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Abstract Background The emergence of COVID-19 precipitated containment policies (e.g., lockdowns, school closures, etc.). These policies disrupted healthcare, potentially eroding gains for Sustainable Development Goals including for neonatal mortality. Our analysis aimed to evaluate indirect effects of COVID-19 containment policies on neonatal admissions and mortality in 67 neonatal units across Kenya, Malawi, Nigeria, and Tanzania between January 2019 and December 2021. Methods The Oxford Stringency Index was applied to quantify COVID-19 policy stringency over time for Kenya, Malawi, Nigeria, and Tanzania. Stringency increased markedly between March and April 2020 for these four countries (although less so in Tanzania), therefore defining the point of interruption. We used March as the primary interruption month, with April for sensitivity analysis. Additional sensitivity analysis excluded data for March and April 2020, modelled the index as a continuous exposure, and examined models for each country. To evaluate changes in neonatal admissions and mortality based on this interruption period, a mixed effects segmented regression was applied. The unit of analysis was the neonatal unit (n = 67), with a total of 266,741 neonatal admissions (January 2019 to December 2021). Results Admission to neonatal units decreased by 15% overall from February to March 2020, with half of the 67 neonatal units showing a decline in admissions. Of the 34 neonatal units with a decline in admissions, 19 (28%) had a significant decrease of ≥ 20%. The month-to-month decrease in admissions was approximately 2% on average from March 2020 to December 2021. Despite the decline in admissions, we found no significant changes in overall inpatient neonatal mortality. The three sensitivity analyses provided consistent findings. Conclusion COVID-19 containment measures had an impact on neonatal admissions, but no significant change in overall inpatient neonatal mortality was detected. Additional qualitative research in these facilities has explored possible reasons. Strengthening healthcare systems to endure unexpected events, such as pandemics, is critical in continuing progress towards achieving Sustainable Development Goals, including reducing neonatal deaths to less than 12 per 1000 live births by 2030.

Abstract Background Service readiness tools are important for assessing hospital capacity to provide quality small and sick newborn care (SSNC). Lack of summary scoring approaches for SSNC service readiness means we are unable to track national targets such as the Every Newborn Action Plan targets. Methods A health facility assessment (HFA) tool was co-designed by Newborn Essential Solutions and Technologies (NEST360) and UNICEF with four African governments. Data were collected in 68 NEST360-implementing neonatal units in Kenya, Malawi, Nigeria, and Tanzania (September 2019-March 2021). Two summary scoring approaches were developed: a) standards-based, including items for SSNC service readiness by health system building block (HSBB), and scored on availability and functionality, and b) level-2 + , scoring items on readiness to provide WHO level-2 + clinical interventions. For each scoring approach, scores were aggregated and summarised as a percentage and equally weighted to obtain an overall score by hospital, HSBB, and clinical intervention. Results Of 1508 HFA items, 1043 (69%) were included in standards-based and 309 (20%) in level-2 + scoring. Sixty-eight neonatal units across four countries had median standards-based scores of 51% [IQR 48–57%] at baseline, with variation by country: 62% [IQR 59–66%] in Kenya, 49% [IQR 46–51%] in Malawi, 50% [IQR 42–58%] in Nigeria, and 55% [IQR 53–62%] in Tanzania. The lowest scoring was family-centred care [27%, IQR 18–40%] with governance highest scoring [76%, IQR 71–82%]. For level-2 + scores, the overall median score was 41% [IQR 35–51%] with variation by country: 50% [IQR 44–53%] in Kenya, 41% [IQR 35–50%] in Malawi, 33% [IQR 27–37%] in Nigeria, and 41% [IQR 32–52%] in Tanzania. Readiness to provide antibiotics by culture report was the highest-scoring intervention [58%, IQR 50–75%] and neonatal encephalopathy management was the lowest-scoring [21%, IQR 8–42%]. In both methods, overall scores were low ( 75%. Discussion Two scoring approaches reveal gaps in SSNC readiness with no neonatal units achieving high scores (> 75%). Government-led quality improvement teams can use these summary scores to identify areas for health systems change. Future analyses could determine which items are most directly linked with quality SSNC and newborn outcomes.

Abstract Background Each year an estimated 2.3 million newborns die in the first 28 days of life. Most of these deaths are preventable, and high-quality neonatal care is fundamental for surviving and thriving. Service readiness is used to assess the capacity of hospitals to provide care, but current health facility assessment (HFA) tools do not fully evaluate inpatient small and sick newborn care (SSNC). Methods Health systems ingredients for SSNC were identified from international guidelines, notably World Health Organization (WHO), and other standards for SSNC. Existing global and national service readiness tools were identified and mapped against this ingredients list. A novel HFA tool was co-designed according to a priori considerations determined by policymakers from four African governments, including that the HFA be completed in one day and assess readiness across the health system. The tool was reviewed by > 150 global experts, and refined and operationalised in 64 hospitals in Kenya, Malawi, Nigeria, and Tanzania between September 2019 and March 2021. Results Eight hundred and sixty-six key health systems ingredients for service readiness for inpatient SSNC were identified and mapped against four global and eight national tools measuring SSNC service readiness. Tools revealed major content gaps particularly for devices and consumables, care guidelines, and facility infrastructure, with a mean of 13.2% (n = 866, range 2.2–34.4%) of ingredients included. Two tools covered 32.7% and 34.4% (n = 866) of ingredients and were used as inputs for the new HFA tool, which included ten modules organised by adapted WHO health system building blocks, including: infrastructure, pharmacy and laboratory, medical devices and supplies, biomedical technician workshop, human resources, information systems, leadership and governance, family-centred care, and infection prevention and control. This HFA tool can be conducted at a hospital by seven assessors in one day and has been used in 64 hospitals in Kenya, Malawi, Nigeria, and Tanzania. Conclusion This HFA tool is available open-access to adapt for use to comprehensively measure service readiness for level-2 SSNC, including respiratory support. The resulting facility-level data enable comparable tracking for Every Newborn Action Plan coverage target four within and between countries, identifying facility and national-level health systems gaps for action.

Abstract Copy number alterations (CNAs) are among the most important genetic events in cancer, but their detection from sequencing data is challenging because of unknown sample purity, tumor ploidy, and general intra-tumor heterogeneity. Here, we present CNAqc, an evolution-inspired method to perform the computational validation of clonal and subclonal CNAs detected from bulk DNA sequencing. CNAqc is validated using single-cell data and simulations, is applied to over 4000 TCGA and PCAWG samples, and is incorporated into the validation process for the clinically accredited bioinformatics pipeline at Genomics England. CNAqc is designed to support automated quality control procedures for tumor somatic data validation.

