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The influence of allopurinol on urinary purine loss after repeated sprint exercise in man.

The influence of allopurinol on urinary purine loss was examined in 7 active male subjects (age 24.9 +/- 3.0 years, weight 82.8 +/- 8.3 kg, V O2peak 48.1 +/- 6.9 mL.kg(-1).min(-1)). These subjects performed, in random order, a trial with 5 days of prior ingestion of a placebo or allopurinol. Each trial consisted of eight 10-second sprints on an air-braked cycle ergometer and was separated by at least a week. A rest period of 50 seconds separated each repeated sprint. Forearm venous plasma inosine, hypoxanthine (Hx) and uric acid concentrations were measured at rest and during 120 minutes of recovery from exercise. Urinary inosine, Hx, xanthine, and uric acid excretion were also measured before and for 24 hours after exercise. During the first 120 minutes of recovery, plasma Hx concentrations, as well as the urinary Hx and xanthine excretion rates, were higher (P < .05) with allopurinol compared with the placebo trial. In contrast, plasma uric acid concentration and urinary uric acid excretion rates were lower (P < .05) with allopurinol. The total urinary excretion of purines (inosine + Hx + xanthine + uric acid) above basal levels was higher in the allopurinol trial compared with placebo. These results indicate that the total urinary purine excretion after intermittent sprint exercise was enhanced with allopurinol treatment. Furthermore, the composition of urinary purines was markedly affected by this drug.

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Effect of phenylpropanolamine hydrochloride on blood pressure in Korean patients with hypertension controlled by hydrochlorothiazide.

The effect of 10 oral doses of phenylpropanolamine hydrochloride 25 mg four times a day on blood pressure and heart rate in Korean patients with hypertension controlled by hydrochlorothiazide was studied. A randomized, placebo-controlled, crossover, double-blind study design was used. Twenty Korean patients with mild hypertension controlled by hydrochlorothiazide were recruited from an ambulatory-care clinic. Blood pressure and heart rate were measured in triplicate before treatment, after a five-day washout period between phases of treatment, and two hours after the last dose in each phase of treatment. Eighteen patients completed both phases of treatment, and one patient completed only the placebo phase. Mean baseline values for systolic and diastolic blood pressures and heart rate before the placebo phase did not significantly differ from mean baseline values before the phenylpropanolamine phase. Comparison of mean baseline values for systolic and diastolic blood pressures and heart rate with mean after-treatment values showed no clinically relevant or statistically significant changes for the 19 patients who completed the placebo phase or the 18 patients who completed the phenylpropanolamine phase. There was no significant difference between the mean change in systolic blood pressure, diastolic blood pressure, or heart rate when the phenylpropanolamine phase was compared with the placebo phase. Phenylpropanolamine hydrochloride 25 mg p.o. four times a day (total, 10 doses) given to Korean patients with hypertension controlled by hydrochlorothiazide did not affect blood pressure or heart rate according to single-point outcome measurements.

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Diuretic induced long term hemodynamic changes in hypertension. A retrospective study in a MRFIT clinical center.

Retrospective analysis of hemodynamic factors was performed on hypertensive participants of our Multiple Risk Factor Intervention Trial (MRFIT) center to determine whether these may have a role in the higher mortality in a subgroup of special intervention (SI) participants with minor baseline electrocardiographic abnormalities. Stroke volume was estimated by a formula [SV = K(LVETxPP)x(1 + LVET/DP) where the K factor was determined using a separate group of individuals undergoing cardiac catheterization. The Pearson correlation between the two methods (dye dilution and above formula) was 0.7744 with a 95% confidence interval of 0.57-0.89 for the true correlation. In 222 SI and 186 usual care (UC) participants with no differences in stroke volume index (SVI) and cardiac output index (CI) at baseline, SVI and CI were systematically lower during the entire period of treatment in SI receiving higher average doses of thiazide diuretics. There was a moderate increase of SVI and CI in SI participants toward baseline after hydrochlorothiazide was replaced by other antihypertensive medication in the fourth year of the trial. We conclude that the lower SVI and CI could have been a contributing factor in the higher mortality in the SI group with ECG abnormalities resulting in decreased coronary flow reserve under stress conditions in these participants with probably pre-existing asymptomatic coronary artery disease.

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Long-term follow-up of patients with low-grade malignant lymphomas treated with doxorubicin-based chemotherapy or chemoimmunotherapy.

We reviewed survival data of patients with low-grade lymphoma entered on Southwest Oncology Group (SWOG) lymphoma trials in 1972 to 1983 to determine the utility of doxorubicin-containing therapy (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP]) in such patients. We identified all patients with low-grade lymphoma, no prior therapy, and stage III or IV disease who were treated with full-dose CHOP induction therapy on any arm of SWOG studies 7204, 7426, or 7713. Survival data for this group of patients were correlated with pretreatment prognostic factors, including histology, patient age, sex, symptom status, performance status, bone marrow or extranodal involvement, and the number of disease sites. The effect of maintenance treatment was also assessed. Four hundred fifteen patients met criteria for inclusion in the study group. With median follow-up periods of 12.8 years (maximum, 19.8 years), the median survival duration was 6.9 years. Survival was significantly shorter in patients with follicular mixed or small lymphocytic histology, age greater than 40 years, male sex, B-symptom status, and SWOG performance status greater than 1. Multivariate regression analysis showed histology, age, and sex to be independent predictors of survival. There was no definite survival plateau of cured patients in any subgroup, although the survival curve for follicular mixed histology patients showed long-term survival of approximately 25%. Maintenance therapy did not prolong survival. Doxorubicin-containing treatment did not prolong the overall median survival of low-grade lymphoma patients compared with results with less-aggressive programs.

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Bupropion associated seizures following acute overdose: who develops late seizures.

<b>Objectives:</b> Bupropion is an antidepressant that is commonly known to cause seizures in overdose. Because of concern for delayed onset of seizures, patients are frequently observed for prolonged periods after overdose. The primary objective is to evaluate the incidence and clinical parameters associated with late seizures following bupropion overdose.<b>Methods:</b> This retrospective study of acute bupropion overdose who presented to 26 different hospitals in California and Arizona during an 8 year time period.<b>Results:</b> 437 patients were identified. Tachycardia and altered mental status were common. A total of 122 (27.9%) patients had seizures following their overdose. Only eight patients (1.8%) had a seizure more than 8 h after hospital arrival. None of these patients were asymptomatic on arrival. Among patients with tachycardia on arrival, the odds of having a seizure was 6.7 (95% CI 3.7-10.9); the odds of a seizure more than 8 h after arrival was 5.24 (95% CI 1.2-23.5). Similarly, altered mental status on arrival was significantly associated with the risk of a seizure; OR 3.93 (95% CI 2.21-7.0).<b>Conclusion:</b> Seizures are relatively common, and are associated with antecedent tachycardia or altered mental status.

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Effect of eight weeks of treatment with salmeterol on bronchoalveolar lavage inflammatory indices in asthmatics.

Using BAL, we studied the effects of 8 wk of treatment with salmeterol on airway inflammation in nine asthmatic subjects in a double-blind crossover placebo-controlled protocol. The study patients were all receiving regular inhaled corticosteroid therapy (400 to 1,000 micrograms beclomethasone dipropionate per day) and inhaled albuterol for symptomatic relief, i.e., subjects who might be considered suitable for treatment with salmeterol. The asthmatic group had significant differences in numbers of epithelial cells and eosinophils in BAL compared with a group of 15 normal control subjects (p < 0.01). During salmeterol treatment mean morning and evening peak flow rates were increased (p < 0.05). There was no significant change in BAL cell profile and no change in percentages of CD4 and CD8 lymphocytes or proportion of lymphocytes expressing HLA-DR after salmeterol. In conclusion, we were unable to demonstrate any significant anti-inflammatory effect of regular salmeterol therapy on airway inflammation using BAL in these asthmatic patients. At the same time, there was equally no evidence of a deterioration in the underlying inflammatory disease process.

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Decreased lipid intermediate levels and lipid oxidation rates despite normal lipolysis in patients with hypothyroidism.

Hypothyroidism decreases energy expenditure and combustion of fuels, but the reported effects on lipid metabolism and insulin sensitivity are divergent and there is a lack of studies assessing rates of lipolysis and lipid oxidation. The present study was conducted to test the hypotheses that hypothyroidism decreases lipolysis, blood concentrations of free fatty acid, lipid oxidation, and insulin sensitivity. We studied 11 hypothyroid patients (thyroid-stimulating hormone: 150 mU/L) with autoimmune thyroiditis (i) before and (ii) after 2 months of triiodothyronine-euthyroidism upon levothyroxine treatment and (iii) compared the patients to 10 healthy volunteers. Subjects underwent a 3-hour study in the basal state followed by a 3-hour euglycemic clamp study, and we used a combination of lipid blood concentrations, palmitate tracer dilution, and indirect calorimetry to assess lipid metabolism. Compared to euthyroid control subjects and/or euthyroid posttreatment values hypothyroid patients were characterized by (i) 40%-50% decreased concentrations of plasma free fatty acids, palmitate, and 3-OH-butyrate (p < 0.05); (ii) >50% decreased lipid oxidation by indirect calorimetry (p < 0.001); (iii) unchanged whole-body lipolysis by palmitate dilution (all p's > 0.45); (iv) 50% increased triglyceride levels (p < 0.05); and (v) approximately 30% decreased insulin sensitivity judged by glucose infusion rate values (p = 0.05). Our data show that hypothyroidism leads to decreased concentrations and oxidation rates of lipid intermediates and increased triglyceride concentrations in the presence of unaltered rates of lipolysis. The combination of normal lipolysis, low lipid oxidation rates, and high triglyceride concentrations is compatible with increased triglyceride synthesis.

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Electrolyte changes and metabolic effects of lisinopril/bendrofluazide treatment. Results from a randomized, double-blind study with parallel groups.

The metabolic effects of lisinopril and bendrofluazide therapy were studied in 61 patients with essential hypertension in a randomized, double-blind study with parallel groups. The insulin sensitivity index, measured by hyperinsulinemic euglycemic clamp test, decreased by 22% (P < .01) during bendrofluazide treatment and by 15% (NS) during lisinopril treatment. The initial insulin response at intravenous glucose tolerance test (IVGTT) increased by 21% (P < .05) during lisinopril treatment but decreased by 13% (P < .05) during treatment with bendrofluazide, and in addition, the glucose disappearance rate decreased by 9% (P < .05) in the latter group. During oral glucose tolerance test (OGTT), the area under the glucose curve (AUCglucose) increased by 17% (P = .05) in the bendrofluazide-treated group but decreased by 19% (P = .05) in the lisinopril group, although there was no difference between the drug effects on AUCinsulin. The LDL/HDL cholesterol ratio increased during bendrofluazide treatment. The serum potassium concentration decreased by 10% (P = .0001) during bendrofluazide treatment but increased by 6% (P = .0001) in the lisinopril-treated group. The change in serum potassium was correlated to the change in initial insulin response and glucose disappearance rate at IVGTT, and inversely correlated to the change in AUCglucose at OGTT. In conclusion, alterations in serum potassium balance may affect the initial insulin release and glucose disposal. Bendrofluazide treatment decreases the serum potassium concentration, reduces the initial insulin release and the glucose disposal, and, in addition, impairs insulin sensitivity. Lisinopril treatment increases serum potassium concentration and the initial insulin response, and decreases AUCglucose, but does not improve insulin sensitivity per se.

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Differential effects of neuropathic analgesics on wind-up-like pain and somatosensory function in healthy volunteers.

To investigate the effects of gabapentin, carbamazepine, and amitriptyline on temporal summation, simple nociceptive pain, and innocuous touch sensation in healthy volunteers. A placebo controlled four-way crossover double-blind randomized protocol was followed. Seventeen healthy subjects, male and female, aged 18 to 24, took part. Punctate pain, temporal summation pain to repeat punctate stimulation, and vibration detection threshold were assessed in triplicate. Study drugs were given as bedtime and early morning doses with assessments carried out midmorning. Gabapentin and carbamazepine significantly reduced the intensity of temporal summation pain (P < 0.001 and P < 0.01 respectively), whereas amitriptyline significantly increased temporal summation pain (P < 0.001). None of the drugs affected pain produced by a single punctate stimulus (P > 0.05). Carbamazepine increased vibration detection thresholds (P < 0.05), but neither gabapentin nor amitriptyline had any detectable effect on vibration. We have shown that gabapentin, carbamazepine, and amitriptyline, three pharmacologically different drugs, have distinct and quantifiable effects on somatosensory pathways in healthy volunteers. These findings provide a link between pharmacology of the study drugs and clinical effectiveness. The effects of gabapentin and carbamazepine on temporal summation pain show that these drugs can block centrally amplified wind-up pain in the absence of a neuropathic disorder.

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Cardiovascular risk and lupus disease.

Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). The aim of this study was to evaluate subclinical atherosclerosis and to determine the prevalence of risk factors for CVD in SLE patients. One hundred fifty-three patients (149 women and 4 men), aged (37±11.6) years with a definite diagnosis of SLE according to the revised criteria of the American College of Rheumatology (ACR), underwent physical examination, carotid and leg arteries B-mode ultrasound with a measure of ankle-brachial pressure index (ABPI); 94 patients had myocardial tomoscintigraphy. The laboratory check-up was: total cholesterol (TC), HDLc, LDLc, homocystein, glycemia, vascular cell adhesion molecules (VCAM-I). All patients had a normal renal function at the time of the study. The mean age is 37 years. Cardiovascular events were noticed in 15 patients (6 angina, 2 myocardial infarction and 7 strokes). Cardiovascular risk factors (CVRF) were: dyslipidemia (62.8%), moderate homocysteinemia (55%), BMI>25 (39%) and hypertension (35%) which is associated with a stroke (P<0.0006). The cumulative prednisone dose per patient was 45.5g. V.C.A.M-I level was high in 86.2 % of cases.95% of our patients had at least two CVRF. Myocardial perfusion stress scanning showed abnormalities in 21 patients (22.3%). Perfusion defects were linked with a stroke (P<0.01) and coronary events (P<0.02). Carotid atheroma was present in 32 patients (20.9%). Carotid plaques were associated with age (P<0.01), total cholesterol (TC)(P<0.05), and steroid dose (P<0.01). Intima-media-thickness was correlated with age (P<0.0003), TC (P<0.0007), LDLc (P<0.002), and homocysteine (P<0.03). 70% patients had a mediacalcinosis in femoral and popliteal arteries. The ABPI was correlated with V.C.A.M-I (P<0.0005). In Algeria, as elsewhere, young women with SLE have subclinical atherosclerosis which must be detected and they are at high risk of a vascular event.

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Methylphenidate in children with attention-deficit hyperactivity disorder (ADHD): experience from a Sri Lankan Tertiary Children's Hospital.

The response to methylphenidate was assessed in children diagnosed as having attention-deficit hyperactivity disorder (ADHD) in 2000 at the Lady Ridgeway Tertiary Hospital for Children in Sri Lanka. They were managed in outpatient child psychiatry clinics. ADHD was diagnosed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV). The severity of the symptoms was determined with a validated Sinhala assessment form based on DSM-IV criteria. The data on problems experienced by the diagnosed children and their families were obtained using an interviewer-administered questionnaire. The severity of the symptoms and problems experienced by the children and their families were reassessed at 6 weeks and 6 months of methylphenidate therapy. Thirty-seven new subjects were diagnosed as having ADHD in 2000, and 36 of them were treated with methylphenidate. The severity of the symptoms and the number of subjects receiving frequent complaints from school were significantly lower 6 weeks after methylphenidate treatment. At 6 months of treatment, the severity of the symptoms was not significantly reduced when compared with the severity assessed 6 weeks after treatment. Methylphenidate did help with school-related problems in the short term, but the long-term effects of methylphenidate were not convincing in this group of subjects and showed poor long-term compliance, probably owing to inadequate improvement seen in symptoms.

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Mother-infant antidepressant concentrations, maternal depression, and perinatal events.

The authors explored the relationship of cord-maternal antidepressant concentration ratios and maternal depression with perinatal events and preterm birth. The investigators examined 21 mother-infant pairs that had antidepressant exposure during pregnancy. The antidepressants included serotonin reuptake inhibitors (SRIs) and nortriptyline (a norepinephrine inhibitor and mild SRI). The mothers were evaluated with the Structured Clinical Interview for DSM-IV. Depression ratings were repeated at 20, 30, and 36 weeks' pregnancy. At delivery, investigators assessed cord and maternal antidepressant concentrations, neonatal outcomes on the Peripartum Events Scale (PES), and gestational weeks at birth. The investigators performed this study at the Women's Behavioral HealthCARE Program, Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, Pennsylvania, from April 2003 until September 2006. Mean ± SD cord-to-maternal concentration ratios were 0.52 ± 0.35 (range, 0.00-1.64) for the parent drug and 0.54 ± 0.17 (range, 0.28-0.79) for the metabolite. Nine of 21 mothers (43%) had a major depressive episode. From examining the maximum depression ratings, the mean ± SD Structured Interview Guide for the Hamilton Depression Rating Scale, Atypical Depression Symptoms Version score was 16.0 ± 7.6. One third (7/21) of infants had at least 1 perinatal event (PES ≥ 1). The frequency of deliveries complicated by any perinatal event was similar in depressed and nondepressed mothers. There was no significant association between perinatal events and cord-to-maternal antidepressant concentration ratios or maternal depression levels. Exposure to short half-life antidepressants compared to fluoxetine resulted in more perinatal events (7/16 = 44% vs 0/5 = 0%; P = .06). Fourteen percent (3/21) of infants were preterm. Preterm birth was not associated with cord-to-maternal metabolite concentration ratios, depression levels, or exposure to fluoxetine. Antidepressant-exposed infants experienced a limited number of transient perinatal events. No association between cord-maternal concentration ratios or maternal depression and perinatal events could be identified. Contrary to other reports, we detected no increased risk for perinatal events with fluoxetine therapy compared to the short half-life antidepressants. clinicaltrials.gov Identifier: NCT00279370.

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Association between low plasma vitamin E concentration and progression of early cortical lens opacities.

The authors evaluated the association between plasma vitamin E content and progression of eye lens opacities. A total of 410 hypercholesterolemic eastern Finnish men participated in the study from January 1990 to September 1993 in Kuopio, Finland. Lens opacities were classified three times at 18-month intervals using the Lens Opacities Classification System II. A low plasma vitamin E level (lowest quartile) was associated with a 3.7-fold excess risk (95% confidence interval 1.2-11.8) of the progression of early cortical lens opacities compared with the highest quartile (p = 0.028). In addition, the number of cigarettes smoked daily was a significant predictor of the progression of cortical lens opacity (relative risk = 1.06 per cigarette, 95% confidence interval 1.003-1.12). The progression of nuclear lens opacities was not associated with either the plasma vitamin E content or smoking. The data suggest that low plasma vitamin E content may be associated with increased risk of the progression of early cortical lens opacity.

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Anti-inflammatory effects of rosuvastatin treatment on coronary artery ectasia patients of different age groups.

