ApoE Isoforms Inhibit Amyloid Aggregation of Proinflammatory Protein S100A9.

Increasing evidence suggests that the calcium-binding and proinflammatory protein S100A9 is an important player in neuroinflammation-mediated Alzheimer's disease (AD). The amyloid co-aggregation of S100A9 with amyloid-ß (Aß) is an important hallmark of this pathology. Apolipoprotein E (ApoE) is also known to be one of the important genetic risk factors of AD. ApoE primarily exists in three isoforms, ApoE2 (Cys112/Cys158), ApoE3 (Cys112/Arg158), and ApoE4 (Arg112/Arg158). Even though the difference lies in just two amino acid residues, ApoE isoforms produce differential effects on the neuroinflammation and activation of the microglial state in AD. Here, we aim to understand the effect of the ApoE isoforms on the amyloid aggregation of S100A9. We found that both ApoE3 and ApoE4 suppress the aggregation of S100A9 in a concentration-dependent manner, even at sub-stoichiometric ratios compared to S100A9. These interactions lead to a reduction in the quantity and length of S100A9 fibrils. The inhibitory effect is more pronounced if ApoE isoforms are added in the lipid-free state versus lipidated ApoE. We found that, upon prolonged incubation, S100A9 and ApoE form low molecular weight complexes with stochiometric ratios of 1:1 and 2:1, which remain stable under SDS-gel conditions. These complexes self-assemble also under the native conditions; however, their interactions are transient, as revealed by glutaraldehyde cross-linking experiments and molecular dynamics (MD) simulation. MD simulation demonstrated that the lipid-binding C-terminal domain of ApoE and the second EF-hand calcium-binding motif of S100A9 are involved in these interactions. We found that amyloids of S100A9 are cytotoxic to neuroblastoma cells, and the presence of either ApoE isoforms does not change the level of their cytotoxicity. A significant inhibitory effect produced by both ApoE isoforms on S100A9 amyloid aggregation can modulate the amyloid-neuroinflammatory cascade in AD.

SOD1-Related Cerebellar Ataxia and Motor Neuron Disease: Cp Variant as Functional Modifier?

We describe a novel superoxide dismutase (SOD1) mutation-associated clinical phenotype of cerebellar ataxia and motor neuron disease with a variant in the ceruloplasmin (Cp) gene, which may have possibly contributed to a multi-factorial phenotype, supported by genetic and protein structure analyses.

Dissecting the genetic landscape of GPCR signaling through phenotypic profiling in C. elegans.

G protein-coupled receptors (GPCRs) mediate responses to various extracellular and intracellular cues. However, the large number of GPCR genes and their substantial functional redundancy make it challenging to systematically dissect GPCR functions in vivo. Here, we employ a CRISPR/Cas9-based approach, disrupting 1654 GPCR-encoding genes in 284 strains and mutating 152 neuropeptide-encoding genes in 38 strains in C. elegans. These two mutant libraries enable effective deorphanization of chemoreceptors, and characterization of receptors for neuropeptides in various cellular processes. Mutating a set of closely related GPCRs in a single strain permits the assignment of functions to GPCRs with functional redundancy. Our analyses identify a neuropeptide that interacts with three receptors in hypoxia-evoked locomotory responses, unveil a collection of regulators in pathogen-induced immune responses, and define receptors for the volatile food-related odorants. These results establish our GPCR and neuropeptide mutant libraries as valuable resources for the C. elegans community to expedite studies of GPCR signaling in multiple contexts.

Care and three-year outcomes of children with Benign Epilepsy with Centro-Temporal Spikes in England.

