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Context An important aspect of end-of-life care, place of death is understudied in advanced chronic (CKD) and end-stage kidney disease (ESKD). Objective We sought to examine trends and factors associated with where advanced CKD/ESKD patients die. Methods We conducted a retrospective cross-sectional study using mortality data from 2003 to 2017 for deaths attributed primarily to advanced CKD/ESKD in the United States. Results Between 2003 and 2017, 222,247 deaths were attributed to advanced CKD/ESKD. From 2003 to 2017, deaths occurring in hospitals declined from 56.0% (n = 5356) to 35.6% (n = 7764), whereas increases occurred in deaths at home (13.5% [n = 1292] to 24.3% [n = 5306]), nursing facilities (18.6% [n = 1776] to 19.3% [n = 4221]), and hospice facilities (0.3% [n = 29] to 13.4% [n = 2917]). Nonwhite race was associated with increased odds of hospital death (Black [OR = 1.59; 95% CI = 1.55, 1.62]; Native American [OR = 1.47; 95% CI = 1.32, 1.63]; Asian [OR = 1.43; 95% CI = 1.32, 1.55] and reduced odds of nursing facility (Black [OR = 0.622; 95% CI = 0.600, 0.645]; Native American [OR = 0.638; 95% CI = 0.572, 0.712]; Asian [OR = 0.574; 95% CI = 0.533, 0.619], or hospice facility death (Black [OR = 0.843; 95% CI = 0.773, 0.918]; Native American [OR = 0.380; 95% CI = 0.289, 0.500]; Asian [OR = 0.609; 95% CI = 0.502, 0.739]). Older age was associated with reduced odds of hospital death (≥85 [OR = 0.334; 95% CI = 0.312, 0.358]) and increased odds of home (≥85 [OR = 1.55; 95% CI = 1.43, 1.68]), nursing facility (≥85 [OR = 3.09; 95% CI = 2.76, 3.45]) or hospice facility death (≥85 [OR = 1.60; 95% CI = 1.49, 1.72]). Conclusions Hospitals remain the most common place of death from advanced CKD/ESKD; however, the proportion of home, nursing facility, and hospice facility deaths have increased.

ObjectiveTo identify and characterize myeloid cell populations within the CSF of patients with MS and anti-myelin oligodendrocyte glycoprotein (MOG) disorder by high-resolution single-cell gene expression analysis.MethodsSingle-cell RNA sequencing (scRNA-seq) was used to profile individual cells of CSF and blood from 2 subjects with relapsing-remitting MS (RRMS) and one with anti-MOG disorder. Publicly available scRNA-seq data from the blood and CSF of 2 subjects with HIV were also analyzed. An informatics pipeline was used to cluster cell populations by transcriptomic profiling. Based on gene expression by CSF myeloid cells, a flow cytometry panel was devised to examine myeloid cell populations from the CSF of 11 additional subjects, including individuals with RRMS, anti-MOG disorder, and control subjects without inflammatory demyelination.ResultsCommon myeloid populations were identified within the CSF of subjects with RRMS, anti-MOG disorder, and HIV. These included monocytes, conventional and plasmacytoid dendritic cells, and cells with a transcriptomic signature matching microglia. Microglia could be discriminated from other myeloid cell populations in the CSF by flow cytometry.ConclusionsHigh-resolution single-cell gene expression analysis clearly distinguishes distinct myeloid cell types present within the CSF of subjects with neuroinflammation. A population of microglia exists within the human CSF, which is detectable by surface protein expression. The function of these cells during immunity and disease requires further investigation.

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

The use of immunomodulatory and immunosuppressive therapies in multiple sclerosis (MS) has allowed practitioners to regulate MS disease activity, with the caveat that these potent medications may render patients susceptible to opportunistic infections. The approval of fingolimod presented the first oral option for relapsing MS. Since 2015, postmarketing safety data have documented several published cases of cryptococcal meningitis and disseminated cryptococcosis associated with fingolimod use. However, surveillance mechanisms for opportunistic infections and management of active demyelinating disease with ongoing infection have not been adequately addressed. We present a case of isolated pulmonary cryptococcosis with the use of fingolimod to highlight the hurdles in balancing efficacious disease-modifying therapies for MS while treating an opportunistic infection associated with that therapy.

