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ABSTRACT An essential connection between critique and the millenarian has been proposed with particular reference to the study of Melanesian cargo cults. It is argued here that all critique is not necessarily millenarian. Rather, what is crucial for critique to have a millenarian form is for local cosmological ideas and practices to become transformed into the source of a new kind of future; a future that appears delimited by outside power relations (colonial, mission, capitalist) that now define what is possible. Often this involves altering local cosmological ideas of the outside (e.g. the dead) as the new source of future fecundity. The article considers two cases, among Fuyuge and Manus Islands peoples, where forms of critique and the millenarian have radically different outcomes. [ABSTRACT FROM AUTHOR]

Immunotactoid glomerulopathy (ITG), a condition characterised by highly organised microtubules on electron microscopy, and cryoglobulin glomerulopathy (CG) are rare forms of kidney injury that may be encountered in patients with cryoglobulinaemia. It has been proposed these two entities are part of the same disease process following observed clinical and histological similarities. [ABSTRACT FROM AUTHOR]

Objective: To understand rural older farmers' perspectives and attitudes toward skin cancer risk and prevention. Design and sample: This study used a grounded theory approach and semi‐structured interviews with 12 rural older farmers (farm owners, farmworkers ages 50 years or older) in Washington. Participants' perspectives were explored relative to Health Belief Model constructs. Inductive and deductive analyses were used to generate relevant themes. COREQ guidelines were followed. Results: The findings fit well and extended the Health Belief Model, which was used to arrange key themes identified in relation to skin cancer risk and prevention, specifically participants' perceived barriers to accessing primary care and protection when outdoors, perceived benefits of sun‐protective behaviors, perceived hereditary susceptibility to skin cancer, perceived severity of the increased skin cancer risk, and cues to action for skin checks. A new construct of hope was identified to emphasize the importance of establishing emotional, instrumental, and informational support systems for promoting skin cancer prevention. Participants also indicated their hope of raising awareness of skin cancer prevention among all ages. Conclusions: Findings highlighted the importance of integrating skin cancer prevention services for rural older farmers and across the lifespan. Public health approaches are needed to enhance the awareness of and access to preventive care in these underserved populations. [ABSTRACT FROM AUTHOR]

Aim: The real‐world benefits of continuous glucose monitoring (CGM) in the broad type 2 diabetes (T2D) population are not well studied. Our study evaluated the impact of CGM use on health care resource utilization over 12 months in adults with T2D. Materials and Methods: This retrospective cohort analysis used Optum's de‐identified Market Clarity data of >79 million people to evaluate CGM use in people with T2D who were treated with non‐insulin (NIT), basal insulin (BIT) and prandial insulin therapy (PIT). The primary outcomes were changes in all‐cause hospitalizations, acute diabetes‐related hospitalizations and acute diabetes‐related emergency room visits during the 6‐ and 12‐month post‐index period following transition from blood glucose monitoring to CGM. A pre‐specified subgroup analysis assessed glucose control and medication changes among people with T2D over 1 year. Results: The analysis included 74 679 adults with T2D (NIT; n = 25 269), (BIT; n = 16 264) and (PIT; n = 33 146). Significant reductions in all‐cause hospitalizations, acute diabetes‐related hospitalizations and acute diabetes‐related emergency room visits were observed in the 6‐month post‐index period that were sustained during the 6–12 month post‐index period (NIT, −10.1%, −31.0%, −30.7%; BIT, −13.9%, −47.6%, −28.2%; and PIT, −22.6%, −52.7%, −36.6%, respectively). A subgroup analysis of 6030 people showed mean glycated haemoglobin reductions at approximately 3 months, which were also sustained throughout the post‐index period: NIT, −1.1 (0.05)%; BIT, −1.1 (0.06)%; and PIT, −0.9 (0.04)%, p < 0.0001. Conclusions: CGM use in real‐life across different therapeutic regimens in adults with T2D was associated with reductions in health care resource utilization with improved glucose control over 1 year. [ABSTRACT FROM AUTHOR]

Radical‐right parties have gradually penetrated the political mainstream in many liberal democracies, marking a trend of 'democratic backsliding'. We propose that women's increasing visibility as representatives of radical‐right agendas makes democratic backsliders, their policies and their parties seem more legitimate, and may help explain their growing public acceptance. Our studies provide the first systematic examination of this hypothesis in three countries – Israel, Germany and the United States (N = 7203). In Studies 1a‐c, we show that voters perceive democracy‐eroding policies through a gendered lens – they attribute gender stereotypes to the parties promoting these policies and to the public supporting these policies. In Studies 2a‐c, we experimentally demonstrate the effect of politicians' gender on public acceptance of democracy‐eroding policies, politicians and parties, and demonstrate the role of gender stereotypes in mediating this effect. Finally, we show that the audiences susceptible to the mainstreaming effect of politicians' gender are precisely those that are often particularly repelled by radical‐right agendas and their perceived masculine image: Women and left‐wing voters. [ABSTRACT FROM AUTHOR]

