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Abstract Background The COVID-19 pandemic has had an unprecedented impact in the global research production and has also increased research waste. Living evidence syntheses (LESs) seek to regularly update a body of evidence addressing a specific question. During the COVID-19 pandemic, the production and dissemination of LESs emerged as a cornerstone of the evidence infrastructure. This critical interpretive synthesis answers the questions: What constitutes an LES to support decision-making?; when should one be produced, updated, and discontinued?; and how should one be disseminated? Methods Searches included the Cochrane Library, EMBASE (Ovid), Health Systems Evidence, MEDLINE (Ovid), PubMed, and Web of Science up to 23 April 2024 and included articles that provide any insights on addressing the compass questions on LESs. Articles were selected and appraised, and their insights extracted. An interpretive and iterative coding process was used to identify relevant thematic categories and create a conceptual framework. Results Among the 16,630 non-duplicate records identified, 208 publications proved eligible. Most were non-empirical articles, followed by actual LESs. Approximately one in three articles were published in response to the COVID-19 pandemic. The conceptual framework addresses six thematic categories: (1) what is an LES; (2) what methodological approaches facilitate LESs production; (3) when to produce an LES; (4) when to update an LES; (5) how to make available the findings of an LES; and (6) when to discontinue LES updates. Conclusion LESs can play a critical role in reducing research waste and ensuring alignment with advisory and decision-making processes. This critical interpretive synthesis provides relevant insights on how to better organize the global evidence architecture to support their production. Trial registration PROSPERO registration: CRD42021241875.

In this paper, we determine the fuzzy similarity measures of the U. S. state rankings with respect to domestic violence, female homicide, and sexual violence against teens. We find that the fuzzy similarity measures are low. We then consider the best state rankings and determine the fuzzy similarity measures of this ranking a with the previous three rankings. We also develop some theoretical results concerning fuzzy similarity measures.

Abstract Patients with post-treatment Lyme disease (PTLD) report negative perceptions of care and significant invalidation from medical professionals. However, the relationship of invalidation to illness severity has not been examined, nor have risk factors for invalidation been identified. This cross-sectional study enrolled 80 patients who met stringent criteria for PTLD. We examined correlations between the Illness Invalidation Inventory and measures of symptom severity, quality of life, and trust in physicians. To study the relationship between invalidation and potential demographic and clinical factors, we generated simple unadjusted and multivariate adjusted linear regression models. We found that higher ‘lack of understanding’ and ‘discounting’ subscale scores of the Illness Invalidation Inventory were significantly positively correlated with higher symptom severity, lower quality of life, and lower trust in physicians. In adjusted linear regression models, older age (lack of understanding: β = − 0.17, p = 0.008, discounting: β = − 0.19, p = 0.001, every 10 years) and male gender (lack of understanding: β = − 0.49, p = 0.016, discounting: β = − 0.51, p = 0.006) were associated with less invalidation. We also identified receiving an alternative diagnosis for PTLD as a mediator in the relationship between gender and invalidation. Based on our findings, we hypothesize that reducing invalidation within the clinical encounter could positively affect illness burden and quality of life for patients with PTLD.

Abstract Background Autism spectrum disorder (ASD), a neurodevelopmental disorder defined by social communication deficits plus repetitive behaviors and restricted interests, currently affects 1/36 children in the general population. Recent advances in functional brain imaging show promise to provide useful biomarkers of ASD diagnostic likelihood, behavioral trait severity, and even response to therapeutic intervention. However, current gold-standard neuroimaging methods (e.g., functional magnetic resonance imaging, fMRI) are limited in naturalistic studies of brain function underlying ASD-associated behaviors due to the constrained imaging environment. Compared to fMRI, high-density diffuse optical tomography (HD-DOT), a non-invasive and minimally constraining optical neuroimaging modality, can overcome these limitations. Herein, we aimed to establish HD-DOT to evaluate brain function in autistic and non-autistic school-age children as they performed a biological motion perception task previously shown to yield results related to both ASD diagnosis and behavioral traits. Methods We used HD-DOT to image brain function in 46 ASD school-age participants and 49 non-autistic individuals (NAI) as they viewed dynamic point-light displays of coherent biological and scrambled motion. We assessed group-level cortical brain function with statistical parametric mapping. Additionally, we tested for brain-behavior associations with dimensional metrics of autism traits, as measured with the Social Responsiveness Scale-2, with hierarchical regression models. Results We found that NAI participants presented stronger brain activity contrast (coherent > scrambled) than ASD children in cortical regions related to visual, motor, and social processing. Additionally, regression models revealed multiple cortical regions in autistic participants where brain function is significantly associated with dimensional measures of ASD traits. Limitations Optical imaging methods are limited in depth sensitivity and so cannot measure brain activity within deep subcortical regions. However, the field of view of this HD-DOT system includes multiple brain regions previously implicated in both task-based and task-free studies on autism. Conclusions This study demonstrates that HD-DOT is sensitive to brain function that both differentiates between NAI and ASD groups and correlates with dimensional measures of ASD traits. These findings establish HD-DOT as an effective tool for investigating brain function in autistic and non-autistic children. Moreover, this study established neural correlates related to biological motion perception and its association with dimensional measures of ASD traits.

Abstract Objectives The purpose of this study is to assess the diagnostic efficacy of contrast-enhanced CT scans for small bowel bleeding. Methods This retrospective study evaluated patients diagnosed with non-neoplastic small intestinal bleeding (including duodenum) who underwent abdominal CT at our institution from December 2013 to March 2023. Patients were categorized into diverticulum and non-diverticulum groups based on the cause of bleeding. Active bleeding was defined on the CT images as extravasation of contrast material in the intestinal lumen during the arterial phase and/or progressive accumulation of contrast material during the venous phase. We have documented the original report (extracted from the medical record system and additional consultation opinions from senior radiologists), including the presence of active bleeding and its potential bleeding location. Furthermore, two radiologists reassessed the CT images, seeking consensus on the diagnosis between them. Results The study included 165 patients, predominantly male, with a median age of 30 years. Active bleeding was identified in 48.3% of patients. Notably, all identified bleeding diverticula in the diverticulum group exhibited cul-de-sac termination. Among the identified causes of bleeding, Crohn’s disease was most prevalent (46.7%, N of causes = 64). Significant differences were observed in the diagnostic methods between the diverticulum and non-diverticulum groups, with surgery predominantly applied in the diverticulum group, and endoscopy in the non-diverticulum group (n = 49 vs n = 15, p = 0.001). Contrast agent extravasation was significantly higher in the diverticulum group (n = 54 vs n = 16, p = 0.001), and Meckel’s diverticulum cases appearing tubular were significantly higher than in other diverticulum cases (n = 25 vs n = 3, p

Rabies, a viral disease that causes lethal encephalitis, kills ≈59,000 persons worldwide annually, despite availability of effective countermeasures. Rabies is endemic in Kenya and is mainly transmitted to humans through bites from rabid domestic dogs. We analyzed 164 brain stems collected from rabid animals in western and eastern Kenya and evaluated the phylogenetic relationships of rabies virus (RABV) from the 2 regions. We also analyzed RABV genomes for potential amino acid changes in the vaccine antigenic sites of nucleoprotein and glycoprotein compared with RABV vaccine strains commonly used in Kenya. We found that RABV genomes from eastern Kenya overwhelmingly clustered with the Africa-1b subclade and RABV from western Kenya clustered with Africa-1a. We noted minimal amino acid variances between the wild and vaccine virus strains. These data confirm minimal viral migration between the 2 regions and that rabies endemicity is the result of limited vaccine coverage rather than limited efficacy.