Summary Background Health care-associated infections (HCAI) in neonatal units in low- and middle-income countries (LMIC) are a major cause of mortality. This scoping review aimed to synthesise published literature on infection prevention and care bundles addressing neonatal HCAI in LMICs and to construct a Classification Framework for their components (elements). Methods Five electronic databases were searched between January 2001 and July 2020. A mixed-methods approach was applied: qualitative content analysis was used to build a classification framework to categorise bundle elements and the contents of the classification groups were then described quantitatively. Findings 3619 records were screened, with 44 eligible studies identified. The bundle element Classification Framework created involved: (1) Primary prevention, (2) Detection, (3) Case management, and Implementation (3 + I). The 44 studies included 56 care bundles with 295 elements that were then classified. Primary prevention elements (128, 43%) predominated of which 71 (55%) focused on central line catheters and mechanical ventilators. Only 12 elements (4%) were related to detection. A further 75 (25%) elements addressed case management and 66 (88%) of these aimed at outbreak control. Interpretation The 3 + I Classification Framework was a feasible approach to reporting and synthesising research for infection-relevant bundled interventions in neonatal units. A shift towards the use in infection prevention and care bundles of primary prevention elements focused on the neonate and on commonly used hospital devices in LMIC (e.g., self-inflating bags, suctioning equipment) would be valuable to reduce HCAI transmission. Detection elements were a major gap. Funding This work was made possible in part by the John D. and Catherine T. MacArthur Foundation, the Bill & Melinda Gates Foundation, ELMA Philanthropies, The Children's Investment Fund Foundation UK, The Lemelson Foundation, and the Ting Tsung and Wei Fong Chao Foundation under agreements to William Marsh Rice University. The project leading to these results has also received the support of a fellowship from the “la Caixa” Foundation (ID 100010434). The fellowship code is LCF/BQ/EU19/11710040. EJAF is an Academic Clinical Fellow whose salary is funded by the UK National Institute for Health Research (NIHR). NES receives a Research Training Program Scholarship (Australian Commonwealth Government).

Misdiagnosis of multiple sclerosis (MS) (the incorrect assignment of a diagnosis of MS) remains a problem in contemporary clinical practice. Studies indicate that misdiagnosed patients are often exposed to prolonged unnecessary health care risks and morbidity. The recently published 2017 revision of the McDonald criteria for the diagnosis of MS provides an opportunity to consider the effect of these revisions on the problem of MS misdiagnosis. The 2017 McDonald criteria include several new recommendations to reduce potential for misdiagnoses. The criteria should be used for the types of patients in which validation studies were performed, specifically those patients who present with typical demyelinating syndromes. MRI lesion characteristics were defined for which McDonald criteria would be expected to perform with accuracy. However, 2017 revisions, which now include assessment for cortical lesions, and the inclusion of symptomatic lesions and positive oligoclonal bands for the fulfillment of diagnostic criteria, may have the potential to lead to misdiagnosis of MS if not applied appropriately. While the 2017 McDonald criteria integrate issues relating to MS misdiagnosis and incorporate specific recommendations for its prevention more prominently than prior criteria, the interpretation of clinical and radiologic assessments upon which these criteria depend will continue to allow misdiagnoses. In patients with atypical clinical presentations, the revised McDonald criteria may not be readily applied. In those situations, further evaluation or monitoring rather than immediate diagnosis of MS is prudent.

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., Author summary Having the correct eye size is important, too large and you will be short-sighted and too small and you will be far-sighted. Nanophthalmos, literally very small eye from the Greek, is a condition where the eye is very small but structurally normal. In addition to being farsighted such eyes are prone to glaucoma which can lead to loss of vision. Here we studied a protein called TMEM98 which is found in the membranes of the cells which form a layer at the back of eye called the retinal pigment epithelium (RPE). Mutations in TMEM98 have been found in nanophthalmos patients. Patients have one normal copy of the gene and one carrying a mutation. We removed Tmem98 from the RPE of mice in order to ascertain its function. We found, surprisingly, that rather than having small eyes this led to the development of very large eyes that were structurally fragile. We went on to identify protein partners of TMEM98 and found that it interacts with a protein called MYRF, mutations in which also cause nanophthalmos. This work demonstrates the importance of TMEM98 in eye size specification.

BACKGROUND Multiple sclerosis (MS) is a chronic disease affecting the human central nervous system (CNS) and leading to neurologic disability. Although conventional MRI techniques can readily detect focal white matter (WM) lesions, it remains challenging to quantify tissue damage in normal-appearing gray matter (GM) and WM. PURPOSE To demonstrate that a new MRI biomarker, R2t*, can provide quantitative analysis of tissue damage across the brain in MS patients in a single scan. STUDY TYPE Prospective. SUBJECTS Forty-four MS patients and 19 healthy controls (HC). FIELD STRENGTH/SEQUENCE 3T, quantitative gradient-recalled-echo (qGRE), Magnetization-prepared rapid gradient-echo, fluid-attenuated inversion recovery. ASSESSMENT Severity of tissue damage was assessed by reduced R2t*. Tissue atrophy was assessed by cortical thickness and cervical spinal cord cross-sectional area (CSA). Multiple Sclerosis Functional Composite was used for clinical assessment. RESULTS R2t* in cortical GM was more sensitive to MS damage than cortical atrophy. Using more than two standard deviations (SD) reduction versus age-matched HC as the cutoff, 48% of MS patients showed lower R2t*, versus only 9% with lower cortical thickness. Significant correlations between severities of tissue injury were identified among 1) upper cervical cord and several cortical regions, including motor cortex (P