PURPOSE: Benign Epilepsy with Centro-Temporal Spikes (BECTS) is a pediatric epilepsy with typically good seizure control. Although BECTS may increase patients' risk of developing neurological comorbidities, their clinical care and short-term outcomes are poorly quantified. METHODS: We retrospectively assessed adherence to National Institute for Health and Care Excellence (NICE) guidelines relating to specialist referral, electroencephalogram (EEG) conduct and annual review in the care of patients with BECTS, and measured their seizure, neurodevelopmental and learning outcomes at three years post-diagnosis. RESULTS: Across ten centers in England, we identified 124 patients (74 male) diagnosed with BECTS between 2015 and 2017. Patients had a mean age at diagnosis of 8.0 (95% CI = 7.6-8.4) years. 24/95 (25%) patients were seen by a specialist within two weeks of presentation; 59/100 (59%) received an EEG within two weeks of request; and 59/114 (52%) were reviewed annually. At three years post-diagnosis, 32/114 (28%) experienced ongoing seizures; 26/114 (23%) had reported poor school progress; 15/114 (13%) were diagnosed with a neurodevelopmental disorder (six autism spectrum disorder, six attention-deficit/hyperactivity disorder); and 10/114 (8.8%) were diagnosed with a learning difficulty (three processing deficit, three dyslexia). Center-level random effects models estimated neurodevelopmental diagnoses in 9% (95% CI: 2-16%) of patients and learning difficulty diagnoses in 7% (95% CI: 2-12%). CONCLUSIONS: In this multicenter work, we found variable adherence to NICE guidelines in the care of patients with BECTS and identified a notable level of neurological comorbidity. Patients with BECTS may benefit from enhanced cognitive and behavioral assessment and monitoring.

A narrative review of potential drug treatments for nephritis in children with IgA vasculitis (HSP).

Immunoglobulin A (IgA) vasculitis (IgAV, also known as Henoch-Schoenlein purpura, HSP) is the most common vasculitis of childhood. It usually presents with a simple, self-limiting disease course; however, a small subset of patients may develop kidney involvement (IgAV-N) which occurs 4-12 weeks after disease onset and is the biggest contributor to long-term morbidity. Treatment currently targets patients with established kidney involvement; however; there is a desire to work towards early prevention of inflammation during the window of opportunity between disease presentation and onset of significant nephritis. There are no clinical trials evaluating drugs which may prevent or halt the progression of nephritis in children with IgAV apart from the early use of corticosteroids which have no benefit. This article summarises the latest scientific evidence and clinical trials that support potential therapeutic targets for IgAV-N that are currently being developed based on the evolving understanding of the pathophysiology of IgAV-N. These span the mucosal immunity, B-cell and T-cell modulation, RAAS inhibition, and regulation of complement pathways, amongst others. Novel drugs that may be considered for use in early nephritis include TRF-budesonide; B-cell inhibiting agents including belimumab, telitacicept, blisibimod, VIS649, and BION-1301; B-cell depleting agents such as rituximab, ofatumumab, and bortezomib; sparsentan; angiotensin converting enzyme inhibitors (ACE-Is); and complement pathway inhibitors including avacopan, iptacopan, and narsoplimab. Further clinical trials, as well as pre-clinical scientific studies, are needed to identify mechanistic pathways as there may be an opportunity to prevent nephritis in this condition. Key Points • Kidney involvement is the main cause of long-term morbidity and mortality in IgA vasculitis despite the current treatment recommendations. • The evolving understanding of the pathophysiology of IgA vasculitis is allowing exploration of novel treatment options which target underlying immune pathways. • Novel treatments currently being trialled in IgA nephropathy may have benefit in IgA vasculitis due to the similarities in the underlying pathophysiology, such as TRF-budesonide, B-cell modulators, and complement inhibitors. • Further studies, including clinical trials of novel drugs, are urgently needed to improve the long-term outcomes for children with IgA vasculitis nephritis.

Analysis of proteome-wide degradation dynamics in ALS SOD1 iPSC-derived patient neurons reveals disrupted VCP homeostasis.

Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS) through gain-of-function effects, yet the mechanisms by which misfolded mutant SOD1 (mutSOD1) protein impairs human motor neurons (MNs) remain unclear. Here, we use induced-pluripotent-stem-cell-derived MNs coupled to metabolic stable isotope labeling and mass spectrometry to investigate proteome-wide degradation dynamics. We find several proteins, including the ALS-causal valosin-containing protein (VCP), which predominantly acts in proteasome degradation and autophagy, that degrade slower in mutSOD1 relative to isogenic control MNs. The interactome of VCP is altered in mutSOD1 MNs in vitro, while VCP selectively accumulates in the affected motor cortex of ALS-SOD1 patients. Overexpression of VCP rescues mutSOD1 toxicity in MNs in vitro and in a C. elegans model in vivo, in part due to its ability to modulate the degradation of insoluble mutSOD1. Our results demonstrate that VCP contributes to mutSOD1-dependent degeneration, link two distinct ALS-causal genes, and highlight selective protein degradation impairment in ALS pathophysiology.

