Miracle-dz/UniFAR-FTUs huggingface dataset:
Follow‐up of Prostatectomy versus Observation for Early Prostate Cancer

BACKGROUND We previously found no significant differences in mortality between men who underwent surgery for localized prostate cancer and those who were treated with observation only. Uncertainty persists regarding nonfatal health outcomes and long‐term mortality. METHODS From November 1994 through January 2002, we randomly assigned 731 men with localized prostate cancer to radical prostatectomy or observation. We extended follow‐up through August 2014 for our primary outcome, all‐cause mortality, and the main secondary outcome, prostate‐cancer mortality. We describe disease progression, treatments received, and patient‐reported outcomes through January 2010 (original follow‐up). RESULTS During 19.5 years of follow‐up (median, 12.7 years), death occurred in 223 of 364 men (61.3%) assigned to surgery and in 245 of 367 (66.8%) assigned to observation (absolute difference in risk, 5.5 percentage points; 95% confidence interval [CI], ‐1.5 to 12.4; hazard ratio, 0.84; 95% CI, 0.70 to 1.01; P=0.06). Death attributed to prostate cancer or treatment occurred in 27 men (7.4%) assigned to surgery and in 42 men (11.4%) assigned to observation (absolute difference in risk, 4.0 percentage points; 95% CI, ‐0.2 to 8.3; hazard ratio, 0.63; 95% CI, 0.39 to 1.02; P=0.06). Surgery may have been associated with lower all‐cause mortality than observation among men with intermediate‐risk disease (absolute difference, 14.5 percentage points; 95% CI, 2.8 to 25.6) but not among those with low‐risk disease (absolute difference, 0.7 percentage points; 95% CI, ‐10.5 to 11.8) or high‐risk disease (absolute difference, 2.3 percentage points; 95% CI, ‐11.5 to 16.1) (P=0.08 for interaction). Treatment for disease progression was less frequent with surgery than with observation (absolute difference, 26.2 percentage points; 95% CI, 19.0 to 32.9); treatment was primarily for asymptomatic, local, or biochemical (prostate‐specific antigen) progression. Urinary incontinence and erectile and sexual dysfunction were each greater with surgery than with observation through 10 years. Disease‐related or treatment‐related limitations in activities of daily living were greater with surgery than with observation through 2 years. CONCLUSIONS After nearly 20 years of follow‐up among men with localized prostate cancer, surgery was not associated with significantly lower all‐cause or prostate‐cancer mortality than observation. Surgery was associated with a higher frequency of adverse events than observation but a lower frequency of treatment for disease progression, mostly for asymptomatic, local, or biochemical progression. (Funded by the Department of Veterans Affairs and others; PIVOT ClinicalTrials.gov number, NCT00007644.)
Tibial plateau angles with and without cranial cruciate ligament rupture

Summary The tibial plateau angles (TPA) of dogs with and without cranial cruciate ligament (CrCL) injuries were evaluated and further compared to the TPAs of dogs from a previous population and of wolves. Similar TPA measurements were found in all groups, suggesting that any possible changes in breeding practises, breed preferences, nutrition or other factors have not significantly influenced the TPA over time. Moreover, a difference was not found in the TPA between any group and the group affected with CrCL injury, suggesting that the TPA is not a clinically relevant predisposing factor in the development of canine CrCL rupture.
Surgical or Transcatheter Aortic‐Valve Replacement in Intermediate‐Risk Patients