Background: Several studies have demonstrated that early childhood and adolescent obesity are risk factors for multiple sclerosis (MS) susceptibility. Obesity is thought to share inflammatory components with MS through overproduction of pro-inflammatory adipokines (e.g., leptin) and reduction of anti-inflammatory adipokines (e.g, adiponectin). Recently, drug repurposing (i.e. identifying new indications for existing drugs) has garnered significant attention. The US Food and Drug Administration Adverse Event Reporting System (FAERS) database serves not only as a resource for mining adverse drug reactions and safety signals but also for identifying inverse associations and potential medication repurposing opportunities. Objective: We aimed to explore the association between weight-loss-inducing drugs and MS using real-world reports from the FAERS database. Design: Secondary analysis of existing data from the FAERS database. Methods: We conducted a disproportionality analysis using the FAERS database between the fourth quarter of 2003 and the second quarter of 2023 to explore associations between MS and weight loss-inducing drugs. Disproportionality was quantified using the reporting odds ratio (ROR). An inverse association was defined when the upper limit of the 95% confidence interval for ROR was

Abstract Background Thirty million small and sick newborns worldwide require inpatient care each year. Many receive antibiotics for clinically diagnosed infections without blood cultures, the current ‘gold standard’ for neonatal infection detection. Low neonatal blood culture use hampers appropriate antibiotic use, fuelling antimicrobial resistance (AMR) which threatens newborn survival. This study analysed the gap between blood culture use and antibiotic prescribing in hospitals implementing with Newborn Essential Solutions and Technologies (NEST360) in Kenya, Malawi, Nigeria, and Tanzania. Methods Inpatient data from every newborn admission record (July 2019–August 2022) were included to describe hospital-level blood culture use and antibiotic prescription. Health Facility Assessment data informed performance categorisation of hospitals into four tiers: (Tier 1) no laboratory, (Tier 2) laboratory but no microbiology, (Tier 3) neonatal blood culture use 50%. Results A total of 144,146 newborn records from 61 hospitals were analysed. Mean hospital antibiotic prescription was 70% (range = 25–100%), with 6% mean blood culture use (range = 0–56%). Of the 10,575 blood cultures performed, only 24% (95%CI 23–25) had results, with 10% (10–11) positivity. Overall, 40% (24/61) of hospitals performed no blood cultures for newborns. No hospitals were categorised as Tier 1 because all had laboratories. Of Tier 2 hospitals, 87% (20/23) were District hospitals. Most hospitals could do blood cultures (38/61), yet the majority were categorised as Tier 3 (36/61). Only two hospitals performed > 50% blood cultures for newborns on antibiotics (Tier 4). Conclusions The two Tier 4 hospitals, with higher use of blood cultures for newborns, underline potential for higher blood culture coverage in other similar hospitals. Understanding why these hospitals are positive outliers requires more research into local barriers and enablers to performing blood cultures. Tier 3 facilities are missing opportunities for infection detection, and quality improvement strategies in neonatal units could increase coverage rapidly. Tier 2 facilities could close coverage gaps, but further laboratory strengthening is required. Closing this culture gap is doable and a priority for advancing locally-driven antibiotic stewardship programmes, preventing AMR, and reducing infection-related newborn deaths.

Abstract Background Every Newborn Action Plan (ENAP) coverage target 4 necessitates national scale-up of Level-2 Small and Sick Newborn Care (SSNC) (with Continuous Positive Airway Pressure (CPAP)) in 80% of districts by 2025. Routine neonatal inpatient data is important for improving quality of care, targeting equity gaps, and enabling data-driven decision-making at individual, district, and national-levels. Existing neonatal inpatient datasets vary in purpose, size, definitions, and collection processes. We describe the co-design and operationalisation of a core inpatient dataset for use to track outcomes and improve quality of care for small and sick newborns in high-mortality settings. Methods A three-step systematic framework was used to review, co-design, and operationalise this novel neonatal inpatient dataset in four countries (Malawi, Kenya, Tanzania, and Nigeria) implementing with the Newborn Essential Solutions and Technologies (NEST360) Alliance. Existing global and national datasets were identified, and variables were mapped according to categories. A priori considerations for variable inclusion were determined by clinicians and policymakers from the four African governments by facilitated group discussions. These included prioritising clinical care and newborn outcomes data, a parsimonious variable list, and electronic data entry. The tool was designed and refined by > 40 implementers and policymakers during a multi-stakeholder workshop and online interactions. Results Identified national and international datasets (n = 6) contained a median of 89 (IQR:61–154) variables, with many relating to research-specific initiatives. Maternal antenatal/intrapartum history was the largest variable category (21, 23.3%). The Neonatal Inpatient Dataset (NID) includes 60 core variables organised in six categories: (1) birth details/maternal history; (2) admission details/identifiers; (3) clinical complications/observations; (4) interventions/investigations; (5) discharge outcomes; and (6) diagnosis/cause-of-death. Categories were informed through the mapping process. The NID has been implemented at 69 neonatal units in four African countries and links to a facility-level quality improvement (QI) dashboard used in real-time by facility staff. Conclusion The NEST360 NID is a novel, parsimonious tool for use in routine information systems to inform inpatient SSNC quality. Available on the NEST360/United Nations Children's Fund (UNICEF) Implementation Toolkit for SSNC, this adaptable tool enables facility and country-level comparisons to accelerate progress toward ENAP targets. Additional linked modules could include neonatal at-risk follow-up, retinopathy of prematurity, and Level-3 intensive care.

Abstract Human neonates elicit a profound hypoferremia which may protect against bacterial sepsis. We examined the transience of this hypoferremia by measuring iron and its chaperone proteins, inflammatory and haematological parameters over the first post-partum week. We prospectively studied term, normal weight Gambian newborns. Umbilical cord vein and artery, and serial venous blood samples up to day 7 were collected. Hepcidin, serum iron, transferrin, transferrin saturation, haptoglobin, c-reactive protein, α1-acid-glycoprotein, soluble transferrin receptor, ferritin, unbound iron-binding capacity and full blood count were assayed. In 278 neonates we confirmed the profound early postnatal decrease in serum iron (22.7 ± 7.0 µmol/L at birth to 7.3 ± 4.6 µmol/L during the first 6–24 h after birth) and transferrin saturation (50.2 ± 16.7% to 14.4 ± 6.1%). Both variables increased steadily to reach 16.5 ± 3.9 µmol/L and 36.6 ± 9.2% at day 7. Hepcidin increased rapidly during the first 24 h of life (19.4 ± 14.4 ng/ml to 38.9 ± 23.9 ng/ml) and then dipped (32.7 ± 18.4 ng/ml) before rising again at one week after birth (45.2 ± 19.1 ng/ml). Inflammatory markers increased during the first week of life. The acute postnatal hypoferremia in human neonates on the first day of life is highly reproducible but transient. The rise in serum iron during the first week of life occurs despite very high hepcidin levels indicating partial hepcidin resistance. Trial Registration: clinicaltrials.gov (NCT03353051). Registration date: November 27, 2017.

