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BackgroundFifty-one percent of individuals with multiple sclerosis (MS) develop cognitive impairment (CI) in information processing speed (IPS). Although IPS scores are associated with health and well-being, neural changes that underlie IPS impairments in MS are not understood. Resting state fMRI can provide insight into brain function changes underlying impairment in persons with MS.ObjectivesWe aimed to assess functional connectivity (FC) differences in (i) persons with MS compared to healthy controls (HC), (ii) persons with both MS and CI (MS-CI) compared to HC, (iii) persons with MS that are cognitively preserved (MS-CP) compared to HC, (iv) MS-CI compared to MS-CP, and (v) in relation to cognition within the MS group.MethodsWe included 107 participants with MS (age 49.5 ± 12.9, 82% women), and 94 controls (age 37.9 ± 15.4, 66% women). Each participant was administered the Symbol Digit Modalities Test (SDMT) and underwent a resting state fMRI scan. The MS-CI group was created by applying a z-score cut-off of ≤−1.5 to locally normalized SDMT scores. The MS-CP group was created by applying a z-score of ≥0. Control groups (HCMS-CI and HCMS-CP) were based on the nearest age-matched HC participants. A whole-brain ROI-to-ROI analysis was performed followed by specific contrasts and a regression analysis.ResultsIndividuals with MS showed FC differences compared to HC that involved the cerebellum, visual and language-associated brain regions, and the thalamus, hippocampus, and basal ganglia. The MS-CI showed FC differences compared to HCMS-CI that involved the cerebellum, visual and language-associated areas, thalamus, and caudate. SDMT scores were correlated with FC between the cerebellum and lateral occipital cortex in MS. No differences were observed between the MS-CP and HCMS-CP or MS-CI and MS-CP groups.ConclusionOur findings emphasize FC changes of cerebellar, visual, and language-associated areas in persons with MS. These differences were apparent for (i) all MS participants compared to HC, (ii) MS-CI subgroup and their matched controls, and (iii) the association between FC and SDMT scores within the MS group. Our findings strongly suggest that future work that examines the associations between FC and IPS impairments in MS should focus on the involvement of these regions.

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by inflammation of the gastrointestinal tract and is a disorder of the brain-gut axis. Neuroimaging studies of brain function and structure have helped better understand the relationships between the brain, gut, and comorbidity in IBD. Studies of brain structure have primarily employed voxel-based morphometry to measure grey matter volume and surface-based morphometry to measure cortical thickness. Far fewer studies have employed other surface-based morphometry metrics such as gyrification, cortical complexity, and sulcal depth. In this study, brain structure differences between 72 adults with IBD and 90 healthy controls were assessed using all five metrics. Significant differences were found for cortical thickness with the IBD group showing extensive left-lateralized thinning, and for cortical complexity with the IBD group showing greater complexity in the left fusiform and right posterior cingulate. No significant differences were found in grey matter volume, gyrification, or sulcal depth. Within the IBD group, a post hoc analysis identified that disease duration is associated with cortical complexity of the right supramarginal gyrus, albeit with a more lenient threshold applied.

Summary: The vast majority of human populations and individuals have mixed ancestry. Consequently, adjustment for locus-specific ancestry is essential for genetic association studies. To empower association studies for all populations, it is necessary to integrate effects of locus-specific ancestry and genotype. We developed a joint test of ancestry and association that can be performed with summary statistics, is independent of study design, can take advantage of locus-specific ancestry effects to boost power in association testing, and can utilize association effects to fine map admixture peaks. We illustrate the test using the association between serum triglycerides and LPL. By combining data from African Americans, European Americans, and West Africans, we identify three conditionally independent variants with varying amounts of ancestrally differentiated allele frequencies. Using out-of-sample data, we demonstrate improved prediction achievable by accounting for multiple causal variants and locus-specific ancestry effects at a single locus.

In this article, an image processing-based localization system is developed for remote nondestructive evaluation of welds within industrial assets. Manual ultrasonic inspection of large-scale structures is often repetitive, time-consuming, and benefits greatly from robotic support, however, these robotic systems are often fixed to a single purpose, lack self-awareness of their surrounding environment, and can be limited to simple geometry. For the inspection of welds, which are often carried out using phased array ultrasonic testing, there is a reliance on the use of surface features for automated tracking such as the laser profiling of a weld cap. For the inspection of more complex geometry such as nonlinear or saddle welds, a more positionally sensitive method is required. The proposed system utilizes information already available to a nondestructive inspector in the form of live phased array ultrasonic images to estimate the location of the weld using nonsurface, volumetric data. Data is captured using a 64-element, 10-MHz phased array probe mounted to the end effector of a small robotic manipulator which increases the scope of applications due to its heightened flexibility when compared to on-the-market alternatives. Morphological operations are applied to the ultrasonic data to reduce the noise apparent from regions of parent material and promote the data reflected from grain boundaries within the weld material. Through a series of image processing techniques, it is possible to predict the position of a weld under inspection with an absolute mean positional error of $\mathrm {0.8 \text {m} \text { m} }$ . From this study, the localization system is to be embedded within a remote system for extensive data acquisition of welds on large structures.

Abstract Tyrosyl-DNA phosphodiesterase I (Tdp1) hydrolyzes phosphodiester-linked adducts from both ends of DNA. This includes the topoisomerase I (TOP1)-DNA covalent reaction intermediate that is the target of the camptothecin class of chemotherapeutics. Tdp1 two-step catalysis is centered on the formation of a Tdp1-DNA covalent complex (Tdp1cc) using two catalytic histidines. Here, we examined the role of the understudied, structurally undefined, and poorly conserved N-terminal domain (NTD) of Tdp1 in context of full-length protein in its ability to remove TOP1cc in cells. Using toxic Tdp1 mutants, we observed that the NTD is critical for Tdp1’s ability to remove TOP1-DNA adducts in yeast. Full-length and N-terminal truncated Tdp1 mutants showed similar expression levels and cellular distribution yet an inversed TOP1-dependent toxicity. Single turnover catalysis was significantly different between full-length and truncated catalytic mutants but not wild-type enzyme, suggesting that Tdp1 mutants depend on the NTD for catalysis. These observations suggest that the NTD plays a critical role in the regulation of Tdp1 activity and interaction with protein-DNA adducts such as TOP1cc in cells. We propose that the NTD is a regulatory domain and coordinates stabilization of the DNA-adducted end within the catalytic pocket to access the phosphodiester linkage for hydrolysis.

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Structured Illumination Microscopy allows for the visualization of biological structures at resolutions below the diffraction limit, but this imaging modality is still hampered by high experimental complexity. Here, the authors present a combination of interferometry and machine learning to construct a structured illumination microscope for super resolution imaging of dynamic sub-cellular biological structures in multiple colors.