Background Although transcatheter aortic‐valve replacement (TAVR) is an accepted alternative to surgery in patients with severe aortic stenosis who are at high surgical risk, less is known about comparative outcomes among patients with aortic stenosis who are at intermediate surgical risk. Methods We evaluated the clinical outcomes in intermediate‐risk patients with severe, symptomatic aortic stenosis in a randomized trial comparing TAVR (performed with the use of a self‐expanding prosthesis) with surgical aortic‐valve replacement. The primary end point was a composite of death from any cause or disabling stroke at 24 months in patients undergoing attempted aortic‐valve replacement. We used Bayesian analytical methods (with a margin of 0.07) to evaluate the noninferiority of TAVR as compared with surgical valve replacement. Results A total of 1746 patients underwent randomization at 87 centers. Of these patients, 1660 underwent an attempted TAVR or surgical procedure. The mean (±SD) age of the patients was 79.8±6.2 years, and all were at intermediate risk for surgery (Society of Thoracic Surgeons Predicted Risk of Mortality, 4.5±1.6%). At 24 months, the estimated incidence of the primary end point was 12.6% in the TAVR group and 14.0% in the surgery group (95% credible interval [Bayesian analysis] for difference, ‐5.2 to 2.3%; posterior probability of noninferiority, >0.999). Surgery was associated with higher rates of acute kidney injury, atrial fibrillation, and transfusion requirements, whereas TAVR had higher rates of residual aortic regurgitation and need for pacemaker implantation. TAVR resulted in lower mean gradients and larger aortic‐valve areas than surgery. Structural valve deterioration at 24 months did not occur in either group. Conclusions TAVR was a noninferior alternative to surgery in patients with severe aortic stenosis at intermediate surgical risk, with a different pattern of adverse events associated with each procedure. (Funded by Medtronic; SURTAVI ClinicalTrials.gov number, NCT01586910.)
Obesity and health in Europeans age 50 and above

The authors use a unique cross-country data set covering nearly 22,000 elderly individuals (age 50+) from 10 European Countries. Cross-country differences in the prevalence of obesity in older Europeans are substantial and exceed sociodemographic differentials in obesity. Obesity is strongly associated with major health risk factors, yet cross-country differences exist in how obesity is related to depression, heart disease and high cholesterol levels. Large heterogeneity in obesity across European countries should be investigated further to identify areas for effective public policy. (This abstract was borrowed from another version of this item.)
Glecaprevir–Pibrentasvir for 8 or 12 Weeks in HCV Genotype 1 or 3 Infection

BACKGROUND Glecaprevir and pibrentasvir are direct‐acting antiviral agents with pangenotypic activity and a high barrier to resistance. We evaluated the efficacy and safety of 8‐week and 12‐week courses of treatment with 300 mg of glecaprevir plus 120 mg of pibrentasvir in patients without cirrhosis who had hepatitis C virus (HCV) genotype 1 or 3 infection. METHODS We conducted two phase 3, randomized, open‐label, multicenter trials. Patients with genotype 1 infection were randomly assigned in a 1:1 ratio to receive once‐daily glecaprevir–pibrentasvir for either 8 or 12 weeks. Patients with genotype 3 infection were randomly assigned in a 2:1 ratio to receive 12 weeks of treatment with either glecaprevir–pibrentasvir or sofosbuvir–daclatasvir. Additional patients with genotype 3 infection were subsequently enrolled and nonrandomly assigned to receive 8 weeks of treatment with glecaprevir–pibrentasvir. The primary end point was the rate of sustained virologic response 12 weeks after the end of treatment. RESULTS In total, 1208 patients were treated. The rate of sustained virologic response at 12 weeks among genotype 1–infected patients was 99.1% (95% confidence interval [CI], 98 to 100) in the 8‐week group and 99.7% (95% CI, 99 to 100) in the 12‐week group. Genotype 3–infected patients who were treated for 12 weeks had a rate of sustained virologic response at 12 weeks of 95% (95% CI, 93 to 98; 222 of 233 patients) with glecaprevir–pibrentasvir and 97% (95% CI, 93 to 99.9; 111 of 115) with sofosbuvir–daclatasvir; 8 weeks of treatment with glecaprevir–pibrentasvir yielded a rate of 95% (95% CI, 91 to 98; 149 of 157 patients). Adverse events led to discontinuation of treatment in no more than 1% of patients in any treatment group. CONCLUSIONS Once‐daily treatment with glecaprevir–pibrentasvir for either 8 weeks or 12 weeks achieved high rates of sustained virologic response among patients with HCV genotype 1 or 3 infection who did not have cirrhosis. (Funded by AbbVie; ENDURANCE‐1 and ENDURANCE‐3 ClinicalTrials.gov numbers, NCT02604017 and NCT02640157.)
Clinical implications of QRS duration in patients hospitalized with worsening heart failure and reduced left ventricular ejection fraction.