Coronary artery ectasia (CAE) is an angiographic finding of abnormal coronary dilatation. Inflammation plays a major role in all phases of atherosclerosis. We investigated the relationship between CAE and serum high-sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6) levels to test our hypothesis that patient age is associated with the efficacy of anti-inflammatory therapy for CAE. We conducted a prospective analysis of 217 patients with CAE treated at the Department of Cardiology, Shanghai East Hospital, Ji'an Campus and the Baoshan People's Hospital, from January 1, 2015 to July 30, 2019. Baseline data of patients, including sex; age; and history of hypertension, hyperlipidemia, and diabetes, were collected from patient medical records. Study participants were grouped by age as follows: CAE-A (n = 60, age ≤ 50 years), CAE-B (n = 83, 50 years <age ≤ 70 years), and CAE-C (n = 74, age > 70). Additionally, there was a control (NC) group (n = 73) with normal coronary arteries. All patients received oral rosuvastatin therapy (10 mg, QN quaque nocte) when they were diagnosed with CAE and maintained good follow-up, with a loss rate of 0.0% at the end of the 6-month follow-up. The NC group received regular symptom-relieving treatments and rosuvastatin therapy. Of these four groups, the inflammatory markers, hs-CRP and IL-6, were significantly higher in patients with CAE than in the NCs (p < 0.05). Post-hoc tests showed that hs-CRP and Il-6 levels had significant differences between the CAE-A and CAE-C groups (P = 0.048, P = 0.025). Logistic regression analysis showed that hs-CRP (OR = 1.782, 95% CI: 1.124-2.014, P = 0.021) and IL-6 (OR = 1.584, 95% CI: 1.112-1.986, P = 0.030) were independent predictors of CAE. The inflammatory markers were higher in the CAE-A group than in the CAE-B group and higher in the CAE-B group than in the CAE-C group. Follow-up after 6 months of rosuvastatin therapy showed a significantly greater reduction in hs-CRP and IL-6 levels in the CAE-A group than in the CAE-B group, which again were greater in the CAE-B group than in the CAE-C group. Anti-inflammatory therapy using rosuvastatin was more effective in younger CAE patients, indicating the need for early statin therapy in CAE.

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Adding once-daily omeprazole 20 mg to metronidazole/amoxicillin treatment for Helicobacter pylori gastritis: a randomized, double-blind trial showing the importance of metronidazole resistance.

We compared the Helicobacter pylori eradication rate after a 14-day treatment with amoxicillin 500 mg t.i.d. and metronidazole 500 mg t.i.d. with or without omeprazole 20 mg once daily. This was a randomized, controlled trial in which omeprazole was given in double-blind fashion. Patients with H. pylori-associated gastritis were enrolled in four centers in Canada from July 1991 to January 1994. Eradication of H. pylori was assessed by histological evaluation and culture of endoscopic biopsies obtained from the antrum and corpus of the stomach. The H. pylori eradication rate was 73% (33 of 45) in the omeprazole-amoxicillin-metronidazole group, compared with 66% (31 of 47) in the amoxicillin-metronidazole group. This 7% difference was not statistically significant (p = 0.43, 95% confidence interval for difference -11% to 26%). Metronidazole primary resistance in the prestudy cultures was found more frequently in the omeprazole-amoxicillin-metronidazole group than in the amoxicillin-metronidazole group. Resistance to metronidazole was an important predictor of treatment failure. The H. pylori eradication rate was 61% (19 of 31) for patients infected with metronidazole-resistant H. pylori strains, compared with 91% (30 of 33) eradication for those infected with metronidazole-sensitive strains (p < 0.01). Vaginal candidiasis was reported in four patients. The H. pylori eradication rate was higher (73%) for omeprazole-amoxicillin-metronidazole than for the dual antibiotic therapy given without omeprazole (66%); however, this difference was not statistically significant. Metronidazole resistance significantly reduces H. pylori eradication rates.

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Specific treatment for Trypanosoma cruzi: lack of efficacy of allopurinol in the human chronic phase of Chagas disease.

Thirty-five individuals from endemic areas of Central Brazil (age range, 18-64 years; 19 women) in the chronic phase of Chagas disease, with positive serology and presence of circulating parasites detected by one or more recent positive xenodiagnosis, were selected for this study. Allopurinol (900 mg/d) or placebo was administered in a double-blind clinical trial for 60 days. After codes were broken, 23 had been allocated to the intervention group and 12 to the placebo group. Side effects were observed in 11 patients in the intervention group and in 1 in the placebo group. Seventeen patients in the intervention group and 10 in the placebo group completed the trial. Follow-up was performed by monthly xenodiagnosis and serologic tests every 3 months during the first year and at the end of the trial. Xenodiagnosis remained positive in all 17 of the treated group and in all 10 of the placebo group. Serologic tests were persistently positive in both groups after treatment. We concluded that, at the doses used, allopurinol was not effective to clear, in our region, Trypanosoma cruzi from peripheral blood of infected individuals.

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Mortality in patients who discontinue low-dose acetylsalicylic acid therapy after upper gastrointestinal bleeding.

Discontinuing low-dose acetylsalicylic acid (ASA) therapy after upper gastrointestinal bleeding (UGIB) may increase the risk of cardiovascular-related death. Our aim was to compare mortality in UK primary care patients who discontinue ASA after UGIB with that in patients who continue therapy. ASA users at the time of UGIB and who were alive 30 days after were selected using The Health Improvement Network. Predictors of survival were assessed using adjusted Cox proportional hazards regression models. Of 547 ASA users, half did not re-initiate ASA during a mean follow-up of 4.1 years. Increasing age (a 10% increased risk for each yearly increase in age; hazard ratio [HR]: 1.10; 95% confidence interval [CI]: 1.07-1.14), female sex (HR: 1.61; 95%CI: 1.09-2.38), current smoking (HR: 2.11; 95%CI: 1.23-3.63), heavy alcohol use (HR: 3.31; 95%CI: 1.50-7.31), diabetes mellitus (HR: 1.93; 95%CI: 1.25-3.00), and chronic obstructive pulmonary disease (HR: 1.75; 95%CI: 1.03-2.99) were significantly associated with increased mortality. Most deaths (115/139) occurred in patients taking ASA for secondary prevention. In these patients, mortality tended to be lower among ASA continuer periods (HR: 0.74; 95%CI: 0.34-1.62) and higher among discontinuer periods (HR: 1.37; 95%CI: 0.81-2.30) than among non-users. Current use of clopidogrel was associated with decreased mortality in this population (HR: 0.49; 95%CI: 0.28-0.86). ASA therapy for secondary prevention should continue after UGIB because the risk of death tends to increase when ASA is stopped. However, a significantly increased risk was not found in these patients, likely owing to the relatively small number of ASA users and deaths that occurred during follow-up. Further studies with larger samples sizes are needed to confirm these findings among UGIB survivors taking ASA at the time of UGIB. Copyright © 2016 John Wiley & Sons, Ltd.

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A prospective, randomized, open labeled crossover trial of fosinopril and theophylline in post renal transplant erythrocytosis.

Angiotensin converting enzyme inhibitors (ACEI) and theophylline have been reported to decrease the elevated hemoglobin (Hgb) and hematocrit (Hct) levels in the renal transplant recipients with erythrocytosis. We conducted a prospective randomized, open labeled, crossover trial with theophylline, and an ACEI, fosinopril in nine stable renal transplant recipients with erythrocytosis. Aim of the study was to determine and compare the efficacy of these medications in stable renal transplant patients. At three months, compared to baseline, fosinopril significantly reduced the elevated hemoglobin (Hgb 17.2 +/- 0.6 vs. 14.9 +/- 1.4 gm/dL, p = 0.0023), and hematocrit levels (Hct 51.3 +/- 2.4 vs. 43.7 +/- 4.6%, p = 0.003). In contrast theophylline therapy was associated with a non-significant rise in hemoglobin (17.4 +/- 0.7 vs. 18.1 +/- 0.9gm/dL, p > 0.05) and hematocrit (52.4 +/- 2.7 vs. 54.7 +/- 3.9%, p > 0.05). With fosinopril compared to theophylline, there was a significant difference in the change in hemoglobin (baseline to three months 2.8 +/- 1.7 vs. -0.7 +/- 0.69 gm/dL respectively, p = 0.017), and the change in hematocrit (baseline to three months 9 +/- 6 vs. -2.3 +/- 2.7% respectively, p = 0.027). Four patients (44.4%) did not tolerate theophylline and did not complete the theophylline arm. To conclude, in our study, fosinopril effectively decreased the elevated hemoglobin and hematocrit in patients with post transplant erythrocytosis, and was superior to theophylline, while theophylline was ineffective and poorly tolerated in this condition.

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Venlafaxine in adults with attention-deficit/hyperactivity disorder: an open clinical trial.

It is becoming commonly recognized that adults suffer from attention-deficit/hyperactivity disorder (ADHD). Since medications used in the past of treat adults with ADHD may be ineffective or poorly tolerated by some patients, it is important to determine if newly available medications can safely ameliorate symptoms of ADHD in adults. An open clinical trial was undertaken to examine whether venlafaxine was safe and effective in the treatment of adults with ADHD. Ten subjects who met DSM-IV criteria for ADHD were enrolled in this 8-week trial. Individuals were started on 37.5 mg of venlafaxine b.i.d. If moderate ADHD symptoms persisted at the end of Week 4, the dose of venlafaxine was increased to 75 mg b.i.d. Assessments of ADHD symptomatology included the ADHD Rating Scale, Self-Report Version (ARS) and the Clinical Global Impressions (CGI) scale. Nine patients completed the study. At the end of the study, 7 patients were receiving 37.5 mg b.i.d. of venlafaxine. Repeated measures ANOVA demonstrated that treatment with venlafaxine was associated with significant reductions in ADHD symptomatology (p < .02 for the ARS; p < .005 for the CGI). Of the 9 subjects who completed the trial, 7 were considered responders. Venlafaxine was well tolerated, and most patients experienced only mild side effects. Venlafaxine may be a promising agent for the treatment of ADHD in adults. Controlled clinical trials are needed to further examine this issue.

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Significant association between statin-associated myalgia and vitamin D deficiency among treated HIV-infected patients.

Several studies have shown a significant association between vitamin D deficiency and an increased risk of statin-related symptomatic myalgia in the general population, but there are no data among HIV-infected persons. A retrospective, cohort study was conducted to assess the incidence of symptomatic myalgia and elevation in serum creatine kinase level among HIV-positive adults on combination antiretroviral therapy and treated with atorvastatin or rosuvastatin for at least 12 months between 2011 and 2015 in our outpatient unit. A total of 545 patients (mean age 53.4 years) were enrolled into the study. Atorvastatin was prescribed in 55.8% of patients and rosuvastatin in 44.2%. After a mean duration of statin therapy of 29 months, an isolated symptomatic myalgia was diagnosed in 42 patients (7.7%) and a myalgia associated with elevated creatine kinase level in 25 (4.6%). The mean concentration of 25-hydroxyvitamin D was significantly lower in patients with myalgia (19.4 ng/ml) and with creatine kinase elevation and myalgia (22.8 ng/ml) than in those without muscle toxicity (32.1 ng/ml; P = 0.017 and 0.024, respectively). In stratified multivariable-adjusted logistic regression models, there was a statistically significant association between vitamin D deficiency and occurrence of symptomatic myalgia (P = 0.009) or creatine kinase elevation and myalgia (P = 0.046). Other factors significantly associated with development of myalgia were duration of statin therapy more than 24 months, history of myalgia, and age older than 60 years. In our observational study, vitamin D deficiency was significantly associated with a statin-induced myalgia among HIV-infected patients on combination antiretroviral therapy, in conformity with data of the general population.

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Evaluating the effectiveness of bupropion and varenicline for smoking cessation using an internet-based delivery system: A pragmatic randomized controlled trial (MATCH study).

Traditional randomized controlled trials have demonstrated the efficacy of pharmacotherapy for smoking cessation. However, accessibility to treatments remains a barrier, necessitating the remote delivery of evidence-based cessation interventions. The aim of this study was to evaluate the effectiveness of an online treatment that included first-line prescription medications using a pragmatic randomized controlled trial design. This study was a two-group, parallel block randomized, open label, controlled trial, and conducted exclusively online. Participants were randomised (1:1) to either bupropion (150 mg) or varenicline (1 mg) for twelve weeks. Medication was couriered to participants. The primary outcome was 7-day point prevalence abstinence (PPA; defined as 0 cigarette puffs in the last 7 days) at 12 weeks. Secondary outcomes were 7-day PPA at 4-, 8-, 26-, and 52-weeks follow-up. Adverse events were evaluated at each follow-up session during treatment. The varenicline group (n = 499) had significantly higher 7-day PPA (30.3%) compared to the bupropion group (n = 465; 19.6%) at end of treatment (OR=2.08, 95% CI: 1.49-2.90, p < 0.001). Seven-day PPA was also higher for the varenicline group at 4-weeks (OR=1.71, 95% CI: 1.23-2.40 p = 0.0001), and 8-weeks follow-up (OR=1.95, 95% CI: 1.43-2.67 p < 0.0001), but not at post-treatment follow-up. More adverse events were reported in the varenicline group, compared to bupropion. This internet-based pharmacotherapy intervention was a feasible and effective method of treatment delivery for smoking cessation. This method can be used to increase the accessibility and availability of cessation interventions, decreasing the burden of smoking-related diseases. This trial was registered with clinical trials.gov under NCT02146911. Registered 26 May 2014, https://clinicaltrials.gov/ct2/show/NCT02146911.

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Reduction of LDL cholesterol by pravastatin does not influence platelet activation in patients with mild hypercholesterolaemia at risk of coronary heart disease.

The effect of pravastatin on low density lipoprotein (LDL) cholesterol and platelet activation was studied in 16 patients with mild hypercholesterolaemia who had two or more additional cardiovascular risk factors. Patients were treated with either pravastatin (20-40 mg day-1) or placebo for 1 year. Plasma LDL and urinary excretion of 2,3-dinor-thromboxane B2 (an index of platelet activation in vivo) were determined at 0, 3, 6 and 12 months. There was a significant reduction in LDL at 6 and 12 months (2P less than 0.05) but this was not associated with any significant change in thromboxane metabolite excretion.

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Antihypertensive effect of beta blockade in renal transplant recipients with or without host kidneys.

Host kidneys may contribute considerably to hypertension after renal transplantation. Their role in sustaining hypertension is more prominent if glomerulonephritis (GN) than if interstitial nephritis (IN) is the original renal disease. We compared the antihypertensive effect of beta-blockade in IN (n = 10) and GN (n = 19) hypertensive renal transplant recipients with host kidneys in situ with those who had undergone bilateral nephrectomy (BN, n = 10). Pretreatment blood pressures were comparable in BN, IN, and GN patients, being 165 +/- 6/108 +/- 3, 172 +/- 5/104 +/- 3, and 161 +/- 3/104 +/- 1, mmHg, respectively. Blood pressure did not change on beta-blockade in BN patients, whereas it decreased significantly more (P less than 0.001) in GN than in IN patients, changes of mean arterial pressure being -107 +/- 1.0, -14.9 +/- 1.3, and -6.8 +/- 1.6%, respectively. This failure to respond to beta-blockade in patients without host kidneys may be related to low activity of the renin-angiotensin system or to functional denervation of the grafted kidney. Further investigations of this phenomenon may clarify the mechanism of antihypertensive action of beta-blockade as well as the nature of hypertension after renal transplantation.

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Lack of effect of prednisone administration on bleeding time and platelet function of normal subjects.

The effect of 80 mg prednisone given orally for 2 d on normal and post-aspirin bleeding times and platelet function has been studied in a randomized, multiple cross-over, double-blind controlled trial in 12 normal volunteers. Mean template bleeding times were 6.6 min (placebo/placebo), 5.9 min (prednisone/placebo), 10.0 min (placebo/aspirin) and 8.7 min (prednisone/aspirin). The shortening after prednisone administration was not statistically significant. Prednisone had no effect on platelet glass bead retention nor on platelet aggregation by collagen, adrenalin and adenosine diphosphate. Thus conventional clinical doses of prednisone did not impair platelet function and did not enhance primary haemostatis in normal subjects as measured by the bleeding time.

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Double-blind, placebo-controlled study of the efficacy of trazodone in alcohol post-withdrawal syndrome: polysomnographic and clinical evaluations.

Alcohol detoxification is accompanied by sustained difficulties in sleep initiation and maintenance. These difficulties are thought to be an important cause of relapse to alcohol use. However, the treatment of sleep problems with hypnotic drug is made difficult by cross-tolerance between benzodiazepines and alcohol. In this report, we evaluated the capacity of trazodone (TRZ), a second-generation antidepressant with anxiolytic and sedative properties, to increase the sleep efficiency in alcohol-dependent patients after detoxification. Sixteen patients completed the TRZ (n = 8) or the placebo (PL; n = 8) treatment arms. Polysomnographies were performed at baseline, after the 1st drug dose, and after 4 weeks of treatment. The main outcome was sleep efficiency. Secondary outcomes included changes in other sleep parameters, Hamilton Depression Rating and Clinical Global Impression scales. Sleep efficiency was increased in the TRZ group when it was computed after sleep onset, both immediately after 1st administration of the drug and after 4 weeks of treatment. No benefit was observed in the PL group. Sleep improvement under TRZ also included the number of awakenings, intermittent wake sleep time, and non-rapid eye movement sleep. Hamilton and Clinical Global scales were better for the TRZ group. TRZ is thus a potential option in the treatment of alcohol post-withdrawal insomnia.

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Open trial of bupropion SR in adolescent major depression.

There are few studies of sustained-release bupropion in adolescents with major depression. Twenty-one adolescents with DSM-IV major depression were recruited through advertisement and self-referral; 11 began study medication and were rated weekly with an expanded Hamilton Depression Rating Scale (SIGH-SAD), as well as Clinical Global Impression-Improvement (CGI-I). Of 11 subjects enrolled, 8 completed an 8-week trial of bupropion SR. Mean baseline SIGH-SAD scores of 31.3 decreased significantly by 74% to mean endpoint score of 8.2. Improvement on CGI-I that agreed closely between raters and patients was found in 8 of 11 subjects (72.3%). The mean daily dose of bupropion SR was 362 mg +/- 52 mg and was well tolerated; insomnia and weight loss were experienced by 55%; other adverse effects of dry mouth, headache, agitation, light-headedness, diarrhea, or rash were noted in a minority of subjects. In this preliminary, small open study, depressed adolescents showed a marked response to bupropion SR.

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Circadian variation of heart rate variability and the rate of autonomic change in the morning hours in healthy subjects and angina patients.

