The brain microvasculature is a primary mediator of interferon-α neurotoxicity in human cerebral interferonopathies.

Aicardi-Goutières syndrome (AGS) is an autoinflammatory disease characterized by aberrant interferon (IFN)-α production. The major cause of morbidity in AGS is brain disease, yet the primary source and target of neurotoxic IFN-α remain unclear. Here, we demonstrated that the brain was the primary source of neurotoxic IFN-α in AGS and confirmed the neurotoxicity of intracerebral IFN-α using astrocyte-driven Ifna1 misexpression in mice. Using single-cell RNA sequencing, we demonstrated that intracerebral IFN-α-activated receptor (IFNAR) signaling within cerebral endothelial cells caused a distinctive cerebral small vessel disease similar to that observed in individuals with AGS. Magnetic resonance imaging (MRI) and single-molecule ELISA revealed that central and not peripheral IFN-α was the primary determinant of microvascular disease in humans. Ablation of endothelial Ifnar1 in mice rescued microvascular disease, stopped the development of diffuse brain disease, and prolonged lifespan. These results identify the cerebral microvasculature as a primary mediator of IFN-α neurotoxicity in AGS, representing an accessible target for therapeutic intervention.

Counter-gradient variation in gene expression between fish populations facilitates colonization of low-dissolved oxygen environments.

The role of phenotypic plasticity during colonization remains unclear due to the shifting importance of plasticity across timescales. In the early stages of colonization, plasticity can facilitate persistence in a novel environment; but over evolutionary time, processes such as genetic assimilation may reduce variation in plastic traits such that species with a longer evolutionary history in an environment can show lower levels of plasticity than recent invaders. Therefore, comparing species in the early stages of colonization to long-established species provides a powerful approach for uncovering the role of phenotypic plasticity during different stages of colonization. We compared gene expression between low-dissolved oxygen (DO) and high-DO populations of two cyprinid fish: Enteromius apleurogramma, a species that has undergone a recent range expansion, and E. neumayeri, a long-established native species in the same region. We sampled tissue either immediately after capture from the field or after a 2-week acclimation under high-DO conditions, allowing us to test for both evolved and plastic differences in low-DO vs high-DO populations of each species. We found that most genes showing candidate-evolved differences in gene expression did not overlap with those showing plastic differences in gene expression. However, in the genes that did overlap, there was counter-gradient variation such that plastic and evolved gene expression responses were in opposite directions in both species. Additionally, E. apleurogramma had higher levels of plasticity and evolved divergence in gene expression between field populations. We suggest that the higher level of plasticity and counter-gradient variation may have allowed rapid genetic adaptation in E. apleurogramma and facilitated colonization. This study shows how counter-gradient variation may impact the colonization of divergent oxygen environments.

Neutrophil-Derived Peptidyl Arginine Deiminase Activity Contributes to Pulmonary Emphysema by Enhancing Elastin Degradation.

In chronic obstructive pulmonary disease (COPD), inflammation gives rise to protease-mediated degradation of the key extracellular matrix protein, elastin, which causes irreversible loss of pulmonary function. Intervention against proteolysis has met with limited success in COPD, due in part to our incomplete understanding of the mechanisms that underlie disease pathogenesis. Peptidyl arginine deiminase (PAD) enzymes are a known modifier of proteolytic susceptibility, but their involvement in COPD in the lungs of affected individuals is underexplored. In this study, we showed that enzyme isotypes PAD2 and PAD4 are present in primary granules of neutrophils and that cells from people with COPD release increased levels of PADs when compared with neutrophils of healthy control subjects. By examining bronchoalveolar lavage and lung tissue samples of patients with COPD or matched smoking and nonsmoking counterparts with normal lung function, we reveal that COPD presents with markedly increased airway concentrations of PADs. Ex vivo, we established citrullinated elastin in the peripheral airways of people with COPD, and in vitro, elastin citrullination significantly enhanced its proteolytic degradation by serine and matrix metalloproteinases, including neutrophil elastase and matrix metalloprotease-12, respectively. These results provide a mechanism by which neutrophil-released PADs affect lung function decline, indicating promise for the future development of PAD-based therapeutics for preserving lung function in patients with COPD.