Abstract Background According to the most recent U.S. CDC surveillance data, the rise in prevalence of childhood autism spectrum disorder among minority children has begun to outpace that of non-Hispanic white children. Since prior research has identified possible differences in the extent of mate selection for autistic traits across families of different ethnicity, this study examined variation in autism related traits in contemporaneous, epidemiologically ascertained samples of spousal pairs representing Hispanic and non-Hispanic white populations. The purpose was to determine whether discrepancies by ethnicity could contribute to differential increases in prevalence in the current generation of young children. Methods Birth records were used to identify all twin pairs born between 2011 and 2013 in California and Missouri. Families were selected at random from pools of English-speaking Hispanic families in California and Non-Hispanic White families in Missouri. Autistic trait data of parents was obtained using the Adult Report Form of the Social Responsiveness Scale (SRS-2). Results We did not identify a statistically significant difference in the degree of mate selection for autism related traits between Hispanic and non-Hispanic white spousal pairs. However, the degree of spousal correlation observed in this recent cohort was pronounced (on the order of ICC 0.45) and exceeded that typically reported in prior research (on the order of 0.30), surpassing also widely reported estimates for sibling correlation (also on the order of 0.30). Limitations The sample did not allow for a direct appraisal of change in the magnitude of spousal correlation over time and the ascertainments of trait burden were derived from spouse report. Conclusion Across two epidemiologically ascertained samples of spousal pairs representing Hispanic and non-Hispanic white families across two U.S. states (respectively, California and Missouri), the extent of autism-related trait co-variation for parents of the current generation of young children is substantial and exceeds correlations typically observed for siblings. Given the heritability of these traits and their relation to autism risk, societal trends in the degree of mate selection for these traits should be considered as possible contributors to subtle increases in the incidence of autism over time and across generations.

Abstract Populations consuming saline drinking water are at greater risk of high blood pressure and potentially other adverse health outcomes. We modelled data and used available datasets to identify countries of higher vulnerability to future saltwater intrusion associated with climate change in 2050 under Representative Concentration Pathways (RCP)4.5 and RCP8.5. We developed three vulnerability criteria to capture geographies with: (1) any coastal areas with projected inland saltwater intrusion of ≥ 1 km inland, (2) > 50% of the population in coastal secondary administrative areas with reliance on groundwater for drinking water, and 3) high national average sodium urinary excretion (i.e., > 3 g/day). We identified 41 nations across all continents (except Antarctica) with ≥ 1 km of inland saltwater intrusion by 2050. Seven low- and middle-income countries of higher vulnerability were all concentrated in South/Southeast Asia. Based on these initial findings, future research should study geological nuances at the local level in higher-risk areas and co-produce with local communities contextually appropriate solutions to secure equitable access to clean drinking water.

Abstract Background Globally, a growing number of calls to formalize and strengthen evidence-support systems have been released, all of which emphasize the importance of evidence-informed decision making. To achieve this, it is critical that evidence producers and decision-makers interact, and that decision-makers’ evidence needs can be efficiently translated into questions to which evidence producers can respond. This paper aims to create a taxonomy of demand-driven questions for use by evidence producers, intermediaries (i.e., people working in between researchers and decision-makers) and decision-makers. Methods We conducted a global cross-sectional survey of units providing some type of evidence support at the explicit request of decision-makers. Unit representatives were invited to answer an online questionnaire where they were asked to provide a list of the questions that they have addressed through their evidence-support mechanism. Descriptive analyses were used to analyze the survey responses, while the questions collected from each unit were iteratively analyzed to create a mutually exclusive and collectively exhaustive list of types of questions that can be answered with some form of evidence. Results Twenty-nine individuals completed the questionnaire, and more than 250 submitted questions were analysed to create a taxonomy of 41 different types of demand-driven questions. These 41 questions were organized by the goal to be achieved, and the goals were grouped in the four decision-making stages (i) clarifying a societal problem, its causes and potential impacts; (ii) finding and selecting options to address a problem; (iii) implementing or scaling-up an option; and (iv) monitoring implementation and evaluating impacts. Conclusion The mutually exclusive and collectively exhaustive list of demand-driven questions will help decision-makers (to ask and prioritize questions), evidence producers (to organize and present their work), and evidence-intermediaries (to connect evidence needs with evidence supply).

Background: The Latarjet procedure was developed for the treatment of anterior shoulder instability in young, high-demand patients with attritional glenoid bone loss, whose risk of redislocation following primary dislocation may exceed 90%. Coracoid graft osteolysis and prominent screws are commonly observed in late computed tomography (CT) scans of patients who re-present following the procedure, but the clinical relevance of osteolysis in the overall Latarjet cohort is undetermined. We aimed to evaluate clinical and radiological outcomes in patients who underwent the Latarjet procedure, and to determine if severe coracoid graft osteolysis compromised clinical outcomes. Methods: This was a retrospective analysis of patients who underwent the open Latarjet procedure. Patients were invited via an e-questionnaire that contained a Western Ontario Shoulder Instability Index (WOSI), and queried about redislocation and reoperation since index surgery. Preoperative glenoid bone loss was calculated on CT using the best-fit circle method. Osteolysis was graded (0, screw head buried in graft; 1, screw head exposed; 2, threads exposed; 3, complete resorption/severe osteolysis) at the level of the proximal and distal screws respectively, on axial CT scans performed ≥ 12 months postoperatively. Results: Between 2011 and 2022, a single surgeon performed 442 Latarjet procedures. One hundred fifty eight patients responded to the questionnaire at median (interquartile range [IQR]) 44 (27-70) months postoperatively, among whom the median (IQR) WOSI score was 352 (142-666) points (0 = best, 2100 = worst). Recurrent anterior instability occurred in 3/158 (2%) patients. One patient required reoperation for this indication. Among patients who had CT scans ≥ 12 months postoperatively (median [IQR] 40 [29-69] months), 1 patient developed severe osteolysis around both screws (WOSI = 90), 17/62 (27%) patients developed severe osteolysis around 1 screw, all of which were proximal (median [IQR] WOSI = 235 [135-644]), and 44/62 (71%) patients did not develop severe osteolysis around either screw (median [IQR] WOSI = 487 [177-815]). There were no statistically significant differences in WOSI scores between groups based on the presence of severe osteolysis. Conclusion: The Latarjet is reliable procedure that has a low rate of redislocation and reoperation. Severe coracoid graft osteolysis occurs with time, and always affects the proximal graft first. The presence of severe osteolysis did not compromise clinical outcomes.

Access to soft loans is an important tool in the promotion of self-economic sustenance and job creation. Moreover, globally the rate of unemployment is on the rise and particularly so for the youth and women. Therefore, the study aimed at assessing how access to soft loans issued by local government authority (LGA) contribute to job creation among the marginalised groups in the city of Dodoma, Tanzania. A cross sectional research design was used whereby using a questionnaire, data was collected from 336 randomly selected respondents. The collected data was analyzed using SPSS and STATA whereby both descriptive and inferential statistics were determined. In addition, binomial regression analysis was used to determine factors associated with the marginalised groups’ job creation following their access to LGA soft loans. Generally, findings from the study show that on average two jobs were created by the soft loan beneficiaries. In addition, findings show that the soft loan beneficiaries’ education, soft loan duration and type of income generating activity on which the loans were used were significantly (p ≤ 0.001) associated with job creation (p

Abstract Population-representative estimates of SARS-CoV-2 infection prevalence and antibody levels in specific geographic areas at different time points are needed to optimise policy responses. However, even population-wide surveys are potentially impacted by biases arising from differences in participation rates across key groups. Here, we used spatio-temporal regression and post-stratification models to UK’s national COVID-19 Infection Survey (CIS) to obtain representative estimates of PCR positivity (6,496,052 tests) and antibody prevalence (1,941,333 tests) for different regions, ages and ethnicities (7-December-2020 to 4-May-2022). Not accounting for vaccination status through post-stratification led to small underestimation of PCR positivity, but more substantial overestimations of antibody levels in the population (up to 21 percentage points), particularly in groups with low vaccine uptake in the general population. There was marked variation in the relative contribution of different areas and age-groups to each wave. Future analyses of infectious disease surveys should take into account major drivers of outcomes of interest that may also influence participation, with vaccination being an important factor to consider.