Incidence of sudden cardiac death peaks during the early morning hours when there is a rapid withdrawal of vagal and an increase of sympathetic tone. The rate of autonomic change could be of prognostic importance. A total of 65 patients with angina pectoris, free from other diseases and drug free, were Holter monitored for 24 h. A total of 30 patients were also monitored on isosorbide-5-mononitrate (IS-5-MN) and on metoprolol respectively. A total of 33 age-matched healthy subjects served as controls. Spectral components of heart rate variability (HRV) were analysed hourly, with special reference to the rapid changes of autonomic tone during the night and early morning hours. Circadian variation was assessed in two ways: (1) Mean HRV day (8 a.m.-8 p.m.) and night (0-5 a.m.) were compared. (2) For the morning/night hours (0-10 a.m.), individual hourly values for max. and min. HRV, the difference max.-min. (gradient), the rate of change per hour between max. and min. (velocity) and the largest difference between two consecutive hours (max. velocity) were recorded and the mean value for the group calculated. During the night/morning hours, healthy controls demonstrated faster HF max. velocity (P=0.002) and higher HF gradient (P=0.011) than angina patients. Metoprolol and IS-5-MN increased the HF gradient (P=0.008 and P=0.003, respectively), and metoprolol tended to increase the max. velocity (P=0.02). Metoprolol substantially decreased the LF/HF gradient (P=0.001), velocity (P=0.008) and max. velocity (P=0.0001). Rapid vagal withdrawal seemed to be a sign of a healthy autonomic nervous system in the control group but was significantly slower in angina patients. IS-5-MN and metoprolol tended to normalise vagal withdrawal and metoprolol slowed down the rapid increase in sympathetic predominance in the morning in patients.

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Comparison of vortioxetine versus venlafaxine XR in adults in Asia with major depressive disorder: a randomized, double-blind study.

This randomized, double-blind 8 week study compared the efficacy and tolerability of fixed-dose treatment with vortioxetine (10 mg/day) and venlafaxine extended release (XR) (150 mg/day) in major depressive disorder (MDD) patients. Patients aged 18-65 years with a primary diagnosis of recurrent MDD, a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥26 and a Clinical Global Impression-Severity (CGI-S) score ≥4 were randomized (1:1) to treatment with either vortioxetine or venlafaxine XR. The primary endpoint was change from baseline to Week 8 in MADRS total score (analysis of covariance [ANCOVA], full-analysis set [FAS], last observation carried forward [LOCF]), using a non-inferiority margin of +2.5 points. Pre-specified secondary endpoints included MADRS response and remission rates, anxiety symptoms (HAM-A), CGI, overall functioning (SDS), and health-related quality of life (Q-LES-Q). This study (SOLUTION) has the www.ClinicalTrials.gov identifier: NCT01571453. On the primary efficacy endpoint at Week 8, non-inferiority was established with a difference of -1.2 MADRS points in favor of vortioxetine (95% CI: -3.0 to 0.6). The MADRS total score decreased (improved) from 32.3 ± 4.6 at baseline to 13.6 ± 9.6 (vortioxetine: n = 209) and from 32.3 ± 4.5 to 14.8 ± 10.4 (venlafaxine XR: n = 215) (FAS, LOCF). At Week 8, the HAM-A and SDS total scores, CGI and Q-LES-Q scores, and response and remission rates demonstrated similar improvement for vortioxetine and venlafaxine XR, with remission rates (MADRS ≤10) of 43.1% (vortioxetine) versus 41.4% (venlafaxine XR) (LOCF). Fewer vortioxetine than venlafaxine XR patients withdrew for any reason (18.0% versus 27.4%) or for adverse events (6.6% versus 13.7%). The most frequent adverse events (≥5%) for both treatments were nausea, dizziness, headache, and dry mouth. In addition, accidental overdose, decreased appetite, constipation and insomnia were reported by (≥5%) of patients treated with venlafaxine XR. The inclusion and exclusion criteria may limit the generalizability of the study. Since patients with a history of lack of response to venlafaxine XR were excluded from this study, there is a selection bias in favor of venlafaxine XR. Vortioxetine was at least as efficacious as venlafaxine XR and was safe and better tolerated than venlafaxine XR.

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Tolerance to the protective effect of salmeterol in mild untreated asthmatics.

The aim of this study was to assess the distribution of the occurrence of tolerance to the protective effect of salmeterol on allergen challenge in a large sample of asthmatic subjects. We investigated 53 subjects (45 male and eight female), mean age 24+/-8.2 years, with mild intermittent asthma, in stable phase of the disease, never previously treated with regular beta2-agonists. All subjects with a previous positive early airway response (EAR) to a screening allergen challenge underwent, in double blind randomized, cross-over manner, three further allergen challenges: after placebo (T0), after a single dose (50 microg) of inhaled salmeterol (T1), and after regular treatment with inhaled salmeterol (50 microg bid) for 1 week (T2). All subjects showed an EAR after placebo treatment (T0), and were completely protected against EAR by the single dose of salmeterol (T1). After 1-week regular treatment with salmeterol (T2). 24 out of 53 subjects (45%) were still protected, whereas 29 subjects (55%) showed a significant EAR. The distribution of the response to allergen challenge, which was quite homogeneous at T0 and T1, showed considerable heterogeneity at T2. Tolerance to the protective effect of salmeterol on allergen challenge can be observed in a large group of previously untreated mild asthmatic subjects. This phenomenon is heterogeneously distributed, with some subjects still showing a complete protection similar to that obtained after a single dose of salmeterol and others showing a response similar to that obtained after placebo. The reason of this heterogeneity needs to be elucidated.

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Statin therapy and saphenous vein graft disease after coronary bypass surgery: analysis from the CASCADE randomized trial.

Current guidelines recommend statin therapy after coronary artery bypass grafting (CABG) to attain low-density lipoprotein (LDL) levels less than 100 mg/dL. Whether achieving LDL levels less than 70 mg/dL improves postoperative graft patency remains unknown. The CASCADE (Clopidogrel after Surgery for Coronary Artery Disease) trial was a randomized study that evaluated the addition of clopidogrel to aspirin on the development of saphenous vein graft disease after CABG. Patients received the standard of care regarding postoperative statin therapy with targeted LDL levels less than 100 mg/dL. Twelve months postoperatively, patients returned for a coronary angiogram and saphenous vein graft (SVG) intravascular ultrasonogram. In this post hoc analysis, the impact of statin therapy on graft patency and vein graft intimal hyperplasia was assessed. LDL levels significantly declined over the period of the trial (p = 0.002). Twelve months postoperatively, 58.4% patients achieved LDL levels less than 70 mg/dL. Twelve-month graft patency was higher for patients with LDL levels less than 100 mg/dL (96.5%) compared with patients with LDL levels >100 mg/dL (83.3%, p = 0.03), even after adjustment in multivariate analysis (odds ratio [OR], 5.2; 95% confidence interval [CI], 1.3-21.6; p = 0.02). However, no improvement in graft patency was noted with further LDL reduction to less than 70 mg/dL (p = 1.00). Consistent statin use throughout the trial period was independently associated with less vein graft intimal hyperplasia documented by intravascular ultrasound at 12 months (p = 0.04). Statin therapy to achieve LDL levels less than 100 mg/dL was independently associated with improved graft patency in the CASCADE trial. Randomized clinical trials are warranted to prospectively evaluate postoperative LDL reduction to less than 70 mg/dL and its impact on graft patency after CABG.

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Nitrate therapy is an alternative to furosemide/morphine therapy in the management of acute cardiogenic pulmonary edema.

Nitrates are superior to furosemide in the management of acute pulmonary edema associated with myocardial infarction; however, their role in the absence of infarction is unclear. A randomized comparison was undertaken of the relative effectiveness of primary therapy with either intravenous morphine/furosemide (men/women; n = 32) or nitroglycerin/N-acetylcysteine (NTG/NAC; n = 37) in consecutive patients with acute pulmonary edema. The primary end point was change in PaO2/FIO2 over the first 60 minutes of therapy. Secondary end points were needed for mechanical respiratory assistance (ie, continuous positive airway pressure via mask or intubation and ventilation) and changes in other gas exchange parameters. Both treatment groups showed improvement in oxygenation after 60 minutes of therapy; however, this reached statistical significance only with NTG/NAC therapy. There was no significant difference between groups in the assessed parameters (95% CI for differences in Pao2/FIO2: furosemide/morphine -12 to 23 and NTG/NAC 4 to 44), a finding also confirmed in 32 patients presenting with respiratory failure. Only 11% of the study group required mechanical ventilatory assistance (continuous positive airway pressure in 4 patients and intubation and ventilation in 3 patients). NTG/NAC therapy is as effective as furosemide/morphine in the initial management of acute pulmonary edema, regardless of the presence or absence of respiratory failure. The necessity for mechanical ventilatory assistance is infrequent in these patients, regardless of the initial medical treatment regimen.

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Therapeutic ratio of hydrofluoroalkane and chlorofluorocarbon formulations of fluticasone propionate.

To compare the therapeutic ratio of chlorofluorocarbon (CFC) and hydrofluoroalkane-134a (HFA) formulations of fluticasone propionate (FP). We performed a randomized, placebo-controlled, crossover study comparing 6 weeks of treatment with FP using 500 micro g/d and 1,000 microg/d formulations of CFC and HFA. The primary end points were provocative dose of methacholine causing a 20% fall in FEV1 (PD20) and overnight urinary cortisol/creatinine excretion. Eighteen patients with mild-to-moderate asthma and geometric mean (SEM) PD20 of 82.3 micro g (19.2 micro g) completed the study. All treatments significantly improved PD20 values and morning peak expiratory flow vs placebo, while 1,000 microg/d was significantly better than 500 microg/d for the CFC formulation of FP (CFC-FP) but not the HFA formulation of FP (HFA-FP). Only 1,000 microg/d of CFC-FP caused significant suppression of overnight urinary cortisol/creatinine compared to placebo. There were no differences between formulations at either dose. The increased airway benefit with CFC-FP > 500 microg/d was offset by greater systemic effects. Although HFA-FP had fewer systemic effects than CFC-FP at 1,000 microg/d, there was no benefit to increasing HFA-FP to > 500 microg/d.

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Minimally invasive surgery in cancer. Immunological response.

Minimally invasive surgery produced major changes in treating abdominal malignancies and early stage lung cancer. Laparoscopy and thoracoscopy are less traumatic than open surgery: allow faster recovery, shorter hospital stay, better cosmesis. Although these clinical benefits are important, prolonged disease-free interval, long-term survival with improved quality of life are most important endpoints for oncologic surgery. Major surgery causes significant alteration of immunological response, of particular importance in oncologic patients, as postoperative immunosuppression has been related to septic complications, lower survival rate, tumor spread and metastases. Clinical studies have shown laparoscopic surgery preserves better the patient's immunological function. Postoperative plasma peak concentrations of IL-6, IL-10, C-reactive protein (CRP) and TNF-alpha were lower after laparoscopic colonic resection. Prospective thoracoscopic VATS lobectomy trials found better preservation of lymphocyte T-cell function and quicker return of proliferative responses to normal, lower levels of CRP, thromboxane and prostacyclin. Immune function is influenced by the extent of surgical trauma. Minimally invasive surgery show reduced acute-phase responses compared with open procedures and better preservation of cellular immune mechanisms.

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CHOP alone compared with CHOP plus radiotherapy for localized aggressive lymphoma in elderly patients: a study by the Groupe d'Etude des Lymphomes de l'Adulte.

Chemoradiotherapy has been considered standard treatment for patients with limited-stage aggressive lymphoma on the basis of trials conducted before the introduction of the International Prognostic Index. To evaluate this approach in elderly patients with low-risk localized lymphoma, we conducted a trial comparing chemoradiotherapy with chemotherapy alone. Previously untreated patients older than 60 years with localized stage I or II histologically aggressive lymphoma and no adverse prognostic factors of the International Prognostic Index were randomly assigned to receive either four cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus involved-field radiotherapy (299 patients) or chemotherapy alone with four cycles of CHOP (277 patients). With a median follow-up time of 7 years, event-free and overall survival did not differ between the two treatment groups (P = .6 and P = .5, respectively). The 5-year estimates of event-free survival were 61% for patients receiving chemotherapy alone and 64% for patients receiving CHOP plus radiotherapy; the 5-year estimates of overall survival were 72% and 68%, respectively. In a multivariate analysis, overall survival was affected by stage II disease (P < .001) and male sex (P = .03). In this large prospective study, CHOP plus radiotherapy did not provide any advantage over CHOP alone for the treatment of low-risk localized aggressive lymphoma in elderly patients.

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Variants in ADRB1 and CYP2C9: Association with Response to Atenolol and Losartan in Marfan Syndrome.

To test whether variants in ADRB1 and CYP2C9 genes identify subgroups of individuals with differential response to treatment for Marfan syndrome through analysis of data from a large, randomized trial. In a subset of 250 white, non-Hispanic participants with Marfan syndrome in a prior randomized trial of atenolol vs losartan, the common variants rs1801252 and rs1801253 in ADRB1 and rs1799853 and rs1057910 in CYP2C9 were analyzed. The primary outcome was baseline-adjusted annual rate of change in the maximum aortic root diameter z-score over 3 years, assessed using mixed effects models. Among 122 atenolol-assigned participants, the 70 with rs1801253 CC genotype had greater rate of improvement in aortic root z-score compared with 52 participants with CG or GG genotypes (Time × Genotype interaction P = .005, mean annual z-score change ± SE -0.20 ± 0.03 vs -0.09 ± 0.03). Among participants with the CC genotype in both treatment arms, those assigned to atenolol had greater rate of improvement compared with the 71 of the 121 assigned to losartan (interaction P = .002; -0.20 ± 0.02 vs -0.07 ± 0.02; P < .001). There were no differences in atenolol response by rs1801252 genotype or in losartan response by CYP2C9 metabolizer status. In this exploratory study, ADRB1-rs1801253 was associated with atenolol response in children and young adults with Marfan syndrome. If these findings are confirmed in future studies, ADRB1 genotyping has the potential to guide therapy by identifying those who are likely to have greater therapeutic response to atenolol than losartan.

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Response of obstructive sleep apnea to fluoxetine and protriptyline.

Protripyline is the pharmacologic agent most commonly used to treat obstructive sleep apnea (OSA); however, its anticholinergic side effects make it intolerable to many patients. Because serotonin may be a central respiratory stimulant and because the serotonin-uptake inhibitor, fluoxetine, is usually well tolerated, we wanted to try fluoxetine in the treatment of OSA. Therefore, we compared the effect of fluoxetine to that of protriptyline in 12 patients with OSA. Both drugs significantly decreased the proportion of REM sleep time and decreased the number of apneas or hypopneas in NREM sleep. The response to fluoxetine was equivalent to that of protriptyline; however, for the group as a whole, there was no significant improvement in the number of arterial oxygen desaturation events, the level of arterial oxygen desaturation, or the number of arousals with either agent. Although there was wide variability in the response to each medication, six of the 12 patients had good responses, including improvement in oxygenation, to either fluoxetine or protriptyline. Three patients could not complete the trial of protriptyline. We conclude that fluoxetine is beneficial to some, but not all, patients with OSA. Fluoxetine was better tolerated than protriptyline.

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Aspirin versus clopidogrel for chronic maintenance monotherapy after percutaneous coronary intervention (HOST-EXAM): an investigator-initiated, prospective, randomised, open-label, multicentre trial.

Optimal antiplatelet monotherapy during the chronic maintenance period in patients who undergo coronary stenting is unknown. We aimed to compare head to head the efficacy and safety of aspirin and clopidogrel monotherapy in this population. We did an investigator-initiated, prospective, randomised, open-label, multicentre trial at 37 study sites in South Korea. We enrolled patients aged at least 20 years who maintained dual antiplatelet therapy without clinical events for 6-18 months after percutaneous coronary intervention with drug-eluting stents (DES). We excluded patients with any ischaemic and major bleeding complications. Patients were randomly assigned (1:1) to receive a monotherapy agent of clopidogrel 75 mg once daily or aspirin 100 mg once daily for 24 months. The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and Bleeding Academic Research Consortium (BARC) bleeding type 3 or greater, in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02044250. Between March 26, 2014, and May 29, 2018, we enrolled 5530 patients. 5438 (98·3%) patients were randomly assigned to either the clopidogrel group (2710 [49·8%]) or to the aspirin group (2728 [50·2%]). Ascertainment of the primary endpoint was completed in 5338 (98·2%) patients. During 24-month follow-up, the primary outcome occurred in 152 (5·7%) patients in the clopidogrel group and 207 (7·7%) in the aspirin group (hazard ratio 0·73 [95% CI 0·59-0·90]; p=0·0035). Clopidogrel monotherapy, compared with aspirin monotherapy during the chronic maintenance period after percutaneous coronary intervention with DES significantly reduced the risk of the composite of all-cause death, non-fatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and BARC bleeding type 3 or greater. In patients requiring indefinite antiplatelet monotherapy after percutaneous coronary intervention, clopidogrel monotherapy was superior to aspirin monotherapy in preventing future adverse clinical events. ChongKunDang, SamJin, HanMi, DaeWoong, and the South Korea Ministry of Health and Welfare.

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Effects of acute and chronic ibopamine administration on resting and exercise hemodynamics, plasma catecholamines and functional capacity of patients with chronic congestive heart failure.

The effects of acute and chronic ibopamine treatment on resting and exercise hemodynamics, exercise capacity and plasma catecholamines were evaluated in 25 patients with chronic heart failure, using a double-blind, parallel, placebo-controlled design. During 2 months of therapy with either placebo or ibopamine (100 mg, 3 times daily), 1 patient was withdrawn from each group for worsening heart failure, New York Heart Association functional class improved in 4 patients on ibopamine and in 1 on placebo, and furosemide dose could be decreased in 4 on ibopamine and in no patient on placebo. Acute ibopamine administration induced, in comparison with placebo, a significant increase of cardiac and stroke volume indexes both at rest and peak exercise, with a reduction of systemic vascular resistance. These hemodynamic changes were maintained also after chronic therapy, with no evidence of tolerance development. Exercise capacity (evaluated as peak exercise duration and oxygen consumption, and ventilatory threshold) did not significantly change. Resting and peak exercise norepinephrine plasma levels were significantly reduced after both acute and chronic ibopamine administration. Thus, the hemodynamic and neurohumoral effects of ibopamine make this drug potentially useful for the chronic treatment of congestive heart failure.

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A double blind placebo RCT to investigate the effects of serotonergic modulation on brain excitability and motor recovery in stroke patients.

Motor excitability is increased in both hemispheres in stroke patients during motor recovery. Pharmacologically controlled changes of cortical excitability might be beneficial for synaptic plasticity and therefore facilitate functional recovery after a brain lesion. In particular, it has been suggested that antidepressant drugs can modulate motor excitability. Several recent reports suggest the possibility of monitoring pharmacological effects on brain excitability through transcranial magnetic stimulation (TMS). The aim of this study was to investigate motor area excitability in patients with stroke after oral administration of citalopram. We conducted a prospective randomised placebo controlled study. Twenty patients with unilateral stroke were included in the study: ten patients treated by antidepressive drug and ten patients with placebo. A selective serotonergic drug (citalopram) or a placebo was administered using a mean dosage of 10 mg/day in combination with physiotherapy. Motor cortex excitability was studied by single and paired transcranial magnetic stimulation. TMS recording was tested before (T1) and 1 month after (T2) beginning drug treatment. Patients treated by the serotonergic drug, compared to patients that received a placebo, showed a significant improvement in neurological status as measured by NIHSS and a decrease of motor excitability over the unaffected hemisphere, while no differences were observed over the affected hemisphere. Our findings suggest that treatment with serotonergic drugs can bring about a significant decrease of the motor cortex excitability in stroke patients with effects on both the affected and unaffected hemispheres associated with a better motor recovery.