Bits are a common and invasive piece of equipment used in equestrian sports. A bit should be carefully chosen to suit the individual horse according to the pressure points it is willing to accept. Bit pressure is poorly understood due to a lack of accessible research instruments. The objective of this study was to describe a method to estimate pressure points from the bit on the tongue without the need for radiographs. The method uses photographic images of horses under static rein tension. Using design features on the bit, the angle at which these features press into the tongue were calculated. Ten riding school horses wearing a snaffle bridle without a noseband, were used to measure the degree to which a bit rotates under 2 kg of static rein tension for a Turtle Top snaffle bit, French Link snaffle bit, Herm Sprenger single-jointed snaffle bit, and ported Weymouth bit. Six dressage and eventing horses were used to measure the effect of rein tension, in 0.5 kg increments, on the degree of rotation of the bit. The bit rotated, but not significantly ( P > .008), over the rein tensions used (up to 2 kg). The reliability of the proposed method was confirmed by comparing anatomical reference lines in photographs with those in radiographs. The findings provide a reliable estimate to determine pressure points from a bit on the tongue, under rein tension without the need for invasive techniques and in the absence of technologically adequate equipment.

Diffusion basis spectrum imaging (DBSI) models diffusion-weighted magnetic resonance imaging (MRI) signals as a combination of discrete anisotropic diffusion tensors and a spectrum of isotropic diffusion tensors. Here, we report the histopathological correlates of DBSI in the biopsied brain tissue of a patient with an inflammatory demyelinating lesion typical of multiple sclerosis (MS). Increased radial diffusivity (marker of demyelination), decreased fiber fraction (apparent axonal density), elevated nonrestricted isotropic fraction (marker of vasogenic edema), but unchanged axial diffusivity (marker of integrity of residual axons) seen in the lesion appeared consistent with histopathological findings of inflammatory demyelination with relative axonal sparing. Our report supports the application of DBSI as a biomarker in human studies of MS.

Background Improved imaging methods are critical to assess neurodegeneration and remyelination in multiple sclerosis. Chronic hypointensities observed on T1-weighted brain MRI, "persistent black holes," reflect severe focal tissue damage. Present measures consist of determining persistent black holes numbers and volumes, but do not quantitate severity of individual lesions. Objective Develop a method to differentiate black and gray holes and estimate the severity of individual multiple sclerosis lesions using standard magnetic resonance imaging. Methods 38 multiple sclerosis patients contributed images. Intensities of lesions on T1-weighted scans were assessed relative to cerebrospinal fluid intensity using commercial software. Magnetization transfer imaging, diffusion tensor imaging and clinical testing were performed to assess associations with T1w intensity-based measures. Results Intensity-based assessments of T1w hypointensities were reproducible and achieved > 90% concordance with expert rater determinations of "black" and "gray" holes. Intensity ratio values correlated with magnetization transfer ratios (R = 0.473) and diffusion tensor imaging metrics (R values ranging from 0.283 to −0.531) that have been associated with demyelination and axon loss. Intensity ratio values incorporated into T1w hypointensity volumes correlated with clinical measures of cognition. Conclusions This method of determining the degree of hypointensity within multiple sclerosis lesions can add information to conventional imaging.

Background and ObjectiveTo describe the impact of coronavirus disease 2019 (COVID-19) on people with neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD).MethodsThe COVID-19 Infections in Multiple Sclerosis (MS) and Related Diseases (COViMS) Registry collected data on North American patients with MS and related diseases with laboratory-positive or highly suspected SARS-CoV-2 infection. Deidentified data were entered into a web-based registry by health care providers. Data were analyzed using t-tests, Pearson χ2 tests, or Fisher exact tests for categorical variables. Univariate logistic regression models examined effects of risk factors and COVID-19 clinical severity.ResultsAs of June 7, 2021, 77 patients with NMOSD and 20 patients with MOGAD were reported in the COViMS Registry. Most patients with NMOSD were laboratory positive for SARS-CoV-2 and taking rituximab at the time of COVID-19 diagnosis. Most patients with NMOSD were not hospitalized (64.9% [95% CI: 53.2%–75.5%]), whereas 15.6% (95% CI: 8.3%–25.6%) were hospitalized only, 9.1% (95% CI: 3.7%–17.8%) were admitted to the ICU and/or ventilated, and 10.4% (95% CI: 4.6%–19.5%) died. In patients with NMOSD, having a comorbidity was the sole factor identified for poorer COVID-19 outcome (OR = 6.0, 95% CI: 1.79–19.98). Most patients with MOGAD were laboratory positive for SARS-CoV-2, and almost half were taking rituximab. Among patients with MOGAD, 75.0% were not hospitalized, and no deaths were recorded; no factors were different between those not hospitalized and those hospitalized, admitted to the ICU, or ventilated.DiscussionAmong the reported patients with NMOSD, a high mortality rate was observed, and the presence of comorbid conditions was associated with worse COVID-19 outcome. There were no deaths reported in the patients with MOGAD, although these observations are limited due to small sample size.

