Debate: Do all patients with heart failure require implantable defibrillators to prevent sudden death?

Sudden death is a major cause of mortality in patients with ventricular dysfunction. The highest risk occurs among patients with less severe functional impairment. Current methods of risk stratification are inadequate, and a rational therapy for prevention of sudden death is not available. The implantable cardioverter-defibrillator (ICD) has proven to be more effective than drugs in reducing sudden-death risk in some subsets of patients. Empiric ICD therapy, targeting the general population with mild to moderate heart failure, will maximize the impact of such a strategy to prevent sudden death and improve long-term survival

Impact of cyclooxygenase inhibitors in the Women's Health Initiative hormone trials: secondary analysis of a randomized trial.

OBJECTIVES: We evaluated the hypothesis that cyclooxygenase (COX) inhibitor use might have counteracted a beneficial effect of postmenopausal hormone therapy, and account for the absence of cardioprotection in the Women's Health Initiative hormone trials. Estrogen increases COX expression, and inhibitors of COX such as nonsteroidal anti-inflammatory agents appear to increase coronary risk, raising the possibility of a clinically important interaction in the trials. DESIGN: The hormone trials were randomized, double-blind, and placebo-controlled. Use of nonsteroidal anti-inflammatory drugs was assessed at baseline and at years 1, 3, and 6. SETTING: The Women's Health Initiative hormone trials were conducted at 40 clinical sites in the United States. PARTICIPANTS: The trials enrolled 27,347 postmenopausal women, aged 50-79 y. INTERVENTIONS: We randomized 16,608 women with intact uterus to conjugated estrogens 0.625 mg with medroxyprogesterone acetate 2.5 mg daily or to placebo, and 10,739 women with prior hysterectomy to conjugated estrogens 0.625 mg daily or placebo. OUTCOME MEASURES: Myocardial infarction, coronary death, and coronary revascularization were ascertained during 5.6 y of follow-up in the estrogen plus progestin trial and 6.8 y of follow-up in the estrogen alone trial. RESULTS: Hazard ratios with 95% confidence intervals were calculated from Cox proportional hazard models stratified by COX inhibitor use. The hazard ratio for myocardial infarction/coronary death with estrogen plus progestin was 1.13 (95% confidence interval 0.68-1.89) among non-users of COX inhibitors, and 1.35 (95% confidence interval 0.86-2.10) among continuous users. The hazard ratio with estrogen alone was 0.92 (95% confidence interval 0.57-1.48) among non-users of COX inhibitors, and 1.08 (95% confidence interval 0.69-1.70) among continuous users. In a second analytic approach, hazard ratios were calculated from Cox models that included hormone trial assignment as well as a time-dependent covariate for medication use, and an interaction term. No significant interaction was identified. CONCLUSIONS: Use of COX inhibitors did not significantly affect the Women's Health Initiative hormone trial results

Collapse of stamps for soft lithography due to interfacial adhesion

Collapse of elastomeric elements used for pattern transfer in soft lithography is studied through experimental measurements and theoretical modehng. The objective is to identify the driving force for such collapse. Two potential driving forces, the self-weight of the stamp and the interfacial adhesion, are investigated. An idealized configuration of periodic rectangular grooves and flat punches is considered. Experimental observations demonstrate that groove collapse occurs regardless of whether the gravitational force promotes or suppresses such collapse, indicating that self-weight is not the driving force. On the other hand, model predictions based on the postulation that interfacial adhesion is the driving force exhibit excellent agreement with the experimentally measured collapse behavior. The interfacial adhesion energy is also evaluated by matching an adhesion parameter in the model with the experimental data.open546

Rationale and design for the study of rivaroxaban to reduce thrombotic events, hospitalization and death in outpatients with COVID-19: The PREVENT-HD study

© 2021 Elsevier Inc. Background: COVID-19 is associated with both venous and arterial thrombotic complications. While prophylactic anticoagulation is now widely recommended for hospitalized patients with COVID-19, the effectiveness and safety of thromboprophylaxis in outpatients with COVID-19 has not been established. Study Design: PREVENT-HD is a double-blind, placebo-controlled, pragmatic, event-driven phase 3 trial to evaluate the efficacy and safety of rivaroxaban in symptomatic outpatients with laboratory-confirmed COVID-19 at risk for thrombotic events, hospitalization, and death. Several challenges posed by the pandemic have necessitated innovative approaches to clinical trial design, start-up, and conduct. Participants are randomized in a 1:1 ratio, stratified by time from COVID-19 confirmation, to either rivaroxaban 10 mg once daily or placebo for 35 days. The primary efficacy end point is a composite of symptomatic venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, non-central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality. The primary safety end point is fatal and critical site bleeding according to the International Society on Thrombosis and Haemostasis definition. Enrollment began in August 2020 and is expected to enroll approximately 4,000 participants to yield the required number of end point events. Conclusions: PREVENT-HD is a pragmatic trial evaluating the efficacy and safety of the direct oral anticoagulant rivaroxaban in the outpatient setting to reduce major venous and arterial thrombotic events, hospitalization, and mortality associated with COVID-19