Abstract We report the first cryoEM structure of the Hendra henipavirus nucleoprotein in complex with RNA, at 3.5 Å resolution, derived from single particle analysis of a double homotetradecameric RNA-bound N protein ring assembly exhibiting D14 symmetry. The structure of the HeV N protein adopts the common bi-lobed paramyxoviral N protein fold; the N-terminal and C-terminal globular domains are bisected by an RNA binding cleft containing six RNA nucleotides and are flanked by the N-terminal and C-terminal arms, respectively. In common with other paramyxoviral nucleocapsids, the lateral interface between adjacent Ni and Ni+1 protomers involves electrostatic and hydrophobic interactions mediated primarily through the N-terminal arm and globular domains with minor contribution from the C-terminal arm. However, the HeV N multimeric assembly uniquely identifies an additional protomer-protomer contact between the Ni+1 N-terminus and Ni−1 C-terminal arm linker. The model presented here broadens the understanding of RNA-bound paramyxoviral nucleocapsid architectures and provides a platform for further insight into the molecular biology of HeV, as well as the development of antiviral interventions.

IntroductionAlthough lymphopenia has been described in acute Lyme disease (LD), the complete blood count (CBC) has not been comprehensively examined, nor have sex-based analyses been conducted. We analyzed CBC values and identified sex-based trends among patients with early LD by comparing both to controls without a history of LD and to patients’ pre-morbid values.MethodsWe enrolled participants from the Mid-Atlantic US with diagnostic erythema migrans and controls with no history of LD. CBC results were obtained, and patient information was recorded using standardized instruments. We also calculated a neutrophil-to-lymphocyte ratio (NLR). We used linear regression to test that CBC results would differ (a) between antibiotic-naive patients with early LD and controls and (b) by measures of acute disease severity. We also performed stratified analyses to assess sex-based differences.ResultsIn total, 236 antibiotic-naive patients with early LD had significantly lower lymphocytes (β = −0.34, p

IntroductionAutosomal dominant retinitis pigmentosa type 17 (adRP, type RP17) is caused by complex structural variants (SVs) affecting a locus on chromosome 17 (chr17q22). The SVs disrupt the 3D regulatory landscape by altering the topologically associating domain (TAD) structure of the locus, creating novel TAD structures (neo-TADs) and ectopic enhancer-gene contacts. Currently, screening for RP17-associated SVs is not included in routine diagnostics given the complexity of the variants and a lack of cost-effective detection methods. The aim of this study was to accurately detect novel RP17-SVs by establishing a systematic and efficient workflow.MethodsGenetically unexplained probands diagnosed with adRP (n = 509) from an international cohort were screened using a smMIPs or genomic qPCR-based approach tailored for the RP17 locus. Suspected copy number changes were validated using high-density SNP-array genotyping, and SV breakpoint characterization was performed by mutation-specific breakpoint PCR, genome sequencing and, if required, optical genome mapping. In silico modeling of novel SVs was performed to predict the formation of neo-TADs and whether ectopic contacts between the retinal enhancers and the GDPD1-promoter could be formed.ResultsUsing this workflow, potential RP17-SVs were detected in eight probands of which seven were confirmed. Two novel SVs were identified that are predicted to cause TAD rearrangement and retinal enhancer-GDPD1 contact, one from Germany (DE-SV9) and three with the same SV from the United States (US-SV10). Previously reported RP17-SVs were also identified in three Australian probands, one with UK-SV2 and two with SA-SV3.DiscussionIn summary, we describe a validated multi-step pipeline for reliable and efficient RP17-SV discovery and expand the range of disease-associated SVs. Based on these data, RP17-SVs can be considered a frequent cause of adRP which warrants the inclusion of RP17-screening as a standard diagnostic test for this disease.

Background: Podcasts are a popular form of extracurricular education. They provide a range of benefits for listeners including an opportunity for learning whilst mobile. We aimed to assess the interest of medical students in a podcast series as a part of their formal paediatric surgery teaching resources; to determine the optimal format for such a podcast and, following their introduction, if they were considered to have a beneficial effect on student learning. Method: We conducted focus groups with medical students to explore interest in a podcast series and to determine the optimal format. Our findings guided production and introduction of 5 short-format podcast episodes as an adjunct to available formal learning resources. We ran student focus groups to evaluate the podcasts until data saturation was reached. Transcripts were analysed through thematic analysis by two researchers, who used the constant comparison process to produce a coding framework, through which they identified relevant themes. Results: Medical students utilised outsourced medical podcasts as an adjunct to formal medical school curricula. All students supported the introduction of a podcast series into formal teaching resources to extend paediatric surgical teaching. The preferred medical podcast format was a short, conversational style podcast that begins with a clinical case and ends with a summary. The introduction of podcasts increased student engagement in, and understanding of, podcast topics. Conclusion: Medical students enthusiastically embraced paediatric surgical podcasts in their curriculum. The addition of short-medium format podcasts enhances learning and engagement. Medical schools should utilize the teaching benefits that podcasts offer.

The basal ganglia are involved in motor control and action selection, and their impairment manifests in movement disorders such as Parkinson’s disease (PD) and dystonia, among others. The complex neuronal circuitry of the basal ganglia is located deep inside the brain and presents significant treatment challenges. Conventional treatment strategies, such as invasive surgeries and medications, may have limited effectiveness and may result in considerable side effects. Non-invasive ultrasound (US) treatment approaches are becoming increasingly recognized for their therapeutic potential for reversibly permeabilizing the blood–brain barrier (BBB), targeting therapeutic delivery deep into the brain, and neuromodulation. Studies conducted on animals and early clinical trials using ultrasound as a therapeutic modality have demonstrated promising outcomes for controlling symptom severity while preserving neural tissue. These results could improve the quality of life for patients living with basal ganglia impairments. This review article explores the therapeutic frontiers of ultrasound technology, describing the brain mechanisms that are triggered and engaged by ultrasound. We demonstrate that this cutting-edge method could transform the way neurological disorders associated with the basal ganglia are managed, opening the door to less invasive and more effective treatments.

The risk of infection remains a significant concern with cardiovascular implantable electronic devices, necessitating the development of new strategies. This study explores the efficacy of a novel antibiotic-eluting biologic envelope designed to mitigate infection risk through localized antibiotic delivery while preserving the regenerative properties of biological matrix. Antibiotics, rifampin and minocycline, are released through polymer discs, ensuring extended drug release. Utilizing an established model of infection in a New Zealand White rabbit, the study assessed performance against Gram-positive bacterial strains, including common pathogens such as Staphylococcus aureus and S. epidermidis associated with CIED infections, and Gram-negative bacterial strains. Results demonstrated strong antibacterial activity, achieving complete eradication of bacterial colonies and greater than 6-log reductions in colonization for all strains. Pharmacokinetic analysis revealed sustained local antibiotic concentrations at the implantation site for up to 14 days, with minimal systemic exposure, demonstrating the advantages of localized drug delivery. Health outcomes in the antibiotic bioenvelope group were significantly improved, with no signs of infection or abnormal body temperatures, in contrast to the control group. Macroscopic examinations post-necropsy confirmed the absence of infection at the implantation sites of animals receiving the antibiotic bioenvelope. The combination of localized antibiotic delivery in a regenerative matrix positions the antibiotic bioenvelope as a promising solution for preventing CIED-related infections.

Abstract The Crimean-Congo hemorrhagic fever virus (CCHFV) is an emerging pathogen of the Orthonairovirus genus that can cause severe and often lethal hemorrhagic diseases in humans. CCHFV has a broad tropism and can infect a variety of species and tissues. Here, by using gene silencing, blocking antibodies or soluble receptor fragments, we identify the low-density lipoprotein receptor (LDL-R) as a CCHFV entry factor. The LDL-R facilitates binding of CCHFV particles but does not allow entry of Hazara virus (HAZV), another member of the genus. In addition, we show that apolipoprotein E (apoE), an exchangeable protein that mediates LDL/LDL-R interaction, is incorporated on CCHFV particles, though not on HAZV particles, and enhances their specific infectivity by promoting an LDL-R dependent entry. Finally, we show that molecules that decrease LDL-R from the surface of target cells could inhibit CCHFV infection. Our study highlights that CCHFV takes advantage of a lipoprotein receptor and recruits its natural ligand to promote entry into cells.

