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Abstract Background Nematodes are the most abundant and diverse metazoans on Earth, and are known to significantly affect ecosystem functioning. A better understanding of their biology and ecology, including potential adaptations to diverse habitats and lifestyles, is key to understanding their response to global change scenarios. Mitochondrial genomes offer high species level characterization, low cost of sequencing, and an ease of data handling that can provide insights into nematode evolutionary pressures. Results Generally, nematode mitochondrial genomes exhibited similar structural characteristics (e.g., gene size and GC content), but displayed remarkable variability around these general patterns. Compositional strand biases showed strong codon position specific G skews and relationships with nematode life traits (especially parasitic feeding habits) equal to or greater than with predicted phylogeny. On average, nematode mitochondrial genomes showed low non-synonymous substitution rates, but also high clade specific deviations from these means. Despite the presence of significant mutational saturation, non-synonymous (dN) and synonymous (dS) substitution rates could still be significantly explained by feeding habit and/or habitat. Low ratios of dN:dS rates, particularly associated with the parasitic lifestyles, suggested the presence of strong purifying selection. Conclusions Nematode mitochondrial genomes demonstrated a capacity to accumulate diversity in composition, structure, and content while still maintaining functional genes. Moreover, they demonstrated a capacity for rapid evolutionary change pointing to a potential interaction between multi-level selection pressures and rapid evolution. In conclusion, this study helps establish a background for our understanding of the potential evolutionary pressures shaping nematode mitochondrial genomes, while outlining likely routes of future inquiry.

Abstract The objective of this study is to determine characteristics of patients with myofascial pain syndrome (MPS) of the low back and the degree to which the low back pain in the patients examined can be attributed to MPS. Twenty-five subjects with myofascial trigger point(s) [MTrP(s)] on the low back participated in this cross-sectional study. The location, number, and type of selected MTrPs were identified by palpation and verified by ultrasound. Pain pressure threshold, physical function, and other self-reported outcomes were measured. Significant differences were found in Group 1 (Active), 2 (Latent), 3 (Atypical, no twitching but with spontaneous pain), and 4 (Atypical, no twitching and no spontaneous pain) of participants in the number of MTrPs, current pain, and worst pain in the past 24 h (p = .001–.01). There were interaction effects between spontaneous pain and twitching response on reports of physical function, current pain, and worst pain (p = .002–.04). Participants in Group 3 reported lower levels of physical function, and higher levels of current pain and worst pain compared to those in Group 4. Participants in Group 1 and 2 had similar levels of physical function, current pain, and worst pain. The number of MTrPs is most closely associated with the level of pain. Spontaneous pain report seems to be a decisive factor associated with poor physical function; however, twitching response is not.

Abstract It is essential that people with limb amputation maintain proper prosthetic socket fit to prevent injury. Monitoring and adjusting socket fit, for example by removing the prosthesis to add prosthetic socks, is burdensome and can adversely affect users’ function and quality-of-life. This study presents results from take-home testing of a motor-driven adaptive socket that automatically adjusted socket size during walking. A socket fit metric was calculated from inductive sensor measurements of the distance between the elastomeric liner surrounding the residual limb and the socket’s inner surface. A proportional-integral controller was implemented to adjust socket size. When tested on 12 participants with transtibial amputation, the controller was active a mean of 68% of the walking time. In general, participants who walked more than 20 min/day demonstrated greater activity, less doff time, and fewer manual socket size adjustments for the adaptive socket compared with a locked non-adjustable socket and a motor-driven socket that participants adjusted with a smartphone application. Nine of 12 participants reported that they would use a motor-driven adjustable socket if it were available as it would limit their socket fit issues. The size and weight of the adaptive socket were considered the most important variables to improve.

Background: Management of radiography departments requires skilled and competent managers. This task becomes complex if there is no management development and collaborative performance monitoring. Aim: The study aimed to explore and describe the radiography managers’ perceptions regarding management training and skills required. Setting: The research was conducted in public health institutions of Gauteng, South Africa. Methods: Qualitative, exploratory and descriptive approach was adopted, and a purposive sampling method was used to select twenty-three (23) managers from the radiography departments; however, data saturation guided the sample size. Data were collected through online focus group discussions (FGDs). Ethical approval was obtained through Departmental Research Committee (DRC) of Medical Imaging and Radiation Sciences (MIRS) department, Higher Degrees Committee (HDC), Research Ethics Committee and Gauteng Department of Health Research Committees. Data trustworthiness was obtained through member checking, data verification and an independent coder to verify the accuracy of the data. Thematic data analysis method was used to analyse the data. Results: Five themes emerged from the thematic analysis and centred on: difficulties in transitioning into management, lack of management support, the need for postgraduate management qualification, coaching and mentoring and required skills for radiography managers. Conclusion: Public health institutions continuously face transitions in service delivery frameworks. This requires competent and skilled radiography managers to survive in this environment. The study revealed that new managers experience difficulties and require management support to succeed in their roles. Contribution: Awareness of managers developmental needs relative to the real-life dynamics of radiography management in Gauteng public health environment.

Although highly active antiretroviral therapy (HAART) has changed infection with human immunodeficiency virus (HIV) from a diagnosis with imminent mortality to a chronic illness, HIV positive patients who do not develop acquired immunodeficiency syndrome (AIDs) still suffer from a high rate of cardiac dysfunction and fibrosis. Regardless of viral load and CD count, HIV-associated cardiomyopathy (HIVAC) still causes a high rate of mortality and morbidity amongst HIV patients. While this is a well characterized clinical phenomena, the molecular mechanism of HIVAC is not well understood. In this review, we consolidate, analyze, and discuss current research on the intersection between autophagy and HIVAC. Multiple studies have linked dysregulation in various regulators and functional components of autophagy to HIV infection regardless of mode of viral entry, i.e., coronary, cardiac chamber, or pericardial space. HIV proteins, including negative regulatory factor (Nef), glycoprotein 120 (gp120), and transactivator (Tat), have been shown to interact with type II microtubule-associated protein-1 β light chain (LC3-II), Rubiquitin, SQSTM1/p62, Rab7, autophagy-specific gene 7 (ATG7), and lysosomal-associated membrane protein 1 (LAMP1), all molecules critical to normal autophagy. HIV infection can also induce dysregulation of mitochondrial bioenergetics by altering production and equilibrium of adenosine triphosphate (ATP), mitochondrial reactive oxygen species (ROS), and calcium. These changes alter mitochondrial mass and morphology, which normally trigger autophagy to clear away dysfunctional organelles. However, with HIV infection also triggering autophagy dysfunction, these abnormal mitochondria accumulate and contribute to myocardial dysfunction. Likewise, use of HAART, azidothymidine and Abacavir, have been shown to induce cardiac dysfunction and fibrosis by inducing abnormal autophagy during antiretroviral therapy. Conversely, studies have shown that increasing autophagy can reduce the accumulation of dysfunctional mitochondria and restore cardiomyocyte function. Interestingly, Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, has also been shown to reduce HIV-induced cytotoxicity by regulating autophagy-related proteins, making it a non-antiviral agent with the potential to treat HIVAC. In this review, we synthesize these findings to provide a better understanding of the role autophagy plays in HIVAC and discuss the potential pharmacologic targets unveiled by this research.

