Hospital Variation in Epinephrine Administration Before Defibrillation for Cardiac Arrest Due to Shockable Rhythm.

OBJECTIVES: Contrary to advanced cardiac life support guidelines that recommend immediate defibrillation for shockable in-hospital cardiac arrest (IHCA), epinephrine administration before first defibrillation is common and associated with lower survival at a "patient-level." Whether this practice varies across hospitals and its association with "hospital-level" IHCA survival remains unknown. The purpose of this study was to determine hospital variation in rates of epinephrine administration before defibrillation for shockable IHCA and its association with IHCA survival. DESIGN: Observational cohort study. SETTING: Five hundred thirteen hospitals participating in the Get With The Guidelines Resuscitation Registry. PATIENTS: A total of 37,668 adult patients with IHCA due to an initial shockable rhythm from 2000 to 2019. INTERVENTIONS: Epinephrine before first defibrillation. MEASUREMENTS AND MAIN RESULTS: Using multivariable hierarchical regression, we examined hospital variation in epinephrine administration before first defibrillation and its association with hospital-level rates of risk-adjusted survival. The median hospital rate of epinephrine administration before defibrillation was 18.8%, with large variation across sites (range, 0-68.8%; median odds ratio: 1.54; 95% CI, 1.47-1.61). Major teaching status and annual IHCA volume were associated with hospital rate of epinephrine administration before defibrillation. Compared with hospitals with the lowest rate of epinephrine administration before defibrillation (Q1), there was a stepwise decline in risk-adjusted survival at hospitals with higher rates of epinephrine administration before defibrillation (Q1: 44.3%, Q2: 43.4%; Q3: 41.9%; Q4: 40.3%; p for trend < 0.001). CONCLUSIONS: Administration of epinephrine before defibrillation in shockable IHCA is common and varies markedly across U.S. hospitals. Hospital rates of epinephrine administration before defibrillation were associated with a significant stepwise decrease in hospital rates of risk-adjusted survival. Efforts to prioritize immediate defibrillation for patients with shockable IHCA and avoid early epinephrine administration are urgently needed.

Insights into Factors Affecting Ethylene-Vinyl Acetate Copolymer Crystallinity in Islatravir Implant.

Islatravir, a highly potent nucleoside reverse transcriptase translocation inhibitor (NRTTI) for the treatment of HIV, has great potential to be formulated as ethylene-vinyl acetate (EVA) copolymer-based implants via hot melt extrusion. The crystallinity of EVA determines its physical and rheological properties and may impact the drug-eluting implant performance. Herein, we describe the systematic analysis of factors affecting the EVA crystallinity in islatravir implants. Differential scanning calorimetry (DSC) on EVA and solid-state NMR revealed drug loading promoted EVA crystallization, whereas BaSO4 loading had negligible impact on EVA crystallinity. The sterilization through γ-irradiation appeared to significantly impact the EVA crystallinity and surface characteristics of the implants. Furthermore, DSC analysis of thin implant slices prepared with an ultramicrotome indicated that the surface layer of the implant was more crystalline than the core. These findings provide critical insights into factors affecting the crystallinity, mechanical properties, and physicochemical properties of the EVA polymer matrix of extruded islatravir implants.

IKK2 controls the inflammatory potential of tissue-resident regulatory T cells in a murine gain of function model.

Loss-of-function mutations have provided crucial insights into the immunoregulatory actions of Foxp3+ regulatory T cells (Tregs). By contrast, we know very little about the consequences of defects that amplify aspects of Treg function or differentiation. Here we show that mice heterozygous for an Ikbkb gain-of-function mutation develop psoriasis. Doubling the gene dose (IkbkbGoF/GoF) results in dactylitis, spondylitis, and characteristic nail changes, which are features of psoriatic arthritis. IkbkbGoF mice exhibit a selective expansion of Foxp3 + CD25+ Tregs of which a subset express IL-17. These modified Tregs are enriched in both inflamed tissues, blood and spleen, and their transfer is sufficient to induce disease without conventional T cells. Single-cell transcriptional and phenotyping analyses of isolated Tregs reveal expansion of non-lymphoid tissue (tissue-resident) Tregs expressing Th17-related genes, Helios, tissue-resident markers including CD103 and CD69, and a prominent NF-κB transcriptome. Thus, IKK2 regulates tissue-resident Treg differentiation, and overactivity drives dose-dependent skin and systemic inflammation.