Abstract Background People living with human immunodeficiency virus (HIV) are living longer with health-related disability associated with ageing, including complex conditions. However, health systems in Canada have not adapted to meet these comprehensive care needs. Methods We convened three citizen panels and a national stakeholder dialogue. The panels were informed by a plain-language citizen brief that outlined data and evidence about the challenge/problem, elements of an approach for addressing it and implementation considerations. The national dialogue was informed by a more detailed version of the same brief that included a thematic analysis of the findings from the panels. Results The 31 citizen panel participants emphasized the need for more prevention, testing and social supports, increased public education to address stigma and access to more timely data to inform system changes. The 21 system leaders emphasized the need to enhance person-centred care and for implementing learning and improvement across provinces, territories and Indigenous communities. Citizens and system leaders highlighted that policy actions need to acknowledge that HIV remains unique among conditions faced by Canadians. Conclusions Action will require a national learning collaborative to support spread and scale of successful prevention, care and support initiatives. Such a collaborative should be grounded in a rapid-learning and improvement approach that is anchored on the needs, perspectives and aspirations of people living with HIV; driven by timely data and evidence; supported by appropriate decision supports and aligned governance, financial and delivery arrangements; and enabled with a culture of and competencies for rapid learning and improvement.

Abstract Human glial progenitor cells (hGPCs) exhibit diminished expansion competence with age, as well as after recurrent demyelination. Using RNA-sequencing to compare the gene expression of fetal and adult hGPCs, we identify age-related changes in transcription consistent with the repression of genes enabling mitotic expansion, concurrent with the onset of aging-associated transcriptional programs. Adult hGPCs develop a repressive transcription factor network centered on MYC, and regulated by ZNF274, MAX, IKZF3, and E2F6. Individual over-expression of these factors in iPSC-derived hGPCs lead to a loss of proliferative gene expression and an induction of mitotic senescence, replicating the transcriptional changes incurred during glial aging. miRNA profiling identifies the appearance of an adult-selective miRNA signature, imposing further constraints on the expansion competence of aged GPCs. hGPC aging is thus associated with acquisition of a MYC-repressive environment, suggesting that suppression of these repressors of glial expansion may permit the rejuvenation of aged hGPCs.

Abstract Carotid artery webs (CaW) are non-atherosclerotic projections into the vascular lumen and have been linked to up to one-third of cryptogenic strokes in younger patients. Determining how CaW affects local hemodynamics is essential for understanding clot formation and stroke risk. Computational fluid dynamics simulations were used to investigate patient-specific hemodynamics in carotid artery bifurcations with CaW, bifurcations with atherosclerotic lesions having a similar degree of lumen narrowing, and with healthy carotid bifurcations. Simulations were conducted using segmented computed tomography angiography geometries with inlet boundary conditions extracted from 2D phase contrast MRI scans. The study included carotid bifurcations with CaW (n = 13), mild atherosclerosis (n = 7), and healthy bifurcation geometries (n = 6). Hemodynamic parameters associated with vascular dysfunction and clot formation, including shear rate, oscillatory shear index (OSI), low velocity, and flow stasis were calculated and compared between the subject groups. Patients with CaW had significantly larger regions containing low shear rate, high OSI, low velocity, and flow stasis in comparison to subjects with mild atherosclerosis or normal bifurcations. These abnormal hemodynamic metrics in patients with CaW are associated with clot formation and vascular dysfunction and suggest that hemodynamic assessment may be a tool to assess stroke risk in these patients.

Abstract Monogenic disorders account for a large proportion of population-attributable risk for neurodevelopmental disabilities. However, the data necessary to infer a causal relationship between a given genetic variant and a particular neurodevelopmental disorder is often lacking. Recognizing this scientific roadblock, 13 Intellectual and Developmental Disabilities Research Centers (IDDRCs) formed a consortium to create the Brain Gene Registry (BGR), a repository pairing clinical genetic data with phenotypic data from participants with variants in putative brain genes. Phenotypic profiles are assembled from the electronic health record (EHR) and a battery of remotely administered standardized assessments collectively referred to as the Rapid Neurobehavioral Assessment Protocol (RNAP), which include cognitive, neurologic, and neuropsychiatric assessments, as well as assessments for attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Co-enrollment of BGR participants in the Clinical Genome Resource’s (ClinGen’s) GenomeConnect enables display of variant information in ClinVar. The BGR currently contains data on 479 participants who are 55% male, 6% Asian, 6% Black or African American, 76% white, and 12% Hispanic/Latine. Over 200 genes are represented in the BGR, with 12 or more participants harboring variants in each of these genes: CACNA1A, DNMT3A, SLC6A1, SETD5, and MYT1L. More than 30% of variants are de novo and 43% are classified as variants of uncertain significance (VUSs). Mean standard scores on cognitive or developmental screens are below average for the BGR cohort. EHR data reveal developmental delay as the earliest and most common diagnosis in this sample, followed by speech and language disorders, ASD, and ADHD. BGR data has already been used to accelerate gene-disease validity curation of 36 genes evaluated by ClinGen’s BGR Intellectual Disability (ID)-Autism (ASD) Gene Curation Expert Panel. In summary, the BGR is a resource for use by stakeholders interested in advancing translational research for brain genes and continues to recruit participants with clinically reported variants to establish a rich and well-characterized national resource to promote research on neurodevelopmental disorders.

Abstract With the acceleration of the global biodiversity and climate crises, the need to protect and sustainably manage ocean resources has never been greater. However, the science needed to integrate ocean protection (through marine protected areas and OECMs) and sustainable production in the blue economy (particularly pelagic fisheries) remains underdeveloped and contested. The scientific divide and the knowledge gaps still remaining have created serious real-world challenges for practitioners seeking to reconcile protection and production approaches, and is hindering progress in achieving global conservation targets. Here, we identify the vital science necessary to bring together the “twin pillars” of protection and production, integrating mutually reinforcing meaningful protections at scale, while also driving management of production systems to internationally accepted sustainability standards. The research community must rapidly develop this new horizon of ocean science – particularly in pelagic ecosystems - to aid countries and practitioners in achieving global conservation and sustainable development targets.

Background: The Latarjet procedure is a common bony augmentation procedure for anterior shoulder instability. Historically, screw fixation is used to secure the coracoid graft to the anterior glenoid surface; however, malpositioning of the graft leads to oblique screw insertion that contributes to complications. Suture buttons (SBs) are a more recent fixation technique that have not been studied alongside standard screw fixation in the context of biomechanical models of angulated fixation. This study aims to compare the biomechanical strength of single and double, screw and SB fixation at various levels of angulation. Methods: Testing was performed using polyurethane models from Sawbones. The graft piece was secured with screw fixation (Arthrex, Naples, FL, USA) or suspensory button (ABS Tightrope, Arthrex, Naples, FL, USA). Single or double constructs of screws and SBs were affixed at 0°, 15°, and 30° angles to the face of the glenoid component. An aluminum testing jig held the samples securely while a materials testing system applied loads. Five constructs were used for each condition and assessed load to failure testing. Results: For single fixation constructs, suspensory buttons were 60% stronger than screws at 0° (P

Summary: Background: Individuals with Down syndrome (DS) are at high risk of early-onset Alzheimer's disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome 21. Methods: We examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium–Down syndrome study (ABC-DS) (n = 357); and a legacy study (n = 468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma AD biomarkers (Aβ40, Aβ42, tau, and NfL) and longitudinal cognitive measures. A subset had cerebrospinal fluid biomarkers (Aβ40, Aβ42, tau, ptau181, and NfL) and amyloid and tau PET data. Findings: For both cohorts, the prevalence of mosaicism was