Research indicates that specialized trauma centers, especially those of level I and II designation, can generate revenue if financial support is provided, and most importantly provide better outcomes for an injured patient by reducing length of stay and mortality when compared with treatment at hospitals without trauma center designation.Costs associated with trauma center operation have risen over the past few years in association with growing patient volumes and inflation. Documentation regarding costs for trauma center operations is sparse, and there exists a large variance between reported numbers based on their region. In most cases, the greatest proportion of funds are spent on clinical personnel while the smallest fraction is dedicated to educational and prevention programs. Studies confirm that as a product of these rising costs and a lack of state and federal funding that trauma centers remain uniquely financially vulnerable.Multiple strategies have been implemented to mitigate these costs but have proven insufficient. Legislations providing patients with expanded access to healthcare such as the Affordable Healthcare Act have failed to deliver on their intended purposes, and managed care organizations have moved to protect their own interest at the expense of trauma patient mortality. In lieu of concerted federal support, states and municipalities have explored solutions to support trauma centers such as small fees added to fines or encouraging charitable donations, although these programs have not seen ubiquitous implementation. Most trauma centers have begun incorporating activation costs to recoup losses from their low reimbursement rate, but these have continued to inflate, and pose a growing burden on vulnerable patients.Lack of funding from external sources such as state or federal appropriations poses a tangible threat to trauma centers for closure, and with multiple trauma centers acting as critical pillars of healthcare infrastructure for disadvantaged communities as well as the impact of this lack of funding being so broad and systemic, multiple ‘trauma deserts’ may emerge, leaving communities—especially disadvantaged communities which rely on the safety-net function of many high designation trauma centers—deprived of an essential treatment resource and increasing annual mortalities that could have otherwise been averted.

Background: COVID-19 has had an unprecedented impact worldwide. Evidence for management interventions emerged rapidly but was difficult for clinicians and others to assess and decide how to use. Our team in India set up a national and international collaboration preparing guidance in real time to help guide clinical practice in the country during a pandemic setting. We describe our methods and the product in this paper. Methods: Specialized groups comprising core, steering, methodology, evidence synthesis, dissemination and intervention expert working groups were formed. A Cochrane Rapid Review approach was used for prioritized questions in areas of clinical equipoise in management of COVID-19. GRADE methodology was incorporated into this process and expert working groups tailored guidelines for India using the WHO Evidence to Decision framework. This was then disseminated on a widely accessible platform: indiacovidguidelines.org. A questionnaire was then used to obtain end-user feedback on the guidelines. Results: Since May 2021, a total of 20 guidelines have been developed spanning pharmacological, respiratory and other supportive interventions for management of COVID-19, with over 83,600 unique page views up to December 2023. Results from a pilot survey suggest usefulness of the guidelines, but also highlighted areas for improvement. A key output was adoption of our anticoagulation recommendation in state level COVID-19 guidelines (Kerala, India). National and institutional capacity for evidence synthesis and guidelines was strengthened. Conclusions: The COVID Guidelines India project successfully developed contextually relevant, nationally applicable, evidence-based guidelines in a timely manner, and disseminated these freely through a dedicated website while successfully building capacity amongst Indian clinicians for evidence-based guideline development. Throughout the ongoing COVID Guidelines India project, the team has maintained a 'living' approach, continuously updating and refining recommendations in response to emerging evidence during the ever-evolving pandemic landscape.

We describe the complete mitogenomes of the black corals Alternatipathes mirabilis Opresko & Molodtsova, 2021 and Parantipathes larix (Esper, 1790) (Cnidaria, Anthozoa, Hexacorallia, Antipatharia, Schizopathidae). The analysed specimens include the holotype of Alternatipathes mirabilis, collected from Derickson Seamount (North Pacific Ocean; Gulf of Alaska) at 4,685 m depth and a potential topotype of Parantipathes larix, collected from Secca dei Candelieri (Mediterranean Sea; Tyrrhenian Sea; Salerno Gulf; Italy) at 131 m depth. We also assemble, annotate and make available nine additional black coral mitogenomes that were included in a recent phylogeny (Quattrini et al. 2023b), but not made easily accessible on GenBank. This is the first study to present and compare two mitogenomes from the same species of black coral (Stauropathes arctica (Lütken, 1871)) and, thus, place minimum boundaries on the expected level of intraspecific variation at the mitogenome level. We also compare interspecific variation at the mitogenome-level across five different specimens of Parantipathes Brook, 1889 (representing at least two different species) from the NE Atlantic and Mediterranean Sea.

Abstract Alcohol consumption during pregnancy can result in a range of adverse postnatal outcomes among exposed children. However, identifying at-risk children is challenging given the difficulty to confirm prenatal alcohol exposure and the lack of early diagnostic tools. Placental surveys present an important opportunity to uncover early biomarkers to identify those at risk. Here, we report the first transcriptome-wide evaluation to comprehensively evaluate human placental pathways altered by fetal alcohol exposure. In a prospective longitudinal birth cohort in Cape Town, South Africa, we performed bulk tissue RNAseq in placenta samples from 32 women reporting heavy drinking during pregnancy and 30 abstainers/light drinkers. Weighted gene co-expression network analysis (WGCNA) and differential gene expression analysis were performed to assess associations between fetal alcohol exposure and placental gene expression patterns at a network-wide and single gene level, respectively. The results revealed altered expression in genes related to erythropoiesis and angiogenesis, which are implicated in established postnatal phenotypes related to alcohol exposure, including disruptions in iron homeostasis, growth, and neurodevelopment. The reported findings provide insights into the molecular pathways affected by prenatal alcohol exposure and highlight the potential of placental biomarkers for detecting and understanding the effects of alcohol on fetal development.

Abstract Highly pathogenic avian influenza virus (HPAIV) A H5, particularly clade 2.3.4.4, has caused worldwide outbreaks in domestic poultry, occasional spillover to humans, and increasing deaths of diverse species of wild birds since 2014. Wild bird migration is currently acknowledged as an important ecological process contributing to the global dispersal of HPAIV H5. However, this mechanism has not been quantified using bird movement data from different species, and the timing and location of exposure of different species is unclear. We sought to explore these questions through phylodynamic analyses based on empirical data of bird movement tracking and virus genome sequences of clade 2.3.4.4 and 2.3.2.1. First, we demonstrate that seasonal bird migration can explain salient features of the global dispersal of clade 2.3.4.4. Second, we detect synchrony between the seasonality of bird annual cycle phases and virus lineage movements. We reveal the differing exposed bird orders at geographical origins and destinations of HPAIV H5 clade 2.3.4.4 lineage movements, including relatively under-discussed orders. Our study provides a phylodynamic framework that links the bird movement ecology and genomic epidemiology of avian influenza; it highlights the importance of integrating bird behavior and life history in avian influenza studies.

Abstract Antimicrobial resistant lower respiratory tract infections are an increasing public health threat and an important cause of global mortality. The lung microbiome can influence susceptibility of respiratory tract infections and represents an important reservoir for exchange of antimicrobial resistance genes. Studies of the gut microbiome have found an association between age and increasing antimicrobial resistance gene burden, however, corollary studies in the lung microbiome remain absent. We performed an observational study of children and adults with acute respiratory failure admitted to the intensive care unit. From tracheal aspirate RNA sequencing data, we evaluated age-related differences in detectable antimicrobial resistance gene expression in the lung microbiome. Using a multivariable logistic regression model, we find that detection of antimicrobial resistance gene expression was significantly higher in adults compared with children after adjusting for demographic and clinical characteristics. This association remained significant after additionally adjusting for lung bacterial microbiome characteristics, and when modeling age as a continuous variable. The proportion of adults expressing beta-lactam, aminoglycoside, and tetracycline antimicrobial resistance genes was higher compared to children. Together, these findings shape our understanding of the lung resistome in critically ill patients across the lifespan, which may have implications for clinical management and global public health.

