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Abstract Background Risk scores facilitate the assessment of mortality risk in patients with community-acquired pneumonia (CAP). Despite their utilities, there is a scarcity of evidence comparing the various RS simultaneously. This study aims to evaluate and compare multiple risk scores reported in the literature for predicting 30-day mortality in adult patients with CAP. Methods A retrospective cohort study on patients diagnosed with CAP was conducted across two hospitals in Colombia. The areas under receiver operating characteristic curves (ROC-curves) were calculated for the outcome of survival or death at 30 days using the scores obtained for each of the analyzed questionnaires. Results A total of 7454 potentially eligible patients were included, with 4350 in the final analysis, of whom 15.2% (662/4350) died within 30 days. The average age was 65.4 years (SD: 21.31), and 59.5% (2563/4350) were male. Chronic kidney disease was 3.7% (9.2% vs. 5.5%; p

Abstract Social prescribing has become a global phenomenon. A Delphi study was recently conducted with 48 social prescribing experts from 26 countries to establish global agreement on the definition of social prescribing. We reflect on the use and utility of the outputs of this work, and where we go from here.

Abstract Dendritic cells (DCs) are crucial for initiating protective immune responses and have also been implicated in the generation and regulation of Foxp3+ regulatory T cells (Treg cells). Here, we show that in the lamina propria of the small intestine, the alternative NF-κB family member RelB is necessary for the differentiation of cryptopatch and isolated lymphoid follicle-associated DCs (CIA-DCs). Moreover, single-cell RNA sequencing reveals a RelB-dependent signature in migratory DCs in mesenteric lymph nodes favoring DC-Treg cell interaction including elevated expression and release of the chemokine CCL22 from RelB-deficient conventional DCs (cDCs). In line with the key role of CCL22 to facilitate DC-Treg cell interaction, RelB-deficient DCs have a selective advantage to interact with Treg cells in an antigen-specific manner. In addition, DC-specific RelB knockout animals show increased total Foxp3+ Treg cell numbers irrespective of inflammatory status. Consequently, DC-specific RelB knockout animals fail to mount protective Th2-dominated immune responses in the intestine after infection with Heligmosomoides polygyrus bakeri. Thus, RelB expression in cDCs acts as a rheostat to establish a tolerogenic set point that is maintained even during strong type 2 immune conditions and thereby is a key regulator of intestinal homeostasis.

Background and Purpose The management of acute ischemic stroke (AIS) due to distal medium vessel occlusion (DMVO) remains uncertain, particularly in comparing the effectiveness of intravenous thrombolysis (IVT) plus mechanical thrombectomy (MT) versus IVT alone. This study aimed to evaluate the safety and efficacy in DMVO patients treated with either MT-IVT or IVT alone. Methods This multinational study analyzed data from 37 centers across North America, Asia, and Europe. Patients with AIS due to DMVO were included, with data collected from September 2017 to July 2023. The primary outcome was functional independence, with secondary outcomes including mortality and safety measures such as types of intracerebral hemorrhage. Results The study involved 1,057 patients before matching, and 640 patients post-matching. Functional outcomes at 90 days showed no significant difference between groups in achieving good functional recovery (modified Rankin Scale 0–1 and 0–2), with adjusted odds ratios (OR) of 1.21 (95% confidence interval [CI] 0.81 to 1.79; P=0.35) and 1.00 (95% CI 0.66 to 1.51; P>0.99), respectively. Mortality rates at 90 days were similar between the two groups (OR 0.75, 95% CI 0.44 to 1.29; P=0.30). The incidence of symptomatic intracerebral hemorrhage was comparable, but any type of intracranial hemorrhage was significantly higher in the MT-IVT group (OR 0.43, 95% CI 0.29 to 0.63; P

Abstract Introduction Uncontrolled non-infectious uveitis affecting the posterior segment (NIU-PS) can lead to vision loss due to repeated bouts of inflammation and consequent tissue damage. Patients with chronic NIU-PS who experience recurrent uveitis after being treated with systemic and short-acting local corticosteroids may benefit from the sustained-release 0.18-mg fluocinolone acetonide implant (FAi). Methods In this case series, 18 eyes with chronic, recurrent NIU-PS and cystoid macular edema (CME) treated with the 0.18-mg FAi were analyzed retrospectively. Data on patient demographics, clinical history, previous and concomitant treatments for uveitis recurrence, time to and number of uveitis recurrences, intraocular pressure (IOP), central subfield thickness (CST), and visual acuity (VA) were collected and summarized. Results A majority of patients (14/15 [93%]) had a history of ocular surgery, largely cataract extraction, and all developed chronic and recurrent NIU-PS and CME. At baseline, patients had a mean age of 72 years (range: 46 to 93), were 53% male, and had a mean duration of NIU-PS of 3 years (range: 1 to 19). Patients were followed for an average of 16.5 months (range: 2 to 42.5 months) post FAi. Eleven of the 18 eyes (61%) had ≥ 5 recurrences of uveitis since diagnosis, with an average time to recurrence of approximately 12 weeks (range: 1 to 27). All eyes treated with the 0.18-mg FAi showed reduced NIU-PS recurrence and visual and anatomical improvement, as measured by VA and CST, respectively. Two eyes had an IOP elevation that was managed with topical therapy, and one eye was treated with topical prednisolone for additional inflammation management. Two eyes required adjunct therapy with short-acting intravitreal corticosteroids at 7 and 16 weeks for NIU-PS recurrence after 0.18-mg FAi insertion. Conclusion After receiving the 0.18-mg FAi, eyes with uncontrolled NIU-PS had sustained resolution of CME and inflammation with limited need for supplementary steroid drops or injections and minimal steroid class-specific adverse effects; none required incisional IOP-lowering surgery.

Abstract Background Lung cancer is a heterogeneous disease and the primary cause of cancer-related mortality worldwide. Somatic mutations, including large structural variants, are important biomarkers in lung cancer for selecting targeted therapy. Genomic studies in lung cancer have been conducted using short-read sequencing. Emerging long-read sequencing technologies are a promising alternative to study somatic structural variants, however there is no current consensus on how to process data and call somatic events. In this study, we preformed whole genome sequencing of lung cancer and matched non-tumour samples using long and short read sequencing to comprehensively benchmark three sequence aligners and seven structural variant callers comprised of generic callers (SVIM, Sniffles2, DELLY in generic mode and cuteSV) and somatic callers (Severus, SAVANA, nanomonsv and DELLY in somatic modes). Results Different combinations of aligners and variant callers influenced somatic structural variant detection. The choice of caller had a significant influence on somatic structural variant detection in terms of variant type, size, sensitivity, and accuracy. The performance of each variant caller was assessed by comparing to somatic structural variants identified by short-read sequencing. When compared to somatic structural variants detected with short-read sequencing, more events were detected with long-read sequencing. The mean recall of somatic variant events identified by long-read sequencing was higher for the somatic callers (72%) than generic callers (53%). Among the somatic callers when using the minimap2 aligner, SAVANA and Severus achieved the highest recall at 79.5% and 79.25% respectively, followed by nanomonsv with a recall of 72.5%. Conclusion Long-read sequencing can identify somatic structural variants in clincal samples. The longer reads have the potential to improve our understanding of cancer development and inform personalized cancer treatment.