The complement system in neurodegenerative diseases.

Complement is an important component of innate immune defence against pathogens and crucial for efficient immune complex disposal. These core protective activities are dependent in large part on properly regulated complement-mediated inflammation. Dysregulated complement activation, often driven by persistence of activating triggers, is a cause of pathological inflammation in numerous diseases, including neurological diseases. Increasingly, this has become apparent not only in well-recognized neuroinflammatory diseases like multiple sclerosis but also in neurodegenerative and neuropsychiatric diseases where inflammation was previously either ignored or dismissed as a secondary event. There is now a large and rapidly growing body of evidence implicating complement in neurological diseases that cannot be comprehensively addressed in a brief review. Here, we will focus on neurodegenerative diseases, including not only the 'classical' neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, but also two other neurological diseases where neurodegeneration is a neglected feature and complement is implicated, namely, schizophrenia, a neurodevelopmental disorder with many mechanistic features of neurodegeneration, and multiple sclerosis, a demyelinating disorder where neurodegeneration is a major cause of progressive decline. We will discuss the evidence implicating complement as a driver of pathology in these diverse diseases and address briefly the potential and pitfalls of anti-complement drug therapy for neurodegenerative diseases.

Current Insights and a Potential Role of NAD in the Reproductive Health of Aging Fathers and Their Children.

In brief: In light of the increasing age of first-time fathers, this article summarizes the current scientific knowledge base on reproductive aging in the male, including sperm quality and health impacts for the offspring. The emerging role of NAD decline in reproductive aging is highlighted. Abstract: Over the past decades, the age of first-time fathers has been steadily increasing due to socio-economic pressures. While general mechanisms of aging are subject to intensive research, male reproductive aging has remained an understudied area, and the effects of increased age on the male reproductive system are still only poorly understood, despite new insights into the potential dire consequences of advanced paternal age for the health of their progeny. There is also growing evidence that reproductive aging is linked to overall health in men, but this review focuses mainly on pathophysiological consequences of old age in men, such as low sperm count and diminished sperm genetic integrity, with an emphasis on mechanisms underlying reproductive aging. The steady decline of NAD levels observed in aging men represents one of the emerging concepts in that regard. Because it offers some mechanistic rationale explaining the effects of old age on the male reproductive system, some of the NAD-dependent functions in male reproduction are briefly outlined in this review. The overview also provides many questions that remain open about the basic science of male reproductive aging.

The burden of skin and soft tissue, bone and joint infections in an Australian cohort of people who inject drugs.