Despite the numerous advantages of soil fertility management (SFM) practices and substantial investments to promote adoption, uptake of these technologies remains low across sub-Saharan Africa. We study the adoption and intensity of key SFM practices - improved fallow, animal manure, compost, crop residue retention, minimum tillage, inorganic fertilizer, and intercropping among rural farmers in Zambia. Data from 1234 rural farms and the multivariate probit (MVP) and generalized Poisson regression models are used. The MVP model highlights interconnections among practices, emphasizing the need for integrated interventions. Socio-demographics like gender, age, education, and household labor availability significantly influence adoption of SFM practices. Farm characteristics including experience, land ownership, livestock, and off-farm income also play pivotal roles. Accessibility of information via phones, radio, and farmer groups emerged as a crucial enabler, while extension services, credit, and proximity to markets and roads shape adoption decisions. Results indicate education, household labor, off-farm income, and group membership drive intensity of adoption. Extension contacts, training, and agro-ecological region location also affect intensity with regional variations. Key policy implications emerge. First, the complementarities among practices underscore the need for holistic strategies recognizing these synergies. Second, enhancing education specifically for younger farmers can promote adoption of SFM technologies by increasing knowledge. Third, spurring farmer groups facilitates knowledge exchange, input access, and collaborative adoption. Fourth, strategic extension services and training programs are vital to address knowledge gaps for sustained adoption. Overall, this study provides insights to guide policies for promoting SFM practices among rural farms.

IntroductionThe implementation of evidence-informed policies and practices across systems is a complex, multifaceted endeavor, often requiring the mobilization of multiple organizations from a range of contexts. In order to facilitate this process, policy makers, innovation developers and service deliverers are increasingly calling upon intermediaries to support implementation, yet relatively little is known about precisely how they contribute to implementation. This study examines the role of intermediaries supporting the implementation of evidence-informed policies and practices in the mental health and addictions systems of New Zealand, Ontario, Canada and Sweden.MethodsUsing a comparative case study methodology and taking an integrated knowledge translation approach, we drew from established explanatory frameworks and implementation theory to address three questions: (1) Why were the intermediaries established? (2) How are intermediaries structured and what strategies do they use in systems to support the implementation of policy directions? and (3) What explains the lack of use of particular strategies? Data collection included three site visits, 49 key informant interviews and document analysis.ResultsIn each jurisdiction, a unique set of problems (e.g., negative events involving people with mental illness), policies (e.g., feedback on effectiveness of existing policies) and political events (e.g., changes in government) were coupled by a policy entrepreneur to bring intermediaries onto the decision agenda. While intermediaries varied greatly in their structure and characteristics, both the strategies they used and the strategies they didn't use were surprisingly similar. Specifically it was notable that none of the intermediaries used strategies that directly targeted the public, nor used audit and feedback. This emerged as the principle policy puzzle. Our analysis identified five reasons for these strategies not being employed: (1) their need to build/maintain healthy relationships with policy actors; (2) their need to build/maintain healthy relationships with service delivery system actors; (3) role differentiation with other system actors; (4) perceived lack of “fit” with the role of policy intermediaries; and (5) resource limitations that preclude intensive distributed (program-level) work.ConclusionPolicy makers and implementers must consider capacity to support implementation, and our study identifies how intermediaries can be developed and harnessed to support the implementation process.

Crimean-Congo Haemorrhagic Fever Virus (CCHFV) is spread by infected ticks or direct contact with blood, tissues and fluids from infected patients or livestock. Infection with CCHFV causes severe haemorrhagic fever in humans which is fatal in up to 83 % of cases. CCHFV is listed as a priority pathogen by the World Health Organization (WHO) and there are currently no widely-approved vaccines. Defining a serological correlate of protection against CCHFV infection would support the development of vaccines by providing a ‘target threshold’ for pre-clinical and clinical immunogenicity studies to achieve in subjects and potentially obviate the need for in vivo protection studies. We therefore sought to establish titratable protection against CCHFV using pooled human convalescent plasma, in a mouse model. Convalescent plasma collected from seven individuals with a known previous CCHFV virus infection were characterised using binding antibody and neutralisation assays. All plasma recognised nucleoprotein and the Gc glycoprotein, but some had a lower Gn glycoprotein response by ELISA. Pooled plasma and two individual donations from convalescent donors were administered intraperitoneally to A129 mice 24 h prior to intradermal challenge with CCHFV (strain IbAr10200). A partial protective effect was observed with all three convalescent plasmas characterised by longer survival post-challenge and reduced clinical score. These protective responses were titratable. Further characterisation of the serological reactivities within these samples will establish their value as reference materials to support assay harmonisation and accelerate vaccine development for CCHFV.

Summary: The relationship between transcription and protein expression is complex. We identified polysome-associated RNA transcripts in the somata and central terminals of mouse sensory neurons in control, painful (plus nerve growth factor), and pain-free conditions (Nav1.7-null mice). The majority (98%) of translated transcripts are shared between male and female mice in both the somata and terminals. Some transcripts are highly enriched in the somata or terminals. Changes in the translatome in painful and pain-free conditions include novel and known regulators of pain pathways. Antisense knockdown of selected somatic and terminal polysome-associated transcripts that correlate with pain states diminished pain behavior. Terminal-enriched transcripts included those encoding synaptic proteins (e.g., synaptotagmin), non-coding RNAs, transcription factors (e.g., Znf431), proteins associated with transsynaptic trafficking (HoxC9), GABA-generating enzymes (Gad1 and Gad2), and neuropeptides (Penk). Thus, central terminal translation may well be a significant regulatory locus for peripheral input from sensory neurons.

ABSTRACT Lymphocytic choriomeningitis virus (LCMV) is an enveloped and segmented negative-sense RNA virus classified within the Arenaviridae family of the Bunyavirales order. LCMV is associated with fatal disease in immunocompromised populations and, as the prototypical arenavirus member, acts as a model for the many highly pathogenic members of the Arenaviridae family, such as Junín, Lassa, and Lujo viruses, all of which are associated with devastating hemorrhagic fevers. To enter cells, the LCMV envelope fuses with late endosomal membranes, for which two established requirements are low pH and interaction between the LCMV glycoprotein (GP) spike and secondary receptor CD164. LCMV subsequently uncoats, where the RNA genome-associated nucleoprotein (NP) separates from the Z protein matrix layer, releasing the viral genome into the cytosol. To further examine LCMV endosome escape, we performed an siRNA screen which identified host cell potassium ion (K+) channels as important for LCMV infection, with pharmacological inhibition confirming K+ channel involvement during the LCMV entry phase completely abrogating productive infection. To better understand the K+-mediated block in infection, we tracked incoming virions along their entry pathway under physiological conditions, where uncoating was signified by separation of NP and Z proteins. In contrast, K+ channel blockade prevented uncoating, trapping virions within Rab7 and CD164-positive endosomes, identifying K+ as a third LCMV entry requirement. K+ did not increase GP-CD164 binding or alter GP-CD164-dependent fusion. Thus, we propose that K+ mediates uncoating by modulating NP-Z interactions within the virion interior. These results suggest K+ channels represent a potential anti-arenaviral target.IMPORTANCEArenaviruses can cause fatal human disease for which approved preventative or therapeutic options are not available. Here, using the prototypical LCMV, we identified K+ channels as critical for arenavirus infection, playing a vital role during the entry phase of the infection cycle. We showed that blocking K+ channel function resulted in entrapment of LCMV particles within late endosomal compartments, thus preventing productive replication. Our data suggest K+ is required for LCMV uncoating and genome release by modulating interactions between the viral nucleoprotein and the matrix protein layer inside the virus particle.