Aims: Recently, SOX17 has emerged as a promising biomarker for non‐mucinous Müllerian (ovarian and endometrial) carcinomas, demonstrating increased specificity in comparison to PAX8 while maintaining similar sensitivity. However, expression of SOX17 in mesonephric‐like adenocarcinoma (MLA), a carcinoma of the female genital tract with uncertain, but probably Müllerian histogenesis, remains unexplored. This study aims to address this gap. Methods and results: SOX17 immunohistochemistry was performed on whole tissue sections from 68 MLAs originating from the endometrium or ovary and seven cervical mesonephric carcinomas, as well as six mesonephric remnants/hyperplasias. Using a four‐tiered scoring system based on distribution and intensity of staining, 68% of MLA displayed a negative/low (< 10%) SOX17 expression pattern, which contrasts with the high expression observed in most Müllerian carcinomas. However, 22% of MLA demonstrated high SOX17 expression, similar to other endometrial and ovarian carcinomas. Similarly, five of seven (72%) mesonephric carcinomas of the cervix were SOX17‐negative, but two cases (28%) were positive. All mesonephric remnants/hyperplasias were SOX17 negative. Conclusions: The majority of MLA are negative or exhibit low SOX17 expression, in contrast to the diffuse and strong expression commonly seen in other types of Müllerian carcinoma. However, a subset of MLAs demonstrate high SOX17 expression. Therefore, absence of SOX17 staining is supportive for MLA when the differential includes another non‐mucinous Müllerian carcinoma. SOX17 may also be useful for differentiating mesonephric remnants/hyperplasias from Müllerian malignancies and benign Müllerian glandular lesions. [ABSTRACT FROM AUTHOR]

This study investigates the potential of energy‐coupling factor (ECF) transporters as promising anti‐infective targets to combat antimicrobial resistance (AMR). ECF transporters, a subclass of ATP‐binding cassette (ABC) transporters, facilitate the uptake of B‐vitamins across bacterial membranes by utilizing ATP as an energy source. Vitamins are essential cofactors for bacterial metabolism and growth, and they can either be synthesized de novo or absorbed from the environment. These transporters are considered promising drug targets, underscoring the need for further research to harness their medicinal potential and develop selective inhibitors that block vitamin uptake in bacteria. Herein, we focused on the ECF transporter for pantothenate (vitamin B5) from Streptococcus pneumoniae and the ECF transporter for folate (vitamin B9) from Lactobacillus delbrueckii as a reference protein. We also included the energizing module for pantothenate along with both full transporter complexes. Initially, we transformed and purified the transporters, followed by an assessment of their thermal stability under various buffer composition, pH, and salt concentrations. Additionally, we monitored the melting temperature over six days to confirm their stability for further assays. We then measured the binding affinities of six ECF inhibitors using surface plasmon resonance (SPR) and evaluated their inhibitory effects through in vitro assays, including bacterial growth assay, whole‐cell uptake, and transport‐activity assays. After determining cytotoxicity in two human cell lines, we established an in vivo infection model using Galleria mellonella larvae to further validate our findings. [ABSTRACT FROM AUTHOR]

Hypoxic ischaemic brain injury after resuscitation from cardiac arrest is associated with dismal clinical outcomes. To date, most clinical interventions have been geared towards the restoration of cerebral oxygen delivery after resuscitation; however, outcomes in clinical trials are disappointing. Therefore, alternative disease mechanism(s) are likely to be at play, of which the response of the innate immune system to sterile injured tissue in vivo after reperfusion has garnered significant interest. The innate immune system is composed of three pillars: (i) cytokines and signalling molecules; (ii) leucocyte migration and activation; and (iii) the complement cascade. In animal models of hypoxic ischaemic brain injury, pro‐inflammatory cytokines are central to propagation of the response of the innate immune system to cerebral ischaemia–reperfusion. In particular, interleukin‐1 beta and downstream signalling can result in direct neural injury that culminates in cell death, termed pyroptosis. Leucocyte chemotaxis and activation are central to the in vivo response to cerebral ischaemia–reperfusion. Both parenchymal microglial activation and possible infiltration of peripherally circulating monocytes might account for exacerbation of an immunopathological response in humans. Finally, activation of the complement cascade intersects with multiple aspects of the innate immune response by facilitating leucocyte activation, further cytokine release and endothelial activation. To date, large studies of immunomodulatory therapies have not been conducted; however, lessons learned from historical studies using therapeutic hypothermia in humans suggest that quelling an immunopathological response might be efficacious. Future work should delineate the precise pathways involved in vivo in humans to target specific signalling molecules. [ABSTRACT FROM AUTHOR]

