Live-attenuated chikungunya virus vaccine.

Although Chikungunya fever does not a have a high fatality rate (<10%), it has a huge morbidity toll due to lingering chronic arthralgia. The recent FDA approval of Ixchiq, a vaccine designed to prevent infection caused by the chikungunya virus (CHIKV), provides hope that its use can prevent future CHIKV outbreaks. To view this Bench to Bedside, open or download the PDF.

A local regulatory T cell feedback circuit maintains immune homeostasis by pruning self-activated T cells.

A fraction of mature T cells can be activated by peripheral self-antigens, potentially eliciting host autoimmunity. We investigated homeostatic control of self-activated T cells within unperturbed tissue environments by combining high-resolution multiplexed and volumetric imaging with computational modeling. In lymph nodes, self-activated T cells produced interleukin (IL)-2, which enhanced local regulatory T cell (Treg) proliferation and inhibitory functionality. The resulting micro-domains reciprocally constrained inputs required for damaging effector responses, including CD28 co-stimulation and IL-2 signaling, constituting a negative feedback circuit. Due to these local constraints, self-activated T cells underwent transient clonal expansion, followed by rapid death ("pruning"). Computational simulations and experimental manipulations revealed the feedback machinery's quantitative limits: modest reductions in Treg micro-domain density or functionality produced non-linear breakdowns in control, enabling self-activated T cells to subvert pruning. This fine-tuned, paracrine feedback process not only enforces immune homeostasis but also establishes a sharp boundary between autoimmune and host-protective T cell responses.

Human Epistatic Interaction Controls IL7R Splicing and Increases Multiple Sclerosis Risk.

Multiple sclerosis (MS) is an autoimmune disorder where T cells attack neurons in the central nervous system (CNS) leading to demyelination and neurological deficits. A driver of increased MS risk is the soluble form of the interleukin-7 receptor alpha chain gene (sIL7R) produced by alternative splicing of IL7R exon 6. Here, we identified the RNA helicase DDX39B as a potent activator of this exon and consequently a repressor of sIL7R, and we found strong genetic association of DDX39B with MS risk. Indeed, we showed that a genetic variant in the 5' UTR of DDX39B reduces translation of DDX39B mRNAs and increases MS risk. Importantly, this DDX39B variant showed strong genetic and functional epistasis with allelic variants in IL7R exon 6. This study establishes the occurrence of biological epistasis in humans and provides mechanistic insight into the regulation of IL7R exon 6 splicing and its impact on MS risk.

Evidence supports a causal association between allele-specific vitamin D receptor binding and multiple sclerosis among Europeans.

Although evidence exists for a causal association between 25-hydroxyvitamin D (25(OH)D) serum levels, and multiple sclerosis (MS), the role of variation in vitamin D receptor (VDR) binding in MS is unknown. Here, we leveraged previously identified variants associated with allele imbalance in VDR binding (VDR-binding variant; VDR-BV) in ChIP-exo data from calcitriol-stimulated lymphoblastoid cell lines and 25(OH)D serum levels from genome-wide association studies to construct genetic instrumental variables (GIVs). GIVs are composed of one or more genetic variants that serve as proxies for exposures of interest. Here, GIVs for both VDR-BVs and 25(OH)D were used in a two-sample Mendelian Randomization study to investigate the relationship between VDR binding at a locus, 25(OH)D serum levels, and MS risk. Data for 13,598 MS cases and 38,887 controls of European ancestry from Kaiser Permanente Northern California, Swedish MS studies, and the UK Biobank were included. We estimated the association between each VDR-BV GIV and MS. Significant interaction between a VDR-BV GIV and a GIV for serum 25OH(D) was evidence for a causal association between VDR-BVs and MS unbiased by pleiotropy. We observed evidence for associations between two VDR-BVs (rs2881514, rs2531804) and MS after correction for multiple tests. There was evidence of interaction between rs2881514 and a 25(OH)D GIV, providing evidence of a causal association between rs2881514 and MS. This study is the first to demonstrate evidence that variation in VDR binding at a locus contributes to MS risk. Our results are relevant to other autoimmune diseases in which vitamin D plays a role.