Abstract Objective Neurodegenerative conditions often manifest radiologically with the appearance of premature aging. Multiple sclerosis (MS) biomarkers related to lesion burden are well developed, but measures of neurodegeneration are less well‐developed. The appearance of premature aging quantified by machine learning applied to structural MRI assesses neurodegenerative pathology. We assess the explanatory and predictive power of “brain age” analysis on disability in MS using a large, real‐world dataset. Methods Brain age analysis is predicated on the over‐estimation of predicted brain age in patients with more advanced pathology. We compared the performance of three brain age algorithms in a large, longitudinal dataset (>13,000 imaging sessions from >6,000 individual MS patients). Effects of MS, MS disease course, disability, lesion burden, and DMT efficacy were assessed using linear mixed effects models. Results MS was associated with advanced predicted brain age cross‐sectionally and accelerated brain aging longitudinally in all techniques. While MS disease course (relapsing vs. progressive) did contribute to advanced brain age, disability was the primary correlate of advanced brain age. We found that advanced brain age at study enrollment predicted more disability accumulation longitudinally. Lastly, a more youthful appearing brain (predicted brain age less than actual age) was associated with decreased disability. Interpretation Brain age is a technically tractable and clinically relevant biomarker of disease pathology that correlates with and predicts increasing disability in MS. Advanced brain age predicts future disability accumulation.

Abstract Background Polymorphisms in ATP2B4 coding for PMCA4b, the primary regulator of erythrocyte calcium concentration, have been shown by GWAS and cross-sectional studies to protect against severe malaria but the mechanism remains unknown. Methods Using a recall-by-genotype design, we investigated the impact of a common haplotype variant in ATP2B4 using in vitro assays that model erythrocyte stage malaria pathogenesis. Ninety-six donors representing homozygotes (carriers of the minor alleles, T/T (variant), heterozygote T/C and wildtype C/C (ancestral)) carriers of the tagging SNP rs1541252 were selected from a cohort of over 12,000 participants in the Keneba Biobank. Results Red blood cells (RBCs) from homozygotes showed reduced PMCA4b protein expression (mean fluorescence intensities (MFI = 2428 ± 124, 3544 ± 159 and 4261 ± 283], for homozygotes, heterozygotes and wildtypes respectively, p

Abstract Objective Multiple sclerosis (MS) is a common demyelinating central nervous system disease. MRI methods that can quantify myelin loss are needed for trials of putative remyelinating agents. Quantitative magnetization transfer MRI introduced the macromolecule proton fraction (MPF), which correlates with myelin concentration. We developed an alternative approach, Simultaneous‐Multi‐Angular‐Relaxometry‐of‐Tissue (SMART) MRI, to generate MPF. Our objective was to test SMART‐derived MPF metric as a potential imaging biomarker of demyelination. Methods Twenty healthy control (HC), 11 relapsing–remitting MS (RRMS), 22 progressive MS (PMS), and one subject with a biopsied tumefactive demyelinating lesion were scanned at 3T using SMART MRI. SMART‐derived MPF metric was determined in normal‐appearing cortical gray matter (NAGM), normal‐appearing subcortical white matter (NAWM), and demyelinating lesions. MPF metric was evaluated for correlations with physical and cognitive test scores. Comparisons were made between HC and MS and between MS subtypes. Furthermore, correlations were determined between MPF and neuropathology in the biopsied person. Results SMART‐derived MPF in NAGM and NAWM were lower in MS than HC (p

Summary: Background: Neurofilament light chain (NfL), a neuronal cytoskeletal protein that is released upon neuroaxonal injury, is associated with multiple sclerosis (MS) relapsing activity and has demonstrated some prognostic ability for future relapse-related disease progression, yet its value in assessing non-relapsing disease progression remains unclear. Methods: We examined baseline and longitudinal blood NfL levels in 1421 persons with relapsing MS (RMS) and 596 persons with primary progressive MS (PPMS) from the pivotal ocrelizumab MS trials. NfL treatment-response and risk for disease worsening (including disability progression into the open-label extension period and slowly expanding lesions [SELs] on brain MRI) at baseline and following treatment with ocrelizumab were evaluated using time-to-event analysis and linear regression models. Findings: In persons from the RMS control arms without acute disease activity and in the entire PPMS control arm, higher baseline NfL was prognostic for greater whole brain and thalamic atrophy, greater volume expansion of SELs, and clinical progression. Ocrelizumab reduced NfL levels vs. controls in persons with RMS and those with PPMS, and abrogated the prognostic value of baseline NfL on disability progression. Following effective suppression of relapse activity by ocrelizumab, NfL levels at weeks 24 and 48 were significantly associated with long-term risk for disability progression, including up to 9 years of observation in RMS and PPMS. Interpretation: Highly elevated NfL from acute MS disease activity may mask a more subtle NfL abnormality that reflects underlying non-relapsing progressive biology. Ocrelizumab significantly reduced NfL levels, consistent with its effects on acute disease activity and disability progression. Persistently elevated NfL levels, observed in a subgroup of persons under ocrelizumab treatment, demonstrate potential clinical utility as a predictive biomarker of increased risk for clinical progression. Suppression of relapsing biology with high-efficacy immunotherapy provides a window into the relationship between NfL levels and future non-relapsing progression. Funding: F. Hoffmann-La Roche Ltd.

Integration of mathematical modeling, ecological analyses of patient biopsies, and neoantigen heterogeneity suggests recruitment of immunosuppressive cells is key to initializing transformation from adenoma to carcinoma in human colorectal cancer.

Abstract Objective To enable use of clinical magnetic resonance images (MRIs) to quantify abnormalities in normal appearing (NA) white matter (WM) and gray matter (GM) in multiple sclerosis (MS) and to determine associations with MS‐related disability. Identification of these abnormalities heretofore has required specialized scans not routinely available in clinical practice. Methods We developed an analytic technique which normalizes image intensities based on an intensity atlas for quantification of WM and GM abnormalities in standardized MRIs obtained with clinical sequences. Gaussian mixture modeling is applied to summarize image intensity distributions from T1‐weighted and 3D‐FLAIR (T2‐weighted) images from 5010 participants enrolled in a multinational database of MS patients which collected imaging, neuroperformance and disability measures. Results Intensity distribution metrics distinguished MS patients from control participants based on normalized non‐lesional signal differences. This analysis revealed non‐lesional differences between relapsing MS versus progressive MS subtypes. Further, the correlation between our non‐lesional measures and disability was approximately three times greater than that between total lesion volume and disability, measured using the patient derived disease steps. Multivariate modeling revealed that measures of extra‐lesional tissue integrity and atrophy contribute uniquely, and approximately equally, to the prediction of MS‐related disability. Interpretation These results support the notion that non‐lesional abnormalities correlate more strongly with MS‐related disability than lesion burden and provide new insight into the basis of abnormalities in NA WM. Non‐lesional abnormalities distinguish relapsing from progressive MS but do not distinguish between progressive subtypes suggesting a common progressive pathophysiology. Image intensity parameters and existing biomarkers each independently correlate with MS‐related disability.

