Comprehensive rehabilitation in chronic heart failure - better psycho-emotional status related to quality of life, brain natriuretic peptide concentrations, and clinical severity of disease

To evaluate the effects of a comprehensive outpatient rehabilitation program in chronic heart failure (CHF) on quality of life (QoL) in relation to emotional status and clinical severity of disease.

Learning from failure--rationale and design for a study about discontinuation of randomized trials (DISCO study)

Background Randomized controlled trials (RCTs) may be discontinued because of apparent harm, benefit, or futility. Other RCTs are discontinued early because of insufficient recruitment. Trial discontinuation has ethical implications, because participants consent on the premise of contributing to new medical knowledge, Research Ethics Committees (RECs) spend considerable effort reviewing study protocols, and limited resources for conducting research are wasted. Currently, little is known regarding the frequency and characteristics of discontinued RCTs. Methods/Design Our aims are, first, to determine the prevalence of RCT discontinuation for specific reasons; second, to determine whether the risk of RCT discontinuation for specific reasons differs between investigator- and industry-initiated RCTs; third, to identify risk factors for RCT discontinuation due to insufficient recruitment; fourth, to determine at what stage RCTs are discontinued; and fifth, to examine the publication history of discontinued RCTs. We are currently assembling a multicenter cohort of RCTs based on protocols approved between 2000 and 2002/3 by 6 RECs in Switzerland, Germany, and Canada. We are extracting data on RCT characteristics and planned recruitment for all included protocols. Completion and publication status is determined using information from correspondence between investigators and RECs, publications identified through literature searches, or by contacting the investigators. We will use multivariable regression models to identify risk factors for trial discontinuation due to insufficient recruitment. We aim to include over 1000 RCTs of which an anticipated 150 will have been discontinued due to insufficient recruitment. Discussion Our study will provide insights into the prevalence and characteristics of RCTs that were discontinued. Effective recruitment strategies and the anticipation of problems are key issues in the planning and evaluation of trials by investigators, Clinical Trial Units, RECs and funding agencies. Identification and modification of barriers to successful study completion at an early stage could help to reduce the risk of trial discontinuation, save limited resources, and enable RCTs to better meet their ethical requirements.

Effects of a comprehensive rehabilitation program on quality of life in patients with chronic heart failure

This evaluation was performed to assess the effects of a new, comprehensive outpatient rehabilitation program on generic and disease-specific quality of life related to exercise tolerance in stable chronic heart failure patients. Fifty-one patients (aged 59+/-11 years; 84% men) were treated for 12 weeks. Patients underwent optimized drug treatment, exercise training, and counseling and education. At baseline and at the end of the program, functional status, exercise capacity, and quality of life were assessed using the Medical Outcomes Study 36-item Short-Form Health Survey and the Minnesota Living with Heart Failure Questionnaire. Left ventricular ejection fraction and New York Heart Association functional class, as well as measures of physical fitness and walking distance covered in 6 minutes, improved significantly (by 11%-20% and by 58% on average, respectively). Physical functioning (effect size, 0.38; p<0.0001), role functioning (effect size, 0.17; p<0.05), and mental component score (effect size, 0.47; p<0.0001) on the questionnaire improved significantly. Disease-specific quality of life improved in sum score (effect size, 0.24; p<0.0001) and physical component score (effect size, 0.35; p<0.0001). The latter was inversely correlated to improvement in peak power output (r= -0.31; p<0.05). In patients with stable chronic heart failure, significant improvements in both generic and disease-specific quality of life related to improved exercise tolerance can be achieved within 12 weeks of comprehensive rehabilitation.

Implant Failure Predictors in the Posterior Maxilla: A Retrospective Study of 273 Consecutive Implants

Background: The goal of this study was to retrospectively analyze a cohort of 136 patients who underwent dental implant placement in the posterior maxilla at the University of Connecticut Health Center to assess and identify predictors for implant failure in the posterior maxilla. Methods: Data were retrieved from patient charts to identify subjects older than 21 years of age who received dental implant(s) in the posterior maxilla. Patients without a postoperative baseline radiograph were excluded. A recall radiograph was taken 3 to 6 months after implant placement. If there was no recall radiograph, the subject was contacted for a recall visit that included a clinical evaluation and radiographs to determine the implant status. Based on a univariate screening, variables considered potential implant failure predictors included gender, diabetes, smoking, implant length, implant diameter, membrane use, sinus-elevation technique, and surgical complications. These parameters were further assessed, and a multivariable logistic regression was performed with implant failure as a dependant variable. All tests of significance were evaluated at the 0.05 error level. Results: Two hundred seventy-three implants were placed in the posterior maxilla. Fourteen implants failed (early and late failures combined), resulting in a 94.9% overall survival rate. The survival rates for the sinus-elevation group and native bone group were 92.2% and 96.7%, respectively (P = 0.090). Based on the multivariable analysis, sinus floor-elevation procedures were not associated with increased risk for implant failure (P = 0.702). In contrast, smoking and surgical complications had a statistically significant effect on implant failure; the odds ratios for implant failure were 6.4 (P = 0.025) and 8.2 (P = 0.004), respectively. Conclusion: Sinus-elevation procedures with simultaneous or staged implant placement do not increase the risk for implant failure, whereas smoking and surgical complications markedly increase the risk for implant failure.

