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.

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.

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.

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.

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.

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.

Development of human ectocervical tissue models with physiologic endocrine and paracrine signaling†.

There is a shortage of research models that adequately represent the unique mucosal environment of human ectocervix, limiting development of new therapies for treating infertility, infection, or cancer. We developed three microphysiologic human ectocervix models to study hormone action during homeostasis. First, we reconstructed ectocervix using decellularized extracellular matrix scaffolds, which supported cell integration and could be clinically useful. Secondly, we generated organotypic systems consisting of ectocervical explants co-cultured with murine ovaries or cycling exogenous hormones, which mimicked human menstrual cycles. Finally, we engineered ectocervix tissue consisting of tissue-specific stromal-equivalents and fully-differentiated epithelium that mimicked in vivo physiology, including squamous maturation, hormone response, and mucin production, and remained viable for 28 days in vitro. The localization of differentiation-dependent mucins in native and engineered tissue was identified for the first time, which will allow increased efficiency in mucin targeting for drug delivery. In summary, we developed and characterized three microphysiologic human ectocervical tissue models that will be useful for a variety of research applications, including preventative and therapeutic treatments, drug and toxicology studies, and fundamental research on hormone action in a historically understudied tissue that is critical for women's health.

Vinyl Carbocations Generated under Basic Conditions and Their Intramolecular C-H Insertion Reactions.

Here we report the surprising discovery that high-energy vinyl carbocations can be generated under strongly basic conditions, and that they engage in intramolecular sp3 C-H insertion reactions through the catalysis of weakly coordinating anion salts. This approach relies on the unconventional combination of lithium hexamethyldisilazide base and the commercially available catalyst, triphenylmethylium tetrakis(pentafluorophenyl)borate. These reagents form a catalytically active lithium species that enables the application of vinyl cation C-H insertion reactions to heteroatom-containing substrates.

Restrictive Intraoperative Fluid Therapy is Associated with Decreased Morbidity and Length of Stay Following Hyperthermic Intraperitoneal Chemoperfusion.

BACKGROUND: Recent data have demonstrated multiple benefits of intra- and postoperative fluid restriction in major abdominal surgery; however, data regarding the outcomes of fluid restriction in cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion (CRS/HIPEC) are limited. This study evaluates the safety and short-term clinical outcomes of restricted intraoperative fluid therapy in CRS/HIPEC. METHODS: This was a single-institution, retrospective review of all CRS/HIPEC procedures performed at the University of Massachusetts Medical School between January 2009 and July 2017. Recorded variables included demographics, intraoperative factors, 60-day postoperative complications, and length of stay (LOS). Outcomes based on the use of intraoperative permissive fluid therapy (PFT) versus restrictive fluid therapy (RFT) were compared. RESULTS: Overall, 169 CRS/HIPEC cases were performed during the study period; 84 were managed with PFT and 85 were managed with RFT. No significant differences were identified in patient demographics. There was a decrease in intraoperative administration of crystalloid (8.0 vs. 4.4 L, p < 0.01), colloid (900 vs. 300 mL, p < 0.01), and blood transfusion (0.26 vs. 0.04 units, p < 0.01) in the RFT cohort. LOS was reduced from 11.5 to 9.7 days (p < 0.01) and the incidence of any 60-day complication decreased from 45 to 28% (p = 0.02) in the RFT group. The overall 90-day mortality rate was 0.6% (n = 1). Adjusted logistic regression demonstrated the odds of having a Clavien-Dindo grade III or higher complication was 0.31 (95% confidence interval 0.10-0.95) with RFT. CONCLUSION: Intraoperative RFT with standard anesthesia monitoring devices can be safely used in CRS/HIPEC and is associated with a decreased LOS and decreased rate of postoperative complications.

Gold-Catalyzed Dearomative Spirocyclization of N-Aryl Alkynamides for the Synthesis of Spirolactams.

A catalytic redox-neutral method for the synthesis of spirolactams proceeding through the dearomative spirocyclization of N-aryl alkynamides is reported. In contrast to stoichiometric activating agents employed for related transformations, we show that the use of 5 mol % of Au(PPh3)Cl and AgOTf in dichloroethane at 50-80 °C leads to selective spirocyclization, furnishing the products in yields of 35-87%. The substrate scope of the reaction is good, with both electron-donating and electron-withdrawing groups being tolerated around the arene ring, as well as substitution at the amide nitrogen. The identity of the para-alkoxy group on the arene ring is key to achieving selectivity for spirocyclization over alternative mechanistic pathways. While the presence of a para-methoxy group leads to trace amounts of the desired spirolactams, the para-tert-butoxy or para-hydroxy substrate analogues furnish the spirolactams in good yield with high selectivity.

