Patients with diabetes mellitus, prior myocardial infarction, older age, and a relatively preserved left ventricular ejection fraction remain at risk for sudden cardiac death that is potentially ...amenable by the subcutaneous implantable cardioverter defibrillator with a good risk-benefit profile. The launched MADIT S-ICD study is designed to test the hypothesis that post–myocardial infarction diabetes patients with relatively preserved ejection fraction of 36%-50% will have a survival benefit from a subcutaneous implantable cardioverter defibrillator.
Favorable clinical outcomes are difficult to achieve in long-standing persistent atrial fibrillation (LSPAF) with catheter ablation (CA). The CONVERGE (Convergence of Epicardial and Endocardial ...Ablation for the Treatment of Symptomatic Persistent Atrial FIbrillation) trial evaluated the effectiveness of hybrid convergent (HC) ablation vs endocardial CA.
The study sought to evaluate the safety and effectiveness of HC vs CA in the LSPAF subgroup from the CONVERGE trial.
The CONVERGE trial was a prospective, multicenter, randomized trial that enrolled 153 patients at 27 sites. A post hoc analysis was performed on LSPAF patients. The primary effectiveness was freedom from atrial arrhythmias off new or increased dose of previously failed or intolerant antiarrhythmic drugs (AADs) through 12 months. The primary safety endpoint was major adverse event incidence through 30 days with HC. Key secondary effectiveness measures included (1) percent of patients achieving ≥90% AF burden reduction vs baseline and (2) AF freedom.
Sixty-five patients (42.5% of total enrollment) had LSPAF; 38 in HC and 27 in CA. Primary effectiveness was 65.8% (95% confidence interval CI 50.7%–80.9%) with HC vs 37.0% (95% CI 5.1%–52.4%) with CA (P = .022). Through 18 months, these rates were 60.5% (95% CI 50.0%–76.1%) with HC vs 25.9% (95% CI 9.4%–42.5%) with CA (P = .006). Secondary effectiveness rates were higher than CA with HC at 12 and 18 months. Freedom from atrial arrhythmias off AADs was 52.6% (95% CI 36.8%–68.5%) and 47.4% (95% CI 31.5%–63.2%) with HC at 12 and 18 months vs 25.9% (95% CI 9.4%–42.5%) and 22.2% (95% CI 6.5%–37.9%) with CA, respectively (12 months: P = .031; 18 months: P = .038). Three (7.9%) major adverse events occurred within 30 days of HC.
Post hoc analysis demonstrated effectiveness and acceptable safety of HC compared with CA in LSPAF.
Background Major depressive disorder (MDD) is a global health concern. This study examined the efficacy, safety and tolerability of an extended-release (ER) formulation of levomilnacipran, an ...antidepressant approved for the treatment of MDD in adults. Methods This 10- week (1-week placebo run-in period, 8-week double-blind treatment, 1-week down-taper), multicentre, double-blind, placebo-controlled, parallel-group, fixed-dose study was conducted between June 2011 and March 2012. Adult outpatients (age 18-75 yr) with MDD were randomly assigned (1:1:1) to placebo or to levomilnacipran ER 40 mg/day or 80 mg/day. For primary efficacy, we analyzed the Montgomery-Asberg Depression Rating Scale (MADRS) change from baseline to week 8 using a mixed-effects model for repeated- measures approach on the intent-to-treat (ITT) population. For secondary efficacy, we used the Sheehan Disability Scale (SDS), and for safety, we examined adverse events and laboratory, vital sign/physical and electrocardiography findings. Results The ITT population consisted of 185 patients in the placebo group, 185 in the levomilnacipran ER 40 mg/day group and 187 in the levomilnacipran ER 80 mg/ day group. Study completion rates were similar among the groups (76%–83%). On MADRS change from baseline the least squares mean difference (LSMD) and 95% confidence interval (CI) versus placebo was significant for levomilnacipran ER 40 mg/day (–3.3 –5.5 to –1.1, p = 0.003) and 80 mg/day (–3.1, –5.3 to –1.0, p = 0.004). On SDS change from baseline the LSMD (and 95% CI) versus placebo was also significant for levomilnacipran ER 40 mg/day (–1.8, 95% –3.6 to 0, p = 0.046) and 80 mg/day (–2.7 –4.5 to –0.9, p = 0.003). More patients in the levomilnacipran ER than the placebo group prematurely exited the study owing to adverse events; common adverse events (> 5% and > double the rate of placebo) were nausea, dry mouth, increased heart rate, constipation, dizziness, hyperhidrosis, urinary hesitation and erectile dysfunction. Limitations Limitations to our study included short treatment duration and lack of an active control arm. Conclusion Levomilnacipran ER at doses of 40 mg/day and 80 mg/day demonstrated efficacy on symptomatic and functional measures of MDD and was generally well tolerated in this patient population. Clinical trial registration NCT01377194.