The multifaceted consequences and economic costs of child anxiety problems: A systematic review and meta-analysis.

Background: Over a quarter of people have an anxiety disorder at some point in their life, with many first experiencing difficulties during childhood or adolescence. Despite this, gaps still exist in the current evidence base of the multiple consequences of childhood anxiety problems and their costs. Methods: A systematic review of Medline, PsycINFO, EconLit and the National Health Service Economic Evaluation Database was conducted for longitudinal and economic studies reporting on the association between childhood anxiety problems and at least one individual-, family- or societal-level outcome or cost. All studies were synthesised narratively. For longitudinal studies, 'effect direction' was used as a common metric, with random effects meta-analysis undertaken where possible. Results: Eighty-three studies met inclusion criteria and were synthesised narratively. We identified 788 separate analyses from the longitudinal studies, which we grouped into 15 overarching outcome domains. Thirteen of the studies were incorporated into 13 meta-analyses, which indicated that childhood anxiety disorders were associated with future anxiety, mood, behaviour and substance disorders. Narrative synthesis also suggested associations between anxiety problems and worse physical health, behaviour, self-harm, eating, relationship, educational, health care, employment, and financial outcomes. 'Effect direction' was conflicting in some domains due to a sparse evidence base. Higher economic costs were identified for the child, their families, healthcare providers and wider society, although evidence was limited and only covered short follow-up periods, up to a maximum of 2 years. Total annual societal costs per anxious child were up to £4040 (2021 GBP). Conclusions: Childhood anxiety problems are associated with impaired outcomes in numerous domains, and considerable economic costs, which highlight the need for cost-effective interventions and policies to tackle them. More economic evidence is needed to inform models of the long-term, economic-related, consequences of childhood anxiety problems.

A case series on recurrent and persisting IgA vasculitis (Henoch Schonlein purpura) in children.

BACKGROUND: IgA vasculitis (IgAV) is a small vessel vasculitis that is more common in childhood. Very limited evidence exists on patients who experience an atypical disease course. The aim of this study was to describe a cohort of children diagnosed with recurrent or persisting IgAV to identify any themes associated with their disease course and areas of unmet needs. METHODS: A single centre retrospective study of children diagnosed with recurrent or persisting IgAV at Alder Hey Children's Hospital (Liverpool, UK). Clinical data, including features at presentation and during follow up, potential triggers, abnormal laboratory and histology results, treatment and outcome at last clinical review were retrospectively collected. Key themes were identified. RESULTS: A total of 13 children met the inclusion criteria (recurrent disease, n = 4; persisting disease, n = 9). Median age at first presentation was 10.2 years [2.6-15.5], female:male ratio 1.2:1. Children in the atypical cohort were significantly older than a larger cohort of children who followed a non-complicated disease course (median age 5.5 years (range [0.6-16.7], p = 0.003)). All children re-presented with a purpuric rash (either recurring or persisting), accompanied by joint involvement in 92% of patients (12/13). Disease-modifying anti-rheumatic drugs (DMARDs) were used in 8/13 (62%) children. The median time from first presentation to diagnosis of atypical disease was 18.4 months [5.3-150.8] and the time from first presentation to treatment was 24.1 months [1.8-95.4]. Use of corticosteroids was significantly higher in children with renal involvement (p = 0.026). During follow up, 8/13 (62%) children were admitted at least once, whilst 10/13 (77%) had re-presented at least once to the emergency department. Five (38%) children were referred to psychology services and 7 (54%) children reported feelings of frustration. CONCLUSIONS: This series describes some characteristics of a small cohort of children with atypical IgAV. It also identifies unmet needs in children with atypical IgAV, which includes delays in diagnosis and lengthy waits for treatment, lack of high-quality evidence regarding treatment choices and a high unrecognised disease burden. Further research is needed to study this subgroup of children as evidence is lacking.

α-Vinylation of Ester Equivalents via Main Group Catalysis for the Construction of Quaternary Centers.