Abstract Background Double-strand break repair (DSBR) is a highly regulated process involving dozens of proteins acting in a defined order to repair a DNA lesion that is fatal for any living cell. Model organisms such as Saccharomyces cerevisiae have been used to study the mechanisms underlying DSBR, including factors influencing its efficiency such as the presence of distinct combinations of microsatellites and endonucleases, mainly by bulk analysis of millions of cells undergoing repair of a broken chromosome. Here, we use a microfluidic device to demonstrate in yeast that DSBR may be studied at a single-cell level in a time-resolved manner, on a large number of independent lineages undergoing repair. Results We used engineered S. cerevisiae cells in which GFP is expressed following the successful repair of a DSB induced by Cas9 or Cpf1 endonucleases, and different genetic backgrounds were screened to detect key events leading to the DSBR efficiency. Per condition, the progenies of 80–150 individual cells were analyzed over 24 h. The observed DSBR dynamics, which revealed heterogeneity of individual cell fates and their contributions to global repair efficacy, was confronted with a coupled differential equation model to obtain repair process rates. Good agreement was found between the mathematical model and experimental results at different scales, and quantitative comparisons of the different experimental conditions with image analysis of cell shape enabled the identification of three types of DSB repair events previously not recognized: high-efficacy error-free, low-efficacy error-free, and low-efficacy error-prone repair. Conclusions Our analysis paves the way to a significant advance in understanding the complex molecular mechanism of DSB repair, with potential implications beyond yeast cell biology. This multiscale and multidisciplinary approach more generally allows unique insights into the relation between in vivo microscopic processes within each cell and their impact on the population dynamics, which were inaccessible by previous approaches using molecular genetics tools alone.

In this study, the authors provide a global overview of SARS-CoV-2 genome sequencing, and estimate the proportion of cases sequenced and time to genome upload. They identify disparities and highlight the need to strengthen surveillance in lower and middle income countries.

Abstract Adiponectin has been associated with cardiometabolic traits in observational studies across populations, yet it is unclear if these associations are causal. We performed Mendelian randomization (MR) analysis to assess the relationship between adiponectin and cardiometabolic traits in sub-Saharan Africans. We constructed a polygenic risk score (PRS) for adiponectin levels across 3354 unrelated sub-Saharan Africans. The PRS was used as the instrumental variable in two-stage least-squares MR analysis to assess its association with insulin resistance, HDL, LDL, total cholesterol, triglycerides, blood pressure, Type 2 Diabetes (T2D), and hypertension. The adiponectin PRS was causally related with LDL (β = 0.55, 95%CI 0.07–1.04, P-value = 0.024) but not the other traits. This association was observed in both overweight/obese and normal weight individuals, but only reached statistical significance among overweight/obese individuals (β = 0.55, 95%CI 0.01–1.08, P-value = 0.045). In normal weight individuals, the adiponectin PRS was associated with T2D (OR = 0.13, 95%CI 0.02–0.73, P-value = 0.021), and in men with HDL (β = 1.03, 95%CI 0.14–1.92, P-value = 0.023). The findings of this first MR study in sub-Saharan Africans support a causal relationship of adiponectin with LDL, with T2D in normal weight individuals only, and with HDL in men only. These observations add to the small but growing literature on adiponectin MR studies.

Abstract Many conjunctival inflammatory diseases differ between the sexes and altered conjunctival goblet cells (CGCs) response is often involved. Inflammation is initiated by the release of pro-inflammatory mediators and terminated by the biosynthesis of specialized pro-resolution mediators (SPMs). Herein, we determined the sex-based difference in the responses of CGCs to inflammatory stimuli or pro-resolving lipid SPMs and their interaction with sex hormones. GCs were cultured from pieces of human conjunctiva in RPMI media. CGCs were transferred 24 h before the start of experiments to phenol red-free and FBS-free media to minimize exogenous hormones. RT-PCR, immunofluorescence microscopy (IF), and Western Blot (WB) were performed to determine the presence of sex hormone receptors. Cellular response to pro-inflammatory stimuli or SPMs was studied by measuring the increase in intracellular [Ca2+] ([Ca2+]i) using fura 2/AM microscopy. Use of RT-PCR demonstrated estrogen receptor (ER) α in 4/5 males and 3/3 females; ERβ in 2/4 males and 2/3 females; and androgen receptors (AR) in 3/3 male and 3/3 female CGCs. Positive immunoreactivity by IF and protein expression by WB was detected using antibodies for the ERα and ERβ in 3/3 males and 3/3 females, while AR were only present in males. Significantly different Ca2+ responses between sexes were found with carbachol only at 10–3 M, but not with histamine or leukotriene (LT) B4 at any concentration used. Incubation with dihydrotestosterone (DHT), estrone (E1), or estradiol (E2) at 10–7 M for 30 min significantly inhibited the LTB4-stimulated [Ca2+]i increase in male and female CGCs. Incubation with DHT, E1, and E2 overnight significantly inhibited the LTB4 response in females, while DHT and E2 significantly inhibited the LTB4 response in males. The SPM lipoxin A4 (LXA4) (10–9–10−8 M), but not the resolvins D1 or D2, induced an [Ca2+]i increase that was significantly higher in males compared to females. We conclude that male and female CGCs showed differences in the expression of sex hormone receptors. Treatment with sex hormones altered pro-inflammatory mediator LTB4-induced response. Males compared to females have a higher response to the ω-6-fatty acid derived SPM LXA4, indicating males may terminate inflammation in conjunctival goblet cells faster than females.

Objectives Among people with immune-mediated inflammatory disease (IMID), including multiple sclerosis (MS), inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) most research has focused on mental illness rather than on mental health. We assessed dimensions of mental health among persons with IMID and compared them across IMID. We also evaluated demographic and clinical characteristics associated with flourishing mental health.Design Participants: Adults with an IMID (MS, 239; IBD, 225; RA 134; total 598) who were participating in a cohort study.Setting Tertiary care centre in Manitoba, Canada.Primary outcome measure Participants completed the Mental Health Continuum Short-Form (MHC-SF), which measures emotional, psychological and social well-being, and identifies flourishing mental health. This outcome was added midway through the study on the advice of the patient advisory group. Depression, anxiety, pain, fatigue and physical function were also assessed.Results Total MHC-SF and subscale scores were similar across IMID groups. Nearly 60% of participants were considered to have flourishing mental health, with similar proportions across disease types (MS 56.5%; IBD 58.7%; RA 59%, p=0.95). Older age was associated with a 2% increased odds of flourishing mental health per year of age (OR 1.02; 95% CI: 1.01 to 1.04). Clinically meaningful elevations in anxiety (OR 0.25; 95% CI: 0.12 to 0.51) and depressive symptoms (OR 0.074; 95% CI: 0.009 to 0.61) were associated with lower odds. Higher levels of pain, anxiety and depressive symptoms were associated with lower total Mental Health Continuum scores at the 50th quantile.Conclusions Over half of people with MS, IBD and RA reported flourishing mental health, with levels similar across the disease groups. Interventions targeting symptoms of depression and anxiety, and upper limb impairments, as well as resilience training may help a higher proportion of the IMID population achieve flourishing mental health.

