dose group) were included. The non-recovery rate without IPW-PS was 13.8% in the low-dose and 8.2% in the high-dose group. After IPW-PS adjustment, the non-recovery rate was 13.1% in the low-dose and 7.8% in the high-dose group (difference=-5.28%, 95% confidence interval [CI] -12.7% to -2.1%, p=0.040). High-dose corticosteroid decreased the non-recovery rate in severe Bell's palsy patients with a Yanagihara score of 0-10 (difference=-16.1%, 95% CI -38.5% to -6.2%, p=0.012), but did not decrease in moderate Bell's palsy patients with a Yanagihara score of 12-18 (difference=-2.0%, 95% CI -11.0% to 7.0%, p=0.591). Subgroup analysis revealed that the efficacy of high-dose corticosteroids was higher when patients were treated within 3days after disease onset, but not when patients were treated at 4days or later after disease onset. Physicians would be better to treat severe Bell's palsy patients with high-dose corticosteroids when the patients are treated within 3days after disease onset.

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Prostate specific antigen response to mitoxantrone and prednisone in patients with refractory prostate cancer: prognostic factors and generalizability of a multicenter trial to clinical practice.

We determine prostate specific antigen (PSA) response and durability, and prognostic factors associated with response and survival in patients with symptomatic hormone refractory prostate cancer treated with mitoxantrone and prednisone at a single institution. We then compare the results with those of a randomized phase III clinical trial. A retrospective review of all 133 patients treated with mitoxantrone and prednisone at Princess Margaret Hospital since 1994 was performed. PSA response and duration, and overall survival were determined as well as the influence of baseline factors on these outcome parameters. Results were compared to those for patients randomized to receive mitoxantrone and prednisone in the Canadian clinical trial which demonstrated palliative benefit of this regimen. Patients treated after trial closure had shorter survival (p = 0.003) but represented a poorer prognosis cohort. PSA response of the trial and post-trial cases was 34% and 28%, respectively (p = 0.36), and median duration of response was 118 and 175 days or greater, respectively. Factors predictive of PSA response in the non-trial cohort were longer time from diagnosis of prostate cancer (p = 0. 027) and higher baseline PSA (p = 0.013). Factors predictive of increased survival in both groups were younger age (p <0.04), better baseline Eastern Cooperative Oncology Group performance status (p <0. 02), and higher hemoglobin (p </=0.05) and PSA response (p <0.0001). Gleason score was not predictive of response or survival. Although patients treated outside of the trial had poorer prognostic features, rates of PSA response to mitoxantrone and prednisone were comparable. Factors predictive of survival were similar in the 2 cohorts. Results of the randomized trial are generalizable to clinical practice.

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Effect of coadministration of ezetimibe and simvastatin on high-sensitivity C-reactive protein.

This study assessed the effect of ezetimibe coadministered with simvastatin on high-sensitivity C-reactive protein (hs-CRP) in patients with primary hypercholesterolemia. After dietary stabilization, a 2- to 12-week washout period, and a 4-week, single-blind, placebo lead-in period, patients with baseline low-density lipoprotein cholesterol > or =145 and < or =250 mg/dl and triglycerides < or =350 mg/dl were randomized to one of these daily treatments for 12 consecutive weeks: ezetimibe 10 mg; simvastatin monotherapy (10, 20, 40, or 80 mg); ezetimibe 10 mg plus simvastatin (10, 20, 40, or 80 mg); or placebo. The primary analysis was the change in hs-CRP for the pooled ezetimibe plus simvastatin versus simvastatin monotherapy groups. Ezetimibe plus simvastatin significantly reduced median hs-CRP levels compared with simvastatin monotherapy (-34.8% vs -18.2%, p<0.01), and incremental reductions were observed at each simvastatin dose level. Combination therapy-induced significant changes in individual lipid parameters did not explain the observed decreases in hs-CRP. Thus, ezetimibe coadministered with simvastatin resulted in significant incremental decreases in hs-CRP, possibly consistent with an additional anti-inflammatory effect compared with simvastatin monotherapy.

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Comparison of the antihypertensive effect of enalapril and propranolol in black South Africans.

Angiotensin-converting enzyme (ACE) inhibitors are useful antihypertensive agents. Enalapril maleate is a new ACE inhibitor with actions similar to those of captopril but with fewer side-effects. A study was conducted on 19 black South Africans with mild or moderate essential hypertension; enalapril was compared with propranolol as monotherapy or together with hydrochlorothiazide in a 1-year randomized, double-blind, parallel study. Neither enalapril nor propranolol alone produced consistent, significant reductions in blood pressure. There were no significant differences between the blood pressure responses to enalapril and to propranolol (either with or without hydrochlorothiazide). It is concluded that neither enalapril nor propranolol is effective as monotherapy in the treatment of hypertension in South African blacks, but that both require the addition of a thiazide diuretic.

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Treatment Patterns in Essential Tremor: A Retrospective Analysis.

Although first line therapies for essential tremor have been identified from small clinical trials, responses are variable. We conducted a survey of tremor management in a large sample of ET cases. The Movement Disorders Clinical Case Registry within a US Veterans Health Administration medical center was used to identify 1468 patients with ET. Of 1468 charts reviewed, 1074 (73.19%) met criteria for ET with characterization of temporal course and treatment; 291/1074 subjects (27.1%) did not receive any treatment. Almost half (500/1074; 46.6%) of the patients received monotherapy, 196/1074 (18.2%) two, 66/1074 (6.1%) three, and 21/1074 (2.0%) four or more medications. Of all prescriptions, primidone was the most used (546/1172; 46.6%), followed by propranolol (419; 35.8%), topiramate (122; 10.4%) and gabapentin (35; 3.0%). Medication response was available for a total of 1030 prescriptions, of which 138 (13.4%) were discontinued due to side effects; 180 (17.5%) prescriptions were ineffective. Furthermore, 52/1074 patients (4.8%) were treated with botulinum toxin injections and 41/1074 (3.8%) underwent deep brain stimulation surgery. Our data suggest that more widespread recognition of limitations underlying conventional approaches, as well as increased referrals for nonpharmacological therapies, may be necessary to achieve improved outcomes in ET populations.

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Use of statins and prostate cancer recurrence among patients treated with radical prostatectomy.

WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Statins have shown broad spectrum anti-cancer properties in laboratory studies. In epidemiological studies, use of statins has been associated with reduced risk of advanced prostate cancer. However, the effects of statins on prostate cancer disease progression following curative treatment have not been extensively studied, and previous studies reported conflicting results. This study found no clear association between overall statin use and risk of disease progression, as well as lack of a monotone dose-response relationship between the use of statins, whether it was use before or after prostatectomy, and prostate cancer disease progression. To investigate whether use of HMG-CoA reductase inhibitors ('statins'), which have shown broad spectrum anti-cancer properties in laboratory studies, is associated with a reduced risk of recurrence in patients with prostate cancer who undergo radical prostatectomy. All men with incident prostate cancer diagnosed between 2004 and 2005 who subsequently underwent radical prostatectomy by the end of 2005 in the Kaiser Permanente Southern California (KPSC) health plan were identified using KPSC's cancer registry. Subjects were followed for up to 5 years after prostatectomy for (i) biochemical recurrence, defined as a single PSA measurement >0.2 ng/mL, and (ii) clinical disease progression, defined as diagnosis of metastatic disease or prostate-cancer-related death. Information on statin use, demographics, comorbidities, patho-clinical factors and outcomes were ascertained from KPSC's electronic medical records. The effects of statin use prior to and after prostatectomy were both examined using bivariate and multivariate Cox models, adjusting for known prognostic factors. For postoperative statin exposure, a time-dependent Cox model was used. A total of 1200 men were included; 37% had preoperative and 56% had postoperative statin use. Neither preoperative nor postoperative statin use was associated with biochemical recurrence (hazard ratio [HR] = 1.00 [0.72-1.39] and 1.05 [0.76-1.46], respectively) or clinical disease progression (HR = 0.63 [0.31-1.27] and 1.20 [0.63-2.30], respectively). No clear dose-response relationship was found for duration of use. Statin use may not prevent prostate cancer progression following radical prostatectomy. These findings do not provide support for the pursuit of a prospective clinical trial of statin use as a secondary prevention among surgically treated patients with prostate cancer.

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Four cycles of R-CHOP followed by two applications of rituximab based on negative interim PET/CT: an analysis of a prospective trial.

R-CHOP with or without radiotherapy is the standard treatment for limited-stage diffuse large B-cell lymphoma (DLBCL). To prevent overtreatment, we assessed whether four cycles of CHOP plus six applications of rituximab was adequate with negative interim PET/CT and the role of consolidation radiotherapy specifically for patients with Waldeyer's ring DLBCL. One hundred and twenty-nine patients with limited-stage DLBCL were enrolled in this open-label, nonrandomized, single-arm, phase 2 clinical trial (NCT01804127). All patients were initially treated with 4 cycles of R-CHOP and underwent interim PET/CT. Patients with negative PET/CT (Deauville scores 1-2) received 2 additional cycles of rituximab monotherapy, unless they had any risk factors (primary mediastinal large B-cell lymphoma, extranodal primary or bulky disease). Otherwise, patients received another 2 cycles of R-CHOP. Patients with partial response on interim PET/CT received another 4 cycles of R-CHOP. No radiotherapy was conducted in Waldeyer's ring DLBCL patients with negative PET/CT. The primary endpoint was 3-year progression-free survival (PFS). Overall survival (OS) in this study was compared with those from a historical study (NCT 00854568159). One hundred fifteen interim PET/CT scans (89.1%) were negative after 4 cycles of R-CHOP. An elevated lactate dehydrogenase level was significantly associated with positive interim PET/CT (P < 0.05). A trend of inferior outcome was observed in patients with positive interim PET/CT in terms of 3-year PFS (78.6% vs. 91.9%, P = 0.24) and 3-year OS (85.7% vs. 95.6%, P = 0.16). There were no PFS or OS differences found between patients treated with 4R-CHOP+2R and those treated with 6R-CHOP from a historical control study. Patients with Waldeyer's ring DLBCL and negative interim PET/CT achieved a 3-year PFS of 87.2% and a 3-year OS of 89.7%. Our results suggested that for interim PET/CT-negative patients without risk factors, the extra 2 cycles of CHOP might be omitted, and radiotherapy might also be omitted in patients with Waldeyer's ring DLBCL without compromising the efficacy. These results need to be confirmed in a randomized study. clinicaltrials.gov ,  NCT01804127 . Date of first registration: 05/03/2013.

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An investigational ovarian stimulation protocol increased significantly the psychological burden in women with premature ovarian failure.