CONTEXT Hospitalization for heart failure is associated with high postdischarge mortality and morbidity. The predictive value of the QRS duration during admission for heart failure has not been well studied. OBJECTIVE To investigate the predictive value of the QRS duration in patients hospitalized for heart failure with reduced left ventricular ejection fraction (LVEF). DESIGN, SETTING, AND PARTICIPANTS Retrospective, post hoc analysis from the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST), an event-driven, randomized, double-blind, placebo-controlled study in patients hospitalized for heart failure and having an LVEF of 40% or less. A total of 4133 patients were enrolled at 359 North American, South American, and European sites between October 7, 2003, and February 3, 2006. After excluding 1029 patients with a pacemaker, implantable cardioverter-defibrillator, or both at enrollment and 142 patients without a reported baseline QRS duration, 2962 patients were included in the analysis: 1641 had a normal QRS duration (< 120 ms) and 1321 had a prolonged QRS duration (> or = 120 ms). MAIN OUTCOME MEASURES Dual primary end points were all-cause mortality and the composite of cardiovascular death or hospitalization for heart failure. RESULTS During a median follow-up of 9.9 months, all-cause mortality was 18.7% for patients with a normal baseline QRS duration and 28.1% for patients with a prolonged baseline QRS duration (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.38-1.87). The composite of cardiovascular death or hospitalization for heart failure was 32.4% for patients with a baseline QRS duration less than 120 ms and 41.6% for patients with a baseline QRS duration of 120 ms or greater (HR, 1.40; 95% CI, 1.24-1.58). The increased risk associated with prolonged QRS duration was confirmed after adjusting for multiple variables for all-cause mortality (HR, 1.24; 95% CI, 1.02-1.50) and the composite of cardiovascular death or hospitalization for heart failure (HR, 1.28; 95% CI, 1.10-1.49). Only 105 patients (3.6%) who presented with a prolonged baseline QRS duration had a normal QRS duration on their last inpatient electrocardiogram. CONCLUSION A prolonged QRS duration appears common in patients with reduced LVEF who are hospitalized for heart failure and is an independent predictor of high postdischarge morbidity and mortality.
rTMS over human motor cortex can modulate tremor during movement

Abnormally large tremor during movement is a symptom of many movement disorders and significantly impairs activities of daily living. The aim of this study was to investigate whether repetitive magnetic brain stimulation (rTMS) can reduce tremor size during human movement. We hypothesised that inhibitory rTMS over motor cortex would reduce tremor size during subsequent movement. The study involved 26 healthy young adults (21 ± 2 years) and began with application of single TMS stimuli to measure baseline corticospinal excitability. The response to stimulation was recorded in hand muscles with electromyography. Subjects then performed a 3‐min task to measure baseline tremor during movement. This involved matching index finger position with a moving target on a computer screen. Tremor was recorded with an accelerometer on the fingernail. Finger acceleration was analysed with fast‐Fourier transform to quantify tremor in the physiological range (7.8–12.2 Hz). Subjects then received 10 min of real (n = 13) or sham (n = 13) inhibitory rTMS. Tremor and corticospinal excitability were then remeasured. Real rTMS significantly decreased corticospinal excitability by ~30% (P = 0.022) and increased tremor size during movement by ~120% (P = 0.047) relative to sham rTMS. However, the direction of tremor change was opposite to that hypothesised for inhibitory rTMS. The results suggest that rTMS over human motor cortex can modulate action tremor and the level of corticospinal excitability may be important for setting the amplitude of action tremor in healthy young adults.
Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct

BACKGROUND The effect of endovascular thrombectomy that is performed more than 6 hours after the onset of ischemic stroke is uncertain. Patients with a clinical deficit that is disproportionately severe relative to the infarct volume may benefit from late thrombectomy. METHODS We enrolled patients with occlusion of the intracranial internal carotid artery or proximal middle cerebral artery who had last been known to be well 6 to 24 hours earlier and who had a mismatch between the severity of the clinical deficit and the infarct volume, with mismatch criteria defined according to age (<80 years or ≥80 years). Patients were randomly assigned to thrombectomy plus standard care (the thrombectomy group) or to standard care alone (the control group). The coprimary end points were the mean score for disability on the utility‐weighted modified Rankin scale (which ranges from 0 [death] to 10 [no symptoms or disability]) and the rate of functional independence (a score of 0, 1, or 2 on the modified Rankin scale, which ranges from 0 to 6, with higher scores indicating more severe disability) at 90 days. RESULTS A total of 206 patients were enrolled; 107 were assigned to the thrombectomy group and 99 to the control group. At 31 months, enrollment in the trial was stopped because of the results of a prespecified interim analysis. The mean score on the utility‐weighted modified Rankin scale at 90 days was 5.5 in the thrombectomy group as compared with 3.4 in the control group (adjusted difference [Bayesian analysis], 2.0 points; 95% credible interval, 1.1 to 3.0; posterior probability of superiority, >0.999), and the rate of functional independence at 90 days was 49% in the thrombectomy group as compared with 13% in the control group (adjusted difference, 33 percentage points; 95% credible interval, 24 to 44; posterior probability of superiority, >0.999). The rate of symptomatic intracranial hemorrhage did not differ significantly between the two groups (6% in the thrombectomy group and 3% in the control group, P=0.50), nor did 90‐day mortality (19% and 18%, respectively; P=1.00). CONCLUSIONS Among patients with acute stroke who had last been known to be well 6 to 24 hours earlier and who had a mismatch between clinical deficit and infarct, outcomes for disability at 90 days were better with thrombectomy plus standard care than with standard care alone. (Funded by Stryker Neurovascular; DAWN ClinicalTrials.gov number, NCT02142283.)
Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation

BACKGROUND Olaparib is an oral poly(adenosine diphosphate–ribose) polymerase inhibitor that has promising antitumor activity in patients with metastatic breast cancer and a germline BRCA mutation. METHODS We conducted a randomized, open‐label, phase 3 trial in which olaparib monotherapy was compared with standard therapy in patients with a germline BRCA mutation and human epidermal growth factor receptor type 2 (HER2)–negative metastatic breast cancer who had received no more than two previous chemotherapy regimens for metastatic disease. Patients were randomly assigned, in a 2:1 ratio, to receive olaparib tablets (300 mg twice daily) or standard therapy with single‐agent chemotherapy of the physician's choice (capecitabine, eribulin, or vinorelbine in 21‐day cycles). The primary end point was progression‐free survival, which was assessed by blinded independent central review and was analyzed on an intention‐to‐treat basis. RESULTS Of the 302 patients who underwent randomization, 205 were assigned to receive olaparib and 97 were assigned to receive standard therapy. Median progression‐free survival was significantly longer in the olaparib group than in the standard‐therapy group (7.0 months vs. 4.2 months; hazard ratio for disease progression or death, 0.58; 95% confidence interval, 0.43 to 0.80; P<0.001). The response rate was 59.9% in the olaparib group and 28.8% in the standard‐therapy group. The rate of grade 3 or higher adverse events was 36.6% in the olaparib group and 50.5% in the standard‐therapy group, and the rate of treatment discontinuation due to toxic effects was 4.9% and 7.7%, respectively. CONCLUSIONS Among patients with HER2‐negative metastatic breast cancer and a germline BRCA mutation, olaparib monotherapy provided a significant benefit over standard therapy; median progression‐free survival was 2.8 months longer and the risk of disease progression or death was 42% lower with olaparib monotherapy than with standard therapy. (Funded by AstraZeneca; OlympiAD ClinicalTrials.gov number, NCT02000622.)
Idarucizumab for Dabigatran Reversal — Full Cohort Analysis