A plethora of coronal models, from empirical to more complex magnetohydrodynamic (MHD) ones, are being used for reconstructing the coronal magnetic field topology and estimating the open magnetic flux. However, no individual solution fully agrees with coronal hole observations and in situ measurements of open flux at 1 au, as there is a strong deficit between the model and observations contributing to the known problem of the missing open flux. In this paper, we investigate the possible origin of the discrepancy between modeled and observed magnetic field topology by assessing the effect on the simulation output by the choice of the input boundary conditions and the simulation setup, including the choice of numerical schemes and the parameter initialization. In the frame of this work, we considered four potential field source surface-based models and one fully MHD model, different types of global magnetic field maps, and model initiation parameters. After assessing the model outputs using a variety of metrics, we conclude that they are highly comparable regardless of the differences set at initiation. When comparing all models to coronal hole boundaries extracted by extreme-ultraviolet filtergrams, we find that they do not compare well. This mismatch between observed and modeled regions of the open field is a candidate contributing to the open flux problem.

Coronal holes are recognized as the primary sources of heliospheric open magnetic flux (OMF). However, a noticeable gap exists between in situ measured OMF and that derived from remote-sensing observations of the Sun. In this study, we investigate the OMF evolution and its connection to solar structures throughout 2014, with special emphasis on the period from September to October, where a sudden and significant OMF increase was reported. By deriving the OMF evolution at 1 au, modeling it at the source surface, and analyzing solar photospheric data, we provide a comprehensive analysis of the observed phenomenon. First, we establish a strong correlation between the OMF increase and the solar magnetic field derived from a potential-field source-surface model ( cc _Pearson = 0.94). Moreover, we find a good correlation between the OMF and the open flux derived from solar coronal holes ( cc _Pearson = 0.88), although the coronal holes only contain 14%–32% of the Sun’s total open flux. However, we note that while the OMF evolution correlates with coronal hole open flux, there is no correlation with the coronal hole area evolution ( cc _Pearson = 0.0). The temporal increase in OMF correlates with the vanishing remnant magnetic field at the southern pole, caused by poleward flux circulations from the decay of numerous active regions months earlier. Additionally, our analysis suggests a potential link between the OMF enhancement and the concurrent emergence of the largest active region in solar cycle 24. In conclusion, our study provides insights into the strong increase in OMF observed during 2014 September–October.

Automated detection schemes are nowadays the standard approach for locating coronal holes in extreme-UV images from the Solar Dynamics Observatory (SDO). However, factors such as the noisy nature of solar imagery, instrumental effects, and others make it challenging to identify coronal holes using these automated schemes. While discrepancies between detection schemes have been noted in the literature, a comprehensive assessment of these discrepancies is still lacking. The contribution of the Coronal Hole Boundary Working Team in the COSPAR ISWAT initiative to close this gap is threefold. First, we present the first community data set for comparing automated coronal hole detection schemes. This data set consists of 29 SDO images, all of which were selected by experienced observers to challenge automated schemes. Second, we use this community data set as input to 14 widely applied automated schemes to study coronal holes and collect their detection results. Third, we study three SDO images from the data set that exemplify the most important lessons learned from this effort. Our findings show that the choice of the automated detection scheme can have a significant effect on the physical properties of coronal holes, and we discuss the implications of these findings for open questions in solar and heliospheric physics. We envision that this community data set will serve the scientific community as a benchmark data set for future developments in the field.

Abstract Background Kenya introduced Rotarix® (GlaxoSmithKline Biologicals, Rixensart, Belgium) vaccination into its national immunization programme beginning July 2014. The impact of this vaccination program on the local epidemiology of various known enteropathogens is not fully understood. Methods We used a custom TaqMan Array Card (TAC) to screen for 28 different enteropathogens in 718 stools from children aged less than 13 years admitted to Kilifi County Hospital, coastal Kenya, following presentation with diarrhea in 2013 (before vaccine introduction) and in 2016–2018 (after vaccine introduction). Pathogen positivity rate differences between pre- and post-Rotarix® vaccination introduction were examined using both univariate and multivariable logistic regression models. Results In 665 specimens (92.6%), one or more enteropathogen was detected, while in 323 specimens (48.6%) three or more enteropathogens were detected. The top six detected enteropathogens were: enteroaggregative Escherichia coli (EAggEC; 42.1%), enteropathogenic Escherichia coli (EPEC; 30.2%), enterovirus (26.9%), rotavirus group A (RVA; 24.8%), parechovirus (16.6%) and norovirus GI/GII (14.4%). Post-rotavirus vaccine introduction, there was a significant increase in the proportion of samples testing positive for EAggEC (35.7% vs. 45.3%, p = 0.014), cytomegalovirus (4.2% vs. 9.9%, p = 0.008), Vibrio cholerae (0.0% vs. 2.3%, p = 0.019), Strongyloides species (0.8% vs. 3.6%, p = 0.048) and Dientamoeba fragilis (2.1% vs. 7.8%, p = 0.004). Although not reaching statistical significance, the positivity rate of adenovirus 40/41 (5.8% vs. 7.3%, p = 0.444), norovirus GI/GII (11.2% vs. 15.9%, p = 0.089), Shigella species (8.7% vs. 13.0%, p = 0.092) and Cryptosporidium spp. (11.6% vs. 14.7%, p = 0.261) appeared to increase post-vaccine introduction. Conversely, the positivity rate of sapovirus decreased significantly post-vaccine introduction (7.8% vs. 4.0%, p = 0.030) while that of RVA appeared not to change (27.4% vs. 23.5%, p = 0.253). More enteropathogen coinfections were detected per child post-vaccine introduction compared to before (mean: 2.7 vs. 2.3; p = 0.0025). Conclusions In this rural Coastal Kenya setting, childhood enteropathogen infection burden was high both pre- and post-rotavirus vaccination introduction. Children who had diarrheal admissions post-vaccination showed an increase in coinfections and changes in specific enteropathogen positivity rates. This study highlights the utility of multipathogen detection platforms such as TAC in understanding etiology of childhood acute gastroenteritis in resource-limited regions.

Abstract Background Microscopy techniques and image segmentation algorithms have improved dramatically this decade, leading to an ever increasing amount of biological images and a greater reliance on imaging to investigate biological questions. This has created a need for methods to extract the relevant information on the behaviors of cells and their interactions, while reducing the amount of computing power required to organize this information. Results This task can be performed by using a network representation in which the cells and their properties are encoded in the nodes, while the neighborhood interactions are encoded by the links. Here, we introduce Griottes, an open-source tool to build the “network twin” of 2D and 3D tissues from segmented microscopy images. We show how the library can provide a wide range of biologically relevant metrics on individual cells and their neighborhoods, with the objective of providing multi-scale biological insights. The library’s capacities are demonstrated on different image and data types. Conclusions This library is provided as an open-source tool that can be integrated into common image analysis workflows to increase their capacities.

Anti-cancer cytotoxic T cell responses largely vary among individuals. Here authors show, by stochastic modeling on high throughput T cell behavior and matched tumor spheroid fate data generated by a microfluidics system, that tumor killing is dependent on T cell cooperativity, which might contribute to the heterogeneity of T cell responses.