To assess the psychological impact (Hospital Anxiety and Depression Scale) of an investigational ovarian stimulation protocol in women with premature ovarian failure (POF). Prospective longitudinal study. Ten women with POF. Women with idiopathic POF were placed on three consecutive treatment cycles consisting of gonadotropin ovarian stimulation after estrogen priming, gonadotropin-releasing hormone agonist pituitary desensitization, and corticosteroid immune suppression. Median anxiety and depression scores increased significantly from baseline following three consecutive treatment cycles from 4.0 (range 2.0-8.0) to 11.0 (range 10.0-14.0) (p-value 0.041) and from 1.5 (range 0-6.0) to 9.0 (range 7.0-10.0) (p-value 0.039), respectively. There were nine "probable" anxiety (90%) and three "probable" depression (30%) cases on the final treatment cycle compared with none (0%) on baseline (p-value 0.004 and 0.250, respectively). The use of investigational ovarian stimulation protocols in women with idiopathic POF was associated with excessive psychological strain. Women with POF should be cautioned against the potentially harmful aspect of similar treatments of unproven benefit.

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Development of congestive heart failure after treatment with metoprolol in acute myocardial infarction.

In a double blind study of metoprolol in the treatment of suspected acute myocardial infarction 698 patients (study group) received metoprolol and 697 a placebo (control group). Metoprolol was given in an intravenous dose of 15 mg as soon as possible after admission to hospital followed by 50 g by mouth four times a day for two days and thereafter 100 mg twice a day for three months. A placebo was similarly given. Congestive heart failure occurred in a similar percentage of patients in both the study (27%) and the control groups (30%). Its severity was estimated by calculating the total dose of frusemide given during the first four days in hospital. Less frusemide was given to patients treated with metoprolol compared with those given a placebo in the total series. An appreciably lower total dose of frusemide was given to patients included in the trial less than or equal to 12 hours after the onset of pain and treated with metoprolol compared with a placebo, while no difference was seen among patients treated later. The initial heart rate, systolic blood pressure, and infarct site affected the results.

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Conversion from cyclosporine to azathioprine improves renal function without increased risk of graft failure.

Thirty of 110 HLA-mismatched renal allograft recipients were converted from CsA to Aza due to CsA nephrotoxicity or side effects, persistent posttransplant ATN, noncompliance, or patient desire to reduce the cost of maintenance immunosuppression. The majority of patients studied were cadaver transplant recipients. Renal function improved significantly in all patients following conversion. Converted patients did not demonstrate an increased incidence of rejection or hospitalization for fever or infection when compared with nonconverted, matched controls. The rate of allograft loss in converted patients did not differ from that of all nonconverted patients during the study period. The monthly cost of maintenance immunosuppression was significantly less in converted patients, resulting in an annual savings of $2,489 per patient. Posttransplant conversion from CsA to Aza appears to be safe and cost-beneficial.

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ETV6/RUNX1-positive childhood acute lymphoblastic leukemia in China: excellent prognosis with improved BFM protocol.

In childhood B-precursor acute lymphoblastic leukemia (B-ALL), the ETV6/RUNX1 fusion transcript is considered to have an excellent outcome. However, few studies of children with ETV6/RUNX1-positive ALL from China have been conducted. It is largely unknown whether clinical outcomes for patients with this genotype and important factors that influence such outcomes are similar to those reported in other countries. Therefore, it is important to analyze the outcomes of children with ETV6/RUNX1-positive ALL treated at our institution with the aim of identifying significant prognostic variables in a Chinese population. We studied the clinical characteristics and treatment outcomes for 77 pediatric patients diagnosed with ETV6/RUNX1-positive ALL between 2005 and 2015 at our institution. The 5-year event-free survival (EFS) and the disease-free survival (DFS) were reported to be 90% ± 3% and 96% ± 3% respectively. Two patients had a relapse at a median of 42 months from diagnosis and the 5-year cumulative incidence of relapse was 2.1%. Despite intensive chemotherapy or allogeneic hematopoietic cell transplantation, the 2 relapsed patients succumbed to the disease progression and the 5-year overall survival (OS) was 97% ± 2%. Multivariate analysis for EFS revealed that the minimal residual disease (MRD) ≥10^- 3 on Day + 33 negatively affected the outcome. In conclusion, patients with ETV6/RUNX1 fusion transcript can achieve a high rate of complete remission and the long-term curative effect was excellent under risk-stratified treatment. In case of relapse, the MRD level at the end of induction therapy should be taken into consideration while deciding the appropriate chemotherapy dosage.

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Effects of atorvastatin and atorvastatin withdrawal on soluble CD40L and adipocytokines in patients with hypercholesterolaemia.

Beyond lipid lowering, statins have pleiotropic effects with favourable benefits against atherogenesis. Withdrawal of statin therapy has been demonstrated to abrogate vascular protective activity and even increase the incidence of thrombotic vascular events. The purpose of this study is to investigate the serial changes of soluble CD40 ligand (sCD40L) and two adipocytokines, adiponectin and resistin, after short-term atorvastatin therapy and withdrawal in patients with hypercholesterolaemia. Thirty-two patients with hypercholesterolaemia received atorvastatin 10 mg/day for 3 months. Serum lipid profiles, and levels of sCD40L, adiponectin and resistin, were assessed before and immediately after 3 months' statin therapy. Serum levels of sCD40L and adiponectin were also measured on the 3 consecutive days after statin withdrawal. After 3 months' statin therapy, levels of sCD40L (1.93 +/- 1.13 vs. 1.30 +/- 0.97 ng/mL), total cholesterol and low-density lipoprotein cholesterol (LDL-C) were all reduced significantly (p < 0.05). However, sCD40L level tended to increase towards baseline on the first and second days after statin withdrawal, but was not significantly elevated until the third day after withdrawal (1.89 +/- 1.28 vs. 1.30 +/- 0.97 ng/mL, p < 0.05). Total cholesterol and LDL-C levels did not increase during the 3 days of statin withdrawal. No significant changes of adiponectin and resistin levels were shown after statin therapy. These results indicate that the effect of statin on sCD40L level was abrogated after therapy withdrawal, and was independent of serum cholesterol level. Statin therapy did not significantly alter levels of adiponectin and resistin.

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Use of isotonic nebulised magnesium sulphate as an adjuvant to salbutamol in treatment of severe asthma in adults: randomised placebo-controlled trial.

Intravenous magnesium can cause bronchodilation in treatment of severe asthma, however its effect by the nebulised route is uncertain. We aimed to assess the effectiveness of isotonic magnesium sulphate as an adjuvant to nebulised salbutamol in severe attacks of asthma. We enrolled 52 patients with severe exacerbations of asthma presenting to the emergency departments at two hospitals in New Zealand. A severe exacerbation was defined as a forced expiratory volume at 1 s (FEV(1)) of less than 50% predicted 30 min after initial administration of 2.5 mg salbutamol via nebulisation. In this randomised double-blind placebo-controlled trial patients received 2.5 mg nebulised salbutamol mixed with either 2.5 mL isotonic magnesium sulphate or isotonic saline on three occasions at 30 min intervals. The primary outcome measure was FEV(1) at 90 min. Analysis was per protocol. At 90 min the mean FEV1 in the magnesium group was 1.96 L (95% CI 1.68-2.24) and in the saline group 1.55 L (1.24-1.87). The difference in the mean FEV(1) between the magnesium and saline groups was 0.37 L (0.13-0.61, p=0.003). Use of isotonic magnesium as an adjuvant to nebulised salbutamol results in an enhanced bronchodilator response in treatment of severe asthma.

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Analysis of serious adverse events in a paediatric fast breathing pneumonia clinical trial in Malawi.

Pneumonia is the leading infectious killer of children. We conducted a double-blind, randomised controlled non-inferiority trial comparing placebo to amoxicillin treatment for fast breathing pneumonia in HIV-negative children aged 2-59 months in Malawi. Occurrence of serious adverse events (SAEs) during the trial were examined to assess disease progression, co-morbidities, recurrence of pneumonia and side effects of amoxicillin. Enrolled children with fast breathing for age and a history of cough <14 days or difficult breathing were randomised to either placebo or amoxicillin for 3 days, and followed for 14 days to track clinical characteristics and outcomes. Medical history, physical exam, laboratory results and any chest radiographs collected at screening, enrolment and during hospitalisation were evaluated. All SAE reports were reviewed for additional information regarding hospitalisation, course of treatment and outcome. In total, 102/1126 (9.0%) enrolled children with fast breathing pneumonia were reported to have a SAE. Seventy-five per cent (n=77) of SAEs were pneumonia-related (p<0.01). Children<2 years of age represented the greatest proportion (61/77, 79.2%) of those with a pneumonia-related SAE. In the amoxicillin group, there were 46 SAEs and 5 (10.9%) cases were identified as possibly related to study drug (4 gastroenteritis and 1 fever). There were no life-threatening pneumonia SAEs or deaths in either group, and by the time of exit from the study, all children recovered without sequelae. In this fast breathing pneumonia clinical trial, SAEs occurred infrequently in both the amoxicillin and placebo groups, and amoxicillin was well tolerated. NCT02760420. https://clinicaltrials.gov/ct2/show/NCT02760420?term=ginsburg&rank=9.

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Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B).

The superiority of a chemotherapy with doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone (ACVBP) in comparison with cyclophosphamide, doxorubicin, vincristin and prednisone plus radiotherapy for young patients with localized diffuse large B-cell lymphoma (DLBCL) was previously demonstrated. We report the results of a trial which evaluates the role of rituximab combined with ACVBP (R-ACVBP) in these patients. Untreated patients younger than 66 years with stage I or II DLBCL and no adverse prognostic factors of the age-adjusted International Prognostic Index were randomly assigned to receive three cycles of ACVBP plus sequential consolidation with or without the addition of four infusions of rituximab. A total of 223 patients were randomly allocated to the study, 110 in the R-ACVBP group and 113 in the ACVBP group. After a median follow-up of 43 months, our 3-year estimate of event-free survival was 93% in the R-ACVBP group and 82% in the ACVBP group (P = 0.0487). Three-year estimate of progression-free survival was increased in the R-ACVBP group (95% versus 83%, P = 0.0205). Overall survival did not differ between the two groups with a 3-year estimates of 98% and 97%, respectively (P = 0.686). In young patients with low-risk localized DLBCL, rituximab combined with three cycles of ACVBP plus consolidation is significantly superior to ACVBP plus consolidation alone.

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The effect of prostacyclin on asthma precipitated by aspirin.