This article examines heterogeneity in adverse events and conditions and how low-income African American young adults respond. Although nearly all individuals in the sample report at least one instance of adversity, the nature and frequency of adversity varies, as do the responses. Some individuals see their lives and plans derailed; others engage in more protective strategies. For still others, adversity presents a difficult trade-off between surviving and thriving. We formalize this trade-off as an extension of a basic model of costly human capital investments. The model shows that a rational, fully informed individual facing this brutal trade-off, in an effort to survive the fallout of adversity, may optimally choose not to make high-return investments that promote thriving in the future. Improved policy design would recognize this type of trade-off.

Abstract Higher birth order is associated with altered risk of many disease states. Changes in placentation and exposures to in utero growth factors with successive pregnancies may impact later life disease risk via persistent DNA methylation alterations. We investigated birth order with Illumina DNA methylation array data in each of 16 birth cohorts (8164 newborns) with European, African, and Latino ancestries from the Pregnancy and Childhood Epigenetics Consortium. Meta-analyzed data demonstrated systematic DNA methylation variation in 341 CpGs (FDR adjusted P

The Department of Commerce (DOC) uses differential pricing analysis in order to detect whether a foreign exporter dumps goods in the U.S. market at prices lower than the exporter sells the goods for in its domestic market. A dumping duty is then levied on the exporter, the amount of which depends on the dumping margin. Several recent cases at the Federal Circuit Court of Appeals have challenged the DOC’s methodology on statistical grounds. In this article, the DOC’s procedure for calculating the dumping margin is described in detail, including the rules for the controversial zeroing policy. Several statistical issues with the DOC’s approach are identified and some potential improvements are proposed.

Algorithms for the detection of COVID-19 illness from wearable sensor devices tend to implicitly treat the disease as causing a stereotyped (and therefore recognizable) deviation from healthy physiology. In contrast, a substantial diversity of bodily responses to SARS-CoV-2 infection have been reported in the clinical milieu. This raises the question of how to characterize the diversity of illness manifestations, and whether such characterization could reveal meaningful relationships across different illness manifestations. Here, we present a framework motivated by information theory to generate quantified maps of illness presentation, which we term “manifestations,” as resolved by continuous physiological data from a wearable device (Oura Ring). We test this framework on five physiological data streams (heart rate, heart rate variability, respiratory rate, metabolic activity, and sleep temperature) assessed at the time of reported illness onset in a previously reported COVID-19-positive cohort (N = 73). We find that the number of distinct manifestations are few in this cohort, compared to the space of all possible manifestations. In addition, manifestation frequency correlates with the rough number of symptoms reported by a given individual, over a several-day period prior to their imputed onset of illness. These findings suggest that information-theoretic approaches can be used to sort COVID-19 illness manifestations into types with real-world value. This proof of concept supports the use of information-theoretic approaches to map illness manifestations from continuous physiological data. Such approaches could likely inform algorithm design and real-time treatment decisions if developed on large, diverse samples.

BackgroundTranscranial focused ultrasound (TFUS) is an emerging neuromodulation tool for temporarily altering brain activity and probing network functioning. The effects of TFUS on the default mode network (DMN) are unknown.ObjectiveThe study examined the effects of transcranial focused ultrasound (TFUS) on the functional connectivity of the default mode network (DMN), specifically by targeting the posterior cingulate cortex (PCC). Additionally, we investigated the subjective effects of TFUS on mood, mindfulness, and self-related processing.MethodsThe study employed a randomized, single-blind design involving 30 healthy subjects. Participants were randomly assigned to either the active TFUS group or the sham TFUS group. Resting-state functional magnetic resonance imaging (rs-fMRI) scans were conducted before and after the TFUS application. To measure subjective effects, the Toronto Mindfulness Scale, the Visual Analog Mood Scale, and the Amsterdam Resting State Questionnaire were administered at baseline and 30 min after sonication. The Self Scale and an unstructured interview were also administered 30 min after sonication.ResultsThe active TFUS group exhibited significant reductions in functional connectivity along the midline of the DMN, while the sham TFUS group showed no changes. The active TFUS group demonstrated increased state mindfulness, reduced Global Vigor, and temporary alterations in the sense of ego, sense of time, and recollection of memories. The sham TFUS group showed an increase in state mindfulness, too, with no other subjective effects.ConclusionsTFUS targeted at the PCC can alter DMN connectivity and cause changes in subjective experience. These findings support the potential of TFUS to serve both as a research tool and as a potential therapeutic intervention.

Farber Disease is a debilitating and lethal childhood disease of ceramide accumulation caused by acid ceramidase deficiency. The potent induction of a ligand-gated neutral ceramidase activity promoted by adiponectin may provide sufficient lowering of ceramides to allow for the treatment of Farber Disease. In vitro, adiponectin or adiponectin receptor agonist treatments lowered total ceramide concentrations in human fibroblasts from a patient with Farber Disease. However, adiponectin overexpression in a Farber Disease mouse model did not improve lifespan or immune infiltration. Intriguingly, mice heterozygous for the Farber Disease mutation were more prone to glucose intolerance and insulin resistance when fed a high-fat diet, and adiponectin overexpression protected from these metabolic perturbations. These studies suggest that adiponectin evokes a ceramidase activity that is not reliant on the functional expression of acid ceramidase, but indicates that additional strategies are required to ameliorate outcomes of Farber Disease.

Objectives: Suicide risk is elevated in lesbian, gay, bisexual, and transgender (LGBT) individuals. Limited data on LGBT status in healthcare systems hinder our understanding of this risk. This study used natural language processing to extract LGBT status and a deep neural network (DNN) to examine suicidal death risk factors among US Veterans.Methods: Data on 8.8 million veterans with visits between 2010 and 2017 was used. A case-control study was performed, and suicide death risk was analyzed by a DNN. Feature impacts and interactions on the outcome were evaluated.Results: The crude suicide mortality rate was higher in LGBT patients. However, after adjusting for over 200 risk and protective factors, known LGBT status was associated with reduced risk compared to LGBT-Unknown status. Among LGBT patients, black, female, married, and older Veterans have a higher risk, while Veterans of various religions have a lower risk.Conclusion: Our results suggest that disclosed LGBT status is not directly associated with an increase suicide death risk, however, other factors (e.g., depression and anxiety caused by stigma) are associated with suicide death risks.