Experimental Structures of Antibody/MHC-I Complexes Reveal Details of Epitopes Overlooked by Computational Prediction.

mAbs to MHC class I (MHC-I) molecules have proved to be crucial reagents for tissue typing and fundamental studies of immune recognition. To augment our understanding of epitopic sites seen by a set of anti-MHC-I mAb, we determined X-ray crystal structures of four complexes of anti-MHC-I Fabs bound to peptide/MHC-I/ß2-microglobulin (pMHC-I). An anti-H2-Dd mAb, two anti-MHC-I α3 domain mAbs, and an anti-ß2-microglobulin mAb bind pMHC-I at sites consistent with earlier mutational and functional experiments, and the structures explain allelomorph specificity. Comparison of the experimentally determined structures with computationally derived models using AlphaFold Multimer showed that although predictions of the individual pMHC-I heterodimers were quite acceptable, the computational models failed to properly identify the docking sites of the mAb on pMHC-I. The experimental and predicted structures provide insight into strengths and weaknesses of purely computational approaches and suggest areas that merit additional attention.

Functional and Immunologic Mapping of Domains of the Reticulocyte-Binding Protein Plasmodium vivax PvRBP2a.

We previously described a novel Plasmodium vivax invasion mechanism into human reticulocytes via the PvRBP2a-CD98 receptor-ligand pair. Using linear epitope mapping, we assessed the PvRBP2a epitopes involved in CD98 binding and recognized by antibodies from patients who were infected. We identified 2 epitope clusters mediating PvRBP2a-CD98 interaction. Cluster B (PvRBP2a431-448, TAALKEKGKLLANLYNKL) was the target of antibody responses in humans infected by P vivax. Peptides from each cluster were able to prevent live parasite invasion of human reticulocytes. These results provide new insights for development of a malaria blood-stage vaccine against P vivax.

Growth, physical, and cognitive function in children who are born HIV-free: School-age follow-up of a cluster-randomised trial in rural Zimbabwe.

BACKGROUND: Globally, over 16 million children were exposed to HIV during pregnancy but remain HIV-free at birth and throughout childhood by 2022. Children born HIV-free (CBHF) have higher morbidity and mortality and poorer neurodevelopment in early life compared to children who are HIV-unexposed (CHU), but long-term outcomes remain uncertain. We characterised school-age growth, cognitive and physical function in CBHF and CHU previously enrolled in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe. METHODS AND FINDINGS: The SHINE trial enrolled pregnant women between 2012 and 2015 across 2 rural Zimbabwean districts. Co-primary outcomes were height-for-age Z-score and haemoglobin at age 18 months (clinicaltrials.gov NCT01824940). Children were re-enrolled if they were aged 7 years, resident in Shurugwi district, and had known pregnancy HIV-exposure status. From 5,280 pregnant women originally enrolled, 376 CBHF and 2016 CHU reached the trial endpoint at 18 months in Shurugwi; of these, 264 CBHF and 990 CHU were evaluated at age 7 years using the School-Age Health, Activity, Resilience, Anthropometry and Neurocognitive (SAHARAN) toolbox. Cognitive function was evaluated using the Kaufman Assessment Battery for Children (KABC-II), with additional tools measuring executive function, literacy, numeracy, fine motor skills, and socioemotional function. Physical function was assessed using standing broad jump and handgrip for strength, and the shuttle-run test for cardiovascular fitness. Growth was assessed by anthropometry. Body composition was assessed by bioimpedance analysis and skinfold thicknesses. A caregiver questionnaire measured demographics, socioeconomic status, nurturing, child discipline, food, and water insecurity. We prespecified the primary comparisons and used generalised estimating equations with an exchangeable working correlation structure to account for clustering. Adjusted models used covariates from the trial (study arm, study nurse, exact child age, sex, calendar month measured, and ambient temperature). They also included covariates derived from directed acyclic graphs, with separate models adjusted for contemporary variables (socioeconomic status, household food insecurity, religion, social support, gender norms, caregiver depression, age, caregiver education, adversity score, and number of children's books) and early-life variables (length-for-age-Z-score) at 18 months, birthweight, maternal baseline depression, household diet, maternal schooling and haemoglobin, socioeconomic status, facility birth, and gender norms. We applied a Bonferroni correction for the 27 comparisons (0.05/27) with threshold of p < 0.00185 as significant. We found strong evidence that cognitive function was lower in CBHF compared to CHU across multiple domains. The KABC-II mental processing index was 45.2 (standard deviation (SD) 10.5) in CBHF and 48.3 (11.3) in CHU (mean difference 3.3 points [95% confidence interval (95% CI) 2.0, 4.5]; p < 0.001). The school achievement test score was 39.0 (SD 26.0) in CBHF and 45.7 (27.8) in CHU (mean difference 7.3 points [95% CI 3.6, 10.9]; p < 0.001); differences remained significant in adjusted analyses. Executive function was reduced but not significantly in adjusted analyses. We found no consistent evidence of differences in growth or physical function outcomes. The main limitation of our study was the restriction to one of two previous study districts, with possible survivor and selection bias. CONCLUSIONS: In this study, we found that CBHF had reductions in cognitive function compared to CHU at 7 years of age across multiple domains. Further research is needed to define the biological and psychosocial mechanisms underlying these differences to inform future interventions that help CBHF thrive across the life-course. TRIAL REGISTRATION: ClinicalTrials.gov The SHINE follow-up study was registered with the Pan-African Clinical Trials Registry (PACTR202201828512110). The original SHINE trial was registered at NCT https://clinicaltrials.gov/study/NCT01824940.