Inhibition of prostacyclin biosynthesis by aspirin might be expected to promote asthmatic attacks in aspirin-intolerant patients. In vitro, prostacyclin inhibits generation of leukotrienes and opposes their bronchoconstrictive action. In a double-blind study we compared the effects of intravenous infusions of prostacyclin with those of its solvent on bronchoconstriction provoked by threshold doses of aspirin in 9 known aspirin-sensitive asthmatics. The intensity of bronchial obstruction precipitated by aspirin was similar during prostacyclin and placebo infusions. There was no difference in other symptoms of intolerance, except for rhinorrhea which seemed accentuated by prostacyclin (possibly because of nasal vasodilatation). Our results suggest that either the inhibitory effects of prostacyclin on leukotrienes described in vitro do not apply in vivo, or the importance of leukotrienes have been overestimated in this type of asthma. Idiosyncrasy to aspirin, which affects 5-10% of adult asthmatics, was thought several decades to be of allergic background, while in fact numerous and extensive immunological studies ruled out typical IgE--mediated allergic mechanisms for aspirin--induced asthma. In 1974, at the Department of Allergy and Clinical Immunology in Cracow, a novel hypothesis was put forward. If stated that in sensitive patients, precipitation of asthmatic attacks by aspirin and by certain nonsteroidal antiinflammatory drugs (NSAID) results from inhibition of specific enzyme in the bronchi, cyclooxygenase, leading to an imbalance of prostanoids in the respiratory tract. Over the years which followed evidence has been accumulated which strongly support this hypothesis.(ABSTRACT TRUNCATED AT 250 WORDS)

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[Intratarsal triamcinolone acetonide injection for treatment of refractory chronic tropical endemic limboconjunctivitis (TELC): experience at Aristide-Le-Dantec university hospital in Dakar].

To evaluate the efficacy of intratarsal triamcinolone acetonide (TA) injection versus dexamethasone ointment in the treatment of refractory chronic tropical endemic limboconjunctivitis (TELC). This one-year prospective study enrolled 20 patients with refractory TELC. One millilitre containing 40 mg TA was injected intratarsally on the most affected eye and dexamethasone ointment applied in the fellow eye. Efficacy was judged by clinical criteria according to a specially designed scale for the study. Statistical analysis was carried out using Fisher's chi(2) test and Student's t test with comparisons of the means of paired samples. In both cases, symptoms improved in all patients, as early as the following day or week, and clinical signs improved from the second week through the first month after injection, with an effective dose of 1 mL TA and three weeks of dexamethasone, with no recurrence at three months. Efficacy of the ointment alone was less (33.3-75%) than that with injection (90.9-100%) and could only be maintained after the first month by repeated application. Intratarsal TA injection, relatively easy and well-tolerated by patients, may be a better alternative to dexamethasone ointment in the treatment of refractory TELC.

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[Risk-adapted therapy of highly malignant non-Hodgkin's lymphomas with COP-BLAM/IMVP-16: a prospective multicenter study].

In a prospective multicenter therapy trial the remission-inducing potential of the COP-BLAM (5 courses) and the possibly not cross-resistant IMVP-16 (2 courses) regimen for advanced diffuse large cell lymphomas were investigated. Inadequately responding patients were switched early after 2-3 courses to the IMVP-16 protocol. Between January 1986 and August 1988 349 previously untreated patients were recruited who fulfilled the entry criteria: age 15-75 (mean 56 years), stage II-IV. A first restaging after 3 courses of chemotherapy was documented for 280 cases, a second restaging following 7 courses of chemotherapy or a final report was available for 221 patients, 130 of which where in CR (59%). These figures include 29 cases who died already during induction-chemotherapy of progressive disease (n = 17) as well as of therapy-related complications in CR (n = 12). Thirty-three patients were switched early to IMVP-16 due to incomplete response at the first restaging; 13 of those achieved CR by the new regimen (39%), 9 achieved a partial remission which was turned into CR by additional radiotherapy in 5 cases. Dose reductions and interval prolongations were necessary at increasing rates with subsequent chemotherapy courses (20-50% of the cycles). Relapses have occurred in 32 patients so far (14 early, 18 after stop of treatment). The median survival was 24 months (n = 309 patients). These data show that this treatment strategy is effective in a large unselected group of patients of relatively high age. However, patients showing only delayed response with this protocol probably need more aggressive regimens to obtain durable remissions.

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Somatostatin analogs and prednisone in advanced refractory thymic tumors.

Therapeutic options to cure advanced, recurrent, and metastatic thymic tumors are limited. Evidence of a high uptake of indium-labeled octreotide ((111)In-DTPA-D-Phe(1)-octreotide) in thymic tumors and the curative application of somatostatin analogs and prednisone in one patient with thymoma and pure red cell aplasia led the authors to start a Phase II study. Sixteen patients with advanced thymic tumors, unresponsive to conventional chemotherapeutic regimens, were enrolled in the study. The schedule includes administration of somatostatin analog octreotide (1.5 mg/day subcutaneously) associated with prednisone (0.6 mg/kg/day orally for 3 months, 0.2 mg/kg/day orally during follow-up). In 8 cases, octreotide was replaced by the long-acting analog lanreotide (30 mg/every 14 days intramuscolarly). Treatment was prolonged until progression of disease was documented. Overall response rate, survival, progression free survival, and toxicity were evaluated. The overall response rate among 16 evaluable patients was 37%. One patient (6%) had a complete response, 5 (31%) had a partial response, 6 obtained a stabilization of disease, and 4 progressed during the treatment. After a median follow-up of 43 months, the median survival was 15 months, and median time to progression was 14 months. Treatment was generally well tolerated with acceptable toxicity: cholelithiasis (1 patient), Grade 2 cushingoid appearance (3 patients), Grade 1 diarrhea (5 patients), Grade 2 hyperglycemia (3 patients). Treatment with somatostatin analogs and prednisone has shown efficacy in patients with recurrent and metastatic malignant thymic tumors refractory to standard therapeutic options. The results obtained are very satisfactory given the lack of effective alternative treatments. Such therapy is not burdened by the same toxicity of chemotherapy; thus, it can be administered to heavily pretreated patients. Somatostatin analogs and prednisone are well tolerated, and the long-acting analog lanreotide, which requires fewer injections, improves patients' compliance.

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Does levothyroxine administration impact parathyroid localization?

Proper localization is crucial in performing minimally invasive parathyroidectomy for primary hyperparathyroidism. Ultrasonography (US) and Tc-99m sestamibi (MIBI) scintigraphy are common methods used for localization. As the appearance and activity of the thyroid gland may impact parathyroid localization, the purpose of this study was to determine how exogenous use of the thyroid hormone, levothyroxine (LT), affects parathyroid localization. Adult patients with non-familial primary hyperparathyroidism who underwent initial parathyroidectomy from 2000-2014 were retrospectively identified. LT (+LT) and non-LT (-LT) patients were matched 1:3 based on age, gender, goiter status, and preoperative parathyroid hormone levels. Subgroup analysis was performed on patients previously treated with radioactive iodine and patients undergoing single adenoma resection. Of the 1737 patients that met inclusion criteria, 286 were on LT at the time of their parathyroid localization scan. Use of LT did not impact the percentage of correct MIBI localization scans when compared with -LT patients (P = 0.83). Interestingly, use of LT significantly hindered localization by US in comparison with the -LT group (48.4 versus 62.2%, P < 0.01). When examining only patients where a single upper gland was removed, the +LT group was less likely to have a correct US compared with the -LT group (50 versus 72.8%, P < 0.01). However, there was no difference in US accuracy for patients who only had a single lower gland removed (P = 0.51). Exogenous LT is associated with impaired parathyroid localization with US but not MIBI. Surgeons should be aware of localization efficiency for this subset of patients in the era of personalized medicine and cost effectiveness.

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Multicenter randomized study of single-dose ofloxacin versus amoxicillin-probenecid for treatment of uncomplicated gonococcal infection.

The safety and efficacy of ofloxacin, 400 mg orally, were compared with those of amoxicillin, 3.0 g, plus probenecid, 1.0 g orally, as single-dose therapy in 201 heterosexual patients (101 men and 100 women) with uncomplicated gonococcal infection. Treatment groups were comparable in age, duration of symptoms, number of sexual partners within the previous month, and number of previous episodes of sexually transmitted diseases. The cure rate for men treated with ofloxacin was 98% (47 of 48), and that for women was 100% (52 of 52). Cure rates for both men and women treated with amoxicillin-probenecid were 96% (51 of 53 men; 46 of 48 women). All 13 patients with positive rectal cultures and 7 of 8 patients with positive pharyngeal cultures treated with ofloxacin were cured. Neither regimen reliably eradicated coexistent infection with Chlamydia trachomatis. The MIC of ofloxacin for all but two of 198 pretreatment isolates was 0.3 microgram/ml or less. The MIC of amoxicillin for 90% of isolates tested was 1.0 microgram/ml. Single oral doses of ofloxacin and of amoxicillin plus probenecid were equally effective for treatment of urethral and cervical gonorrhea. Ofloxacin appears promising as treatment for rectal and pharyngeal infection, but studies with larger numbers of patients with rectal or pharyngeal infection or both are required for confirmation. Relative contraindications in children and possibly pregnant women plus the potential for single-step, high-level resistance may limit the usefulness of quinolone therapy for gonorrhea.

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[A case study regarding the use of antibiotic therapies for the treatment of preterm premature rupture of fetal membranes, and emergence of antibiotic resistant bacteria].

The objective of this retrospective study is to compare two types of antimicrobial management used to treat premature rupture of membranes in pregnancy. This study evaluates both duration and the type of antibiotic therapy used for treatment. The antimicrobials used to treat premature rupture of membranes include a first generation cephalosporin in one group and amoxicillin in the other group. Cephalosporin was used over a 7-day period to treat 38 cases, whereas amoxicillin was used through delivery in 52 cases. Emergence of multidrug-resistant Gram negative bacteria (GNB) on maternal of neonatal sampling was the primary outcome. Emergence of antibiotic resistant GNB can be seen under both antibiotic regimens and appears to be linked to the duration of latency, and to duration of antibiotic treatment. Other outcomes (duration of latency period, gestational age at delivery, maternal and neonatal complications) were similar in both groups. Antibiotic treatment in PPROM favors a selection of GNB. This emergence is positively linked with the duration of latency between rupture of membranes and delivery and with the length of antibiotic administration. The extension of antibiotherapy does not alter other maternal or neonatal parameters.

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Association between methylphenidate treatment and risk of seizure: a population-based, self-controlled case-series study.