Introduction: Fall-related mortality is increasing among older adults, yet trends and changes in the location of fall-attributed deaths are unknown; additionally, potential disparities are understudied. Methods: To assess trends/factors associated with place of death among older adult fall deaths in the US, a cross-sectional analysis of deaths using mortality data from 2003–2017 was performed. Results: Most deaths occurred in hospitals, however, the proportion decreased from 66.4% ( n = 9,095) to 50.7% ( n = 15,817). The proportion occurring in nursing facilities decreased from 15.9% ( n = 2175) to 15.3% ( n = 4,778), while deaths at home and in hospice facilities increased. Male, Black, Native American, and married decedents had increased odds of hospital death. Conclusion: As fall deaths increase among older adults, end-of-life needs of this population deserve increased attention. Research should explore needs and preferences of older adults who experience falls and their caregivers to reduce disparities in place of death and to ensure high quality of care is received.

ObjectiveThis study aims to confirm the prognostic value of baseline serum neurofilament light chain (sNfL) for on-study disease activity and worsening in patients with relapsing MS (RMS).BackgroundPrevious post-hoc studies suggested that sNfL could be a prognostic biomarker in RMS. In the phase 3 ASCLEPIOS I/II trials in which ofatumumab demonstrated better efficacy outcomes than teriflunomide, treatment with ofatumumab also led to significantly reduced sNfL levels compared to teriflunomide treatment.Design/MethodsIn this study, we report protocol-planned analyses from the pooled ASCLEPIOS I/II trials (N=1882). Per protocol, patients were stratified by median baseline sNfL levels (9.3 pg/ml) into high (>median) and low (≤median) categories to prognosticate: annualized rate of new/enlarging T2 (neT2) lesions in year 1 and 2, annualized relapse rate, annual percentage change in whole brain (WB) and regional brain volume [thalamus, white matter (WM), cortical gray matter (cGM)], and disability outcomes. Similar analyses were performed for the recently diagnosed (within 3 years), treatment-naive patients (no prior disease-modifying therapy) subgroup.ResultsHigh versus low sNfL at baseline was prognostic of increased on-study T2 lesion formation at year 1 (relative increase: ofatumumab +158%; teriflunomide +69%, both p

Background Multiple sclerosis (MS) lesions typically form around a central vein that can be visualized with FLAIR* MRI, creating the central vein sign (CVS) which may reflect lesion pathophysiology. Herein we used gradient echo plural contrast imaging (GEPCI) MRI to simultaneously visualize CVS and measure tissue damage in MS lesions. We examined CVS in relation to tissue integrity in white matter (WM) lesions and among MS subtypes. Objective We aimed to determine if CVS positive lesions were specific to MS subtype, if CVS can be detected consistently among readers using the GEPCI method, and if there were differences in tissue damage in lesions with vs without CVS. Subjects and Methods Thirty relapsing-remitting MS (RRMS) subjects and 38 primary and secondary progressive MS (PMS) subjects were scanned with GEPCI protocol at 3T. GEPCI T2*-SWI images were generated to visualize CVS. Two investigators independently evaluated WM lesions for CVS and measured lesion volumes. To estimate tissue damage severity, total lesion volume, and mean lesion volume, R2t*-based tissue damage score (TDS) of individual lesions and tissue damage load (TDL) were measured for CVS+, CVS-, and confluent lesions. Spearman correlations were made between MRI and clinical data. One-way ANCOVA with age and sex as covariates was used to compare measurements of CVS+ vs CVS- lesions in each individual. Results 398 of 548 lesions meeting inclusion criteria showed CVS. Most patients had ≥40% CVS+ lesions. CVS+ lesions were present in similar proportion among MS subtypes. Interobserver agreement was high for CVS detection. CVS+ and confluent lesions had higher average and total volumes vs CVS- lesions. CVS+ and confluent lesions had more tissue damage than CVS- lesions based on TDL and mean TDS. Conclusion CVS occurred in RRMS and PMS in similar proportions. CVS+ lesions had greater tissue damage and larger size than CVS- lesions.

Abstract A 35‐year‐old man with an enhancing tumefactive brain lesion underwent biopsy, revealing inflammatory demyelination. We used quantitative Gradient‐Recalled‐Echo (qGRE) MRI to visualize and measure tissue damage in the lesion. Two weeks after biopsy, qGRE showed significant R2t* reduction in the left optic radiation and surrounding tissue, consistent with the histopathological and clinical findings. qGRE was repeated 6 and 14 months later, demonstrating partially recovered optic radiation R2t*, in concert with improvement of the hemianopia to ultimately involve only the lower right visual quadrant. These results support qGRE metrics as in vivo biomarkers for tissue damage and longitudinal monitoring of demyelinating disease.

Abstract Objective Multiple sclerosis (MS) lesions are heterogeneous with regard to inflammation, demyelination, axonal injury, and neuronal loss. We previously developed a diffusion basis spectrum imaging (DBSI) technique to better address MS lesion heterogeneity. We hypothesized that the profiles of multiple DBSI metrics can identify lesion‐defining patterns. Here we test this hypothesis by combining a deep learning algorithm using deep neural network (DNN) with DBSI and other imaging methods. Methods Thirty‐eight MS patients were scanned with diffusion‐weighted imaging, magnetization transfer imaging, and standard conventional MRI sequences (cMRI). A total of 499 regions of interest were identified on standard MRI and labeled as persistent black holes (PBH), persistent gray holes (PGH), acute black holes (ABH), acute gray holes (AGH), nonblack or gray holes (NBH), and normal appearing white matter (NAWM). DBSI, diffusion tensor imaging (DTI), and magnetization transfer ratio (MTR) were applied to the 43,261 imaging voxels extracted from these ROIs. The optimized DNN with 10 fully connected hidden layers was trained using the imaging metrics of the lesion subtypes and NAWM. Results Concordance, sensitivity, specificity, and accuracy were determined for the different imaging methods. DBSI‐DNN derived lesion classification achieved 93.4% overall concordance with predetermined lesion types, compared with 80.2% for DTI‐DNN model, 78.3% for MTR‐DNN model, and 74.2% for cMRI‐DNN model. DBSI‐DNN also produced the highest specificity, sensitivity, and accuracy. Conclusions DBSI‐DNN improves the classification of different MS lesion subtypes, which could aid clinical decision making. The efficacy and efficiency of DBSI‐DNN shows great promise for clinical applications in automatic MS lesion detection and classification.