Summary: Mechanically activating (MA) channels transduce numerous physiological functions. Tentonin 3/TMEM150C (TTN3) confers MA currents with slow inactivation kinetics in somato- and barosensory neurons. However, questions were raised about its role as a Piezo1 regulator and its potential as a channel pore. Here, we demonstrate that purified TTN3 proteins incorporated into the lipid bilayer displayed spontaneous and pressure-sensitive channel currents. These MA currents were conserved across vertebrates and differ from Piezo1 in activation threshold and pharmacological response. Deep neural network structure prediction programs coupled with mutagenetic analysis predicted a rectangular-shaped, tetrameric structure with six transmembrane helices and a pore at the inter-subunit center. The putative pore aligned with two helices of each subunit and had constriction sites whose mutations changed the MA currents. These findings suggest that TTN3 is a pore-forming subunit of a distinct slow inactivation MA channel, potentially possessing a tetrameric structure.

Chemical activation was employed to convert algal biochar obtained from hydrothermal carbonization of lipid-extracted algae (LEA) to activated carbon. Potassium hydroxide, previously utilized on cellulosic biomass but not on algal biomass, was employed as activating agent and the impact of the activation conditions, namely temperature, activation time, and amount of activating agent, were investigated. The yield of activated carbon from biochar ranged from 28 % to 52% and decreased as the temperature was raised from 400 to 600 °C, the residence time from 30 to 60 min, and the KOH/biochar mass ratio from 0.25 to 1.0. In contrast, surface area increased by 2.1-fold when the activation temperature was raised to 600 °C and by 1.5-fold when the KOH: biochar ratio was raised to 1.0. Maximum BET surface area of 847 m2/g was achieved at 600 °C after 30 min at a mass ratio of 1:1. The integrated hydrothermal carbonization and activation process of LEA was simulated in Aspen Plus® and the technoeconomic feasibility was assessed based on our experimental data at 1,000 and 10,000 acres of cultivation area. For the latter, net present value analysis determined a minimum selling price of $2,200/ton for algal activated carbon with a financial breakeven achieved in 3.5 years. This is cost-competitive with the current price of commercial fossil-derived activated carbon, which is $1,543-$2,645/ton. Sensitivity analysis showed that the minimum selling price is significantly affected by algal biomass yield during cultivation and is more sensitive to the operating expenses than to the capital investment.

Abstract Recent advancements in diagnostic CT detector technology have made it possible to resolve anatomical features smaller than 20 LP/cm, referred to as ultra-high-resolution (UHR) CT. Subtle biological motions that did not affect standard-resolution (SR) CT may not be neglected in UHR. This study aimed to quantify the cardiac-induced motion of the pancreas and simulate its impact on the image quality of UHR-CT. We measured the displacement of the head of the pancreas in three healthy volunteers using Displacement Encoding with Stimulated Echoes (DENSE) MRI. The results were used to simulate SR- and UHR-CT acquisitions affected by pancreatic motion. We found pancreatic displacement in the 0.24–1.59 mm range during one cardiac cycle across the subjects. The greatest displacement was observed in the anterior–posterior direction. The time to peak displacement varied across subjects. Both SR and UHR images showed reduced image quality, as measured by radial modulation transfer function, due to cardiac-induced motion, but the motion artifacts caused more severe degradation in UHR acquisitions. Our investigation of cardiac-induced pancreatic displacement reveals its potential to degrade both standard and UHR-CT scans. To fully utilize the improvement in spatial resolution offered by UHR-CT, the effects of cardiac-induced motion in the abdomen need to be understood and corrected. Relevance statement Advancements in CT detector technology have enhanced CT scanner spatial resolution to approximately 100 µm. Consequently, previously ignored biological motions such as the cardiac-induced motion of the pancreas now demand attention to fully utilize this improved resolution. Graphical Abstract

Background: The mastoid process can be utilized in forensic identification due to its resistance to alterations and population variations in its morphology. The study investigated the role of mastoid parameters in the determination of sex in a Nigerian population. Aims and Objectives: The aim of this study was to determine the gender differences in measurements of the mastoid process. Furthermore, the study aimed at assessing the percentage accuracy of using the mastoid variables in sex discrimination. Materials and Methods: This cross-sectional study used computed tomographic images of the brain, stored in the radiology unit of a referral hospital in Delta State, Nigeria. Permission was granted by the hospital's Ethics Board. The measurements of the mastoid process were taken on images of 310 patients (170 males and 140 females) aged 20–80 years. Data were summarized using means and standard deviations. Gender, side, and age group comparisons were assessed using the independent t-test, paired t-test, and analysis of variance, respectively. The association between variables was probed using Pearson's correlation test. The discriminant function analysis was used to determine the accuracy of correct sex allocation. The probability value was set at

Abstract Background The spleen plays a significant role in the clearance of circulating microorganisms. Sequelae of splenectomy, especially immunodeficiency, can have a deleterious effect on a patient’s health and even lead to death. Hence, splenectomy should be avoided and spleen preservation during elective surgery has become a treatment goal. However, this cannot be achieved in every patient due to intraoperative technical difficulties or oncological reasons. Autogenic splenic implantation (ASI) is currently the only possible way to preserve splenic function when a splenectomy is necessary. Experience largely stems from trauma patients with a splenic rupture. Splenic immune function can be measured by the body’s clearing capacity of encapsulated bacteria. The aim of this study is to assess the splenic immune function after ASI was performed during minimally invasive (laparoscopic or robotic) distal pancreatectomy with splenectomy. Methods This is the protocol for a multicentre, randomized, open-labelled trial. Thirty participants with benign or low-grade malignant lesions of the distal pancreas requiring minimally invasive distal pancreatectomy and splenectomy will be allocated to either additional intraoperative ASI (intervention) or no further intervention (control). An additional 15 patients who will undergo spleen-preserving distal pancreatectomy serve as the control group with normal splenic function. Six months postoperatively, after assumed restoration of splenic function, patients will be given a Salmonella typhi (Typhim Vi™) vaccine. The Salmonella typhi vaccine is a polysaccharide vaccine. The specific antibody titres immediately before and 4 to 6 weeks after vaccination will be measured. The ratio between pre- and post-vaccination antibody count is the primary outcome measure and secondary outcome measures include intraoperative details, length of hospital stay, 30-day mortality and morbidity. Discussion This study will investigate the splenic immune function of patients who undergo ASI during minimally invasive distal pancreatectomy with splenectomy. The splenic immune function will be measured using the surrogate outcome of specific antibody titre after vaccination with a Salmonella typhi vaccine. The results will reveal details about splenic function after ASI and guide further treatment options for patients when a splenectomy cannot be avoided. It might eventually lead to a new standard of care making sometimes more demanding and time-consuming spleen-preserving procedures redundant. Trial registration International Standard Randomized Controlled Trials Number (ISRCTN) ISRCTN10171587. Prospectively registered on 18 February 2019.

Abstract The escalating threat of natural disasters to public safety worldwide underlines the crucial role of effective environmental risk management tools, such as insurance. This is particularly evident in the case of earthquakes that occurred in Oklahoma between 2011 and 2020, which were linked to wastewater injection, underscoring the need for earthquake insurance. In this regard, from a survey of 812 respondents in Oklahoma, USA, we used supervised machine learning techniques (i.e., logit, ridge, least absolute shrinkage and selection operator (LASSO), decision tree, and random forest classifiers) to identify the factors that influence earthquake insurance uptake and to predict individuals who would acquire earthquake insurance. Our findings reveal that influential factors that affect earthquake insurance uptake include demographic factors such as older age, male gender, race, and ethnicity. These were found to significantly influence the decision to purchase earthquake insurance. Additionally, individuals residing in rental properties were less likely to purchase earthquake insurance, while longer residency in Oklahoma had a positive influence. Past experience of earthquakes was also found to positively influence the decision to purchase earthquake insurance. Both decision trees and random forests demonstrated good predictive capabilities for identifying earthquake insurance uptake. Notably, random forests exhibited higher precision and robustness, emerging as an encouraging choice for earthquake insurance modeling and other classification problems. Empirically, we highlight the importance of insurance as an environmental risk management tool and emphasize the need for awareness and education on earthquake insurance as well as the use of supervised machine learning algorithms for classification problems.