Individuals with attention-deficit hyperactivity disorder (ADHD) are at increased risk of seizures. Stimulant medications such as methylphenidate are the most commonly prescribed treatment for ADHD, but the association between their therapeutic use and the risk of seizures is unclear. We aimed to investigate the association between methylphenidate treatment and the risk of seizure. For this population-based observational study, we used the electronic medical record database of the Hong Kong Clinical Data Analysis And Reporting System to identify individuals aged 6-25 years who received at least one methylphenidate prescription during the study period. Individuals with records of seizure or epilepsy before the study period were excluded. Individuals treated with methylphenidate who had seizures during the study period were included in the subsequent analyses, and a self-controlled case-series design was used to control for time-invariant individual characteristics. We did additional analyses using skin infection as a negative control outcome. We compared relative incidence of seizure during periods when individuals were exposed to methylphenidate with that during non-exposed periods. Of 29 604 individuals prescribed methylphenidate between Jan 1, 2001, and Dec 31, 2017, 269 (199 males and 70 females) had incident seizures. The mean age at baseline was 6·66 years (SD 2·01) and the median age at the incident seizure was 9·69 years (IQR 7·62-12·99). The overall incidence of seizure during methylphenidate treatment was 4·4 per 10 000 patient-years. We detected an increased risk of seizure during the first 30 days of methylphenidate treatment compared with that during non-exposed periods, with an incidence rate ratio of 4·01 (95% CI 2·09-7·68). No increase in risk was identified during the following 31-180 days of treatment (1·13, 0·56-2·25) or during subsequent treatment (1·38, 0·92-2·07). We did not identify an increased risk in any risk window for the negative control outcome analysis. No individuals died because of a seizure during the study period. The incidence of seizures was higher in the period immediately after the start of methylphenidate treatment than in the non-exposed period. No increased risk was observed during continuation of methylphenidate treatment. The association between methylphenidate treatment and seizures immediately after initiation of medication can be seen as a potential safety signal. Monitoring of neurological outcomes in individuals with ADHD is recommended when they first start methylphenidate treatment. Hong Kong Research Grants Council.

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Effects of postoperative non-steroidal anti-inflammatory drugs on long-term survival and recurrence of patients with non-small cell lung cancer.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to relieve postoperative fever, surgery pain, and inflammation. In addition, NSAIDs have anticancer activity and may reduce the risk and mortality of several cancers. However, the association between postoperative NSAIDs and the clinical outcome of non-small cell lung cancer (NSCLC) patients with fever after surgery is not fully understood. We performed a retrospective study of NSCLC patients who underwent surgery between July 2011 and June 2012, aiming to evaluate the effect of postoperative NSAIDs on overall survival (OS) and progression-free survival (PFS). Differences in clinical data between the postoperative NSAIDs group and non-NSAIDs groups were analyzed by Chi-square tests. Kaplan-Meier curves method and Cox regression analysis were conducted for survival analysis. The primary and secondary endpoints were OS and PFS, respectively. This retrospective study included 347 NSCLC patients. There were no significant differences in the clinical characteristics between the NSAIDs group and non-NSAIDs group except for age (P = .024) and differential degree (P = .040). Administration of postoperative NSAIDs was related to longer OS (hazards ratio [HR] 0.528, 95% confidence interval [CI] 0.278-0.884, P = .006) and longer PFS (HR 0.557, 95% CI 0.317-0.841, P = .002) in the multivariate Cox regression model. Subgroup analysis showed statistically significant differences in elderly individuals, male subjects, low smoking index, poor differentiation, and non-adenocarcinoma subgroups, respectively. In conclusion, the administration of postoperative NSAIDs was related to longer OS and PFS in NSCLC patients with postoperative fever.

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Effect of pre-procedural interrupted apixaban on heparin anticoagulation during catheter ablation for atrial fibrillation: a prospective observational study.

Effective intraprocedural anticoagulation is considered essential to minimize the risk of thromboembolism in catheter ablation (CA) of atrial fibrillation (AF). The effect of interrupted apixaban on intraprocedural heparin dosing requirements and levels of achieved anticoagulation with heparin has not been well studied. The purpose of the present study was to compare heparin administration and activated clotted times (ACTs) for patients undergoing CA for AF treated with interrupted apixaban before the procedure with patients on uninterrupted warfarin. Consecutive patients undergoing CA for AF treated with interrupted apixaban or uninterrupted warfarin were prospectively enrolled. Heparin administration determined by a standard protocol and normalized to patient weight and procedure duration, as well as rapidity, and degree of anticoagulation with heparin (as measured by mean ACT, peak ACT, time to ACT ≥300 s, and time to ACT ≥350 s) were compared between the groups. Forty-eight patients were enrolled (25 apixaban and 23 warfarin). Heparin administered by bolus (51.3 ± 21.5 vs 27.8 ± 9.6 units/kg/h; p < 0.001) and mean heparin drip rate (25.3 ± 3.6 vs 20.7 ± 2.4 units/kg/h; p < 0.001) were significantly higher in the apixaban group compared to the warfarin group. Despite greater heparin administration, apixaban patients achieved a significantly lower mean ACT (332.3 ± 17.0 vs 384.5 ± 53.9; p < 0.001) and peak ACT (369.5 ± 22.6 vs 432.3 ± 75.8, p < 0.001) compared to the warfarin group. The time to ACT ≥350 s (66.7 ± 35.8 vs 26.9 ± 34.0; p < 0.001) was significantly longer for apixaban-treated patients. Outcome differences persisted after analysis using linear models and Cox proportional hazard regression with adjustment for propensity scores. A standard intraprocedural heparin protocol results in delayed and lower levels of anticoagulation as measured by the ACT for interrupted apixaban-treated patients in comparison to those on uninterrupted warfarin during CA of AF.

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Efficacy of beta-blockers in migraine. A critical review.

Five double-blind trials of the prophylactic treatment of migraine with beta-blockers were reviewed critically with regard to problem investigated, design, "blindness" of patient, side effects, statistical validity, and conclusions. The initial use of a "responder-finding" period may limit the validity of results from a subsequent double-blind crossover placebo-controlled study because it may impair "blindness". A d-propranolol versus racemic propranolol versus placebo study was reanalysed with conventional statistical methods, which showed that d-propranolol had no significant effect. In a multicentre study including 96 patients calculation of 95% confidence limits demonstrated that timolol and propranolol are equally effective in common migraine prophylaxis. Metopropolol and propranolol were apparently equally effective in 34 patients, but the calculation of confidence limits showed that a larger study is needed to confirm this conclusion. A group comparison study with three doses of nadolol and placebo lacked statistical evaluation of the results, thereby making it impossible to draw a conclusion about the efficacy of nadolol. It is concluded that there are considerable methodological problems in published papers on beta-blocker and migraine.

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Pulmonary function in bronchopulmonary dysplasia.

The purpose of this study was to examine lung function and bronchodilator responsiveness in infants with a history of prematurity and bronchopulmonary dysplasia (BPD), using the raised volume rapid thoracoabdominal compression technique as well as with whole-body plethysmography. Spirometric measurements were obtained in 28 infants with a history of BPD, defined as preterm birth with O2 requirement at 36 weeks postmenstrual age (gestational age at birth, 26.4 +/- 2.1 weeks, mean +/- SD; birthweight, 898 +/- 353 g; age at study, 68.0 +/- 35.6 weeks). Fractional lung volumes were measured in 27 subjects. Values were expressed as percentage of predicted normal values. Compared to normal infants, those with a history of BPD exhibited decreases in forced expiratory flows including forced expiratory volume in 0.5 sec (76.3 +/- 19.6%), forced expiratory flow at 75% of expired forced vital capacity (FEF75; 59.5 +/- 30.7%), and FEF(25-75) (74.0 +/- 26.8%; P<0.01 for all). Functional residual capacity (107.9 +/- 25.3%), residual volume (RV, 124.5 +/- 42.7%), and RV/total lung capacity (RV/TLC, 128.2 +/- 35.3%) were increased in infants with a history of BPD (P<0.05 for each). There was no difference in TLC between groups. Seventeen infants were studied both pre- and postalbuterol, and 6 (35%) demonstrated significant bronchodilator responsiveness. Infants with recurrent wheezing showed greater expiratory flow limitation, hyperinflation, and airways responsiveness, whereas those without wheezing showed only modest airway dysfunction. We conclude that infants with a history of BPD have pulmonary function abnormalities characterized by mild to moderate airflow obstruction and air trapping.

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[Antithrombotic Therapy in Patients with Acute Coronary Syndrome and Atrial Fibrillation].

The number of patients with atrial fibrillation (AF) is increasing due to the aging of the population. In addition, the number of patients with AF and an indication for oral anticoagulation (OAC) for the prevention of strokes increases, who are in need for a dual antiplatelet therapy (DAPT) with acetyl salicylic acid (ASA) plus a P2Y₁₂-Inhibitor because of an acute coronary syndrome and/or coronary stent implantation. These patients did receive a triple therapy (TT) for 3-12 months in the past. Triple therapy never has been studied for efficacy or safety, however, the rate of bleeding complications in comparison to OAC or DAPT is significantly higher.Registries and smaller trials showed that dual therapy with an OAC plus a single platelet inhibitor may be sufficient to prevent strokes and stent thromboses/myocardial infarctions. Four prospective randomized trials involving all four NOACs (Non-Vitamin K oral anticoagulants) approved for stroke prevention in AF have been undertaken. The NOACs plus one antiplatelet agent were tested versus vitamin K-antagonists plus DAPT. In the meantime, the trials involving rivaroxaban (PIONEER AF-PCI), dabigatran (RE-DUAL PCI), apixaban (AUGUSTUS), and edoxaban (ENTRUST-AF-PCI) have been published. The current status is that a NOAC plus a single antiplatelet agent, mostly clopidogrel, is superior to TT with respect to the bleeding complications, without any obvious and statistically significant disadvantage for stroke rates or cardiac ischemic events. The international guidelines already recommend to treat with a NOAC and one antiplatelet agent instead of TT in case the patients bleeding risk is prevailing. Thus, TT seems not to be indicated anymore for most patients with AF and ACS or PCI.

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Combination of thiopurines and allopurinol: adverse events and clinical benefit in IBD.