A methodology for the construction of sterically congested quaternary centers via the trapping of vinyl carbocations with silyl ketene acetals is disclosed. This main group-catalyzed α-vinylation reaction is advantageous as methods to access these congested motifs are limited. Moreover, ß,γ-unsaturated carbonyl moieties and tetrasubstituted alkenes are present in various bioactive natural products and pharmaceuticals, and this catalytic platform offers a means of accessing them using simple and inexpensive materials.

Short term starvation potentiates the efficacy of chemotherapy in triple negative breast cancer via metabolic reprogramming.

BACKGROUND: Chemotherapy (CT) is central to the treatment of triple negative breast cancer (TNBC), but drug toxicity and resistance place strong restrictions on treatment regimes. Fasting sensitizes cancer cells to a range of chemotherapeutic agents and also ameliorates CT-associated adverse effects. However, the molecular mechanism(s) by which fasting, or short-term starvation (STS), improves the efficacy of CT is poorly characterized. METHODS: The differential responses of breast cancer or near normal cell lines to combined STS and CT were assessed by cellular viability and integrity assays (Hoechst and PI staining, MTT or H2DCFDA staining, immunofluorescence), metabolic profiling (Seahorse analysis, metabolomics), gene expression (quantitative real-time PCR) and iRNA-mediated silencing. The clinical significance of the in vitro data was evaluated by bioinformatical integration of transcriptomic data from patient data bases: The Cancer Genome Atlas (TCGA), European Genome-phenome Archive (EGA), Gene Expression Omnibus (GEO) and a TNBC cohort. We further examined the translatability of our findings in vivo by establishing a murine syngeneic orthotopic mammary tumor-bearing model. RESULTS: We provide mechanistic insights into how preconditioning with STS enhances the susceptibility of breast cancer cells to CT. We showed that combined STS and CT enhanced cell death and increased reactive oxygen species (ROS) levels, in association with higher levels of DNA damage and decreased mRNA levels for the NRF2 targets genes NQO1 and TXNRD1 in TNBC cells compared to near normal cells. ROS enhancement was associated with compromised mitochondrial respiration and changes in the metabolic profile, which have a significant clinical prognostic and predictive value. Furthermore, we validate the safety and efficacy of combined periodic hypocaloric diet and CT in a TNBC mouse model. CONCLUSIONS: Our in vitro, in vivo and clinical findings provide a robust rationale for clinical trials on the therapeutic benefit of short-term caloric restriction as an adjuvant to CT in triple breast cancer treatment.

Distressed Communities Index Is Not Associated with Mortality for Critically Ill Surgical Patients with Sepsis.

Background: The impact of socioeconomic metrics on outcomes after sepsis is unclear. The Distressed Communities Index (DCI) is a composite score quantifying socioeconomic well-being by zip code. The primary objective of this study was to evaluate the association between DCI and mortality in patients with sepsis admitted to the surgical intensive care unit (SICU). Patients and Methods: All patients with sepsis admitted to the SICU (Sequential Organ Failure Assessment [SOFA] score ≥2) were reviewed retrospectively. Composite DCI scores were obtained for each patient and classified into high-distress (DCI ≥75th percentile; n = 331) and control distress (DCI <50th percentile; n = 666) groups. Baseline demographic and clinical characteristics were compared between groups. The primary outcomes were in-hospital and 90-day mortality. Results: The high-distress cohort was younger and more likely to be African American (19.6% vs. 6.2%), transferred from an outside facility (52% vs. 42%), have chronic obstructive pulmonary disease (25.1% vs. 18.8%), and baseline liver disease (8.2% vs. 4.2%). Sepsis presentation was comparable between groups. Compared with the control cohort, high-distress patients had similar in-house (23% vs. 24%) and 90-day mortality (30% vs. 28%) but were associated with longer hospital stay (23 vs. 19 days). High DCI failed to predict in-hospital or 90-day mortality but was an independent risk factor for longer hospital length of stay (odds ratio [OR], 2.83 ± 1.42; p = 0.047). Conclusions: High DCI was not associated with mortality but did independently predict longer length of stay. This may reflect limitations of DCI score in evaluating mortality for patients with sepsis. Future studies should elucidate its association with length of stay, re-admissions, and follow-up.

Catalytic asymmetric C-H insertion reactions of vinyl carbocations.