Importance Emergence of SARS-CoV-2 causing COVID-19 prompted the need to gather information on clinical outcomes and risk factors associated with morbidity and mortality in patients with multiple sclerosis (MS) and concomitant SARS-CoV-2 infections. Objective To examine outcomes and risk factors associated with COVID-19 clinical severity in a large, diverse cohort of North American patients with MS. Design, Setting, and Participants This analysis used deidentified, cross-sectional data on patients with MS and SARS-CoV-2 infection reported by health care professionals in North American academic and community practices between April 1, 2020, and December 12, 2020, in the COVID-19 Infections in MS Registry. Health care professionals were asked to report patients after a minimum of 7 days from initial symptom onset and after sufficient time had passed to observe the COVID-19 disease course through resolution of acute illness or death. Data collection began April 1, 2020, and is ongoing. Exposures Laboratory-positive SARS-CoV-2 infection or highly suspected COVID-19. Main Outcomes and Measures Clinical outcome with 4 levels of increasing severity: not hospitalized, hospitalization only, admission to the intensive care unit and/or required ventilator support, and death. Results Of 1626 patients, most had laboratory-positive SARS-CoV-2 infection (1345 [82.7%]), were female (1202 [74.0%]), and had relapsing-remitting MS (1255 [80.4%]). A total of 996 patients (61.5%) were non-Hispanic White, 337 (20.8%) were Black, and 190 (11.7%) were Hispanic/Latinx. The mean (SD) age was 47.7 (13.2) years, and 797 (49.5%) had 1 or more comorbidity. The overall mortality rate was 3.3% (95% CI, 2.5%-4.3%). Ambulatory disability and older age were each independently associated with increased odds of all clinical severity levels compared with those not hospitalized after adjusting for other risk factors (nonambulatory: hospitalization only, odds ratio [OR], 2.8 [95% CI, 1.6-4.8]; intensive care unit/required ventilator support, OR, 3.5 [95% CI, 1.6-7.8]; death, OR, 25.4 [95% CI, 9.3-69.1]; age [every 10 years]: hospitalization only, OR, 1.3 [95% CI, 1.1-1.6]; intensive care unit/required ventilator support, OR, 1.3 [95% CI, 0.99-1.7]; death, OR, 1.8 [95% CI, 1.2-2.6]). Conclusions and Relevance In this registry-based cross-sectional study, increased disability was independently associated with worse clinical severity including death from COVID-19. Other risk factors for worse outcomes included older age, Black race, cardiovascular comorbidities, and recent treatment with corticosteroids. Knowledge of these risk factors may improve the treatment of patients with MS and COVID-19 by helping clinicians identify patients requiring more intense monitoring or COVID-19 treatment.

Background: The Expanded Disability Status Scale (EDSS) is the standard measure of disability in multiple sclerosis clinical trials. The EDSS has limited application in the clinical setting due to required completion time and scoring complexity. Systematically recording an objective, simplified, less time-intensive, and neurologist-derived disability score would be beneficial for patient care. Objective: To develop and validate a streamlined version of the Expanded Disability Status Scale (sEDSS) for clinical monitoring. Methods: The EDSS was modified by eliminating maneuvers with no impact on function, consolidating redundancies, and simplifying scoring. This sEDSS was refined and preliminarily validated using a pilot cohort of 102 patients. Subsequently, the sEDSS was retrospectively validated using 968 patients from the CombiRx trial. We evaluated correlation and agreement between each functional system as well as the overall sEDSS and EDSS. Results: The sEDSS correlated strongly with the EDSS, both overall (Spearman’s rho = 0.93) and for each functional system (Spearman’s rho 0.65–0.97). Correlation was slightly lower for functional systems where scoring was modified for consolidation and simplification. Conclusion: The sEDSS had strong agreement and correlation with the existing EDSS and can provide a useful measure of disability in clinical practice.

Background: Dimethyl fumarate (DMF) is used to treat relapsing multiple sclerosis and causes lymphopenia in a subpopulation of treated individuals. Much remains to be learned about how the drug affects B- and T-lymphocytes. Objectives: To characterize changes in B- and T-cell phenotype and function induced by DMF and to investigate whether low absolute lymphocyte count (ALC) is associated with unique functional changes. Methods: Peripheral blood mononuclear cells (PBMCs) were collected from DMF-treated patients, untreated patients, and healthy controls. A subset of DMF-treated patients was lymphopenic (ALC Results: DMF reduced circulating memory B-cells regardless of ALC. Follicular T-helper cells (CD4+ CXCR5+) and mucosal invariant T-cells (CD8+ CD161+) were also reduced. DMF reduced T-cell production of pro-inflammatory cytokines in response to polyclonal (PMA/ionomycin) and viral peptide stimulation, regardless of ALC. No differences in activation-induced cell death or circulating progenitors were observed between lymphopenic and non-lymphopenic DMF-treated patients. Conclusion: These data implicate DMF-induced changes in lymphocytes as an important component of the drug’s efficacy and expand our understanding of the functional significance of DMF-induced lymphopenia.