INTRODUCTION: There are currently limited data regarding the clinical and economic significance of skin and soft tissue infections (SSTI) and bone and joint infections in Australian people who inject drugs (PWID). METHODS: Retrospective cohort study in adult PWID admitted to Monash Health, a large heath care network with six hospitals in Victoria, Australia. Inpatients were identified using administrative datasets and International Classification of Disease (ICD-10) coding for specific infection-related conditions. Cost analysis was based on mean ward, intensive care and hospital-in-the-home (HITH) lengths of stay. Spinal infections and endocarditis were excluded as part of previous studies. RESULTS: A total of 185 PWID (61 female, 124 male, median age 37) meeting the study criteria were admitted to Monash Health between January 2010 and January 2021. Admitting diagnoses included 78 skin abscesses, 80 cellulitis, 17 septic arthritis, 4 osteomyelitis, 3 thrombophlebitis and 1 each of necrotising fasciitis, vasculitis and myositis. Pain (87.5%) and swelling (75.1%) were the most common presenting complaints. Opioids (67.4%) and methamphetamine (37.5%) were the most common primary drugs injected. Almost half (46.5%) of patients had concurrent active hepatitis C (HCV) infection on admission. Hepatitis B (HBV) and Human Immunodeficiency Virus (HIV) were uncommon. The most significant causative organism was methicillin-susceptible Staphylococcus aureus (24.9%). In 40.0% (74/185) no organism was identified. Patients required a median acute hospital stay of 5 days (2-51 days). There were 15 patients admitted to the intensive care unit (ICU) with median duration 2 days. PICC line insertion for antibiotics was required in 16.8% of patients, while 51.4% required surgical intervention. Median duration of both oral and IV antibiotic therapy was 11 days. Almost half (48.6%) of patients were enrolled in an opioid maintenance program on discharge. Average estimated expenditure was AUD $16, 528 per admission. CONCLUSION: Skin and soft tissue and joint infections are a major cause of morbidity for PWID. Admission to hospital provides opportunistic involvement of addiction specialty services.

Complement dysregulation is a prevalent and therapeutically amenable feature of long COVID.

BACKGROUND: Long COVID encompasses a heterogeneous set of ongoing symptoms that affect many individuals after recovery from infection with SARS-CoV-2. The underlying biological mechanisms nonetheless remain obscure, precluding accurate diagnosis and effective intervention. Complement dysregulation is a hallmark of acute COVID-19 but has not been investigated as a potential determinant of long COVID. METHODS: We quantified a series of complement proteins, including markers of activation and regulation, in plasma samples from healthy convalescent individuals with a confirmed history of infection with SARS-CoV-2 and age/ethnicity/sex/infection/vaccine-matched patients with long COVID. FINDINGS: Markers of classical (C1s-C1INH complex), alternative (Ba, iC3b), and terminal pathway (C5a, TCC) activation were significantly elevated in patients with long COVID. These markers in combination had a receiver operating characteristic predictive power of 0.794. Other complement proteins and regulators were also quantitatively different between healthy convalescent individuals and patients with long COVID. Generalized linear modeling further revealed that a clinically tractable combination of just four of these markers, namely the activation fragments iC3b, TCC, Ba, and C5a, had a predictive power of 0.785. CONCLUSIONS: These findings suggest that complement biomarkers could facilitate the diagnosis of long COVID and further suggest that currently available inhibitors of complement activation could be used to treat long COVID. FUNDING: This work was funded by the National Institute for Health Research (COV-LT2-0041), the PolyBio Research Foundation, and the UK Dementia Research Institute.

Multi-Material Volumetric Additive Manufacturing of Hydrogels using Gelatin as a Sacrificial Network and 3D Suspension Bath.

Volumetric additive manufacturing (VAM) is an emerging layerless method for the rapid processing of reactive resins into 3D structures, where printing is much faster (seconds) than other lithography and direct ink writing methods (minutes to hours). As a vial of resin rotates in the VAM process, patterned light exposure defines a 3D object and then resin that has not undergone gelation can be washed away. Despite the promise of VAM, there are challenges with the printing of soft hydrogel materials from non-viscous precursors, including multi-material constructs. To address this, sacrificial gelatin is used to modulate resin viscosity to support the cytocompatible VAM printing of macromers based on poly(ethylene glycol) (PEG), hyaluronic acid (HA), and polyacrylamide (PA). After printing, gelatin is removed by washing at an elevated temperature. To print multi-material constructs, the gelatin-containing resin is used as a shear-yielding suspension bath (including HA to further modulate bath properties) where ink can be extruded into the bath to define a multi-material resin that can then be processed with VAM into a defined object. Multi-material constructs of methacrylated HA (MeHA) and gelatin methacrylamide (GelMA) are printed (as proof-of-concept) with encapsulated mesenchymal stromal cells (MSCs), where the local hydrogel properties guide cell spreading behavior with culture.