Allopurinol has been presented as a safe and effective adjunct to thiopurine therapy in inflammatory bowel disease (IBD). We aimed to determine the rate of infectious complications and clinical successes with a combination of thiopurine/allopurinol in IBD, and to identify which variables predict 6-thioguanine, 6-methylmercaptopurine, and white blood cell levels. Additionally we aimed to identify which variables predict complications. A retrospective database search identified patients with inflammatory bowel disease on both thiopurines and allopurinol. Regression modeling was used to identify which variables predicted metabolite levels, white blood cell levels, and complications. Twenty-seven subjects were found, with 20 treated intentionally and 7 inadvertently after a concurrent gout diagnosis. Thirteen of 20 patients had a major clinical improvement and 7 of 16 stopped steroids. Five infectious complications occurred. These included 2 cases of shingles, and one each of PCP, EBV, and viral meningitis. Significant predictors of metabolite levels included the dose of thiopurine and allopurinol, age, and BMI. Low white blood cell count levels were associated with increased doses, high BMI, and older age. Despite having only 5 events, there was a difference in absolute lymphocyte count between patients with and without infection (median 200 per mm³ vs 850 per mm³ respectively, p=0.0503). Adjunctive allopurinol therapy in shunting patients produced major clinical improvement in 48% of patients. However, a surprising number of opportunistic infections have occurred. Low absolute lymphocyte count may be a previously unrecognized indicator of risk of opportunistic infections.

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Gabapentin is effective in the treatment of cancer-related neuropathic pain: a prospective, open-label study.

Gabapentin has been evaluated in the treatment of nonmalignant neuropathic pain, however, there is little direct evidence evaluating its efficacy in cancer-related neuropathic pain. This study evaluated the effectiveness of gabapentin to treat cancer-related neuropathic pain. This was an open-label study. Two parallel groups of patients were recruited with either treatment-related (radiotherapy, surgery, chemotherapy) or tumor-related neuropathic pain. Gabapentin was dose-escalated from 300 mg/d to 1.8 g/d. The primary outcome, pain, was assessed using the modified brief pain inventory. In addition patient descriptors of pain and scores of activities of daily living were collated together with demographic data. We recruited 62 patients with treatment-related (n = 25) or tumor-related (n = 37) neuropathic pain. There was a significant reduction in the worst, average, and current pain scores (p < 0.002), but not the least pain score (p = 0.21). Twenty-eight of 62 (45.2%) of patients achieved at least a one third reduction in pain score (95% confidence interval [CI] 32.5-58.3); the number needed to treat to obtain this benefit is 2.2 (95% CI 1.7-3.1). There was a significant reduction in all scores measuring the impact of pain on daily living (p < 0.003). There was no significant difference in pain scores at day 8 compared to day 15. Analysis of variance suggested that gender, but not etiology, or type of neuropathic pain, was a significant predictor of analgesic response and this warrants further investigation. We conclude that gabapentin is an effective treatment for cancer-related neuropathic pain.

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Chemoprophylaxis with oral amoxycillin against bacterial endocarditis: when should second doses be administered after dentistry?

The adequacy of serum bactericidal activity after oral amoxycillin given as prophylaxis against infective endocarditis was studied using a double blind randomised protocol in healthy volunteers having dentistry. One hour before their procedure 38 patients received 3 g amoxycillin syrup and 12 received matching placebo. Venous blood samples were drawn before and one and nine hours after dosing and serum amoxycillin concentrations determined using a standard bioassay. Samples containing amoxycillin had inhibitory titres measured against two reference isolates of viridans streptococci known to have caused infective endocarditis. The susceptibility to amoxycillin of one strain was high and the other low, respective minimal bactericidal and inhibitory concentrations being 0.08 and 0.04 mumol/l (0.03 and 0.015 microgram/ml) and 2.74 and 1.37 mumol/l (1 and 0.5 microgram/ml). Amoxycillin was detected in only post-treatment samples of patients given the active drug. There were no significant correlations between one or nine hour drug concentrations and age or physical characteristics, nor was there any relation to preceding food consumption. Correlations between drug concentrations at one and nine hours were weak (r = 0.34; p less than 0.05), but between corresponding drug concentrations and serum inhibitory titres there were consistent correlations (r = 0.46-0.48; p less than 0.005). Against the low susceptibility reference isolate bactericidal amoxycillin concentrations were encountered in only 20 of the 38 nine hour samples (95% confidence limits 34% and 66%). When repeat doses of amoxycillin are indicated after dentistry they should be given about four hours later, not eight hours later as commonly practised.

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Optimizing the MIC breakpoints of amoxicillin and tetracycline for antibiotic selection in the rescue therapy of H. pylori with bismuth quadruple regimen.

H. pylori with triple-drug resistance (TR) to clarithromycin, metronidazole, and levofloxacin limits the success of rescue therapy. We aimed to identify the optimal breakpoints of antibiotic minimal inhibitory concentration (MIC) to predict the success of rescue therapy for TR H. pylori infection. We consecutively enrolled 430 patients with at least one course of failed H. pylori eradications to receive an H. pylori culture for antibiotic MIC test. Seventy-three (17%) had TR H. pylori infection (MIC of clarithromycin > 0.5, levofloxacin > 1, and metronidazole > 8 mg/L, respectively). Sixty-nine cases with TR H. pylori infection received rescue therapy with either ATBP (amoxicillin, tetracycline, bismuth, and PPI) or MTBP (metronidazole, tetracycline, bismuth and PPI) for 7-14 days. Fourteen patients with positive ¹³C-urea breath test after the first rescue therapy were retreated with a crossover second rescue therapy. The MTBP regimen had higher eradication success than the ATBP regimen as the first rescue therapy for TR H. pylori (intent-to-treat (ITT) analysis, 70.3 vs. 46.9%, p = 0.048; per protocol (PP) analysis, 78.8% vs. 51.7%, p = 0.025). For MTBP regimen, tetracycline MIC ≤ 0.094 mg/L (p < 0.001) with a 14-day treatment duration (p = 0.037) could predict eradication success with 100% accuracy. For the ATBP regimen, amoxicillin MIC selected as ≤ 0.032 mg/L could optimally determine eradication success (72.2 vs. 33.3%, p = 0.025). Optimizing the MIC breakpoints of amoxicillin and tetracycline resistance better predicts the outcome of bismuth quadruple therapy. Further prospective studies using the revised MIC breakpoints to select antibiotics are warranted.

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Statin use and survival after colorectal cancer: the importance of comprehensive confounder adjustment.

Statins have been associated with moderate reductions in mortality among colorectal cancer (CRC) patients, but these studies lacked adjustment for some potentially relevant factors associated with statin use. We aimed to provide more detailed results on this association from a population-based patient cohort study. Use of statins and other risk or protective factors were assessed in standardized interviews with 2697 patients from southern Germany with a diagnosis of incident CRC between 2003 and 2009 (Darmkrebs: Chancen der Verhütung durch Screening [DACHS] study). Follow-up included assessment of therapy details, recurrence, vital status, and cause of death. Information about molecular pathological subtypes of CRC was available for 1209 patients. Cox proportional hazard regression models were used to estimate adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs). All statistical tests were two-sided. Patients were age 68 years on average, 412 used statins (15%), and 769 died during follow-up (29%). After a median follow-up time of 3.4 years, use of statins was not associated with overall (HR = 1.10, 95% CI = 0.85 to 1.41), CRC-specific (HR = 1.11, 95% CI = 0.82 to 1.50), or recurrence-free survival (HR = 0.90, 95% CI = 0.63 to 1.27). Analyses in relevant subgroups also showed no association of statin use with overall and CRC-specific survival, and no associations were observed after stratifying for major pathological subtypes. Among stage I and II patients, statin use was associated with better recurrence-free but not with better CRC-specific survival. Statin use was not associated with reduced mortality among CRC patients. Effects reported in previous studies might reflect incomplete control for stage at diagnosis and other factors associated with the use of statins.

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Clinical efficacy and safety of fluticasone propionate 250 microg twice daily administered via a HFA 134a pressurized metered dose inhaler to patients with mild to moderate asthma. French study group.

This study compared the efficacy and safety of the fluticasone propionate 125 microg pressurized metered dose inhaler (pMDI) propelled by either hydrofluoroalkane (HFA) 134a or chlorofluorocarbon (CFC) propellants, in adult patients with asthma. HFA 134a is a non-ozone depleting propellant used as a replacement for the CFC propellants 11 and 12 which are being phased out in accordance with the Montreal Protocol. Three hundred and eighty patients with mild to moderate asthma and 'room for improvement' in their treatment were randomized to receive fluticasone propionate 250 microg twice daily via pMDIs propelled by either CFC propellants 11 and 12 (n = 195) or HFA 134a (n = 185). Fluticasone propionate significantly improved lung function over the 4-week treatment period in both treatment groups. The improvement in mean morning peak expiratory flow (PEF) after 7 days of treatment was approximately 12 l min(-1) in both groups, rising to approximately 22 l min(-1) at the end of the 4-week treatment period. The adjusted mean difference between the two formulations over weeks 1-4 was -1 l min(-1) (90% confidence interval: -7, 5 l min(-1)), confirming their equivalence. Clinical comparability was also demonstrated with respect to secondary efficacy variables, including daily symptom scores, evening PEF and clinic visit expiratory measurements. There were no clinically relevant differences in adverse events or serum cortisol levels between the two groups. The fluticasone propionate 125 microg HFA 134a pMDI is an effective and well tolerated product and is a suitable replacement for the fluticasone propionate 125 microg CFC pMDI at a microgram equivalent dose.

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[Veracity of smokers' reports of abstinence at smoking cessation clinics].

To assess the reliability of smokers' response as criteria for measuring abstinence and the necessity or not of confirming abstinence with carbon monoxide (CO) measurement. A multicenter, prospective, longitudinal study was carried out on patients over 18 years of age from 5 smoking cessation clinics who underwent treatment with nicotine or bupropion. When the patient attended the clinic at 15, 30, 60, 90, and 180 days, abstinence was checked by self-reporting and expired-air CO levels. Sensitivity, specificity, and positive, negative, and overall predictive value of patient reporting, measured CO levels, and the 2 procedures in combination were calculated. A total of 904 smokers (476 men and 428 women) with a mean (SD) age of 42.51 (10.09) years were enrolled in the study. Of the 904 patients that made up the study population, 820, 776, 687, 719, and 679, respectively, attended the scheduled visits to check abstinence. Self-reported point-prevalence abstinence at 15 days was 74.5% and at 180 days was 57.6% while abstinence determined by expired-air CO was 75.7% and 59.4% respectively. Results according to self-reporting, CO measurement, and the 2 methods in combination were not significantly different (P<.05) at any of the points in time. Neither sensitivity nor specificity showed significant differences in relation to patient variables. The reliability of self-reported abstinence from smoking is high. Measurement of CO is therefore not essential, although it could be advisable for motivating patients rather than as a way of confirming abstinence.

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Body build and risk of cardiovascular events in hypertension and left ventricular hypertrophy: the LIFE (Losartan Intervention For Endpoint reduction in hypertension) study.