We describe a novel imaging method to assess central nervous system pathology called “Diffusion Basis Spectrum Imaging” (DBSI). Diffusion tensor imaging (DTI) has been widely used to estimate axonpathology and demyelination. However, in the settings of acute inflammation and chronic tissue loss asare common in multiple sclerosis, DTI signals can lead to false interpretations. DBSI is a computationallynovel method that separates isotropic from anisotropic components in imaging voxels. Isotropicdiffusion is believed to reflect inflammatory components (cells, edema), as well as intrinsic cells andextracellular space. DBSI enables the measurement of axial and radial diffusivities within the anisotropiccomponents of imaging voxels, which reflect the integrity of axon fibers and myelin, respectively.

Changes in Where Americans Die Between 2003 and 2017, there were nearly 35.2 million natural deaths in the United States. This analysis shows that home has surpassed the hospital as the most common...

Although chronic lung disease is a common cause of mortality, little is known about where individuals with chronic lung disease die.The aim of this study was to determine the trends and factors associated with place of death among individuals with chronic lung disease.This cross-sectional analysis of natural deaths was conducted by using the Centers for Disease Control and Prevention Wide-ranging OnLine Data for Epidemiologic Research from 2003 to 2017 for which COPD, interstitial lung disease (ILD), or cystic fibrosis (CF) was the underlying cause. Place of death was categorized as hospital, home, nursing facility, hospice facility, and other.From 2003 to 2017, more than 2.2. million deaths were primarily attributed to chronic lung disease (51.6% female, 92.4% white). Most were attributed to COPD (88.9%), followed by ILD (10.8.%), and CF (0.3%). Hospital and nursing facility deaths declined from 44.4% (n = 59,470) and 22.6% (n = 30,285) to 28.3% (n = 49,655) and 19.7% (n = 34,495), while home and hospice facility deaths increased from 23.3% (n = 31,296) and 0.1% (n = 192) to 34.7% (n = 60,851) and 9.0% (n = 15,861), respectively. Male sex, being married, and having some college education were associated with increased odds of home death, whereas non-white race and Hispanic ethnicity were associated with increased odds of hospital death. Compared with individuals with COPD, individuals with ILD and CF had increased odds of hospital death and reduced odds of home, nursing facility, or hospice facility death.Home deaths are rising among decedents from chronic lung disease, increasing the need for quality end-of-life care in this setting. Further research should explore the end-of-life needs and preferences of these patients and their caregivers, with particular attention paid to patients with ILD and CF who continue to have high rates of hospital death.

BackgroundDiagnosing MS through magnetic resonance imaging (MRI) requires extensive clinical experience and tedious work. Furthermore, MRI-indicated MS lesion locations rarely align with the patients’ symptoms and often contradict with pathology studies. Our lab has developed and modified a novel diffusion basis spectrum imaging (DBSI) technique to address the shortcomings of MRI-based MS diagnoses. Although primary DBSI metrics have been demonstrated to be associated with axonal injury/loss, demyelination and inflammation, a more detailed analysis using multiple DBSI-structural metrics to improve the accuracy of MS lesion detection and differentiation is still needed. Here we report that Diffusion Histology Imaging (DHI), an improved approach that combines a deep neural network (DNN) algorithm with improved DBSI analyses, accurately detected and classified various MS lesion types.MethodsThirty-eight multiple sclerosis patients were scanned with T2-weighted imaging (T2WI) using fluid attenuated inversion recovery (FLAIR), T1-weighted imaging (T1WI) using magnetization-prepared rapid acquisition with gradient echo (MPRAGE), magnetization transfer contrast (MTR) imaging and diffusion-weighted imaging. The imaging results identified 43,261 voxels from 91 persistent black hole (PBH) lesions, 89 persistent gray hole (PGH) lesions, 16 acute gray hole (AGH) lesions, 189 non-black hole (NBH) lesions and 113 normal-appearing white matter (NAWM) areas. Data extracted from these lesions were randomly split into training, validation, and testing groups with an 8:1:1 ratio. The DNN was constructed with 10 fully-connected hidden layers using TensorFlow 2.0 in Python. Batch normalization and dropout regularization were used for model optimization.ResultsEach MS lesion type had unique DBSI derived diffusion metric profiles. Based on these DBSI diffusion metric profiles, DHI achieved a 93.6% overall concordance with neurologist determinations of all five MS lesions, compared with 74.3% from conventional MRI (cMRI)-DNN model, 78.2% from MTR-DNN model, and 80% from DTI-DNN model. DHI also achieved greater performances on detecting individual MS lesion types compared to other models. Specifically, DHI showed great performances on prediction of PBH (AUC: 0.991; F1-score: 0.923), PGH (AUC: 0.977; F1-score: 0.823) and AGH (AUC: 0.987; F1-score: 0.887), which significantly outperformed other models.ConclusionsDHI significantly improves the detection and classification accuracy for various MS lesion types, which could greatly aid the clinical decisions of neurologists and neuroradiologists. The efficacy and efficiency of this DNN model shows great promise for clinical application.