Abstract Background While there has been widespread global acceptance of the importance of evidence-informed policy, many opportunities to inform health policy with research are missed, often because of a mismatch between when and where reliable evidence is needed, and when and where it is available. ‘Living evidence’ is an approach where systematic evidence syntheses (e.g. living reviews, living guidelines, living policy briefs, etc.) are continually updated to incorporate new relevant evidence as it becomes available. Living evidence approaches have the potential to overcome a major barrier to evidence-informed policy, making up-to-date systematic summaries of policy-relevant research available at any time that policy-makers need them. These approaches are likely to be particularly beneficial given increasing calls for policy that is responsive, and rapidly adaptive to changes in the policy context. We describe the opportunities presented by living evidence for evidence-informed policy-making and highlight areas for further exploration. Discussion There are several elements of living approaches to evidence synthesis that might support increased and improved use of evidence to inform policy. Reviews are explicitly prioritised to be ‘living’ by partnerships between policy-makers and researchers based on relevance to decision-making, as well as uncertainty of existing evidence, and likelihood that new evidence will arise. The ongoing nature of the work means evidence synthesis teams can be dynamic and engage with policy-makers in a variety of ways over time; and synthesis topics, questions and methods can be adapted as policy interests or contextual factors shift. Policy-makers can sign-up to be notified when relevant new evidence is found, and can be confident that living syntheses are up-to-date and contain all research whenever they access them. The always up-to-date nature of living evidence syntheses means producers can rapidly demonstrate availability of relevant, reliable evidence when it is needed, addressing a frequently cited barrier to evidence-informed policymaking. Conclusions While there are challenges to be overcome, living evidence provides opportunities to enable policy-makers to access up-to-date evidence whenever they need it and also enable researchers to respond to the issues of the day with up-to-date research; and update policy-makers on changes in the evidence base as they arise. It also provides an opportunity to build flexible partnerships between researchers and policy-makers to ensure that evidence syntheses reflect the changing needs of policy-makers.

Abstract Ocean sustainability initiatives – in research, policy, management and development – will be more effective in delivering comprehensive benefits when they proactively engage with, invest in and use social knowledge. We synthesize five intervention areas for social engagement and collaboration with marine social scientists, and in doing so we appeal to all ocean science disciplines and non-academics working in ocean initiatives in industry, government, funding agencies and civil society. The five social intervention areas are: (1) Using ethics to guide decision-making, (2) Improving governance, (3) Aligning human behavior with goals and values, (4) Addressing impacts on people, and (5) Building transdisciplinary partnerships and co-producing sustainability transformation pathways. These focal areas can guide the four phases of most ocean sustainability initiatives (Intention, Design, Implementation, Evaluation) to improve social benefits and avoid harm. Early integration of social knowledge from the five areas during intention setting and design phases offers the deepest potential for delivering benefits. Later stage collaborations can leverage opportunities in existing projects to reflect and learn while improving impact assessments, transparency and reporting for future activities.

Accurately quantifying rates of soil erosion requires capturing both the volumetric nature of the visible, convergent fluvial pathways (also known as rills) and the subtle nature of the less-visible, diffuse pathways (interrill areas). The aim of this study was to use Rare Earth Oxide (REO) tracers and Structure-from-Motion (SfM) photogrammetry to elucidate retrospective information about soil erosion rates and sediment sources during different soil erosion conditions, within a controlled laboratory environment. The experimental conditions created erosion events consistent with diffuse and convergent erosion processes. REO tracers allowed the sediment transport distances of over 2 m to be described, and helped resolved the relative contribution of diffuse and convergent soil erosion; interrill areas were also identified as a significant sediment sources soil loss under convergent erosion conditions. While the potential for SfM photogrammetry to resolve sub-millimetre elevations changes was demonstrated, under some conditions non-erosional changes in surface elevation, such as compaction, exceeded volumes of soil loss via diffuse erosion. The discrepancies between SfM Photogrammetry calculations and REO tagged sediment export were beneficial, identifying that during soil erosion events sediment in both aggregate and particle form is deposited within the convergent features, even when the rill extended the full length of the soil surface. The combination of SfM photogrammetry and REO tracers has provided a novel platform for building a spatial understanding of patterns of soil loss and source apportionment between rill and interrill erosion.

Three novel series of N-methylsulfonylindole derivatives 3a&b, 4a–e, and 5a–e were synthesised. Different biological activities of the synthesised compounds were studied. Antimicrobial activity showed that, compounds 4b, 4e and 5d had selective antibacterial activity against the Gram-negative bacteria, Salmonella enterica and/or E. coli. The anti-oxidant activity of the synthesised compounds was evaluated by DPPH radical scavenging activity. In vitro anti-inflammatory activity was estimated. Compounds 4d, 4e, 5b, and 5d showed the highest anti-inflammatory activity. The COX-1, COX-2 and 5-LOX inhibitory activities were measured using enzyme immune assay (EIA) kits. Due to the dual COX-2/5-LOX inhibitory activity of compound 5d, its cardiovascular profile was determined by measuring cardiac biomarkers (LDH, CK-MB, and Tn-I). Besides, the histopathological study of the heart muscle and stomach were examined for the most active COX-2 inhibitors 4e and 5d. Finally, a molecular modelling study and pharmacokinetic properties were obtained using different computational methods.

Introducing grain legumes, i.e., pulses, into any food pattern effectively increases dietary fiber and other bioactive food components of public health concern; however, the impact depends on the amount consumed. Given the convergence of preclinical and clinical data indicating that intake of at least 300 g (1.5 cup) of cooked pulse per day has clinically observable benefit, the feasibility for a typical consumer was demonstrated by creation of a fourteen-day menu plan that met this criterion. This menu plan, named Bean Cuisine, was comprised of a combination of five cooked pulses: dry beans, chickpeas, cowpeas, dry peas, and lentils. As reported herein, the impact of each menu day of the fourteen-day plan on gut microbial composition and predicted function was evaluated in female C57BL/6J mice, a strain commonly used in studies of metabolic dysfunction-associated chronic diseases. We report that pulse-related effects were observed across a wide variety of food item combinations. In comparison to a pulse-free human cuisine, all pulse menu days enriched for a gut ecosystem were associated with changes in predicted metabolic pathways involving amino acids (lysine, tryptophan, cysteine), short-chain fatty acids (butyrate, acetate), and vitamins (B1, B6, B9, B12, K2) albeit via different combinations of microbiota, according to the PICRUSt2 estimates. The predicted metabolic functions correlating with the various pulses in the menus, indicate the value of a food pattern comprised of all pulse types consumed on a regular basis. This type of multi-pulse food pattern has the potential to enhance the taxonomic and functional diversity of the gut microbiome as a means of strengthening the resilience of the gut ecosystem to the challenges associated with the daily activities of living.

Background/Objectives: The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD), a condition linked to the ongoing obesity pandemic, is rapidly increasing worldwide. In turn, its multifactorial etiology is consistently associated with low dietary quality. Changing dietary macronutrient and phytochemical quality via incorporating cooked common bean into an obesogenic diet formulation has measurable health benefits on the occurrence of both obesity and hepatic steatosis in C57BL/6 mice. Methods: A cohort of C57BL/6 mice were randomized into experimental diets containing multiple dietary concentrations of common bean. The primary endpoint of this study was comparing metabolomic analyses from liver and plasma of different treatment groups. Additionally, RNA sequencing and protein expression analysis via nanocapillary immunoelectrophoresis were used to elucidate signaling mediators involved. Results: Herein, global metabolomic profiling of liver and plasma identified sphingolipids as a lipid subcategory on which bean consumption exerted significant effects. Of note, C16 and C18 ceramides were significantly decreased in bean-fed animals. Hepatic RNAseq data revealed patterns of transcript expression of genes involved in sphingolipid metabolism that were consistent with metabolite profiles. Conclusions: Bean incorporation into an otherwise obesogenic diet induces effects on synthesis, biotransformation, and degradation of sphingolipids that inhibit the accumulation of ceramide species that exert pathological activity. These effects are consistent with a mechanistic role for altered sphingolipid metabolism in explaining how bean inhibits the development of MASLD.

