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Background: Measurement of trough levels for calcineurin inhibitors by venipuncture sampling is a mainstay of patient management in solid organ transplant recipients but challenging in pediatric patients. Volumetric Absorptive Microsampling (VAMS) is a patient-friendly, minimally invasive sampling technique to accurately collect blood. An assay for measurement of tacrolimus in blood using VAMS, coupled with parallel reaction monitoring (PRM) mass spectrometry, was validated in pediatric heart transplant patients. Methods: Tacrolimus was measured by a newly developed high-resolution PRM assay and compared with low-resolution tandem mass spectrometry (MRM). Dried blood samples were collected from pediatric heart transplant patients (n = 35) using VAMS devices and a satisfaction survey was completed by patients/guardians. Tacrolimus concentrations were compared across whole liquid blood, dried blood spots, and capillary blood, and shipping stability determined. Results: The PRM assay was linear over a range 1–50 ng/mL, similar to MRM but had greater specificity due to reduced background noise. No significant differences in tacrolimus concentrations were observed between VAMS and venous blood. Tacrolimus dried on VAM tips was stable for 14 days and concentrations were unaffected by postal shipping. The variability in two simultaneously collected at-home patient samples was minimal – average concentration difference was 0.12 ± 0.94 ng/mL (p = 0.6) between paired samples. Conclusion: A high resolution PRM mass spectrometry assay was developed for home-based dried blood collections for therapeutic monitoring of tacrolimus. The advantage of PRM was enhanced specificity and the VAMS devices provided a simple and convenient approach to blood sampling at home in pediatric heart transplant patients.

Background and Aims: Children with very early onset inflammatory bowel disease (VEO-IBD) are uniquely at risk of inadequate infliximab (IFX) exposure. We studied the association between standard body weight (BW)-based and body surface area (BSA)-based dosing strategies and outcomes. Methods: We identified VEO-IBD patients treated with IFX before 9 years at a single center. Patients were separated into those that received a BSA-based dose (200 mg/m2) and standard BW dosing (5 mg/kg). IFX drug levels, dose intensification, time on steroids, and long-term outcomes were compared. Receiver operator characteristic curves determined the optimal BW- and BSA-based dose to achieve a trough ≥10 μg/ml at dose 4 (IFX#4). Results: Forty-three children with VEO-IBD were identified. Receiver operator characteristic curves demonstrated optimal BW- and BSA-based doses to achieve IFX trough ≥10 μg/ml at IFX#4 were 7.5 mg/kg and 180mg/m2. Children were classified to standard BW dosing (22/43) and BSA dosing (10/43). IFX#4 trough was significantly higher in those who received BSA dosing (BSA 18.6 μg/ml [interquartile range 10.8–28.1] vs BW 5.1 μg/ml [interquartile range 2.6–10.7], P = .04). BSA dosing was more likely to achieve a target drug level >10 μg/ml at IFX#4 (BSA 70% vs BW 18%, P = .02). BW dosing was associated with a greater likelihood of dose escalation (BW 82% vs BSA 30%, P < .01) and a shorter time to first escalation. BSA dosing was associated with shorter time spent on steroids (P = .02). Conclusion: Young children require higher IFX dosing to achieve adequate drug exposure. Our data support the use of a BSA-based dose of 200 mg/m2 or, if a BW-based approach is used, 7.5 mg/kg. BSA dosing allows the use of a consistent dose over the age and weight spectrum.

Abstract The water surface provides a highly effective platform for the synthesis of two-dimensional polymers (2DP). In this study, we present an efficient on-water surface synthesis of crystalline monolayer 2D polyimide (2DPI) through the imidization reaction between tetra (4-aminophenyl) porphyrin (M1) and perylenetracarboxylic dianhydride (M2), resulting in excellent stability and coverage over a large area (tens of cm2). We further fabricate innovative organic-inorganic hybrid van der Waals heterostructures (vdWHs) by combining with exfoliated few-layer molybdenum sulfide (MoS2). High-resolution transmission electron microscopy (HRTEM) reveals face-to-face stacking between MoS2 and 2DPI within the vdWH. This stacking configuration facilitates remarkable charge transfer and noticeable n-type doping effects from monolayer 2DPI to MoS2, as corroborated by Raman spectroscopy, photoluminescence measurements, and field-effect transistor (FET) characterizations. Notably, the 2DPI-MoS2 vdWH exhibits an impressive electron mobility of 50 cm2/V·s, signifying a substantial improvement over pristine MoS2 (8 cm2/V·s). This study unveils the immense potential of integrating 2D polymers to enhance semiconductor device functionality through tailored vdWHs, thereby opening up exciting new avenues for exploring unique interfacial physical phenomena.

Abstract Bone morphogenetic protein (BMP15) and growth differentiation factor (GDF9) are critical for ovarian follicular development and fertility and are associated with litter size in mammals. These proteins initially exist as pre-pro-mature proteins, that are subsequently cleaved into biologically active forms. Thus, the molecular forms of GDF9 and BMP15 may provide the key to understanding the differences in litter size determination in mammals. Herein, we compared GDF9 and BMP15 forms in mammals with high (pigs) and low to moderate (sheep) and low (red deer) ovulation-rate. In all species, oocyte lysates and secretions contained both promature and mature forms of BMP15 and GDF9. Whilst promature and mature GDF9 levels were similar between species, deer produced more BMP15 and exhibited, together with sheep, a higher promature:mature BMP15 ratio. N-linked glycosylation was prominant in proregion and mature GDF9 and in proregion BMP15 of pigs, and present in proregion GDF9 of sheep. There was no evidence of secreted native homo- or hetero-dimers although a GDF9 dimer in red deer oocyte lysate was detected. In summary, GDF9 appeared to be equally important in all species regardless of litter size, whilst BMP15 levels were highest in strict monovulatory species.

Unmanned Aerial Vehicles (UAVs), commonly known as drones, are omnipresent and have grown in popularity due to their wide potential use in many civilian sectors. Equipped with sophisticated sensors and communication devices, drones can potentially form a multi-UAV system, also called an autonomous swarm, in which UAVs work together with little or no operator control. According to the complexity of the mission and coverage area, swarm operations require important considerations regarding the intelligence and self-organization of the UAVs. Factors including the types of drones, the communication protocol and architecture, task planning, consensus control, and many other swarm mobility considerations must be investigated. While several papers highlight the use cases for UAV swarms, there is a lack of research that addresses in depth the challenges posed by deploying an intelligent UAV swarm. Against this backdrop, we propose a computation framework of a self-organized swarm for autonomous and collaborative missions. The proposed approach is based on the Leader–Followers paradigm, which involves the distribution of ROS nodes among follower UAVs, while leaders perform supervision. Additionally, we have integrated background services that autonomously manage the complexities relating to task coordination, control policy, and failure management. In comparison with several research efforts, the proposed multi-UAV system is more autonomous and resilient since it can recover swiftly from system failure. It is also reliable and has been deployed on real UAVs for outdoor survey missions. This validates the applicability of the theoretical underpinnings of the proposed swarming concept. Experimental tests carried out as part of an area coverage mission with 6 quadcopters (2 leaders and 4 followers) reveal that the proposed swarming concept is very promising and inspiring for aerial vehicle technology. Compared with the conventional planning approach, the results are highly satisfactory, highlighting a significant gain in terms of flight time, and enabling missions to be achieved rapidly while optimizing energy consumption. This gives the advantage of exploring large areas without having to make frequent downtime to recharge and/or charge the batteries. This manuscript has the potential to be extremely useful for future research into the application of unmanned swarms for autonomous missions.