Safety outcomes following COVID-19 vaccination and infection in 5.1 million children in England.

The risk-benefit profile of COVID-19 vaccination in children remains uncertain. A self-controlled case-series study was conducted using linked data of 5.1 million children in England to compare risks of hospitalisation from vaccine safety outcomes after COVID-19 vaccination and infection. In 5-11-year-olds, we found no increased risks of adverse events 1-42 days following vaccination with BNT162b2, mRNA-1273 or ChAdOX1. In 12-17-year-olds, we estimated 3 (95%CI 0-5) and 5 (95%CI 3-6) additional cases of myocarditis per million following a first and second dose with BNT162b2, respectively. An additional 12 (95%CI 0-23) hospitalisations with epilepsy and 4 (95%CI 0-6) with demyelinating disease (in females only, mainly optic neuritis) were estimated per million following a second dose with BNT162b2. SARS-CoV-2 infection was associated with increased risks of hospitalisation from seven outcomes including multisystem inflammatory syndrome and myocarditis, but these risks were largely absent in those vaccinated prior to infection. We report a favourable safety profile of COVID-19 vaccination in under-18s.

brainlife.io: a decentralized and open-source cloud platform to support neuroscience research.

Neuroscience is advancing standardization and tool development to support rigor and transparency. Consequently, data pipeline complexity has increased, hindering FAIR (findable, accessible, interoperable and reusable) access. brainlife.io was developed to democratize neuroimaging research. The platform provides data standardization, management, visualization and processing and automatically tracks the provenance history of thousands of data objects. Here, brainlife.io is described and evaluated for validity, reliability, reproducibility, replicability and scientific utility using four data modalities and 3,200 participants.

NMDAR-mediated activation of pannexin1 channels contributes to the detonator properties of hippocampal mossy fiber synapses.

Pannexins are large-pore ion channels expressed throughout the mammalian brain that participate in various neuropathologies; however, their physiological roles remain obscure. Here, we report that pannexin1 channels (Panx1) can be synaptically activated under physiological recording conditions in rodent acute hippocampal slices. Specifically, NMDA receptor (NMDAR)-mediated responses at the mossy fiber to CA3 pyramidal cell synapse were followed by a slow postsynaptic inward current that could activate CA3 pyramidal cells but was absent in Panx1 knockout mice. Immunoelectron microscopy revealed that Panx1 was localized near the postsynaptic density. Further, Panx1-mediated currents were potentiated by metabotropic receptors and bidirectionally modulated by burst-timing-dependent plasticity of NMDAR-mediated transmission. Lastly, Panx1 channels were preferentially recruited when NMDAR activation enters a supralinear regime, resulting in temporally delayed burst-firing. Thus, Panx1 can contribute to synaptic amplification and broadening the temporal associativity window for co-activated pyramidal cells, thereby supporting the auto-associative functions of the CA3 region.

Diffusive persistence on disordered lattices and random networks.

To better understand the temporal characteristics and the lifetime of fluctuations in stochastic processes in networks, we investigated diffusive persistence in various graphs. Global diffusive persistence is defined as the fraction of nodes for which the diffusive field at a site (or node) has not changed sign up to time t (or, in general, that the node remained active or inactive in discrete models). Here we investigate disordered and random networks and show that the behavior of the persistence depends on the topology of the network. In two-dimensional (2D) disordered networks, we find that above the percolation threshold diffusive persistence scales similarly as in the original 2D regular lattice, according to a power law P(t,L)∼t^{-θ} with an exponent θ≃0.186, in the limit of large linear system size L. At the percolation threshold, however, the scaling exponent changes to θ≃0.141, as the result of the interplay of diffusive persistence and the underlying structural transition in the disordered lattice at the percolation threshold. Moreover, studying finite-size effects for 2D lattices at and above the percolation threshold, we find that at the percolation threshold, the long-time asymptotic value obeys a power law P(t,L)∼L^{-zθ} with z≃2.86 instead of the value of z=2 normally associated with finite-size effects on 2D regular lattices. In contrast, we observe that in random networks without a local regular structure, such as Erdos-Rényi networks, no simple power-law scaling behavior exists above the percolation threshold.