Introduction: Recent years have witnessed the emergence of antimicrobial-resistant strains of Mycobacterium tuberculosis, resulting in drug-resistant tuberculosis (DR-TB). DR-TB is difficult to treat, necessitating prolonged therapy with multiple medications. However, attempts have been made to shorten the therapeutic regimen in DR-TB. Objective: This systematic review was undertaken to investigate the efficacy and safety of short-term regimens (STRs) for the treatment of DR-TB in children. Methods: We conducted a comprehensive literature search across PubMed, EMBASE, Scopus, CINHAL, Web of Science, Cochrane Library, major trial registries, and grey literature. We searched for randomized controlled trials, and observational studies, comparing World Health Organization (WHO) approved treatment regimens of ≤12 months duration (shorter regimens) versus >12 months duration (longer regimens), in children (

Objective: This Health Technology Assessment (HTA) was undertaken to assess the clinical-effectiveness, cost-effectiveness, and operational feasibility of using otoscopes in primary healthcare settings in India, for diagnosing otitis media in children. Methods: We undertook a three-step process sequentially determining (i) clinical effectiveness of video as well as conventional otoscopy (compared to otic microscope as the reference standard); (ii)cost-effectiveness analysis of the video otoscope; and (iii)operational feasibility and health equity considerations. The systematic review for clinical effectiveness involved literature search across five databases, screening and inclusion of relevant studies, and data synthesis. Cost-effectiveness analysis was performed using data from published literature, specialist interviews, and cost assumptions if neither was available. The Progress Plus tool was used to explore health equity and operational feasibility was taken into account. Results: The systematic review on clinical effectiveness include three relevant studies from a total of 1361 identified. The pooled sensitivity and specificity of video otoscope were 0.70 (95%CI 0.60, 0.84) and 0.92 (CI95% 0.89, 0.95) to be 0.88 (95% CI, 0.84 to 0.91). The cost-effectiveness analysis identified the incremental cost-effectiveness ratio (compared to conventional otoscope) as INR 1008.4 per QALY, with an overall gain of 413 QALYs per year. This was well below the willingness-to-pay threshold for India. There was potential of enhancing health equity and no insurmountable operational barriers, to the use of video otoscope in primary healthcare settings. Conclusion: This HTA concluded that video otoscope is clinically effective, cost-effective, and operationally feasible in Indian primary health settings, for diagnosing otitis media in children.

Background: Brain infections are a major cause of morbidity and mortality globally. India lacks systematically evidence-informed guidelines for brain infections. Methods: We had set up a group of experts in brain infections, evidence synthesis and guideline development to produce guidelines for hospital clinicians diagnosing and treating patients with suspected and confirmed brain infections in India. Questions are being drafted and prioritised, and a plan for GRADE-informed evidence synthesis and guideline development is in place, using methods to increase efficiency of the process where possible. Dissemination and outputs: The guidelines will be disseminated through publication as well as on a dedicated website. Training of clinicians in evidence synthesis and guideline development, and setting up a network of institutions and professional societies, will provide lasting impact in terms of national capacity strengthening.

A prospective cohort study was conducted to evaluate the 1-year survival of cancer patients with sepsis and vasopressor requirements. Eligible patients were admitted a Comprehensive Cancer Center’s ICU and were compared based on their admission lactate levels. Of the 132 included patients, 87 (66%) had high lactate (HL; > 2.0 mmol/L), and 45 (34%) had normal lactate (NL; ≤ 2.0 mmol/L). The 1-year survival rates of the two groups were similar (HL 16% vs. NL 18%; p = 0.0921). After adjustment for ICU baseline characteristics, HL was not significantly associated with a 1-year survival (Hazards ratio, 1.39; 95% CI, 0.94–2.05). Critically ill cancer patients with sepsis and vasopressor requirements, regardless of the lactate level, had 1-year survival of less than 20%. Large multicenter cancer registries would enable to confirm our findings and better understand the long-term trajectories of sepsis in this vulnerable population.

Abstract Sugar transport proteins (STPs) are high‐affinity H+‐coupled hexose symporters. Recently, the contribution of STP13 to bacterial and fungal pathogen resistance across multiple plant species has garnered significant interest. Quantitative PCR analysis of source leaves, developing embryos, and seed coats of Phaseolus vulgaris L. (common bean) revealed that PvSTP13.1 was expressed in source leaves and seed coats throughout seed development. In contrast, PvSTP13.1 transcripts were detected at exceedingly low levels in developing embryos. To characterize the transport mechanism, PvSTP13.1 was expressed in Xenopus laevis oocytes, and inward‐directed currents were analyzed using two‐electrode voltage clamping. PvSTP13.1 was shown to function as an H+‐coupled monosaccharide symporter exhibiting a unique high affinity for hexoses and aldopentoses at depolarized membrane potentials. Specifically, of the 31 assessed substrates, which included aldohexoses, deoxyhexoses, fructose, 3‐O‐methyl‐D‐glucose, aldopentoses, polyols, glycosides, disaccharides, trisaccharides, and glucuronic acid, PvSTP13.1 displayed the highest affinity (K0.5) for glucose (43 μM), mannose (92 μM), galactose (145 μM), fructose (224 μM), xylose (1.0 mM), and fucose (3.7 mM) at pH 5.6 at a depolarized membrane potential of −40 mV. The results presented here suggest PvSTP13.1 contributes to retrieval of hexoses from the apoplasmic space in source leaves and coats of developing seeds.

OBJECTIVES:. In 2020, cefiderocol became the first Food and Drug Administration-approved medication with continuous renal replacement therapy (CRRT) dosing recommendations based on effluent flow rates (QE). We aimed to evaluate the magnitude and frequency of factors that may influence these recommendations, that is, QE intrapatient variability and residual renal function. DESIGN:. Retrospective observational cohort study. SETTING:. ICUs within Hartford Hospital (890-bed, acute-care hospital) in Connecticut from 2017 to 2023. PATIENTS:. Adult ICU patients receiving CRRT for greater than 72 hours. MEASUREMENTS AND MAIN RESULTS:. CRRT settings including QE and urine output (UOP) were extracted from the time of CRRT initiation (0 hr) and trends were assessed. To assess the impact on antibiotic dosing, cefiderocol doses were assigned to 0 hour, 24 hours, 48 hours, and 72 hours QE values per product label, and the proportion of antibiotic dose changes required as a result of changes in inpatient’s QE was evaluated. Among the 380 ICU patients receiving CRRT for greater than 72 hours, the median (interquartile range) 0 hour QE was 2.96 (2.35–3.29) L/hr. Approximately 9 QE values were documented per patient per 24-hour window. QE changes of greater than 0.75 L/hr were observed in 21.6% of patients over the first 24 hours and in 7.9% (24–48 hr) and 5.8% (48–72 hr) of patients. Approximately 40% of patients had UOP greater than 500 mL at 24 hours post-CRRT initiation. Due to QE changes within 24 hours of CRRT initiation, a potential cefiderocol dose adjustment would have been warranted in 38% of patients (increase of 21.3%; decrease of 16.6%). QE changes were less common after 24 hours, warranting cefiderocol dose adjustments in less than 15% of patients. CONCLUSIONS:. Results highlight the temporal and variable dynamics of QE and prevalence of residual renal function. Data also demonstrate a risk of antibiotic under-dosing in the first 24 hours of CRRT initiation due to increases in QE. For antibiotics with QE-based dosing recommendations, empiric dose escalation may be warranted in the first 24 hours of CRRT initiation.