Abstract Background Adiposity shows opposing associations with mortality within COVID-19 versus non-COVID-19 respiratory conditions. We assessed the likely causality of adiposity for mortality among intensive care patients with COVID-19 versus non-COVID-19 by examining the consistency of associations across temporal and geographical contexts where biases vary. Methods We used data from 297 intensive care units (ICUs) in England, Wales, and Northern Ireland (Intensive Care National Audit and Research Centre Case Mix Programme). We examined associations of body mass index (BMI) with 30-day mortality, overall and by date and region of ICU admission, among patients admitted with COVID-19 (N = 34,701; February 2020–August 2021) and non-COVID-19 respiratory conditions (N = 25,205; February 2018–August 2019). Results Compared with non-COVID-19 patients, COVID-19 patients were younger, less often of a white ethnic group, and more often with extreme obesity. COVID-19 patients had fewer comorbidities but higher mortality. Socio-demographic and comorbidity factors and their associations with BMI and mortality varied more by date than region of ICU admission. Among COVID-19 patients, higher BMI was associated with excess mortality (hazard ratio (HR) per standard deviation (SD) = 1.05; 95% CI = 1.03–1.07). This was evident only for extreme obesity and only during February–April 2020 (HR = 1.52, 95% CI = 1.30–1.77 vs. recommended weight); this weakened thereafter. Among non-COVID-19 patients, higher BMI was associated with lower mortality (HR per SD = 0.83; 95% CI = 0.81–0.86), seen across all overweight/obesity groups and across dates and regions, albeit with a magnitude that varied over time. Conclusions Obesity is associated with higher mortality among COVID-19 patients, but lower mortality among non-COVID-19 respiratory patients. These associations appear vulnerable to confounding/selection bias in both patient groups, questioning the existence or stability of causal effects.

Abstract Cell state control is crucial for normal tissue development and cancer cell mimicry of stem/progenitor states, contributing to tumor heterogeneity, therapy resistance, and progression. Here, we demonstrate that the cell surface glycoprotein Mcam maintains the tumorigenic luminal progenitor (LP)-like epithelial cell state, leading to Basal-like mammary cancers. In the Py230 mouse mammary carcinoma model, Mcam knockdown (KD) destabilized the LP state by deregulating the Ck2/Stat3 axis, causing a switch to alveolar and basal states, loss of an estrogen-sensing subpopulation, and resistance to tamoxifen—an effect reversed by Ck2 and Stat3 inhibitors. In vivo, Mcam KD blocked generation of Basal-like tumors and Sox10+Krt14+ cells. In human tumors, MCAM loss was largely exclusive of the Basal-like subtype, linked instead to proliferative Luminal subtypes, including often endocrine-resistant Luminal B cancers. This study has implications for developing therapies targeting MCAM, CK2, and STAT3 and their likely effective contexts.

Abstract Analyses of mitochondrial adaptations in human skeletal muscle have mostly used whole-muscle samples, where results may be confounded by the presence of a mixture of type I and II muscle fibres. Using our adapted mass spectrometry-based proteomics workflow, we provide insights into fibre-specific mitochondrial differences in the human skeletal muscle of men before and after training. Our findings challenge previous conclusions regarding the extent of fibre-type-specific remodelling of the mitochondrial proteome and suggest that most baseline differences in mitochondrial protein abundances between fibre types reported by us, and others, might be due to differences in total mitochondrial content or a consequence of adaptations to habitual physical activity (or inactivity). Most training-induced changes in different mitochondrial functional groups, in both fibre types, were no longer significant in our study when normalised to changes in markers of mitochondrial content.

Abstract Chemotherapy induced ovarian failure and infertility is an important concern in female cancer patients of reproductive age or younger, and non-invasive, pharmacological approaches to maintain ovarian function are urgently needed. Given the role of reduced nicotinamide adenine dinucleotide phosphate (NADPH) as an essential cofactor for drug detoxification, we sought to test whether boosting the NAD(P)+ metabolome could protect ovarian function. We show that pharmacological or transgenic strategies to replenish the NAD+ metabolome ameliorates chemotherapy induced female infertility in mice, as measured by oocyte yield, follicle health, and functional breeding trials. Importantly, treatment of a triple-negative breast cancer mouse model with the NAD+ precursor nicotinamide mononucleotide (NMN) reduced tumour growth and did not impair the efficacy of chemotherapy drugs in vivo or in diverse cancer cell lines. Overall, these findings raise the possibility that NAD+ precursors could be a non-invasive strategy for maintaining ovarian function in cancer patients, with potential benefits in cancer therapy.

Abstract Developmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells. Human induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division with an inherent propensity to differentiate into neurons. These phenotypes result from misalignment of the mitotic spindle in apical neural progenitors. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state, ultimately shortening the period of neurogenesis. This study provides a mechanism for DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families.

Before introducing new treatment techniques, an investigation of hazards due to unintentional radiation exposures is a reasonable activity for proactively increasing patient safety. As dedicated software is scarce, we developed a tool for risk assessment to design a quality management program based on best practice methods, i.e., process mapping, failure modes and effects analysis and fault tree analysis. Implemented as a web database application, a single dataset was used to describe the treatment process and its failure modes. The design of the system and dataset allowed failure modes to be represented both visually as fault trees and in a tabular form. Following the commissioning of the software for our department, previously conducted risk assessments were migrated to the new system after being fully re-assessed which revealed a shift in risk priorities. Furthermore, a weighting factor was investigated to bring risk levels of the migrated assessments into perspective. The compensation did not affect high priorities but did re-prioritize in the midrange of the ranking. We conclude that the tool is suitable to conduct multiple risk assessments and concomitantly keep track of the overall quality management activities.

Abstract Resonant inelastic x-ray scattering (RIXS) is a widely used spectroscopic technique, providing access to the electronic structure and dynamics of atoms, molecules, and solids. However, RIXS requires a narrow bandwidth x-ray probe to achieve high spectral resolution. The challenges in delivering an energetic monochromated beam from an x-ray free electron laser (XFEL) thus limit its use in few-shot experiments, including for the study of high energy density systems. Here we demonstrate that by correlating the measurements of the self-amplified spontaneous emission (SASE) spectrum of an XFEL with the RIXS signal, using a dynamic kernel deconvolution with a neural surrogate, we can achieve electronic structure resolutions substantially higher than those normally afforded by the bandwidth of the incoming x-ray beam. We further show how this technique allows us to discriminate between the valence structures of Fe and Fe2O3, and provides access to temperature measurements as well as M-shell binding energies estimates in warm-dense Fe compounds.

Abstract Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and emerging therapeutic target that is overexpressed in most castration-resistant prostate cancers and implicated as a driver of disease progression and resistance to hormonal therapies. Here we define the lineage-specific action and differential activity of EZH2 in both prostate adenocarcinoma and neuroendocrine prostate cancer (NEPC) subtypes of advanced prostate cancer to better understand the role of EZH2 in modulating differentiation, lineage plasticity, and to identify mediators of response and resistance to EZH2 inhibitor therapy. Mechanistically, EZH2 modulates bivalent genes that results in upregulation of NEPC-associated transcriptional drivers (e.g., ASCL1) and neuronal gene programs in NEPC, and leads to forward differentiation after targeting EZH2 in NEPC. Subtype-specific downstream effects of EZH2 inhibition on cell cycle genes support the potential rationale for co-targeting cyclin/CDK to overcome resistance to EZH2 inhibition.

