The capacity of a population to adapt to selection (evolvability) depends on whether the structure of genetic variation permits the evolution of fitter trait combinations. Selection, genetic variance ...and genetic covariance can change under environmental stress, and males and females are not genetically independent, yet the combined effects of stress and dioecy on evolvability are not well understood. Here, we estimate selection, genetic (co)variance and evolvability in both sexes of Tribolium castaneum flour beetles under stressful and benign conditions, using a half‐sib breeding design. Although stress uncovered substantial latent heritability, stress also affected genetic covariance, such that evolvability remained low under stress. Sexual selection on males and natural selection on females favoured a similar phenotype, and there was positive intersex genetic covariance. Consequently, sexual selection on males augmented adaptation in females, and intralocus sexual conflict was weak or absent. This study highlights that increased heritability does not necessarily increase evolvability, suggests that selection can deplete genetic variance for multivariate trait combinations with strong effects on fitness, and tests the recent hypothesis that sexual conflict is weaker in stressful or novel environments.
Cardiac arrest is the leading cause of natural death in the United States, and most surviving patients suffer from neurological dysfunction. Although this is recognized as a problem, there have been ...very few changes to the cardiopulmonary resuscitation (CPR) procedure. Tourniquets have been recognized for their ability to increase truncal blood pressure and have been shown to improve CPR outcomes in animal models. However, the relationship between tourniquet application and blood pressure elevation has not been adequately explored in healthy human adults.
The objective of this study is to demonstrate that bilateral, non-invasive, peripheral vascular occlusion in the thighs results in an increased proximal systolic blood pressure ≥ 10 mmHg.
This is a single-center, non-blinded clinical trial. Volunteers will be screened for eligibility at least 24 hours before the day of the trial. On the day of the trial, volunteers will undergo an informed consent process. If they choose to participate in the trial after informed consent, their baseline blood pressure will be measured. Volunteers will then have a Combat Application Tourniquet (CAT) applied to each thigh, and the windlasses will be tightened by IRB-approved personnel. Once no pulse can be felt in the lower extremity, blood pressure will be measured in the arm. This will be replicated three times, and the tourniquets will be loosened between trials to allow the volunteers to rest. Any complications that arise during the trial will be handled by the physician that is present.
Changes in systolic blood pressure and diastolic blood pressure will be analyzed using a Shapiro-Wilk test. Then, a one-way repeated measures analysis of variance (ANOVA) will be performed with a Holm-Sidak post-hoc test to determine the mean differences. The significance level will be set to 5% for statistical significance.
Clinicaltrials.gov, NCT05324306.
Right ventricular failure (RVF) increases morbidity and mortality. The RECOVER RIGHT study evaluated the safety and efficacy of a novel percutaneous right ventricular assist device, the Impella RP ...(Abiomed, Danvers, MA), in a prospective, multicenter trial.
Thirty patients with RVF refractory to medical treatment received the Impella RP device at 15 United States institutions. The study population included 2 cohorts: 18 patients with RVF after left ventricular assist device (LVAD) implantation (Cohort A) and 12 patients with RVF after cardiotomy or myocardial infarction (Cohort B). The primary end point was survival to 30 days or hospital discharge (whichever was longer). Major secondary end points included indices of safety and efficacy.
The patients (77% male) were a mean age of 59 ± 15 years, 53% had diabetes, 88.5% had a history of congestive heart failure, and 37.5% had renal dysfunction. Patients were on an average of 3.2 inotropes/pressors. Device delivery was achieved in all but 1 patient. Hemodynamics improved immediately after initiation of Impella RP support, with an increase in cardiac index from 1.8 ± 0.2 to 3.3 ± 0.23 liters/min/m(2) (p < 0.001) and a decrease in central venous pressure from 19.2 ± 4 to 12.6 ± 1 mm Hg (p < 0.001). Patients were supported for an average of 3.0 ± 1.5 days (range, 0.5-7.8 days). The overall survival at 30 days was 73.3%. All patients discharged were alive at 180 days.
In patients with life-threatening RVF, the novel percutaneous Impella RP device was safe, easy to deploy, and reliably resulted in immediate hemodynamic benefit. These data support its probable benefit in this gravely ill patient population.