Combining 5-azacitidine with the E-selectin antagonist uproleselan is an effective strategy to augment responses in myelodysplasia and acute myeloid leukaemia.

The interaction of acute myeloid leukaemic (AML) blasts with the bone marrow (BM) microenvironment is a major determinant governing disease progression and resistance to treatment. The constitutive expression of E-selectin in the vascular compartment of BM, a key endothelial cell factor, directly mediates chemoresistance via E-selectin ligand/receptors. Despite the success of hypomethylating agent (HMA)-containing regimens to induce remissions in older AML patients, the development of primary or secondary resistance is common. We report that following treatment with 5-azacitidine, promoter regions regulating the biosynthesis of the E-selectin ligands, sialyl Lewis X, become further hypomethylated. The resultant upregulation of these gene products, in particular α(1,3)-fucosyltransferase VII (FUT7) and α(2,3)-sialyltransferase IV (ST3GAL4), likely causes functional E-selectin binding. When combined with the E-selectin antagonist uproleselan, the adhesion to E-selectin is reversed and the survival of mice transplanted with AML cells is prolonged. Finally, we present clinical evidence showing that BM myeloid cells from higher risk MDS and AML patients have the potential to bind E-selectin, and these cells are more abundant in 5-azacitidine-non-responsive patients. The collective data provide a strong rationale to evaluate 5-azacitidine in combination with the E-selectin antagonist, uproleselan, in this patient population.

The WOPR family protein Ryp1 is a key regulator of gene expression, development, and virulence in the thermally dimorphic fungal pathogen Coccidioides posadasii.

Coccidioides spp. are mammalian fungal pathogens endemic to the Southwestern US and other desert regions of Mexico, Central and South America, with the bulk of US infections occurring in California and Arizona. In the soil, Coccidioides grows in a hyphal form that differentiates into 3-5 micron asexual spores (arthroconidia). When arthroconidia are inhaled by mammals they undergo a unique developmental transition from polar hyphal growth to isotropic expansion with multiple rounds of nuclear division, prior to segmentation, forming large spherules filled with endospores. Very little is understood about the molecular basis of spherule formation. Here we characterize the role of the conserved transcription factor Ryp1 in Coccidioides development. We show that Coccidioides Δryp1 mutants have altered colony morphology under hypha-promoting conditions and are unable to form mature spherules under spherule-promoting conditions. We analyze the transcriptional profile of wild-type and Δryp1 mutant cells under hypha- and spherule-promoting conditions, thereby defining a set of hypha- or spherule-enriched transcripts ("morphology-regulated" genes) that are dependent on Ryp1 for their expression. Forty percent of morphology-regulated expression is Ryp1-dependent, indicating that Ryp1 plays a dual role in both hyphal and spherule development. Ryp1-dependent transcripts include key virulence factors such as SOWgp, which encodes the spherule outer wall glycoprotein. Concordant with its role in spherule development, we find that the Δryp1 mutant is completely avirulent in the mouse model of coccidioidomycosis, indicating that Ryp1-dependent pathways are essential for the ability of Coccidioides to cause disease. Vaccination of C57BL/6 mice with live Δryp1 spores does not provide any protection from lethal C. posadasii intranasal infection, consistent with our findings that the Δryp1 mutant fails to make mature spherules and likely does not express key antigens required for effective vaccination. Taken together, this work identifies the first transcription factor that drives mature spherulation and virulence in Coccidioides.