Abstract Current treatment outcome of patients with glioblastoma (GBM) remains poor. Following standard therapy, recurrence is universal with limited survival. Tumors from 173 GBM patients are analysed for somatic mutations to generate a personalized peptide vaccine targeting tumor-specific neoantigens. All patients were treated within the scope of an individual healing attempt. Among all vaccinated patients, including 70 treated prior to progression (primary) and 103 treated after progression (recurrent), the median overall survival from first diagnosis is 31.9 months (95% CI: 25.0–36.5). Adverse events are infrequent and are predominantly grade 1 or 2. A vaccine-induced immune response to at least one of the vaccinated peptides is detected in blood samples of 87 of 97 (90%) monitored patients. Vaccine-specific T-cell responses are durable in most patients. Significantly prolonged survival is observed for patients with multiple vaccine-induced T-cell responses (53 months) compared to those with no/low induced responses (27 months; P = 0.03). Altogether, our results highlight that the application of personalized neoantigen-targeting peptide vaccine is feasible and represents a promising potential treatment option for GBM patients.

Abstract Background Lung cancer constitutes the leading cause of cancer mortality. High levels of endothelin-1 (ET-1), its cognate receptor ETAR and its activating enzyme, the endothelin-converting enzyme-1 (ECE-1), have been reported in several cancer types, including lung cancer. ECE-1 comprises four isoforms, which only differ in their cytoplasmic N-terminus. Protein kinase CK2 phosphorylates the N-terminus of isoform ECE-1c, increasing its stability and leading to enhanced invasiveness in glioblastoma and colorectal cancer cells, which is believed to be mediated by the amino acid residue Lys-6, a conserved putative ubiquitination site neighboring the CK2-phosphorylated residues Ser-18 and Ser-20. Whether Lys-6 is linked to the acquisition of a cancer stem cell (CSC)-like phenotype and aggressiveness in human non–small cell lung cancer (NSCLC) cells has not been studied. Methods In order to establish the role of Lys-6 in the stability of ECE-1c and its involvement in lung cancer aggressiveness, we mutated this residue to a non-ubiquitinable arginine and constitutively expressed the wild-type (ECE-1cWT) and mutant (ECE-1cK6R) proteins in A549 and H1299 human NSCLC cells by lentiviral transduction. We determined the protein stability of these clones alone or in the presence of the CK2 inhibitor silmitasertib, compared to ECE-1cWT and mock-transduced cells. In addition, the concentration of secreted ET-1 in the growth media was determined by ELISA. Expression of stemness genes were determined by Western blot and RT-qPCR. Chemoresistance to cisplatin was studied by MTS viability assay. Migration and invasion were measured through transwell and Matrigel assays, respectively, and the side-population was determined using flow cytometry. Results ECE-1cK6R displayed higher stability in NSCLC cells compared to ECE-1cWT-expressing cells, but ET-1 secreted levels showed no difference up to 48 h. Most importantly, ECE-1cK6R promoted expression of the stemness genes c-Myc, Sox-2, Oct-4, CD44 and CD133, which enhance cellular self-renewal capability. Also, the ECE-1cK6R-expressing cells showed higher cisplatin chemoresistance, correlating with an augmented side-population abundance due to the increased expression of the ABCG2 efflux pump. Finally, the ECE-1cK6R-expressing cells showed enhanced invasiveness, which correlated with the regulated expression of known EMT markers. Conclusions Our findings suggest an important role of ECE-1c in lung cancer. ECE-1c is key in a non-canonical ET-1-independent mechanism which triggers a CSC-like phenotype, leading to enhanced lung cancer aggressiveness. Underlying this mechanism, ECE-1c is stabilized upon phosphorylation by CK2, which is upregulated in many cancers. Thus, phospho-ECE-1c may be considered as a novel prognostic biomarker of recurrence, as well as the CK2 inhibitor silmitasertib as a potential therapy for lung cancer patients.

Abstract Background United States military policies regarding service by transgender service members have shifted several times within the past decade. The relationships between policy changes and electronic health record documentation of gender dysphoria, a current and historic policy requisite for gender affirming care receipt, in active duty service members remain unknown. Methods Bayesian estimator of abrupt change, seasonality, and trend models identified changepoints in the proportion of service members who had new and then historical medical record documentation consistent with gender dysphoria from January 2015 to August 2022. Changepoints were evaluated as they related to salient military policy-related events. Results Approximately 3,853 active duty and activated National Guard or Reserve service members received a documented diagnosis corresponding to gender dysphoria from January 2015 to August 2022. Four significant changepoints were identified across both time series. Salient historical events that occurred during the changepoint periods were identified for contextualization. Conclusions Clinical documentation of gender dysphoria oscillated with changes to policies and public statements by government leaders, which may in turn, impact military recruitment and retention. This study highlights the need for equitable policies that optimize the strength of a diverse military force. Equity-oriented monitoring is needed to continually examine the impact of military service policies on readiness and retention to support actionable, data-driven improvements to policies and their implementation.

Abstract The transition to a bioeconomy is attracting the use of wood powders for developing bio-based chemicals, fuels, and products to replace fossil-based products. Wood powder-based products depend on the properties and quality of wood powders. Despite many studies on their morphological and physical properties, studies on micromorphology and extractive micro-distribution are scarce. Here we investigated the effect of milling type and wood quality in terms of moisture content on microstructural changes and native extractive distribution in wood powders. The findings showed that non-dried and dried multi-blade shaft mill (MBSM) powders had smooth surfaces and less undamaged cellulosic fibre walls, and extractives were located in the cell lumen. Non-dried and dried hammer mill powders had a rough surface and fibres with structural deformations in their cell walls (e.g. dislocations). Extractives were redistributed on the particle surface as well as dispersed in the cell lumen for both types of hammer mill powders. In a word, the powders obtained from MBSM technology are more native in structure. The findings of the study can have implications for downstream processes.

Abstract Age-related cataracts is a highly prevalent eye disorder that results in the clouding of the crystalline lens and is one of the leading causes of visual impairment and blindness. The disease is influenced by multiple factors including genetics, prolonged exposure to ultraviolet radiation, and a history of diabetes. However, the extent to which each of these factors contributes to the development of cataracts remains unclear. Our study identified 101 independent genome-wide significant loci, 57 of which are novel. We identified multiple genes and biological pathways associated with the cataracts, including four drug-gene interactions. Our results suggest a causal association between type 1 diabetes and cataracts. Also, we highlighted a surrogate measure of UV light exposure as a marker of cataract risk in adults.

Abstract Background Senescent immune cells exhibit altered gene expression and resistance to apoptosis. The prevalence of these cells increases with age and emerging data implicate senescence-associated maladaptive signaling as a potential contributor to sepsis and septic shock. The senolytic drug fisetin promotes clearance of senescent cells and is hypothesized to mitigate septic responses to infection. Methods We are conducting a multi-center, randomized, double-blinded, adaptive allocation phase 2 clinical trial to assess the efficacy of the senolytic drug fisetin in preventing clinical deterioration of elderly patients diagnosed with sepsis. We intend to enroll and randomize 220 elderly patients (age > 65) with the clinical diagnosis of sepsis to receive either fisetin as a single oral dose of 20 mg/kg, fisetin in two oral doses of 20 mg/kg each spaced 1 day apart, or placebo. The primary outcome will be changed in the composite of cardiovascular, respiratory, and renal sequential organ failure assessment scores at 7 days from enrollment. Secondary outcomes include quantification of senescent CD3 + cells at 7 days, and 28-day assessments of organ failure-free days, days in an intensive care unit, and all-cause mortality. Discussion This multi-center, randomized, double-blinded trial will assess the efficacy of fisetin in preventing clinical deterioration in elderly patients with sepsis and measure the effects of this drug on the prevalence of senescent immune cells. We intend that the results of this phase 2 trial will inform the design of a larger phase 3 study. Trial registration This trial is registered to ClinicalTrials.gov under identifier NCT05758246, first posted on March 7, 2023.