Obesity may independently increase the risk of adverse events in hypertension with target-organ damage. We investigated whether body build was independently associated with higher cardiovascular risk and whether treatment with losartan relative to atenolol influenced the impact of body build on the primary composite end point of cardiovascular death, stroke, and myocardial infarction and on cardiovascular death in patients with hypertension and left ventricular hypertrophy in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. The population of 9079 patients was divided as follows: thin (body mass index [BMI] <20 kg/m2, 2%), normal weight (BMI 20 to 24.9, 24%), overweight (BMI 25 to 29.9, 45%), and obese (class I: BMI 30 to 34.9, 21%; class II: BMI 35 to 39.9, 6%; class III: BMI > or =40, 2%). Incident diabetes increased progressively with BMI and was somewhat higher in the atenolol arm. Differences in gender and race were detected among the body build groups. Rates (Cox proportional hazard analysis) of the primary composite end point did not differ among body build groups after adjustment for age, gender, race, smoking habit, prevalent cardiovascular disease, and left ventricular hypertrophy. Cardiovascular death was more frequent among thin (P<0.05) and pooled class II-III obesity (both P<0.04) than normal-weight groups. Risk was not attenuated significantly by losartan treatment, nor did it interfere with the greater benefit of losartan- as opposed to atenolol-based treatment. In the LIFE study, stratification for classes of body build identified increased risk of cardiovascular mortality in both thin and moderately-to-severely obese individuals. This risk was not attenuated significantly by losartan treatment, nor did it interfere with the greater benefit of losartan-based treatment as opposed to atenolol-based treatment.

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Esophageal motility disorders and their coexistence with pathologic acid reflux in patients with noncardiac chest pain.

The aim of this study was to determine which motility data of patients with noncardiac chest pain (NCCP) differ from those of controls on the basis of long-term manometry and to evaluate the coexistence of motility disorders and pathologic acid reflux. Further, motility disorders were tested as to whether they were secondary to acid reflux. Combined long-term pH/manometry was performed in 95 patients with NCCP, using one pH-electrode and two pressure transducers. The motility data were compared with those of healthy controls (n = 40). In addition, an intraindividual patient-oriented motility analysis was performed. Evaluated were the amplitude, the duration in the distal and proximal esophagus, and the type of propagation, propulsive and simultaneous, of esophageal contractions. Ten patients with pathologic acid reflux and hypermotility disorders received 20 mg omeprazole twice daily and were investigated again 4 weeks after therapy began. The median distal pressure amplitude (39.4 versus 28.9 mmHg, p < 0.0001) and the median percentage of simultaneous contractions (18.5% versus 10%; p < 0.0001) were significantly higher in patients with NCCP than in controls. In addition, patients whose symptoms correlated with abnormal motility (n = 18) had a significantly higher median duration of contractions (3.8 sec versus 3.2 sec; p < 0.03) than controls Patients with pathologic acid reflux showed a higher median distal pressure amplitude (38.3 mmHg versus 28.9 mmHg; p < 0.0001) and median percentage of simultaneous contractions (18% versus 10%; p < 0.0001) than controls. Furthermore, a high rate of coexistence with hypermotility disorders was observed (64%). These disorders persisted after acid suppression therapy. Patients with NCCP differ from controls in their esophageal motility. Simultaneous contractions of increased amplitude and duration are pathologic. The intraindividual patient-oriented motility analysis is an appropriate evaluation method. Hypermotility disorders occur often in patients with pathologic acid reflux, but apparently they are not dependent on it.

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Serum oxidized low-density lipoprotein decreases in response to statin therapy and relates independently to reductions in coronary plaque in patients with HIV.

Circulating oxidized low-density lipoprotein (oxLDL) levels are elevated in HIV-infected patients and have been associated with atherosclerosis. Statins have been shown to reduce plaque on coronary computed tomography angiography (cCTA) in HIV-infected individuals. Thus, we investigated the effect of statins on serum oxLDL levels and the relationship between changes in oxLDL and coronary atherosclerosis on cCTA in patients with HIV. We previously conducted a 12-month randomized, placebo-controlled trial with atorvastatin in 40 HIV-infected patients on stable antiretroviral therapy with subclinical coronary atherosclerosis and low-density lipoprotein (LDL)-cholesterol less than 130 mg/dl. In the current analysis, patients underwent cCTA and measurements of serum oxLDL, sCD14, sCD163, lipoprotein phospholipase-A2, and fasting lipids at baseline and end of the study. Nineteen patients were randomized to atorvastatin and 21 patients to placebo. Serum oxLDL decreased -22.7% (95% CI -28.7 to -16.7) in the atorvastatin group and increased 7.5% (95% CI -3.3 to 18.4) in the placebo group (P < 0.0001). Change in oxLDL significantly correlated with changes in noncalcified plaque volume, total plaque volume, positively remodeled plaque, and low attenuation plaque. The association between changes in oxLDL and noncalcified plaque volume was independent of the baseline 10-year Framingham risk, LDL, CD4 cell count, and viral load. Statins lower oxLDL levels in HIV-infected patients, and reductions in oxLDL are related to improvements in coronary atherosclerosis, independent of traditional cardiovascular risk factors. Reductions in oxLDL may be one mechanism through which statins exert beneficial effects on reducing atherosclerosis in HIV-infected individuals.

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Effect of Opioids vs NSAIDs and Larger vs Smaller Chest Tube Size on Pain Control and Pleurodesis Efficacy Among Patients With Malignant Pleural Effusion: The TIME1 Randomized Clinical Trial.

For treatment of malignant pleural effusion, nonsteroidal anti-inflammatory drugs (NSAIDs) are avoided because they may reduce pleurodesis efficacy. Smaller chest tubes may be less painful than larger tubes, but efficacy in pleurodesis has not been proven. To assess the effect of chest tube size and analgesia (NSAIDs vs opiates) on pain and clinical efficacy related to pleurodesis in patients with malignant pleural effusion. A 2×2 factorial phase 3 randomized clinical trial among 320 patients requiring pleurodesis in 16 UK hospitals from 2007 to 2013. Patients undergoing thoracoscopy (n = 206; clinical decision if biopsy was required) received a 24F chest tube and were randomized to receive opiates (n = 103) vs NSAIDs (n = 103), and those not undergoing thoracoscopy (n = 114) were randomized to 1 of 4 groups (24F chest tube and opioids [n = 28]; 24F chest tube and NSAIDs [n = 29]; 12F chest tube and opioids [n = 29]; or 12F chest tube and NSAIDs [n = 28]). Pain while chest tube was in place (0- to 100-mm visual analog scale [VAS] 4 times/d; superiority comparison) and pleurodesis efficacy at 3 months (failure defined as need for further pleural intervention; noninferiority comparison; margin, 15%). Pain scores in the opiate group (n = 150) vs the NSAID group (n = 144) were not significantly different (mean VAS score, 23.8 mm vs 22.1 mm; adjusted difference, -1.5 mm; 95% CI, -5.0 to 2.0 mm; P = .40), but the NSAID group required more rescue analgesia (26.3% vs 38.1%; rate ratio, 2.1; 95% CI, 1.3-3.4; P = .003). Pleurodesis failure occurred in 30 patients (20%) in the opiate group and 33 (23%) in the NSAID group, meeting criteria for noninferiority (difference, -3%; 1-sided 95% CI, -10% to ∞; P = .004 for noninferiority). Pain scores were lower among patients in the 12F chest tube group (n = 54) vs the 24F group (n = 56) (mean VAS score, 22.0 mm vs 26.8 mm; adjusted difference, -6.0 mm; 95% CI, -11.7 to -0.2 mm; P = .04) and 12F chest tubes vs 24F chest tubes were associated with higher pleurodesis failure (30% vs 24%), failing to meet noninferiority criteria (difference, -6%; 1-sided 95% CI, -20% to ∞; P = .14 for noninferiority). Complications during chest tube insertion occurred more commonly with 12F tubes (14% vs 24%; odds ratio, 1.91; P = .20). Use of NSAIDs vs opiates resulted in no significant difference in pain scores but was associated with more rescue medication. NSAID use resulted in noninferior rates of pleurodesis efficacy at 3 months. Placement of 12F chest tubes vs 24F chest tubes was associated with a statistically significant but clinically modest reduction in pain but failed to meet noninferiority criteria for pleurodesis efficacy. isrctn.org Identifier: ISRCTN33288337.

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The effect of losartan and amlodipine on serum adiponectin in Japanese adults with essential hypertension.

Adiponectin, an adipocyte-derived protein, is reduced in patients with hypertension and insulin resistance (IR). Angiotensin II receptor blockers (ARBs) have been reported to improve IR and reduce albuminuria. The purpose of this study was to evaluate the influence of an ARB and a calcium channel blocker on serum adiponectin levels in Japanese patients with hypertension who were treated with losartan or amlodipine for 3 months. Patients with essential hypertension (EHT) were randomized to treatment prospectively with losartan (50-100 mg/d) or amlodipine (5-10 mg/d) for 3 months. Patients with renal damage and/or macroproteinuria were excluded. The urine albumin/creatinine ratio, homeostasis model assessment (HOMA) index, adiponectin concentration, and tumor necrosis factor-alpha (TNF-alpha) concentration of each patient were evaluated before and after 3 months of treatment. When the HOMA index exceeded 1.73, a patient was considered to have IR. All 40 participants completed both 3-month treatment periods. Study patients were primarily male (52.5%) with a mean (SD) age of 63.8 (10.6) years and a mean body weight of 60.7 (10.8) kg. Patients with EHT and diabetes mellitus (n = 9) and IR (n = 12) had significantly lower adiponectin concentrations than patients who had EHT without diabetes or IR (n = 19; mean [SD], 7.84 [5.54] vs 12.81 [7.36] microg/mL, P = 0.034; and 6.12 [3.04] vs 12.81 [7.36] microg/mL, P = 0.004, respectively). Adiponectin concentrations correlated negatively with body mass index (r = -0.393; P = 0.012) and HOMA index (r = -0.440; P = 0.005) and positively with high-density lipoprotein cholesterol (r = 0.441; P = 0.004) before treatment. Systolic blood pressure was significantly decreased in patients treated with losartan (n = 20; mean [SD], 166 [19] to 140 [15] mm Hg; P < 0.001) or amlodipine (n = 20; 164 [15] to 136 [15] mmHg; P < 0.001), and diastolic blood pressure also was significantly decreased with losartan (93 [14] to 83 [10] mm Hg; P = 0.031) or amlodipine (96 [12] to 82 [10] mm Hg; P < 0.001). Losartan increased adiponectin concentrations (9.56 [6.75] to 10.36 [6.94] microg/mL; P = 0.038), whereas amlodipine had no significant effect (9.67 [6.62] to 10.01 [6.79] microg/mL). The difference in TNF-alpha concentration before and after treatment with losartan and amlodipine did not reach statistical significance (mean [SD], 15.2 [1.4] to 14.8 [1.5] pg/mL; and 14.3 [1.4] to 14.5 [1.7] pg/mL, respectively). In this study, Japanese adults with EHT had significant increases in adiponectin after 3 months of treatment with 50 to 100 mg/d of losartan, but not with 5 to 10 mg/d of amlodipine.