Summary: Background: Multiple sclerosis (MS) has a complex genetic, immune and metabolic pathophysiology. Recent studies implicated the gut microbiome in MS pathogenesis. However, interactions between the microbiome and host immune system, metabolism and diet have not been studied over time in this disorder. Methods: We performed a six-month longitudinal multi-omics study of 49 participants (24 untreated relapse remitting MS patients and 25 age, sex, race matched healthy control individuals. Gut microbiome composition and function were characterized using 16S and metagenomic shotgun sequencing. Flow cytometry was used to characterize blood immune cell populations and cytokine profiles. Circulating metabolites were profiled by untargeted UPLC-MS. A four-day food diary was recorded to capture the habitual dietary pattern of study participants. Findings: Together with changes in blood immune cells, metagenomic analysis identified a number of gut microbiota decreased in MS patients compared to healthy controls, and microbiota positively or negatively correlated with degree of disability in MS patients. MS patients demonstrated perturbations of their blood metabolome, such as linoleate metabolic pathway, fatty acid biosynthesis, chalcone, dihydrochalcone, 4-nitrocatechol and methionine. Global correlations between multi-omics demonstrated a disrupted immune-microbiome relationship and a positive blood metabolome-microbiome correlation in MS. Specific feature association analysis identified a potential correlation network linking meat servings with decreased gut microbe B. thetaiotaomicron, increased Th17 cell and greater abundance of meat-associated blood metabolites. The microbiome and metabolome profiles remained stable over six months in MS and control individuals. Interpretation: Our study identified multi-system alterations in gut microbiota, immune and blood metabolome of MS patients at global and individual feature level. Multi-OMICS data integration deciphered a potential important biological network that links meat intakes with increased meat-associated blood metabolite, decreased polysaccharides digesting bacteria, and increased circulating proinflammatory marker. Funding: This work was supported by the Washington University in St. Louis Institute of Clinical and Translational Sciences, funded, in part, by Grant Number # UL1 TR000448 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award (Zhou Y, Piccio, L, Lovett-Racke A and Tarr PI); R01 NS10263304 (Zhou Y, Piccio L); the Leon and Harriet Felman Fund for Human MS Research (Piccio L and Cross AH). Cantoni C. was supported by the National MS Society Career Transition Fellowship (TA-180531003) and by donations from Whitelaw Terry, Jr. / Valerie Terry Fund. Ghezzi L. was supported by the Italian Multiple Sclerosis Society research fellowship (FISM 2018/B/1) and the National Multiple Sclerosis Society Post-Doctoral Fellowship (FG-190734474). Anne Cross was supported by The Manny & Rosalyn Rosenthal-Dr. John L. Trotter MS Center Chair in Neuroimmunology of the Barnes-Jewish Hospital Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Background: The mycobiome is the fungal component of the gut microbiome and is implicated in several autoimmune diseases. However, its role in MS has not been studied. Methods: In this case-control observational study, we performed ITS sequencing and characterised the gut mycobiome in people with MS (pwMS) and healthy controls at baseline and after six months. Findings: The mycobiome had significantly higher alpha diversity and inter-subject variation in pwMS than controls. Saccharomyces and Aspergillus were over-represented in pwMS. Saccharomyces was positively correlated with circulating basophils and negatively correlated with regulatory B cells, while Aspergillus was positively correlated with activated CD16+ dendritic cells in pwMS. Different mycobiome profiles, defined as mycotypes, were associated with different bacterial microbiome and immune cell subsets in the blood. Initial treatment with dimethyl fumarate, a common immunomodulatory therapy which also has fungicidal activity, did not cause uniform gut mycobiome changes across all pwMS. Interpretation: There is an alteration of the gut mycobiome in pwMS, compared to healthy controls. Further study is required to assess any causal association of the mycobiome with MS and its direct or indirect interactions with bacteria and autoimmunity. Funding: This work was supported by the Washington University in St. Louis Institute of Clinical and Translational Sciences, funded, in part, by Grant Number # UL1 TR000448 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award (Zhou Y, Piccio, L, Lovett-Racke A and Tarr PI); R01 NS102633-04 (Zhou Y, Piccio L); the Leon and Harriet Felman Fund for Human MS Research (Piccio L and Cross AH). Cantoni C. was supported by the National MS Society Career Transition Fellowship (TA-1805-31003) and by donations from Whitelaw Terry, Jr. / Valerie Terry Fund. Ghezzi L. was supported by the Italian Multiple Sclerosis Society research fellowship (FISM 2018/B/1) and the National Multiple Sclerosis Society Post-Doctoral Fellowship (FG- 1907-34474). Anne Cross was supported by The Manny & Rosalyn Rosenthal-Dr. John L. Trotter MS Center Chair in Neuroimmunology of the Barnes-Jewish Hospital Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Abstract Diffusion basis spectrum imaging (DBSI) combines discrete anisotropic diffusion tensors and the spectrum of isotropic diffusion tensors to model the underlying multiple sclerosis (MS) pathologies. We used clinical MS subtypes as a surrogate of underlying pathologies to assess DBSI as a biomarker of pathology in 55 individuals with MS. Restricted isotropic fraction (reflecting cellularity) and fiber fraction (representing apparent axonal density) were the most important DBSI metrics to classify MS using brain white matter lesions. These DBSI metrics outperformed lesion volume. When analyzing the normal‐appearing corpus callosum, the most significant DBSI metrics were fiber fraction, radial diffusivity (reflecting myelination), and nonrestricted isotropic fraction (representing edema). This study provides preliminary evidence supporting the ability of DBSI as a potential noninvasive biomarker of MS neuropathology.

Despite its many benefits, hospice care is underused for patients with heart failure. This paper discusses the factors contributing to this underuse and offers recommendations to optimise use for patients with heart failure and proposes metrics to optimise quality of hospice care for this patient group.

Ketogenic diet therapies (KDT) are high-fat, low carbohydrate diets used as an effective treatment option for drug-resistant epilepsy. There is limited research on the efficacy of KDT for super-refractory status epilepticus (SRSE). We systematically review evidence for use of KDT in children with SRSE and present a single UK tertiary centre's experience. Thirty one articles were included, of which 24 were “medium” or “low” quality. One hundred and forty seven children with SRSE started KDT, of which 141 (96%) achieved ketosis. KDT was started mean 5.3 days (range 1–420) after status epilepticus (SE) started. SRSE resolved in 85/141 (60%) children after mean 6.3 days (range 0–19) post SE onset, but it is unclear whether further treatments were initiated post-KDT. 13/141 (9%) children died. Response to KDT was more likely when initiated earlier (p = 0.03) and in females (p = 0.01). Adverse side effects were reported in 48/141 (34%), mostly gastrointestinal; potentially serious adverse effects occurred in ≤4%. Eight children with SRSE, all diagnosed with febrile infection-related epilepsy syndrome, were treated with KDT at Great Ormond Street Hospital for Children. KDT was initiated enterally at mean day 13.6+/− 5.1 of admission. Seven of 8 (88%) children reported adverse side effects, which were potentially serious in 4/8 (50%), including metabolic acidosis, hypoglycaemia and raised amylase. SE ceased in 6/8 (75%) children after mean 25+/− 9.4 days post onset, but other treatments were often started concomitantly and all children started other treatments post-KDT. Two of 8 (25%) children died during admission and another died post-admission. Four of the remaining 5 children continue to have drug-resistant seizures, one of whom remains on KDT; seizure burden was unknown for one child. Our findings indicate that KDT is possible and safe in children with SRSE. Cessation of SRSE may occur in almost two-thirds of children initiated with KDT, but a causal effect is difficult to determine due to concomitant treatments, treatments started post-KDT and the variable length of time post-KDT onset when SRSE cessation occurs. Given that serious adverse side effects seem rare and response rates are (cautiously) favorable, KDT should be considered as an early treatment option in this group.