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[Control of postoperative pain in heart surgery. Comparison of analgesics].

Evaluation of the efficacy of three analgesic drugs (tramadol, ketorolac, and morphine) for the control of postoperative pain in cardiac surgery. prospective randomized study. University Hospital, Postoperative intensive care unit. sixty patients, who underwent cardiac surgery, were studied. They were randomly allocated in four groups, treated with a different postoperative analgesic therapy: A) tramadol in continuous infusion; B) ketorolac in continuous infusion; C) tramadol, in repeated boluses; D) morphine, in repeated boluses. the analgesic efficacy of each drug and administration protocol was evaluated by hemodynamic stability, arterial blood gases analysis, Visual Analogue Scale (VAS), resting and after cough, the VAS derivatives PID and SPID, the concentration of plasma epinephrine and norepinephrine, at eight postoperative times. Adverse effects were also registered. Only tramadol, in continuous i.v. infusion, achieves the required analgesic effect, significantly decreasing both VAS scores, at the end of the administration of the drug. This treatment reduced epinephrine plasma levels in the first postoperative day, when the residual analgesic effect of surgical anesthesia can be considered disappeared. Tramadol in continuous infusion (dose 12 mg/h) proved to be effective for the control of postoperative pain after cardiac surgery. The proposed dose represents a good compromise between analgesic efficacy and interference with the vital functions of operated patients.

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International multicentre observational study to assess the efficacy and safety of a 0·5 mg kg^-1 per day starting dose of oral corticosteroids to treat bullous pemphigoid.

European guidelines propose a 0·5 mg kg^-1 per day dose of oral prednisone as initial treatment for bullous pemphigoid (BP). We assessed the safety and efficacy of this regimen depending on BP extent and general condition of the patients. In a prospective international study, we consecutively included all patients diagnosed with BP. Patients received a 0·5 mg kg^-1 per day dose of prednisone, which was then gradually tapered 15 days after disease control, with the aim of stopping prednisone or maintaining minimal treatment (0·1 mg kg^-1 per day) within 6 months after the start of treatment. The two coprimary endpoints were control of disease activity at day 21 and 1-year overall survival. Disease severity was assessed according to the Bullous Pemphigoid Disease Area Index (BPDAI) score. In total, 198 patients were included between 2015 and 2017. The final analysis comprised 190 patients with a mean age of 80·9 (SD 9·1) years. Control of disease activity was achieved at day 21 in 119 patients [62·6%, 95% confidence interval (CI) 55·3-69.5]; 18 of 24 patients (75%, 95% CI 53·3-90·2), 75 of 110 patients (68·8%, 95% CI 59·2-77·3) and 26 of 56 patients (46.4%, 95% CI 33·0-60·3) had mild, moderate and severe BP, respectively (P = 0·0218). A total of 30 patients died during the study. The overall Kaplan-Meier 1-year survival was 82·6% (95% CI 76·3-87·4) corresponding to 90·9%, 83·0% and 80·0% rates in patients with mild, moderate and severe BP, respectively (P = 0·5). Thresholds of 49 points for BPDAI score and 70 points for Karnofsky score yielded maximal Youden index values with respect to disease control at day 21 and 1-year survival, respectively. A 0·5 mg kg^-1 per day dose of prednisone is a valuable therapeutic option in patients with mild or moderate BP whose general condition allows them to be autonomous.

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Ritodrine versus salbutamol for external cephalic version.

Treatment with beta-agonist tocolytics preceding external cephalic version (ECV) attempt increases success rates. Most studies have focused on intravenously and orally administered beta-agonists, while other administration routes including intramuscularly (IM) and subcutaneously (SC) are understudied. The aim of this study was to compare the efficacy of IM ritodrine to SC salbutamol given prior to ECV. A retrospective study of patients who underwent ECV between 1/2012 and 12/2019 at two medical centers. We compared patients undergoing ECV following IM ritodrine versus SC salbutamol. We matched the two groups by parity and placental location. Maternal, pregnancy, ECV procedure and neonatal characteristics were compared. Overall, 601 women were included in each group. Median maternal age and amniotic fluid index (AFI) were lower in the Ritodrine group (27 vs. 32 years, P<0.001, 11 vs. 15 AFI cm, P<0.001, respectively). The median gestational age at ECV was higher in the Ritodrine group (38^0/7 vs. 37^0/7 weeks gestation). Success rate was higher in the Ritodrine group (71.7% vs. 63.8%, P=0.003). Vaginal delivery rate was higher in the Ritodrine group (70.7% vs. 60.1%, P<0.001). The number needed to treat to benefit was 10. In a multivariate analysis, Ritodrine was independently associated with higher ECV success rates as compared with Salbutamol (aOR 2.1, 95%CI 1.52-2.89). Intramuscular ritodrine significantly improved the success rate of ECV compared to SC salbutamol, and both drugs were safe and acceptable before ECV.

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Outcomes after radioiodine ablation in patients with thyroid cancer: Long-term follow-up of a Chinese randomized clinicaltrial.

Two large randomized trials of patients with differentiated thyroid cancer (DTC) reported recently (HiLo and ESTIMABL1) found that the recurrence rate among patients who underwent 1.1 GBq radioactive iodine (RAI) ablation was not higher than that of patients who underwent 3.7 GBq radioactive iodine (RAI) ablation. However, no similar studies have been conducted in China. We aimed to report clinical outcomes in Chinese patients with low/intermediate risk of recurrence DTC after long-term follow-up, and evaluate the risk factors that influence the presence or absence of incomplete response at the final follow-up. A long-term follow-up of a Chinese randomized clinical trial (October 2014 and February 2021) was conducted. A total of 506 DTC patients at low/intermediate risk of recurrence who were randomized into two groups to receive 1.1 (n = 251) or 3.7 GBq (n = 255) RAI ablation following thyroid hormone withdrawal were followed on levothyroxine treatment for a median of 4.5 years (range: 1.6-6.3). Suppressed serum thyroglobulin (Tg) and anti-thyroglobulin antibody (TgAb) levels were determined, and neck ultrasonography was performed. At the final follow-up, 499 (98.6%) patients showed an excellent response. The other seven patients (two patients underwent 1.1 GBq and five patients underwent 3.7 GBq RAI ablation, respectively) showed either structural incomplete response (lymph node metastasis, n = 1), biochemical incomplete response (increased serum Tg ≥ 1 ng/ml, or increased positive TgAb levels, n = 5), or indeterminate response (stable positive TgAb levels, n = 1). The risk of incomplete response at the final follow-up was significantly increased in patients with stimulated serum Tg ≥ 10 ng/ml at ablation (p = .003) and in patients with unsuccessful ablation (p = .008). Our findings indicated that there was no difference in the long-term outcomes with RAI ablation using either 1.1 or 3.7 GBq in patients with low/intermediate risk of recurrence DTC, and 1.1 GBq RAI might be suitable for patients who are recommended for ablation.

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Efficacy of low-dose pravastatin in patients with mild hyperlipidemia associated with type II diabetes mellitus.

A 16 week, randomized, double-blind, parallel, placebo-controlled study was designed to determine the effects of low-dose pravastatin on cholesterol concentrations in patients with mild hypercholesterolemia and non-insulin-dependent diabetes mellitus (NIDDM). Following a 6-to 8-week dietary run-in period, a mean serum total cholesterol (TC) level > 5.2 mmol/L (200 mg/dL), but < 7.8 mmol/L (300 mg/dL) was required for entry. Metabolic control of diabetes was determined by a hemoglobin Alc (HbAlc) level less than twice the upper limit of normal on two occasions. Eighty six (86) patients recruited in 5 French diabetic clinics, were randomized in a ratio of 1:1 (pravastatin 10 mg or placebo), and 74 completed the study. There were 12 discontinuations: 5 (11.6%) in the pravastatin group and 7 (16.3%) in the placebo group. Drop-out was due to an adverse event in 1 patient (2.3%) in the pravastatin group and in 5 patients (11.6%) in the placebo group. Thirty five (35) placebo patients and 14 pravastatin patients had their dose of treatment doubled at week 8: the dose of treatment was to be doubled at week 8 in the event of non-response to treatment (TC at week 7 > 5.2 mmol/L and TC decrease < 15% from baseline). At week 16, pravastatin lowered TC from 6.4 to 5.6 mmol/L (-13.8%, p < 0.001 versus placebo), low-density lipoprotein cholesterol (LDL-C) from 4.3 to 3.4 mmol/L (-20.4%, p < 0.001 versus placebo) and slightly increased high-density lipoprotein cholesterol (HDL-C) from 1.18 to 1.25 mmol/L (+6.7%). Side effects were similar in both groups. Blood glucose control was not altered as assessed by serial HbAlc measurements which were unchanged during treatment. This study demonstrated that low-dose pravastatin is effective in lowering cholesterol levels in patients with hypercholesterolemia and NIDDM.

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Increased systolic blood pressure with rofecoxib in congenital furosemide-like salt loss.

To analyse whether congenital furosemide- or thiazide-like renal salt loss protects against the potential prohypertensive effects of two cyclooxygenase (COX) inhibitors: rofecoxib, a COX-2 selective inhibitor, and indomethacin, an unselective COX-inhibitor. In a retrospective analysis, the effects of rofecoxib and indomethacin on blood pressure (bp: transformed into age-independent standard deviation scores (SDS) values), creatinine clearance (CRC), fractional excretion of sodium (FeNa), and renal excretion of systemic prostaglandins were studied in 28 patients with a genetically proven congenital hypokalaemic salt-losing tubulopathy (SLT) (11 female and 17 male, age: 2-25 years), 19 with a furosemide-like SLT, and nine with a thiazide-like SLT. In furosemide-like SLT patients, systolic SDS bp values were significantly higher with rofecoxib (1.03 +/- 0.16 SDS, n = 107) compared with indomethacin (0.56 +/- 0.09 SDS, n = 282; P = 0.007, 95% CI: 0.12-0.8). Without the drugs, systolic SDS bp values were elevated by 0.63 +/- 0.11 SDS, n = 164. Both drugs reduced renin and aldosterone-plasma levels to a similar extent. SDS values were significantly correlated with the excretion of the vasoconstrictor thromboxane (T x B2) (R2: 0.038, P = 0.021, n: 159), but not with CRC or FeNa. Blood pressure was not increased in thiazide-like SLT patients treated with rofecoxib. Congenital furosemide-like renal salt loss does not protect against the prohypertensive effects of rofecoxib. The positive correlation between bp SDS values with T x B2 but not with FeNa or CRC point towards an altered vascular homeostasis as one mechanism increasing blood pressure.

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A randomized clinical trial of hydroxymethylglutaryl- coenzyme a reductase inhibition for acute lung injury (The HARP Study).

There is no effective pharmacological treatment for acute lung injury (ALI). Statins are a potential new therapy because they modify many of the underlying processes important in ALI. To test whether simvastatin improves physiological and biological outcomes in ALI. We conducted a randomized, double-blinded, placebo-controlled trial in patients with ALI. Patients received 80 mg simvastatin or placebo until cessation of mechanical ventilation or up to 14 days. Extravascular lung water was measured using thermodilution. Measures of pulmonary and nonpulmonary organ function were assessed daily. Pulmonary and systemic inflammation was assessed by bronchoalveolar lavage fluid and plasma cytokines. Systemic inflammation was also measured by plasma C-reactive protein. Sixty patients were recruited. Baseline characteristics, including demographics and severity of illness scores, were similar in both groups. At Day 7, there was no difference in extravascular lung water. By Day 14, the simvastatin-treated group had improvements in nonpulmonary organ dysfunction. Oxygenation and respiratory mechanics improved, although these parameters failed to reach statistical significance. Intensive care unit mortality was 30% in both groups. Simvastatin was well tolerated, with no increase in adverse events. Simvastatin decreased bronchoalveolar lavage IL-8 by 2.5-fold (P = 0.04). Plasma C-reactive protein decreased in both groups but failed to achieve significance in the placebo-treated group. Treatment with simvastatin appears to be safe and may be associated with an improvement in organ dysfunction in ALI. These clinical effects may be mediated by a reduction in pulmonary and systemic inflammation. Clinical trial registered with www.controlled-trials.com (ISRCTN70127774).

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Risk of serious asthma exacerbations associated with long-acting beta agonists among patients with asthma: a retrospective cohort study.

After the Serevent Nationwide Surveillance clinical trial, controversy has surrounded the safety of long-acting beta agonists (LABAs). Examine the association between LABAs and severe asthma exacerbations (SAEs). From a multistate Medicaid database, for the years 2002-2007, a total of 940,449 patients (age <40) with asthma were selected and divided into a cohort with newly-diagnosed asthma and one with pre-existing asthma. SAEs included asthma-related emergency department (ED) visits, hospitalizations, and intubations. Patients' asthma severity was determined based on medication regimen as suggested by the 2002 National Asthma Guidelines. Specific use of inhaled corticosteroids (ICSs), LABAs, ICS/LABA combination drugs, short-acting beta agonists (SABAs), and other drugs was tracked. Cox proportional hazard regressions were estimated to assess the risk of SAEs associated with patient severity, drug use, and covariates. Compared to patients taking a SABA only, estimated SAE hazard ratios for newly diagnosed and pre-existing-asthma patients were as follows: 0.63 (95% CI 0.58-0.69) and 0.74 (0.70-0.79) for patients on a LABA without ICS, and 0.79 (0.77-0.81) and 0.90 (0.87-0.92) for those on a LABA/ICS single inhaler. Although hazard ratios were estimated to be similar for ED visits, LABA use was found to be positively associated with hospitalizations and intubations. Other key risk factors (P < .0001) included being African American, an alcohol/substance use disorder, pregnancy, and obesity. Relative to SABA-only therapy, LABA use is associated with a lower risk of ED visit. Certain patients with asthma, such as pregnant women and African Americans, are particularly vulnerable to SAE risk of all types.

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Autologous bone marrow transplantation in multiple myeloma: identification of prognostic factors.

Multiple myeloma remains a universally fatal malignancy with a median survival time not exceeding 3 years. A clinical trial was undertaken to determine feasibility and efficacy of marrow-ablative chemoradiotherapy supported by unpurged autologous bone marrow (ABMT) and to define prognostic variables. Total body irradiation and either melphalan or thiotepa were administered to 55 patients (median age 53 years; range 20 to 66 years). The group of 21 patients with resistance to standard melphalan-prednisone and to continuous infusions of vincristine and Adriamycin with high dose dexamethasone (VAD) included 7 with primary unresponsive disease and 14 with resistant relapse; among the 34 patients achieving remission with the VAD regimen, 14 were in first and 20 in a subsequent remission. Marked cytoreduction by greater than or equal to 75% was observed among all 21 patients with refractory myeloma, whereas further cytoreduction of this magnitude was noted in only 56% of the 34 patients already in remission after VAD. Five of the 6 early deaths among all 55 patients occurred in the 14 patients with resistant relapse, none of whom achieved complete remission and who, as a group, had median durations of relapse-free and overall survival of only 8 and 7 months, respectively. Among the 41 remaining patients, there was only one early death, and 27% achieved complete remission including a 36% incidence among the 14 patients treated in first remission; their projected 4-year survival rate was 82% regardless of their disease status (first or later remission or primary resistance). When information about sensitivity to prior therapy is unavailable, the presence before ABMT of both high beta-2-microglobulin levels (greater than 3 mg/L) and non-IgG isotype helped identify 9 among the 55 patients with a very poor prognosis: all 8 responders relapsed within 9 months, and 8 patients died within 15 months. By contrast, a 4-year projected survival rate of over 70% for the other patients (about 80% of this series) justifies further investigation of this novel treatment approach in comparison with standard dose regimens. Our results indicate that marrow-ablative therapy cannot be recommended for myeloma patients with resistant relapse or those with a combination of risk factors (advanced tumor burden, absence of IgG isotype). The apparent lack of an adverse effect of even marked plasmacytosis in autografts (up to 30%) emphasizes the need for better cytoreduction rather than bone marrow purging.

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A randomised determination of the Effect of Fluvastatin and Atorvastatin on top of dual antiplatelet treatment on platelet aggregation after implantation of coronary drug-eluting stents. The EFA-Trial.

Drug-drug interaction between statins metabolised by cytochrome P450 3A4 and clopidogrel have been claimed to attenuate the inhibitory effect of clopidogrel. However, published data regarding this drug-drug interaction are controversial. We aimed to determine the effect of fluvastatin and atorvastatin on the inhibitory effect of dual antiplatelet therapy with acetylsalicylic acid (ASA) and clopidogrel. One hundred one patients with symptomatic stable coronary artery disease undergoing percutaneous coronary intervention and drug-eluting stent implantation were enrolled in this prospective randomised study. After an interval of two weeks under dual antiplatelet therapy with ASA and clopidogrel, without any lipid-lowering drug, 87 patients were randomised to receive a treatment with either fluvastatin 80 mg daily or atorvastatin 40 mg daily in addition to the dual antiplatelet therapy for one month. Platelet aggregation was assessed using light transmission aggregometry and whole blood impedance platelet aggregometry prior to randomisation and after one month of receiving assigned statin and dual antiplatelet treatment. Platelet function assessment after one month of statin and dual antiplatelet therapy did not show a significant change in platelet aggregation from 1st to 2nd assessment for either statin group. There was also no difference between atorvastatin and fluvastatin treatment arms. In conclusion, neither atorvastatin 40 mg daily nor fluvastatin 80 mg daily administered in combination with standard dual antiplatelet therapy following coronary drug-eluting stent implantation significantly interfere with the antiaggregatory effect of ASA and clopidogrel.

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Statins, aspirin and risk of venous thromboembolic events in breast cancer patients.

Venous thromboembolic events (VTE's) are associated with decreased survival in breast cancer patients. Studies suggested that statins reduce the risk of VTE's in the general population. Low dose Aspirin reduces risk of VTE's in high risk populations. The Breast Cancer in Northern Israel Study is a case-control study of consecutive breast cancer cases diagnosed in northern Israel and matched controls. The present analysis was limited to cases with breast cancer enrolled in the study. Data was extracted from Clalit Health Services (CHS) database and from computerized pharmacy records. Out of 3,585 patients enrolled, 261 (7.3%) had a VTE during median follow up of 4.2 years. The 1 and 2 year cumulative incidence was 2.64 and 3.65%. 55.7% of patients used statins, predominantly simvastatin (75.8%). 44.5% used aspirin. In multivariate analysis neither statins nor aspirin use was associated with a reduced risk for a VTE. Unadjusted HR for statin and aspirin was 1.461 (1.018-2.096) and 1.293 (0.846-1.976), respectively, and the adjusted HR were 0.86 (0.648-1.14) and 1.013 (0.737-1.392). Results were similar when only simvastatin use was assessed. Metastatic disease, chemotherapy, age, BMI and presence of comorbidities were significantly associated with risk of VTE's. Our study is the first to look at the effect of statins and aspirin on the incidence of VTE's in patients with breast cancer. In our cohort, statin and aspirin use did not decrease the risk for a VTE. Our results might be explained by use of low potency statins (simvastatin and pravastatin) and by alternate mechanisms for VTE formation in patients with cancer.