Abstract As people age, they learn and store new knowledge in their semantic memory. Despite learning a tremendous amount of information, people can still recall information relevant to the current situation with ease. To accomplish this, the mind must efficiently organize and search a vast store of information. It also must continue to retrieve information effectively despite changes in cognitive mechanisms due to healthy aging, including a general slowing in information processing and a decline in executive functioning. How effectively does the mind of an individual adjust its search to account for changes due to aging? We tested 746 people ages 25 through 69 on a semantic fluency task (free listing animals) and found that, on average, retrieval follows an optimal path through semantic memory. Participants tended to list a sequence of semantically related animals (e.g., lion, tiger, puma) before switching to a semantically unrelated animal (e.g., whale). We found that the timing of these transitions to semantically unrelated animals was remarkably consistent with an optimal strategy for maximizing the overall rate of retrieval (i.e., the number of animals listed per unit time). Age did not affect an individual’s deviation from the optimal strategy given their general performance, suggesting that people adapt and continue to search memory optimally throughout their lives. We argue that this result is more likely due to compensating for a general slowing than a decline in executive functioning.

Abstract Circadian clocks generate rhythms of arousal, but the underlying molecular and cellular mechanisms remain unclear. In Drosophila, the clock output molecule WIDE AWAKE (WAKE) labels rhythmic neural networks and cyclically regulates sleep and arousal. Here, we show, in a male mouse model, that mWAKE/ANKFN1 labels a subpopulation of dorsomedial hypothalamus (DMH) neurons involved in rhythmic arousal and acts in the DMH to reduce arousal at night. In vivo Ca2+ imaging reveals elevated DMHmWAKE activity during wakefulness and rapid eye movement (REM) sleep, while patch-clamp recordings show that DMHmWAKE neurons fire more frequently at night. Chemogenetic manipulations demonstrate that DMHmWAKE neurons are necessary and sufficient for arousal. Single-cell profiling coupled with optogenetic activation experiments suggest that GABAergic DMHmWAKE neurons promote arousal. Surprisingly, our data suggest that mWAKE acts as a clock-dependent brake on arousal during the night, when mice are normally active. mWAKE levels peak at night under clock control, and loss of mWAKE leads to hyperarousal and greater DMHmWAKE neuronal excitability specifically at night. These results suggest that the clock does not solely promote arousal during an animal’s active period, but instead uses opposing processes to produce appropriate levels of arousal in a time-dependent manner.

Abstract Genomic and proteomic screens have identified numerous host factors of SARS-CoV-2, but efficient delineation of their molecular roles during infection remains a challenge. Here we use Perturb-seq, combining genetic perturbations with a single-cell readout, to investigate how inactivation of host factors changes the course of SARS-CoV-2 infection and the host response in human lung epithelial cells. Our high-dimensional data resolve complex phenotypes such as shifts in the stages of infection and modulations of the interferon response. However, only a small percentage of host factors showed such phenotypes upon perturbation. We further identified the NF-κB inhibitor IκBα (NFKBIA), as well as the translation factors EIF4E2 and EIF4H as strong host dependency factors acting early in infection. Overall, our study provides massively parallel functional characterization of host factors of SARS-CoV-2 and quantitatively defines their roles both in virus-infected and bystander cells.

In Arabidopsis thaliana (Arabidopsis), microRNA160 (miR160) regulates the expression of AUXIN RESPONSE FACTOR10 (ARF10), ARF16 and ARF17 throughout development, including the development of the root system. We have previously shown that in addition to DOUBLE-STRANDED RNA BINDING1 (DRB1), DRB2 is also involved in controlling the rate of production of specific miRNA cohorts in the tissues where DRB2 is expressed in wild-type Arabidopsis plants. In this study, a miR160 overexpression transgene (MIR160B) and miR160-resistant transgene versions of ARF10 and ARF16 (mARF10 and mARF16) were introduced into wild-type Arabidopsis plants and the drb1 and drb2 single mutants to determine the degree of requirement of DRB2 to regulate the miR160 expression module as part of root development. Via this molecular modification approach, we show that in addition to DRB1, DRB2 is required to regulate the level of miR160 production from its precursor transcripts in Arabidopsis roots. Furthermore, we go on to correlate the altered abundance of miR160 or its ARF10, ARF16 and ARF17 target genes in the generated series of transformant lines with the enhanced development of the root system displayed by these plant lines. More specifically, promotion of primary root elongation likely stemmed from enhancement of miR160-directed ARF17 expression repression, while the promotion of lateral and adventitious root formation was the result of an elevated degree of miR160-directed regulation of ARF17 expression, and to a lesser degree, ARF10 and ARF16 expression. Taken together, the results presented in this study identify the requirement of the functional interplay between DRB1 and DRB2 to tightly control the rate of miR160 production, to in turn ensure the appropriate degree of miR160-directed ARF10, ARF16 and ARF17 gene expression regulation as part of normal root system development in Arabidopsis.

Addressing missed opportunities for vaccination requires a nuanced and context-specific approach. The five-step P-Process provides a robust framework to develop a clearly defined strategy that addresses social and behavioral drivers, integrates into existing health delivery systems, and facilitates collaboration with local experts. This approach allows teams to design, implement, monitor, and evaluate strategies to address public health issues. However, its specific application in vaccination communication programs remains relatively underexplored and under-documented. Our team designed a multi-pronged communication intervention aimed at enhancing vaccine uptake among hospitalized children in two tertiary hospitals in India and Nigeria. In the Inquiry stage, we conducted in-depth interviews with caregivers of hospitalized children to assess barriers to vaccination in a hospital setting. In the Strategic Development stage, we developed a blueprint for activities, identifying target audiences and communication channels and developing implementation plans. During the Create and Test stage, we brought together a range of stakeholders to co-develop a communication intervention through human-centered design workshops, after which we piloted the materials in both hospitals. We then Mobilized and Monitored progress of the activities to identify potential gaps that our materials did not initially address. Lastly, in the Evaluate and Evolve stage, we conducted in-depth interviews with healthcare workers and caregivers to measure outcomes and assess the impact on caregivers’ decisions to vaccinate their hospitalized children. By following the P-Process for the design, caregivers reported that many of their concerns about vaccines were alleviated, and HCWs reported that they were able to communicate with caregivers more effectively about vaccination. By harnessing the power of the P-Process, researchers can forge a context-specific path towards impactful vaccination communication interventions, one step at a time.

In 1979, NASA established the Great Observatory program, which included four telescopes (Hubble, Compton, Chandra, and Spitzer) to explore the Universe. The Spitzer Space Telescope was launched in 2003 into solar orbit, gradually drifting away from the Earth. Spitzer was operated very successfully until 2020 when NASA terminated observations and placed the telescope in safe mode. In 2028, the U.S. Space Force has the opportunity to demonstrate satellite servicing by telerobotically reactivating Spitzer for astronomical observations, and in a separate experiment, carry out novel Space Weather research and operations capabilities by observing solar Coronal Mass Ejections. This will be accomplished by launching a small satellite, the Spitzer-Resurrector Mission (SRM), to rendezvous with Spitzer in 2030, positioning itself around it, and serving as a relay for recommissioning and science operations. A sample of science goals for Spitzer is briefly described, but the focus of this paper is on the unique opportunity offered by SRM to demonstrate novel Space Weather research and operations capabilities.