Flexible and Stretchable Self-Powered Multi-Sensors Based on the N-Type Thermoelectric Response of Polyurethane/Na-x(Ni-ett)(n) Composites

Flexible and stretchable electronic devices have a broad range of potential uses, from biomedicine, soft robotics, and health monitoring to the internet‐of‐things. Unfortunately, finding a robust and reliable power source remains challenging, particularly in off‐the‐grid and maintenance‐free applications. A sought‐after development overcome this challenge is the development of autonomous, self‐powered devices. A potential solution is reported exploiting a promising n‐type thermoelectric compound, poly nickel‐ethenetetrathiolates (Na_{x}(Ni‐ett)_{n}). Highly stretchable n‐type composite films are obtained by combining Nax(Ni‐ett)n with commercial polyurethane (Lycra). As high as 50 wt% Na_{x}(Ni‐ett)_{n} content composite film can withstand deformations of ≈500% and show conductivities of ≈10^{-2} S cm^{-1} and Seebeck coefficients of approx. −40 µV K^{-1}. These novel materials can be easily synthesized on a large scale with continuous processes. When subjected to a small temperature difference (<20 °C), the films generate sufficient thermopower to be used for sensing strain (gauge factor ≈20) and visible light (sensitivity factor ≈36% (kW m^{-2})^{-1}), independent of humidity (sensitivity factor ≈0.1 (%RH)^{-1}. As a proof‐of‐concept, a wearable self‐powered sensor is demonstrated by using n‐type Na_{x}(Ni‐ett)_{n}/Lycra and PEDOT:PSS/Lycra elements, connected in series by hot pressing, without employing any metal connections, hence preserving good mechanical ductility and ease of processing

Impact of cyclooxygenase inhibitors in the Women\u27s Health Initiative hormone trials: secondary analysis of a randomized trial

OBJECTIVES: We evaluated the hypothesis that cyclooxygenase (COX) inhibitor use might have counteracted a beneficial effect of postmenopausal hormone therapy, and account for the absence of cardioprotection in the Women\u27s Health Initiative hormone trials. Estrogen increases COX expression, and inhibitors of COX such as nonsteroidal anti-inflammatory agents appear to increase coronary risk, raising the possibility of a clinically important interaction in the trials. DESIGN: The hormone trials were randomized, double-blind, and placebo-controlled. Use of nonsteroidal anti-inflammatory drugs was assessed at baseline and at years 1, 3, and 6. SETTING: The Women\u27s Health Initiative hormone trials were conducted at 40 clinical sites in the United States. PARTICIPANTS: The trials enrolled 27,347 postmenopausal women, aged 50-79 y. INTERVENTIONS: We randomized 16,608 women with intact uterus to conjugated estrogens 0.625 mg with medroxyprogesterone acetate 2.5 mg daily or to placebo, and 10,739 women with prior hysterectomy to conjugated estrogens 0.625 mg daily or placebo. OUTCOME MEASURES: Myocardial infarction, coronary death, and coronary revascularization were ascertained during 5.6 y of follow-up in the estrogen plus progestin trial and 6.8 y of follow-up in the estrogen alone trial. RESULTS: Hazard ratios with 95% confidence intervals were calculated from Cox proportional hazard models stratified by COX inhibitor use. The hazard ratio for myocardial infarction/coronary death with estrogen plus progestin was 1.13 (95% confidence interval 0.68-1.89) among non-users of COX inhibitors, and 1.35 (95% confidence interval 0.86-2.10) among continuous users. The hazard ratio with estrogen alone was 0.92 (95% confidence interval 0.57-1.48) among non-users of COX inhibitors, and 1.08 (95% confidence interval 0.69-1.70) among continuous users. In a second analytic approach, hazard ratios were calculated from Cox models that included hormone trial assignment as well as a time-dependent covariate for medication use, and an interaction term. No significant interaction was identified. CONCLUSIONS: Use of COX inhibitors did not significantly affect the Women\u27s Health Initiative hormone trial results

Applied Plasma Research

Contains research objectives and reports on three research projects.National Science Foundation (Grant GK-18185)Lincoln Laboratory Purchase Order No. CC-554U. S. Navy (Office of Naval Research) under Contract N00014-67-A-0204-0019Air Force Office of Scientific Researc

'Unable to have a proper conversation over the phone about my concerns': a multimethods evaluation of the impact of COVID-19 on routine childhood vaccination services in London, UK