Summary Klebsiella pneumoniae is the most clinically relevant species of this genus, known to cause both community-acquired and nosocomial infections worldwide. In the past two decades, a distinct ...hypervirulent strain of K pneumoniae , characterised by its hypermucoviscous phenotype, has emerged as a clinically significant pathogen responsible for highly invasive infections. We present a case of osteomyelitis due to hypervirulent K pneumoniae reported in the USA. Genomic testing of the K pneumoniae isolate was performed due to the striking clinical presentation of the infection as well as the hypermucoid nature of the isolates, raising the suspicion for possible infection with the hypervirulent strain. Whole-genome sequencing and additional PCR testing demonstrated the isolate to be a K1 serotype, sequence type 23 strain expressing rmpA and rmpA2 . Given the multiple reports of this pathogen causing invasive infections, clinicians should be aware of the possible presentation of metastatic and severe infection, including osteomyelitis, due to the hypervirulent strain of K pneumoniae not typical of classic K pneumoniae variants. In this Grand Round, we review the clinical features of hypervirulent K pneumoniae and its link to invasive infections, and discuss the need for improved awareness and identification of the pathogen.
Abstract In posterior-stabilized total knee arthroplasties, a femoral cam and polyethylene tibial post are commonly used to restore posterior stability after sacrifice of the posterior cruciate ...ligament. This article reports a high incidence of early tibial post failures in one design of prosthesis and examines the variables that may have contributed to such. Five hundred sixty-four consecutive posterior-stabilized total knees were implanted in 512 patients, using a total knee prosthesis with a polyethylene tibial post and femoral cam. Clinical and radiographic outcomes were measured at a mean follow-up of 40 months after surgery (range, 24-83 months). At follow-up, 70 knees in 62 patients (12%) had undergone revision surgery because of symptoms related to catastrophic failure of the tibial post.
Summary Background Hypomethylating drugs are the standard treatment for patients with high-risk myelodysplastic syndromes. Survival is poor after failure of these drugs; there is no approved ...second-line therapy. We compared the overall survival of patients receiving rigosertib and best supportive care with that of patients receiving best supportive care only in patients with myelodysplastic syndromes with excess blasts after failure of azacitidine or decitabine treatment. Methods We did this randomised controlled trial at 74 hospitals and university medical centres in the USA and Europe. We enrolled patients with diagnosis of refractory anaemia with excess blasts (RAEB)-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukaemia based on local site assessment, and treatment failure with a hypomethylating drug in the past 2 years. Patients were randomly assigned (2:1) to receive rigosertib 1800 mg per 24 h via 72-h continuous intravenous infusion administered every other week or best supportive care with or without low-dose cytarabine. Randomisation was stratified by pretreatment bone marrow blast percentage. Neither patients nor investigators were masked to treatment assignment. The primary outcome was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov , NCT01241500. Findings From Dec 13, 2010, to Aug 15, 2013, we enrolled 299 patients: 199 assigned to rigosertib, 100 assigned to best supportive care. Median follow-up was 19·5 months (IQR 11·9–27·3). As of Feb 1, 2014, median overall survival was 8·2 months (95% CI 6·1–10·1) in the rigosertib group and 5·9 months (4·1–9·3) in the best supportive care group (hazard ratio 0·87, 95% CI 0·67–1·14; p=0·33). The most common grade 3 or higher adverse events were anaemia (34 18% of 184 patients in the rigosertib group vs seven 8% of 91 patients in the best supportive care group), thrombocytopenia (35 19% vs six 7%), neutropenia (31 17% vs seven 8%), febrile neutropenia (22 12% vs ten 11%), and pneumonia (22 12% vs ten 11%). 41 (22%) of 184 patients in the rigosertib group and 30 (33%) of 91 patients in the best supportive care group died due to adverse events and three deaths were attributed to rigosertib treatment. Interpretation Rigosertib did not significantly improve overall survival compared with best supportive care. A randomised phase 3 trial of rigosertib ( NCT 02562443 ) is underway in specific subgroups of patients deemed to be at high risk, including patients with very high risk per the Revised International Prognostic Scoring System criteria. Funding Onconova Therapeutics, Leukemia & Lymphoma Society.