Proposal for an optimised definition of adverse pathology (unfavourable histology) that predicts metastatic risk in prostatic adenocarcinoma independent of grade group and pathological stage.

AIMS: Histological grading of prostate cancer is a powerful prognostic tool, but current criteria for grade assignment are not fully optimised. Our goal was to develop and test a simplified histological grading model, based heavily on large cribriform/intraductal carcinoma, with optimised sensitivity for predicting metastatic potential. METHODS AND RESULTS: Two separate non-overlapping cohorts were identified: a 419-patient post-radical prostatectomy cohort with long term clinical follow-up and a 209-patient post-radical prostatectomy cohort in which all patients had pathologically confirmed metastatic disease. All prostatectomies were re-reviewed for high-risk histological patterns of carcinoma termed 'unfavourable histology'. Unfavourable histology is defined by any classic Gleason pattern 5 component, any large cribriform morphology (> 0.25 mm) or intraductal carcinoma, complex intraluminal papillary architecture, grade 3 stromogenic carcinoma and complex anastomosing cord-like growth. For the outcome cohort, Kaplan-Meier analysis compared biochemical recurrence, metastasis and death between subjects with favourable and unfavourable histology, stratified by pathological stage and grade group. Multivariable Cox proportional hazards models evaluated adding unfavourable histology to the Memorial Sloan Kettering Cancer Center (MSKCC) post-prostatectomy nomogram and stratification by percentage of unfavourable histology. At 15 years unfavourable histology predicted biochemical recurrence, with sensitivity of 93% and specificity of 88%, metastatic disease at 100 and 48% and death at 100 and 46%. Grade group 2 prostate cancers with unfavourable histology were associated with metastasis independent of pathological stage, while those without had no risk. Histological models for prediction of metastasis based on only large cribriform/intraductal carcinoma or increasing diameter of cribriform size improved specificity, but with lower sensitivity. Multivariable Cox proportional hazards models demonstrated that unfavourable histology significantly improved discriminatory power of the MSKCC post-prostatectomy nomogram for biochemical failure (likelihood ratio test P < 0.001). In the retrospective review of a separate RP cohort in which all patients had confirmed metastatic disease, none had unequivocal favourable histology. CONCLUSIONS: Unfavourable histology at radical prostatectomy is associated with metastatic risk, predicted adverse outcomes better than current grading and staging systems and improved the MSKCC post-prostatectomy nomogram. Most importantly, unfavourable histology stratified grade group 2 prostate cancers into those with and without metastatic potential, independent of stage. While unfavourable histology is driven predominantly by large cribriform/intraductal carcinoma, the recognition and inclusion of other specific architectural patterns add to the sensitivity for predicting metastatic disease. Moreover, a simplified dichotomous model improves communication and could increase implementation.

Distinct plasma lipids predict axonal injury and multiple sclerosis activity.

BACKGROUND: Lipids are of particular interest for the study of neuroinjury and neuroinflammation as structural lipids are major components of myelin, and a variety of lipid species modulate inflammation. In this study, we performed an in-depth lipidomics analysis to identify lipids associated with injury and disease activity. METHODS: Plasma samples were collected from paediatric-onset multiple sclerosis (MS) cases within 4 years of disease onset from 17 sites. The lipidome was measured using untargeted and targeted mass spectrometry. For cross-sectional analyses, the agreement between multiple machine learning models was used to predict neurofilament light chain (NfL) levels. In longitudinal analyses, the association between clinical (relapse count) and imaging (MRI count with ≥1 enhancing or new T2 lesion) outcomes with each metabolite was estimated using adjusted negative binomial regression. RESULTS: At sample collection, 68% of the 435 included individuals were treatment-naive, with a median disease duration of 0.8 years (IQR 0.3-1.7). For longitudinal analyses, 381 and 335 subjects had at least 1 year of clinical and imaging follow-up, respectively. In cross-sectional analyses, NfL chain levels identified structural lipids (phosphatidylcholines and phosphatidylethanolamines) as the highest-performing predictors, including external validation. In contrast, longitudinal analyses found polyunsaturated fatty acids (PUFAs) and their derivatives to be protective from subsequent disease activity (q<0.001, multiple outcomes). CONCLUSION: There are two categories of lipids associated with MS processes. First, structural lipids strongly associated with NfL levels may result from cell lysis secondary to acute inflammation. In contrast, PUFAs, especially ω-3, had a protective effect on subsequent disease activity.