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Pathogenesis of gastric metaplasia of the human duodenum: role of Helicobacter pylori, gastric acid, and ulceration.

The pathogenesis of gastric metaplasia (GM) in the duodenum is unclear. The aim of this investigation was to study the effect on the extent of GM of ulcer healing, Helicobacter pylori eradication, and acid suppression singly and in combination. The relationship between GM and gastroduodenal inflammation and H. pylori infection density was also studied. Duodenal and gastric antral biopsy specimens were obtained from H. pylori-positive patients with duodenal ulcer and from H. pylori-positive nonulcer subjects. Biopsy procedures from patients with duodenal ulcer were repeated after 6 months of treatment. Nonulcer subjects were treated symptomatically and did not undergo re-endoscopy. Ulcer healing alone produced no change in GM or in gastroduodenal inflammation. H. pylori eradication produced a 42% reduction in GM and improvement in inflammation. Acid suppression produced a 43% reduction in GM but without a significant change in inflammation. A combination of H. pylori eradication and acid suppression produced an additive effect with a 66% reduction in GM. A positive relationship was detected between the extent of GM and antral H. pylori density, duodenitis score, and antral gastritis score. This study shows that the extent of duodenal GM is unrelated to the presence or absence of ulceration but is partly due to H. pylori and partly due to acid.

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Vitamin D status and effect of low-dose cholecalciferol and high-dose ergocalciferol supplementation in multiple sclerosis.

Vitamin D is important for bone health and immune regulation, and has been shown to be low in multiple sclerosis (MS). We sought to determine the effect of over the counter low dose cholecalciferol (LDC) and high dose ergocalciferol (HDE) on the vitamin D levels in MS patients. We retrospectively evaluated serum 25-hydroxy-vitamin D [25(OH)D] levels of 199 patients (CIS, n = 32; RRMS, n = 115; PPMS, n = 10; SPMS, n = 16; Transverse Myelitis (TM), n = 9; other neurological diseases, n = 16) attending our clinic between 2004 and 2008. We examined the change in 25(OH)D levels in 40 MS patients who took either LDC (< or =800 IU/day) or HDE (50,000 IU/day for 7-10 days, followed by 50,000 IU weekly or biweekly). The average 25(OH)D level was 71 +/- 39 nmol/L (Mean +/- SD), and 167(84%) patients had insufficient levels (< or =100 nmol/L) of 25(OH)D. The patients supplemented with LDC did not have a significant increase in their 25(OH)D levels. However, 25(OH)D levels increased by 42 nmol/L (P = 0.01) in the patients originally taking LDC and then prescribed HDE. Optimal levels (> or =100 nmol/L) were only achieved in less than 40% of patients. We conclude that large numbers of patients with MS and TM in our cohort are deficient in vitamin D. HDE significantly elevated 25(OH)D levels in MS patients and was more effective at increasing 25(OH)D levels than LDC. Prospective studies are required to determine appropriate dosing regimen to achieve optimal levels in the majority of MS patients and to ascertain the safety, immunological response, and ultimately the clinical efficacy of vitamin D replacement therapy.

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Efficacy and safety of the single pill combination of amlodipine 10 mg plus valsartan 160 mg in hypertensive patients not controlled by amlodipine 10 mg plus olmesartan 20 mg in free combination.

For patients with moderate hypertension (grade 2, defined as systolic blood pressure [SBP] 160-179 mmHg and/or diastolic blood pressure [DBP] 100-109 mmHg), current guidelines recommend initial combination therapy and rapid dose-adjustment to achieve blood pressure goal. In this study we investigated the efficacy and tolerability of the single pill combination of amlodipine 10 mg plus valsartan 160 mg (A 10 + Val 160) in patients not controlled by the free combination of amlodipine 10 mg plus olmesartan 20 mg (A 10 + O 20). In this prospective, open-label, non-randomized trial, 257 patients with mean sitting DBP of 100-109 mmHg at trough entered a 4 week treatment phase with A 10 + O 20 in free combination once daily. Patients in whom DBP remained uncontrolled were switched in a second 4 week treatment phase to A 10 + Val 160. The primary efficacy variable was the reduction in DBP at week 8 compared to week 4 in the intent-to-treat population. In the total cohort, baseline SBP/DBP of 164.2 +/- 9.8/103.6 +/- 2.1 mmHg decreased by 19.2 +/- 12.4/14.1 +/- 7.4 mmHg at week 4. In patients who did not achieve BP control (n = 175), subsequent treatment with A 10 + Val 160 for 4 weeks reduced SBP from 149.6 +/- 11.1 at week 4 by 7.9 mmHg at week 8 (95% CI: 6.1-9.6, p < 0.0001) and DBP from 93.4 +/- 3.9 mmHg by 9.1 mmHg (95% confidence interval: 8.1-10.2, p < 0.0001). The combination of A 10 + Val 160 was well tolerated, and the observed adverse events (15.3% of patients in phase 2) were consistent with the known drug profiles. In a study designed to reflect typical clinical practice, in patients not controlled by the free combination of A 10 + O 20, the single pill combination of A 10 + Val 160 produced a statistically and clinically significant additional BP reduction and was well tolerated. Potential limitations of the design (open-label, non-controlled design, short term treatment) have to be taken into account.

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Laryngopharyngeal reflux: prospective cohort study evaluating optimal dose of proton-pump inhibitor therapy and pretherapy predictors of response.

Laryngopharyngeal reflux (LPR) is frequently treated with empiric proton-pump inhibitors (PPI), but the optimal dosing and duration is unknown. We performed an open label prospective cohort study to evaluate whether twice-daily (BID) PPI is more effective than once-daily (QD) PPI for the treatment of LPR. Patients diagnosed with LPR based on ear, nose, and throat (ENT) symptoms and laryngoscopy findings were enrolled. Questionnaire assessed demographics, ENT symptoms, symptom severity, and exposure to other potential laryngeal irritants. Esophageal manometry, ambulatory 24-hour pH monitoring, and upper gastrointestinal endoscopy were performed before initiation of therapy. Patients were consecutively assigned to three groups: BID PPI (lansoprazole 30 mg BID), BID PPI + H2 receptor antagonist (H2RA; omeprazole 20 mg BID + ranitidine 300 mg each night), or QD PPI (esomeprazole 40 mg QD). Greater than 50% primary symptom improvement from baseline defined symptom response. At 2 month follow-up, the same PPI dose was continued for responders, and PPIs were doubled for nonresponders for an additional 2 months. Repeat symptom assessment and laryngoscopy performed at 4 month follow-up. Eighty-five patients were enrolled (median age 49 years, interquartile range 44.0 - 65.0; 76% white; 34% male). Treatment groups were BID PPI for 30 patients, BID PPI + H2RA for 30 patients, and QD PPI for 25 patients. RESPONSE TO THERAPY: At 2 months, BID response occurred among 15 of 30 (50%) patients, BID + H2RA for 15 of 30 (50%), and QD for 7 of 25 (28%) (P = .03). No statistical difference found between the two BID PPI groups with and without H2RA. Among the QD group nonresponders, 7 of 13 (54%) achieved symptom response with additional 2 months of BID dosing. At 4 month follow-up, an additional 22% of responses were obtained from the two BID groups (43/60, 72%). The overall response rate for all three groups was 70% (54/77). PREDICTORS OF OUTCOME: Pretherapy interarytenoid mucosa and true vocal folds abnormalities were associated with twofold increase in symptom response (odds ratio 1.99 and 1.96, respectively, P = .017). BID PPI appears to be more effective than QD PPI in achieving clinical symptom response in suspected LPR. More response was achieved at 4 months compared with 2 months. Therefore, aggressive acid suppression with BID PPI for at least 4 months is warranted for treatment of LPR.

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Soluble platelet/endothelial cell adhesion molecule (sPECAM)-1 is increased in polycystic ovary syndrome and related to endothelial dysfunction.

Striking evidence indicates endothelial impairment in polycystic ovary syndrome (PCOS) but the mechanisms linking PCOS status to cardiovascular risk remain elusive. Platelet/endothelial cell adhesion molecule (PECAM)-1 is a soluble (s) signaling molecule involved in inflammation and angiogenesis with predictive value for endothelial dysfunction in patients at risk. In a prospective, controlled study, sPECAM-1 levels and the relationships to metabolic, inflammatory and vascular PCOS traits were evaluated in 26 patients and 29-age- and body mass index-matched controls. To assess endothelial injury, carotid artery intimae-media thickness (CIMT) and brachial artery flow-mediated vasodilatation (FMD) were employed. Of the 26 women with PCOS, 25 completed a six-month metformin combined with ethinylestradiol 0.3 mg/drospirenone 3 mg therapy. Soluble PECAM-1 levels were increased in PCOS (p = 0.018 vs. Controls) and significantly decreased at follow-up (p = 0.0002). Smoking and weight had no effect on sPECAM-1 dynamics. In both univariate and multivariate analysis, basal sPECAM-1 was inversely related to FMD (r = -0.311, p = 0.021) but not CIMT. To conclude, sPECAM-1 is increased in PCOS, an effect reversed by combined metformin and anti-androgenic contraceptive therapy. Elevated sPECAM-1 contributes to endothelial dysfunction however further studies are inquired to assess its relevance as biomarker and potential therapeutic target in PCOS.

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Ezetimibe effectively lowers LDL-cholesterol in cardiac allograft recipients on stable statin therapy.