Children with cerebral palsy (CP) exhibit head instability during simple overground walking, which may comprise sensory input and reduce stepping accuracy. Investigations of head stability during more challenging tasks, where fall risk may be increased, are limited. This study explored differences in head stability between ambulatory children with hemiplegic CP (N = 9) and diplegia (N = 9) (GMFCS I and II) and typically developing (TD) children (N = 8) during a targeted stepping task. All children completed five trials stepping into two successive rectangular floor-based targets whilst walking along an 8 m walkway. Three-dimensional motion capture enabled calculation of head stability and foot placement within and before each target. A two-way mixed-design ANOVA compared differences between all groups and target approach. Children with diplegic CP showed greater sagittal, frontal, and resultant head-to-laboratory and head-to-trunk head instability compared to children with hemiplegic CP and TD children. Anteroposterior foot placement error was significantly greater in children with hemiplegic CP (8.5 ± 5.0 cm) compared to TD children (3.8 ± 1.5 cm). Group differences in head instability were not consistent with group differences in foot placement error. To better understand how head instability might affect fall risk in children with CP, more challenging environments should be tested in future.

Abstract PARP inhibitors (PARPi)‐based synthetic lethal therapy demonstrates limited efficacy for most cancer types that are homologous recombination (HR) proficient. To potentiate the PARPi application, a nanocarrier based on 5‐azacytidine (AZA)‐conjugated polymer (PAZA) for the codelivery of AZA and a PARP inhibitor, BMN673 (BMN) is developed. AZA conjugation significantly decreased the nanoparticle (NP) size and increased BMN loading. Molecular dynamics simulation and experimental validations shed mechanistic insights into the self‐assembly of effective NPs. The small PAZA NPs demonstrated higher efficiency of tumor targeting and penetration than larger NPs, which is mediated by a new mechanism of active targeting that involves the recruitment of fibronectin from serum proteins following systemic administration of PAZA NPs. Furthermore, it is found that PAZA carrier sensitize the HR‐proficient nonsmall cell lung cancer (NSCLC) to BMN, a combination therapy that is more effective at a lower AZA/BMN dosage. To investigate the underlying mechanism, the tumor immune microenvironment and various gene expressions by RNAseq are explored. Moreover, the BMN/PAZA combination increased the immunogenicity and synergized with PD‐1 antibody in improving the overall therapeutic effect in an orthotopic model of lung cancer (LLC).

The impact of Alzheimer’s disease (AD) and its related dementias is rapidly expanding, and its mitigation remains an urgent social and technical challenge. To date there are no effective treatments or interventions for AD, but recent studies suggest that alcohol consumption is correlated with the risk of developing dementia. In this review, we synthesize data from preclinical, clinical, and epidemiological models to evaluate the combined role of alcohol consumption and serotonergic dysfunction in AD, underscoring the need for further research on this topic. We first discuss the limitations inherent to current data-collection methods, and how neuropsychiatric symptoms common among AD, alcohol use disorder, and serotonergic dysfunction may mask their co-occurrence. We additionally describe how excess alcohol consumption may accelerate the development of AD via direct effects on serotonergic function, and we explore the roles of neuroinflammation and proteostasis in mediating the relationship between serotonin, alcohol consumption, and AD. Lastly, we argue for a shift in current research to disentangle the pathogenic effects of alcohol on early-affected brainstem structures in AD.

Aims Direct-acting oral anticoagulants (DOACs) have, to a substantial degree, replaced vitamin K antagonists (VKA) as treatments for stroke prevention in atrial fibrillation (AF) patients. However, evidence on the real-world causal effects of switching patients from VKA to DOAC is lacking. We aimed to assess the empirical incremental cost-effectiveness of switching patients to DOAC compared with maintaining VKA treatment.Methods The target trial approach was applied to the prospective observational Swiss-AF cohort, which enrolled 2415 AF patients from 2014 to 2017. Clinical data, healthcare resource utilisation and EQ-5D-based utilities representing quality of life were collected in yearly follow-ups. Health insurance claims were available for 1024 patients (42.4%). Overall survival, quality-of-life, costs from the Swiss statutory health insurance perspective and cost-effectiveness were estimated by emulating a target trial in which patients were randomly assigned to switch to DOAC or maintain VKA treatment.Results 228 patients switching from VKA to DOAC compared with 563 patients maintaining VKA treatment had no overall survival advantage over a 5-year observation period (HR 0.99, 95% CI 0.45, 1.55). The estimated gain in quality-adjusted life years (QALYs) was 0.003 over the 5-year period at an incremental costs of CHF 23 033 (€ 20 940). The estimated incremental cost-effectiveness ratio was CHF 425 852 (€ 387 138) per QALY gained.Conclusions Applying a causal inference method to real-world data, we could not demonstrate switching to DOACs to be cost-effective for AF patients with at least 1 year of VKA treatment. Our estimates align with results from a previous randomised trial.

Introduction Acute kidney injury (AKI) is a common complication of sepsis associated with increased risk of death. Preclinical data and observational human studies suggest that activation of AMP-activated protein kinase, an ubiquitous master regulator of energy that can limit mitochondrial injury, with metformin may protect against sepsis-associated AKI (SA-AKI) and mortality. The Randomized Clinical Trial of the Safety and FeasibiLity of Metformin as a Treatment for sepsis-associated AKI (LiMiT AKI) aims to evaluate the safety and feasibility of enteral metformin in patients with sepsis at risk of developing SA-AKI.Methods and analysis Blind, randomised, placebo-controlled clinical trial in a single-centre, quaternary teaching hospital in the USA. We will enrol adult patients (18 years of age or older) within 48 hours of meeting Sepsis-3 criteria, admitted to intensive care unit, with oral or enteral access. Patients will be randomised 1:1:1 to low-dose metformin (500 mg two times per day), high-dose metformin (1000 mg two times per day) or placebo for 5 days. Primary safety outcome will be the proportion of metformin-associated serious adverse events. Feasibility assessment will be based on acceptability by patients and clinicians, and by enrolment rate.Ethics and dissemination This study has been approved by the Institutional Review Board. All patients or surrogates will provide written consent prior to enrolment and any study intervention. Metformin is a widely available, inexpensive medication with a long track record for safety, which if effective would be accessible and easy to deploy. We describe the study methods using the Standard Protocol Items for Randomized Trials framework and discuss key design features and methodological decisions. LiMiT AKI will investigate the feasibility and safety of metformin in critically ill patients with sepsis at risk of SA-AKI, in preparation for a future large-scale efficacy study. Main results will be published as soon as available after final analysis.Trial registration number NCT05900284.

Background:. Facial skin cancer and its surgical treatment can affect health-related quality of life. The FACE-Q Skin Cancer Module is a patient-reported outcome measure that measures different aspects of health-related quality of life and has recently been translated into Dutch. This study aimed to evaluate the performance of the translated version in a Dutch cohort using modern psychometric measurement theory (Rasch). Methods:. Dutch participants with facial skin cancer were prospectively recruited and asked to complete the translated FACE-Q Skin Cancer Module. The following assumptions of the Rasch model were tested: unidimensionality, local independence, and monotonicity. Response thresholds, fit statistics, internal consistency, floor and ceiling effects, and targeting were assessed for all scales and items within the scales. Responsiveness was tested for the “cancer worry” scale. Results:. In total, 259 patients completed the preoperative questionnaire and were included in the analysis. All five scales assessed showed a good or sufficient fit to the Rasch model. Unidimensionality and monotonicity were present for all scales. Some items showed a local dependency. Most of the scales demonstrate ordered item thresholds and appropriate fit statistics. Conclusions:. The FACE-Q Skin Cancer Module is a well-designed patient-reported outcome measure that shows psychometric validity for the translated version in a Dutch cohort, using classical and modern test theory.

