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Heart failure is associated with systemic insulin resistance and abnormalities in glucose metabolism but the underlying mechanisms are poorly understood. In the skeletal muscle, the major peripheral site of glucose utilization, we observe an increase in miR-133b in heart failure mice, which reduces the insulin-sensitive glucose transporter (GLUT4), glucose uptake, and metabolism in C2C12 and in myocytes. The antagomir for miR-133b restores GLUT4 protein and markers of metabolism in skeletal myocytes from heart failure mice demonstrating that miR-133b is an exciting target for systemic insulin resistance in heart failure and an important player in the cross talk between the heart and the periphery in the heart failure syndrome.

TRAP-transporters are widespread in bacteria and archaea and are often responsible for the transport of nutrients or virulence factors in pathogens. They consist of three domains, a substrate-binding protein and two membrane domains. Using cryo-EM, we have determined the structure of the membrane domains, revealing a monomeric elevator architecture. Further studies gave insights into the interaction between the domains of TRAP-transporters and how they can be specifically inhibited by using a VHH antibody.

Heterogeneity usually restricts conventional mass spectrometry to molecular weights less than around a megadalton. As a single-particle technique, charge detection mass spectrometry (CDMS) overcomes this limitation. In CDMS, the mass-to-charge (m/z) ratio and charge are measured simultaneously for individual ions, giving a direct mass measurement for each ion. Recent applications include the analysis of viruses, virus-like particles, vaccines, heavily glycosylated proteins, and gene therapy vectors.

COVID-19 has devastated global communities and economies. The pandemic has exposed socioeconomic disparities and weaknesses in health systems worldwide. Long-term health effects and economic recovery are major concerns. Ecosystem restoration—ie, the repair of ecosystems that have been degraded—relates directly to tackling the health and socioeconomic burdens of COVID-19, because stable and resilient ecosystems are fundamental determinants of health and socioeconomic stability. Here, we use COVID-19 as a case study, showing how ecosystem restoration can reduce the risk of infection and adverse sequelae and have an integral role in humanity’s recovery from COVID-19.The next decade will be crucial for humanity’s recovery from COVID-19 and for ecosystem repair. Indeed, in the absence of effective, large-scale restoration, 95% of the Earth’s land could be degraded by 2050. The UN Decade on Ecosystem Restoration (2021–30) declaration reflects the growing urgency and scale at which we should repair ecosystems. Importantly, ecosystem restoration could also help to combat the health and socioeconomic issues that are associated with COVID-19, yet it is poorly integrated into current responses to the disease. Ecosystem restoration can be a core public health intervention and assist in COVID-19 recovery if it is closely integrated with socioeconomic, health, and environmental policies. Refereed/Peer-reviewed

Under the Affordable Care Act, the US Centers for MedicareMedicaid Services created Physician Value-Based Payment Modifier Program and its successor the Merit-Based Incentive Payment System to tie physician payments to quality and cost. The addition of hospital length of stay (LOS) to these value-based physician payment models reflects its increasing importance as a metric of health care cost and efficiency and its association with adverse health outcomes. This study compared the Centers for MedicareMedicaid Services-endorsed LOS risk-adjustment methodology with a novel methodology that accounts for pre-hospitalization clinical, socioeconomic status (SES), and admission-related factors as influential factors of hospital LOS.Using the 2014 New York, Florida, and New Jersey State Inpatient Database, we compared the observed-to-expected LOS of 2373102 adult admissions for 742 medical and surgical diagnosis-related groups (DRGs) by 3 models: (a) current risk-adjustment model (CRM), which adjusted for age, sex, number of chronic conditions, Elixhauser comorbidity score, and DRG severity weight, (b) CRM but modeling LOS using a generalized linear model (C-GLM), and (c) novel risk-adjustment model (NRM), which added to the C-GLM covariates for race/ethnicity, SES, discharge destination, weekend admission, and individual intercepts for DRGs instead of severity weights.The NRM disadvantaged physicians for fewer medical and surgical DRGs, compared with both the C-GLM and CRM models (medical DRGs: 0.49% vs 13.17% and 10.89%, respectively; surgical DRGs: 0.30% vs 13.17% and 10.98%, respectively). In subgroup analysis, the NRM reduced the proportion of physician-penalizing DRGs across all racial/ethnic and socioeconomic groups, with the highest reduction among Whites, followed by low SES patients, and the lowest reduction among Hispanic patients.After accounting for pre-hospitalization socioeconomic and clinical factors, the adjusted LOS using the NRM was lower than estimates from the current Centers for MedicareMedicaid Services-endorsed model. The current model may disadvantage physicians serving communities with higher socioeconomic risks.