Efficacy of the combination of amlodipine and valsartan in patients with hypertension uncontrolled with previous monotherapy: the Exforge in Failure after Single Therapy (EX-FAST) study

In this randomized, double-blind, multicenter study, patients whose blood pressure (BP) was uncontrolled by monotherapy were switched directly to amlodipine/valsartan 5/160 mg (n=443) or 10/160 mg (n=451). After 16 weeks, BP control (levels <140/90 mm Hg or <130/80 mm Hg for diabetics) was achieved in 72.7% (95% confidence interval [CI], 68.6-76.9) of patients receiving amlodipine/valsartan 5/160 mg and in 74.8% (95% CI, 70.8-78.9) receiving amlodipine/valsartan 10/160 mg. Incremental reductions from baseline in mean sitting systolic and diastolic BP were significantly greater with the higher dose (20.0+/-0.7 vs 17.5+/-0.7 mm Hg; P=.0003 and 11.6+/-0.4 vs 10.4+/-0.4 mm Hg; P=.0046). Incremental BP reductions were also achieved with both regimens irrespective of previous monotherapy, hypertension severity, diabetic status, body mass index, and age. Peripheral edema was the most frequent adverse event. These results provide support for the BP-lowering benefits of complementary antihypertensive therapy with amlodipine and valsartan in patients with hypertension uncontrolled by previous monotherapy.

"Rapid two-stage" Norwood operation in a child with multiorgan failure

The Norwood I operation continues to be a procedure with significant operative mortality. One well-accepted risk factor for death after the first step of the Norwood operation is critical preoperative status. We describe herein a new concept for the treatment of patients with hypoplastic left heart syndrome (HLHS) in very poor preoperative condition. This is a case report of a child who was born in a rural hospital. On the second day of life he was referred to our center in multiorgan failure. There were signs of liver dysfunction and the child was anuric. Therapy was started immediately with prostaglandin and vasodilators as well as diuretics, milrinone, and dobutamine. However, systemic perfusion continued to be insufficient. Finally, the child was placed on a ventilator. On the fourth day of life, bilateral pulmonary artery (PA) banding was performed and circulation stabilized immediately. Two hours after the operation urine output started. Liver function stabilized over the next couple of days. Two days after PA banding the child was weaned from the ventilator. On the 12th day of life a Norwood operation with PA debanding and a right ventricle-PA conduit was performed, and 2 days postoperatively the child was weaned from the ventilator. Twenty days after the operation he was discharged home. When the boy was 4 months old a bidirectional cavopulmonary anastomosis was performed. In selected cases of patients with HLHS with very poor hemodynamic conditions, a rapid two-stage approach with bilateral banding followed by a Norwood operation after cardiac stabilization can be recommended.

Intravascular oxygenation for advanced respiratory failure

Severe acute respiratory failure of varying etiology may require the temporary use of artificial gas exchange devices. So far, extracorporeal membrane oxygenation and extracorporeal carbon dioxide removal have been used successfully for this purpose. A totally implantable intravascular oxygenator (IVOX) recently became available. The authors have used IVOX in three patients who presented with severe respiratory failure secondary to pneumonia (n = 2) and post-traumatic adult respiratory distress syndrome (n = 1). At the time of implantation, all patients had hypoxemia (PaO2 less than 60) despite a 100% inspired oxygen concentration and forced mechanical ventilation. The duration of IVOX therapy ranged from 12 to 71 hr. All patients initially showed improvement in arterial oxygenation, allowing for moderate reduction of ventilator therapy after several hours. In one patient the pulmonary status deteriorated further, and she died from multiple organ failure despite IVOX therapy. One patient could be stabilized but died from other causes. The third patient is a long-term survivor 18 months after IVOX therapy. Gas transfer capabilities of IVOX are limited when compared to extracorporeal membrane oxygenation, and this may restrict its clinical applicability in cases of severe adult respiratory distress syndrome. However, IVOX may be used successfully in selected patients with less severe respiratory failure.