Documented Use of Emergency Medical Dispatch Protocols is Associated with Improved Survival in Out of Hospital Cardiac Arrest.

OBJECTIVE: There are over 300,000 out-of-hospital cardiac arrests (OHCA) annually in the United States (US) and despite many scientific advances in the field, the survival rate remains low. We seek to determine if return of spontaneous circulation (ROSC) is higher when use of emergency medical dispatch (EMD) protocols is documented for OHCA calls compared to when no EMD protocol use is documented. We also seek identify care-related processes that differ in calls that use EMD protocols. METHODS: This is a retrospective cohort study of U.S. adults with OHCA prior to emergency medical services (EMS) arrival using 2019 National EMS Information System data. The primary exposure was EMD usage during EMS call. The primary outcome was prehospital ROSC, and secondary outcomes included automated external defibrillator (AED) use before EMS arrival, bystander CPR, and end-of-event EMS survival (survival to the end of the EMS care at transport destination). Multivariable logistic regression adjusted for age, sex, race/ethnicity, primary insurance, rurality, initial rhythm, arrest etiology, and witnessed arrest. RESULTS: Of the 96,269 OHCA cases included, EMD use was documented in 73%. Overall, 26% of subjects achieved ROSC in EMS care. EMD subjects were more likely to achieve ROSC (27.2% vs. 23.5%, uOR 1.22, 95%CI 1.18 - 1.26) even after adjusting for subject and arrest characteristics (aOR 1.13, 95%CI 1.08 - 1.17). EMD subjects also had higher end-of-event survival (19.1% vs. 16.4%, aOR 1.20, 95%CI 1.15 - 1.25). AED use before EMS arrival was more common in the EMD group (28.3% vs. 26.3% %diff 2.0, 95%CI 1.4 to 2.6), as was CPR before EMS arrival (63.8% vs. 55.1%, difference 8.6%, 95%CI 7.9 to 9.3%). CONCLUSIONS: In this retrospective analysis, the rate of ROSC was higher in adult OHCA patients when EMD protocol use was reported compared to when it was not reported. The group with documented EMD use also experienced higher rates of bystander AED use, bystander CPR, and end-of-event survival.

Neuraminidase-induced externalization of phosphatidylserine activates ADAM17 and impairs insulin signaling in endothelial cells.

Endothelial insulin resistance represents a causal factor in the pathogenesis of type 2 diabetes (T2D) and vascular disease, thus the need to identify molecular mechanisms underlying defects in endothelial insulin signaling. We previously have shown that a disintegrin and metalloproteinase-17 (ADAM17) is increased while insulin receptor α-subunit (IRα) is decreased in the vasculature of patients with T2D, leading to impaired insulin-induced vasodilation. We have also demonstrated that ADAM17 sheddase activity targets IRα; however, the mechanisms driving endothelial ADAM17 activity in T2D are largely unknown. Herein, we report that externalization of phosphatidylserine (PS) to the outer leaflet of the plasma membrane causes ADAM17-mediated shedding of IRα and blunting of insulin signaling in endothelial cells. Furthermore, we demonstrate that endothelial PS externalization is mediated by the phospholipid scramblase anoctamin-6 (ANO6) and that this process can be stimulated by neuraminidase, a soluble enzyme that cleaves sialic acid residues. Of note, we demonstrate that men and women with T2D display increased levels of neuraminidase activity in plasma, relative to age-matched healthy individuals, and this occurs in conjunction with increased ADAM17 activity and impaired leg blood flow responses to endogenous insulin. Collectively, this work reveals the neuraminidase-ANO6-ADAM17 axis as a novel potential target for restoring endothelial insulin sensitivity in T2D.NEW & NOTEWORTHY This work provides the first evidence that neuraminidase, an enzyme increased in the circulation of men and women with type 2 diabetes (T2D), promotes anoctamin-6 (ANO6)-dependent externalization of phosphatidylserine in endothelial cells, which in turn leads to activation of a disintegrin and metalloproteinase-17 (ADAM17) and consequent shedding of the insulin receptor-α from the cell surface. Hence, this work supports that consideration should be given to the neuraminidase-ANO6-ADAM17 axis as a novel potential target for restoring endothelial insulin sensitivity in T2D.