Abstract Phenotypic divergence is an important consequence of restricted gene flow in insular populations. This divergence can be challenging to detect when it occurs through subtle shifts in morphological traits, particularly in traits with complex geometries, like insect wing venation. Here, we employed geometric morphometrics to assess the extent of variation in wing venation patterns across reproductively isolated populations of the social sweat bee, Halictus tripartitus. We examined wing morphology of specimens sampled from a reproductively isolated population of H. tripartitus on Santa Cruz Island (Channel Islands, Southern California). Our analysis revealed significant differentiation in wing venation in this island population relative to conspecific mainland populations. We additionally found that this population‐level variation was less pronounced than the species‐level variation in wing venation among three sympatric congeners native to the region, Halictus tripartitus, Halictus ligatus, and Halictus farinosus. Together, these results provide evidence for subtle phenotypic divergence in an island bee population. More broadly, these results emphasize the utility and potential of wing morphometrics for large‐scale assessment of insect population structure.

Objective Among persons with immune-mediated inflammatory diseases (IMIDs) who received SARS-CoV-2 vaccines, we compared postvaccine antibody responses and IMID disease activity/states.Design Single-centre prospective cohort study.Setting Specialty ambulatory clinics in central Canada.Participants People with inflammatory arthritis (n=78; 77% rheumatoid arthritis), systemic autoimmune rheumatic diseases (n=84; 57% lupus), inflammatory bowel disease (n=93; 43% Crohn’s) and multiple sclerosis (n=72; 71% relapsing-remitting) (female 79.4%, white 84.7%, mean (SD) age 56.0 (14.3) years) received COVID-19 vaccinations between March 2021 and September 2022.Primary outcome Postvaccination anti-spike, anti-receptor binding domain (anti-RBD) and anti-nucleocapsid (anti-NC) IgG antibodies tested by multiplex immunoassays compared across vaccine regimens and with responses in 370 age-matched and sex-matched vaccinated controls.Secondary outcomes COVID-19 infection and self-reported IMID disease activity/state.Results Most (216/327, 66.1%) received homologous messenger RNA (mRNA) (BNT162b2 or mRNA1273) vaccines, 2.4% received homologous ChAdOx1 and 30.6% received heterologous vaccines (23.9% ChAdOx1/mRNA, 6.4% heterologous mRNA) for their first two vaccines (V1, V2). Seroconversion rates were 52.0% (91/175) for post-V1 anti-spike and 58.9% (103/175) for anti-RBD; 91.5% (214/234) for post-V2 anti-spike and 90.2% (211/234) for anti-RBD; and were lower than controls (post-V2 anti-spike 98.1% (360/370), p

Summary: Culturing and screening cells in microfluidics, particularly in three-dimensional formats, has the potential to impact diverse areas from fundamental biology to cancer precision medicine. Here, we use a platform based on anchored droplets for drug screening. The response of spheroids of Ewing sarcoma (EwS) A673 cells to simultaneous or sequential combinations of etoposide and cisplatin was evaluated. This was done by culturing spheroids of EwS cells inside 500 nL droplets then merging them with secondary droplets containing fluorescent-barcoded drugs at different concentrations. Differences in EwS spheroid growth and viability were measured by microscopy. After drug exposure such measurements enabled estimation of their IC50 values, which were in agreement with values obtained in standard multiwell plates. Then, synergistic drug combination was evaluated. Sequential combination treatment of EwS with etoposide applied 24 h before cisplatin resulted in amplified synergistic effect. As such, droplet-based microfluidics offers the modularity required for evaluation of drug combinations.

Summary: Background: West Africans and African Americans with substantial (∼80%) West African ancestry are characterized by low levels of triglycerides (TG) compared to East Africans and Europeans. The impact of these varying TG levels on other cardiometabolic risk factors is unclear. We compared the strength of association between TG with hypertension, blood pressure, BMI, waist circumference, type 2 diabetes (T2D), and fasting glucose across West African (WA), East African (EA), and European (EU) ancestry populations residing in three vastly different environmental settings: sub-Saharan Africa, United States, and Europe. Methods: We analysed data from four cross-sectional studies that included WA in sub-Saharan Africa (n = 7201), the U.S. (n = 4390), and Europe (n = 6436), EA in sub-Saharan Africa (n = 781), and EU in the U.S. (n = 8670) and Europe (n = 4541). Linear regression analyses were used to test the association between TG and cardiometabolic risk factors. Findings: Higher adjusted regression coefficients were observed in EU compared with WA ancestry for TG on hypertension (EU β [95% CI]: 0.179 [0.156, 0.203], WA β [95% CI]: 0.102 [0.086, 0.118]), BMI (EU β [95% CI]: 0.028 [0.027, 0.030], WA β [95% CI]: 0.015 [0.014, 0.016]), and waist circumference (EU β [95% CI]: 0.013 [0.013, 0.014], WA β [95% CI]: 0.009 [0.008, 0.009) (all ancestry × trait interaction P-values

Summary: Recent advances in synthetic embryology have opened new avenues for understanding the complex events controlling mammalian peri-implantation development. Here, we show that mouse embryonic stem cells (ESCs) solely exposed to chemical inhibition of SUMOylation generate embryo-like structures comprising anterior neural and trunk-associated regions. HypoSUMOylation-instructed ESCs give rise to spheroids that self-organize into gastrulating structures containing cell types spatially and functionally related to embryonic and extraembryonic compartments. Alternatively, spheroids cultured in a droplet microfluidic device form elongated structures that undergo axial organization reminiscent of natural embryo morphogenesis. Single-cell transcriptomics reveals various cellular lineages, including properly positioned anterior neuronal cell types and paraxial mesoderm segmented into somite-like structures. Transient SUMOylation suppression gradually increases DNA methylation genome wide and repressive mark deposition at Nanog. Interestingly, cell-to-cell variations in SUMOylation levels occur during early embryogenesis. Our approach provides a proof of principle for potentially powerful strategies to explore early embryogenesis by targeting chromatin roadblocks of cell fate change.

Wildfires pose a risk to water supplies in the western U.S. and many other parts of the world, due to the potential for degradation of water quality. However, a lack of adequate data hinders prediction and assessment of post-wildfire impacts and recovery. The dearth of such data is related to lack of funding for monitoring extreme events and the challenge of measuring the outsized hydrologic and erosive response after wildfire. Assessment and prediction of post-wildfire surface water quality would be strengthened by the strategic monitoring of key parameters, and the selection of sampling locations based on the following criteria: (1) streamgage with pre-wildfire data; (2) ability to install equipment that can measure water quality at high temporal resolution, with a focus on storm sampling; (3) minimum of 10% drainage area burned at moderate to high severity; (4) lack of major water management; (5) high-frequency precipitation; and (6) availability of pre-wildfire water-quality data and (or) water-quality data from a comparable unburned basin. Water-quality data focused on parameters that are critical to human and (or) ecosystem health, relevant to water-treatment processes and drinking-water quality, and (or) inform the role of precipitation and discharge on flow paths and water quality are most useful. We discuss strategic post-wildfire water-quality monitoring and identify opportunities for advancing assessment and prediction. Improved estimates of the magnitude, timing, and duration of post-wildfire effects on water quality would aid the water resources community prepare for and mitigate against impacts to water supplies.