The activities of different microbes in the cow rumen have been shown to modulate the host’s ability to utilize plant biomass, while the host–rumen interface has received little attention. As datasets collected worldwide have pointed to Campylobacteraceae as particularly abundant members of the rumen epithelial microbiome, we targeted this group in a subset of seven cows with meta- and isolate genome analysis. We show that the dominant Campylobacteraceae lineage has recently speciated into two populations that were structured by genome-wide selective sweeps followed by population-specific gene import and recombination. These processes led to differences in gene expression and enzyme domain composition that correspond to the ability to utilize acetate, the main carbon source for the host, at the cost of inhibition by propionate. This trade-off in competitive ability further manifests itself in differential dynamics of the two populations in vivo. By exploring population-level adaptations that otherwise remain cryptic in culture-independent analyses, our results highlight how recent evolutionary dynamics can shape key functional roles in the rumen microbiome.

Moral development during emerging adulthood is a topic of growing interest. Several different theories within the study of human development appear to converge on this point of inquiry, as the study of moral development during emerging adulthood recruits different areas of expertise. This paper explores different theoretical approaches to the study of moral development during emerging adulthood and demonstrates the need for interdisciplinary collaboration. The overall shape of the exploration is governed by broad philosophical considerations grounded in the ethics of Aristotle. First, Aristotle’s ideas are adapted to a developmental paradigm, providing an overarching theory of moral development. Second, the study of moral development during emerging adulthood is situated within the relational developmental system metatheory of human development. These first two theories provide a framework for “moral” and “development,” respectively. Additional conceptual and theoretical issues are addressed as they arise, including moral identity and the link between virtue and happiness.

13 species are added to the Portuguese Lepidoptera fauna, of which three are new for the Iberian Peninsula, and two species deleted, mainly as a result of fieldwork undertaken by the authors and others in 2021. In addition, second and third records for the country, new province records and new host-plant data for a number of species are included. A summary of recent papers affecting the Portuguese fauna is included.

FAO specifications for liquid paraquat dichloride SL formulations require the use of an emetic agent to stimulate vomiting within 30 min of ingestion. To date, there is no high-quality evidence of efficacy, despite use of the PP796 emetic since 1979. We first examined the validity of patients' self-reported dose of paraquat ingested by examining the relationship with blood paraquat concentration and time to death for patients ingesting the standard paraquat SL formulation in a Sri Lankan cohort. As a secondary outcome, we assessed whether ingestion resulted in vomiting within 30 min and whether vomiting was associated with good outcome.Patients presenting with paraquat SL self-poisoning were prospectively studied in ten Sri Lankan hospitals in 2003-08. Data on reported dose ingested, incidence and timing of vomiting after ingestion, treatment received, plasma paraquat concentration, and outcome were collected prospectively on presentation to hospital. Time between ingestion and blood sampling was incorporated by covariate adjustment.441 patients were recruited to the case series, presenting a median (IQR) of 3.0 (1.5-8.1] h post ingestion. Outcome was known for 435 patients of whom 322 (74.0%) died within 42 days, a median of 1.3 (0.6-4.4) days post ingestion. Median reported dose ingested was 15 to30 mL. There was a highly significant linear trend between log plasma paraquat and reported dose ingested (Importantly, we found good agreement between reported dose ingested and plasma paraquat concentration, case fatality, and time to death, suggesting that the reported dose is a valid marker for the dose ingested. Vomiting occurred within 30 min for 68.5% of patients, exceeding the characteristics for a purported effective emetic in the FAO specifications. However, vomiting within 30 min was associated with approximately double the risk of death compared to those who did not vomit, larger paraquat ingestions, and higher blood paraquat concentrations. In addition, death occurred in many patients who did not vomit, and the proportion vomiting within 30 min only reached 82.1% for the highest ingested dose group. Overall, we found no evidence of benefit resulting from incorporation of the emetic, suggesting that the current FAO specification is not effective at preventing deaths after ingestion of the paraquat SL formulation.