Objectives Investigating the completion rate of 12-month vaccinations and parental perspectives on vaccine services during COVID-19. Study-design Service evaluation including parental questionnaire. Methods Uptake of 12-month vaccinations in three London general practices during three periods: pre-COVID (1/3/2018–28/2/2019, n = 826), during COVID (1/3/2019–28/2/2020, n = 775) and post-COVID first wave (1/8/2020–31/1/2021, n = 419). Questionnaire of parents whose children were registered at the practices (1/4/2019–1/22/2021, n = 1350). Results Comparing pre-COVID and both COVID cohorts, the completion rates of 12-month vaccines were lower. Haemophilus influenzae type B/meningococcal group C (Hib/MenC) vaccination uptake was 5.6% lower (89.0% vs 83.4%, P=<0.001), meningococcal group B (MenB) booster uptake was 4.4% lower (87.3% vs 82.9%, P = 0.006), pneumococcal conjugate vaccine (PCV) booster uptake was 6% lower (88.0% vs 82.0%, P < 0.001) and measles, mumps and rubella (MMR) vaccine uptake was 5.2% lower (89.1% vs 83.9%, P = 0.003). Black/Black-British ethnicity children had increased odds of missing their 12-month vaccinations compared to White ethnicity children (adjusted odds ratio 0.43 [95% confidence interval 0.24–0.79, P = 0.005; 0.36 [0.20–0.65], P < 0.001; 0.48 [0.27–0.87], P = 0.01; 0.40 [0.22–0.73], P = 0.002; for Hib/MenC, MenB booster, PCV booster and MMR. Comparing pre-COVID and COVID periods, vaccinations coded as not booked increased for MMR (10%), MenB (7%) and PCV booster (8%). Parents reported changes to vaccination services during COVID-19, including difficulties booking and attending appointments and lack of vaccination reminders. Conclusion A sustained decrease in 12-month childhood vaccination uptake disproportionally affected Black/Black British ethnicity infants during the first wave of the pandemic. Vaccination reminders and availability of healthcare professionals to discuss parental vaccine queries are vital to maintaining uptake

Efficacy and safety of rociletinib versus chemotherapy in patients with EGFR-mutated NSCLC: the results of TIGER-3, a phase 3 randomized study

Introduction: The TIGER-3 (NCT02322281) study was initiated to compare the efficacy and safety of rociletinib, a third-generation EGFR tyrosine kinase inhibitor (TKI) that targets EGFR T790M and common EGFR-activating mutations, versus chemotherapy in patients with NSCLC who progressed on first- or second-generation EGFR TKIs. Methods: Patients with advanced or metastatic EGFR-mutated NSCLC with disease progression on standard therapy (previous EGFR TKI and platinum-based chemotherapy) were randomized to oral rociletinib (500 or 625 mg twice daily) or single-agent chemotherapy (pemetrexed, gemcitabine, docetaxel, or paclitaxel). Results: Enrollment was halted when rociletinib development was discontinued in 2016. Of 149 enrolled patients, 75 were randomized to rociletinib (n = 53: 500 mg twice daily; n = 22: 625 mg twice daily) and 74 to chemotherapy. The median investigator-assessed progression-free survival (PFS) was 4.1 months (95% confidence interval [CI]: 2.6-5.4) in the rociletinib 500-mg group and 5.5 months (95% CI: 1.8-8.1) in the 625-mg group versus 2.5 months (95% CI: 1.4-2.9) in the chemotherapy group. An improved PFS was observed in patients with T790M-positive NSCLC treated with rociletinib (n = 25; 500 mg and 625 mg twice daily) versus chemotherapy (n = 20; 6.8 versus 2.7 mo; hazard ratio = 0.55, 95% CI: 0.28-1.07, p = 0.074). Grade 3 or higher hyperglycemia (24.0%), corrected QT prolongation (6.7%), diarrhea (2.7%), and vomiting (1.3%) were more frequent with rociletinib than chemotherapy (0%, 0%, 1.4%, and 0%, respectively). Conclusions: Rociletinib had a more favorable median PFS versus chemotherapy but had higher rates of hyperglycemia and corrected QT prolongation in patients with advanced EGFR-mutated NSCLC who progressed on previous EGFR TKI. Incomplete enrollment prevented evaluation of the primary efficacy end point

Seizure protein 6 controls glycosylation and trafficking of kainate receptor subunits GluK2 and GluK3

Seizure protein 6 (SEZ6) is required for the development and maintenance of the nervous system, is a major substrate of the protease BACE1 and is linked to Alzheimer's disease (AD) and psychiatric disorders, but its molecular functions are not well understood. Here, we demonstrate that SEZ6 controls glycosylation and cell surface localization of kainate receptors composed of GluK2/3 subunits. Loss of SEZ6 reduced surface levels of GluK2/3 in primary neurons and reduced kainate-evoked currents in CA1 pyramidal neurons in acute hippocampal slices. Mechanistically, loss of SEZ6 in vitro and in vivo prevented modification of GluK2/3 with the human natural killer-1 (HNK-1) glycan, a modulator of GluK2/3 function. SEZ6 interacted with GluK2 through its ectodomain and promoted post-endoplasmic reticulum transport of GluK2 in the secretory pathway in heterologous cells and primary neurons. Taken together, SEZ6 acts as a new trafficking factor for GluK2/3. This novel function may help to better understand the role of SEZ6 in neurologic and psychiatric diseases