Abstract Obesity can initiate, promote, and maintain systemic inflammation via metabolic reprogramming of macrophages that encircle adipocytes, termed crown-like structures (CLS). In breast cancer the presence of CLS has been correlated to high body mass index (BMI), larger mammary adipocyte size and postmenopausal status. However, the prognostic significance of CLS in HER2 + breast cancer is still unknown. We investigated the prognostic significance of CLS in a cohort of 69 trastuzumab-naïve and 117 adjuvant trastuzumab-treated patients with primary HER2 + breast cancer. Immunohistochemistry of tumour blocks was performed for CLS and correlated to clinical outcomes. CLS were more commonly found at the adipose-tumour border (B-CLS) (64.8% of patients). The presence of multiple B-CLS was associated with reduced time to metastatic disease (TMD) in trastuzumab treated patients with BMI ≥ 25 kg/m2 but not those with BMI

Abstract Convulxin (CVX), a C-type lectin-like protein isolated from the venom of the snake species, Crotalus durissus terrificus, stimulates platelet aggregation by acting as a collagen receptor agonist for glycoprotein VI found in the platelets. The effect of CVX on platelets has been studied, but its effect on human peripheral blood mononuclear cells (PBMCs) remains unclear. Given the significance of PBMCs in inflammation, this study explored the effect of CVX on PBMCs, specifically regarding NLRP3 inflammasome activation by assessing cell viability, ability to induce cell proliferation, reactive oxygen species (ROS) and nitric oxide production, interleukin (IL)-2 and IL-10 secretion, NLRP3 complex activation, and the role of C-type lectin-like receptors (CTLRs) in these. CVX was not toxic to PBMCs at the investigated concentrations and did not increase PBMC growth or IL-2 release; however, CVX induced IL-10 release and ROS generation via monocyte activation. It also activated the NLRP3 complex, resulting in IL-1β induction. Furthermore, the interaction between CVX and Dectin-2, a CTLR, induced IL-10 production. CVX interaction with CTLR has been demonstrated by laminarin therapy. Because of the involvement of residues near the Dectin-2 carbohydrate-recognition site, the generation of ROS resulted in inflammasome activation and IL-1β secretion. Overall, this work helps elucidate the function of CVX in immune system cells.

Abstract Background Hospitalization admissions and discharge databases (DAD) using the International Classification of Diseases (ICD) codes are often used to describe the epidemiology of Clostridioides difficile infections (CDI) among those with Inflammatory bowel disease (IBD), even though DAD CDI definition can miss many cases of CDI. There are no data comparing the assessment of the epidemiology of CDI among those with IBD by DAD versus laboratory diagnosis. We used a population-based dataset to determine the effect of using DAD versus laboratory CDI diagnosis on CDI assessment among those with IBD. Methods We linked the University of Manitoba IBD Epidemiology Database to the provincial CDI laboratory dataset for the years 2005–2014. Time trends of CDI were assessed using joinpoint analyses. We used stratified logistic regression analysis to assess factors associated with CDI among individuals with IBD. Results Time trends of CDI among hospitalized individuals with IBD were similar when using DAD or the laboratory CDI diagnosis. Prior hospital admission and antibiotic exposure were associated with CDI using either of the CDI definitions, 5-ASA use was associated with CDI using DAD but not laboratory diagnosis, whereas corticosteroid exposure was associated with laboratory-based CDI diagnosis. Using laboratory results as gold standard, DAD had a sensitivity and specificity of 75.4% and 99.6% for CDI among those with IBD. Conclusions Using ICD codes in the DAD for CDI provides similar epidemiological time trend patterns as identifying CDI in the laboratory dataset. Hence, ICD codes are reliable to determine CDI epidemiology among hospitalized individuals with IBD.

L-Amino acid oxidase (LAAO) is an enzyme found in snake venom that has multifaceted effects, including the generation of hydrogen peroxide (H2O2) during oxidative reactions, leading to various biological and pharmacological outcomes such as apoptosis, cytotoxicity, modulation of platelet aggregation, hemorrhage, and neutrophil activation. Human neutrophils respond to LAAO by enhancing chemotaxis, and phagocytosis, and releasing reactive oxygen species (ROS) and pro-inflammatory mediators. Exosomes cellular nanovesicles play vital roles in intercellular communication, including immune responses. This study investigates the impact of Calloselasma rhodostoma snake venom-derived LAAO (Cr-LAAO) on human neutrophil exosome release, including activation patterns, exosome formation, and content. Neutrophils isolated from healthy donors were stimulated with Cr-LAAO (100 μg/mL) for 3 h, followed by exosome isolation and analysis. Results show that Cr-LAAO induces the release of exosomes with distinct protein content compared to the negative control. Proteomic analysis reveals proteins related to the regulation of immune responses and blood coagulation. This study uncovers Cr-LAAO’s ability to activate human neutrophils, leading to exosome release and facilitating intercellular communication, offering insights into potential therapeutic approaches for inflammatory and immunological disorders.

Abstract Pneumonia remains a major cause of mortality and morbidity. Most molecular diagnoses of viruses rely on polymerase chain reaction (PCR) assays that however can fail due to primer mismatch. We investigated the performance of routine virus diagnostics in Kilifi, Kenya, using random-primed viral next generation sequencing (viral NGS) on respiratory samples which tested negative for the common viral respiratory pathogens by a local standard diagnostic panel. Among 95 hospitalised pneumonia patients and 95 household-cohort individuals, analysis of viral NGS identified at least one respiratory-associated virus in 35 (37%) and 23 (24%) samples, respectively. The majority (66%; 42/64) belonged to the Picornaviridae family. The NGS data analysis identified a number of viruses that were missed by the diagnostic panel (rhinovirus, human metapneumovirus, respiratory syncytial virus and parainfluenza virus), and these failures could be attributed to PCR primer/probe binding site mismatches. Unexpected viruses identified included parvovirus B19, enterovirus D68, coxsackievirus A16 and A24 and rubella virus. The regular application of such viral NGS could help evaluate assay performance, identify molecular causes of missed diagnoses and reveal gaps in the respiratory virus set used for local screening assays. The results can provide actionable information to improve the local pneumonia diagnostics and reveal locally important viral pathogens.

Abstract Background Approximately 40% of persons with inflammatory bowel disease (IBD) experience psychiatric comorbidities (PC). Previous studies demonstrated the polygenetic effect on both IBD and PC. In this study, we evaluated the contribution of genetic variants to PC among the IBD population. Additionally, we evaluated whether this effect is mediated by the expression level of the RBPMS gene, which was identified in our previous studies as a potential risk factor of PC in persons with IBD. Materials and methods The polygenic risk score (PRS) was estimated among persons with IBD of European ancestry (n = 240) from the Manitoba IBD Cohort Study by using external genome-wide association studies (GWAS). The association and prediction performance were examined between the estimated PRS and PC status among persons with IBD. Finally, regression-based models were applied to explore whether the imputed expression level of the RBPMS gene is a mediator between estimated PRS and PC status in IBD. Results The estimated PRS had a significantly positive association with PC status (for the highest effect: P-value threshold = 5 × 10–3, odds ratio = 2.0, P-value = 1.5 × 10–5). Around 13% of the causal effect between the PRS and PC status in IBD was mediated by the expression level of the RBPMS gene. The area under the curve of the PRS-based PC prediction model is around 0.7 at the threshold of 5 × 10–4. Conclusion PC status in IBD depends on genetic influences among persons with European ancestry. The PRS could potentially be applied to PC risk screening to identify persons with IBD at a high risk of PC. Around 13% of this genetic influence could be explained by the expression level of the RBPMS gene.