Summary
VRC‐HIVMAB060‐00‐AB (VRC01) is a broadly neutralizing HIV‐1 monoclonal antibody (mAb) isolated from the B cells of an HIV‐infected patient. It is directed against the HIV‐1 CD4 binding site ...and is capable of potently neutralizing the majority of diverse HIV‐1 strains. This Phase I dose‐escalation study in healthy adults was conducted at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD, USA). Primary objectives were the safety, tolerability and pharmacokinetics (PK) of VRC01 intravenous (i.v.) infusion at 5, 20 or 40 mg/kg, given either once (20 mg/kg) or twice 28 days apart (all doses), and of subcutaneous (s.c.) delivery at 5 mg/kg compared to s.c. placebo given twice, 28 days apart. Cumulatively, 28 subjects received 43 VRC01 and nine received placebo administrations. There were no serious adverse events or dose‐limiting toxicities. Mean 28‐day serum trough concentrations after the first infusion were 35 and 57 μg/ml for groups infused with 20 mg/kg (n = 8) and 40 mg/kg (n = 5) doses, respectively. Mean 28‐day trough concentrations after the second infusion were 56 and 89 μg/ml for the same two doses. Over the 5–40 mg/kg i.v. dose range (n = 18), the clearance was 0·016 l/h and terminal half‐life was 15 days. After infusion VRC01 retained expected neutralizing activity in serum, and anti‐VRC01 antibody responses were not detected. The human monoclonal antibody (mAb) VRC01 was well tolerated when delivered i.v. or s.c. The mAb demonstrated expected half‐life and pharmacokinetics for a human immunoglobulin G. The safety and PK results support and inform VRC01 dosing schedules for planning HIV‐1 prevention efficacy studies.
The aim of this study was to examine the tolerability and efficacy of combination bevacizumab rucaparib therapy in patients with recurrent cervical or endometrial cancer.
Thirty-three patients with ...recurrent cervical or endometrial cancer were enrolled. Patients were required to have tumor progression after first line treatment for metastatic, or recurrent disease. Rucaparib was given at 600 mg BID twice daily for each 21-day cycle. Bevacizumab was given at 15 mg/kg on day 1 of each 21-day cycle. The primary endpoint was efficacy as determined by objective response rate or 6-month progression free survival.
Of the 33 patients enrolled, 28 were evaluable. Patients with endometrial cancer had a response rate of 17% while patients with cervical cancer had a response rate of 14%. Median progression free survival was 3.8 months (95% C·I 2.5 to 5.7 months), and median overall survival was 10.1 months (95% C·I 7.0 to 15.1 months). Patients with ARID1A mutations displayed a better response rate (33%) and 6-month progression free survival (PFS6) rate (67%) than the entire study population. Observed toxicity was similar to that of previous studies with bevacizumab and rucaparib.
The combination of bevacizumab with rucaparib did not show significantly increased anti-tumor activity in all patients with recurrent cervical or endometrial cancer. However, patients with ARID1A mutations had a higher response rate and PFS6 suggesting this subgroup may benefit from the combination of bevacizumab and rucaparib. Further study is needed to confirm this observation. No new safety signals were seen.
Queen pheromones are among the most important chemical messages regulating insect societies yet they remain largely undiscovered, hindering research into interesting proximate and ultimate questions. ...Identifying queen pheromones in multiple species would give new insight into the selective pressures and evolutionary constraints acting on these ubiquitous signals. Here, we present experimental and comparative evidence that 3‐methylalkanes, hydrocarbons present on the queen's cuticle, are a queen pheromone throughout the ant genus Lasius. Interspecific variation in the chemical profile is consistent with 3‐methylalkanes evolving more slowly than other types of hydrocarbons, perhaps due to differential selection or evolutionary constraints. We argue that the sensory ecology of the worker response imposes strong stabilizing selection on queen pheromones relative to other hydrocarbons. 3‐Methylalkanes are also strongly physiologically and genetically coupled with fecundity in at least one Lasius species, which may translate into evolutionary constraints. Our results highlight how honest signalling could minimize evolutionary conflict over reproduction, promoting the evolution and maintenance of eusociality.