Abstract A synaptic protein, Neuronal Pentraxin 2 (NPTX2), has emerged as a pivotal biomarker for Alzheimer's dementia (AD). We identified candidate miRNAs targeting NPTX2 and performed association and mediation analyses using multi‐omics data (N = 702). Among 44 candidate miRNAs, miR‐133b was significantly associated with AD and Braak positivity. Higher miR‐133b expression was also associated with higher NPTX2 gene expression and better cognition. Mediation analysis showed that miR‐133b partially influences AD and cognition through the NPTX2 protein. Our integrated approach suggests a potential role of miR‐133b in synaptic integrity and offers new insights into AD pathogenesis.

Abstract Background This study examined onchocerciasis transmission in Kwanware and Ottou in the Wenchi Health District of Ghana, where persistent onchocercal microfilariae (mf) levels have been reported since 2012. Methods This study was conducted from 2019 to 2021 and involved the following: (i) reviewing past records of ivermectin mass drug administration (MDA); (ii) conducting a treatment coverage evaluation survey (CES); (iii) conducting key informant interviews; (iv) prospecting blackfly breeding sites; (v) collecting and dissecting blackflies; and (vi) conducting parasitological and serological surveys. Results (i) The review indicated ongoing MDA treatment for the past 27 years, with a reported coverage of over 65% in the last 17 yearly rounds; (ii) estimated treatment coverage by the CES in 2019 was 71.3%, with most of those not taking medicine stating that they were not offered; (iii) however, the key informant interviews revealed insufficiencies in reaching a significant number of people for treatment due to remote settlement, mobility, transport logistical issues, failure to register some people for treatment, leading to a false impression of good coverage, and a short distribution time; (iv) the most productive breeding was found within 5 km of Kwanware-Ottou; and (v) blackfly daily biting rates were highest in Kwanware and Ottou, with 199 and 160 bites per day, respectively. Infection in blackflies was found only in Kwanware and Ottou, with infectivity rates of 5.9‰ (per 1000) and 6.7‰, respectively. (vi) The mf prevalence in Ottou and Kwanware, respectively, was 40.0% and 30.0% among adults aged ≥ 20 years, and the anti-(Onchocerca volvulus) Ov16 IgG4 antibodies seroprevalence rates were 8.3% and 13.3% among children aged 5–9 years. These values were reduced to undetectable levels at a radius of 10 km from Ottou. Conclusions This study confirms that active onchocerciasis transmission centres on Kwanware/Ottou and is confined to a 10 km radius despite 27 yearly treatment rounds. The main contributing factors are suboptimal coverage and high biting rates. Identifying and targeting such a focus with a combination of interventions will be cost-effective in accelerating onchocerciasis elimination in Ghana.

Abstract Photosynthetic light response curves serve as powerful mathematical tools for quantitatively describing the rate of photosynthesis of plants in response to changes in irradiance. However, in practical applications, the daunting task of selecting an appropriate nonlinear model to accurately fit these curves persists as a significant challenge. Thus, there arises a need for a method to systematically evaluate the efficacy of such models. In the present study, four distinct nonlinear models, namely Exponential Model (EM), Rectangular Hyperbola Model (RHM), Nonrectangular Hyperbola Model (NHM), and Modified Rectangular Hyperbola Model (MRHM), were used to fit the relationship between light intensity and the rate of photosynthesis across 42 empirical datasets. The goodness of fit for each model was assessed using the root-mean-square error, and relative curvature measures of nonlinearity were employed to assess the nonlinear behavior of the models. In terms of goodness of fit, pairwise difference tests of the root-mean-square error revealed that there was little to choose among the four models, although RHM gave a marginally poorer fit. However, in terms of nonlinear behavior, EM not only provided the most favorable linear approximation performance at the global level, but also exhibited the best close-to-linear behavior at the individual parameter level among the four models across the 42 datasets. Consequently, the results strongly advocate for EM as the most suitable mathematical framework for fitting photosynthetic light response curves. These findings provide insights into the model assessment for nonlinear regression in describing the relationship between the photosynthetic rate and light intensity.

Abstract Within the healthcare settings of the United States Department of Veterans Affairs (VA), one patient-centered intervention, Advance Care Planning via Group Visits (ACP-GV), engages veterans and those they trust in advance care planning (ACP) by facilitating a discussion that encourages participants to plan for future healthcare needs. ACP-GV is a one-hour, single session group intervention facilitated by a trained clinical professional (e.g., physician, nurse, social worker, psychologist, chaplain) and delivered in a healthcare or community-based setting. Using reporting guidelines for group-based and educational interventions, this paper aims to describe the ACP-GV Facilitator Training used to prepare clinical professionals to offer the ACP-GV intervention to participants. We provide health professional students and early career health professionals with an overview of the training and key tips for using group modalities in the clinical setting. Although the training is initially directed towards health professionals who are learning to offer ACP-GV for the first time, our tips for teaching also focus on and extend to facilitating ACP-GV directly with veterans, caregivers, and those they trust. The ACP-GV Facilitator Training is sequential in that it expects clinicians to first learn the required educational content and how to plan a group, then it engages clinicians in practicing group facilitation skills. At the conclusion of the training, clinicians are then instructed to use the training materials to transfer the information and skills they learned about ACP-GV to patients they encounter in their respective work settings. The culmination of the ACP-GV Facilitator Training is, therefore, when the clinician is able to facilitate their own group, guide discussions and activities, actively use training materials, and encourage veterans and those they trust to participate in a discussion regarding ACP in a group setting. Finally, we share key resources for publicly available and accessible online trainings to promote spread outside of VA. ACP-GV’s Facilitator Training can assist healthcare professionals in implementing ACP-GV in a variety of care settings.

Abstract Understanding the genetic basis of routinely-acquired blood tests can provide insights into several aspects of human physiology. We report a genome-wide association study of 42 quantitative blood test traits defined using Electronic Healthcare Records (EHRs) of ~50,000 British Bangladeshi and British Pakistani adults. We demonstrate a causal variant within the PIEZO1 locus which was associated with alterations in red cell traits and glycated haemoglobin. Conditional analysis and within-ancestry fine mapping confirmed that this signal is driven by a missense variant - chr16-88716656-G-TT - which is common in South Asian ancestries (MAF 3.9%) but ultra-rare in other ancestries. Carriers of the T allele had lower mean HbA1c values, lower HbA1c values for a given level of random or fasting glucose, and delayed diagnosis of Type 2 Diabetes Mellitus. Our results shed light on the genetic basis of clinically-relevant traits in an under-represented population, and emphasise the importance of ancestral diversity in genetic studies.