Abstract Sulfotransferase 4A1 (SULT4A1) is an orphan member of the cytosolic SULT superfamily that contains enzymes that catalyze the sulfonation of hydrophobic drugs and hormones. SULT4A1 has been assessed through all classical SULT approaches yet no SULT activity has been reported. To ascertain SULT4A1 function and activity, we utilized Saccharomyces cerevisiae as a model system, which exhibits no endogenous SULT activity nor possesses SULT-related genes. We observed that ectopic SULT4A1 expression in yeast displays similar subcellular localization as reported in mouse neurons and observed that SULT4A1 is associated with the outer mitochondria membrane. SULT4A1 expression stimulates colony formation and protects these cells from hydrogen peroxide and metabolism-associated oxidative stress. These SULT4A1-mediated phenotypes are dependent on extracellular sulfate that is converted in yeast to PAPS, the universal sulfonate donor for SULT activity. Thus, heterologous SULT4A1 expression in yeast is correctly distributed and functional, and SULT4A1 antioxidant activity is sulfate dependent supporting the concept that SULT4A1 has sulfate-associated activity.

Inflammatory bowel disease (IBD), once considered a disease of the Western hemisphere, has emerged as a global disease. As the disease prevalence is on a steady rise, management of IBD has come under the spotlight. 5-Aminosalicylates, corticosteroids, immunosuppressive agents and biologics are the backbone of treatment of IBD. With the advent of biologics and small molecules, the need for surgery and hospitalization has decreased. However, economic viability and acceptability is an important determinant of local prescription patterns. Nearly one-third of the patients in West receive biologics as the first/initial therapy. The scenario is different in developing countries where biologics are used only in a small proportion of patients with IBD. Increased risk of reactivation of tuberculosis and high cost of the therapy are limitations to their use. Thiopurines hence become critical for optimal management of patients with IBD in these regions. However, approximately one-third of patients are intolerant or develop adverse effects with their use. This has led to suboptimal use of thiopurines in clinical practice. This review article discusses the clinical aspects of thiopurine use in patients with IBD with the aim of optimizing their use to full therapeutic potential.

In order to explore the functions of glycosylation of κ-Casein (κ-CN) in bovine milk, unglycosylated (UG) and twice glycosylated (2G) forms of κ-CN B were purified by selective precipitation followed by anion exchange chromatography from κ-CN BB milk and tested for their amyloid fibril formation and morphology, oligomerisation states and protein structure. The diameter of self-assembled κ-CN B aggregates of both glyco-form were shown for the first time to be in the same 26.0–28.7 nm range for a 1 mg mL−1 solution. The presence of two bound glycans in the protein structure of 2G κ-CN B led to a greater increase in the maximum amyloid fibril formation rate with increasing protein concentration and a difference in both length (82.0 ± 29.9 vs 50.3 ± 13.7 nm) and width (8.6 ± 2.1 vs 13.9 ± 2.5 nm) for fibril morphology compared to UG κ-CN B. The present results suggest that amyloid fibril formation proceeds at a slow but steady rate via the self-assembly of dissociated, monomeric κ-CN B proteins at concentrations of 0.22–0.44 mg mL−1. However amyloid fibril formation proceeds more rapidly via the assembly of either aggregated κ-CN present in a micelle-like form or dissociated monomeric κ-CN, packed into reorganised formational structures above the critical micellar concentration to form fibrils of differing width. The degree of glycosylation has no effect on the polarity of the adjacent environment, nor non-covalent and disulphide interactions between protein molecules when in the native form. Yet glycosylation can influence protein folding patterns of κ-CN B leading to a reduced tryptophan intrinsic fluorescence intensity for 2G compared to UG κ-CN B. These results demonstrate that glycosylation plays an important role in the modulation of aggregation states of κ-CN and contributes to a better understanding of the role of glycosylation in the formation of amyloid fibrils from intrinsically disordered proteins.

Abstract Objective To examine the gut microbiota in individuals with and without pediatric‐onset multiple sclerosis (MS). Methods We compared stool‐derived microbiota of Canadian Pediatric Demyelinating Disease Network study participants ≤21 years old, with MS (disease‐modifying drug [DMD] exposed and naïve) or monophasic acquired demyelinating syndrome [monoADS] (symptom onset 0.1), taxa‐level and gut community networks did. MS (vs. monoADS) exhibited > fourfold higher relative abundance of the superphylum Patescibacteria (aRR = 4.2;95%CI:1.6–11.2, p = 0.004, Q = 0.01), and lower abundances of short‐chain fatty acid (SCFA)‐producing Lachnospiraceae (Anaerosporobacter) and Ruminococcaceae (p, Q eightfold higher abundance for Candidatus Stoquefichus and Tyzzerella (aRR = 8.8–12.8, p

Objective In this study, we aimed to determine the lifetime prevalence of substance use disorder (SUD) in a Canadian rheumatoid arthritis (RA) cohort and factors associated with SUD in RA. Methods Participants with RA (N = 154) were recruited via rheumatology clinics as part of a larger cohort study of psychiatric comorbidity in immune‐mediated inflammatory diseases. SUD is defined as the uncontrolled use of a substance despite the harmful consequences of its use. To identify lifetime SUD, the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition was administered to participants. Participants’ sociodemographic and RA clinical characteristics were also assessed. We examined factors associated with lifetime SUD using unadjusted and adjusted logistic regression modeling. Results Twenty‐three (14.9%) of 154 participants with RA met the criteria for a lifetime diagnosis of SUD. The majority of the participants were women, were White, had postsecondary education, and were on a disease‐modifying antirheumatic drug. Factors associated with increased odds of SUD were male sex (adjusted odds ratio [aOR]: 3.63, 95% confidence interval [CI]: 1.03‐12.73), younger age (aOR: 0.94, 95% CI: 0.90‐0.98), and ever smoking (aOR: 6.44, 95% CI: 1.53‐27.07). Conclusion We found that approximately 1 in 7 individuals with RA had a lifetime diagnosis of SUD, highlighting the importance of identifying and treating SUD in those with RA. In particular, the following factors were associated with higher odds of SUD: male sex, younger age, and smoking behaviors.