Background: Community participation in democratic societies cannot be overstated, as it is a fundamental pillar that allows community members to have a voice in economic, social, and political discourse. Aim: This article investigated the significance of community participation in LED, identifying the barriers and drivers of community involvement to provide recommendations to enhance and promote greater community engagement in Benoni, South Africa. Methods: The study adopted a mixed methods research approach. It conducted (n = 280) surveys from residents and (n = 5) in-depth interviews with municipal officials regarding the role of community participation in LED. Results: The findings reveal five challenges to community participation: limited avenues for participation, a lack of confidence in leadership, lack of action on residents’ suggestions, limited understanding of the value and importance of participation, and lack of trust in local leadership. However, the study also established that community participation is crucial to LED and contributes to providing legitimacy to local government projects, ensuring leadership accountability and better trust in leadership, and to ascertain that residents affect changes they want to see in their communities. Conclusion: The study concludes that community participation is vital for successful LED in Benoni. Addressing the challenges identified can lead to more effective and sustainable development initiatives. Contribution: This research makes several contributions to the field of LED and community development. It emphasises enabling and encouraging community participation in shaping LED. The study’s insights into the barriers and drivers of community involvement provide a foundation for designing targeted interventions to enhance participation.

Abstract Gut microbiota impacts fish metabolism, nutrient utilization, and health. We know little about how temperature and diet interact with rainbow trout gut microbes. A total of 288 fish (average body weight: 45.6 g) fed four iso‐caloric, ‐lipidic, and ‐nitrogenous diets comprised crude protein (40%) and lipid (20%) manufactured as 100% animal‐based protein (AP) and blend of 50 fish oil (FO)/50 camelina oil (CO), 100% AP and 100% CO, 100% plant‐based protein (PP) and blend of 50 FO/50 CO or 100% PP and 100% CO at 14 or 18°C water temperature. Gut content was analyzed using 16S rRNA gene and shotgun sequencing. Alpha‐diversity did not change significantly. Regardless of diet, Tenericutes, Firmicutes, Proteobacteria, Spirochaetes, Bacteroidetes, and Actinobacteria dominated. At family level, Aeromonadaceae and Enterobacteriaceae dominated at 18°C, while Mycoplasmataceae dominated at 14°C. Moreover, genes relating to amino acid, carbohydrate, fat, and energy metabolisms and fatty acid biosynthesis significantly increased at 18°C. Functional profiles did not vary significantly among diets, except for a higher methionine and cysteine metabolism in fish fed plant ingredient compared animal diet, suggesting trout fed plant‐derived protein mixed with CO could be as effective as those fed fish meals mixed with 50/50 FO and CO.

Early increase in the level of endothelial progenitor cells (EPCs) in the systemic circulation occurs in patients with septic infection/sepsis. The significance and underlying mechanisms of this response remain unclear. This study investigated the bone marrow EPC response in adult mice with septic infection induced by intravenous injection (i.v.) of Escherichia coli. For in vitro experiments, sorted marrow stem/progenitor cells (SPCs) including lineage(lin)-stem cell factor receptor (c-kit)+stem cell antigen-1 (Sca-1)−, lin−c-kit+, and lin− cells were cultured with or without lipopolysaccharides (LPSs) and recombinant murine vascular endothelial growth factor (VEGF) in the absence and presence of anti-Sca-1 crosslinking antibodies. In a separate set of experiments, marrow lin−c-kit+ cells from green fluorescence protein (GFP)+ mice, i.v. challenged with heat-inactivated E. coli or saline for 24 h, were subcutaneously implanted in Matrigel plugs for 5 weeks. Marrow lin−c-kit+ cells from Sca-1 knockout (KO) mice challenged with heat-inactivated E. coli for 24 h were cultured in the Matrigel medium for 8 weeks. The marrow pool of EPCs bearing the lin−c-kit+Sca-1+VEGF receptor 2 (VEGFR2)+ (LKS VEGFR2+) and LKS CD133+VEGFR2+ surface markers expanded rapidly following septic infection, which was supported by both proliferative activation and phenotypic conversion of marrow stem/progenitor cells. Increase in marrow EPCs and their reprogramming for enhancing angiogenic activity correlated with cell-marked upregulation of Sca-1 expression. Sca-1 was coupled with Ras-related C3 botulinum toxin substrate 2 (Rac2) in signaling the marrow EPC response. Septic infection caused a substantial increase in plasma levels of IFN-γ, VEGF, G-CSF, and SDF-1. The early increase in circulating EPCs was accompanied by their active homing and incorporation into pulmonary microvasculature. These results demonstrate that the marrow EPC response is a critical component of the host defense system. Sca-1 signaling plays a pivotal role in the regulation of EPC response in mice with septic infection.

Background: Anti-annexin A2 (AA2) antibodies have been described in Lyme arthritis and erythema migrans, although they have not been described in post-treatment Lyme disease (PTLD). Objectives: Determine whether anti-AA2 antibodies are present among patients with PTLD and determine the clinical relevance of these antibodies. Design and methods: Anti-AA2 levels were tested serially in a longitudinal cohort of 44 patients with acute Lyme disease, 22 with a return to health (EM RTH), and 22 with PTLD. Anti-AA2 antibodies were also assessed in a cross-sectional group of 281 patients with PTLD. Results: Anti-AA2 antibodies were highest after antimicrobial therapy in both the EM RTH and PTLD cohorts. By 6 months, there was no difference between EM RTH and healthy controls. Anti-AA2 antibodies were higher in the cross-sectional PTLD group (79.69 versus 48.22 units, p

Summary: The NLRP3 inflammasome is essential for caspase-1 activation and the release of interleukin (IL)-1β, IL-18, and gasdermin-D in myeloid cells. However, research on species-specific NLRP3’s physiological impact is limited. We engineer mice with the human NLRP3 gene, driven by either the human or mouse promoter, via syntenic replacement at the mouse Nlrp3 locus. Both promoters facilitate hNLRP3 expression in myeloid cells, but the mouse promoter responds more robustly to LPS. Investigating the disease impact of differential NLRP3 regulation, we introduce the D305N gain-of-function mutation into both humanized lines. Chronic inflammation is evident with both promoters; however, CNS outcomes vary significantly. Despite poor response to LPS, the human promoter results in D305N-associated aseptic meningitis, mirroring human pathology. The mouse promoter, although leading to increased CNS expression post-LPS, does not induce meningitis in D305N mutants. Therefore, human-like NLRP3 expression may be crucial for accurate modeling of its role in disease pathogenesis.

Summary: Cardiovagal neurons (CVNs) innervate cardiac ganglia through the vagus nerve to control cardiac function. Although the cardioinhibitory role of CVNs in nucleus ambiguus (CVNNA) is well established, the nature and functionality of CVNs in dorsal motor nucleus of the vagus (CVNDMV) is less clear. We therefore aimed to characterize CVNDMV anatomically, physiologically, and functionally. Optogenetically activating cholinergic DMV neurons resulted in robust bradycardia through peripheral muscarinic (parasympathetic) and nicotinic (ganglionic) acetylcholine receptors, but not beta-1-adrenergic (sympathetic) receptors. Retrograde tracing from the cardiac fat pad labeled CVNNA and CVNDMV through the vagus nerve. Using whole-cell patch-clamp, CVNDMV demonstrated greater hyperexcitability and spontaneous action potential firing ex vivo despite similar resting membrane potentials, compared to CVNNA. Chemogenetically activating DMV also caused significant bradycardia with a correlated reduction in anxiety-like behavior. Thus, DMV contains uniquely hyperexcitable CVNs and is capable of cardioinhibition and robust anxiolysis.