Background Idarucizumab, a monoclonal antibody fragment, was developed to reverse the anticoagulant effect of dabigatran. Methods We performed a multicenter, prospective, open‐label study to determine whether 5 g of intravenous idarucizumab would be able to reverse the anticoagulant effect of dabigatran in patients who had uncontrolled bleeding (group A) or were about to undergo an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the diluted thrombin time or ecarin clotting time. Secondary end points included the restoration of hemostasis and safety measures. Results A total of 503 patients were enrolled: 301 in group A, and 202 in group B. The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100 to 100), on the basis of either the diluted thrombin time or the ecarin clotting time. In group A, 137 patients (45.5%) presented with gastrointestinal bleeding and 98 (32.6%) presented with intracranial hemorrhage; among the patients who could be assessed, the median time to the cessation of bleeding was 2.5 hours. In group B, the median time to the initiation of the intended procedure was 1.6 hours; periprocedural hemostasis was assessed as normal in 93.4% of the patients, mildly abnormal in 5.1%, and moderately abnormal in 1.5%. At 90 days, thrombotic events had occurred in 6.3% of the patients in group A and in 7.4% in group B, and the mortality rate was 18.8% and 18.9%, respectively. There were no serious adverse safety signals. Conclusions In emergency situations, idarucizumab rapidly, durably, and safely reversed the anticoagulant effect of dabigatran. (Funded by Boehringer Ingelheim; RE‐VERSE AD ClinicalTrials.gov number, NCT02104947.)
Axicabtagene Ciloleucel CAR T‐Cell Therapy in Refractory Large B‐Cell Lymphoma

Background In a phase 1 trial, axicabtagene ciloleucel (axi‐cel), an autologous anti‐CD19 chimeric antigen receptor (CAR) T‐cell therapy, showed efficacy in patients with refractory large B‐cell lymphoma after the failure of conventional therapy. Methods In this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B‐cell lymphoma, primary mediastinal B‐cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×106 anti‐CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low‐dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments. Results Among the 111 patients who were enrolled, axi‐cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%. With a median follow‐up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T‐cell levels in blood were associated with response. Conclusions In this multicenter study, patients with refractory large B‐cell lymphoma who received CAR T‐cell therapy with axi‐cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program; ZUMA‐1 ClinicalTrials.gov number, NCT02348216.)
Effects of Sotagliflozin Added to Insulin in Patients with Type 1 Diabetes

BACKGROUND In most patients with type 1 diabetes, adequate glycemic control is not achieved with insulin therapy alone. We evaluated the safety and efficacy of sotagliflozin, an oral inhibitor of sodium–glucose cotransporters 1 and 2, in combination with insulin treatment in patients with type 1 diabetes. METHODS In this phase 3, double‐blind trial, which was conducted at 133 centers worldwide, we randomly assigned 1402 patients with type 1 diabetes who were receiving treatment with any insulin therapy (pump or injections) to receive sotagliflozin (400 mg per day) or placebo for 24 weeks. The primary end point was a glycated hemoglobin level lower than 7.0% at week 24, with no episodes of severe hypoglycemia or diabetic ketoacidosis after randomization. Secondary end points included the change from baseline in glycated hemoglobin level, weight, systolic blood pressure, and mean daily bolus dose of insulin. RESULTS A significantly larger proportion of patients in the sotagliflozin group than in the placebo group achieved the primary end point (200 of 699 patients [28.6%] vs. 107 of 703 [15.2%], P<0.001). The least‐squares mean change from baseline was significantly greater in the sotagliflozin group than in the placebo group for glycated hemoglobin (difference, ‐0.46 percentage points), weight (‐2.98 kg), systolic blood pressure (‐3.5 mm Hg), and mean daily bolus dose of insulin (‐2.8 units per day) (P≤0.002 for all comparisons). The rate of severe hypoglycemia was similar in the sotagliflozin group and the placebo group (3.0% [21 patients] and 2.4% [17], respectively). The rate of documented hypoglycemia with a blood glucose level of 55 mg per deciliter (3.1 mmol per liter) or below was significantly lower in the sotagliflozin group than in the placebo group. The rate of diabetic ketoacidosis was higher in the sotagliflozin group than in the placebo group (3.0% [21 patients] and 0.6% [4], respectively). CONCLUSIONS Among patients with type 1 diabetes who were receiving insulin, the proportion of patients who achieved a glycated hemoglobin level lower than 7.0% with no severe hypoglycemia or diabetic ketoacidosis was larger in the group that received sotagliflozin than in the placebo group. However, the rate of diabetic ketoacidosis was higher in the sotagliflozin group. (Funded by Lexicon Pharmaceuticals; inTandem3 ClinicalTrials.gov number, NCT02531035.)