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Aspirin use and risk of fatal cancer.

Aspirin and other nonsteroidal antiinflammatory drugs inhibit prostaglandin synthesis and tumor growth in many experimental systems, but it is unclear which of these tumor models are relevant to humans. We have reported reduced risk of fatal colon cancer among persons who used aspirin in a large prospective study. This analysis examines other fatal cancers in relation to aspirin among 635,031 adults in that study who provided information in 1982 on the frequency and duration of their aspirin use and did not report cancer. Death rates were measured through 1988. Death rates decreased with more frequent aspirin use for cancers of the esophagus, stomach, colon, and rectum but not generally for other cancers. For each digestive tract cancer, death rates were approximately 40% lower among persons who used aspirin 16 times/month or more for at least 1 year compared to those who used no aspirin. The trend of decreasing risk with more frequent aspirin use was strongest among persons who had used aspirin for 10 years or more; it remained statistically significant, except for esophageal cancer, in multivariate analyses that adjusted for other known risk factors. Biases such as early detection or aspirin avoidance among cases do not appear to explain the results. Our data suggest that regular, prolonged use of aspirin may reduce the risk of fatal cancer of the esophagus, stomach, colon, and rectum. Future epidemiological and basic research should examine all digestive tract cancers in considering the chemopreventive or therapeutic potential of nonsteroidal antiinflammatory drugs.

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Baseline patient characteristics associated with placebo remission and their impact on remission with duloxetine and selected SSRI antidepressants.

We examined whether identification of patients with placebo-remitter characteristics and placebo-nonremitter characteristics enhances the ability to identify drug-placebo treatment differences and, perhaps, differences between agents in major depressive disorder (MDD). We hypothesized: 1) that drug-placebo differences in remission rates would be greater for both duloxetine and selective serotonin reuptake inhibitors (SSRIs) among placebo nonremitters than placebo remitters and: 2) that the difference between active treatments would also be greater in placebo nonremitters than placebo remitters. Data were obtained from seven randomized, parallel, double-blind MDD studies which compared the effects of duloxetine (N = 795), placebo (N = 510), and SSRIs (N = 551). The 17-item Hamilton depression rating scale (HAMD) was used to assess depression severity. The classification of participants as having placebo-remitter or placebo-nonremitter characteristics was based on age, duration of current MDD episode, HAMD anxiety score, and HAMD core score. Odds ratios (ORs) for remission comparing active treatment and placebo were obtained from logistic regression models. Tests of homogeneity were used for between-group comparisons. For placebo nonremitters, both duloxetine (OR = 3.52 [95% CI: 2.21, 5.62; P < 0.0001]) and SSRIs (OR = 2.38 [95% CI: 1.45, 3.89; P = 0.0006]) showed significantly higher remission rates compared to placebo. Drug-placebo differences in remission were significantly greater for placebo nonremitters than for placebo remitters for both duloxetine (P = 0.02) and SSRIs (P = 0.049). For placebo remitters, remission with duloxetine (OR = 1.83 [95% CI: 1.35, 2.47; P = 0.0001]), but not the SSRIs selected for this study (OR = 1.31 [95% CI: 0.93, 1.84; P = 0.12]), was significantly greater than placebo. Contrary to expectation, the advantage of duloxetine over the SSRIs was not greater in placebo nonremitters. However, the fact that our analysis required patient-level data limited the number of agents studied, compromising generalization. Our study suggests that drug-placebo differences in remission rates will be greater in subjects with placebo-nonremitter than with placebo-remitter characteristics.

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Evaluation of individual subjects in the analog classroom setting: I. Examples of graphical and statistical procedures for within-subject ranking of responses to different delivery patterns of methylphenidate.

In this article, we describe graphical and statistical methods developed to evaluate the response patterns of individual children with attention deficit hyperactivity disorder (ADHD) to different conditions of treatment with stimulant medication. We used data from an investigation of drug delivery patterns to demonstrate these methods. Thirty-one children with ADHD participated in a double-blind crossover study of four conditions (three patterns of delivery of methylphenidate and a placebo control). In each condition, the children were evaluated across an 11-hour (7:00 a.m. to 6:00 p.m.) laboratory school day, and ratings of classroom behavior were obtained at regular intervals across the day. Graphical procedures were developed to display, for each individual, time courses of multiple measures of behavior taken across each double-blind test day. Expert clinicians judged these graphs and used this information to rank-order the test days from best to worst. A within-subject variant of Kendall's W was used to evaluate, for each subject, whether the rankings of these multidimensional graphs were reliable (concordant) across judges. A generalized kappa statistic was used to evaluate, for each condition, the reliability of the judges' rankings across subjects. Friedman's analysis of variance of ranks was used to evaluate, for the study, whether the conditions differed in terms of the average (consensus) rank assigned by the judges.

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Lisinopril versus hydrochlorothiazide in obese hypertensive patients: a multicenter placebo-controlled trial. Treatment in Obese Patients With Hypertension (TROPHY) Study Group.

Because obesity-associated hypertension has unique hemodynamic and hormonal profiles, certain classes of antihypertensive agents may be more effective than others as monotherapy. Thus, we compared the efficacy and safety of the angiotensin-converting enzyme inhibitor lisinopril and the diuretic hydrochlorothiazide in a 12-week, multicenter, double-blind trial in 232 obese patients with hypertension. Patients with an office diastolic pressure between 90 and 109 mm Hg were randomized to treatment with daily doses of lisinopril (10, 20, or 40 mg), hydrochlorothiazide (12.5, 25, or 50 mg), or placebo. Mean body mass indexes were similar for all patients. At week 12, lisinopril and hydrochlorothiazide effectively lowered office diastolic (-8.3 and -7.7 versus -3.3 mm Hg, respectively; P<.005) and systolic (-9.2 and -10.0 versus -4.6 mm Hg, respectively; P<.05) pressures compared with placebo. Ambulatory blood pressure monitoring confirmed that lisinopril and hydrochlorothiazide effectively lowered 24-hour blood pressure compared with placebo (P<.001). Significant dose-response differences were observed between treatments. Sixty percent of patients treated with lisinopril had an office diastolic pressure <90 mm Hg compared with 43% of patients treated with hydrochlorothiazide (P<.05). Responses to therapies differed with both race and age. Neither treatment significantly affected insulin or lipid profiles; however, plasma glucose increased significantly after 12 weeks of hydrochlorothiazide therapy compared with lisinopril (+0.31 versus -0.21 mmol/L; P<.001). Hydrochlorothiazide also decreased serum potassium levels by 0.4 mmol/L from baseline. In conclusion, lisinopril was as effective as hydrochlorothiazide in treating obese patients with hypertension. Treatment with angiotensin-converting enzyme inhibitors may show greater efficacy as monotherapy at lower doses compared with thiazide diuretics, may have a more rapid rate of response, and may offer advantages in patients at high risk of metabolic disorders.

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Hyperfibrinogenemia is a poor prognostic factor in diffuse large B cell lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphomas worldwide. Previous studies indicated that hyperfibrinogenemia was a poor predictor in various tumors. The purpose of our study was to evaluate the prognostic effect of hyperfibrinogenemia in DLBCL. Data of 228 patients, who were diagnosed with DLBCL in our hospital between May 2009 and February 2016, were analyzed retrospectively. The Kaplan-Meier method and Cox regression were performed to find prognostic factors associated with progression-free survival (PFS) and overall survival (OS). Receiver operator characteristic (ROC) curve and the areas under the curve were used to evaluate the predictive accuracy of predictors. Comparison of characters between groups indicated that patients with high National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) score (4-8) and advanced stage (III-IV) were more likely to suffer from hyperfibrinogenemia. The Kaplan-Meier method revealed that patients with hyperfibrinogenemia showed inferior PFS (P < 0.001) and OS (P < 0.001) than those without hyperfibrinogenemia. Multivariate analysis showed that hyperfibrinogenemia was an independent prognostic factor associated with poor outcomes (HR = 1.90, 95% CI: 1.15-3.16 for PFS, P = 0.013; HR = 2.65, 95% CI: 1.46-4.79 for OS, P = 0.001). We combined hyperfibrinogenemia and NCCN-IPI to build a new prognostic index (NPI). The NPI was demonstrated to have a superior predictive effect on prognosis (P = 0.0194 for PFS, P = 0.0034 for OS). Hyperfibrinogenemia was demonstrated to be able to predict poor outcome in DLBCL, especially for patients with advanced stage and high NCCN-IPI score. Adding hyperfibrinogenemia to NCCN-IPI could significantly improve the predictive effect of NCCN-IPI.

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Cost-effectiveness analysis of n-3 polyunsaturated fatty acids (PUFA) after myocardial infarction: results from Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto (GISSI)-Prevenzione Trial.

To estimate the cost effectiveness of treatment with n-3 polyunsaturated fatty acids (PUFA) for secondary prevention after myocardial infarction (MI). The cost-effectiveness analysis of n-3 PUFA treatment after MI was based on morbidity and mortality data and the use of resources obtained prospectively during the 3.5 year follow-up period of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto (GISSI)-Prevenzione study. The cost-effectiveness analysis took into account the incremental number of life-years gained and the incremental costs for hospital admissions, diagnostic tests and drugs, applying a 5% discount rate. The value for money of n-3 PUFA treatment was assessed using the cost-effectiveness ratio and the number needed to treat (NNT) approach. Third-party payer. The incremental cost-effectiveness ratio for n-3 PUFA in the basecase scenario was 24,603 euro (EUR, 1999 values) per life-year gained (95% confidence interval: 22,646 to 26,930). Sensitivity analysis included the analysis of extremes, producing estimates varying from EUR15,721 to EUR52,524 per life-year gained. 172 patients would need to be treated per year with n-3 PUFA, at an annual cost of EUR68,000, in order to save 1 patient. This is comparable with the NNT value, and associated annual cost for simvastatin, but less costly than that for pravastatin. The cost effectiveness of long term treatment with n-3 PUFA is comparable with other drugs recently introduced in the routine care of secondary prevention after MI. Since the clinical benefit provided by n-3 PUFA is additive, this therapy should be added to the established routine practice, with additive costs.

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Efficacy of Different Antihypertensive Drugs among newly Diagnosed Hypertensive Patient in Dhulikhel Hospital.

Background Cardiovascular disease represents the largest burden on global health, important modifiable risk factor being hypertension. Difference in response to antihypertensive medication depending on ethnic group is well recognized. There is very few data regarding this difference in the South Asian population especially from Nepal. Objective The aim of this study is to find out which antihypertensive medication has better efficacy in our population. Method One seventy two newly diagnosed hypertensive patients who presented to cardiology OPD were included. Blood Pressure (BP) was recorded in both arms at least three times. Patients were counseled for lifestyle and dietary modification and were prescribed one of the three drugs Hydrochlorthiazide 25 mg or Amlodipine 5 mg or Enalapril 5 mg. Patients were called back in 4-6 weeks time and Blood Pressure was recorded in similar manner. Result Out of 172 patients, 97 were male and 75 female. The mean age was 55.49±1.03 years. Mean Systolic BP before treatment was 156.2±10.6 mm of Hg and Mean Diastolic BP before treatment was 100.5 ±6.8 with no statistically significant difference among different groups. However Systolic BP reduction was 14.6 ±5.1, 21.9±5.9 and 21.8±7.4 by Hydrochlorthiazide , Amlodipine and Enalapril respectively. Diastolic BP reduction was 8.8±2.5, 14.2±2.8 and 14.3±2.9 by Hydrochlorthiazide, Amlodipine and Enalapril respectively. Conclusion Amlodipine and Enalapril are equally effective in controlling BP in our population. Hydrochlorthiazide is less effective than both Amlodipine and Enalapril.

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A surveillance study of escitalopram treatment of depressed patients.

The aim of this surveillance study was to assess the tolerability of, and response to, treatment with escitalopram in 525 psychiatric out-patient clinics in the Czech Republic. Clinical response was evaluated using the Zung Depression Rating Scale (ZDRS) and the Clinical Impressions--Improvement (CGI-I) scale. The change from baseline in the ZDRS, Clinical Impressions--Severity of Illness (CGI-S) and CGI-I scores were analysed for each visit (baseline, weeks 1-2, 4, 8 and 26). There were 2664 patients included, with 2126 patients (79.8%) completing the 6-month treatment. During the course of the study, the patients showed an improvement in their severity of depression, with a response rate (CGI-I < or = 2) of 86.7% and a remission rate (CGI-S < or = 2) of 80.6% for patients completing 6 months of treatment. The most frequent adverse events were nausea (5.5%), headache (2.1%) and sweating (2.0%). Discontinuation due to adverse events occurred in 170 patients (6.4%) and 3.7% of patients withdrew from the study because of non-response and/or worsening of psychopathology. There were no significant differences between baseline and final visit in mean body mass index for men or women. In this large surveillance study, escitalopram was well tolerated by a heterogeneous group of patients, whose depressive symptoms responded to < or = 6 months of treatment.

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Effect of high dose ergocalciferol in chronic kidney disease patients with 25-hydroxyvitamin D deficiency.

To evaluate 25 hydroxyvitamin D (25-OH-D) deficiency in a cohort ofpredialysis CKD patients and the treatment effect and safety of high dose ergocalciferol supplement in predialysis CKD. Fifty-six predialysis CKD patients who came for a regular visit at a single hospital with calculated glomerular filtration rate < or =60 mL/min/1.73 m2 were screened for 25-OH-D levels. Forty-four patients with 25-OH-D deficiency were recruited into this prospective observational study that examined the effect of high dose oral ergocalciferol supplementation. After eight weeks, 37 patients completed the follow-up and biochemical parameters were reevaluated and analyzed. The mean 25-OH-D level of 56 patients was 25.6 +/- 8 ng/mL. Forty-four (78.5%) patients had 25-OH-D levels less than 30 ng/mL and four (7.1%) had severe deficiency with the level less than 15 ng/mL. High dose ergocalciferol supplement successively increased 25-OH-D levels in 35 (95%) patients. 25-OH-D levels increased significantly from 22 +/- 4.8 to 34.5 +/- 10.8 ng/mL after eight weeks (p < 0.001). During the study period, there were no changes in serum calcium, phosphate, and PTH. There was no other side effect associated with the treatment. 25-OH-D deficiency were found in this cohort of predialysis CKD patients. Ergocalciferol was a safe and effective supplement for the 25-OH-D in predialysis CKD.

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Relative effects of drugs and diet on hyperactive behaviors: an experimental study.

In a test of Feingold's hypothesis that food additives trigger the hyperactive response, 26 hyperactive children were randomly assigned to treatment conditions whereby they were given active or placebo medications in combination with challenge cookies with artificial food colors or control cookies without the additives. The children were crossed over into each of the four treatment conditions and experimental procedures were employed, including double-blind assessments through the completion of behavior checklists, by teachers and parents. Stimulant medications were clearly more effective than diet in reducing hyperactive behavior. The parent ratings indicate strong drug effects and inconclusive diet effects. Drug effects are marked in teacher ratings as well. However, when the children were receiving placebos, their hyperactive behaviors in the classroom were greater when eating cookies with artificial colors than when eating cookies without artificial colors. According to the ratings, approximately seven children were no longer hyperactive. There is evidence to suggest that the behavior of three to eight children was diet-responsive, depending on the criteria used. There is evidence, particularly in teacher ratings, in support of Feingold's hypothesis if it is modified. Further research is required to specify which subtypes of hyperactive children respond to a diet free of artificial food colors.

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Efficacy of allopurinol and benzbromarone for the control of hyperuricaemia. A pathogenic approach to the treatment of primary chronic gout.

To study the efficacy of allopurinol and benzbromarone to reduce serum urate concentrations in patients with primary chronic gout. Prospective, parallel, open study of 86 consecutive male patients with primary chronic gout. Forty nine patients (26 normal excretors and 23 under excretors) were given allopurinol 300 mg/day and 37 under excretors benzbromarone 100 mg/day. After achieving steady plasma urate concentrations with such doses, treatment was then adjusted to obtain optimal plasmatic urate concentrations (under 6 mg/dl). Patients receiving allopurinol 300 mg/day showed a mean reduction of plasmatic urate of 2.75 mg/dl (from 8.60 to 5.85 mg/dl) and 3.34 mg/dl (from 9.10 to 5.76 mg/dl) in normal excretors and under excretors respectively. Patients receiving benzbromarone 100 mg/day achieved a reduction of plasmatic urate of 5.04 mg/dl (from 8.58 to 3.54 mg/dl). Fifty three per cent of patients receiving allopurinol and 100% receiving benzbromarone achieved optimal plasma urate concentrations at such doses. The patients with poor results with allopurinol 300 mg/day achieved a proper plasma urate concentration with allopurinol 450 to 600 mg/day, the mean final dose being 372 mg/day. Renal function improved and no case of renal lithiasis was observed among benzbromarone treated patients, whose mean final dose was 76 mg/day. Benzbromarone is very effective to control plasma urate concentrations at doses ranging from 50 to 100 mg/day. Uricosuric treatment is a suitable approach to the treatment of patients with gout who show underexcretion of urate.

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Prospective study with combined low-dose chemotherapy and zidovudine in 37 patients with poor-prognosis AIDS-related non-Hodgkin's lymphoma. French-Italian Cooperative Study Group.

The French-Italian Cooperative Study Group included patients with poor-prognosis AIDS-related non-Hodgkin's lymphoma (NHL), defined as those with performance status (PS) > or = 3 and/or opportunistic infections (OI), in a prospective study with a 50% reduced-dose combination chemotherapy regimen: CHVmP-Vincristine-bleo (cyclophosphamide 300 mg/m2 i.v. day 1, doxorubicin 25 mg/m2 i.v. day 1, teniposide 30 mg/m2 i.v. day 1, prednisone 20 mg/m2 per os days 1-5, vincristine 2 mg i.v. day 15, and bleomycin 10 mg i.v. day 15), given every 21 days for eight cycles, and concomitant zidovudine 500 mg per os per day. The aims of this combined treatment were to reduce bone marrow toxicity and infectious complications related to chemotherapy (with a low-dose chemotherapy regimen), and to control the HIV and related infectious complications (with zidovudine therapy). Thirty-seven patients entered this prospective study. At the time of the NHL diagnosis, 41% of the patients had asymptomatic HIV infection, 27% had ARC and 32% had already had CDC-defined diagnoses of AIDS. The median CD4+ cell count was 35 mm3. Only 29 patients are evaluable for response, since 8 received only one cycle of chemotherapy. Fifteen of 29 (52%) patients obtained objective responses, with only 4 (14%) achieving complete remissions (CR) of 1, 4, 14 and 29+ months. Three (16%) CRs were achieved in 19 evaluable patients included in the study because of poor PS, and only one CR was observed in 10 evaluable patients with histories of OI, either alone or with poor PS. The most common side effect was bone marrow toxicity with 2 related toxic deaths.(ABSTRACT TRUNCATED AT 250 WORDS)

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Definition of acetylsalicylic acid resistance using whole blood impedance aggregometry in patients undergoing coronary artery surgery.