Performance evaluation and model of spacesuit cooling by hydrophobic hollow fiber-membrane based water evaporation through pores.

A comprehensive mathematical model is presented that accurately estimates and predicts failure modes through the computations of heat rejection, temperature drop and lumen side pressure drop of the hollow fiber (HF) membrane-based NASA Spacesuit Water Membrane Evaporator (SWME). The model is based on mass and energy balances in terms of the physical properties of water and membrane transport properties. The mass flux of water vapor through the pores is calculated based on Knudsen diffusion with a membrane structure parameter that accounts for effective mean pore diameter, porosity, thickness, and tortuosity. Lumen-side convective heat transfer coefficients are calculated from laminar flow boundary layer theory using the Nusselt correlation. Lumen side pressure drop is estimated using the Hagen-Poiseuille equation. The coupled ordinary differential equations for mass flow rate, water temperature and lumen side pressure are solved simultaneously with the equations for mass flux and convective heat transfer to determine overall heat rejection, water temperature and lumen side pressure drop. A sensitivity analysis is performed to quantify the effect of input variability on SWME response and identify critical failure modes. The analysis includes the potential effect of organic and/or inorganic contaminants and foulants, partial pore entry due to hydrophilization, and other unexpected operational failures such as bursting or fiber damage. The model can be applied to other hollow fiber membrane-based applications such as low temperature separation and concentration of valuable biomolecules from solution.

Tuned Compositional Feature Replays for Efficient Stream Learning.

Our brains extract durable, generalizable knowledge from transient experiences of the world. Artificial neural networks come nowhere close to this ability. When tasked with learning to classify objects by training on nonrepeating video frames in temporal order (online stream learning), models that learn well from shuffled datasets catastrophically forget old knowledge upon learning new stimuli. We propose a new continual learning algorithm, compositional replay using memory blocks (CRUMB), which mitigates forgetting by replaying feature maps reconstructed by combining generic parts. CRUMB concatenates trainable and reusable memory block vectors to compositionally reconstruct feature map tensors in convolutional neural networks (CNNs). Storing the indices of memory blocks used to reconstruct new stimuli enables memories of the stimuli to be replayed during later tasks. This reconstruction mechanism also primes the neural network to minimize catastrophic forgetting by biasing it toward attending to information about object shapes more than information about image textures and stabilizes the network during stream learning by providing a shared feature-level basis for all training examples. These properties allow CRUMB to outperform an otherwise identical algorithm that stores and replays raw images while occupying only 3.6% as much memory. We stress-tested CRUMB alongside 13 competing methods on seven challenging datasets. To address the limited number of existing online stream learning datasets, we introduce two new benchmarks by adapting existing datasets for stream learning. With only 3.7%-4.1% as much memory and 15%-43% as much runtime, CRUMB mitigates catastrophic forgetting more effectively than the state-of-the-art. Our code is available at https://github.com/MorganBDT/crumb.git.

Pneumococcal Polysaccharide Vaccination (PPSV23) in High-Risk Pediatric Patients With Diabetes.