Background: Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune demyelinating disease. Its pathogenesis involves humoral and cellular immunity, with production of pro- and anti-inflammatory cytokines by T cells. Objective: To analyze the cytokine profile of cerebrospinal fluid (CSF) T cells in patients with relapsing-remitting MS (RRMS) and non-inflammatory controls. Methods: T cell cytokine production was analyzed by flow cytometry in CSF samples collected from 34 untreated RRMS patients and 20 age-matched controls. Immunofluorescence studies were performed in spinal cord MS active lesions. Results: Percentages of CSF-derived IL-17A, IL-17A/IL-22, and IL-17A/GM-CSF producing T cells were significantly higher in RRMS patients compared to controls. Percentages of T cells producing IFN-γ were lower in RRMS patients compared to controls. Patients in relapse showed higher percentages of CD4+ T cells producing IL-13 and GM-CSF compared to patients in remission. We found a positive correlation between percentages of IL-13+ T cells and the Expanded Disability Status Scale (EDSS; ρ = 0.5; p Conclusion: We observed differences in IL-17, IL-22, and IFN-γ production by CSF T cells in RRMS versus controls and a positive correlation between IL-13-producing T cells and EDSS in RRMS patients.

ObjectiveTo use diffusion basis spectrum imaging (DBSI) to assess how damage to normal-appearing white matter (NAWM) in the corpus callosum (CC) influences neurologic impairment in people with MS (pwMS).MethodsUsing standard MRI, the primary pathologies in MS of axonal injury/loss, demyelination, and inflammation are not differentiated well. DBSI has been shown in animal models, phantoms, and in biopsied and autopsied human CNS tissues to distinguish these pathologies. Fifty-five pwMS (22 relapsing-remitting, 17 primary progressive, and 16 secondary progressive) and 13 healthy subjects underwent DBSI analyses of NAWM of the CC, the main WM tract connecting the cerebral hemispheres. Tract-based spatial statistics were used to minimize misalignment. Results were correlated with scores from a battery of clinical tests focused on deficits typical of MS.ResultsNormal-appearing CC in pwMS showed reduced fiber fraction and increased nonrestricted isotropic fraction, with the most extensive abnormalities in secondary progressive MS (SPMS). Reduced DBSI-derived fiber fraction and increased DBSI-derived nonrestricted isotropic fraction of the CC correlated with worse cognitive scores in pwMS. Increased nonrestricted isotropic fraction in the body of the CC correlated with impaired hand function in the SPMS cohort.ConclusionsDBSI fiber fraction and nonrestricted isotropic fraction were the most useful markers of injury in the NAWM CC. These 2 DBSI measures reflect axon loss in animal models. Because of its ability to reveal axonal loss, as well as demyelination, DBSI may be a useful outcome measure for trials of CNS reparative treatments.

The UN Sustainable Development Goals include reduction in premature mortality from non-communicable disease and training of the healthcare workforce. Peer-supported workshop-based training is a proven effective training tool. The PET (Paediatric Epilepsy Training – BPNA/ILAE) programmes have recently expanded across five continents aiming to educate clinical professionals in the recognition, investigation and management of childhood epilepsy. A one-day standardised curriculum promotes evidence-based, safe practice which is delivered by a trained faculty to a target audience, primarily paediatricians and specialist nurses. A pragmatic framework was used to measure the effectiveness of these courses. Data were recorded on attendance, reaction to the course delivery, knowledge gain and changes in practice six months after the course. 6781 clinicians attended a PET Level 1 course over the last 15 years. 29% then 59% of participants scored the course as ‘excellent’ before and after its 2015 revision. Level of seniority and experience did not affect participants’ positive reaction (R2=0.05). Knowledge scores pre and post course increased from 76% to 90%, with incorrect answers identifying areas of clarification subsequently implemented in course material revision. Self-reported changes in practice six months following the course by the 323 participants who responded from India, Kenya, Myanmar, New Zealand, South Africa, Sudan and the UK included 66% reporting significant or moderate changes to their personal practice in epilepsy care. In 2017, specific reported improvements included improved history-taking (82%), ability to distinguish epileptic and non-epileptic events (85%), no longer prescribing anti-epileptic drugs for febrile seizures (42%) and improved prolonged seizure management (54%). A clear trend to greater reported improvements from low and middle-income country settings was seen. In Sudan, 26% had developed a dedicated epilepsy clinic since the course. This international survey included medication and diagnostic resource availability. Intravenous lorazepam was available to only 52% across all sites, emphasising the need for region-specific guidelines of prolonged seizures. Only 51% of respondents from India had access to video EEG and 15% to an epilepsy specialist nurse. These pilot data provide evidence for the effectiveness of short-course epilepsy education for clinicians to improve the quality of care for children with epilepsy globally.