Lenalidomide is an effective maintenance agent for patients with myeloma, prolonging first remission and, in transplant eligible patients, improving overall survival (OS) compared to observation. The 'Myeloma XI' trial, for newly diagnosed patients, aimed to evaluate whether the addition of the histone deacetylase inhibitor vorinostat to the lenalidomide maintenance backbone could improve outcomes further. Patients included in this analysis were randomised to maintenance therapy with lenalidomide alone (10 mg/day on days 1-21 of each 28-day cycle), or in combination with vorinostat (300 mg/day on day 1-7 and 15-21 of each 28-day cycle) with treatment continuing until unacceptable toxicity or progressive disease. There was no significant difference in median progression-free survival between those receiving lenalidomide-vorinostat or lenalidomide alone, 34 and 40 months respectively (hazard ratio [HR] 1.18, 95% confidence interval [CI] 0.96-1.44, p = 0.109). There was also no significant difference in median OS, not estimable and 75 months respectively (HR 0.99, 95% CI 0.76-1.29, p = 0.929). Subgroup analysis demonstrated no statistically significant heterogeneity in outcomes. Combination lenalidomide-vorinostat appeared to be poorly tolerated with more dose modifications, fewer cycles of maintenance therapy delivered and higher rates of discontinuation due to toxicity than lenalidomide alone. The trial did not meet its primary end-point, there was no benefit from the addition of vorinostat to lenalidomide maintenance.

Charge detection mass spectrometry (CDMS) was used to analyze recombinant adeno-associated virus serotype 8 (rAAV8) vectors after incubation at elevated temperatures. rAAV8 vectors with a range of genomes of interest (GOIs) from 2.22 to 4.84 kb were investigated. For the shorter GOIs, GOI release occurred at surprisingly low temperatures (15 min at 45°C for cytomegalovirus [CMV]-GFP). The released DNA and intermediates with the GOI extruded from the capsid were detected. The temperature required to release the short GOIs is well below the 65°C incubation temperature required to disassemble the empty rAAV8 capsid. The temperature for GOI release increased with its GOI length. With the longer GOIs, the GOI stabilized the capsid so that it remained intact under conditions that would disassemble the empty particle. After incubation at 65°C, the main species in the CDMS mass distributions for the longer GOIs was the vector with the GOI. However, for GOIs longer than the wild-type genome (∼4.7 kb), the stability diminished, and genome release occurred at a lower temperature. Heterogeneous DNA fragments from the host cells or plasmids is released at a lower temperature than the longer GOIs, suggesting that the GOIs have a feature that resists early release.

It is well established that human pluripotent stem cells (hPSCs) can acquire genetic and epigenetic changes during culture in vitro. Given the increasing use of hPSCs in research and therapy and the vast expansion in the number of hPSC lines available for researchers, the International Society for Stem Cell Research has recognized the need to reassess quality control standards for ensuring the genetic integrity of hPSCs. Here, we summarize current knowledge of the nature of recurrent genetic and epigenetic variants in hPSC culture, the methods for their detection, and what is known concerning their effects on cell behavior in vitro or in vivo. We argue that the potential consequences of low-level contamination of cell therapy products with cells bearing oncogenic variants are essentially unknown at present. We highlight the key challenges facing the field with particular reference to safety assessment of hPSC-derived cellular therapeutics.