Summary Efforts are underway for early-phase trials of candidate treatments for cerebral amyloid angiopathy, an untreatable cause of haemorrhagic stroke and vascular cognitive impairment. A major ...barrier to these trials is the absence of consensus on measurement of treatment effectiveness. A range of potential outcome markers for cerebral amyloid angiopathy can be measured against the ideal criteria of being clinically meaningful, closely representative of biological progression, efficient for small or short trials, reliably measurable, and cost effective. In practice, outcomes tend either to have high clinical salience but low statistical efficiency, and thus more applicability for late-phase studies, or greater statistical efficiency but more limited clinical meaning. The most statistically efficient markers might be those that are potentially reversible with treatment, although their clinical significance remains unproven. Many of the candidate outcomes for cerebral amyloid angiopathy trials are probably applicable also to other small-vessel brain diseases.
Objective To assess rotavirus vaccine and pneumococcal conjugate vaccines (PCVs) cumulative impact on the pediatric emergency department visits and hospitalization rates in children <2 years of age ...in southern Israel between April 2006 and March 2014. Study design This prospective, population-based observational study calculated the rates of rotavirus gastroenteritis (RVGE), non-RVGE, community-acquired alveolar pneumonia (CAAP), nonalveolar lower respiratory tract infection, and all-cause hospital visits. PCV7, PCV13, and rotavirus vaccination programs were implemented in Israel in July 2009, November 2010, and January 2011, respectively. Results From 2006-2009 to 2013-2014, the rates of hospitilizations for RVGE, non-RVGE, CAAP, and nonalveolar lower respiratory tract infection decreased by 78%, 21%, 46%, and 7%, respectively. In outpatients, the respective decreases were 80%, 16%, 67%, and 14%. All-cause outpatient pediatric emergency department visits and hospitalization rates were reduced by 12% and 11%, respectively. During the peak season (October through March), RVGE, non-RVGE, CAAP, and nonalveolar lower respiratory tract infection hospitalization rates decreased significantly by 86%, 44.6%, 23.3%, and 10.5%, respectively. In outpatients, the respective decreases were 81.7%, 73.5%, 13.8%, and 10.7%. The proportion of RVGE and CAAP (grouped) of all-cause hospitalizations and outpatient pediatric ED visits decreased from 19.9% to 12.3% and from 6.9% to 1.8%, respectively. Conclusions Rotavirus vaccine and PCV introduction cocontributed to a rapid, considerable reduction in hospital burden in children <2 years of age. Because seasonalities of both diseases overlap, this reduction is particularly helpful in relieving burdens of disease and care during the most cumbersome morbidity season.
Background Parathyroidectomy offers the only cure for primary hyperparathyroidism, but today only 50% of primary hyperparathyroidism patients are referred for operation, in large part, because the ...condition is widely under-recognized. The diagnosis of primary hyperparathyroidism can be especially challenging with mild biochemical indices. Machine learning is a collection of methods in which computers build predictive algorithms based on labeled examples. With the aim of facilitating diagnosis, we tested the ability of machine learning to distinguish primary hyperparathyroidism from normal physiology using clinical and laboratory data. Methods This retrospective cohort study used a labeled training set and 10-fold cross-validation to evaluate accuracy of the algorithm. Measures of accuracy included area under the receiver operating characteristic curve, precision (sensitivity), and positive and negative predictive value. Several different algorithms and ensembles of algorithms were tested using the Weka platform. Among 11,830 patients managed operatively at 3 high-volume endocrine surgery programs from March 2001 to August 2013, 6,777 underwent parathyroidectomy for confirmed primary hyperparathyroidism, and 5,053 control patients without primary hyperparathyroidism underwent thyroidectomy. Test-set accuracies for machine learning models were determined using 10-fold cross-validation. Age, sex, and serum levels of preoperative calcium, phosphate, parathyroid hormone, vitamin D, and creatinine were defined as potential predictors of primary hyperparathyroidism. Mild primary hyperparathyroidism was defined as primary hyperparathyroidism with normal preoperative calcium or parathyroid hormone levels. Results After testing a variety of machine learning algorithms, Bayesian network models proved most accurate, classifying correctly 95.2% of all primary hyperparathyroidism patients (area under receiver operating characteristic = 0.989). Omitting parathyroid hormone from the model did not decrease the accuracy significantly (area under receiver operating characteristic = 0.985). In mild disease cases, however, the Bayesian network model classified correctly 71.1% of patients with normal calcium and 92.1% with normal parathyroid hormone levels preoperatively. Bayesian networking and AdaBoost improved the accuracy of all parathyroid hormone patients to 97.2% cases (area under receiver operating characteristic = 0.994), and 91.9% of primary hyperparathyroidism patients with mild disease. This was significantly improved relative to Bayesian networking alone ( P < .0001). Conclusion Machine learning can diagnose accurately primary hyperparathyroidism without human input even in mild disease. Incorporation of this tool into electronic medical record systems may aid in recognition of this under-diagnosed disorder.
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