Variants in the LIM homeobox transcription factor 1-beta (LMX1B) gene predispose individuals to elevated intraocular pressure (IOP), a key risk factor for glaucoma. However, the effect of LMX1B mutations varies widely between individuals. To better understand the mechanisms underlying LMX1B-related phenotypes and individual differences, we backcrossed the Lmx1bV265D (also known as Lmx1bIcst) allele onto the C57BL/6J (B6), 129/Sj (129), C3A/BLiA-Pde6b+/J (C3H) and DBA/2J-Gpnmb+ (D2-G) mouse strain backgrounds. Strain background had a significant effect on the onset and severity of ocular phenotypes in Lmx1bV265D/+ mutant mice. Mice of the B6 background were the most susceptible to developing abnormal IOP distribution, severe anterior segment developmental anomalies (including malformed eccentric pupils, iridocorneal strands and corneal abnormalities) and glaucomatous nerve damage. By contrast, Lmx1bV265D mice of the 129 background were the most resistant to developing anterior segment abnormalities, had less severe IOP elevation than B6 mutants at young ages and showed no detectable nerve damage. To identify genetic modifiers of susceptibility to Lmx1bV265D-induced glaucoma-associated phenotypes, we performed a mapping cross between mice of the B6 (susceptible) and 129 (resistant) backgrounds. We identified a modifier locus on Chromosome 18, with the 129 allele(s) substantially lessening severity of ocular phenotypes, as confirmed by congenic analysis. By demonstrating a clear effect of genetic background in modulating Lmx1b-induced phenotypes, providing a panel of strains with different phenotypic severities and identifying a modifier locus, this study lays a foundation for better understanding the roles of LMX1B in glaucoma with the goal of developing new treatments.

Several clinical trials have demonstrated the efficacy of lytic therapies targeting B cells in the treatment of relapsing multiple sclerosis (MS). More modest efficacy has been noted in the primary progressive subtype of MS. Clinical success has increased interest in the role of B cells in the pathogenesis of MS and in ways to potentially improve upon current B cell therapies. In this mini review, we will critically review previous and ongoing clinical trials of anti-CD20 monoclonal antibodies in MS, including rituximab, ocrelizumab, ofatumumab, and ublituximab. Side effects and adverse event profiles will be discussed. Studies examining the proposed mechanisms of action of B cell depleting therapies will also be reviewed.

Optic neuritis is a frequent first symptom of multiple sclerosis (MS) for which corticosteroids are a widely employed treatment option. The Optic Neuritis Treatment Trial (ONTT) reported that corticosteroid treatment does not improve long-term visual acuity, although the evolution of underlying pathologies is unclear. In this study, we employed non-invasive diffusion basis spectrum imaging (DBSI)-derived fiber volume to quantify 11% axonal loss 2 months after corticosteroid treatment (vs. baseline) in experimental autoimmune encephalomyelitis mouse optic nerves affected by optic neuritis. Longitudinal DBSI was performed at baseline (before immunization), after a 2-week corticosteroid treatment period, and 1 and 2 months after treatment, followed by histological validation of neuropathology. Pathological metrics employed to assess the optic nerve revealed axonal protection and anti-inflammatory effects of dexamethasone treatment that were transient. Two months after treatment, axonal injury and loss were indistinguishable between PBS- and dexamethasone-treated optic nerves, similar to results of the human ONTT. Our findings in mice further support that corticosteroid treatment alone is not sufficient to prevent eventual axonal loss in ON, and strongly support the potential of DBSI as an in vivo imaging outcome measure to assess optic nerve pathology.

Objective: To prospectively determine whether diffusion basis spectrum imaging (DBSI) detects, differentiates and quantitates coexisting inflammation, demyelination, axonal injury and axon loss in mice with optic neuritis (ON) due to experimental autoimmune encephalomyelitis (EAE), and to determine if DBSI accurately measures effects of fingolimod on underlying pathology. Methods: EAE was induced in 7-week-old C57BL/6 female mice. Visual acuity (VA) was assessed daily to detect onset of ON after which daily oral-treatment with either fingolimod (1 mg/kg) or saline was given for ten weeks. In vivo DBSI scans of optic nerves were performed at baseline, 2-, 6- and 10-weeks post treatment. DBSI-derived metrics including restricted isotropic diffusion tensor fraction (putatively reflecting cellularity), non-restricted isotropic diffusion tensor fraction (putatively reflecting vasogenic edema), DBSI-derived axonal volume, axial diffusivity, λ∥ (putatively reflecting axonal integrity), and increased radial diffusivity, λ⊥ (putatively reflecting demyelination). Mice were killed immediately after the last DBSI scan for immunohistochemical assessment. Results: Optic nerves of fingolimod-treated mice exhibited significantly better (p 0.05) from the baseline values in fingolimod-treated mice. Transient DBSI-λ∥ decrease and DBSI-λ⊥ increase were detected during Fingolimod treatment. DBSI-derived metrics assessed in vivo significantly correlated (p

The precise control of eye size is essential for normal vision. TMEM98 is a highly conserved and widely expressed gene which appears to be involved in eye size regulation. Mutations in human TMEM98 are found in patients with nanophthalmos (very small eyes) and variants near the gene are associated in population studies with myopia and increased eye size. As complete loss of function mutations in mouse Tmem98 result in perinatal lethality, we produced mice deficient for Tmem98 in the retinal pigment epithelium (RPE), where Tmem98 is highly expressed. These mice have greatly enlarged eyes that are very fragile with very thin retinas, compressed choroid and thin sclera. To gain insight into the mechanism of action we used a proximity labelling approach to discover interacting proteins and identified MYRF as an interacting partner. Mutations of MYRF are also associated with nanophthalmos. The protein is an endoplasmic reticulum-tethered transcription factor which undergoes autoproteolytic cleavage to liberate the N-terminal part which then translocates to the nucleus where it acts as a transcription factor. We find that TMEM98 inhibits the self-cleavage of MYRF, in a novel regulatory mechanism. In RPE lacking TMEM98, MYRF is ectopically activated and abnormally localised to the nuclei. Our findings highlight the importance of the interplay between TMEM98 and MYRF in determining the size of the eye.