Despite the availability of effective vaccines against COVID-19, booster vaccinations are needed to maintain vaccine-induced protection against variant strains and breakthrough infections. This study aimed to investigate the efficacy, safety, and immunogenicity of the Ad26.COV2.S vaccine (Janssen) as primary vaccination plus a booster dose.ENSEMBLE2 is a randomised, double-blind, placebo-controlled, phase 3 trial including crossover vaccination after emergency authorisation of COVID-19 vaccines. Adults aged at least 18 years without previous COVID-19 vaccination at public and private medical practices and hospitals in Belgium, Brazil, Colombia, France, Germany, the Philippines, South Africa, Spain, the UK, and the USA were randomly assigned 1:1 via a computer algorithm to receive intramuscularly administered Ad26.COV2.S as a primary dose plus a booster dose at 2 months or two placebo injections 2 months apart. The primary endpoint was vaccine efficacy against the first occurrence of molecularly confirmed moderate to severe-critical COVID-19 with onset at least 14 days after booster vaccination, which was assessed in participants who received two doses of vaccine or placebo, were negative for SARS-CoV-2 by PCR at baseline and on serology at baseline and day 71, had no major protocol deviations, and were at risk of COVID-19 (ie, had no PCR-positive result or discontinued the study before day 71). Safety was assessed in all participants; reactogenicity, in terms of solicited local and systemic adverse events, was assessed as a secondary endpoint in a safety subset (approximately 6000 randomly selected participants). The trial is registered with ClinicalTrials.gov, NCT04614948, and is ongoing.Enrolment began on Nov 16, 2020, and the primary analysis data cutoff was June 25, 2021. From 34 571 participants screened, the double-blind phase enrolled 31 300 participants, 14 492 of whom received two doses (7484 in the Ad26.COV2.S group and 7008 in the placebo group) and 11 639 of whom were eligible for inclusion in the assessment of the primary endpoint (6024 in the Ad26.COV2.S group and 5615 in the placebo group). The median (IQR) follow-up post-booster vaccination was 36·0 (15·0-62·0) days. Vaccine efficacy was 75·2% (adjusted 95% CI 54·6-87·3) against moderate to severe-critical COVID-19 (14 cases in the Ad26.COV2.S group and 52 cases in the placebo group). Most cases were due to the variants alpha (B.1.1.7) and mu (B.1.621); endpoints for the primary analysis accrued from Nov 16, 2020, to June 25, 2021, before the global dominance of delta (B.1.617.2) or omicron (B.1.1.529). The booster vaccine exhibited an acceptable safety profile. The overall frequencies of solicited local and systemic adverse events (evaluated in the safety subset, n=6067) were higher among vaccine recipients than placebo recipients after the primary and booster doses. The frequency of solicited adverse events in the Ad26.COV2.S group were similar following the primary and booster vaccinations (local adverse events, 1676 [55·6%] of 3015 vs 896 [57·5%] of 1559, respectively; systemic adverse events, 1764 [58·5%] of 3015 vs 821 [52·7%] of 1559, respectively). Solicited adverse events were transient and mostly grade 1-2 in severity.A homologous Ad26.COV2.S booster administered 2 months after primary single-dose vaccination in adults had an acceptable safety profile and was efficacious against moderate to severe-critical COVID-19. Studies assessing efficacy against newer variants and with longer follow-up are needed.Janssen ResearchDevelopment.