OBJECTIVE: The Advisory Committee on Immunization Practices recommends the pneumococcal polysaccharide vaccine (PPSV23) following the pneumococcal conjugate vaccine (PCV13) for pediatric patients aged 2 to 18 years with high-risk medical conditions. The PPSV23 is not a routine immunization for all pediatric patients and children who meet criteria for high-risk conditions may not consistently receive the PPSV23 vaccine, despite current recommendations. The goal of this study was to determine PPSV23 -vaccination rates in the high-risk pediatric patients with type 1 or type 2 diabetes. METHODS: A single-center retrospective cohort study was conducted. Patients were included if they were 2 to 18 years of age on January 1, 2019, with a diagnosis of diabetes, and had ≥1 encounters within the health care system in 2019. The primary outcome was PPSV23 vaccination rates in the high-risk diabetic pediatric population. Secondary outcomes included identifying missed opportunities for vaccinations and the incidence of invasive pneumococcal infections. RESULTS: A total of 366 patients met criteria for study inclusion. Patients had a mean age of 13.3 years and were predominantly white (69.8%). A total of 32 (8.7%) patients had documentation of PPSV23 vaccination. Baseline characteristics were comparable between the two groups. There were 32 cases of pneumonia charted before patients received the PPSV23 and one case reported after patients received the PPSV23 vaccination. CONCLUSIONS: PPSV23 vaccination rates were low in this high-risk diabetic pediatric group, with many -documented missed opportunities for vaccination. This may be attributed to the vaccine not being a -routinely recommended for all pediatric patients.

Impairment of Endothelial Function by Aerosol From Marijuana Leaf Vaporizers.

BACKGROUND: Marijuana leaf vaporizers, which heat plant material and sublimate Δ-9-tetrahydrocannabinol without combustion, are popular alternatives to smoking cannabis that are generally perceived to be less harmful. We have shown that smoke from tobacco and marijuana, as well as aerosol from e-cigarettes and heated tobacco products, impair vascular endothelial function in rats measured as arterial flow-mediated dilation (FMD). METHODS AND RESULTS: We exposed 8 rats per group to aerosol generated by 2 vaporizer systems (Volcano and handheld Yocan) using marijuana with varying Δ-9-tetrahydrocannabinol levels, in a single pulsatile exposure session of 2 s/min over 5 minutes, and measured changes in FMD. To model secondhand exposure, we exposed rats for 1 minute to diluted aerosol approximating release of uninhaled Volcano aerosol into typical residential rooms. Exposure to aerosol from marijuana with and without cannabinoids impaired FMD by ≈50%. FMD was similarly impaired by aerosols from Yocan (237 °C), and from Volcano at both its standard temperature (185 °C) and the minimum sublimation temperature of Δ-9-tetrahydrocannabinol (157 °C), although the low-temperature aerosol condition did not effectively deliver Δ-9-tetrahydrocannabinol to the circulation. Modeled secondhand exposure based on diluted Volcano aerosol also impaired FMD. FMD was not affected in rats exposed to clean air or water vapor passed through the Volcano system. CONCLUSIONS: Acute direct exposure and modeled secondhand exposure to marijuana leaf vaporizer aerosol, regardless of cannabinoid concentration or aerosol generation temperature, impair endothelial function in rats comparably to marijuana smoke. Our findings indicate that use of leaf vaporizers is unlikely to reduce the vascular risk burden of smoking marijuana.

Complement-membrane regulatory proteins are absent from the nodes of Ranvier in the peripheral nervous system.

BACKGROUND: Homozygous CD59-deficient patients manifest with recurrent peripheral neuropathy resembling Guillain-Barré syndrome (GBS), hemolytic anemia and recurrent strokes. Variable mutations in CD59 leading to loss of function have been described and, overall, 17/18 of patients with any mutation presented with recurrent GBS. Here we determine the localization and possible role of membrane-bound complement regulators, including CD59, in the peripheral nervous systems (PNS) of mice and humans. METHODS: We examined the localization of membrane-bound complement regulators in the peripheral nerves of healthy humans and a CD59-deficient patient, as well as in wild-type (WT) and CD59a-deficient mice. Cross sections of teased sciatic nerves and myelinating dorsal root ganglia (DRG) neuron/Schwann cell cultures were examined by confocal and electron microscopy. RESULTS: We demonstrate that CD59a-deficient mice display normal peripheral nerve morphology but develop myelin abnormalities in older age. They normally express myelin protein zero (P0), ankyrin G (AnkG), Caspr, dystroglycan, and neurofascin. Immunolabeling of WT nerves using antibodies to CD59 and myelin basic protein (MBP), P0, and AnkG revealed that CD59 was localized along the internode but was absent from the nodes of Ranvier. CD59 was also detected in blood vessels within the nerve. Finally, we show that the nodes of Ranvier lack other complement-membrane regulatory proteins, including CD46, CD55, CD35, and CR1-related gene-y (Crry), rendering this area highly exposed to complement attack. CONCLUSION: The Nodes of Ranvier lack CD59 and are hence not protected from complement terminal attack. The myelin unit in human PNS is protected by CD59 and CD55, but not by CD46 or CD35. This renders the nodes and myelin in the PNS vulnerable to complement attack and demyelination in autoinflammatory Guillain-Barré syndrome, as seen in CD59 deficiency.