Increasing placental perfusion (PP) could improve outcomes of growth‐restricted fetuses. One way of increasing PP may be by using phosphodiesterase (PDE)‐5 inhibitors, which induce vasodilatation of ...vascular beds. We used a combination of clinically relevant magnetic resonance imaging (MRI) techniques to characterize the impact that tadalafil infusion has on maternal, placental and fetal circulations. At 116–117 days’ gestational age (dGA; term, 150 days), pregnant ewes (n = 6) underwent fetal catheterization surgery. At 120–123 dGA ewes were anaesthetized and MRI scans were performed during three acquisition windows: a basal state and then ∼15–75 min (TAD 1) and ∼75–135 min (TAD 2) post maternal administration (24 mg; intravenous bolus) of tadalafil. Phase contrast MRI and T2 oximetry were used to measure blood flow and oxygen delivery. Placental diffusion and PP were assessed using the Diffusion‐Relaxation Combined Imaging for Detailed Placental Evaluation—‘DECIDE’ technique. Uterine artery (UtA) blood flow when normalized to maternal left ventricular cardiac output (LVCO) was reduced in both TAD periods. DECIDE imaging found no impact of tadalafil on placental diffusivity or fetoplacental blood volume fraction. Maternal‐placental blood volume fraction was increased in the TAD 2 period. Fetal DO2${D_{{{\mathrm{O}}_2}}}$ and V̇O2${\dot V_{{{\mathrm{O}}_2}}}$ were not affected by maternal tadalafil administration. Maternal tadalafil administration did not increase UtA blood flow and thus may not be an effective vasodilator at the level of the UtAs. The increased maternal–placental blood volume fraction may indicate local vasodilatation of the maternal intervillous space, which may have compensated for the reduced proportion of UtA DO2${D_{{{\mathrm{O}}_2}}}$.
What is the central question of this study?
Tadalafil is under consideration as an intervention strategy for fetal growth restriction: what is the impact of tadalafil on uterine artery blood flow, placental perfusion and fetal oxygen delivery?
What is the main finding and its importance?
Tadalafil does not increase uterine artery blood flow, placental perfusion or fetal oxygen delivery. Tadalafil may not be suitable as an intervention strategy for fetal growth restriction. The MRI techniques used herein would aid in the appropriate selection of future intervention strategies.
Ventricular Assist Device in Acute Myocardial Infarction Acharya, Deepak, MD, MSPH; Loyaga-Rendon, Renzo Y., MD, PhD; Pamboukian, Salpy V., MD, MSPH ...
Journal of the American College of Cardiology,
04/2016, Letnik:
67, Številka:
16
Journal Article
Recenzirano
Odprti dostop
Abstract Background Patients with acute myocardial infarction (AMI) complicated by acute heart failure or cardiogenic shock have high mortality with conventional management. Objectives This study ...evaluated outcomes of patients with AMI who received durable ventricular assist devices (VAD). Methods Patients in the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) registry who underwent VAD placement in the setting of AMI were included and compared with patients who received VAD for non-AMI indications. Results VAD were implanted in 502 patients with AMI: 443 left ventricular assist devices; 33 biventricular assist devices; and 26 total artificial hearts. Median age was 58.3 years, and 77.1% were male. At implantation, 66% were INTERMACS profile 1. A higher proportion of AMI than non-AMI patients had pre-operative intra-aortic balloon pumps (57.6% vs. 25.3%; p < 0.01), intubation (58% vs. 8.3%; p < 0.01), extracorporeal membrane oxygenation (17.9% vs. 1.7%, p < 0.01), cardiac arrest (33.5% vs. 3.3%, p < 0.01), and higher-acuity INTERMACS profiles. At 1 month post-VAD, 91.8% of AMI patients were alive with ongoing device support, 7.2% had died on device, and 1% had been transplanted. At 1-year post-VAD, 52% of AMI patients were alive with ongoing device support, 25.7% had been transplanted, 1.6% had left VAD explanted for recovery, and 20.7% had died on device. The AMI group had higher unadjusted early phase hazard (hazard ratio HR: 1.24; p = 0.04) and reduced late-phase hazard of death (HR: 0.57; p = 0.04) than the non-AMI group did. After accounting for established risk factors, the AMI group no longer had higher early mortality hazard (HR: 0.89; p = 0.30), but it had lower late mortality hazard (HR: 0.55; p = 0.02). Conclusions Patients with AMI who receive VAD have outcomes similar to other VAD populations, despite being more critically ill pre-implantation. VAD therapy is an effective strategy for patients with AMI and acute heart failure or shock in whom medical therapy is failing.
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