The phytohormone auxin is the major coordinative signal in plant development

Lung stereotactic body radiotherapy (SBRT) has proven an effective treatment for medically inoperable lung tumors, even for (ultra-)central tumors. Recently, there has been growing interest in radiation-induced cardiac toxicity in lung radiotherapy. More specifically, dose to cardiac (sub-)structures (CS) was found to correlate with survival after radiotherapy.Our goal is first, to investigate the percentage of patients who require CS sparing in an magnetic resonance imaging guided lung SBRT workflow, and second, to quantify how successful implementation of cardiac sparing would be.The patient cohort consists of 34 patients with stage II-IV lung cancer who were treated with SBRT between 2017 and 2020. A mid-position computed tomography (CT) image was used to create treatment plans for the 1.5 T Unity MR-linac (Elekta AB, Stockholm, Sweden) following clinical templates. Under guidance of a cardio-thoracic radiologist, 11 CS were contoured manually for each patient. Dose constraints for five CS were extracted from the literature. Patients were stratified according to their need for cardiac sparing depending on the CS dose in their non-CS constrained MR-linac treatment plans. Cardiac sparing treatment plans (CSPs) were then created and dosimetrically compared with their non-CS constrained treatment plan counterparts. CSPs complied with the departmental constraints and were considered successful when fulfilling all CS constraints, and partially successful if some CS constraints could be fulfilled. Predictors for the need for and feasibility of cardiac sparing were explored, specifically planning target volume (PTV) size, cranio-caudal (CC) distance, 3D distance, and in-field overlap volume histograms (iOVH).47% of the patients (16 out of 34) were in need of cardiac sparing. A successful CSP could be created for 62.5% (10 out of 16) of these patients. Partially successful CSPs still complied with two to four CS constraints. No significant difference in dose to organs at risk (OARs) or targets was identified between CSPs and the corresponding non-CS constrained MR-linac plans. The need for cardiac sparing was found to correlate with distance in the CC direction between target and all of the individual CS (Mann-Whitney U-test p-values10We demonstrated that CS can be successfully spared in lung SBRT on the MR-linac for most of this patient cohort, without compromising doses to the tumor or to other OARs. CC distance between the target and CS can be used to predict the need for cardiac sparing. iOVHs, in combination with PTV size, can be used to predict if cardiac sparing will be successful for all constrained CS except the left ventricle.

VMAT is not currently available on MR-linacs but could maximize plan conformality. To mitigate respiration without compromising delivery efficiency, MRI-guided MLC tumour tracking was recently developed for the 1.5 T Unity MR-linac (Elekta AB, Stockholm, Sweden) in combination with IMRT. Here, we provide a first experimental demonstration of VMAT + MLC tracking for several lung SBRT indications.We created central patient and phantom VMAT plans (8×7.5 Gy, 2 arcs) and we created peripheral phantom plans (3×181×34 Gy, 4 arcs). A motion phantom mimicked subject-recorded respiratory motion (A‾=11 mm, f‾=0.33 Hz, drift‾=0.3 mm/min). This was monitored using 2D-cine MRI at 4 Hz to continuously realign the beam with the target. VMAT + MLC tracking performance was evaluated using 2D film dosimetry and a novel motion-encoded and time-resolved pseudo-3D dosimetry approach.We found an MLC leaf and jaw end-to-end latency of 328.05(±3.78) ms and 317.33(±4.64) ms, which was mitigated by a predictor. The VMAT plans required maximum MLC speeds of 12.1 cm/s and MLC tracking superimposed an additional 1.48 cm/s. A local 2%/1 mm gamma analysis with a static measurement as reference, revealed pass-rates of 28-46% without MLC tracking and 88-100% with MLC tracking for the 2D film analysis. Similarly, the pseudo-3D gamma passing-rates increased from 22-77% to 92-100%. The dose area histograms showed that MLC tracking increased the GTV DMRI-guided VMAT + MLC tracking is technically feasible on the MR-linac and results in highly conformal dose distribution.