Effects of Different Thawing and Warming Processes on Human Milk Composition.

The composition of human milk is influenced by storage and processing practices. The effects of thawing and warming practices on human milk composition remain poorly studied despite their prevalence in home, research, and donor milk bank settings. This review comprehensively examines the impact of different thawing and warming methods on nutritional and bioactive human milk components. While some components such as carbohydrates and minerals remain stable under most typical thawing and warming conditions, others, such as fat, immune proteins, bacterial and human cells, and peptide amine hormones, are sensitive to warming. This review has identified that the data on the effects of milk thawing and warming is limited and often contradictory. Given that numerous important components of milk are diminished during cold storage, it is important that thawing and warming practices do not lead to further loss of or alterations to beneficial milk components. Further work in this field will facilitate greater standardization of thawing methods among researchers and underpin recommendations for thawing and warming of expressed milk for parents.

From hype to hope: Considerations in conducting robust microbiome science.

Microbiome science has been one of the most exciting and rapidly evolving research fields in the past two decades. Breakthroughs in technologies including DNA sequencing have meant that the trillions of microbes (particularly bacteria) inhabiting human biological niches (particularly the gut) can be profiled and analysed in exquisite detail. This microbiome profiling has profound impacts across many fields of research, especially biomedical science, with implications for how we understand and ultimately treat a wide range of human disorders. However, like many great scientific frontiers in human history, the pioneering nature of microbiome research comes with a multitude of challenges and potential pitfalls. These include the reproducibility and robustness of microbiome science, especially in its applications to human health outcomes. In this article, we address the enormous promise of microbiome science and its many challenges, proposing constructive solutions to enhance the reproducibility and robustness of research in this nascent field. The optimisation of microbiome science spans research design, implementation and analysis, and we discuss specific aspects such as the importance of ecological principals and functionality, challenges with microbiome-modulating therapies and the consideration of confounding, alternative options for microbiome sequencing, and the potential of machine learning and computational science to advance the field. The power of microbiome science promises to revolutionise our understanding of many diseases and provide new approaches to prevention, early diagnosis, and treatment.

Gene-environment interactions: Epstein-Barr virus infection and risk of pediatric-onset multiple sclerosis.

BACKGROUND AND OBJECTIVE: Prior Epstein-Barr virus (EBV) infection is associated with an increased risk of pediatric-onset multiple sclerosis (POMS) and adult-onset multiple sclerosis (MS). It has been challenging to elucidate the biological mechanisms underlying this association. We examined the interactions between candidate human leukocyte antigen (HLA) and non-HLA variants and childhood EBV infection as it may provide mechanistic insights into EBV-associated MS. METHODS: Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. Participants were categorized as seropositive and seronegative for EBV-viral capsid antigen (VCA). The association between prior EBV infection and having POMS was estimated with logistic regression. Interactions between EBV serostatus, major HLA MS risk factors, and non-HLA POMS risk variants associated with response to EBV infection were also evaluated with logistic regression. Models were adjusted for sex, age, genetic ancestry, and the mother's education. Additive interactions were calculated using relative risk due to interaction (RERI) and attributable proportions (APs). RESULTS: A total of 473 POMS cases and 702 controls contributed to the analyses. Anti-VCA seropositivity was significantly higher in POMS cases compared to controls (94.6% vs 60.7%, p < 0.001). There was evidence for additive interaction between childhood EBV infection and the presence of the HLA-DRB1*15 allele (RERI = 10.25, 95% confidence interval (CI) = 3.78 to 16.72; AP = 0.61, 95% CI = 0.47 to 0.75). There was evidence for multiplicative interaction (p < 0.05) between childhood EBV infection and the presence of DRB1*15 alleles (odds ratio (OR) = 3.43, 95% CI = 1.06 to 11.07). Among the pediatric MS variants also associated with EBV infection, we detected evidence for additive interaction (p = 0.02) between prior EBV infection and the presence of the GG genotype in risk variant (rs2255214) within CD86 (AP = 0.30, 95% CI = 0.03 to 0.58). CONCLUSION: We report evidence for interactions between childhood EBV infection and DRB1*15 and the GG genotype of CD86 POMS risk variant. Our results suggest an important role of antigen-presenting cells (APCs) in EBV-associated POMS risk.