Summary: Phenotypic plasticity describes a genotype's ability to produce different phenotypes in response to different environments. Breeding crops that exhibit appropriate levels of plasticity for future climates will be crucial to meeting global demand, but knowledge of the critical environmental factors is limited to a handful of well‐studied major crops.Using 727 maize (Zea mays L.) hybrids phenotyped for grain yield in 45 environments, we investigated the ability of a genetic algorithm and two other methods to identify environmental determinants of grain yield from a large set of candidate environmental variables constructed using minimal assumptions.The genetic algorithm identified pre‐ and postanthesis maximum temperature, mid‐season solar radiation, and whole season net evapotranspiration as the four most important variables from a candidate set of 9150. Importantly, these four variables are supported by previous literature. After calculating reaction norms for each environmental variable, candidate genes were identified and gene annotations investigated to demonstrate how this method can generate insights into phenotypic plasticity.The genetic algorithm successfully identified known environmental determinants of hybrid maize grain yield. This demonstrates that the methodology could be applied to other less well‐studied phenotypes and crops to improve understanding of phenotypic plasticity and facilitate breeding crops for future climates. [ABSTRACT FROM AUTHOR]

We report the synthesis and characterization of library of new 2,3–disubstituted norbornadiene/quadricyclane couples. For the first time, the para–tolylsulfone moiety was employed as electron–withdrawing substituent in combination with a variety of different electron donors as counterparts. Comprehensive characterization was conducted for every interconversion couple. By comparison with structurally related molecules published before we established the tosyl moiety as suitable alternative to previously investigated ester functionalities by providing similar photophysical properties. The photo–induced interconversion behavior was investigated via UV/Vis‐ and NMR–spectroscopy. The UV/Vis experiments were carried out exclusively in acetonitrile, whereas several solvents were investigated in the NMR studies. A detailed description and comparison of the isomerization behavior is provided, while examining relevant optical properties like λmax and λonset. Thereby, an enhanced red‐shift up to λmax=394 nm combined with an λonset value of 469 nm could be generated which is necessary for potential applications. [ABSTRACT FROM AUTHOR]

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Summary: This S2k guideline was developed on the initiative and under the German Society of Phlebology and Lymphology (DGPL) leadership. The guideline aims to optimize the diagnosis and treatment of lipedema. It is intended to bring together the different approaches of the respective professional groups in a consensus‐based manner and thus offer a basic concept for the best possible treatment of patients with lipedema. Sixty recommendations were formulated and agreed on in diagnostics, conservative and surgical treatment options, psychosocial factors and self‐management. The guideline is intended to reflect the current scientific knowledge and be widely used for diagnosis and treatment recommendations for patients with lipedema. In particular, the guideline comments on diagnostic criteria, differential diagnoses, and coinciding clinical pictures, their influence on diagnosis and treatment, sensible treatment measures, and self‐management options. The lipedema guideline summarizes the current national and international evidence and the German expert consensus and derives recommendations for the best treatment for patients with lipedema. The recommendations in the guideline are intended as an orientation aid in the sense of action and decision‐making corridors from which deviations are possible in justified cases. [ABSTRACT FROM AUTHOR]