Abstract Background Infertility presents both medical and public health challenges, with in vitro fertilization (IVF) emerging as a prominent solution, particularly when other alternatives are exhausted. However, IVF treatment raises significant ethical questions that have been under explored in the Ghanaian context. This study aimed to explore ethical constraints and dilemmas in the provision of in vitro fertilization (IVF) treatment in Ghana. Methods A descriptive phenomenological qualitative design was employed. Purposive sampling techniques were used to recruit 12 participants including ART experts from three in vitro fertilization (IVF) centres, ethicists and a legal practitioner. In-depth face-to-face interviews guided by an open-ended interview guide were conducted. Thematic analysis of the interviews was performed to identify major themes. Results Providing IVF treatment in Ghana raises several ethical issues, including inequitable access due to high costs and limited availability, which favour wealthier individuals and leave marginalized populations with fewer options. There are significant ethical considerations in balancing the potential benefits of successful IVF treatment outcomes against the health risks and emotional tolls on patients. Decisions about the fate of surplus embryos present moral dilemmas, including whether to preserve, donate, or discard them. Differing personal beliefs about the moral status of the embryo further complicate the ethical landscape. Ensuring informed consent is challenging due to the complex medical, ethical, and emotional implications of IVF treatment, potentially leading to compromised consent. Additionally, there are ongoing risks of breaches in confidentiality, given the sensitive nature of reproductive health data and the importance of protecting patient privacy. Conclusion This study revealed that several ethical dilemmas confront both healthcare providers and couples in the process of IVF. There is an urgent need for the development of clear and uniform regulations to govern the practice of IVF treatment in Ghana, with further attention given to mitigating financial barriers and enhancing support systems for couples considering IVF treatment.

Abstract Robust data privacy regulations hinder the exchange of healthcare data among institutions, crucial for global insights and developing generalised clinical models. Federated learning (FL) is ideal for training global models using datasets from different institutions without compromising privacy. However, disparities in electronic healthcare records (EHRs) lead to inconsistencies in ML-ready data views, making FL challenging without extensive preprocessing and information loss. These differences arise from variations in services, care standards, and record-keeping practices. This paper addresses data view heterogeneity by introducing a knowledge abstraction and filtering-based FL framework that allows FL over heterogeneous data views without manual alignment or information loss. The knowledge abstraction and filtering mechanism maps raw input representations to a unified, semantically rich shared space for effective global model training. Experiments on three healthcare datasets demonstrate the framework’s effectiveness in overcoming data view heterogeneity and facilitating information sharing in a federated setup.

Abstract Background In the central nervous system, type 2 vesicular monoamine transporters (VMAT2) are responsible for the reuptake of monoamines from synaptic junction back to pre-synaptic terminal vesicles. These transporters are functionally crucial as they reflect the integrity of monoamine neurons. D6-[18F]FP-(+)-DTBZ, a novel deuterated VMAT2 radioligand, has shown promise as a potential PET tracer for the diagnosis of Parkinson’s disease (PD). This study evaluates the biodistribution and dosimetry of D6-[18F]FP-(+)-DTBZ and includes a head-to-head comparison with its non-deuterated version, [18F]FP-(+)-DTBZ (AV-133), in healthy individuals and PD patients. Results The automated synthesis of D6-[18F]FP-(+)-DTBZ using the SPE method was accomplished in 35 min, yielding a high radiochemical purity (> 99%) and high radiochemical yields (35 ± 5%). The biodistribution and dosimetry study indicated an effective dose of 37.1 ± 7.2 μSv/MBq, with the liver receiving the highest radiation dose (289.6 ± 42.1 μGy/MBq), followed by pancreas (185.2 ± 29.1 μGy/MBq). Brain imaging with D6-[18F]FP-(+)-DTBZ exhibited a significantly increased uptake in VMAT2-rich regions, particularly the striatum. In a head-to-head comparison between [18F]FP-(+)-DTBZ and D6-[18F]FP-(+)-DTBZ, the latter exhibited approximately 15% higher SUVR in the caudate, putamen, and nucleus accumbens. Preliminary studies in PD patients showed a substantial reduction in VMAT2 uptake in the striatum, with the most pronounced decrease observed in the putamen (a 53% decline). Conclusions D6-[18F]FP-(+)-DTBZ is a safe and improved VMAT2-specific imaging agent, which may be suitable for diagnosing PD by evaluating changes in VMAT2 binding of monoamine neurons in the brain. Trial registration Chinese Clinical Trial Registry, ChiCTR2200057218, Registered 16 August 2021, https://www.chictr.org.cn/bin/project/edit?pid=142725 .

Abstract As they become more common, automated systems are also becoming increasingly opaque, challenging their users’ abilities to explain and interpret their outputs. In this study, we test the predictions of fuzzy-trace theory—a leading theory of how people interpret quantitative information—on user decision making after interacting with an online decision aid. We recruited a sample of 205 online crowdworkers and asked them to use a system that was designed to detect URLs that were part of coordinated misinformation campaigns. We examined how user endorsements of system interpretability covaried with performance on this coordinated misinformation detection task and found that subjects who endorsed system interpretability displayed enhanced discernment. This interpretability was, in turn, associated with both objective mathematical ability and mathematical self-confidence. Beyond these individual differences, we evaluated the impact of a theoretically motivated intervention that was designed to promote sensemaking of system output. Participants provided with a “gist” version of system output, expressing the bottom-line meaning of that output, were better able to identify URLs that might have been part of a coordinated misinformation campaign, compared to users given the same information presented as verbatim quantitative metrics. This work highlights the importance of enabling users to grasp the essential, gist meaning of the information they receive from automated systems, which benefits users regardless of individual differences.

Abstract Background Medication reconciliation is essential for optimizing medication use. In part to promote effective medication reconciliation, the Department of Veterans Affairs (VA) invested substantial resources in health information exchange (HIE) technologies. The objectives of this qualitative study were to characterize VA clinicians’ use of HIE tools for medication reconciliation in their clinical practice and to identify facilitators and barriers. Methods We recruited inpatient and outpatient prescribers (physicians, nurse practitioners, physician assistants) and pharmacists at four geographically distinct VA medical centers for observations and interviews. Participants were observed as they interacted with HIE or medication reconciliation tools during routine work. Participants were interviewed about clinical decision-making pertaining to medication reconciliation and use of HIE tools, and about barriers and facilitators to use of the tools. Qualitative data were analyzed via inductive and deductive approaches using a priori codes. Results A total of 63 clinicians participated. Over half (58%) were female, and the mean duration of VA clinical experience was 7 (range 0–32) years. Underlying motivators for clinicians seeking data external to their VA medical center were having new patients, current patients receiving care from an external institution, and clinicians’ concerns about possible medication discrepancies among institutions. Facilitators for using HIE software were clinicians’ familiarity with the HIE software, clinicians’ belief that medication information would be available within HIE, and their confidence in the ability to find HIE medication-related data of interest quickly. Six overarching barriers to HIE software use for medication coordination included visual clutter and information overload within the HIE display; challenges with HIE interface navigation; lack of integration between HIE and other electronic health record interfaces, necessitating multiple logins and application switching; concerns with the dependability of HIE medication information; unfamiliarity with HIE tools; and a lack of HIE data from non-VA facilities. Conclusions This study is believed to be the first to qualitatively characterize clinicians’ HIE use with respect to medication reconciliation. Results inform recommendations to optimize HIE use for medication management activities. We expect that healthcare organizations and software vendors will be able to apply the findings to develop more effective and usable HIE information displays.