Palliative care improves patient and family outcomes and may reduce the cost of care, but this service is underutilized among Medicare beneficiaries.To describe enrollment patterns and outcomes associated with the Center for Medicare and Medicaid Innovation expansion of a multisetting community palliative care program in North and South Carolina.This observational study characterizes the Center for Medicare and Medicaid Innovation cohort's care and cost trajectories after enrollment. Program participants were age-eligible Medicare fee-for-service beneficiaries living in Western North Carolina and South Carolina who enrolled in a palliative care program from September 1, 2014, to August 31, 2017. End-of-life costs were compared between enrolled and nonenrolled decedents. Program administrative data and 100% Medicare claims data were used.A total of 5243 Medicare beneficiaries enrolled in the program from community (19%), facility (21%), small hospital (27%), or large hospital (33%) settings. Changes in Medicare expenditures in the 30 days after enrollment varied by setting. Adjusted odds of hospice use were 60% higher (OR = 1.60; CI = 1.47, 1.75) for enrolled decedents relative to nonenrolled decedents. Participants discharged to hospice vs. participants not had 17% (OR = 0.83 CI = 0.72, 0.94) lower costs. Among enrolled decedents those enrolled for at least 30 days vs.30 days had 42% (OR = 0.58, CI = 0.49, 0.69) lower costs in the last 30 days of life.Expansion of community palliative care programs into multiple enrollment settings is feasible. It may improve hospice utilization among enrollees. Heterogeneous program participation by program setting pose challenges to a standardizing reimbursement policy.

PURPOSEWe previously found a dominant mutation,Rwhs, causing white spots on the retina accompanied by retinal folds. Here we identify the mutant gene to beTmem98.In humans, mutations in the orthologous gene cause nanophthalmos. We modelled these mutations in mice and characterised the mutant eye phenotypes of these andRwhs.METHODSTheRwhsmutation was identified to be a missense mutation inTmem98by genetic mapping and sequencing. The humanTMEM98nanophthalmos missense mutations were made in the mouse gene by CRISPR-Cas9. Eyes were examined by indirect ophthalmoscopy and the retinas imaged using a retinal camera. Electroretinography was used to study retinal function. Histology, immunohistochemistry and electron microscopy techniques were used to study adult eyes.RESULTSAn I135T mutation ofTmem98causes the dominantRwhsphenotype and is perinatally lethal when homozygous. Two dominant missense mutations ofTMEM98, A193P and H196P are associated with human nanophthalmos. In the mouse these mutations cause recessive retinal defects similar to theRwhsphenotype, either alone or in combination with each other, but do not cause nanophthalmos. The retinal folds did not affect retinal function as assessed by electroretinography. Within the folds there was accumulation of disorganised outer segment material as demonstrated by immunohistochemistry and electron microscopy, and macrophages had infiltrated into these regions.CONCLUSIONSMutations in the mouse orthologue of the human nanophthalmos geneTMEM98do not result in small eyes. Rather, there is localised disruption of the laminar structure of the photoreceptors.

Background: Iron deficiency is the most prevalent nutritional deficiency worldwide. WHO recommends daily iron supplementation for all pregnant women where anaemia exceeds 40%, but adherence is limited by side-effects, effectiveness is low, and there are concerns around possible harm. The iron-regulatory hormone, hepcidin, signals 'ready-and-safe' to receive iron. We tested a hepcidin-guided screen-and-treat (S&T) approach to combat iron deficiency anaemia (IDA) aimed at achieving equivalent efficacy to universal administration but at lower levels of supplemental iron exposure. Methods: We conducted a 3-arm randomised-controlled double-blind trial in rural Gambia to assess non-inferiority of two ST b) daily UNIMMAP containing 60mg iron for 7d if weekly hepcidin was

Determining the genetic bases of age-related disease remains a major challenge requiring a spectrum of approaches from human and clinical genetics to the utilization of model organism studies. Here we report a large-scale genetic screen in mice employing a phenotype-driven discovery platform to identify mutations resulting in age-related disease, both late-onset and progressive. We have utilized N-ethyl-N-nitrosourea mutagenesis to generate pedigrees of mutagenized mice that were subject to recurrent screens for mutant phenotypes as the mice aged. In total, we identify 105 distinct mutant lines from 157 pedigrees analysed, out of which 27 are late-onset phenotypes across a range of physiological systems. Using whole-genome sequencing we uncover the underlying genes for 44 of these mutant phenotypes, including 12 late-onset phenotypes. These genes reveal a number of novel pathways involved with age-related disease. We illustrate our findings by the recovery and characterization of a novel mouse model of age-related hearing loss., 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.