Aims: The 2021 European Society of Cardiology (ESC) screening recommendations for individuals carrying a pathogenic transthyretin amyloidosis variant (ATTRv) are based on expert opinion. We aimed to (i) determine the penetrance of ATTRv cardiomyopathy (ATTRv‐CM) at baseline; (ii) examine the value of serial evaluation; and (iii) establish the yield of first‐line diagnostic tests (i.e. electrocardiogram, echocardiogram, and laboratory tests) as per 2021 ESC position statement. Methods and results: We included 159 relatives (median age 55.6 [43.2–65.9] years, 52% male) at risk for ATTRv‐CM from 10 centres. The primary endpoint, ATTRv‐CM diagnosis, was defined as the presence of (i) cardiac tracer uptake in bone scintigraphy; or (ii) transthyretin‐positive cardiac biopsy. The secondary endpoint was a composite of heart failure (New York Heart Association class ≥II) and pacemaker‐requiring conduction disorders. At baseline, 40/159 (25%) relatives were diagnosed with ATTRv‐CM. Of those, 20 (50%) met the secondary endpoint. Indication to screen (≤10 years prior to predicted disease onset and absence of extracardiac amyloidosis) had an excellent negative predictive value (97%). Other pre‐screening predictors for ATTRv‐CM were infrequently identified variants and male sex. Importantly, 13% of relatives with ATTRv‐CM did not show any signs of cardiac involvement on first‐line diagnostic tests. The yield of serial evaluation (n = 41 relatives; follow‐up 3.1 [2.2–5.2] years) at 3‐year interval was 9.4%. Conclusions: Screening according to the 2021 ESC position statement performs well in daily clinical practice. Clinicians should adhere to repeating bone scintigraphy after 3 years, as progressing to ATTRv‐CM without signs of ATTRv‐CM on first‐line diagnostic tests or symptoms is common. [ABSTRACT FROM AUTHOR]

Objective: To compare the cost‐effectiveness of different treatments for cervical intraepithelial neoplasia (CIN). Design: A cost‐effectiveness analysis based on data available in the literature and expert opinion. Setting: England. Population: Women treated for CIN. Methods: We developed a decision‐analytic model to simulate the clinical course of 1000 women who received local treatment for CIN and were followed up for 10 years after treatment. In the model we considered surgical complications as well as oncological and reproductive outcomes over the 10‐year period. The costs calculated were those incurred by the National Health Service (NHS) of England. Main outcome measures: Cost per one CIN2+ recurrence averted (oncological outcome); cost per one preterm birth averted (reproductive outcome); overall cost per one adverse oncological or reproductive outcome averted. Results: For young women of reproductive age, large loop excision of the transformation zone (LLETZ) was the most cost‐effective treatment overall at all willingness‐to‐pay thresholds. For postmenopausal women, LLETZ remained the most cost‐effective treatment up to a threshold of £31,500, but laser conisation became the most cost‐effective treatment above that threshold. Conclusions: LLETZ is the most cost‐effective treatment for both younger and older women. However, for older women, more radical excision with laser conisation could also be considered if the NHS is willing to spend more than £31,500 to avert one CIN2+ recurrence. [ABSTRACT FROM AUTHOR]

Objective: Severe fatigue is a prevalent and disabling symptom in multiple sclerosis (MS). This study tested if a fatigue‐ and physical activity‐related attentional bias (AB) and a somatic interpretation bias (IB) are present in severely fatigued patients with MS. Biases were compared to healthy controls and patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Method: Severely fatigued patients with MS or ME/CFS and healthy controls completed a Visual Probe Task (VPT) assessing fatigue‐ and physical activity‐related AB and an IB task that assesses the tendency to interpret ambiguous information in either a somatically threatening way or in a more neutral manner. The VPT was completed by 38 MS patients, 44 ME/CFS patients, and 46 healthy controls; the IB task was completed by 156, 40 and 46 participants respectively. Results: ANOVA showed no statistically significant group differences in a fatigue‐related AB or physical activity‐related AB (omnibus test of interaction between topic × condition: F2,125 = 1.87; p =.159). Both patient groups showed a tendency to interpret ambiguous information in a somatically threatening way compared to healthy controls (F1,2 = 27.61, p <.001). This IB was significantly stronger in MS patients compared to ME/CFS patients. IB was significantly correlated with cognitive responses to symptoms in MS patients. Conclusion: MS patients tend to interpret ambiguous information in a somatically threatening way. This may feed into unhelpful ways of dealing with symptoms, possibly contributing to the perpetuation of severe fatigue in MS. [ABSTRACT FROM AUTHOR]

The docking of an acyl carrier protein (ACP) domain with a downstream ketosynthase (KS) domain in each module of a polyketide synthase (PKS) helps ensure accurate biosynthesis. If the polyketide chain bound to the ACP has been properly modified by upstream processing enzymes and is compatible with gatekeeping residues in the KS tunnel, a transacylation reaction can transfer it from the 18.1‐Å phosphopantetheinyl arm of the ACP to the reactive cysteine of the KS. AlphaFold‐Multimer predicts a general interface for these transacylation checkpoints. Half of the solutions obtained for 50 ACP/KS pairs show the KS motif TxLGDP forming the first turn of an α‐helix, as in reported structures, while half show it forming a type I β‐turn not previously observed. Solutions with the latter conformation may represent how these domains are relatively positioned during the transacylation reaction, as the entrance to the KS active site is relatively open and the phosphopantetheinylated ACP serine and the reactive KS cysteine are relatively closer—17.2 versus 20.9 Å, on average. To probe the predicted interface, 20 mutations were made to KS surface residues within the model triketide lactone synthase P1‐P6‐P7. The activities of these mutants are consistent with the proposed interface. [ABSTRACT FROM AUTHOR]