The benefits of nature exposure: The need for research that better informs implementation.

Concern about humanity's detachment from nature has spawned a global push to increase the availability of green spaces within cities. One impetus for this movement is a growing collection of studies documenting an association between improved human well-being and exposure to nature. The challenge lies in translating this research into pragmatic recommendations for cities. The usefulness of the existing research portfolio is diminished by the limitations of prevailing research designs. For example, most nature exposure studies (>80%) are observational. The rare randomized manipulative experiments tend to be indoors or virtual and rely on nature exposures on the order of ten to fifteen minutes. "Nature" and "biodiversity" are commonly invoked together as benefiting human well-being despite little evidence that biodiversity has particular importance for human psychological and emotional health. The most glaring gap in nature exposure research is the neglect of differences among cultures and ethnic groups with respect to the nature they prefer. In the few cases where researchers looked for differences among groups, they often found heterogeneous responses. Finally, few studies have compared greening interventions to other possible efforts to improve urban life. Thus, the utopian city of the future might be resplendent with urban parks on every block, but it is not clear whether those parks should offer basketball and pickleball courts, or small woodlands with a cornucopia of birds. We advocate for the next generation of nature exposure research that better informs the envisioning of our future sustainable cities with enhanced and equitable access to nature.

Shiga toxin targets the podocyte causing hemolytic uremic syndrome through endothelial complement activation.

BACKGROUND: Shiga toxin (Stx)-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS) is the leading cause of acute kidney injury in children, with an associated mortality of up to 5%. The mechanisms underlying STEC-HUS and why the glomerular microvasculature is so susceptible to injury following systemic Stx infection are unclear. METHODS: Transgenic mice were engineered to express the Stx receptor (Gb3) exclusively in their kidney podocytes (Pod-Gb3) and challenged with systemic Stx. Human glomerular cell models and kidney biopsies from patients with STEC-HUS were also studied. FINDINGS: Stx-challenged Pod-Gb3 mice developed STEC-HUS. This was mediated by a reduction in podocyte vascular endothelial growth factor A (VEGF-A), which led to loss of glomerular endothelial cell (GEnC) glycocalyx, a reduction in GEnC inhibitory complement factor H binding, and local activation of the complement pathway. Early therapeutic inhibition of the terminal complement pathway with a C5 inhibitor rescued this podocyte-driven, Stx-induced HUS phenotype. CONCLUSIONS: This study potentially explains why systemic Stx exposure targets the glomerulus and supports the early use of terminal complement pathway inhibition in this devastating disease. FUNDING: This work was supported by the UK Medical Research Council (MRC) (grant nos. G0901987 and MR/K010492/1) and Kidney Research UK (grant nos. TF_007_20151127, RP42/2012, and SP/FSGS1/2013). The Mary Lyon Center is part of the MRC Harwell Institute and is funded by the MRC (A410).

Voluntary Self-Exclusion and Contingency Management for the Treatment of Problematic and Harmful Gambling in the UK: An Exploratory Study.