Challenges and directions in epilepsy diagnostics and therapeutics: Proceedings of the 17th Epilepsy Therapies and Diagnostics Development conference.

Substantial efforts are underway toward optimizing the diagnosis, monitoring, and treatment of seizures and epilepsy. We describe preclinical programs in place for screening investigational therapeutic candidates in animal models, with particular attention to identifying and eliminating drugs that might paradoxically aggravate seizure burden. After preclinical development, we discuss challenges and solutions in the design and regulatory logistics of clinical trial execution, and efforts to develop disease biomarkers and interventions that may be not only seizure-suppressing, but also disease-modifying. As disease-modifying treatments are designed, there is clear recognition that, although seizures represent one critical therapeutic target, targeting nonseizure outcomes like cognitive development or functional outcomes requires changes to traditional designs. This reflects our increasing understanding that epilepsy is a disease with profound impact on quality of life for the patient and caregivers due to both seizures themselves and other nonseizure factors. This review examines selected key challenges and future directions in epilepsy diagnostics and therapeutics, from drug discovery to translational application.

Current state of the epilepsy drug and device pipeline.

The field of epilepsy has undergone substantial advances as we develop novel drugs and devices. Yet considerable challenges remain in developing broadly effective, well-tolerated treatments, but also precision treatments for rare epilepsies and seizure-monitoring devices. We summarize major recent and ongoing innovations in diagnostic and therapeutic products presented at the seventeenth Epilepsy Therapies & Diagnostics Development (ETDD) conference, which occurred May 31 to June 2, 2023, in Aventura, Florida. Therapeutics under development are targeting genetics, ion channels and other neurotransmitters, and many other potentially first-in-class interventions such as stem cells, glycogen metabolism, cholesterol, the gut microbiome, and novel modalities for delivering electrical neuromodulation.

Phrenic neuropathy etiologies and recovery trajectories in outpatient rehabilitation and neuromuscular medicine clinics: A retrospective analysis.

INTRODUCTION/AIMS: Phrenic neuropathy (PhN) impairs diaphragm muscle function, causing a spectrum of breathing disability. PhN etiologies and their natural history are ill-defined. This knowledge gap hinders informed prognosis and management decisions. This study aims to help fill this knowledge gap on PhN etiologies, outcomes, and recovery patterns, especially in the context of nonsurgical clinical practice. METHODS: This was a retrospective study from two interdisciplinary clinics, physiatry and neurology based. Patients were included if PhN was identified, and other causes of hemi-diaphragm muscle dysfunction excluded. Patients were followed serially at the discretion of the neuromuscular-trained neurologist or physiatrist. Recovery was assessed using pulmonary function tests (PFTs), diaphragm muscle ultrasound (US) thickening ratio, and patient-reported outcomes in patients presenting within 2 years of PhN onset. RESULTS: We identified 151 patients with PhN. The most common etiologies were idiopathic (27%), associated with cardiothoracic procedure (24%), and intensive care unit (17%). Of these patients, 117 (77%) were evaluated within 2 years of PhN onset. Of patients included in outcome analyses, 64% saw improvement on serial US, 50% on serial PFTs and 79% reported symptomatic improvement at an average of 15, 16, and 17 months, respectively. DISCUSSION: A clear majority of PhN patients show improvement in diaphragm muscle function, but on average, improvements took 15-17 months depending on the assessment type. These insights are vital for developing tailored treatments and can guide physicians in prognosis and decision-making, especially if more invasive interventions are being considered.

Polygenic risk score association with multiple sclerosis susceptibility and phenotype in Europeans.