Comparison of brain imaging and physical health between research and clinical neuroimaging cohorts of ageing.

OBJECTIVES: To compare brain MRI measures between Adult Changes in Thought (ACT) participants who underwent research, clinical, or both MRI scans, and clinical health measures across the groups and non-MRI subjects. METHODS: Retrospective cohort study leveraging MRI, clinical, demographic, and medication data from ACT. Three neuroradiologists reviewed MRI scans using NIH Neuroimaging Common Data Elements (CDEs). Total brain and white matter hyperintensity (WMH) volumes, clinical characteristics, and outcome measures of brain and overall health were compared between groups. 1166 MRIs were included (77 research, 1043 clinical, and 46 both) and an additional 3146 participants with no MRI were compared. RESULTS: Compared to the group with research MRI only, the clinical MRI group had higher prevalence of the following: acute infarcts, chronic haematoma, subarachnoid haemorrhage, subdural haemorrhage, haemorrhagic transformation, and hydrocephalus (each P < .001). Quantitative WMH burden was significantly lower (P < .001) and total brain volume significantly higher (P < .001) in research MRI participants compared to other MRI groups. Prevalence of hypertension, self-reported cerebrovascular disease, congestive heart failure, dementia, and recent hospitalization (all P < .001) and diabetes (P = .002) differed significantly across groups, with smaller proportions in the research MRI group. CONCLUSION: In ageing populations, significant differences were observed in MRI metrics between research MRI and clinical MRI groups, and clinical health metric differences between research MRI, clinical MRI, and no-MRI groups. ADVANCES IN KNOWLEDGE: This questions whether research cohorts can adequately represent the greater ageing population undergoing imaging. These findings may also be useful to radiologists when interpreting neuroimaging of ageing.

Reducing use of seclusion on a male medium secure forensic ward.

The reduction of restrictive practices is a priority for mental health inpatient services. Often such practices are considered to increase patients' feelings of anger, loneliness, hopelessness and vulnerability. Moreover, such approaches are counterintuitive to both recovery-orientated and trauma-informed practice.Our project, based in a male 15-bed secure forensic ward, aimed to reduce the duration (outcome measure) and frequency (balancing measure) of the use of seclusion by 10% over 6 months. Following the analysis of our local data systems and feedback from both patients and staff, we identified the high levels of use of seclusion, and reluctance to terminate it. These included a lack of awareness of the effective and appropriate use of such a facility, a hesitancy to use de-escalation techniques and an over-reliance on multidisciplinary team and consultant decision making.We subsequently designed and implemented three tests of change which reviewed seclusion processes, enhanced de-escalation skills and improved decision making. Our tests of change were applied over a 6-month period. During this period, we surpassed our original target of a reduction of frequency and duration by 10% and achieved a 33% reduction overall. Patients reported feeling safer on the ward, and the team reported improvements in relationships with patients.Our project highlights the importance of relational security within the secure setting and provides a template for other wards wishing to reduce the frequency and duration of seclusions.

White plague among the "forgotten people" from the Barbaricum of the Carpathian Basin-Cases with tuberculosis from the Sarmatian-period (3rd-4th centuries CE) archaeological site of Hódmezovásárhely-Kenyere-ér, Bereczki-tanya (Hungary).