Instruction To help determine the health protectiveness of government regulations and policies for air pollutant control for Americans, our study aimed to investigate the health and economic impacts of work loss due to sickness associated with daily all-source and wildfire-specific PM2.5 (particulate matter with an aerodynamic diameter smaller than 2.5 μm) exposures in California.Methods We linked the 2015–2018 California Health Interview Survey respondents’ geocoded home addresses to daily PM2.5 estimated by satellites and atmospheric modelling simulations and wildfire-related PM2.5 from Community Multiscale Air Quality models. We calculated and applied the coefficient for the association between daily PM2.5 exposure and work loss from regression analyses to the Environmental Benefits Mapping and Analysis Program—Community Edition (BenMAP-CE) platform to assess the health and economic impacts of PM2.5 exposure on work loss due to sickness.Results We observed that each 1 µg/m3 increase in daily total PM2.5 exposure will lead to about 1 million days of work loss per year ranging from 1.1 to 1.6 million person-days, and the related economic loss was $310–390 million. Wildfire smoke alone could contribute to 0.7–2.6 million work-loss days with a related economic loss of $129–521 million per year in 2015–2018. Using the function coefficient in the current BenMAP, the excess work-loss days due to sickness was about 250 000 days and the estimated economic loss was about $45–50 million for each 1 µg/m3 increase in daily total PM2.5 exposure, and wildfire smoke alone would lead to 0.17–0.67 million work-loss days with related economic loss of $31–128 million per year during the same period.Conclusions Both conventional and wildfire-specific sources of PM2.5 produced substantial work loss and cost in California. Updating the current BenMAP-CE calculations for work-loss days will be essential in quantifying the current health impacts of PM2.5 to help inform the policies and regulations to protect public health.

Objective Testing for COVID-19 was a key component of the UK’s response to the COVID-19 pandemic. This strategy relied on positive individuals self-isolating to reduce transmission, making isolation the lynchpin in the public health approach. Therefore, we scoped evidence to systematically identify and categorise barriers and facilitators to compliance with self-isolation guidance during the COVID-19 pandemic in the UK, to inform public health strategies in future pandemics.Design A rapid scoping review was conducted.Search strategy Key terms were used to search literature databases (PubMed, Scopus and the WHO COVID-19 Research Database, on 7 November 2022), Google Scholar and stakeholder-identified manuscripts, ultimately including evidence published in English from UK-based studies conducted between 2020 and 2022.Data extraction and synthesis Data were extracted and synthesised into themes, organised broadly into capability, opportunity and motivation, and reviewed with key stakeholders from the UK Health Security Agency (UKHSA).Results We included 105 sources, with 63 identified from UKHSA and used to inform their decision-making during the pandemic. Influences on the decision to comply with isolation guidance were categorised into six themes: perceived ability to isolate; information and guidance; logistics; social influences, including trust; perceived value; and perceived consequences. Individuals continuously assessed these factors in deciding whether or not to comply with guidance and self-isolate.Conclusions Decisions to self-isolate after a positive test were influenced by multiple factors, including individuals’ beliefs, concerns, priorities and personal circumstances. Future testing strategies must facilitate meaningful financial, practical and mental health support to allow individuals to overcome the perceived and actual negative consequences of isolating. Clear, consistent communication of the purpose and procedures of isolating will also be critical to support compliance with self-isolation guidance, and should leverage people’s perceived value in protecting others. Building public trust is also essential, but requires investment before the next pandemic starts.

The purpose of this study was to determine the training needs of extension agents in Uganda to lead successful education programs on genetically engineered (GE) crops. This was a descriptive survey research study conducted online with public agricultural extension agents in the eastern agro-ecological zone of Uganda. This study used Borich’s method to identify training needs. A survey instrument was designed to determine extension agents’ perceived importance and proficiency of 60 competencies organized under the eight Public Issues Education (PIE) framework competency constructs. The survey received 58 usable responses comprising an 83% response rate. All eight PIE competency constructs were perceived by the extension agents to be important. This study identified additional four competencies important for PIE in addition to the eight competencies in the model. Agents’ greatest training needs were creating partnerships and designing GE education programs. The lowest training needs were creating an environment of professionalism and managing conflicts. The findings indicate the importance of training extension agents on how to engage with farmers in new ways to educate them on GE technology. This study provides implications for determining the training needs of extension agents in PIE such as educating farmers on GE technology.

Abstract A key objective of the Perseverance rover mission is to acquire samples of Martian rocks for future return to Earth. Eventual laboratory analyses of these samples would address key questions about the evolution of the Martian climate, interior, and habitability. Many such investigations would benefit greatly from samples of Martian bedrock that are oriented in absolute Martian geographic coordinates. However, the Mars 2020 mission was designed without a requirement for orienting the samples. Here we describe a methodology that we developed for orienting rover drill cores in the Martian geographic frame and its application to Perseverance's first 20 rock samples. To orient the cores, three angles were measured: the azimuth and hade of the core pointing vector (i.e., vector oriented along the core axis) and the core roll (i.e., the solid body angle of rotation around the pointing vector). We estimated the core pointing vector from the attitude of the rover's Coring Drill during drilling. To orient the core roll, we used oriented images of asymmetric markings on the bedrock surface acquired with the rover's Wide Angle Topographic Sensor for Operations and eNgineering (WATSON) camera. For most samples, these markings were in the form of natural features on the outcrop, while for four samples they were artificial ablation pits produced by the rover's SuperCam laser. These cores are the first geographically‐oriented (

BackgroundPeople living with HIV (PLWHA) smoke at three times the rate of the general population and respond poorly to cessation strategies. Previous studies examined repetitive transcranial magnetic stimulation (rTMS) over left dorsolateral prefrontal cortex (L. dlPFC) to reduce craving, but no studies have explored rTMS among PLWHA who smoke. The current pilot study compared the effects of active and sham intermittent theta-burst stimulation (iTBS) on resting state functional connectivity (rsFC), cigarette cue attentional bias, and cigarette craving in PLWHA who smoke.MethodsEight PLWHA were recruited (single-blind, within-subject design) to receive one session of iTBS (n=8) over the L. dlPFC using neuronavigation and, four weeks later, sham iTBS (n=5). Cigarette craving and attentional bias assessments were completed before and after both iTBS and sham iTBS. rsFC was assessed before iTBS (baseline) and after iTBS and sham iTBS.ResultsCompared to sham iTBS, iTBS enhanced rsFC between the L. dlPFC and bilateral medial prefrontal cortex and pons. iTBS also enhanced rsFC between the right insula and right occipital cortex compared to sham iTBS. iTBS also decreased cigarette craving and cigarette cue attentional bias.ConclusioniTBS could potentially offer a therapeutic option for smoking cessation in PLWHA.

Background: Lead is toxic to children and effects the cognitive development. The primary objective was to assess the association of blood lead level (BLL) with cognitive performance and general intelligence, of urban school going children aged 6–16 years from ten cities of India. Secondary objective was to assess the association of anaemia with cognitive performance and general intelligence. Method: In this cross-sectional multicentric study, general intelligence was assessed by colored progressive matrices (CPM)/standard progressive matrices (SPM) test, visual-spatial ability through coding, attention and concentration ability through digit span and working memory through arithmetic tests. Blood samples of participants were collected to assess lead levels. Socioeconomic status and anthropometric measures were also collected. Results: From April 2019–February 2020, 2247 participants with equal gender distribution were enrolled from 60 schools. The median (IQR) BLL was 8.8 (4.8, 16.4) μg/dl. We found that BLL was significantly associated with attention and concentration ability and 1 μg/dl increase in BLL decreases the performance by odds of 1.02 (95 % CI 1.01–1.03). Anaemia is found to be associated with ‘borderline or dull normal’ performance for general intelligence [Adjusted Odds Ratio (AOR) = 1.93 (95 % CI 1.53–2.45)], visual-spatial [AOR = 1.35 (95 % CI 1.03–1.76)], attention and concentration [AOR = 1.30 (95 % CI 1.02–1.66)], working memory [AOR = 1.69 (95 % CI 1.34–2.12)] abilities. Conclusion: Since increasing BLL decreases cognitive performance and anaemia decreased both cognitive performance and intelligence, attempts must be made to keep BLL as low as possible and prevent exposure in school going children.