Background: Neonates, particularly those born preterm (PTB) and with low birthweight (LBW), are especially susceptible to bacterial and fungal infections that cause an estimated 225,000 deaths annually. Iron is a vital nutrient for the most common organisms causing septicaemia. Full-term babies elicit an immediate postnatal hypoferremia assumed to have evolved as an innate defence. We tested whether PTB and LBW babies are capable of the same response. Methods: We conducted an observational study of 152 babies who were either PTB (born ≥32 to

A high proportion of HIV-positive patients in South Africa receive concomitant efavirenz (EFV) and isoniazid (INH) therapy. EFV is metabolised in the liver via CYP2B6, and genetic polymorphism of CYP2B6 is known to result in slowed metabolism of the drug. INH is also metabolised in the liver, causing inhibition of a pathway that plays an important role in slow EFV metabolisers. Concomitant INH use therefore affects plasma levels of EFV. EFV is well known to cause neuropsychiatric side-effects on initiation, and a recent adult case series described late-onset neurotoxicity in the form of subacute ataxia and encephalopathy in patients treated with EFV for a median of 2 years, in association with toxic plasma levels of the drug. We have seen an increase in cases of EFV toxicity presenting to our neurology referral unit. All cases have been in the context of recent initiation of concomitant INH. We therefore conducted a retrospective case record audit to describe these seven cases with the additional advantage of tertiary-level assessment. We outline the clinical features and investigation results, as well as outcomes after EFV was stopped. Our main objectives are to highlight the probable role of concomitant INH use in the development of this syndrome, and to suggest that only limited work-up may be warranted in suspected cases.

Abstract Background Magnetic resonance imaging markers have been widely used to detect and quantify white matter pathologies in multiple sclerosis. We have recently developed a diffusion basis spectrum imaging (DBSI) to distinguish and quantify co-existing axonal injury, demyelination, and inflammation in multiple sclerosis patients and animal models. It could serve as a longitudinal marker for axonal loss, a primary cause of permanent neurological impairments and disease progression. Methods Eight 10-week-old female C57BL/6 mice underwent optic nerve DBSI, followed by a week-long recuperation prior to active immunization for experimental autoimmune encephalomyelitis (EAE). Visual acuity of all mice was assessed daily. Longitudinal DBSI was performed in mouse optic nerves at baseline (naïve, before immunization), before, during, and after the onset of optic neuritis. Tissues were perfusion fixed after final in vivo scans. The correlation between DBSI detected pathologies and corresponding immunohistochemistry markers was quantitatively assessed. Results In this cohort of EAE mice, monocular vision impairment occurred in all animals. In vivo DBSI detected, differentiated, and quantified optic nerve inflammation, demyelination, and axonal injury/loss, correlating nerve pathologies with visual acuity at different time points of acute optic neuritis. DBSI quantified, in the presence of optic nerve swelling, ~15% axonal loss at the onset of optic neuritis in EAE mice. Conclusions Our findings support the notion that axonal loss could occur early in EAE mice. DBSI detected pathologies in the posterior visual pathway unreachable by optical coherence tomography and without confounding inflammation induced optic nerve swelling. DBSI could thus decipher the interrelationship among various pathological components and the role each plays in disease progression. Quantification of the rate of axonal loss could potentially serve as the biomarker to predict treatment outcome and to determine when progressive disease starts.

Summary: Background: WHO recommends daily iron supplementation for pregnant women, but adherence is poor because of side-effects, effectiveness is low, and there are concerns about possible harm. The iron-regulatory hormone hepcidin can signal when an individual is ready-and-safe to receive iron. We tested whether a hepcidin-guided screen-and-treat approach to combat iron-deficiency anaemia could achieve equivalent efficacy to universal administration, but with lower exposure to iron. Methods: We did a three-arm, randomised, double-blind, non-inferiority trial in 19 rural communities in the Jarra West and Kiang East districts of The Gambia. Eligible participants were pregnant women aged 18–45 years at between 14 weeks and 22 weeks of gestation. We randomly allocated women to either WHO's recommended regimen (ie, a daily UN University, UNICEF, and WHO international multiple-micronutrient preparation [UNIMMAP] containing 60 mg iron), a 60 mg screen-and-treat approach (ie, daily UNIMMAP containing 60 mg iron for 7 days if weekly hepcidin was

Background: Neonatal infection is the third largest cause of death in children under five worldwide. Nutritional immunity is the process by which the host innate immune system limits nutrient availability to invading organisms. Iron is an essential micronutrient for both microbial pathogens and their mammalian hosts. Changes in iron availability and distribution have significant effects on pathogen virulence and on the immune response to infection. Our previously published data shows that, during the first 24 hours of life, full-term neonates have reduced overall serum iron. Transferrin saturation decreases rapidly from 45% in cord blood to ~20% by six hours post-delivery. Methods: To study neonatal nutritional immunity and its role in neonatal susceptibility to infection, we will conduct an observational study on 300 full-term normal birth weight (FTB+NBW), 50 preterm normal birth weight (PTB+NBW), 50 preterm low birth weight (PTB+LBW) and 50 full-term low birth weight (FTB+LBW), vaginally-delivered neonates born at Kanifing General Hospital, The Gambia. We will characterize and quantify iron-related nutritional immunity during the early neonatal period and use ex vivo sentinel bacterial growth assays to assess how differences in serum iron affect bacterial growth. Blood samples will be collected from the umbilical cord (arterial and venous) and at serial time points from the neonates over the first week of life. Discussion: Currently, little is known about nutritional immunity in neonates. In this study, we will increase understanding of how nutritional immunity may protect neonates from infection during the first critical days of life by limiting the pathogenicity and virulence of neonatal sepsis causing organisms by reducing the availability of iron. Additionally, we will investigate the hypothesis that this protective mechanism may not be activated in preterm and low birth weight neonates, potentially putting these babies at an enhanced risk of neonatal infection. Trial registration: clinicaltrials.gov (NCT03353051) 27/11/2017