Introduction Although limited, recent research suggests that contact sport participation might have an adverse long-term effect on brain health. Further work is required to determine whether this includes an increased risk of neurodegenerative disease and/or subsequent changes in cognition and behaviour. The Advanced BiomaRker, Advanced Imaging and Neurocognitive Health Study will prospectively examine the neurological, psychiatric, psychological and general health of retired elite-level rugby union and association football/soccer players.Methods and analysis 400 retired athletes will be recruited (200 rugby union and 200 association football players, male and female). Athletes will undergo a detailed clinical assessment, advanced neuroimaging, blood testing for a range of brain health outcomes and neuropsychological assessment longitudinally. Follow-up assessments will be completed at 2 and 4 years after baseline visit. 60 healthy volunteers will be recruited and undergo an aligned assessment protocol including advanced neuroimaging, blood testing and neuropsychological assessment. We will describe the previous exposure to head injuries across the cohort and investigate relationships between biomarkers of brain injury and clinical outcomes including cognitive performance, clinical diagnoses and psychiatric symptom burden.Ethics and dissemination Relevant ethical approvals have been granted by the Camberwell St Giles Research Ethics Committee (Ref: 17/LO/2066). The study findings will be disseminated through manuscripts in clinical/academic journals, presentations at professional conferences and through participant and stakeholder communications.

Abstract Arginine‐ornithine metabolism plays a crucial role in bacterial homeostasis, as evidenced by numerous studies. However, the utilization of arginine and the downstream products of its metabolism remain undefined in various gut bacteria. To bridge this knowledge gap, we employed genomic screening to pinpoint relevant metabolic targets. We also devised a targeted liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) metabolomics method to measure the levels of arginine, its upstream precursors, and downstream products in cell‐free conditioned media from enteric pathobionts, including Escherichia coli, Klebsiella aerogenes, K. pneumoniae, Pseudomonas fluorescens, Acinetobacter baumannii, Streptococcus agalactiae, Staphylococcus epidermidis, S. aureus, and Enterococcus faecalis. Our findings revealed that all selected bacterial strains consumed glutamine, glutamate, and arginine, and produced citrulline, ornithine, and GABA in our chemically defined medium. Additionally, E. coli, K. pneumoniae, K. aerogenes, and P. fluorescens were found to convert arginine to agmatine and produce putrescine. Interestingly, arginine supplementation promoted biofilm formation in K. pneumoniae, while ornithine supplementation enhanced biofilm formation in S. epidermidis. These findings offer a comprehensive insight into arginine‐ornithine metabolism in enteric pathobionts.

Antibiotics reach agricultural soils via fertilization with manure and biosolids as well as irrigation withwastewater and have the potential to be taken up by growing crops. The fate of antibiotics in terms of uptakefrom soil to plants, as well as translocation from root to leaves, is determined by a combination of antibiotic’sphysio-chemical (e.g. speciation, lipophilicity), soil (e.g. organic carbon content, pH) and plant (e.g.transpiration rates) characteristics. In this meta-analysis, a literature search was executed to obtain an overview of antibiotic uptake to plants, with an aim to identify uptake and translocation patterns of different antibiotic classes. Overall, we found that higher uptake of tetracyclines to plant leaves was observed compared to sulfonamides. Differences were also observed in translocation within the plants, where tetracyclines were found in roots and leaves with close to equal concentrations, while the sulfonamides represented a tendency to accumulate to the root fraction. The antibiotic’s characteristics have a high influence on their fate, for example, the high water-solubility and uncharged speciation in typical agricultural soil pH ranges likely induces tetracycline uptake from soil and translocation in plant. Despite the advances in knowledge over the past decade, our meta-analysis indicated that the available research is focused on a limited number of analytes and antibiotic classes. Furthermore, fastgrowing plant species (e.g. spinach, lettuce, and radish) are overly represented in studies compared to crop species with higher significance for human food sources (e.g. corn, wheat, and potato), requiring more attention in future research.

Background While immunotherapy has been highly successful for the treatment of some cancers, for others, the immune response to tumor antigens is weak leading to treatment failure. The resistance of tumors to checkpoint inhibitor therapy may be caused by T cell exhaustion resulting from checkpoint activation.Methods In this study, lentiviral vectors that expressed T cell epitopes of an experimentally introduced tumor antigen, ovalbumin, or the endogenous tumor antigen, Trp1 were developed. The vectors coexpressed CD40 ligand (CD40L), which served to mature the dendritic cells (DCs), and a soluble programmed cell death protein 1 (PD-1) microbody to prevent checkpoint activation. Vaccination of mice bearing B16.OVA melanomas with vector-transduced DCs induced the proliferation and activation of functional, antigen-specific, cytolytic CD8 T cells.Results Vaccination induced the expansion of CD8 T cells that infiltrated the tumors to suppress tumor growth. Vector-encoded CD40L and PD-1 microbody increased the extent of tumor growth suppression. Adoptive transfer demonstrated that the effect was mediated by CD8 T cells. Direct injection of the vector, without the need for ex vivo transduction of DCs, was also effective.Conclusions This study suggests that therapeutic vaccination that induces tumor antigen-specific CD8 T cells coupled with a vector-expressed checkpoint inhibitor can be an effective means to suppress the growth of tumors that are resistant to conventional immunotherapy.

Abstract Graphene geometric diodes, with applications in THz detection, energy harvesting, and high‐speed rectification, have been previously constrained by graphene quality and geometry feature size. This study presents significant advancements in graphene geometric diodes by employing the h‐BN/monolayer graphene/h‐BN heterojunction and extremely precise electron beam lithography. Two distinct designs of graphene geometric diodes with neck widths of 23 and 26 nm are fabricated, the superior of which demonstrated an asymmetry ratio of 1.97, a zero bias current responsivity of 0.6 A W−1, and a voltage responsivity of 12,000 V W−1, setting new benchmarks for such devices. Integrating this device into a rectification circuit, the experimentally validate that the rectified DC output voltage can be dynamically modulated and even inverted through adjustments to the diode's gate voltage. This behavior aligns seamlessly with graphene's intrinsic tunability of charge carriers, implying promising prospects for the device's application in advanced logic circuits, bidirectional switches, and signal modulation/demodulation techniques.

Pyrogenic carbon capture and storage (PyCCS), which comprises the production of biomass, its pyrolysis, and the non-oxidative use of the biochar to create carbon sinks, has been identified as a promising negative emission technology with co-benefits by improving soil properties. Using biochar as a soil additive becomes increasingly common as farmers seek methods for soil improvement and climate change adaptation. Concurrently, there is growing interest in quantifying soil organic carbon (SOC) at the level of individual plots to remunerate farmers for their good agricultural practices and the resulting (temporary) carbon dioxide removal (CDR). However, methods currently applied in routine analysis quantify SOC, irrespective of its speciation or origin, and do not allow to distinguish biochar-C from SOC. As certification of PyCCS-derived CDR is already established using another quantification method (i.e., analysis of biochar-C content, tracking and registration of its application, and offsetting of carbon expenditures caused by the PyCCS process), the analysis of biochar-C as part of SOC may result in double counting of CDR. Hence, the objectives of this review are (1) to compare the physicochemical properties and the quantities of biochar and SOC fractions on a global and field/site-specific scale, (2) to evaluate the established methods of SOC and pyrogenic carbon (PyC) quantification with regard to their suitability in routine analysis, and (3) to assess whether double counting of SOC and biochar C-sinks can be avoided via analytical techniques. The methods that were found to have the potential to distinguish between non-pyrogenic and PyC in soil are either not fit for routine analysis or require calibration for different soil types, which is extremely laborious and yet to be established at a commercial scale. Moreover, the omnipresence of non-biochar PyC in soils (i.e., from forest fires or soot) that is indistinguishable from biochar-C is an additional challenge that can hardly be solved analytically. This review highlights the risks and limits of only result-based schemes for SOC certification relying on soil sampling and analysis. Carbon sink registers that unite the (spatial) data of biochar application and other forms of land-based CDR are suggested to track biochar applications and to effectively avoid double counting.