A beneficial effect of acetylsalicylic acid (ASA) on vein graft patency has been described, but some patients experience adverse cardiac events despite appropriate ASA treatment. Study aim was to define ASA resistance using Multiple electrode aggregometry (MEA) preoperatively in group of patients undergoing coronary artery bypass grafting (CABG). Prospective observational trial at University Hospital Center Zagreb enrolled 131 patients scheduled for CABG, and divided them into 4 groups with respect to preoperative antiplatelet therapy (APT). Group 1 received 100 mg ASA per day, Group 2 100 mg ASA + 75 mg clopidogrel per day, Group 3 75 mg clopidogrel per day, and Group 4 did not receive any APT. MEA with ASPI test (sensitive to ASA) and ADP test (sensitive to clopidogrel) was performed prior to surgery. In Group 1, patients were characterized as ASA resistant if their ASPI test value exceeded the 75th percentile distribution. Study enrolled 131 patients. Significant differences both in the ASPI (p < 0.001) and the ADP test (p = 0.038) were observed between patients in different APT groups. In Group (1) ASPI test value of 30 AUC presented 75th percentile of distribution, thus indicating ASA resistance. Group 2 patients had slightly lower ADP test values, but no significant difference occurred (mean 60.05 vs. 63.32 AUC, p = 0.469). In Group 1 and 2, significant correlations between the ADP test and both, platelet count (r = 0.347, p < 0.001) and fibrinogen level (r = 0.364, p < 0.001) were observed. Association between low response to ASA and post-CABG major adverse ischemic events risk increase has been described thus indicating need for ASA resistant patients detection. In patients with preoperative ASPI test exceeding 30 AUC postoperative, ASA dose adjustment or clopidogrel addition according to MEA results should be considered.

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Serum dehydroepiandrosterone sulfate concentration as an indicator of adrenocortical suppression in asthmatic children treated with inhaled steroids.

ACTH regulates adrenal androgen production, which may thus be reduced during glucocorticosteroid therapy. Dehydroepiandrosterone sulfate is the most abundant androgen secreted by the adrenals. We wished to evaluate whether serum levels of dehydroepiandrosterone sulfate can be used as an indicator of adrenal suppression during inhaled steroid treatment in children. Sixty school-aged children with newly diagnosed asthma were randomly divided into budesonide (n = 30) and fluticasone propionate (n = 30) groups. Fifteen cromone-treated children served as a control group. The budesonide dose was 800 microg/d during the first 2 months and 400 microg/d thereafter. The respective fluticasone propionate doses were 500 and 200 microg/d. Serum dehydroepiandrosterone sulfate concentrations were measured before and after 2 and 4 months of treatment. In the budesonide group, serum dehydroepiandrosterone sulfate decreased from the baseline by a mean of 21% (95% confidence interval, 13-29%; P < 0.001) after 2 months of high dose treatment and by 16% (95% confidence interval, 8-25%; P < 0.001) after 4 months of treatment. In the fluticasone propionate group, the respective figures were 10% (95% confidence interval, 4-16%; P < 0.01) and 6% (95% confidence interval, 16% decrease-3% increase; P = NS). A low dose ACTH test indicated adrenocortical suppression at 4 months in 14 (23%) steroid-treated children. In these children, dehydroepiandrosterone sulfate decreased by a mean of 21% (95% confidence interval, 14-28%), whereas in those 46 steroid-treated children with normal ACTH test results, dehydroepiandrosterone sulfate decreased by 8% (95% confidence interval, 0-16%; P < 0.05 between these groups). In the control group, dehydroepiandrosterone sulfate levels tended to increase (by a mean of 26%), reflecting the normal physiological change at this age. In conclusion, inhaled steroid treatment suppresses dehydroepiandrosterone sulfate production in a dose-dependent manner. Monitoring of serum dehydroepiandrosterone sulfate concentrations can be used as a practical method to follow adrenocortical function and to detect its suppression during inhaled steroid treatment in children.

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Haemodynamic and renal responses to oral losartan potassium during salt depletion or salt repletion in normal human volunteers.

We examined the haemodynamic and renal response to oral losartan potassium (100 mg) during activation of the renin system in humans. Eight healthy volunteers followed a low-salt (40 mmol sodium) diet for 4 days on four occasions 2 weeks apart. Double-blind salt depletion was achieved by 3-day administration of frusemide (40 mg twice daily, b.i.d.) with placebo salt replacement, salt repletion by placebo frusemide (b.i.d.), and active salt replacement (100 mmol/day). On day 4, subjects received randomised double-blind placebo or losartan. Prestudy salt depletion was associated with nonsignificant decreases in serum sodium (138 +/- 2 mM), potassium (3.5 +/- 0.2 mM) and increased urea (6.5 +/- 1.1 mM), and creatinine (91 +/- 6 microM) as compared with screening. Prestudy (day 3) 24-h urinary volume was similar during deplete preparation (placebo 1.707 +/- 0.81 L, losartan 1.509 +/- 0.626 L) or deplete preparation (placebo 1.726 +/- 0.5 L, losartan 1.764 +/- 0.52 L), but sodium excretion was greater during replete preparation. Salt replete supine blood pressure (BP) profiles showed little effect of losartan (mean maximal supine BP -9 +/- 6 mm Hg) as compared with placebo (-1 +/- 4 mm Hg), with a similar relative result for erect BP. After salt depletion, losartan caused a greater response in both supine (-24 +/- 9) and erect (-33 +/- 15) BP than did placebo (supine -12 +/- 5, erect -14 +/- 9). In this protocol after salt depletion, losartan caused a transient increase in urea and creatinine (143 +/- 40 microML) 8 h after dosing as compared with placebo (105 +/- 13 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

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Patient-initiated mandatory boluses for ambulatory continuous interscalene analgesia: an effective strategy for optimizing analgesia and minimizing side-effects.

This prospective, randomized study tested the hypothesis that a reduced dose continuous interscalene regimen incorporating a low background infusion with mandatory boluses would provide similar shoulder surgery analgesia compared with a dose regimen incorporating a conventional higher background infusion. After rotator cuff surgery, patients received via an interscalene catheter, one of two elastomeric pumps, each having a 5 ml per 60 min bolus function and a 2 ml h⁻¹ (n=38) or 5 ml h⁻¹ (n=43) ropivacaine 2 mg ml⁻¹ infusion. Boluses commenced from the onset of pain and continued for >48 h as required (pro re nata, PRN) up to every hour for a numerical rating pain score (NRPS, 0-10) >2. Group 2 ml h⁻¹ received mandatory 6 hourly boluses irrespective of the NRPS. Rescue tramadol was available. Patients were questioned on postoperative days 1 and 2 for treatment effectiveness and side-effects. Postoperative pain was similar between the groups [Group 2 ml h⁻¹ day 2 median (IQR) (95% confidence interval of the mean) worst movement pain=4 (1-5) (2.8-4.7) vs 4 (2-5) (3.1-4.6), P=0.99], as were night awakenings and tramadol consumption. Numerically rated numbness and weakness were similar between the groups; however, nine patients (21%) in the 5 ml h⁻¹ group vs one (3%) in the 2 ml h⁻¹ group required a temporary infusion cessation due to side-effects (predominantly hand numbness) (P=0.02). Continuous interscalene ropivacaine 0.2% 2 ml h⁻¹ with mandatory 6 hourly (and PRN) boluses provides similar analgesia after rotator cuff repair but with reduced side-effects compared with 5 ml h⁻¹ with PRN only boluses.

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Does colonoscopy cause increased ulcerative colitis symptoms?

Ulcerative colitis (UC) patients often report symptom flares after colonoscopy. However, this has not been documented in the literature. 1. Determine whether colonoscopy is associated with increased UC symptoms. 2. Determine whether there is a need for escalation of UC medications after colonoscopy. 3. Identify baseline variables associated with increased symptoms after colonoscopy. Fifty-five outpatients with a history of UC, intact colon, and quiescent disease were enrolled in a prospective case-crossover study. Subjects were evaluated with the Simple Clinical Colitis Activity Index (SCCAI) before colonoscopy, 1 week and 4 weeks after colonoscopy. A mixed model analysis was used to accommodate nonindependence of repeated measurements on the same patients. Fifty-one (91%) subjects completed the study. Six subjects had clinical relapse defined by a score of 5 or greater on the SCCAI during the week after colonoscopy. Five subjects increased their 5-aminosalicylic acid (5-ASA) medications immediately postcolonoscopy, two of whom had a SCCAI 5 or greater. Multivariate modeling demonstrated a clear association between the week immediately after colonoscopy preparation and increased disease activity, with the time period being predictive of increased SCCAI (week 1 vs. week 4, P = 0.0127). The baseline SCCAI (P value < 0.0001) and prednisone use (P = 0.0120) were predictive of increased SCCAI postcolonoscopy. Thiopurines (P < 0.001) were protective against increased symptoms. In our study, 1 in 8 subjects had UC relapse by SCCAI immediately postcolonoscopy, and 1 in 10 subjects required an increase in their 5-ASA medications. Clinicians should be cognizant of this effect of colonoscopy in patients with UC.

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Sedative Hypnotics and the Risk of Falls and Fractures in the Elderly.

Older age, poor sleep, and the use of the "Z" sedative hypnotic drugs (zopiclone, eszopiclone, zolpidem, and zaleplon) commonly go together. Each of these can increase the risk of falls and fractures through mechanisms related to cognitive and psychomotor impairment. A recent systematic review and meta-analysis examined the risk of falls and fractures associated with the use of the Z-drugs. The authors of that meta-analysis identified 14 relevant cohort and case-control studies. They found that Z-drugs increased the risk of falls in 2 out of 3 studies that provided information on this outcome; in the third, the increased risk narrowly missed statistical significance. Z-drugs increased the fracture risk in 9 of 10 studies (odds ratio [OR] = 1.63; 95% confidence interval [CI], 1.42-1.87). In secondary analyses, the fracture risk associated with the use of Z-drugs was elevated in studies that included a control group diagnosed with insomnia (OR = 1.28; 95% CI, 1.08-1.53) as well as in studies of samples restricted to subjects aged > 65 years (OR = 1.70; 95% CI, 1.36-2.12). In 2 studies, zolpidem was associated with an increased risk of injuries. Whereas confounding by indication may explain a part of the risk of falls and fractures, there is reason to consider that Z-drugs augment the risk. Either way, the use of Z-drugs emerges as a clear marker for the risk of falls and fractures. Nonpharmacologic interventions for insomnia should therefore be considered as alternatives to the use of Z-drugs. Finally, patients prescribed Z-drugs and caregivers of these patients should be warned about the risk of falls and fractures and counseled about practical measures that can reduce the risk.

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Effects of pravastatin treatment on blood pressure regulation after renal transplantation.

Hypertension is one of the main cardiovascular risk factors and has an impact also on long-term kidney graft survival. In addition to their lipid-lowering properties, it was shown that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors also have a blood pressure lowering effect. We examined whether treatment with a statin interferes with blood pressure regulation and antihypertensive treatment after renal transplantation. 74 patients were treated with initially 20 mg of pravastatin daily immediately after kidney transplantation. This group was compared to a matched cohort of 76 patients without statin treatment. All patients received standard immunosuppressive triple therapy with ciclosporin A microemulsion together with an antiproliferative agent and prednisolone. Primary objective of this analysis was systolic and diastolic blood pressure regulation with and without pravastatin. Furthermore, graft function expressed as creatinine clearance and proteinuria, immunosuppressive regimen, and incidence of cardiovascular events and graft loss were recorded for 48 months. The blood pressure regulation was comparable in both groups; however, to achieve this, significantly more antihypertensive drugs had to be used in the statin-treated patients as compared with the controls (2.9 vs. 2.2 agents at 48 months). A slightly higher ciclosporin A exposure of the statin-treated patients could have contributed to this observation. The graft function after 4 years was comparable between the groups (creatinine clearance 56.9 vs. 57.0 ml/min), and a trend of reduced proteinuria could be demonstrated after 4 years of statin treatment (0.4 vs. 0.9 g/day). The low-density lipoprotein cholesterol levels decreased as expected during treatment (3.1 vs. 3.7 mmol/l at 48 months), but the recommended target levels for patients with a high cardiovascular risk have not been reached. A trend towards lower incidences of acute rejection, chronic allograft nephropathy, and graft loss was noted in the statin-treated group. Adverse effects of statin treatment have not been observed. Treatment with pravastatin at low to average dosages does not result in improved blood pressure regulation after kidney transplantation.

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Changes of the brain electrical fields during the continuous performance test in attention-deficit hyperactivity disorder-boys depending on methylphenidate medication.

The continuous performance test (CPT) is successfully applied to evaluate attentional performance in attention-deficit hyperactivity disorder (ADHD)-children. The aim of the present study was to investigate the changes of the topographic P300-features in relation to methylphenidate-medication and to different attentional processes in primer- and distractor-conditions. Twenty-one-channel-ERPs of 17 ADHD-boys were analyzed with reference-independent methods. Four quasi stable microstates within the time frames of conventional P100, P200, P3a and P3b components were identified by means of a data-driven segmentation procedure. In segment 3 topographical assessment yielded a significant occipital and right-shift of the positive centroid, longer centroid distance and higher amplitudes in primer- than in distractor conditions. MPH increased the amplitude and distance in primer and distractor-condition, without changing the topography. In segment 4 the electric field strength of distractor-conditions collapsed, whereas the primer condition showed a strong fronto-parietally oriented potential-field. There was a tendency to higher amplitudes due to MPH-medication. These results indicate a robust neurophysiologic differentiation of cognitive processes. MPH activates an early (P3a) covert attention process indicated by increased amplitudes and centroid. No effects were seen in later processes. Based on these effects, we propose to use the amplitude- and distance-increase in microstate 3 as an indicator of MPH efficacy in ADHD-boys.

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Selective Serotonin Reuptake Inhibitors and Persistent Pulmonary Hypertension of the Newborn: An Update Meta-Analysis.

Persistent pulmonary hypertension of the newborn (PPHN) is a serious condition associated with substantial mortality and morbidity. Previous studies have suggested a possible link between maternal selective serotonin reuptake inhibitor (SSRI) use and the risk of PPHN. This study aimed to provide an up-to-date review and meta-analysis of the topic. Using the search terms [SSRI OR SSRIs OR selective serotonin reuptake inhibitors OR antidepressant OR Prozac OR fluoxetine OR Lexapro OR escitalopram] AND [pregnancy OR maternal OR newborn OR persistent pulmonary hypertension OR PPHN OR neonat* OR fet*], a preliminary search on the PubMed, Medline, EMBASE, Web of Science, and Google Scholar database yielded 7327 articles published in English between January 1, 1960 and October 1, 2017. A total of 9 cohort and case-control studies, with a total of 7,540,265 subjects were systematically reviewed. Random-effects meta-analysis of eight studies revealed a significantly increased risk of PPHN with maternal SSRI use during pregnancy, with a pooled OR of 1.516 (95% confidence interval: 1.035-1.997, p < 0.001). Overall, the absolute increase in risk of PPHN with SSRI use appears small, with an absolute risk difference of 0.619 per 1000 livebirths and a number needed to harm of 1615 women. Current evidence suggests that there were significantly greater odds of PPHN with SSRI use during pregnancy. However, the clinical significance of this association remains modest and likely outweighed by the potential benefits of treatment of perinatal depression. The risk of PPHN associated with SSRI therapy might not warrant the recommendation to withdraw antidepressant therapy, as evidence from other studies show that untreated perinatal depression presents additional adverse maternal and fetal outcomes. Given the increasing prevalence of maternal depression and consequent use of antidepressant medications, further research with robust longitudinal or randomized, controlled studies and mechanistic investigations are needed.

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Assessment of adiponectin and the risk of recurrent cardiovascular events in patients presenting with an acute coronary syndrome: observations from the Pravastatin Or atorVastatin Evaluation and Infection Trial-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22).

Adiponectin, an adipocytokine, is secreted by fatty cells and exerts a regulatory role in atherogenesis, modulating foam cell formation and cellular adhesion. In stable atherosclerosis, plasma adiponectin has been reported to be associated with both increased and decreased cardiovascular risk. Recent data have suggested a possible discordant adverse risk relationship in acute coronary syndrome (ACS). Therefore, we investigated the association between adiponectin and cardiovascular events in patients with ACS. We measured plasma adiponectin in 3,931 patients stabilized following ACS and assessed the relationship with 2-year outcome. Patients were followed for all-cause death and major cardiovascular events. Using multivariable Cox regression, we adjusted for age, sex, race, ACS type, diabetes, smoking status, triglycerides, blood pressure, body mass index, estimated glomerular filtration rate, treatment group (atorvastatin), B-type natriuretic peptide, and C-reactive protein. Adiponectin correlated negatively with age, diabetes, body mass index, and triglycerides (each, P < .001) but showed a positive relationship with the risk of death (P = .01), myocardial infarction (P = .01), and heart failure (P < .001). After adjusting for clinical risk factors, B-type natriuretic peptide, and C-reactive protein, adiponectin greater than the median (4,477 ng/mL) was independently associated with an increased risk of death or myocardial infarction (hazard ratio 1.58, 95% CI 1.10-2.28, P = .013) and congestive heart failure (hazard ratio 2.17, 95% CI 1.21-3.89, P = .010). Higher adiponectin concentrations early after ACS are independently associated with a higher risk of recurrent cardiovascular events. This finding is directionally opposite to that observed in patients at risk for atherosclerosis and reveals the need for investigation to elucidate differences in the pathobiology of adiponectin in stable versus unstable coronary artery disease.

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Effects of rosuvastatin, atorvastatin, simvastatin, and pravastatin on atherogenic dyslipidemia in patients with characteristics of the metabolic syndrome.

The metabolic syndrome (MS) is a constellation of coronary risk factors. Atherogenic dyslipidemia is an important factor in cardiovascular risk in these patients, and treatment of atherogenic dyslipidemia has been identified as an important goal of therapy in patients with MS. This post hoc analysis of data from a 6-week, randomized, open-label, parallel-group, comparative trial (Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin [STELLAR]) assessed the effects of rosuvastatin 10, 20, and 40 mg, atorvastatin 10, 20, 40, and 80 mg, simvastatin 10, 20, 40, and 80 mg, and pravastatin 10, 20, and 40 mg on plasma lipids in hypercholesterolemic patients (low-density lipoprotein cholesterol >/=160 and <250 mg/dl; triglycerides <400 mg/dl) who had >/=3 of the 5 National Cholesterol Education Program Adult Treatment Panel III criteria for MS (body mass index >30 kg/m(2) substituted for waist circumference). Of 2,268 patients, 811 met criteria for MS. Percent reductions in low-density lipoprotein cholesterol ranged from 20% in the pravastatin 10-mg group to 55% in the rosuvastatin 40-mg group. In patients with MS, triglyceride reductions were 22% to 34% with rosuvastatin, 23% to 33% with atorvastatin, 15% to 23% with simvastatin, and 12% to 15% with pravastatin. High-density lipoprotein cholesterol increased by 8% to 11% with rosuvastatin, 5% to 9% with atorvastatin, 8% to 10% with simvastatin, and 3% to 7% with pravastatin. Rosuvastatin, atorvastatin, simvastatin, and pravastatin treatment had favorable effects in hypercholesterolemic patients on the atherogenic dyslipidemia associated with MS. Rosuvastatin had the most favorable effect on the atherogenic lipid profile of MS overall.