Tuberculosis (TB) is a bacterial infection that is well-known in the palaeopathological record because it can affect the skeleton and consequently leaves readily identifiable macroscopic alterations. Palaeopathological case studies provide invaluable information about the spatio-temporal distribution of TB in the past. This is true for those archaeological periods and geographical regions from when and where no or very few TB cases have been published until now-as in the Sarmatian period (1st-5th centuries CE) in the Barbaricum of the Carpathian Basin. The aim of our paper is to discuss five newly discovered TB cases (HK199, HK201, HK225, HK253, and HK309) from the Sarmatian-period archaeological site of Hódmezovásárhely-Kenyere-ér, Bereczki-tanya (Csongrád-Csanád county, Hungary). Detailed macromorphological evaluation of the skeletons focused on the detection of bony changes likely associated with different forms of TB. In all five cases, the presence of endocranial alterations (especially TB-specific granular impressions) suggests that these individuals suffered from TB meningitis. Furthermore, the skeletal lesions observed in the spine and both hip joints of HK225 indicate that this juvenile also had multifocal osteoarticular TB. Thanks to the discovery of HK199, HK201, HK225, HK253, and HK309, the number of TB cases known from the Sarmatian-period Carpathian Basin doubled, implying that the disease was likely more frequent in the Barbaricum than previously thought. Without the application of granular impressions, the diagnosis of TB could not have been established in these five cases. Thus, the identification of TB in these individuals highlights the importance of diagnostics development, especially the refinement of diagnostic criteria. Based on the above, the systematic macromorphological (re-)evaluation of osteoarchaeological series from the Sarmatian-period Carpathian Basin would be advantageous to provide a more accurate picture of how TB may have impacted the ancestral human communities of the Barbaricum.

Power of saying 'I Don't Know': psychological safety and participatory strategies for healthcare leaders.

As healthcare systems grow increasingly complex and integrate with other services and sectors, creating complex patient pathways, this inevitably leads to additional layers within a system. Consequently, high-tier leaders become progressively detached from the inner workings of the systems in which they operate. Several barriers exist that may deter a leader from embracing uncertainty and acknowledging the limits of their expertise in these systems. These barriers range from personal insecurities about perception to organisational stigmas that compound these concerns through expectations of infallible leadership. In this article, I draw on my experience as an embedded researcher and someone who has taught leadership in healthcare settings to examine the importance of leadership vulnerability, considering not only for the leaders themselves but also for fostering a learning and innovative culture within the organisation. I focus on two fundamental tenets: psychological safety and participatory approaches to innovation. In addition, I offer practical considerations for embracing vulnerability and discuss the ensuing benefits. Given the rapidly evolving complexities in healthcare and paradigm-shifting innovations, such as the integration of digital solutions, this article serves as a call to action. It urges leaders to embrace uncertainty, encourage participation and venture into the unknown.

A Panel-Agnostic Strategy 'HiPPo' Improves Diagnostic Efficiency in the UK Genomic Medicine Service.

Genome sequencing is available as a clinical test in the UK through the Genomic Medicine Service (GMS). The GMS analytical strategy predominantly filters genome data on preselected gene panels. Whilst this reduces variants requiring assessment by reporting laboratories, pathogenic variants outside applied panels may be missed, and variants in genes without established disease-gene relationships are largely ignored. This study compares the analysis of a research exome to a GMS clinical genome for the same patients. For the research exome, we applied a panel-agnostic approach filtering for variants with High Pathogenic Potential (HiPPo) using ClinVar, allele frequency, and in silico prediction tools. We then restricted HiPPo variants to Gene Curation Coalition (GenCC) disease genes. These results were compared with the GMS genome panel-based approach. Twenty-four participants from eight families underwent parallel research exome and GMS genome sequencing. Exome HiPPo analysis identified a similar number of variants as the GMS panel-based approach. GMS genome analysis returned two pathogenic variants and one de novo variant. Exome HiPPo analysis returned the same variants plus an additional pathogenic variant and three further de novo variants in novel genes, where case series are underway. When HiPPo was restricted to GenCC disease genes, statistically fewer variants required assessment to identify more pathogenic variants than reported by the GMS, giving a diagnostic rate per variant assessed of 20% for HiPPo versus 3% for the GMS. With UK plans to sequence 5 million genomes, strategies are needed to optimise genome analysis beyond gene panels whilst minimising the burden of variants requiring clinical assessment.