From the preparation of pharmaceuticals to enzymatic construction of natural products, carbocations are central to molecular synthesis. Although these reactive intermediates are engaged in stereoselective processes in nature, exerting enantiocontrol over carbocations with synthetic catalysts remains challenging. Many resonance-stabilized tricoordinated carbocations, such as iminium and oxocarbenium ions, have been applied in catalytic enantioselective reactions. However, their dicoordinated counterparts (aryl and vinyl carbocations) have not, despite their emerging utility in chemical synthesis. We report the discovery of a highly enantioselective vinyl carbocation carbon-hydrogen (C-H) insertion reaction enabled by imidodiphosphorimidate organocatalysts. Active site confinement featured in this catalyst class not only enables effective enantiocontrol but also expands the scope of vinyl cation C-H insertion chemistry, which broadens the utility of this transition metal-free C(sp3)-H functionalization platform.

Identifying Child Anxiety Through Schools-identification to intervention (iCATS-i2i): protocol for single-arm feasibility trial.

BACKGROUND: Anxiety disorders are common among primary-school aged children, but few affected children receive evidence-based treatment. Identifying and supporting children who experience anxiety problems through schools would address substantial treatment access barriers that families and school staff often face. We have worked with families and school staff to co-design procedures that incorporate screening, feedback for parents, and the offer of a brief intervention in primary schools. This study sets out to assess the feasibility of a subsequent school-based cluster randomised controlled trial to evaluate these procedures. Our objectives are to ensure our procedures for identifying and supporting children with anxiety difficulties through primary schools are acceptable and there are no negative impacts, to estimate recruitment and retention rates, and to identify any changes needed to study procedures or measures. METHODS: We will recruit six primary/junior schools in England (2 classes per school), and invite all children (aged 8-9) (n = 360) and their parent/carer and class teacher in participating classes to take part. Children, parents and class teachers will complete questionnaires at baseline and 12-week follow-up. Children who 'screen positive' on a 2-item parent-report child anxiety screen at baseline will be the target population (expected n = 43). Parents receive feedback on screening questionnaire responses, and where the child screens positive the family is offered support (OSI: Online Support and Intervention for child anxiety). OSI is a brief, parent-led online intervention, supported by short telephone sessions with a Children's Wellbeing Practitioner. Participants' experiences of study procedures will be assessed through qualitative interviews/discussion groups. DISCUSSION: Evidence-based procedures for identifying and supporting children with anxiety difficulties through primary schools would improve children's access to timely, effective intervention for anxiety difficulties. TRIAL REGISTRATION: ISRCTN registry: ISRCTN30032471 . Retrospectively registered on 18 May 2021.

ATP-independent molecular chaperone activity generated under reducing conditions.

Molecular chaperones are essential to maintain proteostasis. While the functions of intracellular molecular chaperones that oversee protein synthesis, folding and aggregation, are established, those specialized to work in the extracellular environment are less understood. Extracellular proteins reside in a considerably more oxidizing milieu than cytoplasmic proteins and are stabilized by abundant disulfide bonds. Hence, extracellular proteins are potentially destabilized and sensitive to aggregation under reducing conditions. We combine biochemical and mass spectrometry experiments and elucidate that the molecular chaperone functions of the extracellular protein domain Bri2 BRICHOS only appear under reducing conditions, through the assembly of monomers into large polydisperse oligomers by an intra- to intermolecular disulfide bond relay mechanism. Chaperone-active assemblies of the Bri2 BRICHOS domain are efficiently generated by physiological thiol-containing compounds and proteins, and appear in parallel with reduction-induced aggregation of extracellular proteins. Our results give insights into how potent chaperone activity can be generated from inactive precursors under conditions that are destabilizing to most extracellular proteins and thereby support protein stability/folding in the extracellular space. SIGNIFICANCE: Chaperones are essential to cells as they counteract toxic consequences of protein misfolding particularly under stress conditions. Our work describes a novel activation mechanism of an extracellular molecular chaperone domain, called Bri2 BRICHOS. This mechanism is based on reducing conditions that initiate small subunits to assemble into large oligomers via a disulfide relay mechanism. Activated Bri2 BRICHOS inhibits reduction-induced aggregation of extracellular proteins and could be a means to boost proteostasis in the extracellular environment upon reductive stress.

Alteration of Mitochondrial Integrity as Upstream Event in the Pathophysiology of SOD1-ALS.