We investigated tolerability and efficacy of ezetimibe treatment (10 mg/d) in 25 heart allograft recipients already on stable statin therapy. Total cholesterol (TC), low-density cholesterol (LDL-C), high-density cholesterol (HDL-C), triglycerides (TG), immunosuppressant drug levels, laboratory and clinical parameters were assessed before, four months and one yr after initiation of ezetimibe treatment. Mean equivalent statin dose was 53.5 +/- 12.3 mg of pravastatin, remaining unchanged throughout the study period. Ezetimibe was generally well tolerated, only two patients (8%) discontinued ezetimibe due to stomach pain or headache. Mean TC decreased from 231.8 +/- 6.4 mg/dL before therapy to 202.2 +/- 8.8 mg/dL after four months and 192.9 +/- 7.0 mg/dL after one yr (p < 0.001). Mean LDL-C decreased from 143.1 +/- 5.4 mg/dL to 121.4 +/- 7.9 mg/dL (month 4; p < 0.05) and 107.1 +/- 5.6 mg/dL (one yr; p < 0.001). TG decreased from 182 +/- 14.3 mg/dL to 173.3 +/- 17.5 mg/dL after one yr (p < 0.05), whereas HDL-C was unchanged. Initial LDL-C and cardiac diagnosis before transplantation were identified as predictors of absolute LDL-C reduction. Immunosuppressant drug doses and blood concentrations were unchanged as well as other laboratory and clinical parameters. Ezetimibe appears safe and effective for further reduction of TC and LDL-C in heart allograft recipients already on stable statin therapy. Extent of pre-treatment LDL-C and cardiac disorder prior to transplantation appear to correlate with the efficacy of ezetimibe therapy.

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Mediational g-formula for time-varying treatment and repeated-measured multiple mediators: Application to atorvastatin's effect on cardiovascular disease via cholesterol lowering and anti-inflammatory actions in elderly type 2 diabetics.

Modern causal mediation theory has formalized several types of indirect and direct effects of treatment on outcomes regarding specific mediator variables. We reviewed and unified distinct approaches to estimate the "interventional" direct and indirect effects for multiple mediators and time-varying variables. This study was motivated by a clinical trial of elderly type-2 diabetic patients in which atorvastatin was widely prescribed to control patients' cholesterol levels to reduce diabetic complications, including cardiovascular disease. Among atorvastatin's preventive side-effects (pleiotropic effects), we focus on its anti-inflammatory action as measured by white blood cell counts. Hence, we estimate atorvastatin's interventional indirect effects through cholesterol lowering and through anti-inflammatory action, and interventional direct effect bypassing these two actions. In our analysis, total effect (six-year cardiovascular disease risk difference) estimated by standard plug-in g-formula of -3.65% (95% confidence interval: -10.29%, 4.38%) is decomposed into indirect effect via low-density lipoprotein cholesterol (-0.90% [-1.91%, -0.07%]), via white blood cell counts (-0.03% [-0.22%, 0.11%]), and direct effect (-2.84% [-9.71%, 5.41%]) by the proposed parametric mediational g-formula. The SAS program and its evaluation via simulated datasets are provided in the Supplemental materials.

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Is ACE inhibition with lisinopril helpful in diabetic neuropathy?

Thirteen diabetic patients with hypertension (mean diastolic blood pressure 96.2 +/- 1.1 mmHg) were included in a study to assess the effects of lisinopril (20 mg day-1) on measures of nerve function. Patients had nerve conduction velocity (NCV), temperature discrimination threshold (TDT), and vibration perception threshold (VPT) measurements. At the end of 12 weeks of treatment with lisinopril, there was a significant improvement in median motor NCV (mean change +/- SEM 2.7 +/- 0.6 m s-1, p < 0.0001), median sensory NCV (2.1 +/- 0.9 m s-1, p = 0.03), peroneal motor NCV (1.0 +/- 0.4 m s-1, p = 0.03), and sural sensory NCV (1.9 +/- 0.7 m s-1, p = 0.01) values. There were also significant improvements in warm TDT and VPT. Diastolic BP decreased significantly, but there was no significant change in HbA1. Double blind controlled studies are now needed to confirm the effect of lisinopril on measures of nerve function.

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A placebo-controlled dose-ranging study of lansoprazole in the management of reflux esophagitis.

We compared the efficacy of three different doses of the proton pump inhibitor lansoprazole in the management of reflux esophagitis. Two hundred ninety-two patients with endoscopically confirmed reflux esophagitis were enrolled in a double-blind, multicenter study and were randomized to lansoprazole 15, 30, or 60 mg or placebo administered once daily for 8 wk. Healing rates after 4 wk of lansoprazole 15, 30, and 60 mg/d were 67.6%, 81.3%, and 80.6%, respectively. These were all significantly superior (p < 0.001) to placebo, which produced endoscopic healing in only 32.8% of the patients after 4 wk. The 4-wk healing rates with lansoprazole 30 or 60 mg were significantly higher than that with lansoprazole 15 mg (p < 0.05), confirming a dose-response effect. Cumulative healing rates after 8 wk of treatment were 52.5% with placebo and 90.0%, 95.4%, and 94.4% with lansoprazole 15, 30, and 60 mg, respectively (p < 0.001 for all doses of lansoprazole vs placebo). Lansoprazole was also significantly superior to placebo in relieving symptoms in patients with reflux esophagitis. Lansoprazole was well tolerated, and no serious treatment-related adverse events were encountered. Up to 3 months after discontinuation of treatment, all lansoprazole-treated groups had more patients free of endoscopic evidence of esophagitis than the group treated with placebo. Lansoprazole was safe and effective for the treatment of reflux esophagitis in this trial. This study indicates that the optimum daily dose of lansoprazole for reflux esophagitis is 30 mg.

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The effects of omeprazole-induced hypochlorhydria on absorption of theophylline from a sustained-release formulation.

The present study was designed to investigate the effects of raised intragastric pH on the absorption of theophylline from a sustained-release formulation. Six healthy male volunteers participated in the cross-over randomised study and on one of two occasions were pretreated with 240 mg omeprazole, administered in three divided doses over the 22 h preceding the test. The sulphasalazine/sulphapyridine method of assessing oral-caecal transit time was implemented in order to assess upper bowel and colonic absorption. The mean fraction absorbed-time profile was calculated from serial serum theophylline concentration measurements by a modification of the Wagner-Nelson equation. During hypochlorhydria the mean oral-caecal transit time was 4.6 h, mean time to 90% absorption 6.8 h, and the percentage theophylline presumably to be absorbed from the colon 32.3. The corresponding values with normochlorhydria were, respectively, 3.8 h, 8.5 h, and 57.5%. The shorter oral-caecal transit time and lesser upper bowel absorption during normochlorhydria is postulated to result from motilin release due to duodenal acidification. Gastric hypoacidity resulted in significantly increased cumulative fractions of theophylline absorbed during a 3.5 h period, starting 0.5 h after breakfast. Possibly hypochlorhydria amplifies the increased motility which follows the intake of a meal, resulting in increased peristalsis and antiperistalsis, with more rapid drug absorption.

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Peptic ulcer disease risk in chronic kidney disease: ten-year incidence, ulcer location, and ulcerogenic effect of medications.

We aimed at determining peptic ulcer disease (PUD) incidence among chronic kidney disease (CKD) patients during 1998-2008, compared to patients without CKD, and at examining associations between CKD and PUD. Data for 1998-2008 were extracted from the National Health Insurance Research Database in Taiwan. The annual PUD incidence (cases per thousand persons per year) was calculated separately for patients with and without CKD. Characteristics of patients with newly diagnosed PUD (n = 16322) were compared to those of a control group without PUD (n = 32644). The 2 groups were matched for age, sex, and index year. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression. Over the 10-year period, the PUD incidence was ∼10-12 times higher in CKD patients than in those without CKD. Its incidence in elderly CKD patients increased rapidly over time. For CKD patients, most PUD events (>95%) were managed during hospitalization. Peptic ulcer risk, adjusted for all potential confounders, was much higher in CKD patients undergoing hemodialysis (adjusted OR, 9.74; 95% CI, 7.11-13.31). Maintenance hemodialysis patients were 2 times more likely to have gastric ulcers than duodenal ulcers, while CKD patients not on dialysis had similar risks for both. There were no significant interactions between medications and CKD status on the peptic ulcer risk. Unlike CKD patients on nonsteroidal anti-inflammatory drugs and clopidogrel, those on aspirin did not have a higher peptic ulcer risk (adjusted OR, 0.88; 95% CI, 0.44-1.77). CKD patients have a substantially increased PUD risk, and the majority of CKD patients with PUD require hospital management. Further, peptic ulcer risk is affected by hemodialysis therapy, patient status (inpatient vs. outpatient), and ulcerogenic medications.

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Short-term augmentation of fluoxetine with clonazepam in the treatment of depression: a double-blind study.

Because selective serotonin reuptake inhibitors (SSRIs) require 2-4 weeks to reach efficacy, the authors determined whether clonazepam augmentation of fluoxetine is superior to fluoxetine alone at the beginning of treatment for major depression. Eighty adult outpatients with major depression who were rated as "moderately ill" or "markedly ill" on the Clinical Global Impression of Severity underwent 8 weeks of double-blind, randomized treatment with fluoxetine, 20 mg/day for all patients initially and 40 mg/day if needed after 6 weeks. One-half of these patients received clonazepam, 0.5 mg h.s. adjusted to two tablets by day 10 if needed, and the remainder received placebo, likewise adjusted. Clonazepam/placebo was gradually discontinued during days 21-33. Efficacy was evaluated by means of the Hamilton Depression Rating Scale, the Clinical Global Impression of Improvement, and a patient rating of global improvement. The patients taking clonazepam improved significantly more during the first 3 weeks of treatment according to ratings on the Hamilton scale (> or =50% improvement) and the clinician- and patient-rated global improvement measures ("much" or "very much" improved). Analysis of variance confirmed a significant effect of clonazepam for average Hamilton depression scores. No serious adverse events were found in either treatment group. Taper effects appeared modest and transitory. Clonazepam augmentation of fluoxetine was superior to fluoxetine alone in the first 3 weeks of treatment. This strategy may reduce suffering during early SSRI treatment, may partially suppress SSRI side effects, may increase compliance, and could possibly reduce the risk of suicide.

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Sodium intake and furosemide administration in hypertensive patients with renal insufficiency.

The effects of various levels of sodium intake and loop diuretic (furosemide) administration upon arterial pressure and renal function were studied in 11 patients with impaired renal function and essential hypertension. The patients were hospitalized in a metabolic ward and continued taking their usual antihypertensive medications. After a stabilization period, all patients followed the following regiments for 5 to 7 days: period I, 20 mEq sodium diet without diuretic administration; period II, 80 mEq sodium diet and furosemide, 80 mg daily; and period III, 200 mEq sodium diet and furosemide, 240 mg daily. Supine diastolic pressure was lower (P is less than 0.05) during period II than during period I and both supine and standing systolic and diastolic pressures were significantly lower in period III than in period I (P is less than 0.01). No significant differences in the renal clearance of inulin were noted between any of the study periods. In patients with essential hypertension and impaired renal function, consumption of a moderate or liberal sodium diet combined with administration of a loop diuretic agent (furosemide) appears to result in better control of arterial pressure without significant changes in renal function than does strict sodium restriction without diuretic administration.

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