Polygenic inheritance plays a pivotal role in driving multiple sclerosis susceptibility, an inflammatory demyelinating disease of the CNS. We developed polygenic risk scores (PRS) of multiple sclerosis and assessed associations with both disease status and severity in cohorts of European descent. The largest genome-wide association dataset for multiple sclerosis to date (n = 41 505) was leveraged to generate PRS scores, serving as an informative susceptibility marker, tested in two independent datasets, UK Biobank [area under the curve (AUC) = 0.73, 95% confidence interval (CI): 0.72-0.74, P = 6.41 × 10-146] and Kaiser Permanente in Northern California (KPNC, AUC = 0.8, 95% CI: 0.76-0.82, P = 1.5 × 10-53). Individuals within the top 10% of PRS were at higher than 5-fold increased risk in UK Biobank (95% CI: 4.7-6, P = 2.8 × 10-45) and 15-fold higher risk in KPNC (95% CI: 10.4-24, P = 3.7 × 10-11), relative to the median decile. The cumulative absolute risk of developing multiple sclerosis from age 20 onwards was significantly higher in genetically predisposed individuals according to PRS. Furthermore, inclusion of PRS in clinical risk models increased the risk discrimination by 13% to 26% over models based only on conventional risk factors in UK Biobank and KPNC, respectively. Stratifying disease risk by gene sets representative of curated cellular signalling cascades, nominated promising genetic candidate programmes for functional characterization. These pathways include inflammatory signalling mediation, response to viral infection, oxidative damage, RNA polymerase transcription, and epigenetic regulation of gene expression to be among significant contributors to multiple sclerosis susceptibility. This study also indicates that PRS is a useful measure for estimating susceptibility within related individuals in multicase families. We show a significant association of genetic predisposition with thalamic atrophy within 10 years of disease progression in the UCSF-EPIC cohort (P < 0.001), consistent with a partial overlap between the genetics of susceptibility and end-organ tissue injury. Mendelian randomization analysis suggested an effect of multiple sclerosis susceptibility on thalamic volume, which was further indicated to be through horizontal pleiotropy rather than a causal effect. In summary, this study indicates important, replicable associations of PRS with enhanced risk assessment and radiographic outcomes of tissue injury, potentially informing targeted screening and prevention strategies.

Maternal dietary intervention during lactation impacts the maternal faecal and human milk microbiota.

AIMS: To determine the effect of a two-week reduced fat and sugar and increased fibre maternal dietary intervention on the maternal faecal and human milk (HM) microbiomes. METHODS AND RESULTS: Faecal swabs and HM samples were collected from mothers (n = 11) immediately pre-intervention, immediately post-intervention, and 4 and 8 weeks post-intervention, and were analysed using full-length 16S rRNA gene sequencing. Maternal macronutrient intake was assessed at baseline and during the intervention. Maternal fat and sugar intake during the intervention were significantly lower than pre-intervention (P = <0.001, 0.005, respectively). Significant changes in the bacterial composition of maternal faeces were detected after the dietary intervention, with decreases in the relative abundance of Bacteroides caccae (P = <0.001) and increases in the relative abundance of Faecalibacillus intestinalis (P = 0.006). In HM, the diet resulted in a significant increase in Cutibacterium acnes (P = 0.001) and a decrease in Haemophilus parainfluenzae (P = <0.001). The effect of the diet continued after the intervention, with faecal swabs and HM samples taken 4 and 8 weeks after the diet showing significant differences compared to baseline. CONCLUSION: This pilot study demonstrates that short-term changes in maternal diet during lactation can alter the bacterial composition of the maternal faeces and HM.

Body-size shifts in aquatic and terrestrial urban communities.

Body size is intrinsically linked to metabolic rate and life-history traits, and is a crucial determinant of food webs and community dynamics1,2. The increased temperatures associated with the urban-heat-island effect result in increased metabolic costs and are expected to drive shifts to smaller body sizes 3 . Urban environments are, however, also characterized by substantial habitat fragmentation 4 , which favours mobile species. Here, using a replicated, spatially nested sampling design across ten animal taxonomic groups, we show that urban communities generally consist of smaller species. In addition, although we show urban warming for three habitat types and associated reduced community-weighted mean body sizes for four taxa, three taxa display a shift to larger species along the urbanization gradients. Our results show that the general trend towards smaller-sized species is overruled by filtering for larger species when there is positive covariation between size and dispersal, a process that can mitigate the low connectivity of ecological resources in urban settings 5 . We thus demonstrate that the urban-heat-island effect and urban habitat fragmentation are associated with contrasting community-level shifts in body size that critically depend on the association between body size and dispersal. Because body size determines the structure and dynamics of ecological networks 1 , such shifts may affect urban ecosystem function.