Extreme drought and resulting low streamflows occur throughout the U.S., causing billions of dollars in annual losses, detrimentally impacting ecosystems, as well as agricultural, hydropower, navigation, water supply, recreation, and a myriad of other water resource systems, leading to reductions in both the effectiveness and resiliency of our water resource infrastructure. Since 1966, with the introduction of Bulletin 13 titled ‘Methods of Flow Frequency Analysis’, the U.S. adopted uniform guidelines for performing flood flow frequency analysis to ensure and enable all federal agencies concerned with water resource design, planning, and management under flood conditions to obtain sensible, consistent, and reproducible estimators of flood flow statistics. Remarkably, over one-half century later, no uniform national U.S. guidelines for hydrologic drought streamflow frequency analysis exist, and the various assorted guidelines that do exist are not reliable because (1) they are based on methods developed for floods, which are distinctly different than low streamflows and (2) the methods do not take advantage of the myriad of advances in flood and low streamflow frequency analyses over the last 50 years. We provide a justification for the need for developing national guidelines for streamflow drought frequency analysis as an analog to the existing national guidelines for flood frequency analysis. Those guidelines should result in improved water resources design, planning, operations, and management under low streamflow conditions throughout the U.S. and could prove useful elsewhere. HIGHLIGHTS Since 1966, the U.S. has adopted uniform guidelines for performing flood flow frequency analysis.; Over one-half century later, no analogous uniform national guidelines exist for hydrologic drought streamflow frequency analysis.; Existing low streamflow frequency methods are based mostly on flood frequency analysis and do not take advantage of the myriad of advances in both areas over the last 50 years.; Numerous innovations in low flow frequency analysis are described, using analogies to recent advances in flood frequency analysis.; A justification is provided for the need to develop national guidelines for streamflow drought frequency analysis.; Such guidelines would enable agencies concerned with water resource design, planning, and management under drought conditions to obtain sensible, consistent, and reproducible estimators of low streamflow statistics.;

Though both genetic and lifestyle factors are known to influence cardiometabolic outcomes, less attention has been given to whether lifestyle exposures can alter the association between a genetic variant and these outcomes. The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium’s Gene-Lifestyle Interactions Working Group has recently published investigations of genome-wide gene-environment interactions in large multi-ancestry meta-analyses with a focus on cigarette smoking and alcohol consumption as lifestyle factors and blood pressure and serum lipids as outcomes. Further description of the biological mechanisms underlying these statistical interactions would represent a significant advance in our understanding of gene-environment interactions, yet accessing and harmonizing individual-level genetic and ‘omics data is challenging. Here, we demonstrate the coordinated use of summary-level data for gene-lifestyle interaction associations on up to 600,000 individuals, differential methylation data, and gene expression data for the characterization and prioritization of loci for future follow-up analyses. Using this approach, we identify 48 genes for which there are multiple sources of functional support for the identified gene-lifestyle interaction. We also identified five genes for which differential expression was observed by the same lifestyle factor for which a gene-lifestyle interaction was found. For instance, in gene-lifestyle interaction analysis, the T allele of rs6490056 (ALDH2) was associated with higher systolic blood pressure, and a larger effect was observed in smokers compared to non-smokers. In gene expression studies, this allele is associated with decreased expression of ALDH2, which is part of a major oxidative pathway. Other results show increased expression of ALDH2 among smokers. Oxidative stress is known to contribute to worsening blood pressure. Together these data support the hypothesis that rs6490056 reduces expression of ALDH2, which raises oxidative stress, leading to an increase in blood pressure, with a stronger effect among smokers, in whom the burden of oxidative stress is greater. Other genes for which the aggregation of data types suggest a potential mechanism include: GCNT4×current smoking (HDL), PTPRZ1×ever-smoking (HDL), SYN2×current smoking (pulse pressure), and TMEM116×ever-smoking (mean arterial pressure). This work demonstrates the utility of careful curation of summary-level data from a variety of sources to prioritize gene-lifestyle interaction loci for follow-up analyses.

High-integrity welds found in safety–critical industries require flaw-free joints, but automation is challenging due to low-volume, often-unique nature of the work, alongside high-uncertainty part-localisation. As such, robotic welding still requires tedious manually taught paths or offline approaches based on nominal Computer-Aided-Design (CAD). Optical and laser sensors are commonly deployed to provide online adjustment of pre-defined paths within controlled environments. This paper presents a sensor-driven approach for defect-free welding, based on the as-built joint geometry alongside the requirement for no-accurate part localisation or CAD knowledge. The approach a) autonomously localises the specimen in the scene without CAD requirement, b) adapts and generates accurate welding paths unique to the as-built workpiece and c) generates robot kinematics based on an external-control strategy. The proposed approach is validated through experiments of unconstrained placed joints, where the increased accuracy of the generated welding paths, with no common seam tracking, is validated with an average error of 0.12 mm, 0.4°. Coupling with a multi-pass welding framework, the deployment of fully automated robotic arc welding takes place for different configurations. Non-Destructive-Testing (NDT) in the form of Ultrasound-Testing (UT) inspection validates the repeatable and flaw-free nature of the sensory-driven approach, exploiting direct benefits in quality alongside reduced re-work.

Abstract Axonal loss is the main determinant of disease progression in multiple sclerosis (MS). This study aimed to assess the utility of corneal confocal microscopy (CCM) in detecting corneal axonal loss in different courses of MS. The results were confirmed by two independent segmentation methods. 72 subjects (144 eyes) [(clinically isolated syndrome (n = 9); relapsing–remitting MS (n = 20); secondary-progressive MS (n = 22); and age-matched, healthy controls (n = 21)] underwent CCM and assessment of their disability status. Two independent algorithms (ACCMetrics; and Voxeleron deepNerve) were used to quantify corneal nerve fiber density (CNFD) (ACCMetrics only), corneal nerve fiber length (CNFL) and corneal nerve fractal dimension (CNFrD). Data are expressed as mean ± standard deviation with 95% confidence interval (CI). Compared to controls, patients with MS had significantly lower CNFD (34.76 ± 5.57 vs. 19.85 ± 6.75 fibers/mm2, 95% CI − 18.24 to − 11.59, P

Abstract Background A complex set of perturbations occur in cytokines and hormones in the etiopathogenesis of obesity and related cardiometabolic conditions such as type 2 diabetes (T2D). Evidence for the genetic regulation of these cytokines and hormones is limited, particularly in African-ancestry populations. In order to improve our understanding of the biology of cardiometabolic traits, we investigated the genetic architecture of a large panel of obesity- related cytokines and hormones among Africans with replication analyses in African Americans. Methods We performed genome-wide association studies (GWAS) in 4432 continental Africans, enrolled from Ghana, Kenya, and Nigeria as part of the Africa America Diabetes Mellitus (AADM) study, for 13 obesity-related cytokines and hormones, including adipsin, glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1), interleukin-1 receptor antagonist (IL1-RA), interleukin-6 (IL-6), interleukin-10 (IL-10), leptin, plasminogen activator inhibitor-1 (PAI-1), resistin, visfatin, insulin, glucagon, and ghrelin. Exact and local replication analyses were conducted in African Americans (n = 7990). The effects of sex, body mass index (BMI), and T2D on results were investigated through stratified analyses. Results GWAS identified 39 significant (P value