Little is known about the early pathogenic events by which mutant superoxide dismutase 1 (SOD1) causes amyotrophic lateral sclerosis (ALS). This lack of mechanistic understanding is a major barrier to the development and evaluation of efficient therapies. Although protein aggregation is known to be involved, it is not understood how mutant SOD1 causes degeneration of motoneurons (MNs). Previous research has relied heavily on the overexpression of mutant SOD1, but the clinical relevance of SOD1 overexpression models remains questionable. We used a human induced pluripotent stem cell (iPSC) model of spinal MNs and three different endogenous ALS-associated SOD1 mutations (D90Ahom, R115Ghet or A4Vhet) to investigate early cellular disturbances in MNs. Although enhanced misfolding and aggregation of SOD1 was induced by proteasome inhibition, it was not affected by activation of the stress granule pathway. Interestingly, we identified loss of mitochondrial, but not lysosomal, integrity as the earliest common pathological phenotype, which preceded elevated levels of insoluble, aggregated SOD1. A super-elongated mitochondrial morphology with impaired inner mitochondrial membrane potential was a unifying feature in mutant SOD1 iPSC-derived MNs. Impaired mitochondrial integrity was most prominent in mutant D90Ahom MNs, whereas both soluble disordered and detergent-resistant misfolded SOD1 was more prominent in R115Ghet and A4Vhet mutant lines. Taking advantage of patient-specific models of SOD1-ALS in vitro, our data suggest that mitochondrial dysfunction is one of the first crucial steps in the pathogenic cascade that leads to SOD1-ALS and also highlights the need for individualized medical approaches for SOD1-ALS.

Erratum: Generation and analysis of innovative genomically humanized knockin SOD1, TARDBP (TDP-43), and FUS mouse models.

[This corrects the article DOI: 10.1016/j.isci.2021.103463.].

Vancomycin-associated acute kidney injury epidemiology in children: a systematic review.

INTRODUCTION: Vancomycin is a recognised cause of drug-induced acute kidney injury (AKI). OBJECTIVE: The aim of this systematic review was to summarise the incidence of, and the risk factors for, vancomycin-associated AKI (v-AKI) in children. DESIGN: A systematic search was performed in November 2020 on the search engines PubMed, Web of Science and Medline, using predefined search terms. The inclusion criteria were primary paediatric studies, intervention with vancomycin and studies that included AKI as an outcome. Study quality was assessed using the relevant Critical Appraisal Skills Programme checklist. The data are reported using descriptive statistics. RESULTS: 890 studies were identified and screened with 25 studies suitable for inclusion. A cohort of 12 730 patients with v-AKI were included and the incidence of v-AKI in children was found to be 11.8% (1.6%-27.2%). The median age of the cohort was 2.5 years (range 0-23) and 57% were male patients. Risk factors that increased the likelihood of v-AKI were concomitant use of nephrotoxic medications, increased trough concentrations and, to a lesser extent, increased dose, longer duration of treatment, impaired renal function and if the patient required paediatric intensive care. CONCLUSIONS: The incidence of v-AKI in children is significant and methods to reduce this risk should be considered. Further prospective interventional studies to understand the mechanisms of nephrotoxicity from vancomycin are needed and targeting risk factors may make vancomycin administration safer.

Traumatic Injury Under COVID-19 Stay-at-Home Advisory: Experience of a New England Trauma Center.

BACKGROUND: With the onset of the COVID-19 pandemic and subsequent widespread stay-at-home advisories throughout early 2020, hospitals have noticed a decrease in illnesses unrelated to COVID-19. However, the impact on traumatic injury is relatively unknown. This study aims to characterize patterns of trauma during the COVID-19 pandemic at a Level I Trauma Center. MATERIALS & METHODS: A retrospective review was performed of adult trauma patients from March to June, in the years 2018 through 2020. Primary outcome was the number of trauma activations (volume). Secondary outcomes included activation level, mechanism of injury, mortality rate, and length of stay, and other demographic background. Trauma patterns of the 2018 and 2019 periods were combined as historical control, and compared to patterns of the biweekly-matched period of 2020. RESULTS: A total of 2,187 patients were included in analysis (Pre-COVID n = 1,572; COVID n = 615). Results were significant for decreased trauma volume but longer length of stay during COVID cohort, and for an increased proportion of males. No significant difference was found for other demographic variables, trauma mechanisms, or severity. Trauma volume patterns mirrored COVID rates in the state. CONCLUSIONS: Despite a decline in trauma volume, other trauma patterns including severity and mechanism remained unchanged during the COVID-19 period. The decreased volume was not associated with a markedly lower clinical workload, change in team structure, or provider coverage re-distribution. Our data suggests that trauma volume and severity remained high enough during COVID-19 peak to necessitate full staffing, which may provide guidance in the event of a pandemic resurgence.