Background: Neonatal infection is the third largest cause of death in children under five worldwide. Nutritional immunity is the process by which the host innate immune system limits nutrient availability to invading organisms. Iron is an essential micronutrient for both microbial pathogens and their mammalian hosts. Changes in iron availability and distribution have significant effects on pathogen virulence and on the immune response to infection. Our previously published data shows that, during the first 24 hours of life, full-term neonates have reduced overall serum iron. Transferrin saturation decreases rapidly from 45% in cord blood to ~20% by six hours post-delivery. Methods: To study neonatal nutritional immunity and its role in neonatal susceptibility to infection, we will conduct an observational study on 300 full-term normal birth weight (FTB+NBW), 50 preterm normal birth weight (PTB+NBW), 50 preterm low birth weight (PTB+LBW) and 50 full-term low birth weight (FTB+LBW), vaginally-delivered neonates born at Kanifing General Hospital, The Gambia. We will characterize and quantify iron-related nutritional immunity during the early neonatal period and use ex vivo sentinel bacterial growth assays to assess how differences in serum iron affect bacterial growth. Blood samples will be collected from the umbilical cord (arterial and venous) and at serial time points from the neonates over the first week of life. Discussion: Currently, little is known about nutritional immunity in neonates. In this study, we will increase understanding of how nutritional immunity may protect neonates from infection during the first critical days of life by limiting the pathogenicity and virulence of neonatal sepsis causing organisms by reducing the availability of iron. Additionally, we will investigate the hypothesis that this protective mechanism may not be activated in preterm and low birth weight neonates, potentially putting these babies at an enhanced risk of neonatal infection. Trial registration: clinicaltrials.gov (NCT03353051) 27/11/2017

Isocitrate dehydrogenase (IDH) is an enzyme required for the production of α-ketoglutarate from isocitrate. IDH3 generates the NADH used in the mitochondria for ATP production, and is a tetramer made up of two α, one β and one γ subunit. Loss-of-function and missense mutations in both IDH3A and IDH3B have previously been implicated in families exhibiting retinal degeneration. Using mouse models, we investigated the role of IDH3 in retinal disease and mitochondrial function. We identified mice with late-onset retinal degeneration in a screen of ageing mice carrying an ENU-induced mutation, E229K, in Idh3a. Mice homozygous for this mutation exhibit signs of retinal stress, indicated by GFAP staining, as early as 3 months, but no other tissues appear to be affected. We produced a knockout of Idh3a and found that homozygous mice do not survive past early embryogenesis. Idh3a−/E229K compound heterozygous mutants exhibit a more severe retinal degeneration compared with Idh3aE229K/E229K homozygous mutants. Analysis of mitochondrial function in mutant cell lines highlighted a reduction in mitochondrial maximal respiration and reserve capacity levels in both Idh3aE229K/E229K and Idh3a−/E229K cells. Loss-of-function Idh3b mutants do not exhibit the same retinal degeneration phenotype, with no signs of retinal stress or reduction in mitochondrial respiration. It has previously been reported that the retina operates with a limited mitochondrial reserve capacity and we suggest that this, in combination with the reduced reserve capacity in mutants, explains the degenerative phenotype observed in Idh3a mutant mice. This article has an associated First Person interview with the first author of the paper.

Random mutagenesis can uncover novel genes involved in phenotypic traits. Here the authors perform a large-scale phenotypic screen on over 100 mouse strains generated by ENU mutagenesis to identify mice with age-related diseases, which they attribute to specific mutations revealed by whole-genome sequencing.

Dietary interventions have not been effective in the treatment of multiple sclerosis (MS). Here, we show that periodic 3-day cycles of a fasting mimicking diet (FMD) are effective in ameliorating demyelination and symptoms in a murine experimental autoimmune encephalomyelitis (EAE) model. The FMD reduced clinical severity in all mice and completely reversed symptoms in 20% of animals. These improvements were associated with increased corticosterone levels and regulatory T (Treg) cell numbers and reduced levels of pro-inflammatory cytokines, TH1 and TH17 cells, and antigen-presenting cells (APCs). Moreover, the FMD promoted oligodendrocyte precursor cell regeneration and remyelination in axons in both EAE and cuprizone MS models, supporting its effects on both suppression of autoimmunity and remyelination. We also report preliminary data suggesting that an FMD or a chronic ketogenic diet are safe, feasible, and potentially effective in the treatment of relapsing-remitting multiple sclerosis (RRMS) patients (NCT01538355).

Mitogen-activated protein kinase, MAP3K1, plays an important role in a number of cellular processes, including epithelial migration during eye organogenesis. In addition, studies in keratinocytes indicate that MAP3K1 signalling through JNK is important for actin stress fibre formation and cell migration. However, MAP3K1 can also act independently of JNK in the regulation of cell proliferation and apoptosis. We have identified a mouse mutant, goya, which exhibits the eyes-open-at-birth and microphthalmia phenotypes. In addition, these mice also have hearing loss. The goya mice carry a splice site mutation in the Map3k1 gene. We show that goya and kinase-deficient Map3k1 homozygotes initially develop supernumerary cochlear outer hair cells (OHCs) that subsequently degenerate, and a progressive profound hearing loss is observed by 9 weeks of age. Heterozygote mice also develop supernumerary OHCs, but no cellular degeneration or hearing loss is observed. MAP3K1 is expressed in a number of inner-ear cell types, including outer and inner hair cells, stria vascularis and spiral ganglion. Investigation of targets downstream of MAP3K1 identified an increase in p38 phosphorylation (Thr180/Tyr182) in multiple cochlear tissues. We also show that the extra OHCs do not arise from aberrant control of proliferation via p27KIP1. The identification of the goya mutant reveals a signalling molecule involved with hair-cell development and survival. Mammalian hair cells do not have the ability to regenerate after damage, which can lead to irreversible sensorineural hearing loss. Given the observed goya phenotype, and the many diverse cellular processes that MAP3K1 is known to act upon, further investigation of this model might help to elaborate upon the mechanisms underlying sensory hair cell specification, and pathways important for their survival. In addition, MAP3K1 is revealed as a new candidate gene for human sensorineural hearing loss.

Cortical gray matter (GM) damage is now widely recognized in multiple sclerosis (MS). The standard MRI does not reliably detect cortical GM lesions, although cortical volume loss can be measured. In this study, we demonstrate that the gradient echo MRI can reliably and quantitatively assess cortical GM damage in MS patients using standard clinical scanners. High resolution multi-gradient echo MRI was used for regional mapping of tissue-specific MRI signal transverse relaxation rate values (R2*) in 10 each relapsing–remitting, primary-progressive and secondary-progressive MS subjects. A voxel spread function method was used to correct artifacts induced by background field gradients. R2* values from healthy controls (HCs) of varying ages were obtained to establish baseline data and calculate ΔR2* values – age-adjusted differences between MS patients and HC. Thickness of cortical regions was also measured in all subjects. In cortical regions, ΔR2* values of MS patients were also adjusted for changes in cortical thickness. Symbol digit modalities (SDMT) and paced auditory serial addition (PASAT) neurocognitive tests, as well as Expanded Disability Status Score, 25-foot timed walk and nine-hole peg test results were also obtained on all MS subjects. We found that ΔR2* values were lower in multiple cortical GM and normal appearing white matter (NAWM) regions in MS compared with HC. ΔR2* values of global cortical GM and several specific cortical regions showed significant (p