The Cactaceae of northwestern Mexico and the southwestern United States constitute a major component of the angiosperm biodiversity of the region. The Mammilloid clade, (Cactaceae, tribe Cacteae), composed of the genera Cochemiea, Coryphantha, Cumarinia, Mammillaria, and Pelecyphora is especially species rich. We sought to understand the timing, geographical and climate influences correlated with expansion of the Mammilloid clade, through the Sonoran Desert into Baja California.We reconstructed the historical biogeography of the Mammilloid clade, using Bayesian and maximum likelihood methods, based on a strongly supported molecular phylogeny. We also estimated divergence times, the timing of emergence of key characters, and diversification rates and rate shifts of the Mammilloid clade.We found that the most recent common ancestor of Cochemiea arrived in the Cape region of Baja California from the Sonoran Desert region approximately 5 million years ago, coinciding with the timing of peninsular rifting from the mainland, suggesting dispersal and vicariance as causes of species richness and endemism. The diversification rate for Cochemiea is estimated to be approximately 12 times that of the mean background diversification rate for angiosperms. Divergence time estimation shows that many of the extant taxa in Cochemiea and Baja California Mammillaria emerged from common ancestors 1 million to 200,000 years ago, having a mid-Pleistocene origin.Cochemiea and Mammillaria of the Baja California region are examples of recent, rapid diversification. Geological and climatic forces at multiple spatial and temporal scales are correlated with the western distributions of the Mammilloid clade.

Conventional mass spectrometry is limited by heterogeneity to relatively small molecular weights from a biologics perspective. Charge detection mass spectrometry—where masses of individual ions are directly measured—overcomes this limitation and allows measurements into the gigadalton (GDa) range. An important application of this emerging technology is the analysis of gene therapy vectors. Their large size and complexity present analytical challenges that must be addressed for this promising therapeutic approach to reach its full potential.

Understanding population structure and genetic diversity is important for designing effective conservation strategies. As a critically endangered shrub, the six remaining extant populations of spiny daisy (Acanthocladium dockeri) are restricted to country roadsides in the mid-north of South Australia, where the species faces many ongoing abiotic and biotic threats to survival. Currently the spiny daisy is managed by selecting individuals from the extant populations and translocating them to establish insurance populations. However, there is little information available on the genetic differentiation between populations and diversity within source populations, which are essential components of planning translocations. To help fill this knowledge gap, we analysed population structure within and among all six of its known wild populations using 7,742 SNPs generated by a genotyping-by-sequencing approach. Results indicated that each population was strongly differentiated, had low levels of genetic diversity, and there was no evidence of inter-population gene flow. Individuals within each population were generally closely related, however, the Melrose population consisted entirely of clones. Our results suggest genetic rescue should be applied to wild spiny daisy populations to increase genetic diversity that will subsequently lead to greater intra-population fitness and adaptability. As a starting point, we suggest focussing on improving seed viability via inter-population crosses such as through hand pollination experiments to experimentally assess their sexual compatibility with the hope of increasing spiny daisy sexual reproduction and long-term reproductive fitness.

This investigation characterises the time response and the transient turbulence dynamics undergone by rapidly decelerating turbulent pipe flows. A series of direct numerical simulations of decelerating flows between two steady Reynolds numbers were conducted for this purpose. The statistical analyses reveal that rapidly decelerating turbulent flows undergo four coherent, unambiguous transitional stages: inertial (stage I), a dramatic change of sign in the viscous force associated with the decay of the viscous shear stress at the wall together with a mild turbulence decay in the viscous sublayer; friction recovery (stage II), a recovery in viscous force and progressive decay in the turbulent inertia at the near-wall region; turbulence decay (stage III), a balanced decay in both turbulent inertia and viscous force at the near-wall and overlap regions; core relaxation (stage IV), slow turbulence decay at the core region. The FIK identity derived by Fukagata, Iwamoto and Kasagi (Phys. Fluids, vol. 14, 2002, L73–L76) was used to understand further how the flow dynamics influence the time response of the skin friction coefficient ( $C_f$ ). The results show that although $C_f$ plateaus during the fourth stage, the turbulent contribution keeps decaying, undershoots and finally recovers to attain its final steady value. The time evolution of the azimuthal vorticity ( $\omega _\theta$ ) flux reveals that as the flow is decelerated, a layer of negative $\omega _\theta$ is produced at the wall during the flow excursion. As time progresses, this negative vorticity propagates in the wall-normal direction, attenuating the pre-existing vorticity and producing a decay in the turbulence levels.