Improving the standardisation, timeliness and efficiency of the occupational therapy admission process in an older adult inpatient service.

Occupational therapists (OTs) are at the forefront of providing recovery-oriented care for older people through timely assessments of patient's engagement in daily living activities among many other interventions. This aids a timely, safe and successful discharge from hospital.This project built on the foundations of previous work while considering the context and requirements of two older adult wards, the rates of admission and staff retention. The specific aim agreed was for 90% of patients admitted to the older adults' inpatient units to be assessed by the occupational therapy (OTY) team within days of admission by December 2022.The OTs worked in collaboration to initiate two tests of change with a total of five PDSA cycles.Our tests of change resulted in an increase of patients engaging in OTY initial assessments within seven days of admission from 47.65% (May to November 2021) to 78% (December 2021 to December 2022).Our team embarked on a quality improvement project to improve standardisation, efficiency and timeliness of the OTY process in an older adult inpatient service by using a pragmatic measure and tests of change evidenced in a previous study. This evidenced the generalisability of the findings of this study. While we were able to improve the timeliness of OTY initial assessments, we concluded that the overall impact on outcomes such as timely discharge was also dependent on other clinical and social factors.

Compensatory Cone-Mediated Mechanisms in Inherited Retinal Degeneration Mouse Models: A Functional and Gene Expression Analysis.

The retina undergoes compensatory changes in response to progressive photoreceptor loss/dysfunction; however, studies of inherited retinal diseases (IRDs) often lack a temporal connection between gene expression and visual function. Here, we used three mouse models of IRD - Cnga3-/-, Pde6ccpfl1, and Rd1 - to investigate over time the effect of photoreceptor degeneration, particularly cones, on visual function and gene expression. Changes to gene expression include increases in cell survival and cell death genes in Pde6ccpfl1 before significant cell loss, as well as an increase in cone-specific genes in the Rd1 at the peak of rod death. We show that Cnga3-/- and Pde6ccpfl1 mice maintained photopic visual acuity via optomotor responses, despite no recordable cone electroretinogram (ERG), while functional measures and photoreceptors loss were correlated in Rd1 mice. There were also significant changes to oscillatory potentials (OPs) in Cnga3-/- and Pde6ccpfl1, implying an effect on inner retinal cells as a result of cone degeneration. These results indicate a potentially malleable retinal environment following cone degeneration; however, further investigation is needed to elucidate how these changes compensate for the loss of cone function.

Relationship Between In-Hospital Adverse Events and Hospital Performance on 30-Day All-cause Mortality and Readmission for Patients With Heart Failure.

BACKGROUND: Hospitals with high mortality and readmission rates for patients with heart failure (HF) might also perform poorly in other quality concepts. We sought to evaluate the association between hospital performance on mortality and readmission with hospital performance rates of safety adverse events. METHODS: This cross-sectional study linked the 2009 to 2019 patient-level adverse events data from the Medicare Patient Safety Monitoring System, a randomly selected medical records-abstracted patient safety database, to the 2005 to 2016 hospital-level HF-specific 30-day all-cause mortality and readmissions data from the United States Centers for Medicare & Medicaid Services. Hospitals were classified to one of 3 performance categories based on their risk-standardized 30-day all-cause mortality and readmission rates: better (both in <25th percentile), worse (both >75th percentile), and average (otherwise). Our main outcome was the occurrence (yes/no) of one or more adverse events during hospitalization. A mixed-effect model was fit to assess the relationship between a patient's risk of having adverse events and hospital performance categories, adjusted for patient and hospital characteristics. RESULTS: The study included 39 597 patients with HF from 3108 hospitals, of which 252 hospitals (8.1%) and 215 (6.9%) were in the better and worse categories, respectively. The rate of patients with one or more adverse events during a hospitalization was 12.5% (95% CI, 12.1-12.8). Compared with patients admitted to better hospitals, patients admitted to worse hospitals had a higher risk of one or more hospital-acquired adverse events (adjusted risk ratio, 1.24 [95% CI, 1.06-1.44]). CONCLUSIONS: Patients admitted with HF to hospitals with high 30-day all-cause mortality and readmission rates had a higher risk of in-hospital adverse events. There may be common quality issues among these 3 measure concepts in these hospitals that produce poor performance for patients with HF.