Sex is determined by multiple factors derived from somatic and germ cells in vertebrates. We have identified amhy, dmrt1, gsdf as male and foxl2, foxl3, cyp19a1a as female sex determination pathway genes in Nile tilapia. However, the relationship among these genes is largely unclear. Here, we found that the gonads of dmrt1;cyp19a1a double mutants developed as ovaries or underdeveloped testes with no germ cells irrespective of their genetic sex. In addition, the gonads of dmrt1;cyp19a1a;cyp19a1b triple mutants still developed as ovaries. The gonads of foxl3;cyp19a1a double mutants developed as testes, while the gonads of dmrt1;cyp19a1a;foxl3 triple mutants eventually developed as ovaries. In contrast, the gonads of amhy;cyp19a1a, gsdf;cyp19a1a, amhy;foxl2, gsdf;foxl2 double and amhy;cyp19a1a;cyp19a1b, gsdf;cyp19a1a;cyp19a1b triple mutants developed as testes with spermatogenesis via up-regulation of dmrt1 in both somatic and germ cells. The gonads of amhy;foxl3 and gsdf;foxl3 double mutants developed as ovaries but with germ cells in spermatogenesis due to up-regulation of dmrt1. Taking the respective ovary and underdeveloped testis of dmrt1;foxl3 and dmrt1;foxl2 double mutants reported previously into consideration, we demonstrated that once dmrt1 mutated, the gonad could not be rescued to functional testis by mutating any female pathway gene. The sex reversal caused by mutation of male pathway genes other than dmrt1, including its upstream amhy and downstream gsdf, could be rescued by mutating female pathway gene. Overall, our data suggested that dmrt1 is the only male pathway gene tested indispensable for sex determination and functional testis development in tilapia.

The nutritional requirements of sows change during lactation and thus require adapted and dynamic feeding regimes that consider the sows’ behavioral needs and production traits. The present study evaluated the effect of four different feeding systems on productivity and aspects of the welfare of 61 sows and their piglets during lactation. A non-ad libitum system (CON) was compared with two computer-monitored (COMP, COMP + ) ad libitum feeding systems, that allowed sows to access feed via displacement of an electronic sensor, as well as a third purely mechanical ad libitum feeding system (MECH). Daily feed disappearance, piglet growth, piglet growth per feed disappearance as well as sows’ weight and conception rate were recorded. Health indicators of sows and piglets were scored as well as sow behavior analyzed for a total of 96 hours/sow from video recordings taken on days 2–4 and 23 postfarrowing (n = 35 sows). Sows from all three ad libitum systems (COMP, COMP+, MECH) showed a lower feed disappearance than CON (P

Improving the seed protein concentration (SPC) of pea (Pisum sativum L.) has turned into an important breeding objective because of the consumer demand for plant-based protein and demand from protein fractionation industries. To support the marker-assisted selection (MAS) of SPC towards accelerated breeding of improved cultivars, we have explored two diverse recombinant inbred line (RIL) populations to identify the quantitative trait loci (QTLs) associated with SPC. The two RIL populations, MP 1918 × P0540-91 (PR-30) and Ballet × Cameor (PR-31), were derived from crosses between moderate SPC × high SPC accessions. A total of 166 and 159 RILs of PR-30 and PR-31, respectively, were genotyped using an Axiom® 90K SNP array and 13.2K SNP arrays, respectively. The RILs were phenotyped in replicated trials in two and three locations of Saskatchewan, Canada in 2020 and 2021, respectively, for agronomic assessment and SPC. Using composite interval mapping, we identified three QTLs associated with SPC in PR-30 and five QTLs in PR-31, with the LOD value ranging from 3.0 to 11.0. A majority of these QTLs were unique to these populations compared to the previously known QTLs for SPC. The QTL SPC-Ps-5.1 overlapped with the earlier reported SPC associated QTL PC-QTL-3. Three QTLs, SPC-Ps-4.2, SPC-Ps-5.1, and SPC-Ps-7.2 with LOD scores of 7.2, 7.9, and 11.3, and which explained 14.5%, 11.6%, and 11.3% of the phenotypic variance, respectively, can be used for marker-assisted breeding to increase SPC in peas. Eight QTLs associated with the grain yield were identified with LOD scores ranging from 3.1 to 8.2. Two sets of QTLs, SPC-Ps-2.1 and GY-Ps-2.1, and SPC-Ps-5.1 and GY-Ps-5.3, shared the QTL/peak regions. Each set of QTLs contributed to either SPC or grain yield depending on which parent the QTL region is derived from, thus confirming that breeding for SPC should take into consideration the effects on grain yield.

Background: Acinar ductal metaplasia (ADM) is among the earliest initiating events in pancreatic ductal adenocarcinoma (PDAC) development.Methods: We developed a novel morphology-based screen using organoids from wildtype and p48Cre/+ (Cre) mice to discover epigenetic modulators that inhibit or reverse pancreatic ADM more effectively than the broad-spectrum HDAC inhibitor trichostatin A (TSA).Results: Of the 144 compounds screened, nine hits and two additional natural product HDAC inhibitors were validated by dose-response analysis. The class I HDAC inhibitors apicidin and FK228, and the histone methyltransferase inhibitor chaetocin demonstrated pronounced ADM inhibition and reversal without inducing significant cytotoxicity at 1 µM. Thioester prodrug class I HDAC inhibitor largazole attenuated ADM while its disulfide homodimer was effective in both ADM inhibition and reversal. Prioritized compounds were validated for ADM reversal in p48Cre/+; LSL-KrasG12D/+ (KC) mouse organoids using both morphological and molecular endpoints. Molecular index analysis of ADM reversal in KC mouse organoids demonstrated improved activity compared to TSA. Improved prodrug stability translated into a stronger phenotypic and molecular response. RNA-sequencing indicated that angiotensinogen was the top inhibited pathway during ADM reversal.Conclusion: Our findings demonstrate a unique epigenetic mechanism and suggest that the phenotypic screen developed here may be applied to discover potential treatments for PDAC.

Aim: The risk of venous thromboembolism (VTE) and arterial thrombosis events (ATE) and potential corresponding risk factors were assessed in patients with cancer diagnosed with COVID-19. Methods: Adults with cancer treated in community health systems who were diagnosed with COVID-19 in 2020 were evaluated for absolute risk (risk) of ATE and VTE. Thrombotic events were ascertained in the 90-day window starting with COVID-19 diagnosis (index). ICD codes defined baseline comorbidities, COVID-19, and thrombotic events. Results: 7591 patients were included with median age of 67, 6% with cardiovascular disease (CVD), 4% with prior VTE, and 24% were hospitalized at index. Risk of ATE and VTE were 2.1% (95%CI: 1.8, 2.5) and 3.2% (95%CI: 2.8, 3.6), respectively. Patients with CVD had increased risk [ATE: 20.1% (95%CI: 16.7, 24.1); VTE: 4.9% (95%CI: 3.3, 7.3)] as did patients with prior VTE [ATE: 3.8% (95%CI: 2.2, 6.6; VTE: 20.5% (95%CI: 16.4, 25.3)] and patients hospitalized with ventilator support [(ATE: 5.7% (95%CI: 2.6, 11.8; VTE: 6.6% (95%CI: 3.2, 13.0)]. Incidence rates for ATE and VTE were 0.094 and 0.141 per person-year, respectively. Conclusions: This study of cancer patients, conducted in a time period prior to vaccine availability, found patients with CVD, prior VTE, and with higher severity of COVID-19 were at increased risk for ATE and VTE. Identifying patients most at risk can help to target interventions.