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Omeprazole and Helicobacter pylori: temporary suppression rather than true eradication.

Twenty-four Helicobacter pylori (H. pylori)-positive patients were treated for 28 days with either 20 mg omeprazole o.m. (n = 12) or 40 mg omeprazole o.m. (n = 12). Clearance (absence of H. pylori at the end of or shortly after treatment) and eradication (absence of H. pylori 1 month after cessation of treatment) were assessed using the 14C-urea breath test. Observed clearance and eradication were: 20 mg omeprazole 3/12 and 0/12; 40 mg omeprazole 6/12 and 1/12 respectively. The effect on H. pylori is probably due to the change in gastric pH from acid to neutral, however it is insufficient to recommend the inclusion of omeprazole in regimens aimed at eradicating H. pylori.

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Analgesic efficacy and safety of tramadol enantiomers in comparison with the racemate: a randomised, double-blind study with gynaecological patients using intravenous patient-controlled analgesia.

The opioid analgesic tramadol is a racemate and consists of 50% (+)- and 50% (-)-enantiomer. This study investigated analgesic efficacy and safety of both enantiomers after intravenous (i.v.) injection in comparison with the racemate. Ninety-eight patients recovering from major gynaecological surgery under opioid-free halothane anaesthesia were treated in a randomised, double-blind study with (+)-tramadol, (-)-tramadol or the racemate. Following an individualised i.v. loading dose up to a maximum of 200 mg, patient-controlled analgesia with demand doses of 20 mg was made available for 24 h. The primary criterion was of efficacy was the decrease of pain intensity on a 5-point verbal rating scale from severe or maximum pain to mild or no pain intensity on a 5-point verbal rating scale from severe or maximum pain to mild or no pain within the first hour after the loading dose. The secondary criterion was patient satisfaction with pain relief during the 24-h observation period stated in the final interview. Patients who terminated the study prematurely were evaluated as non-responders. Of patients treated with (+)-tramadol, tramadol racemate, and (-)-tramadol, 12%, 15%, and 53% of treated patients, respectively, terminated the study prematurely because of inefficacy. Of patients treated with (+)-tramadol, racemate or (-)-tramadol 67%, 48% and 38%, respectively, were considered responders regarding the primary criterion of efficacy (P = 0.061), and 82%, 76%, or 41% with respect to the secondary criterion (P = 0.001). Assessment of laboratory screening, adverse events, vital signs and blood gas monitoring showed no serious drug-related events. Nausea and vomiting were the most frequently reported non-serious side effects and were most often seen with (+)-tramadol. Taking into account both efficacy and safety aspects, the racemate seems to be superior to either enantiomer alone.

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Pharmacokinetics and safety of oral administration of meloxicam to foals.

The pharmacokinetics, efficacy, and safety of meloxicam have been evaluated in adult horses, but not foals. Physiologic differences between neonates and adults might alter drug pharmacokinetics and therapeutic index. The pharmacokinetics of meloxicam will be different in foals compared with adult horses, and foals could be at increased risk for adverse drug effects. Twenty lightbreed foals less than 6 weeks of age at commencement of the study. Single and repeated oral dose pharmacokinetics were determined for meloxicam (0.6 mg/kg) in 10 foals. The safety of the drug was further evaluated in a 2nd group of 10 foals in a randomized blinded prospective study. Plasma concentrations after a single oral dose of meloxicam (0.6 mg/kg) and time to maximum plasma concentration were similar to adult horses. However, drug clearance was much more rapid in foals (elimination half-life 2.48 ± 0.25 hours). Administration of 0.6 mg/kg every 12 hours was well tolerated by foals for up to 3 weeks, with no evidence of drug accumulation in plasma. Adverse effects observed in adult horses at higher dose rates were not observed in foals given 1.8 mg/kg twice daily for 7 days. Meloxicam at an oral dose rate of 0.6 mg/kg every 12 hours provided plasma concentrations likely to be therapeutic. In contrast to findings for other NSAIDs, foals appeared more resilient to the adverse effects of this drug than was observed in adult horses.

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Prognostic value of cardiovascular parameters in computed tomography pulmonary angiography in patients with acute pulmonary embolism.

The value of various computed tomography parameters for prognosis and risk stratification in acute pulmonary embolism is controversial. Our objective was to evaluate the impact of specific cardiovascular computed tomography pulmonary angiography parameters on short- and long-term clinical outcomes.We analysed radiological and clinical data of 1950 patients with acute pulmonary embolism who participated in an international randomised clinical trial on anticoagulants. Parameters included right/left ventricular ratio, septal bowing, cardiothoracic ratio, diameters of pulmonary trunk and aorta, and intrahepatic/azygos vein contrast medium backflow. Associations with mortality, recurrent venous thromboembolism (VTE), hospitalisation, bleeding and adverse events were assessed over the short term (1 week and 1 month) and long term (12 months).Pulmonary trunk enlargement was the only parameter significantly associated with mortality over both the short and long term (OR 4.18 (95% CI 1.04-16.76) at 1 week to OR 2.33 (95% CI 1.36-3.97) after 1 year), as well as with recurrent VTE and hospitalisation.Most of the evaluated radiological parameters do not have strong effects on the short- or long-term outcome in patients with acute pulmonary embolism. Only an enlarged pulmonary trunk diameter carries an increased risk of mortality and recurrent VTE up to 12 months, and can be used for risk stratification.

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Predicting cardiovascular risk using conventional vs ambulatory blood pressure in older patients with systolic hypertension. Systolic Hypertension in Europe Trial Investigators.

The clinical use of ambulatory blood pressure (BP) monitoring requires further validation in prospective outcome studies. To compare the prognostic significance of conventional and ambulatory BP measurement in older patients with isolated systolic hypertension. Substudy to the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) Trial, started in October 1988 with follow up to February 1999. The conventional BP at randomization was the mean of 6 readings (2 measurements in the sitting position at 3 visits 1 month apart). The baseline ambulatory BP was recorded with a noninvasive intermittent technique. Family practices and outpatient clinics at primary and secondary referral hospitals. A total of 808 older (aged > or =60 years) patients whose untreated BP level on conventional measurement at baseline was 160 to 219 mm Hg systolic and less than 95 mm Hg diastolic. For the overall study, patients were randomized to nitrendipine (n = 415; 10-40 mg/d) with the possible addition of enalapril (5-20 mg/d) and/or hydrochlorothiazide (12.5-25.0 mg/d) or to matching placebos (n = 393). Total and cardiovascular mortality, all cardiovascular end points, fatal and nonfatal stroke, and fatal and nonfatal cardiac end points. After adjusting for sex, age, previous cardiovascular complications, smoking, and residence in western Europe, a 10-mm Hg higher conventional systolic BP at randomization was not associated with a worse prognosis, whereas in the placebo group, a 10-mm Hg higher 24-hour BP was associated with an increased relative hazard rate (HR) of most outcome measures (eg, HR, 1.23 [95% confidence interval [CI], 1.00-1.50] for total mortality and 1.34 [95% CI, 1.03-1.75] for cardiovascular mortality). In the placebo group, the nighttime systolic BP (12 AM-6 AM) more accurately predicted end points than the daytime level. Cardiovascular risk increased with a higher night-to-day ratio of systolic BP independent of the 24-hour BP (10% increase in night-to-day ratio; HR for all cardiovascular end points, 1.41; 95% CI, 1.03-1.94). At randomization, the cardiovascular risk conferred by a conventional systolic BP of 160 mm Hg was similar to that associated with a 24-hour daytime or nighttime systolic BP of 142 mm Hg (95% CI, 128-156 mm Hg), 145 mm Hg (95% CI, 126-164 mm Hg) or 132 mm Hg (95% CI, 120-145 mm Hg), respectively. In the active treatment group, systolic BP at randomization did not significantly predict cardiovascular risk, regardless of the technique of BP measurement. In untreated older patients with isolated systolic hypertension, ambulatory systolic BP was a significant predictor of cardiovascular risk over and above conventional BP.

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Naturalistic Pharmacotherapy Compliance among Pediatric Patients with Attention Deficit/Hyperactivity Disorder: a Study Based on Three-Year Nationwide Data.

We examined short- and long-term medication compliance among youth with attention-deficit hyperactivity disorder (ADHD), using data from the National Health Insurance database in Korea. Of the 5,699,202 6-14-year-old youth in 2008, we chose those with at least 1 medical claim containing an ICD-10 code for diagnosis of ADHD (F90.0) and no prescription for ADHD within the previous 365 days. We tracked the data every 6 months between 2008 and 2011, to determine treatment compliance among newly diagnosed, medicated patients. Further, we checked every 1 month of the 6 months after treatment commencement. Treatment continuity for each patient was calculated by sequentially counting the continuous prescriptions. For measuring compliance, we applied the medication possession ratio (MPR) as 0.6, 0.7, and 0.8, and the gap method as 15- and 30-days' intervals. There were 15,133 subjects; 11,934 (78.86%) were boys. Overall 6-month treatment compliance was 59.0%, 47.3%, 39.9%, 34.1%, 28.6%, and 23.1%. Monthly drop-out rates within the first 6 months were 20.6%, 6.5%, 4.7%, 3.7%, 3.0%, and 2.5%, respectively. When applying MPR more strictly or shorter gap days, treatment compliance lessened. This is the first nationwide report on 36-month treatment compliance of the whole population of 6-14-year-olds with ADHD. We found the beginning of the treatment, especially the first month, to be a critical period in pharmacotherapy. These results also suggest the importance of setting appropriate treatment adherence standards for patients with ADHD, considering the chronic course of ADHD.

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Evaluation of reproterol's effectiveness in preventing exercise-induced bronchospasm in children.

The authors have evaluated the effectiveness of the protection of a new beta 2-adrenergic compound, reproterol, against broncho-constriction induced by physical exercise in a group of individuals of paediatric age sensitive to broncho-stimulation. This study has been carried out comparing reproterol with salbutamol, using placebo as a control, following a randomized single-blind crossover trial. The provocation test has been performed following the instructions of the Italian Society of Paediatrics. The drugs have been administered in the oral liquid form at the dose of 0.28 mg/kg and 0.1 mg/kg of reproterol and salbutamol, respectively. The two substances have shown a similar preventive effectiveness in controlling exercise-induced asthma up to 2 hours from administration with reproterol having a stronger action at the beginning of the observation.

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Phase II trial of CHOP chemotherapy followed by tositumomab/iodine I-131 tositumomab for previously untreated follicular non-Hodgkin's lymphoma: five-year follow-up of Southwest Oncology Group Protocol S9911.

Advanced follicular lymphoma (FL) is incurable with conventional chemotherapy and radiotherapy, and optimal front-line management is controversial. This study was performed to determine the efficacy of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy followed by tositumomab/iodine I-131 tositumomab. From 1999 to 2000, the Southwest Oncology Group (SWOG) conducted a phase II trial (S9911) to test a novel new regimen consisting of six cycles of CHOP chemotherapy followed 4 to 8 weeks later by tositumomab/iodine I-131 tositumomab in 90 eligible patients with previously untreated, advanced-stage FL. The overall response rate was 91%, including a 69% complete remission (CR) rate. After a median follow-up time of 5.1 years, the estimated 5-year overall survival (OS) rate was 87%, and the progression-free survival (PFS) rate was 67%. The 5-year estimates of OS and PFS were each 23% better (absolute difference) than the corresponding figures for patients treated on previous SWOG protocols with CHOP alone. An analysis according to the Follicular Lymphoma International Prognostic Index showed that 21% of patients had high-risk features, 44% had intermediate-risk features, and 34% had low-risk features. High-risk patients had worse OS than lower risk patients (P = .05), but differences in PFS were not statistically significant (P = .21). Serial monitoring of the t(14;18) translocation in bone marrow by polymerase chain reaction demonstrated that 32 of 38 informative patients obtained molecular CRs, including seven patients (18%) after CHOP and 24 additional patients (63%) after tositumomab/iodine I-131 tositumomab. (The timing of conversion of one patient was unclear.) A prospective, phase III, randomized Intergroup Trial is currently underway comparing the efficacy of the promising CHOP + tositumomab/iodine I-131 tositumomab regimen with the efficacy of CHOP + rituximab.

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Chemoprevention of prostate cancer: agents and study designs.

With the completion of the Prostate Cancer Prevention Trial and the ongoing performance of several additional large-scale prostate cancer prevention trials interest in this intervention has increased. We review promising agents for prostate cancer prevention, clinical trial designs and how these agents may be used clinically. We reviewed current and completed randomized chemoprevention trials for prostate cancer as well as the most promising agents for which evidence suggests that a decreased prostate cancer risk may result from their use. Evidence suggests that lycopene, decreased dietary fat, antioxidants such as alpha-tocopherol and selenium, nonsteroidal anti-inflammatory drugs and selective estrogen receptor modulators such as toremifene and 5alpha-reductase inhibitors may prove useful for decreasing the risk of prostate cancer in a man. Ongoing studies are examining these agents in the 3 general scenarios of 1) general population studies (finasteride, alpha-tocopherol and selenium), 2) increased prostate specific antigen with negative biopsy (dutasteride) and 3) prostatic intraepithelial neoplasia (toremifene and selenium). There are many agents that may decrease the risk of prostate cancer. It requires careful study of the agents in specific populations to determine whether risk is reduced, the magnitude of the risk reduction and the spectrum of side effects associated with the agent. Physicians caring for men entering the range of age of prostate cancer risk must be aware of these preventive opportunities.

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Mycophenolate mofetil pharmacokinetics in transplant patients receiving cyclosporine or tacrolimus in combination therapy.

Mycophenolate mofetil is a highly effective immunosuppressant drug used in the prophylaxis of organ rejection in combination with cyclosporine or tacrolimus and corticosteroids. The present study is a retrospective data analysis of the routinely estimated mycophenolic acid plasma trough levels in 60 transplant patients (kidney, n = 49; lung, n = 11) receiving mycophenolate mofetil in combination with prednisone and cyclosporine (n = 45) or tacrolimus (n = 15). Coadministration of cyclosporine instead of tacrolimus resulted in a significant increase of median (range) of the ratio of dose-to-concentration 0.92 (0.11-8.33) (n=167) versus 0.38 (0.11-14.28) (n = 66); P < 0.0001. No correlation was seen between mycophenolate mofetil dose and mycophenolic acid trough concentrations. The dose-to-concentration in cyclosporine-treated patients increased significantly (P<0.0001) as the cyclosporine level increased, suggesting a possible interaction between mycophenolate mofetil and cyclosporine. No correlation was seen between dose-to-concentration and tacrolimus blood levels (P x 0.215). Further studies are necessary to investigate this issue.

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[Comparison about the efficacy and tolerability between simvastatin and bezafibrate in the treatment of hypercholesterolemia].

Simvastatin and bezafibrate actions on blood lipids and their side effects were compared in a double-blind trial involving 24 adults with severe type IIa or IIb primary hypercholesterolemia (mean plasma cholesterol = 4.35 g/l). During a 12-week period, the patients received either bezafibrate, 600 mg 3 times a day, or simvastatin, 10 or 20 mg once a day, with a doubling of the dosage at week 6 if the LDL-cholesterol level remained above 1.40 g/l. Simvastatin significantly reduced LDL-cholesterol by -39.5% (p less than 0.001), total cholesterol by 33.9% (p less than 0.005) and apoprotein B by -28% (p less than 0.001). Bezafibrate significantly reduced LDL-cholesterol (-19.8%, p less than 0.001) and total cholesterol (-17.5%, p less than 0.002), but not apoprotein B. Bezafibrate also reduced triglycerides by -26.6% and raised HDL-cholesterol by +27.6%. Simvastatin was more effective than bezafibrate in lowering LDL-cholesterol (p less than 0.002), total cholesterol (p less than 0.005) and apoprotein B (p less than 0.05). Tolerance of both drugs was considered excellent.

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No influence of pantoprazole on the pharmacokinetics of phenytoin.

Twenty-three healthy, male volunteers completed this doubleblind, randomized, placebo controlled, 2-period crossover study to assess the influence of multiple doses of pantoprazole on single-dose phenytoin pharmacokinetics. During each treatment period, the volunteers received either one 40 mg pantoprazole tablet or placebo for 7 days. In addition, a single-dose of 300 mg (3 x 100 mg capsules) phenytoin sodium was administered on day 4 of each treatment period. A 14-day wash-out period was allowed between phenytoin administrations. The results indicate that pantoprazole neither affects the rate nor the extent of absorption, nor the elimination of phenytoin.

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A combined smoking cessation intervention within a lung cancer screening trial: a pilot observational study.

The time of lung cancer screening may provide the ideal setting to discuss and initiate a smoking cessation plan that includes pharmacologic aids. No studies to date have fully investigated the potential effectiveness of such combined approach. We prospectively evaluated the biochemically verified 1-year continuous abstinence rate from smoking of 187 persistent smokers enrolled within the Multicentric Italian Lung Detection Trial (MILD), who received a pharmacologic aid to quit smoking with varenicline along with behavioral counseling. The propensity of study subjects to succeed in smoking cessation was also monitored. At 12 months, the continuous abstinence rate from smoking was achieved in 37 out of 187 patients (19.8%), with a propensity to succeed in smoking cessation for the assisted attempt equal to 1.43, as compared to an unassisted MILD patient. At the end of the third month of therapy, 48.7% of subjects showed a continuous abstinence rate, while only 33.7% of patients were abstinent from smoking at 6 months. At baseline, the subgroup of MILD participants who were originally allocated to lung tomography showed higher smoking intensity than those allocated to no screening. A combined smoking cessation intervention can be implemented with satisfactory results within a lung cancer screening program; this preliminary observation needs to be replicated in a prospective investigation. Clinicians should consider that lung cancer screening may be falsely reassuring for persistent smokers; therefore it should always be coupled with a smoking cessation program.

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Oxidative damage and major depression: the potential antioxidant action of selective serotonin re-uptake inhibitors.

There is evidence of derangement of oxidant and antioxidant defense systems in depression. The present study examined the effects of fluoxetine and citalopram, standard selective serotonin re-uptake inhibitors, on lipid peroxidation, superoxide dismutase (SOD) activity and ascorbic acid concentrations. For this, a prospective open-labeled, randomized design was utilized. Patients with major depression (n = 62) were compared with age- and sex-matched healthy volunteers (n = 40). There was a significant increase in serum SOD, serum MDA and decrease in plasma ascorbic acid levels in patients of major depression as compared to control subjects. The trend reversed significantly after treatment with fluoxetine and citalopram. Results indicate a greater reduction in oxidative stress with citalopram than fluoxetine. The Hamilton Rating Scale for Depression (HRSD) score also improved with fluoxetine and citalopram treatment. These findings indicate that major depression is associated with increased levels of serum SOD, serum MDA and decreased levels of plasma ascorbic acid. Treatment with fluoxetine and citalopram reversed these biochemical parameters. This study can be used as a predictor of drug response by fluoxetine and citalopram in major depression.

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Serum biomarkers and outcomes in patients with moderate COPD: a substudy of the randomised SUMMIT trial.