Summary 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).

PURPOSE Accurate measurement of tissue-specific relaxation parameters is an ultimate goal of quantitative MRI. The objective of this study is to introduce a new technique, simultaneous multiangular relaxometry of tissue with MRI (SMART MRI), which provides naturally coregistered quantitative spin density, longitudinal and transverse relaxation rate constant maps along with parameters characterizing magnetization transfer (MT) effects. THEORY AND METHODS SMART MRI is based on a gradient-recalled echo MRI sequence with multiple flip angles and multiple gradient echoes and a derived theoretical expression for the MR signal generated in this experimental conditions. The theory, based on Bloch-McConnell equations, takes into consideration cross-relaxation between two water pools: "free" and "bound" to macromolecules. It describes the role of cross-relaxation effects in formation of longitudinal and transverse relaxation of "free" water signal, thus providing background for measurements of these effects without using MT pulses. Bayesian analysis is used to optimize SMART MRI sequence parameters. RESULTS Data obtained on three participants demonstrate feasibility of the proposed approach. CONCLUSION SMART MRI provides quantitative measurements of longitudinal and transverse relaxation rate constants of "free" water signal affected by cross-relaxation effects. It also provides information on some essential MT parameters without requiring off-resonance MT pulses. Magn Reson Med 77:1296-1306, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Background Antibodies to myelin oligodendrocyte glycoprotein (MOG) are associated with a CNS inflammatory disorder distinct from multiple sclerosis (MS) and aquaporin-4 antibody-positive neuromyelitis optica (NMO). Knowledge of the clinical spectrum of MOG antibody disease (MOGAD) remains incomplete, particularly in comparison to two related inflammatory demyelinating diseases, MS and NMO. Objective Compare demographics, clinical characteristics, estimated disability, laboratory results, and treatment responses of a U.S. MOGAD cohort with age- and sex-matched MS and NMO patients. Design, setting, and participants This observational, case-control, single-center study identified each group via ICD-10 diagnosis code searches through the electronic medical records of adult patients seen at the John L. Trotter MS Center between January 1, 2019 and January 1, 2020. MOGAD and NMO patients were confirmed to have at least one positive antibody test; those in the MS group had a confirmed diagnosis by a physician with MS subspecialty training. Data were collected after IRB approval. Results Twenty-six patients were included in each group. MOGAD patients were predominantly Caucasian (88.5%) with mean onset age of 43.9 years. MOGAD patients had no comorbid other autoimmune diseases and comparatively lower rates of family members with autoimmune disease (20.0%) than either MS (40.0%) or NMO (34.6%) matched cohorts. 91% of MOGAD attacks were monofocal, and over 70% presented with optic neuritis. Severity of MOGAD attacks was similar to that of seropositive NMO, but the robust degree of recovery was more similar to MS. Four MOGAD patients converted to negative antibody status, with no attacks occurring after conversion. Serum ANA and ENA were less frequently elevated in MOGAD (21.7%, 5.0%) than in seropositive NMO patients (66.7%, 42.9%). Elevated IgG synthesis rate and positive CSF-restricted oligoclonal bands were not seen in our MOGAD cohort, and only one MOGAD patient had an elevated IgG index. Despite anti-CD20 therapy, 28.6% of MOGAD patients continued to suffer relapses. Conclusions MOGAD was characterized by a predominantly monofocal presentation (typically optic neuritis) and severe attacks with better recovery than seen with seropositive NMO attacks. Lack of CSF-restricted oligoclonal bands distinguished MOGAD from MS.

Neonates regulate iron at birth and in early postnatal life. We reviewed literature from PubMed and Ovid Medline containing data on umbilical cord and venous blood concentrations of hepcidin and iron, and transferrin saturation (TSAT), in human neonates from 0 to 1 mo of age. Data from 59 studies were used to create reference ranges for hepcidin, iron, and TSAT for full-term-birth (FTB) neonates over the first month of life. In FTB neonates, venous hepcidin increases 100% over the first month of life (to reach 61.1 ng/mL; 95% CI: 20.1, 102.0 ng/mL) compared with umbilical cord blood (29.7 ng/mL; 95% CI: 21.1, 38.3 ng/mL). Cord blood has a high concentration of serum iron (28.4 μmol/L; 95% CI: 26.0, 31.1 μmol/L) and levels of TSAT (51.7%; 95% CI: 46.5%, 56.9%). After a short-lived immediate postnatal hypoferremia, iron and TSAT rebounded to approximately half the levels in the cord by the end of the first month. There were insufficient data to formulate reference ranges for preterm neonates.