Gallstone ileus is a well-known cause of small bowel obstruction in the radiological literature. In the experience of these authors, gallstone ileus occurs more often in quiz cases for registrars than in the everyday casework of a radiologist. The here presented case of a gallstone ileus provides a good opportunity to summarize cause, clinical presentation, radiological findings, and treatment options for both those studying for the specialist examinations and those whose specialist examinations are long past.

Abstract A wide-field endoscope that is sensitive to fluorescence can be used as an adjunct to conventional white light endoscopy by detecting multiple molecular targets concurrently. We aim to demonstrate a flexible fiber-coupled accessory that can pass forward through the instrument channel of standard medical endoscopes for clinical use to collect fluorescence images. A miniature scan mirror with reflector dimensions of 1.30 × 0.45 mm2 was designed, fabricated, and placed distal to collimated excitation beams at λex = 488, 660, and 785 nm. The mirror was driven at resonance for wide angular deflections in the X and Y-axes. A large image field-of-view (FOV) was generated in real time. The optomechanical components were packaged in a rigid distal tip with dimensions of 2.6 mm diameter and 12 mm length. The scan mirror was driven at 27.6 and 9.04 kHz in the fast (X) and slow (Y) axes, respectively, using a square wave with 50% duty cycle at 60 Vpp to collect fluorescence images at 10 frames per sec. Maximum total divergence angles of ± 27.4° and ± 22.8° were generated to achieve a FOV of 10.4 and 8.4 mm, respectively, at a working distance of 10 mm. Multiplexed fluorescence images were collected in vivo from the rectum of live mice using 3 fluorescently-labeled peptides that bind to unique cell surface targets. The fluorescence images collected were separated into 3 channels. Target-to-background ratios of 2.6, 3.1, and 3.9 were measured. This instrument demonstrates potential for broad clinical use to detect heterogeneous diseases in hollow organs.

Abstract We report a series of 1,3-diphenylureido hydroxamate HDAC inhibitors evaluated against sensitive and drug-resistant P. falciparum strains. Compounds 8a–d show potent antiplasmodial activity, indicating that a phenyl spacer allows improved potency relative to cinnamyl and di-hydrocinnamyl linkers. In vitro, mechanistic studies demonstrated target activity for PfHDAC1 on a recombinant level, which agreed with cell quantification of the acetylated histone levels. Compounds 6c, 7c, and 8c, identified as the most active in phenotypic assays and PfHDAC1 enzymatic inhibition. Compound 8c stands out as a remarkable inhibitor, displaying an impressive 85% inhibition of PfHDAC1, with an IC50 value of 0.74 µM in the phenotypic screening on Pf3D7 and 0.8 µM against multidrug-resistant PfDd2 parasites. Despite its potent inhibition of PfHDAC1, 8c remains the least active on human HDAC1, displaying remarkable selectivity. In silico studies suggest that the phenyl linker has an ideal length in the series for permitting effective interactions of the hydroxamate with PfHDAC1 and that this compound series could bind as well as in HsHDAC1. Taken together, these results highlight the potential of diphenylurea hydroxamates as a privileged scaffold for the generation of potent antimalarial HDAC inhibitors with improved selectivity over human HDACs.

Abstract Background Biallelic variants in OGDHL, encoding part of the α-ketoglutarate dehydrogenase complex, have been associated with highly heterogeneous neurological and neurodevelopmental disorders. However, the validity of this association remains to be confirmed. A second OGDHL patient cohort was recruited to carefully assess the gene-disease relationship. Methods Using an unbiased genotype-first approach, we screened large, multiethnic aggregated sequencing datasets worldwide for biallelic OGDHL variants. We used CRISPR/Cas9 to generate zebrafish knockouts of ogdhl, ogdh paralogs, and dhtkd1 to investigate functional relationships and impact during development. Functional complementation with patient variant transcripts was conducted to systematically assess protein functionality as a readout for pathogenicity. Results A cohort of 14 individuals from 12 unrelated families exhibited highly variable clinical phenotypes, with the majority of them presenting at least one additional variant, potentially accounting for a blended phenotype and complicating phenotypic understanding. We also uncovered extreme clinical heterogeneity and high allele frequencies, occasionally incompatible with a fully penetrant recessive disorder. Human cDNA of previously described and new variants were tested in an ogdhl zebrafish knockout model, adding functional evidence for variant reclassification. We disclosed evidence of hypomorphic alleles as well as a loss-of-function variant without deleterious effects in zebrafish variant testing also showing discordant familial segregation, challenging the relationship of OGDHL as a conventional Mendelian gene. Going further, we uncovered evidence for a complex compensatory relationship among OGDH, OGDHL, and DHTKD1 isoenzymes that are associated with neurodevelopmental disorders and exhibit complex transcriptional compensation patterns with partial functional redundancy. Conclusions Based on the results of genetic, clinical, and functional studies, we formed three hypotheses in which to frame observations: biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all. Our study further highlights the continuing challenges of assessing the validity of reported disease-gene associations and effects of variants identified in these genes. This is particularly more complicated in making genetic diagnoses based on identification of variants in genes presenting a highly heterogenous phenotype such as “OGDHL-related disorders”.

Abstract Graphitic carbon nitride is widely studied in organic photoredox catalysis. Reductive quenching of carbon nitride excited state is postulated in many photocatalytic transformations. However, the reactivity of this species in the turn over step is less explored. In this work, we investigate electron and proton transfer from carbon nitride that is photocharged to a various extent, while the negative charge is compensated either by protons or ammonium cations. Strong stabilization of electrons by ammonium cations makes proton-coupled electron transfer uphill, and affords air-stable persistent carbon nitride radicals. In carbon nitrides, which are photocharged to a smaller extent, protons do not stabilize electrons, which results in spontaneous charge transfer to oxidants. Facile proton-coupled electron transfer is a key step in the photocatalytic oxidative-reductive cascade – tetramerization of benzylic amines. The feasibility of proton-coupled electron transfer is modulated by adjusting the extent of carbon nitride photocharging, type of counterion and temperature.

Abstract Malaria remains one of the deadliest infectious diseases. Transcriptional regulation effects of noncoding variants in this unusual genome of malaria parasites remain elusive. We developed a sequence-based, ab initio deep learning framework, MalariaSED, for predicting chromatin profiles in malaria parasites. The MalariaSED performance was validated by published ChIP-qPCR and TF motifs results. Applying MalariaSED to ~ 1.3 million variants shows that geographically differentiated noncoding variants are associated with parasite invasion and drug resistance. Further analysis reveals chromatin accessibility changes at Plasmodium falciparum rings are partly associated with artemisinin resistance. MalariaSED illuminates the potential functional roles of noncoding variants in malaria parasites.

Abstract The demands of raising dependent young can influence the feeding behaviors of social carnivores, especially for individuals that are primarily responsible for provisioning young. We investigated how the feeding and provisioning behavior of a social carnivore, gray wolves (Canis lupus), are connected and shaped by extrinsic and intrinsic factors, and whether and how these patterns changed throughout the pup-rearing season (April–August). We found breeding wolves had shorter handling times of prey, lower probability of returning to kills, and greater probability of returning to homesites after kills compared to subordinate individuals. However, the feeding and provisioning behaviors of breeding individuals changed considerably over the pup-rearing season. Wolves had longer handling times and returned to provision pups directly after kills less frequently as annual prey abundance decreased. These patterns indicate that adult wolves prioritize meeting their own energetic demands over those of their pups when prey abundance decreases. We suggest that differential provisioning of offspring based on prey abundance is a behavioral mechanism by which group size adjusts to available resources via changes in neonate survival.