Gold-Catalyzed Hydroarylation of N-Aryl Alkynamides for the Synthesis of 2-Quinolinones.

A mild method for the synthesis of 2-quinolinones via hydroarylation of N-aryl alkynamides is reported. While traditional methods have relied on the use of strong Brønsted or Lewis acids, this report describes the development of mild reaction conditions that yield 2-quinolinones in good to excellent yield using a commercially available gold catalyst. Substrates bearing a variety of functional groups are presented, with N-substitution proving to be key to the reactivity of several substrates.

Dietary supplementation with omega-3 polyunsaturated fatty acids modulate matrix metalloproteinase immunoreactivity in a mouse model of pre-abdominal aortic aneurysm.

BACKGROUND: Two-day infusion of angiotensin II to apolipoprotein E-deficient (ApoE(-/-)) mice provides a model of pre-abdominal aortic aneurysm. Long chain omega-3 polyunsaturated fatty acids (n-3 PUFAs) have anti-inflammatory effects. This study examined the effect of an eight-week low or high n-3 PUFA diet in ApoE(-/-) mice on matrix metalloproteinase (MMP) expression and elastin degradation. METHODS: ApoE(-/-) mice were fed a low or high n-3 PUFA diet for eight weeks prior to two-day infusion with angiotensin II. The omega-3 index, MMP-2, MMP-9, TIMP-1, and TGF-ß1 immunoreactivity, and elastin fragmentation were measured. RESULTS: The omega-3 index with the low and high n-3 PUFA diet was 3.78% and 13.03%, respectively. MMP-9 immunoreactive stain intensity was lower in mice fed the high, compared to the low n-3 PUFA diet in endothelial cells (suprarenal aorta), and inflammatory cells (suprarenal and infrarenal aorta). Inflammatory cells had higher TIMP-1 and TGF-ß1 stain intensity in mice fed the high, compared to the low n-3 PUFA diet (suprarenal aorta). MMP-2 immunoreactivity was unaffected by diet. A non-significant trend for reduced elastin fragmentation was observed in mice fed the high n-3 PUFA diet. CONCLUSION: Dietary supplementation with n-3 PUFAs may have protective anti-inflammatory effects mediated through modulation of MMPs and TIMPs.

Themes associated with uncollected paediatric prescriptions at a large tertiary children's hospital: a retrospective, observational study.

OBJECTIVE: This study aimed to assess the number of prescriptions that were uncollected by caregivers to identify any predisposing systemic themes that may act as barriers to children receiving medications. STUDY DESIGN AND SETTING: Data were retrospectively collected on uncollected prescriptions at a single, tertiary paediatric centre over a 2-month period. This included type and classification of the drug, prescriber specialty, the timing of prescription and the child's registered postcode. Key themes were identified. RESULTS: A total of 124 uncollected prescriptions involving 94 patients were included. 103 (83%) of these were clinic prescriptions, and azathioprine was the most frequently uncollected prescription (n=6, 5%). The uncollected prescriptions most commonly fell under the 'gastrointestinal system' (n=26, 21%) and 'skin' (n=24, 19%) categories, and similarly, 24 (19%) were prescribed by the gastroenterology department and 18 (15%) by dermatology. The mean distance from the child's registered postcode was 8.5±11.8 miles (range 0.5-73.4) with a considerable number of children having a registered postcode greater than 10 miles from the hospital (n=24, 27%). Many children lived in areas corresponding to the lowest decile of the Index of Multiple Deprivation (IMD) (n=38, 42%). CONCLUSION: Urgent interventions and further prospective studies are needed to minimise the barriers that caregivers face in collecting their child's prescription.

Main Group-Catalyzed Cationic Claisen Rearrangements via Vinyl Carbocations.

We report a catalytic C-O coupling/Claisen cascade reaction enabled by interception of vinyl carbocations with allyl ethers. The reaction utilizes commercially available borate salts as catalysts and is effective at constructing sterically hindered C-C bonds. The reaction mechanism is studied experimentally and computationally to support a charge-accelerated [3,3] rearrangement of a silyloxonium cation. Our reaction is also applied to the highly stereoselective synthesis of fully substituted vinyl ethers.

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.

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.

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.

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.

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.