Abstract Background Pain, the primary complaint in rheumatoid arthritis (RA), is multifaceted, and may be driven by inflammatory disease activity and central sensitisation. We aimed to ascertain what proportion of RA pain severity is explained by markers of inflammation and quantitative sensory testing (QST) indices of central sensitisation. Methods This was a cross-sectional analysis of data from individuals with clinically active RA. Pain severity was assessed using numerical rating scales and inflammation via 28-joint Disease Activity Score (DAS28) and Ultrasound (Greyscale, Power Doppler). Pain sensitivity was assessed by ‘static’ (tibialis anterior or brachioradialis pressure pain detection threshold-PPT-TA/PPT-BR) and ‘dynamic’ (temporal summation-TS, conditioned pain modulation-CPM) QST. Bivariate associations used Spearman’s correlation coefficients, and multivariable linear regression models determined relative contributions to pain severity. Results In bivariate analyses of N = 96 (age 65 ± 10y, 77% females) people with RA, pain severity was significantly associated with inflammation indices (r = 0.20 to 0.55), and CPM (r=-0.26). In multivariable models that included TS, CPM, age, sex, and body mass index, inflammation indices remained significantly associated with pain severity. Multivariable models explained 22 to 27% of pain variance. Heterogeneity was apparent for associations with pain between subscores for pain now, strongest or average over the past 4-weeks. Conclusions In individuals with clinically active RA, markers of inflammatory disease activity best explain RA pain with only marginal contributions from QST indices of central sensitisation. Although inflammation plays a key role in the experience of RA pain, the greater proportion of pain severity remains unexplained by DAS28 and ultrasound indices of inflammation.

The diversity of Rubus in South America is much understudied and a taxonomic framework needs to be established as a basis for future revisionary and phylogenetic work. Our review identified 110 names based on South American specimens which were published since 1767. Each name was then classified according to its botanical description and type material. Additionally, where necessary, we suggest appropriate lecto-, neo-, or epitypes. A comprehensive list of synonyms is provided and representative herbarium specimens for each country are cited to tentatively document geographical range. In total, we accept 46 species of Rubus recorded across South America, propose 19 new synonyms, restore R. organensis, previously a synonym of R. brasiliensis, provide a replacement name for the latter, and include new country records of R. azuayensis, R. laegaardii and R. rusbyi. This checklist serves as an essential starting point for future monographic and evolutionary studies on Rubus in South America.

Abstract The main chemical, ecotoxicological, and environmental fate characteristics of cyanide, along with its treatment methods for cyanide-contaminated wastewater, were thoroughly examined. A global biogeochemical cycle of cyanide is proposed, covering the key physicochemical processes occurring in aqueous, soil, and atmospheric environments. The principles, advantages, and disadvantages of various treatment methods—including chemical, physicochemical, electrochemical, photochemical, and biological approaches—are evaluated. Finally, the feasibility of reusing cyanide waste is explored.

Abstract Background Apolipoprotein E (APOE) genotypes have been suggested to influence cognitive impairment and clinical onset in presenilin-1 (PSEN1) E280A carriers for autosomal dominant Alzheimer’s disease (ADAD). Less is known about their impact on the trajectory of biomarker changes. Neurofilament light chain (NfL), a marker of neurodegeneration, begins to accumulate in plasma about 20 years prior to the clinical onset of ADAD. In this study we investigated the impact of APOE ε4 and ε2 variants on age-related plasma NfL increases and cognition in PSEN1 E280A mutation carriers. Methods We analyzed cross-sectional data from PSEN1 E280A mutation carriers and non-carriers recruited from the Alzheimer’s Prevention Initiative Registry of ADAD. All participants over 18 years with available APOE genotype, plasma NfL, and neuropsychological evaluation were included in this study. APOE genotypes and plasma NfL concentrations were characterized for each participant. Cubic spline models using a Hamiltonian Markov chain Monte Carlo method were used to characterize the respective impact of at least one APOE ε4 or ε2 allele on age-related log-transformed plasma NfL increases. Linear regression models were estimated to explore the impact of APOE ε4 and ε2 variants and plasma NfL on a composite cognitive test score in the ADAD mutation carrier and non-carrier groups. Results Analyses included 788 PSEN1 E280A mutation carriers (169 APOE ε4 + , 114 ε2 +) and 650 mutation non-carriers (165 APOE ε4 + , 80 ε2 +), aged 18–75 years. APOE ε4 allele carriers were distinguished from ε4 non-carriers by greater age-related NfL elevations in the ADAD mutation carrier group, beginning about three years after the mutation carriers’ estimated median age at mild cognitive impairment onset. APOE ε2 allele carriers had lower plasma NfL concentrations than ε2 non-carriers in both the ADAD mutation carrier and non-carrier groups, unrelated to age, and an attenuated relationship between higher NfL levels on cognitive decline in the ADAD mutation carrier group. Conclusions APOE ε4 accelerates age-related plasma NfL increases and APOE ε2 attenuates the relationship between higher plasma NfL levels and cognitive decline in ADAD. NfL may be a useful biomarker to assess clinical efficacy of APOE-modifying drugs with the potential to help in the treatment and prevention of ADAD.

Abstract Background This case report details a long-term follow-up of a hoof melanoma with dermo-epidermal activity (resembling Spreading Superficial Melanoma (SSM)) in a bay horse with a history of a right front hoof keratoma. Melanomas involving the horse's foot are seldom reported and usually diagnosed as anaplastic melanomas based on signalment and post-mortem examination. The clinical-pathological characteristics of the foot melanoma in this bay horse are consistent with SSM-like described in humans, which is considered an intermediate malignant tumour attending their biological behaviour. However, a definitive diagnosis is limited by the single case and the lack of references in horses. Case presentation A 12-year-old bay Andalusian gelding underwent keratoma removal on the lateral aspect of the hoof wall. A partial resection of the hoof wall was performed for this purpose. Additionally, a plaque-like, hyperkeratotic pigmented lesion, 2 × 2X0,4 cm in size, was observed at the lateral aspect of the coronary band and was also resected for histopathological examination. Microscopically, a melanocytic tumour, characterised by small nests of large polygonal or epithelioid cells infiltrating the basal and suprabasal epidermis, the dermo – epidermal junction, and the superficial dermis, was observed. The neoplastic cells exhibited large euchromatic nuclei, prominent nucleoli, moderate pleomorphism and 4 mitotic figures per 2,37mm2; variable amounts of dark granules (melanin) were present in the cytoplasm, as well as in numerous peritumoral macrophages. The immunophenotype of the tumour cells was PNL2 + + + , S100 + + , AE1/AE3-. A diagnosis of melanoma with dermo-epidermal junction and marked intraepidermal activity (consistent with superficial spreading melanoma) was made. A magnetic resonance imaging (MRI) performed, revealed no further invasion into surrounding structures. Treatment was based on surgical resection and multiple local chemotherapy sessions with cisplatin were applied. The biopsies obtained after treatment showed partial regression of the tumour and different stages of healing. After 26 months of follow-up, there was no signs of malignant spreading into surrounding structures including the pedal bone and distal metastasis but a dark – coloured area persists over the lateral aspect of the coronary band. Conclusions This case presents a concomitant keratoma and melanoma with dermo – epidermal activity, resembling a spreading superficial melanoma. After a follow – up of 26 months the horse remains healthy and sound providing new information for clinicians and pathologists. Despite the poor prognosis associated with foot malignant melanocytic tumours, it is important that an early and accurate diagnosis is reached through different diagnostic modalities such as advanced imaging techniques and histopathology. Additionally, these findings demonstrate that the current classification and prognosis for equine foot melanomas are insufficient.