Patterns of recurrence of early breast cancer according to estrogen receptor status: a therapeutic target for a quarter of a century

The current therapeutic strategy in breast cancer is to identify a target, such as estrogen receptor (ER) status, for tailoring treatments. We investigated the patterns of recurrence with respect to ER status for patients treated in two randomized trials with 25 years' median follow-up. In the ER-negative subpopulations most breast cancer events occurred within the first 5-7 years after randomization, while in the ER-positive subpopulations breast cancer events were spread through 10 years. In the ER-positive subpopulation, 1 year endocrine treatment alone significantly prolonged disease-free survival (DFS) with no additional benefit observed by adding 1 year of chemotherapy. In the small ER-negative subpopulation chemo-endocrine therapy had a significantly better DFS than endocrine alone or no treatment. Despite small numbers of patients, "old-fashioned" treatments, and competing causes of treatment failure, the value of ER status as a target for response to adjuvant treatment is evident through prolonged follow-up.

Genotypic status of the TbAT1/P2 adenosine transporter of Trypanosoma brucei gambiense isolates from Northwestern Uganda following melarsoprol withdrawal

BACKGROUND: The development of arsenical and diamidine resistance in Trypanosoma brucei is associated with loss of drug uptake by the P2 purine transporter as a result of alterations in the corresponding T. brucei adenosine transporter 1 gene (TbAT1). Previously, specific TbAT1 mutant type alleles linked to melarsoprol treatment failure were significantly more prevalent in T. b. gambiense from relapse patients at Omugo health centre in Arua district. Relapse rates of up to 30% prompted a shift from melarsoprol to eflornithine (alpha-difluoromethylornithine, DFMO) as first-line treatment at this centre. The aim of this study was to determine the status of TbAT1 in recent isolates collected from T. b. gambiense sleeping sickness patients from Arua and Moyo districts in Northwestern Uganda after this shift in first-line drug choice. METHODOLOGY AND RESULTS: Blood and cerebrospinal fluids of consenting patients were collected for DNA preparation and subsequent amplification. All of the 105 isolates from Omugo that we successfully analysed by PCR-RFLP possessed the TbAT1 wild type allele. In addition, PCR/RFLP analysis was performed for 74 samples from Moyo, where melarsoprol is still the first line drug; 61 samples displayed the wild genotype while six were mutant and seven had a mixed pattern of both mutant and wild-type TbAT1. The melarsoprol treatment failure rate at Moyo over the same period was nine out of 101 stage II cases that were followed up at least once. Five of the relapse cases harboured mutant TbAT1, one had the wild type, while no amplification was achieved from the remaining three samples. CONCLUSIONS/SIGNIFICANCE: The apparent disappearance of mutant alleles at Omugo may correlate with melarsoprol withdrawal as first-line treatment. Our results suggest that melarsoprol could successfully be reintroduced following a time lag subsequent to its replacement. A field-applicable test to predict melarsoprol treatment outcome and identify patients for whom the drug can still be beneficial is clearly required. This will facilitate cost-effective management of HAT in rural resource-poor settings, given that eflornithine has a much higher logistical requirement for its application.

Are They Really Lost? "True" Status and Reasons for Treatment Discontinuation among HIV Infected Patients on Antiretroviral Therapy Considered Lost to Follow Up in Urban Malawi

INTRODUCTION Patients who are lost to follow-up (LTFU) while on antiretroviral therapy (ART) pose challenges to the long-term success of ART programs. We describe the extent to which patients considered LTFU are misclassified as true disengagement from care when they are still alive on ART and explain reasons for ART discontinuation using our active tracing program to further improve ART retention programs and policies. METHODS We identified adult ART patients who missed clinic appointment by more than 3 weeks between January 2006 and December 2010, assuming that such patients would miss their doses of antiretroviral drugs. Patients considered LTFU who consented during ART registration were traced by phone or home visits; true ART status after tracing was documented. Reasons for ART discontinuation were also recorded for those who stopped ART. RESULTS Of the 4,560 suspected LTFU cases, 1,384 (30%) could not be traced. Of the 3,176 successfully traced patients, 952 (30%) were dead and 2,224 (70%) were alive, of which 2,183 (99.5%) started ART according to phone-based self-reports or physical verification during in-person interviews. Of those who started ART, 957 (44%) stopped ART and 1,226 (56%) reported still taking ART at the time of interview by sourcing drugs from another clinic, using alternative ART sources or making brief ART interruptions. Among 940 cases with reasons for ART discontinuations, failure to remember (17%), too weak/sick (12%), travel (46%), and lack of transport to the clinic (16%) were frequently cited; reasons differed by gender. CONCLUSION The LTFU category comprises sizeable proportions of patients still taking ART that may potentially bias retention estimates and misdirect resources at the clinic and national levels if not properly accounted for. Clinics should consider further decentralization efforts, increasing drug allocations for frequent travels, and improving communication on patient transfers between clinics to increase retention and adherence.