Patterns of brain atrophy in recently-diagnosed relapsing-remitting multiple sclerosis.

Recurrent neuroinflammation in relapsing-remitting MS (RRMS) is thought to lead to neurodegeneration, resulting in progressive disability. Repeated magnetic resonance imaging (MRI) of the brain provides non-invasive measures of atrophy over time, a key marker of neurodegeneration. This study investigates regional neurodegeneration of the brain in recently-diagnosed RRMS using volumetry and voxel-based morphometry (VBM). RRMS patients (N = 354) underwent 3T structural MRI <6 months after diagnosis and 1-year follow-up, as part of the Scottish multicentre 'FutureMS' study. MRI data were processed using FreeSurfer to derive volumetrics, and FSL for VBM (grey matter (GM) only), to establish regional patterns of change in GM and normal-appearing white matter (NAWM) over time throughout the brain. Volumetric analyses showed a decrease over time (q<0.05) in bilateral cortical GM and NAWM, cerebellar GM, brainstem, amygdala, basal ganglia, hippocampus, accumbens, thalamus and ventral diencephalon. Additionally, NAWM and GM volume decreased respectively in the following cortical regions, frontal: 14 out of 26 regions and 16/26; temporal: 18/18 and 15/18; parietal: 14/14 and 11/14; occipital: 7/8 and 8/8. Left GM and NAWM asymmetry was observed in the frontal lobe. GM VBM analysis showed three major clusters of decrease over time: 1) temporal and subcortical areas, 2) cerebellum, 3) anterior cingulum and supplementary motor cortex; and four smaller clusters within the occipital lobe. Widespread GM and NAWM atrophy was observed in this large recently-diagnosed RRMS cohort, particularly in the brainstem, cerebellar GM, and subcortical and occipital-temporal regions; indicative of neurodegeneration across tissue types, and in accord with limited previous studies in early disease. Volumetric and VBM results emphasise different features of longitudinal lobar and loco-regional change, however identify consistent atrophy patterns across individuals. Atrophy measures targeted to specific brain regions may provide improved markers of neurodegeneration, and potential future imaging stratifiers and endpoints for clinical decision making and therapeutic trials.

The origins of the full-field flash electroretinogram b-wave.

The electroretinogram (ERG) measures the electrical activity of retinal neurons and glial cells in response to a light stimulus. Amongst other techniques, clinicians utilize the ERG to diagnose various eye diseases, including inherited conditions such as cone-rod dystrophy, rod-cone dystrophy, retinitis pigmentosa and Usher syndrome, and to assess overall retinal health. An ERG measures the scotopic and photopic systems separately and mainly consists of an a-wave and a b-wave. The other major components of the dark-adapted ERG response include the oscillatory potentials, c-wave, and d-wave. The dark-adapted a-wave is the initial corneal negative wave that arises from the outer segments of the rod and cone photoreceptors hyperpolarizing in response to a light stimulus. This is followed by the slower, positive, and prolonged b-wave, whose origins remain elusive. Despite a large body of work, there remains controversy around the mechanisms involved in the generation of the b-wave. Several hypotheses attribute the origins of the b-wave to bipolar or Müller glial cells or a dual contribution from both cell types. This review will discuss the current hypothesis for the cellular origins of the dark-adapted ERG, with a focus on the b-wave.