Abstract Venous thrombosis (VT) is a common vascular disease associated with reduced survival and a high recurrence rate. VT is initiated by the accumulation of platelets and neutrophils at sites of endothelial cell activation. A role for platelet αIIbβ3 in VT is not established, a task complicated by the increased bleeding risk caused by partial agonists such as tirofiban. Here, we show that m-tirofiban, a modified version of tirofiban, does not agonize αIIbβ3 based on lack of neoepitope expression and the cryo-EM structure of m-tirofiban/full-length αIIbβ3 complex. m-tirofiban abolishes agonist-induced platelet aggregation while preserving clot retraction ex vivo and, unlike tirofiban, it suppresses venous thrombogenesis in a mouse model without increasing bleeding. These findings establish a key role for αIIbβ3 in VT initiation and suggest that m-tirofiban and compounds with a similar structurally-defined mechanism of action merit consideration as potential thromboprophylaxis agents in patients at high risk for VT and hemorrhage.

Abstract One of the most captivating properties of polaritons is their capacity to confine light at the nanoscale. This confinement is even more extreme in two-dimensional (2D) materials. 2D polaritons have been investigated by optical measurements using an external photodetector. However, their effective spectrally resolved electrical detection via far-field excitation remains unexplored. This hinders their exploitation in crucial applications such as sensing, hyperspectral imaging, and optical spectrometry, banking on their potential for integration with silicon technologies. Herein, we present the electrical spectroscopy of polaritonic nanoresonators based on a high-quality 2D-material heterostructure, which serves at the same time as the photodetector and the polaritonic platform. Subsequently, we electrically detect these mid-infrared resonators by near-field coupling to a graphene pn-junction. The nanoresonators simultaneously exhibit extreme lateral confinement and high-quality factors. This work opens a venue for investigating this tunable and complex hybrid system and its use in compact sensing and imaging platforms.

Campylobacteriosis and antimicrobial resistance (AMR) are global public health concerns. Africa is estimated to have the world’s highest incidence of campylobacteriosis and a relatively high prevalence of AMR in Campylobacter spp. from humans and animals. Few studies have compared Campylobacter spp. isolated from humans and poultry in Africa using whole-genome sequencing and antimicrobial susceptibility testing. We explored the population structure and AMR of 178 Campylobacter isolates from East Africa, 81 from patients with diarrhea in Kenya and 97 from 56 poultry samples in Tanzania, collected during 2006–2017. Sequence type diversity was high in both poultry and human isolates, with some sequence types in common. The estimated prevalence of multidrug resistance, defined as resistance to >3 antimicrobial classes, was higher in poultry isolates (40.9%, 95% credible interval 23.6%–59.4%) than in human isolates (2.5%, 95% credible interval 0.3%–6.8%), underlining the importance of antimicrobial stewardship in livestock systems.

We performed chlorine inactivation experiments for Elizabethkingia anophelis and E. meningoseptica bacterial strains from clinical and environmental sources. Free chlorine concentration × contact time values

Abstract Aims It is unclear whether activated partial thromboplastin time (aPTT) or anti‐Xa is more accurate for monitoring heparin anticoagulation in mechanical circulatory support (MCS) patients. This study investigates the relationship between aPTT and anti‐Xa in MCS patients and identifies predictors of discordance. Methods and results aPTT and anti‐Xa were simultaneously measured in a prospective cohort of MCS patients receiving unfractionated heparin at a tertiary academic medical centre. Therapeutic aPTT and anti‐Xa levels were 60–100 s and 0.3–0.7 IU/mL, respectively, and concordance was defined as both levels being subtherapeutic, therapeutic, or supratherapeutic. To identify predictors of discordance, both a machine learning random forest model and a multivariate regression model were applied to patient demographics, device type, and 14 laboratory variables; 23 001 pairs of simultaneously measured aPTT/anti‐Xa were collected from 699 MCS patients. aPTT and anti‐Xa were concordant in 35.5% of paired observations and discordant in 64.5% (aPTT > antiXa 61.5%; aPTT antiXa) was associated with high INR, eGFR, and total bilirubin, as well as low platelets, haemoglobin, pre‐albumin, white blood cell count, and haptoglobin. Total artificial heart and durable ventricular assist devices were more likely to be associated with aPTT > anti‐Xa than temporary MCS devices. Conclusions aPTT and anti‐Xa were frequently discordant in MCS patients receiving heparin anticoagulation. Clinical conditions common in MCS patients such as concurrent warfarin use, malnutrition, haemolysis, and thrombocytopenia, as well as durable type of MCS devices were associated with a high aPTT relative to anti‐Xa.

Background. People living with HIV (PWH) frequently have co-morbid substance use disorders that may have been impacted by the COVID-19 pandemic. This study examined associations between COVID-related stress and increased substance use among PWH in Washington State. Methods. Between August 2020 and March 2021, we conducted an online survey of 397 PWH in western Washington. Logistic regression was used to analyze associations between a COVID-19 stress score and four self-reported outcomes: increased alcohol use, increased cigarette smoking, increased marijuana use, and increased use of illicit substances. Results. Thirty-five (38.0%) of 92 participants who smoked, 61 (23.4%) of 261 participants who used alcohol, 15 (14.6%) of 103 participants who used marijuana, and 35 (33.0%) of 102 participants who used illicit substances reported increased use of these substances. Higher COVID-19 stress scores were associated with higher odds of increased cigarette smoking (adjusted odds ratio [aOR] = 1.15, 95% confidence interval [CI]: 1.04–1.27), even after adjustment for anxiety and depressive symptoms (aOR 1.14, 95%CI: 1.03–1.27). COVID-19 stress was not associated with an increased use of alcohol, marijuana, or illicit substances. Conclusions. COVID-19-related stress was associated with self-reported increased cigarette smoking among PWH in western Washington during the pandemic.

Abstract Determining the genetic architecture of Alzheimer’s disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD.

Abstract In this work, we study the evolution of an evaporating black hole, described by the Kerr–Taub–NUT metric, which emits scalar particles. We found that allowing the black hole to radiate massless scalar particles increases the angular momentum loss rate while decreasing the loss rate of the NUT parameter and black hole mass. In fact, it means that angular momentum will disappear faster than the other black hole parameters (mass and NUT parameter) during the evaporation process. We also calculate the time evolution of the mass, angular momentum, and NUT parameter in order to get the evolution of the Von Neumann entropy of the black hole. We found that the entropy follows approximately the so-called Page curve, where the $$\beta $$ β parameter, which quantifies the amount of radiation, affects the evaporation process. Implying that high $$\beta $$ β values accelerate the evaporation process of a Kerr–Taub–NUT black hole.

Abstract Background The impact of multimorbidity (≥ 2 chronic diseases) on the well-being of older adults is substantial but variable. The burden of multimorbidity varies by the number and kinds of conditions, and timing of onset. The impact varies by age, race, ethnicity, socioeconomic status, and health indicators. Large scale longitudinal surveys linked to medical claims provide unique opportunities to characterize this variability. Methods We analyzed Medicare-linked Health and Retirement Study data for respondents 65 and older with 3 or more years of fee-for-service coverage (n = 17,199; 2000–2016). We applied standardized claims algorithms for operationalizing 21 chronic diseases. We compared multimorbidity levels, demographics, and outcomes at baseline and over time and escalation to high multimorbidity levels (≥ 5 conditions). Results At baseline, 51.2% had no multimorbidity, 36.5% had multimorbidity, and 12.4% had high multimorbidity. Loss of function, cognitive decline, and higher healthcare utilization were up to ten times more prevalent in the high multimorbidity group. Greater rates of high multimorbidity were seen among non-Hispanic Black and Hispanic groups, those with lower wealth, younger birth cohorts, and adults with obesity. Rates of transition to high multimorbidity varied greatly and was highest among Hispanic and respondents with lower education. Conclusions The development and progression of multimorbidity in old age is influenced by many factors. Higher levels of multimorbidity are associated with sociodemographic characteristics, suggesting possible mitigation strategies.