Ketone Bodies Impact on Hypoxic CO2 Retention Protocol During Exercise.

Exogenous ketone esters have demonstrated the capacity to increase oxygen availability during acute hypoxic exposure leading to the potential application of their use to mitigate performance declines at high altitudes. Voluntary hypoventilation (VH) with exercise reliably reduces oxygen availability and increases carbon dioxide retention without alterations to ambient pressure or gas content. Utilizing a double-blind randomized crossover design, fifteen recreational male distance runners performed submaximal exercise (4 × 5 min; 70% VO2 Max) with VH. An exogenous ketone ester (KME; 573 mg⋅kg-1) or iso-caloric flavor matched placebo (PLA) was consumed prior to exercise. Metabolites, blood gases, expired air, heart rate, oxygen saturation, cognition, and perception metrics were collected throughout. KME rapidly elevated R-ß-hydroxybutyrate and reduced blood glucose without altering lactate production. KME lowered pH, bicarbonate, and total carbon dioxide. VH with exercise significantly reduced blood (SpO2) and muscle (SmO2) oxygenation and increased cognitive mean reaction time and respiratory rate regardless of condition. KME administration significantly elevated respiratory exchange ratio (RER) at rest and throughout recovery from VH, compared to PLA. Blood carbon dioxide (PCO2) retention increased in the PLA condition while decreasing in the KME condition, leading to a significantly lower PCO2 value immediately post VH exercise (IPE; p = 0.031) and at recovery (p = 0.001), independent of respiratory rate. The KME's ability to rapidly alter metabolism, acid/base balance, CO2 retention, and respiratory exchange rate independent of respiratory rate changes at rest, during, and/or following VH exercise protocol illustrates a rapid countermeasure to CO2 retention in concert with systemic metabolic changes.

A systematic review of urine biomarkers in children with IgA vasculitis nephritis.

BACKGROUND: Nephritis is a recognised complication of IgA vasculitis (IgAV, Henoch-Schönlein purpura) contributing to 1-2% of all chronic kidney disease (CKD) stage 5. Improved understanding may reduce irreversible damage in IgAV nephritis (IgAV-N). OBJECTIVE: The aim of this study was to perform a comprehensive systematic literature review to identify promising clinical and pre-clinical urine biomarkers in children with IgAV-N that could predict the presence of nephritis and/or determine its severity. METHODS: A systematic literature review was performed using four search engines and a predefined search term strategy. Promising biomarkers were divided in terms of clinical or pre-clinical and ability to predict the presence of nephritis or determine its severity. Results were described using statistical significance (p < 0.05) and area under the curve (AUC) values. RESULTS: One hundred twenty-one studies were identified; 13 were eligible. A total of 2446 paediatric patients were included: healthy controls (n = 761), children with IgAV-N (n = 1236) and children with IgAV without nephritis (IgAV-noN, n = 449). Fifty-one percent were male, median age 7.9 years. The clinical markers, 24-h protein quantity and urine protein:creatinine ratio, were deemed acceptable for assessing severity of nephritis (AUC < 0.8). Urinary albumin concentration (Malb) performed well (AUC 0.81-0.98). The most promising pre-clinical urinary biomarkers in predicting presence of nephritis were as follows: kidney injury molecule-1 (KIM-1) (AUC 0.93), monocyte chemotactic protein-1 (MCP-1) (AUC 0.83), N-acetyl-ß-glucosaminidase (NAG) (0.76-0.96), and angiotensinogen (AGT) (AUC not available). Urinary KIM-1, MCP-1, and NAG appeared to correlate with disease severity. CONCLUSIONS: Longitudinal studies are needed to assess whether pre-clinical biomarkers enhance standard of care in IgAV-N.