Research into self-directed methods for reducing problematic and harmful gambling is still in its infancy. One strategy that individuals use to prevent gambling involves voluntary self-exclusion (VSE) programs. For example, VSE programs can make it challenging to access betting sites or enable banks to block gambling-related transactions. Although individual VSEs can be helpful when used alone, it is unclear whether their efficacy is enhanced when combined. Furthermore, it is unknown how VSE compliance can be improved. We propose that contingency management (CM), an evidence-based strategy to incentivise abstinence, could encourage continued VSE use, promoting long-lasting recovery from problematic or harmful gambling. Here, we conducted exploratory analyses on VSE use and CM for gambling in two populations (members of the UK general population recruited and students). Participants responded favourably regarding combined VSE use. They felt that providing vouchers exchangeable for goods/services could incentivise gambling abstinence during VSE. However, some were concerned about people potentially "gaming" the system. Participants believed supplementing VSE and CM with social support could encourage abstinence. These attitudes, and recent research on treatment providers' opinions on CM for gambling, suggest that experimental evidence should be sought to determine the efficacy of combined VSE use and CM for gambling.

Impact of changing from autopsy to post-mortem CT in an entire HM Coroner region due to a shortage of available pathologists.

A significant problem facing routine medicolegal coroner-referred autopsies is a shortfall of pathologists prepared to perform them. This was particularly acute in Lancashire, where the coroner decided to initiate a service that relied on post-mortem computed tomography (PMCT). This involved training anatomical pathology technologists (APTs) to perform external examinations, radiographers to perform scans, and radiologists to interpret them. The service started in 2018 and now examines over 1,500 cases per year. This study outlines the PMCT process using NHS staff, with CT equipment and logistics managed by the commercial sector. It compares the demographics and outcomes of PM investigations for two 6-month periods: the autopsy service prior to 2018, and then the PMCT service. These data were then compared with previous UK PMCT data. Referrals for adult non-suspicious deaths were made in 913 cases of which 793 (87%) had PMCT between 01/10/2018 and 31/03/2019. Fifty-six cases had autopsy after PMCT, so 81% of cases potentially avoided autopsy. The PMCT service did not delay release of bodies to the next-of-kin. Comparing the cause of death given shows no difference in the proportions of natural and unnatural deaths. There was an increase in diagnosis of coronary artery disease for PMCT, with less respiratory diagnoses, a feature not previously demonstrated. These data suggest PMCT is a practical solution for potentially failing autopsy services. By necessity, this involves changes in diagnoses, as PMCT and autopsy have different strengths and weakness, but the ability to pick up unnatural death appears unaffected.

Impact of the COVID-19 pandemic on a post-mortem CT service for adult non-suspicious death.

Due to the COVID-19 pandemic, the post-mortem computed tomography (PMCT) service was expanded from three to seven cases per day to help mortuary services and avoid invasive autopsy. Additional targeted angiography and pulmonary ventilation procedures were stopped and triage rules relaxed to allow more indications to be scanned, including those requiring toxicology. A service evaluation was performed for the first 3-months of the COVID-19 pandemic compared to the equivalent period the previous year to study the impact of these changes. It was found that, despite the increase in deaths regionally, coronial referrals remained about 100 per month, a reduction in referral rate. The number undergoing PMCT rose from 28% to 74% of cases. Turnaround time remained the same. For cases triaged to PMCT, the need for subsequent autopsy increased from 7.9% to 15.8%. No significant changes were seen in diagnosis rates, including cardiac or respiratory. There was an increase in patients with coronary death without severe coronary calcification who underwent autopsy after PMCT. These may have been diagnosed by targeted coronary angiography. Fifty-three cases requiring toxicology/biochemistry had PMCT, with 38 having PMCT only. In 8/11 (72.7%) cases with normal PMCT and toxicology as the key diagnostic test, autopsy was performed prior to results. This suggests the pathology team were reluctant to risk an "unascertained" outcome. This study shows that it is possible to increase PMCT services by widening referral criteria and by limiting the use of enhanced imaging techniques, without significantly changing diagnosis rates of key diseases; however, selectively restarting targeted angiography may help avoid autopsy in some cases.