Abstract Optical phenomena always display some degree of partial coherence between their respective degrees of freedom. Partial coherence is of particular interest in multimodal systems, where classical and quantum correlations between spatial, polarization, and spectral degrees of freedom can lead to fascinating phenomena (e.g., entanglement) and be leveraged for advanced imaging and sensing modalities (e.g., in hyperspectral, polarization, and ghost imaging). Here, we present a universal method to analyze, process, and generate spatially partially coherent light in multimode systems by using self-configuring optical networks. Our method relies on cascaded self-configuring layers whose average power outputs are sequentially optimized. Once optimized, the network separates the input light into its mutually incoherent components, which is formally equivalent to a diagonalization of the input density matrix. We illustrate our method with numerical simulations of Mach-Zehnder interferometer arrays and show how this method can be used to perform partially coherent environmental light sensing, generation of multimode partially coherent light with arbitrary coherency matrices, and unscrambling of quantum optical mixtures. We provide guidelines for the experimental realization of this method, including the influence of losses, paving the way for self-configuring photonic devices that can automatically learn optimal modal representations of partially coherent light fields.

Abstract Background Feed costs account for a high proportion of the variable cost of beef production, ultimately impacting overall profitability. Thus, improving feed efficiency of beef cattle, by way of determining the underlying genomic control and selecting for feed efficient cattle provides a method through which feed input costs may be reduced whilst also contributing to the environmental sustainability of beef production. The rumen microbiome dictates the feed degradation capacity and consequent nutrient supply in ruminants, thus potentially impacted by feed efficiency phenotype. Equally, liver tissue has been shown to be responsive to feed efficiency phenotype as well as dietary intake. However, although both the rumen microbiome and liver transcriptome have been shown to be impacted by host feed efficiency phenotype, knowledge of the interaction between the rumen microbiome and other peripheral tissues within the body, including the liver is lacking. Thus, the objective of this study was to compare two contrasting breed types (Charolais and Holstein-Friesian) divergent for residual feed intake (RFI) over contrasting dietary phases (zero-grazed grass and high-concentrate), based on gene co-expression network analysis of liver transcriptome data and microbe co-abundance network of rumen microbiome data. Traits including RFI, dry matter intake (DMI) and growth rate (ADG), as well as rumen concentrations of volatile fatty acids were also included within the network analysis. Results Overall, DMI had the greatest number of connections followed by RFI, with ADG displaying the fewest number of significant connections. Hepatic genes related to lipid metabolism were correlated to both RFI and DMI phenotypes, whilst genes related to immune response were correlated to DMI. Despite the known relationship between RFI and DMI, the same microbes were not directly connected to these phenotypes, the Succiniclasticum genus was however, negatively connected to both RFI and ADG. Additionally, a stepwise regression analysis revealed significant roles for both Succiniclasticum genus and Roseburia.faecis sp. in predicting RFI, DMI and ADG. Conclusions Results from this study highlight the interactive relationships between rumen microbiome and hepatic transcriptome data of cattle divergent for RFI, whilst also increasing our understanding of the underlying biology of both DMI and ADG in beef cattle.

Abstract The malaria parasites Plasmodium falciparum and Plasmodium vivax differ in key biological processes and associated clinical effects, but consequences on population-level transmission dynamics are difficult to predict. This co-endemic malaria study from Guyana details important epidemiological contrasts between the species by coupling population genomics (1396 spatiotemporally matched parasite genomes, primarily from 2020–21) with sociodemographic analysis (nationwide patient census from 2019). We describe how P. falciparum forms large, interrelated subpopulations that sporadically expand but generally exhibit restrained dispersal, whereby spatial distance and patient travel statistics predict parasite identity-by-descent (IBD). Case bias towards working-age adults is also strongly pronounced. P. vivax exhibits 46% higher average nucleotide diversity (π) and 6.5x lower average IBD. It occupies a wider geographic range, without evidence for outbreak-like expansions, only microgeographic patterns of isolation-by-distance, and weaker case bias towards adults. Possible latency-relapse effects also manifest in various analyses. For example, 11.0% of patients diagnosed with P. vivax in Greater Georgetown report no recent travel to endemic zones, and P. vivax clones recur in 11 of 46 patients incidentally sampled twice during the study. Polyclonality rate is also 2.1x higher than in P. falciparum, does not trend positively with estimated incidence, and correlates uniquely to selected demographics. We discuss possible underlying mechanisms and implications for malaria control.

Liver transplantation is the most effective treatment for end-stage liver disease. Despite improvements in surgical techniques, transplant rejection remains a significant concern. The liver is considered an immune-privileged organ due to its unique microenvironment and complex interactions among various cell types. Alloimmune responses mediated by T cells and antigen-presenting cells (APCs) play crucial roles in transplant rejection. The liver’s dual blood supply and unique composition of its sinusoidal endothelial cells (LSECs), Kupffer cells (KCs), hepatocytes, and hepatic stellate cells (HSCs) contribute to its immune privilege. Alloantigen recognition by T cells occurs through direct, indirect, and semidirect pathways, leading to acute cellular rejection (ACR) and chronic rejection. ACR is a T cell-mediated process that typically occurs within the first few weeks to months after transplantation. Chronic rejection, on the other hand, is a gradual process characterized by progressive fibrosis and graft dysfunction, often leading to graft loss. Acute antibody-mediated rejection (AMR) is less common following surgery compared to other solid organ transplants due to the liver’s unique anatomy and immune privilege. However, when it does occur, AMR can be aggressive and lead to rapid graft dysfunction. Despite improvements in immunosuppression, rejection remains a challenge, particularly chronic rejection. Understanding the mechanisms of rejection and immune tolerance, including the roles of regulatory T cells (Tregs) and hepatic dendritic cells (DCs), is crucial for improving transplant outcomes. Strategies to induce immune tolerance, such as modulating DC function or promoting Treg activity, hold promise for reducing rejection and improving long-term graft survival. This review focuses on the liver’s unique predisposition to rejection and tolerance, highlighting the roles of individual cell types in these processes. Continued research into the mechanisms of alloimmune responses and immune tolerance in liver transplantation is essential for developing more effective therapies and improving long-term outcomes for patients with end-stage liver disease.

This paper assessed the phytoplankton structure and its relationship with the physical environment in the coastal region off Mazatlán, Mexico, in two seasons of 2022, a year in which a strong La Niña event took place: (1) the warmer (August) and (2) the transitional period to the cold phase (November), based on hydrographic data and samples collected in two systematic scientific expeditions. The results showed clear differences between both seasons. Regarding total abundance, August reached 125,200 cells L−1, while November amounted to 219,900 cells L−1. Regarding species composition, the diatoms Cylindrotheca closterium and Planktoniella sol were dominant in August, while Thalassionema nitzschioides and Tetramphora decussata dominated the assemblages in November. The dinoflagellate Protoperidinium punctulatum was dominant in both seasons. However, very marked differences in its abundance are reported. The differences observed in the species richness and abundance could be attributed to the physical configuration of the water column, particularly the surface temperature, which showed clear changes between both seasons. The results presented here confirmed the high phytoplankton richness (some of them with the potential to generate harmful algal blooms), abundance, and diversity values of the region, suggesting a strong relationship with the physical environment.