Systemic levels of C reactive protein (CRP), surfactant protein D (SPD), fibrinogen, soluble receptor of activated glycogen end-product (sRAGE) and club cell protein 16 (CC-16) have been associated with chronic obstructive pulmonary disease (COPD) outcomes. However, they require validation in different cohorts. Relate systemic levels of those proteins to forced expiratory volume in 1 s (FEV₁) decline, exacerbations, hospitalisations and mortality in COPD patients (FEV₁ of ≥50 and ≤70% predicted) and heightened cardiovascular risk in a substudy of the Study to Understand Mortality and MorbidITy trial. Participants were randomised to daily inhalations of placebo, vilanterol 25 µg (VI), fluticasone furoate 100 µg (FF) or their combination (VI 25/FF 100) and followed quarterly until 1000 deaths in the overall 16 485 participants occurred. Biomarker blood samples were available from 1673 patients. The FEV₁ decline (mL/year), COPD exacerbations, hospitalisations and death were determined. Associations between biomarker levels and outcomes were adjusted by age and gender. Systemic levels of CC-16, CRP, sRAGE, SPD and fibrinogen did not relate to baseline FEV₁, FEV₁ decline, exacerbations or hospitalisations. Fibrinogen and CRP were related to mortality over a median follow-up of 2.3 years. Only the CC-16 changed with study therapy (VI, FF and FF/VI, p<0.01) at 3 months. In COPD, systemic levels of CC-16, CRP, sRAGE, SPD and fibrinogen were not associated with FEV₁ decline, exacerbations or hospitalisations. These results cast doubts about the clinical usefulness of the systemic levels of these proteins as surrogate markers of these COPD outcomes. The study confirms that CRP and fibrinogen are associated with increased risk of death in patients with COPD. NCT01313676.

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Clonazepam versus alprazolam in the treatment of panic disorder: interim analysis of data from a prospective, double-blind, placebo-controlled trial.

The authors present interim results of a prospective, random assignment, double-blind, placebo-controlled trial conducted to determine whether clonazepam is as effective as alprazolam in reducing the frequency of panic attacks and whether both agents are superior to placebo. Analysis on 44 of 60 randomized subjects showed no statistically significant differences between the clonazepam and alprazolam groups on the following clinically meaningful outcome measures: total number of panic attacks and percent of time subjects experienced anticipatory anxiety, extent of phobic avoidance, and fear. Statistically significant differences did exist among the drug and placebo groups on these measures. The authors conclude that this interim analysis of the data supports the inclusion of clonazepam in the treatment of panic disorder.

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Effect of high-dose continuous albuterol nebulization on clinical variables in children with status asthmaticus.

Continuous albuterol nebulization is generally administered at 2.5-20 mg/hr at most centers. We examined the effect of high-dose (75 or 150 mg/hr) albuterol on clinical variables in children with status asthmaticus. Retrospective analysis of inpatient medical records and prospectively collected computerized PICU respiratory therapy database. Twenty-five-bed multidisciplinary PICU in a tertiary care children's hospital. Children admitted to the PICU between January 2006 and December 2007 with status asthmaticus receiving high-dose continuous albuterol nebulization. (Those with cerebral palsy, cardiac pathology, and ventilator dependence were excluded.) : Chart review for PICU length of stay, albuterol dose, duration of nebulization, occurrence of chest pain, vomiting, tremors, hypokalemia (serum potassium < 3.0 mEq/L), and cardiac arrhythmia. Maximal heart rate, lowest diastolic blood pressure, and mean arterial pressure were compared to the variables at initiation of therapy and at hospital discharge. Forty-two patients (22 boys and 20 girls) received high-dose continuous albuterol nebulization. Twenty-three received 75 mg/hr and 19 received 150 mg/hr (3.7 mg/kg/hr [interquartile range, 2.4-5.8 mg/kg/hr]) for a duration of 22.3 hours (interquartile range, 6.6-31.7 hr). Heart rate increased and diastolic blood pressure and mean arterial pressure were significantly lower during nebulization compared to initiation of therapy or at hospital discharge (p < 0.05). No patient required fluid resuscitation or inotropic support, and one had self-limited premature ventricular contractions. Hypokalemia occurred in five of 33 patients who had serum electrolytes measured but did not require supplementation. One patient required endotracheal intubation after initiation of nebulization, and seven patients (16.7%) received noninvasive ventilation. PICU length of stay was 2.3 ± 1.7 days; there were no deaths. High-dose continuous albuterol nebulization is associated with a low rate of subsequent mechanical ventilation and fairly short PICU length of stay without significant toxicity. Prospective studies comparing conventional and high-dose albuterol nebulization are needed to determine the optimum dose providing maximum efficacy with the least adverse effects.

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Pulmonary function and sputum production in patients with cystic fibrosis: a pilot study comparing the PercussiveTech HF device and standard chest physiotherapy.

To compare the PercussiveTech HF (PTHF) device (Vortran Medical Technology 1; Sacramento, CA) to standard manual chest physiotherapy (CPT) with respect to acute changes in pulmonary function, sputum production, and pulse oximetry in patients with cystic fibrosis (CF). Randomized crossover. University-affiliated, community-based CF center. Ten clinically stable patients with CF (age range, 10 to 21 years; mean age, 15.3 years) with Shwachman scores from 55 to 95 (mean 75). Two treatment regimens were used: 2.5 mg of albuterol delivered via updraft nebulizer followed by standard CPT, and 2.5 mg of albuterol delivered via the PTHF device without CPT. Outcome measures included pulmonary function test (PFT) results 4 h after treatment and quantitative sputum production during the 4 h after treatment. Pulse oximetry was performed during treatment. A patient satisfaction questionnaire was administered at the end of the study. No PFT parameters were significantly changed 4 h after CPT or PTHF, although there was a trend to decreasing residual volume after both treatments. There was a trend for more sputum production after PTHF compared to CPT, but this did not reach statistical significance. There were no episodes of hemoglobin-oxygen desaturation during or after either treatment. One patient had minor hemoptysis after CPT. No adverse effects occurred after PTHF. Eight patients found the PTHF device easy to use, and six patients would prefer the PTHF device to CPT. The PTHF device appears to be a safe and effective method of airway clearance in CF patients in this small pilot study.

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Impact of ticagrelor and aspirin versus clopidogrel and aspirin in symptomatic patients with peripheral arterial disease: Thrombus burden assessed by optical coherence tomography.

To compare OCT identified white thrombus decline, neointimal hyperplasia and clinical outcomes of patients treated with ticagrelor plus aspirin with those patients treated with clopidogrel plus aspirin after peripheral interventions. Ticagrelor is a potent platelet inhibitor. In patients with coronary artery disease, ticagrelor and aspirin demonstrated reduced rates of stent thrombosis, compared to aspirin and clopidogrel. The clinical importance of potent antiplatelet inhibition after peripheral endovascular interventions is unknown. We enrolled 18 patients with superficial femoral artery disease and the presence of OCT-detected clot post-stent placement. Patients were randomized to 75 mg clopidogrel once daily for 1 month vs. 90 mg ticagrelor twice daily for 6 months, both in addition to 81 mg aspirin for 6 months. Clot volumes, ankle-brachial index (ABI), 6-minute walk test, and Rutherford classification were measured at baseline and 6-month follow-up. Neointimal hyperplasia and neovascularization were calculated at 6-month follow-up. N = 11 patients were enrolled in the clopidogrel group and N = 7 in the ticagrelor group. There was a significantly greater decrease in white thrombus in the ticagrelor group (median volume/stent length (0.067 vs 0.014 mm³/mm, p = 0.05)). No differences were found in % neointima (0.412 vs 0.536 mm³/mm, p = 0.44) and neovascularization (28 vs 44, p = 0.16). ABI and Rutherford classification were improved significantly after 6 months in the clopidogrel group, with no difference between groups at 6 months in ABI or Rutherford. In symptomatic patients with PAD, ticagrelor showed significant improvement relative to clopidogrel with respect to white thrombus burden decline.

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Helicobacter pylori eradication with proton pump inhibitor-based triple therapies and re-treatment with ranitidine bismuth citrate-based triple therapy.

It has been suggested that short-term triple therapy comprising a proton pump inhibitor, plus clarithromycin and amoxycillin be used as first choice in treating H. pylori infection, while eradication failure patients should be further treated with a quadruple therapy. Nevertheless, conflicting results have been reported using these treatment regimens in different countries. A total of 278 patients with H. pylori infection were randomised to receive one-week triple therapy, comprising clarithromycin 500 mg b.d., amoxycillin 1 g b.d., and either omeprazole 20 mg b.d. (OAC; 90 patients), or pantoprazole 40 mg b.d. (PAC; 95 patients), or lansoprazole 30 mg b.d. (LAC; 93 patients). H. pylori infection at entry, and eradication 4-6 weeks after therapy had ended, were assessed by rapid urease test and histology on biopsies from the antrum and the corpus. When eradication did not occur, patients were given a 2-week treatment comprising ranitidine bismuth citrate 400 mg b.d., tetracycline 500 mg t.d.s. and tinidazole 500 mg b.d. (RBTT). Eradication in these patients was assessed 4-6 weeks after conclusion of treatment by a further endoscopy. Six patients were lost to the follow-up. At the end of the first course of treatment, the overall H. pylori eradication rate was 78% (95% CI: 73-83) and 79% (95% CI: 75-84) at 'intention-to-treat' (ITT) and 'per protocol' (PP) analysis, respectively, without any statistically significant difference between treatment regimens, although a trend for better results with the omeprazole combination was observed. Moreover, H. pylori eradication was achieved in 82% (95% CI: 75-97) (ITT) and 86% (95% CI: 69-94) (PP) of 38 patients re-treated with RBTT regimen. Our data found that this short-term triple therapy is not a satisfactory treatment (< 80% eradication rate) for H. pylori infection. The 2-week triple therapy used as re-treatment in eradication failure patients yielded more promising results.

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Assessment and treatment of mental fatigue after a traumatic brain injury.

Mental fatigue is a frequently occurring symptom after mild, moderate or severe traumatic brain injury (TBI). Such mental fatigue may become a long-lasting problem, irrespective of severity and even after recovery from other neurological or psychiatric symptoms. Two characteristics of this mental fatigue are that patients easily become exhausted and there is generally a long recovery time. There is a need to increase knowledge and awareness of mental fatigue as it interferes considerably with work, studies, and social activities. Assessment is difficult and few treatment studies have been carried out. For the purposes of assessment, the development of the Mental Fatigue Scale is described here, and we also summarise the few treatment studies found for fatigue after TBI. Symptom alleviation is reported through Mindfulness-Based Stress Reduction (MBSR), light therapy and for the psychostimulant methylphenidate and the dopamine stabiliser (-)-OSU6162. However, more knowledge of the origin of mental fatigue and its underlying mechanisms is needed for development of more efficient therapeutic methods. Prospective randomised trials focusing on long-term outcomes are warranted and should include both pharmacological and non-pharmacological treatments.

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Gemcitabine, vinorelbine and prednisone for refractory or relapsed aggressive lymphoma, results of a phase II single center study.

The optimum therapy for patients with relapsed or refractory aggressive non-Hodgkin's lymphomas (NHL) not qualifying for platinum-based and/or high-dose chemotherapy is not known. We conducted a prospective phase II study evaluating a regimen consisting of gemcitabine (1 g/m2, days 1 and 8), vinorelbine (30 mg/m2, days 1 and 8) and prednisone (100 mg/day, days 1-8) (GVP) given every 21 days. Fifteen patients with a median age of 68 years and a median of three previous therapies were enrolled. Diagnoses included B lymphoblastic (n=1), diffuse large B cell (n=10), anaplastic large T cell (n=2) and peripheral T-cell NHL (n=2). The median international prognostic index score was 3 (six patients with a score of 4 or 5). Five patients achieved a complete remission and three patients a partial remission. The median overall survival was 13.8 months, and the median time to next treatment was 4.4 months. Haematological toxicities of World Health Organisation grades 3/4 were leucopenia in 58%, thrombocytopenia in 33% and anaemia in 17% of all courses. Three patients had grade 3 infections. There was no treatment-related mortality. GVP shows substantial activity in poor prognosis relapsed or refractory aggressive lymphomas and is generally well tolerated, but haematological toxicity is dose limiting.

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The hyperactive child syndrome: peripheral sympathetic nervous system function and the effect of d-amphetamine.

We evaluated sympathetic nervous system function in medication-free hyperactive children by measuring plasma levels of norepinephrine (NE) and dopamine-beta-hydroxylase and then comparing the effects of two therapeutics doses of d-amphetamine to placebo in these patients. The medication-free hyperactive patients and controls had similar plasma NE levels and blood pressures while recumbent, and a similar increase in NE on standing, but the patients had a larger pressor response on standing. In the hyperactive patients d-amphetamine significantly increased blood pressure, pulse rate, and NE levels. The change in NE levels correlated with the change in amphetamine levels. The medication-free patients, when more anxious, had higher plasma NE levels.

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Making moves: Transitioning R-EPOCH to the ambulatory setting.

Ambulatory administration of chemotherapy provides benefit to patients and institutions alike. We hypothesized that transitioning rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (R-EPOCH) from an inpatient to ambulatory setting would reduce inpatient bed days and overall healthcare costs. The purpose of this effort was to create a guideline that would transition R-EPOCH to the ambulatory setting. To assess institutional benefit, we assessed inpatient bed days saved and financial impact. A single center, retrospective analysis of inpatient R-EPOCH administration from January 2013 to December 2015 defined the need for medication use guidelines for ambulatory R-EPOCH administration. While this guideline targeted a reduction in inpatient bed days, it also created desired staff-and-patient education on R-EPOCH. Multidisciplinary collaboration enabled this comprehensive approach to outpatient chemotherapy administration. The 42 patients included received 147 cycles of R-EPOCH. Administration was primarily inpatient, amounting to 107 cycles and 799 inpatient days. Concurrently, 40 cycles of R-EPOCH were administered to 11 patients in the ambulatory setting. Only two patients received all cycles as outpatient; the other nine patients received chemotherapy in both settings. Financial analysis showed a 53% reduction in drug acquisition cost and 30% reduction in direct costs with ambulatory R-EPOCH administration. Based on our projection, after guideline implementation, 12 patients will be eligible for ambulatory R-EPOCH annually, resulting in a savings of 360 bed days and approximately $650,000 per year. Transitioning R-EPOCH is a viable option to significantly decrease inpatient bed days and overall healthcare costs. Multidisciplinary collaboration is vital to successfully transitioning regimens to the ambulatory setting and to establishing consistent support for ambulatory administration.

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Admissions for hepatitis B reactivation in patients receiving immunosuppressive therapy remain unchanged from 1999 to 2014.

Reactivation of hepatitis B virus (HBV) replication in patients with chronic or past HBV infection receiving immunosuppressive therapy (IST) can be prevented through HBV screening and prophylactic antiviral therapy. We aimed to determine the occurrence of severe HBV reactivation secondary to IST in the era of HBV nucleos/tide analogs, the implicated IST, and outcomes. We conducted a retrospective chart review of adult patients who were HBsAg+ and HBV DNA+ and had received IST within 90 days of admission to our hospital. Of 1446 patients with HBV diagnosis code admitted from 1999 to 2014, 17 had HBV reactivation, 8 of whom were admitted after 2009. Nine patients had hematologic conditions, three solid organ transplants, one hepatocellular carcinoma, and four other nonmalignant diseases. Implicated IST included chemotherapy, prednisone, antirejection therapies, budesonide, and a JAK-2 inhibitor. Three patients were screened for HBV prior to IST, but none was given antiviral prophylaxis. Six patients were initially admitted to other facilities, only two were tested for HBV, and one was started on antiviral therapy prior to transfer. At admission to our hospital, all 17 were HBsAg+ and HBV DNA+. Despite antiviral therapy, five patients decompensated, three died, and two had a liver transplant. Severe HBV reactivation requiring hospital admission continues to occur because HBV screening was not performed and a prophylactic antiviral not given to those who tested positive. HBV reactivation can occur in a variety of clinical settings and in association with drugs not considered to be highly immunosuppressive.

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Intraarticular tramadol plus pericapsular incisional bupivacaine provides better analgesia than intraarticular plus pericapsular incisional bupivacaine after outpatient arthroscopic partial meniscectomy.

Postoperative analgesic effects of intraarticular tramadol plus periarticular bupivacaine, and intraarticular plus periarticular bupivacaine injections after day-case arthroscopic partial meniscectomy were compared. Seventy-four ASA I/II patients undergoing arthroscopic partial meniscectomy, performed by a single surgeon under general anesthesia were assigned in a randomized, double-blinded manner into two groups: Group TB (n = 41) received intraarticular 100 mg of tramadol in 20 ml normal saline and periarticular incisional injection of 10 ml bupivacaine 0.5%. Group BB (n = 33) received intraarticular 20 ml 0.25% and periarticular incisional 10 ml 0.5% bupivacaine injections. The injections were performed immediately after the portal closures. Pain was assessed with visual analog scale (VAS) at 0, 15, 30 min and at 1, 2, 4 h at rest and active 90 degrees knee flexion by a blinded observer. The first additional analgesic requirement time was recorded. The patients were discharged the same day with a prescription for paracetamol as required, up to six tablets a day and questioned for analgesic use and pain score at 24 h. VAS scores at rest at 15, 30 min and at movement at 0, 15, 30 min were lower in group TB (P < 0.05). First time requiring additional analgesia was lower in group TB (17.1 +/- 21.9, 33.8 +/- 26.6) (P < 0.05) and total paracetamol dose at the end of 24 h was 1.2 +/- 1.5 g in group BB and 0.9 +/- 1.3 g in group TB (P < 0.05). Intraarticular tramadol plus periarticular bupivacaine combination provides better pain relief and less analgesic requirement following arthroscopic outpatient partial meniscectomy surgery.

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Variability of diuresis renography interpretation due to method of post-diuretic renal pelvic clearance half-time determination.

We assessed variability in the interpretation of diuresis renography that may result from using different methods of clearance half-time determination. We reviewed 152 diuresis renography studies performed at diagnosis or during followup of 53 children enrolled in a prospective study assessing the natural history of unilateral neonatal hydronephrosis. Studies were classified as nonobstructive, indeterminate or obstructive using 4 methods of half-time determination. Intermethod correlation and agreement were evaluated. We compared the proportion of nonobstructive, indeterminate and obstructive classifications by each method, and the interpretation of individual studies based on each method. Among methods we noted a high degree of correlation and fair to excellent agreement (Spearman rho = 0.86 to 0.92 and kappa = 0.57 to 0.86, respectively). However, in 27.8% of intermethod comparisons the proportion of studies classified as nonobstructive, indeterminate and obstructive differed significantly (p <0.05). The classification of pelvicaliceal drainage varied by method for all but the most severely dilated systems. In individual studies classification by 1 method was discordant with classification by another in 19% of comparisons. Of the discordant interpretations 97.7% involved nonobstructive versus indeterminate or indeterminate versus obstructive classifications. Variability in classifying drainage patterns based on half-time requires that practitioners be circumspect when applying this parameter for managing asymptomatic hydronephrosis. It also necessitates the description of quantitative methodology in published series of this important clinical problem.

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