Abstract Background In men with metastatic castration‐resistant prostate cancer (mCRPC) with primarily bone metastases, radium‐223 (223Ra) improves overall survival (OS). However, the selection of 223Ra is not guided by specific validated clinicopathologic factors, and thus outcomes are heterogeneous. Patients and methods This retrospective survival analysis was performed in men with mCRPC treated with 223Ra at our cancer center. Demographics and disease characteristics were collected. OS was calculated using the Kaplan–Meier method (log‐rank). The potential prognostic factors were determined using both univariable (UVA) and multivariable analysis (MVA) (Cox‐regression) methods. Results In total, 150 patients with a median age of 74 years (52–93) received 223Ra between May 2015 and July 2018, and 58% had 6–20 bone metastases. Ninety‐four (63%) patients received >4 223Ra doses, and 56 (37%) received ≤4. The following pre‐treatment factors were analyzed (median [range]): eastern cooperative oncology group performance status (ECOG PS), (1 [0–3]); Albumin (ALB), (39 g/L [24–47]); alkaline phosphatase (ALP), (110 U/L [35–1633]); and prostate‐specific antigen (PSA), (49 µg/L [0.83–7238]). The median OS for all patients was 14.5 months (95% CI: 11.2–18). These factors were associated with poor survival outcomes in UVA and MVA: ALB 150 U/L, ECOG PS 2–3, and PSA >80 µg/L. By assigning one point for each of these factors, a prognostic model was developed, wherein three distinct risk groups were identified: good, 0–1 (n = 103); intermediate, 2 (n = 30); and poor risk, 3–4 points (n = 17). The median OS was 19.4, 10.0, and 3.1 months, respectively (p

IntroductionThe high burden of respiratory syncytial virus (RSV) infection in young children disproportionately occurs in low- and middle-income countries (LMICs). The PROUD (Preventing RespiratOry syncytial virUs in unDerdeveloped countries) Taskforce of 24 RSV worldwide experts assessed key needs for RSV prevention in LMICs, including vaccine and newer preventive measures.MethodsA global, survey-based study was undertaken in 2021. An online questionnaire was developed following three meetings of the Taskforce panellists wherein factors related to RSV infection, its prevention and management were identified using iterative questioning. Each factor was scored, by non-panellists interested in RSV, on a scale of zero (very-low-relevance) to 100 (very-high-relevance) within two scenarios: (1) Current and (2) Future expectations for RSV management.ResultsNinety questionnaires were completed: 70 by respondents (71.4% physicians; 27.1% researchers/scientists) from 16 LMICs and 20 from nine high-income (HI) countries (90.0% physicians; 5.0% researchers/scientists), as a reference group. Within LMICs, RSV awareness was perceived to be low, and management was not prioritised. Of the 100 factors scored, those related to improved diagnosis particularly access to affordable point-of-care diagnostics, disease burden data generation, clinical and general education, prompt access to new interventions, and engagement with policymakers/payers were identified of paramount importance. There was a strong need for clinical education and local data generation in the lowest economies, whereas upper-middle income countries were more closely aligned with HI countries in terms of current RSV service provision.ConclusionSeven key actions for improving RSV prevention and management in LMICs are proposed.

New strategies that augment T cell responses are required to broaden the therapeutic arsenal against cancer. CD96, TIGIT, and CD226 are receptors that bind to a communal ligand, CD155, and transduce either inhibitory or activating signals. The function of TIGIT and CD226 is established, whereas the role of CD96 remains ambiguous. Using a panel of engineered antibodies, we discovered that the T cell stimulatory activity of anti-CD96 antibodies requires antibody cross-linking and is potentiated by Fcγ receptors. Thus, soluble “Fc silent” anti-CD96 antibodies failed to stimulate human T cells, whereas the same antibodies were stimulatory after coating onto plastic surfaces. Remarkably, the activity of soluble anti-CD96 antibodies was reinstated by engineering the Fc domain to a human IgG1 isotype, and it was dependent on antibody trans-cross-linking by FcγRI. In contrast, neither human IgG2 nor variants with increased Fcγ receptor IIB binding possessed stimulatory activity. Anti-CD96 antibodies acted directly on T cells and augmented gene expression networks associated with T cell activation, leading to proliferation, cytokine secretion, and resistance to Treg suppression. Furthermore, CD96 expression correlated with survival in HPV+ head and neck squamous cell carcinoma, and its cross-linking activated tumor-infiltrating T cells, thus highlighting the potential of anti-CD96 antibodies in cancer immunotherapy.

Summary: Neutrophil swarming is an emergent host defense mechanism triggered by targets larger than a single neutrophil’s capacity to phagocytose. Swarming synergizes neutrophil functions, including chemotaxis, phagocytosis, and reactive oxygen species (ROS) production, and coordinates their deployment by many interacting neutrophils. The potent inflammatory lipid mediator leukotriene B4 (LTB4) has been established as central to orchestrating neutrophil activities during swarming. However, the details regarding how this eicosanoid choreographs the neutrophils involved in swarming are not well explained. Here we leverage microfluidics, genetically deficient mouse cells, and targeted metabolipidomic analysis to demonstrate that transcellular biosynthesis occurs among neutrophils to generate LTB4. Furthermore, transcellular biosynthesis is an entirely sufficient means of generating LTB4 for the purposes of orchestrating neutrophil swarming. These results further our understanding of how neutrophils coordinate their activities during swarming, which will be critical in the design of eventual therapies that can harness the power of swarming behavior.

Policymakers in Africa need robust estimates of the current and future spread of SARS-CoV-2. We used national surveillance PCR test, serological survey and mobility data to develop and fit a county-specific transmission model for Kenya up to the end of September 2020, which encompasses the first wave of SARS-CoV-2 transmission in the country. We estimate that the first wave of the SARS-CoV-2 pandemic peaked before the end of July 2020 in the major urban counties, with 30-50% of residents infected. Our analysis suggests, first, that the reported low COVID-19 disease burden in Kenya cannot be explained solely by limited spread of the virus, and second, that a 30-50% attack rate was not sufficient to avoid a further wave of transmission.

Background/objective: Poor subjective well-being is a risk factor for poor health; and threatens school administrators' leadership roles and overall occupational and personal outcomes. Online digital care and coaching such as Zoom-delivered GROW (Z-GROW) coaching may be an invaluable approach to building resilience and improving well-being. This study investigated the effectiveness of the Z-GROW coaching model in enhancing self-reported well-being in a sample of school administrators in South-East Nigeria. Method: A randomized control trial was conducted with a sample of 109 school administrators who met the inclusion criteria. Participants were allocated into Z-GROW (N = 55) and waitlist control (N = 54) groups. A 2-hour Z-GROW programme was delivered to the Z-GROW intervention group weekly for 9 weeks. Subjective well-being was measured using the Satisfaction with Life Scale (SWLS), the Scale of Positive and Negative Experience (SPANE), and the Flourishing Scale (FS). Data were collected on three occasions: pre-intervention, post-intervention, and follow-up using the same measures. All data were analyzed using descriptive and inferential statistics. The presentation of data was supported by figures and charts. Results: Results revealed that school administrators' three dimensions of subjective well-being significantly improved following the Z-GROW intervention. It was further shown that the improved state of participants was sustained through a 3-monthfollow-up assessment. Conclusion: Based on the findings, it can be concluded that intervention using GROW coaching in the zoom platform improves the self-reported well-being of school administrators. The outcomes of this study present the Z-GROW model as a viable intervention for subjective well-being and other mental health conditions among school administrators. Through the Z-GROW model, employees can access occupational health coaching from the comfort of their homes.