Abstract Background Technology can support healthy aging and empower older adults to live independently. However, technology adoption by older adults, particularly assistive technology (AT), is limited and little is known about the types of AT used among older adults. This study explored the use of key information and communication technologies (ICT) and AT among community-dwelling adults aged ≥ 65. Methods A cross-sectional study was conducted among community-dwelling adults aged ≥ 65 in southern Germany using a paper-based questionnaire. The questionnaire included questions on the three domains sociodemographic aspects, health status, and technology use. Technology use was considered separately for key ICT (smartphone, computer/laptop, and tablet) and a range of 31 different AT. Data were analyzed using descriptive statistics, univariate analyses, and Bernoulli Naïve Bayes modelling. Results The questionnaire was answered by 616 participants (response rate: 24.64%). ICT were used by 497 (80.68%) participants and were associated with lower age, higher level of education, living together with someone, availability of internet connection, higher interest in technology, and better health status (p

Abstract Neuropsychiatric disorders pose a high societal cost, but their treatment is hindered by lack of objective outcomes and fidelity metrics. AI technologies and specifically Natural Language Processing (NLP) have emerged as tools to study mental health interventions (MHI) at the level of their constituent conversations. However, NLP’s potential to address clinical and research challenges remains unclear. We therefore conducted a pre-registered systematic review of NLP-MHI studies using PRISMA guidelines (osf.io/s52jh) to evaluate their models, clinical applications, and to identify biases and gaps. Candidate studies (n = 19,756), including peer-reviewed AI conference manuscripts, were collected up to January 2023 through PubMed, PsycINFO, Scopus, Google Scholar, and ArXiv. A total of 102 articles were included to investigate their computational characteristics (NLP algorithms, audio features, machine learning pipelines, outcome metrics), clinical characteristics (clinical ground truths, study samples, clinical focus), and limitations. Results indicate a rapid growth of NLP MHI studies since 2019, characterized by increased sample sizes and use of large language models. Digital health platforms were the largest providers of MHI data. Ground truth for supervised learning models was based on clinician ratings (n = 31), patient self-report (n = 29) and annotations by raters (n = 26). Text-based features contributed more to model accuracy than audio markers. Patients’ clinical presentation (n = 34), response to intervention (n = 11), intervention monitoring (n = 20), providers’ characteristics (n = 12), relational dynamics (n = 14), and data preparation (n = 4) were commonly investigated clinical categories. Limitations of reviewed studies included lack of linguistic diversity, limited reproducibility, and population bias. A research framework is developed and validated (NLPxMHI) to assist computational and clinical researchers in addressing the remaining gaps in applying NLP to MHI, with the goal of improving clinical utility, data access, and fairness.

Background: Manipulation of carcinoid tumors during ablation or selective hepatic artery embolization (transarterial embolization, TAE) can release vasoactive mediators inducing hemodynamic instability. The main aim of our study was to review hemodynamics and complications related to minimally invasive treatments of liver carcinoids with TAE or ablation. Methods: Electronic medical records of all patients with metastatic liver carcinoid undergoing ablation or TAE from 2003 to 2019 were abstracted. Noted were severe hypotension (mean arterial pressure [MAP] ..± 55.ßmmHg), severe hypertension (systolic blood pressure ... 180.ßmmHg), and perioperative complications. Associations of procedure type and pre-procedure octreotide use with intraprocedural hemodynamics were assessed using linear regression. A robust covariance approach using generalized estimating equation method was used to account for multiple observations. Results: A total of 161 patients underwent 98 ablations and 207 TAEs. Severe hypertension was observed in 24 (24.5%) vs. 15 (7.3%), severe hypotension in 56 (57.1%) vs. 6 (2.9%), and cutaneous flushing observed in 2 (2.0%) vs. 48 (23.2%) ablations and TAEs, respectively. After adjusting for preprocedural MAP, ablation was associated with lower intraprocedural MAP compared to TAE (estimate -27.ßmmHg, 95%CI -30 to -24.ßmmHg, p.ß

Abstract Turbine wake and local blockage effects are known to alter wind farm power production in two different ways: (1) by changing the wind speed locally in front of each turbine and (2) by changing the overall flow resistance in the farm and thus the so‐called farm blockage effect. To better predict these effects with low computational costs, we develop data‐driven emulators of the ‘local’ or ‘internal’ turbine thrust coefficient CT∗ as a function of turbine layout. We train the model using a multi‐fidelity Gaussian process (GP) regression with a combination of low (engineering wake model) and high‐fidelity (large eddy simulations) simulations of farms with different layouts and wind directions. A large set of low‐fidelity data speeds up the learning process and the high‐fidelity data ensures a high accuracy. The trained multi‐fidelity GP model is shown to give more accurate predictions of CT∗ compared to a standard (single‐fidelity) GP regression applied only to a limited set of high‐fidelity data. We also use the multi‐fidelity GP model of CT∗ with the two‐scale momentum theory (Nishino & Dunstan 2020, J. Fluid Mech. 894, A2) to demonstrate that the model can be used to give fast and accurate predictions of large wind farm performance under various mesoscale atmospheric conditions. This new approach could be beneficial for improving annual energy production (AEP) calculations and farm optimization in the future.

Abstract Animal manure has been used to manage soil fertility since the dawn of agriculture. It provides plant nutrients and improves soil fertility. In the last decades, animal husbandry has been significantly expanded globally. Its economics were optimized via the (international) trade of feed, resulting in a surplus of animal manure in areas with intensive livestock farming. Potentially toxic elements (PTEs), pathogenic microorganisms, antibiotic residues, biocides, and other micropollutants in manure threaten animal, human, and environmental health. Hence, manure application in crop fields is increasingly restricted, especially in hotspot regions with intensive livestock activities. Furthermore, ammonia volatilization and greenhouse gas (GHG) emissions during manure storage, field application, and decomposition contribute to air pollution and climate change. Conventional manure management scenarios such as composting and anaerobic digestion partially improve the system but cannot guarantee to eliminate sanitary and contamination risks and only marginally reducing its climate burden. Hence, this review discusses the potential of pyrolysis, the thermochemical conversion under oxygen‐limited conditions as an alternative treatment for animal manure providing energy and biochar. Manure pyrolysis reduces the bioavailability of PTEs, eliminates pathogenic microorganisms and organic micropollutants, and reduces GHG emissions. Pyrolysis also results in the loss of nitrogen, which can be minimized by pretreatment, that is, after removing soluble nitrogen fraction of manure, for example, by digestion and stripping of ammonia–nitrogen or liquid–solid separation. However, conclusions on the effect of manure pyrolysis on crop yield and fertilization efficiencies are hampered by a lack of nutrient mass balances based on livestock unit equivalent comparisons of manure and manure biochar applications. Hence, it is essential to design and conduct experiments in more practically relevant scenarios and depict the observations based on the amount of manure used to produce a certain amount of biochar.

Achieving negative surgical margins, defined as no tumor found on the edges of the resected tissue, during lumpectomy for breast cancer is critical for mitigating the risk of local recurrence. To identify nonpalpable tumors that cannot be felt, pre-operative placements of wire and wire-free localization devices are typically employed. Wire-free localization approaches have significant practical advantages over wired techniques. In this study, we introduce an innovative localization system comprising a light-emitting diode (LED)-based implantable device and handheld system. The device, which is needle injectable and wire free, utilizes multiple wirelessly powered LEDs to provide direct visual guidance for lumpectomy. Two distinct colors, red and blue, provide a clear indication of tissue depth: blue light is absorbed strongly in tissue, visible within a close range of 2 cm of ex vivo chicken breast and bovine muscle tissue using less than 4 W of transmitted power from a handheld antenna. These miniaturized needle-injectable localization devices show promise for improving surgical guidance of nonpalpable breast tumors.