Massive sequencing of SARS-CoV-2 genomes has urged novel methods that employ existing phylogenies to add new samples efficiently instead of de novo inference. 'TIPars' was developed for such challenge integrating parsimony analysis with pre-computed ancestral sequences. It took about 21 seconds to insert 100 SARS-CoV-2 genomes into a 100k-taxa reference tree using 1.4 gigabytes. Benchmarking on four datasets, TIPars achieved the highest accuracy for phylogenies of moderately similar sequences. For highly similar and divergent scenarios, fully parsimony-based and likelihood-based phylogenetic placement methods performed the best respectively while TIPars was the second best. TIPars accomplished efficient and accurate expansion of phylogenies of both similar and divergent sequences, which would have broad biological applications beyond SARS-CoV-2. TIPars is accessible from https://tipars.hku.hk/ and source codes are available at https://github.com/id-bioinfo/TIPars.

Introduction: Two-component response systems (TCRS) are the main mechanism by which prokaryotes acclimate to changing environments. These systems are composed of a membrane bound histidine kinase (HK) that senses external signals and a response regulator (RR) that activates transcription of response genes. Despite their known role in acclimation, little is known about the role TCRS play in environmental adaptation. Several experimental evolution studies have shown the acquisition of mutations in TCRS during adaptation, therefore here we set out to characterize the adaptive mechanism resulting from these mutations and evaluate whether single nucleotide changes in one gene could induce variable genotype-by-environment (GxE) interactions.Methods: To do this, we assessed fitness changes and differential gene expression for four adaptive mutations in cusS, the gene that encodes the HK CusS, acquired by Escherichia coli during silver adaptation.Results: Fitness assays showed that as the environment changed, each mutant displayed a unique fitness profile with greatest fitness in the original selection environment. RNAseq then indicated that, in ± silver nitrate, each mutant induces a primary response that upregulates cusS, its RR cusR, and constitutively expresses the target response genes cusCFBA. This then induces a secondary response via differential expression of genes regulated by the CusR through TCRS crosstalk. Finally, each mutant undergoes fitness tuning through unique tertiary responses that result in gene expression patterns specific for the genotype, the environment and optimized for the original selection conditions.Discussion: This three-step response shows that different mutations in a single gene leads to individualized phenotypes governed by unique GxE interactions that not only contribute to transcriptional divergence but also to phenotypic plasticity.

Granulomatous amebic encephalitis, caused by the free-living amebae Balamuthia mandrillaris or Acanthamoeba species, is a rare and deadly infectious syndrome with a current mortality rate of >90%. Much work remains to define the optimal treatment for these infections. Here, we provide a comprehensive overview of the supporting evidence behind antimicrobials currently recommended by the Centers for Disease Control and Prevention (CDC) with updated statistics on survival rates and medication usage from the CDC Free-Living Ameba Database. We also discuss promising treatments, especially the emerging therapeutic agent nitroxoline, and provide recommendations for the next steps in this area.

In 2021, global life expectancy at birth was 74 years whereas in sub-Saharan Africa it was 66 years. Yet in that same year, $92 per person was spent on health in sub- Saharan Africa, which is roughly one fifth of what the next lowest geographic region-North Africa and Middle East-spent ($379). The challenges to healthy lives in sub-Saharan Africa are many while health spending remains low. This study uses gross domestic product, government, and health spending data to give a more complete picture of the patterns of future health spending in sub-Saharan Africa. We analyzed trends in growth in gross domestic product, government health spending, development assistance for health and the prioritization of health in national spending to compare countries within sub-Saharan Africa and globally.We found that while gross domestic product was projected to increase through 2050 in sub-Saharan Africa, the share of gross domestic product that goes to health spending is only expected to increase moderately. Our exploration shows that this tepid growth is expected because the percent of overall government spending that is dedicated to health 7·2% (6·3-8·3) compared to average of 12·4% (11·7-13·2) in other regions) is expected to stay low. Even if the amount, of resources provided from donors climbs some, it is not expected to keep pace with growing economies in sub-Saharan Africa and may transition towards other global public health goods. Critically, development assistance for health provided to sub-Saharan Africa is expected to decrease in some countries, and the expected growth in government health spending might not be enough to cover this expected decline. Increases in spending with a concordant prioritization of health and the appropriate health system governance and structural reforms are critical to ensure that people who live in sub-Saharan Africa are not left behind.

Genetic predisposition to hematologic malignancies has historically been addressed utilizing patients recruited from clinical trials and pedigrees constructed at major treatment centers. Such efforts leave unexplored the genetic basis of variations in risk by race/ethnic group shown in population-based surveillance data where cancer registration, compulsory by law, delivers universal enrollment. To address this, we performed exome sequencing on DNA isolated from newborn bloodspots derived from sibling pairs with early-onset cancers across California in which at least one of the siblings developed a hematologic cancer, using unbiased recruitment from the full state population. We identified pathogenic/likely pathogenic (P/LP) variants among 1172 selected cancer genes that were private or present at low allele frequencies in reference populations. Within 64 subjects from 32 families, we found 9 LP variants shared between siblings, and an additional 7 such variants in singleton children (not shared with their sibling). In eight of the shared cases, the ancestral origin of the local haplotype that carries P/LP variants matched the dominant global ancestry of study participant families. This was the case for Latino sibling pairs on FLG and CBLB, non-Latino White sibling pairs in TP53 and NOD2, and a shared GATA2 variant for a non-Latino Black sibling pair. A new inherited mutation in HABP2 was identified in a sibling pair, one with diffuse large B-cell lymphoma and the other with neuroblastoma. Overall, the profile of P/LP germline variants across ancestral/ethnic groups suggests that rare alleles contributing to hematologic diseases originate within their race/ethnic origin parental populations, demonstrating the value of this discovery process in diverse, population-based registries.

Abstract Invasive species are reducing global biodiversity. The Llgaay gwii sdiihlda—Restoring Balance project was initiated to halt and reverse biodiversity loss on six islands on Haida Gwaii, Canada through the eradication of invasive Sitka Black‐tailed deer (Odocoileus hemionus sitkensis). Invasive deer were killed using various hunting methods including bait station, boat, aerial and indicator dog hunting as well as a combination of bailing dogs with boat and aerial hunting. Cost was quantified in terms of helicopter hunting hours ($1965 CAD/hr at the time of the study) to facilitate comparisons. Efficiency was quantified as the expected number of deer per helicopter hour. Hierarchical Bayesian integrated removal models were used to estimate the change in efficiency of the various hunting methods with deer density based on a power function. The models used the number of scent trail detections by dogs at the end of the study to help parameterise the population density. At densities between 2 and 30 deer/km2, boat hunting was estimated as the most efficient method while at lower densities indicator dog hunting was most efficient. The eradication was incomplete. The estimated cost to completion using indicator dog hunting for each island was 43 helicopter hours (~$84,000) on Ramsay Island (95% CI = 19–128), 3.9 helicopter hours on Murchison Island (95% CI = 0.56–18) and no additional hours on House (95% CI = 0–1.6) though the selected method would likely have been indicator dogs with combined hunting due to the variable terrain. Lessons learned: DNA connectivity analysis can be used to determine project durability, pilot studies to confirm method efficiency in local context will increase the chances of success, local knowledge improves efficiency of hunting methods, population and efficiency estimates should be updated throughout operations to allow adaptive management, eradications on ungulates can include pauses to facilitate adaptive management, the level of certainty for determining eradication completion should be determined in advance of operations with explicit trade‐offs identified for managers.