Gammaglobulin and selenium status in healthy neonatal dairy calves in Switzerland

Serum samples from 142 calves and their dams were analyzed for gammaglobulins (gammaG, calves) and selenium concentrations (Se, calves and dams). A questionnaire provided information about birth and colostrum management. The calves and their dams were distributed into two groups according the calves' gammaG concentration (< 10 and >= 10 g/L), Se concentrations were compared between groups. The correlation between gammaG and Se concentrations in the calves and their dams was analyzed. Risk factors for failure of passive transfer and Se deficiency were assessed based on the questionnaire. The gammaG concentration of 42.9 % of the calves was < 10 g/L (median: 10.9). Calves showed significantly higher gammaG values after optimized colostrum administration than calves with suboptimal colostrum administration (p < 0.004). The median Se concentration was 26.8 and 36.5 microg/L for the calves and dams, respectively. A high correlation was observed between the Se concentration of the dam and her calf (r = 0.72, p < 0.001). The calves' Se and gammaG concentrations were not significantly correlated. These results demonstrate that further efforts toward better information of farmers regarding colostrum management and Se supply are warranted.

Clinical Outcomes According to Diabetic Status in Patients Treated With Biodegradable Polymer Sirolimus-Eluting Stents Versus Durable Polymer Everolimus-Eluting Stents: Prespecified Subgroup Analysis of the BIOSCIENCE Trial.

BACKGROUND Ultrathin strut biodegradable polymer sirolimus-eluting stents (BP-SES) proved noninferior to durable polymer everolimus-eluting stents (DP-EES) for a composite clinical end point in a population with minimal exclusion criteria. We performed a prespecified subgroup analysis of the Ultrathin Strut Biodegradable Polymer Sirolimus-Eluting Stent Versus Durable Polymer Everolimus-Eluting Stent for Percutaneous Coronary Revascularisation (BIOSCIENCE) trial to compare the performance of BP-SES and DP-EES in patients with diabetes mellitus. METHODS AND RESULTS BIOSCIENCE trial was an investigator-initiated, single-blind, multicentre, randomized, noninferiority trial comparing BP-SES versus DP-EES. The primary end point, target lesion failure, was a composite of cardiac death, target-vessel myocardial infarction, and clinically indicated target lesion revascularization within 12 months. Among a total of 2119 patients enrolled between February 2012 and May 2013, 486 (22.9%) had diabetes mellitus. Overall diabetic patients experienced a significantly higher risk of target lesion failure compared with patients without diabetes mellitus (10.1% versus 5.7%; hazard ratio [HR], 1.80; 95% confidence interval [CI], 1.27-2.56; P=0.001). At 1 year, there were no differences between BP-SES versus DP-EES in terms of the primary end point in both diabetic (10.9% versus 9.3%; HR, 1.19; 95% CI, 0.67-2.10; P=0.56) and nondiabetic patients (5.3% versus 6.0%; HR, 0.88; 95% CI, 0.58-1.33; P=0.55). Similarly, no significant differences in the risk of definite or probable stent thrombosis were recorded according to treatment arm in both study groups (4.0% versus 3.1%; HR, 1.30; 95% CI, 0.49-3.41; P=0.60 for diabetic patients and 2.4% versus 3.4%; HR, 0.70; 95% CI, 0.39-1.25; P=0.23, in nondiabetics). CONCLUSIONS In the prespecified subgroup analysis of the BIOSCIENCE trial, clinical outcomes among diabetic patients treated with BP-SES or DP-EES were comparable at 1 year. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01443104.

Failure or Voluntary Exit? Reassessing the Female Underperformance Hypothesis

We reevaluate the female underperformance hypothesis by challenging the assumption that female-owned ventures are more likely to fail. Instead of equating exit with failure, we draw on exit literature and feminist theories to argue that female entrepreneurs are actually more likely than males to exit voluntarily. We argue for further gender differences by using an even more fine-grained conceptualization of entrepreneurial exit (failure, exit for personal reasons, and exit for other professional/financial opportunities). Post-hoc analyses also point to withingender heterogeneity depending on family status. A sample probe of 219 Spanish entrepreneurs who had exited their business supports our overall reasoning.