Nutrient requirements for para-athletes will be influenced by a variety of factors secondary to their impairment and, therefore, recommendations for para-athletes cannot be drawn directly from that of able-bodied athletes. Information on the dietary intakes of para-athletes is lacking and therefore needs to be examined. This study assessed the nutrient intakes and diet quality of 31 paracyclists via food frequency questionnaires. Based on the dietary reference intakes, most paracyclists consumed intakes above the recommended dietary allowance (RDA) or adequate intake (AI). Recommendations were not met for iodine (males = 87% RDA; females = 62% RDA) or fibre in males (84% AI). A 26% risk of inadequacy was noted for vitamins D and E in females. A total of 42% of females and 75% of males did not meet fibre recommendations (14 g/1000 kcal), and only three athletes (all females) consumed fatty acids in the recommended omega-6 to omega-3 ratio of 4:1 or less. Athletes consumed grains, fruits, and vegetables frequently, though whole grains, pulses, and oily fish were generally consumed less often. Paracyclists appear to be consuming intakes at or above recommendations for most nutrients, though several nutrients were consumed below the recommended amounts; therefore, increasing the variety of foods consumed is suggested.

Increasing survival rates of children following cancer treatment have resulted in a significant population of adult survivors with the common side effect of infertility. Additionally, the availability of genetic testing has identified Klinefelter syndrome (classic 47,XXY) as the cause of future male infertility for a significant number of prepubertal patients. This study explores new spermatogonia stem cell (SSC)-based fertility therapies to meet the needs of these patients. Testicular cells were isolated from cryopreserved human testes tissue stored from XY and XXY prepubertal patients and propagated in a two-dimensional culture. Cells were then incorporated into a 3D human testicular organoid (HTO) system. During a 3-week culture period, HTOs maintained their structure, viability, and metabolic activity. Cell-specific PCR and flow cytometry markers identified undifferentiated spermatogonia, Sertoli, Leydig, and peritubular cells within the HTOs. Testosterone was produced by the HTOs both with and without hCG stimulation. Upregulation of postmeiotic germ cell markers was detected after 23 days in culture. Fluorescence in situ hybridization (FISH) of chromosomes X, Y, and 18 identified haploid cells in the in vitro differentiated HTOs. Thus, 3D HTOs were successfully generated from isolated immature human testicular cells from both euploid (XY) and Klinefelter (XXY) patients, supporting androgen production and germ cell differentiation in vitro.

Excessive vitamin A (VA) negatively impacts bone. Interactions between VA and vitamin D (VD) in bone health are not well-understood. This study used a traditional two-by-two factorial design. Pigs were weaned and randomized to four treatments (n = 13/group): −A−D, −A+D, +A−D, and +A+D for 3 and 5 wk. Serum, liver, kidney, adrenal glands, spleen, and lung were analyzed by ultra-performance LC. Growth was evaluated by weight measured weekly and BMD by DXA. Weights were higher in −A+D (18.1 ± 1.0 kg) and +A+D (18.2 ± 2.3 kg) at 5 wk than in −A−D (15.5 ± 2.1 kg) and +A−D (15.8 ± 1.5 kg). Serum retinol concentrations were 0.25 ± 0.023, 0.22 ± 0.10, 0.77 ± 0.12, and 0.84 ± 0.28 µmol/L; and liver VA concentrations were 0.016 ± 0.015, 0.0065 ± 0.0035, 2.97 ± 0.43, 3.05 ± 0.68 µmol/g in −A−D, −A+D, +A−D, and +A+D, respectively. Serum 25(OH)D3 concentrations were 1.5 ± 1.11, 1.8 ± 0.43, 27.7 ± 8.91, and 23.9 ± 6.67 ng/mL in −A−D, +A−D, −A+D, +A+D, respectively, indicating a deficiency in −D and adequacy in +D. BMD was highest in +D (p < 0.001). VA and the interaction had no effect on BMD. Dietary VD influenced weight gain, BMD, and health despite VA status.

7-Bromo-4-chloro-1H-indazol-3-amine is a heterocyclic fragment used in the synthesis of Lenacapavir, a potent capsid inhibitor for the treatment of HIV-1 infections. In this manuscript, we describe a new approach to synthesizing 7-bromo-4-chloro-1H-indazol-3-amine from inexpensive 2,6-dichlorobenzonitrile. This synthetic method utilizes a two-step sequence including regioselective bromination and heterocycle formation with hydrazine to give the desired product in an overall isolated yield of 38–45%. The new protocol has been successfully demonstrated on hundred-gram scales without the need for column chromatography purification. This new synthesis provides a potential economical route to the large-scale production of this heterocyclic fragment of Lenacapavir.

Measles and rubella are vaccine-preventable viral diseases and can be prevented by safe, highly effective vaccination with measles- and rubella-containing vaccines. Given the myriad causes of febrile exanthems, laboratory surveillance for both measles and rubella is important to document the incidence of these diseases and to track the progress and maintenance of elimination in near- and post-elimination settings. Diagnostic challenges can hinder effective surveillance and classification challenges can hinder efforts to demonstrate achievement or maintenance of elimination. In this report, we review diagnostic and classification challenges for measles and rubella in near- and post-elimination settings.

Flow-regulated stormwater ponds providing safe outflow discharges prevail as the primary stormwater management tool for stream protections. Detailed pond geometries are essential metrics in pond monitoring technologies, which convert the point-based water level measurements to areal/volumetric ponding water estimations. Unlike labour-intensive surveys (e.g., RTK-GNSS or total stations), UAV-photogrammetry and airborne-LiDAR have been advocated as cost-effective alternatives to acquire high-quality datasets. In this paper, we compare the use of these two approaches for stormwater pond surveys. With reference to RTK-GNSS in-situ observations, we identify their geometric and hydraulic discrepancies based on six stormwater ponds from three aspects: (i) DEMs, (ii) stage-curves and (iii) outflow discharges. Three main findings are outlined: (i) for wet ponds where moisture environments are dominant, UAV-photogrammetry outperforms (infrared) airborne-LiDAR, where airborne-LiDAR yields 0.15–0.54 NSEoutflow, which is unacceptable; (ii) for dry ponds, UAV-photogrammetry obtains 0.88–0.89 NSEoutflow as poor vegetation penetrations; two correction methods (i.e., grass removal and shifted stage-curves) are proposed, indicating good alignment to RTK-GNSS observations and (iii) UAV-photogrammetry delivers

Abstract Lack of proper nutrition has important consequences for the physiology of all organisms, and nutritional status can affect immunity, based on many studies in terrestrial animals. Here we show a positive correlation between nutrition and immunity in the sea anemone Nematostella vectensis. Gene expression profiling of adult anemones shows downregulation of genes involved in nutrient metabolism, cellular respiration, and immunity in starved animals. Starved adult anemones also have reduced protein levels and activity of immunity transcription factor NF-κB. Starved juvenile anemones have increased sensitivity to bacterial infection and also have lower NF-κB protein levels, as compared to fed controls. Weighted Gene Correlation Network Analysis (WGCNA) is used to identify significantly correlated gene networks that were downregulated with starvation. These experiments demonstrate a correlation between nutrition and immunity in an early diverged marine metazoan, and the results have implications for the survival of marine organisms as they encounter changing environments.