Due to a lack of controlled, prospective trials examining the pathophysiology and treatment of catatonia, current guidelines vary regarding how and when to best use antipsychotics in the presence of catatonia and what factors to consider in a thorough risk–benefit analysis. The literature is especially limited in describing the risks and benefits of using long-acting injectable antipsychotics in the presence of catatonia. We describe four cases where patients with preexisting catatonia received long-acting injectable first generation antipsychotics and experienced severe adverse effects (three experienced worsening of catatonia and one experienced neuroleptic malignant syndrome). The evidence base for managing comorbid catatonia and psychosis remains underdeveloped and inconsistent, but there are numerous known risk factors for adverse antipsychotic reactions, which we describe in relation to these cases. Finally, we present best practices to consider when managing comorbid psychosis and catatonia, especially when considering the use of long-acting injectable antipsychotics.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is characterised by the accumulation of lipid droplets (LDs) within hepatocytes. Perilipin 2 (PLIN2) is the most abundant protein in hepatic LDs and its expression correlates with intracellular lipid accumulation. A recently discovered PLIN2 coding variant, Ser251Pro (rs35568725), was found to promote the accumulation of small LDs in embryonic kidney cells. In this study, we investigate the role of PLIN2-Ser251Pro (PLIN2-Pro251) on hepatic LD metabolism in vivo and research the metabolic phenotypes associated with this variant in humans. Methods: For our animal model, we used Plin2 knockout mice in which we expressed either human PLIN2-Pro251 (Pro251 mice) or wild-type human PLIN2-Ser251 (Ser251 mice) in a hepatocyte-specific manner. We fed both cohorts a lipogenic high-fat, high-cholesterol, high-fructose diet for 12 weeks. Results: Pro251 mice were associated with reduced liver triglycerides (TGs) and had lower mRNA expression of fatty acid synthase and diacylglycerol O-acyltransferase-2 compared with Ser251 mice. Moreover, Pro251 mice had a reduction of polyunsaturated fatty acids-TGs and reduced expression of epoxygenase genes. For our human study, we analysed the Penn Medicine BioBank, the Million Veteran Program, and UK Biobank. Across these databases, the minor allele frequency of PLIN2-Pro251 was approximately 5%. There was no association with the clinical diagnosis of NAFLD, however, there was a trend toward reduced liver fat in PLIN2-Pro251 carriers by MRI-spectroscopy in UK Biobank subjects. Conclusions: In mice lacking endogenous Plin2, expression of human PLIN2-Pro251 attenuated high-fat, high-fructose, high-cholesterol, diet-induced hepatic steatosis compared with human wild-type PLIN2-Ser251. Moreover, Pro251 mice had lower polyunsaturated fatty acids-TGs and epoxygenase genes expression, suggesting less liver oxidative stress. In humans, PLIN2-Pro251 is not associated with NAFLD. Impact and Implications: Lipid droplet accumulation in hepatocytes is the distinctive characteristic of non-alcoholic fatty liver disease. Perilipin 2 (PLIN2) is the most abundant protein in hepatic lipid droplets; however, little is known on the role of a specific polymorphism PLIN2-Pro251 on hepatic lipid droplet metabolism. PLIN2-Pro251 attenuates liver triglycerides accumulation after a high-fat-high-glucose-diet. PLIN2-Pro251 may be a novel lipid droplet protein target for the treatment of liver steatosis.

Abstract Objectives This release note describes the Maize GxE project datasets within the Genomes to Fields (G2F) Initiative. The Maize GxE project aims to understand genotype by environment (GxE) interactions and use the information collected to improve resource allocation efficiency and increase genotype predictability and stability, particularly in scenarios of variable environmental patterns. Hybrids and inbreds are evaluated across multiple environments and phenotypic, genotypic, environmental, and metadata information are made publicly available. Data description The datasets include phenotypic data of the hybrids and inbreds evaluated in 30 locations across the US and one location in Germany in 2020 and 2021, soil and climatic measurements and metadata information for all environments (combination of year and location), ReadMe, and description files for each data type. A set of common hybrids is present in each environment to connect with previous evaluations. Each environment had a collaborator responsible for collecting and submitting the data, the GxE coordination team combined all the collected information and removed obvious erroneous data. Collaborators received the combined data to use, verify and declare that the data generated in their own environments was accurate. Combined data is released to the public with minimal filtering to maintain fidelity to the original data.

Abstract Background Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear. Methods We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1–11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points. Results We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values

Abstract Background Checkpoint inhibitor-induced overlap syndrome ([OS] myocarditis, and myositis with or without myasthenia gravis) is rare but life-threatening. Cases presentation Here we present a case series of four cancer patients that developed OS. High troponinemia raised the concern for myocarditis in all the cases. However, the predominant clinical feature differed among the cases. Two patients showed marked myocarditis with a shorter hospital stay. The other two patients had a prolonged ICU stay due to severe neuromuscular involvement secondary to myositis and myasthenia gravis. Treatment was based on steroids, plasmapheresis, intravenous immunoglobulin, and immunosuppressive biological agents. Conclusion The management of respiratory failure is challenging, particularly in those patients with predominant MG. Along with intensive clinical monitoring, bedside respiratory mechanics can guide the decision-making process of selecting a respiratory support method, the timing of elective intubation and extubation.

Recent reviews highlighted low-intensity transcranial focused ultrasound (TUS) as a promising new tool for non-invasive neuromodulation in basic and applied sciences. Our preregistered double-blind within-subjects study (N = 152) utilized TUS targeting the right prefrontal cortex, which, in earlier work, was found to positively enhance self-reported global mood, decrease negative states of self-reported emotional conflict (anxiety/worrying), and modulate related midfrontal functional magnetic resonance imaging activity in affect regulation brain networks. To further explore TUS effects on objective physiological and behavioral variables, we used a virtual T-maze task that has been established in prior studies to measure motivational conflicts regarding whether participants execute approach versus withdrawal behavior (with free-choice responses via continuous joystick movements) while allowing to record related electroencephalographic data such as midfrontal theta activity (MFT). MFT, a reliable marker of conflict representation on a neuronal level, was of particular interest to us since it has repeatedly been shown to explain related behavior, with relatively low MFT typically preceding approach-like risky behavior and relatively high MFT typically preceding withdrawal-like risk aversion. Our central hypothesis is that TUS decreases MFT in T-maze conflict situations and thereby increases approach and reduces withdrawal. Results indicate that TUS led to significant MFT decreases, which significantly explained increases in approach behavior and decreases in withdrawal behavior. This study expands TUS evidence on a physiological and behavioral level with a large sample size of human subjects, suggesting the promise of further research based on this distinct TUS-MFT-behavior link to influence conflict monitoring and its behavioral consequences. Ultimately, this can serve as a foundation for future clinical work to establish TUS interventions for emotional and motivational mental health.