Abstract Background Sunlight contains ultraviolet B (UVB) radiation that triggers the production of vitamin D by skin. Vitamin D has widespread effects on brain function in both developing and adult brains. However, many people live at latitudes (about > 40 N or S) that do not receive enough UVB in winter to produce vitamin D. This exploratory study investigated the association between the age of onset of bipolar I disorder and the threshold for UVB sufficient for vitamin D production in a large global sample. Methods Data for 6972 patients with bipolar I disorder were obtained at 75 collection sites in 41 countries in both hemispheres. The best model to assess the relation between the threshold for UVB sufficient for vitamin D production and age of onset included 1 or more months below the threshold, family history of mood disorders, and birth cohort. All coefficients estimated at P ≤ 0.001. Results The 6972 patients had an onset in 582 locations in 70 countries, with a mean age of onset of 25.6 years. Of the onset locations, 34.0% had at least 1 month below the threshold for UVB sufficient for vitamin D production. The age of onset at locations with 1 or more months of less than or equal to the threshold for UVB was 1.66 years younger. Conclusion UVB and vitamin D may have an important influence on the development of bipolar disorder. Study limitations included a lack of data on patient vitamin D levels, lifestyles, or supplement use. More study of the impacts of UVB and vitamin D in bipolar disorder is needed to evaluate this supposition.

Abstract Background Neuropsychiatric symptoms (NPS) are a core feature of most neurodegenerative and cerebrovascular diseases. White matter hyperintensities and brain atrophy have been implicated in NPS. We aimed to investigate the relative contribution of white matter hyperintensities and cortical thickness to NPS in participants across neurodegenerative and cerebrovascular diseases. Methods Five hundred thirteen participants with one of these conditions, i.e. Alzheimer’s Disease/Mild Cognitive Impairment, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Parkinson’s Disease, or Cerebrovascular Disease, were included in the study. NPS were assessed using the Neuropsychiatric Inventory – Questionnaire and grouped into hyperactivity, psychotic, affective, and apathy subsyndromes. White matter hyperintensities were quantified using a semi-automatic segmentation technique and FreeSurfer cortical thickness was used to measure regional grey matter loss. Results Although NPS were frequent across the five disease groups, participants with frontotemporal dementia had the highest frequency of hyperactivity, apathy, and affective subsyndromes compared to other groups, whilst psychotic subsyndrome was high in both frontotemporal dementia and Parkinson’s disease. Results from univariate and multivariate results showed that various predictors were associated with neuropsychiatric subsyndromes, especially cortical thickness in the inferior frontal, cingulate, and insula regions, sex(female), global cognition, and basal ganglia-thalamus white matter hyperintensities. Conclusions In participants with neurodegenerative and cerebrovascular diseases, our results suggest that smaller cortical thickness and white matter hyperintensity burden in several cortical-subcortical structures may contribute to the development of NPS. Further studies investigating the mechanisms that determine the progression of NPS in various neurodegenerative and cerebrovascular diseases are needed.

Background Sex‐specific risk management may improve outcomes in congenital long QT syndrome (LQTS). We recently developed a prediction score for cardiac events (CEs) and life‐threatening events (LTEs) in postadolescent women with LQTS. In the present study, we aimed to develop personalized risk estimates for the burden of CEs and LTEs in male adolescents with potassium channel‐mediated LQTS. Methods and Results The prognostic model was derived from the LQTS Registry headquartered in Rochester, NY, comprising 611 LQT1 or LQT2 male adolescents from age 10 through 20 years, using the following variables: genotype/mutation location, QTc‐specific thresholds, history of syncope, and β‐blocker therapy. Anderson‐Gill modeling was performed for the end point of CE burden (total number of syncope, aborted cardiac arrest, and appropriate defibrillator shocks). The applicability of the CE prediction model was tested for the end point of the first LTE (excluding syncope and adding sudden cardiac death) using Cox modeling. A total of 270 CEs occurred during follow‐up. The genotype–phenotype risk prediction model identified low‐, intermediate‐, and high‐risk groups, comprising 74%, 14%, and 12% of the study population, respectively. Compared with the low‐risk group, high‐risk male subjects experienced a pronounced 5.2‐fold increased risk of recurrent CEs (P

As cancer therapies increase in effectiveness and patients' life expectancies improve, balancing oncologic efficacy while reducing acute and long-term cardiovascular toxicities has become of paramount importance. To address this pressing need, the Cardiology Oncology Innovation Network (COIN) was formed to bring together domain experts with the overarching goal of collaboratively investigating, applying, and educating widely on various forms of innovation to improve the quality of life and cardiovascular healthcare of patients undergoing and surviving cancer therapies. The COIN mission pillars of innovation, collaboration, and education have been implemented with cross-collaboration among academic institutions, private and public establishments, and industry and technology companies. In this report, we summarize proceedings from the first two annual COIN summits (inaugural in 2020 and subsequent in 2021) including educational sessions on technological innovations for establishing best practices and aligning resources. Herein, we highlight emerging areas for innovation and defining unmet needs to further improve the outcome for cancer patients and survivors of all ages. Additionally, we provide actionable suggestions for advancing innovation, collaboration, and education in cardio-oncology in the digital era.

This Letter presents first observations of distinct solar atmospheric oscillations from signals collected by the Extreme Ultraviolet and X-ray Irradiance Sensors EUVS-C instrument, which is part of each Geostationary Observational Environmental Satellite R-Series instrument payload. The EUVS-C instrument is a full-disk, normal-incidence spectrograph that covers a narrow band in the mid-ultraviolet between 276 and 284 nm, where it can measure the magnesium ii emission doublet at ∼280 nm and the photospheric continuum. The primary goal of EUVS-C data is to construct the well-known Mg ii index, which is often used as a proxy for chromospheric activity. Because of the high temporal and spectral resolution of EUVS-C measurements, the data provide a unique opportunity to observe discernible solar atmospheric waves that have definite signatures of 3 and 5 minute oscillation periods, where the frequency response of these signals is dependent on what part of the spectrum is analyzed (e.g., Mg emission lines). Furthermore, both photospheric and chromospheric waves can simultaneously be examined. With the recent increase in solar activity for Solar Cycle 25, these waves exhibit enhanced amplitudes and phase shifts during the impulsive shock of strong solar flares. This Letter will discuss the analysis for deriving these waves, and results from both a quiescent Sun and an X-class solar flare event will be presented.

This study investigates the frequency of a clinically reported variant in PMS2, NM_000535.7:c.2523G>A p.(W841∗), from next-generation sequencing studies in 2 racially diverse cohorts. We identified clinical reports of the PMS2 c.2523G>A p.(W841∗) variant in the National Precision Oncology Program’s somatic testing database (n = 25,168). We determined frequency of the variant in germline exome sequencing from the Penn Medicine BioBank (n = 44,256) and in gnomAD. The PMS2 c.2523G>A p.(W841∗) was identified as a homozygous variant on tumor testing in an adult patient of self-identified Black race/ethnicity with no evidence of constitutional mismatch repair deficiency. The variant was clinically reported on 35 total tumor and liquid biopsy tests (0.1%), and all individuals with the variant were of self-identified Black race/ethnicity (0.6% of n = 5787). In individuals of African genetic ancestry (AFR), the variant's germline frequency was reported to be 0.2% and 1.3% in the Penn Medicine BioBank (PMBB) and gnomAD, respectively. The variant cannot be found in any individuals of European genetic ancestry (EUR) from either of the databases. The variant is found in a region of PMS2 with 100% homology to the PMS2CL pseudogene. PMS2 c.2523G>A p.(W841∗), when identified, is typically an African-ancestry-specific PMS2CL pseudogene variant, which should be recognized to prevent misdiagnosis of Lynch syndrome in Blacks.