Objective: To compare the effectiveness of endometriosis excision alone to excision plus hysterectomy, with and without bilateral oophorectomy, for endometriosis‐related symptoms. Design: Multicentre prospective cohort. Setting: Eighty‐six specialist endometriosis centres. Population: Women undergoing rectovaginal endometriosis surgery between 2009 and 2021. Methods: We performed multivariable regression with random effects for patient and centre, controlling for age, BMI, smoking, laparoscopic versus open approach and type of bowel surgery performed, with sensitivity analysis for loss to follow‐up. Main Outcome Measures: Pain scores, bowel symptoms and quality‐of‐life measures. Results: Compared to endometriosis excision alone, women undergoing hysterectomy with conservation of ovaries had greater improvement in non‐cyclical pain (MD: 1.41/10, 95% CI: 1.03–1.78, p < 0.001), dyspareunia (MD: 1.12/10, 95% CI: 0.71–1.53, p < 0.001), back pain (MD: 1.29/10, 95% CI: 0.92–1.67, p < 0.001) and quality‐of‐life scores (MD: 8.77/100, 95% CI: 5.79–11.75, p < 0.001) at 24 months post‐operatively. Women undergoing hysterectomy with bilateral oophorectomy also had greater improvement in non‐cyclical pelvic pain (MD: 2.22/10, 95% CI: 1.80–2.63, p < 0.001), dyspareunia (MD: 1.05/10, 95% CI: 0.59–1.52, p < 0.001), back pain (MD: 1.18/10, 95% CI: 0.77–1.59, p < 0.001) and quality of life (MD: 12.41/100, 95% CI: 9.07–15.74, p < 0.001) at 24 months compared to endometriosis excision alone. Compared to hysterectomy with ovarian conservation, hysterectomy with bilateral oophorectomy was associated with greater improvement in non‐cyclical pelvic pain (MD: 0.81/10, 95% CI: 0.32–1.30, p = 0.001) at 24 months and quality of life (MD: 3.74/100, 95% CI: 0.56–6.92, p = 0.021) at 12 months, although this result was sensitive to loss to follow‐up. Conclusions: Patients who undergo endometriosis excision plus hysterectomy experience greater improvement in pain and quality of life compared to those who have endometriosis excision alone. There are additional benefits of bilateral oophorectomy with hysterectomy, although its value is less clear due to loss of follow‐up. [ABSTRACT FROM AUTHOR]

Background and Purpose: To date, there are limited options for severe Coronavirus disease 2019 (COVID‐19), caused by SARS‐CoV‐2 virus. As ADP‐ribosylation events are involved in regulating the life cycle of coronaviruses and the inflammatory reactions of the host; we have, here, assessed the repurposing of registered PARP inhibitors for the treatment of COVID‐19. Experimental Approach: The effects of PARP inhibitors on virus uptake were assessed in cell‐based experiments using multiple variants of SARS‐CoV‐2. The binding of rucaparib to spike protein was tested by molecular modelling and microcalorimetry. The anti‐inflammatory properties of rucaparib were demonstrated in cell‐based models upon challenging with recombinant spike protein or SARS‐CoV‐2 RNA vaccine. Key Results: We detected high levels of oxidative stress and strong PARylation in all cell types in the lungs of COVID‐19 patients, both of which negatively correlated with lymphocytopaenia. Interestingly, rucaparib, unlike other tested PARP inhibitors, reduced the SARS‐CoV‐2 infection rate through binding to the conserved 493–498 amino acid region located in the spike‐ACE2 interface in the spike protein and prevented viruses from binding to ACE2. In addition, the spike protein and viral RNA‐induced overexpression of cytokines was down‐regulated by the inhibition of PARP1 by rucaparib at pharmacologically relevant concentrations. Conclusion and Implications: These results point towards repurposing rucaparib for treating inflammatory responses in COVID‐19. [ABSTRACT FROM AUTHOR]

Objectives: Bacterial meningitis is a leading cause of acquired sensorineural hearing loss (SNHL). Treatment and prevention of bacterial meningitis have improved over time, but rates of neurologic complications have not been recently studied. The objective here is to present an updated population‐based review of hearing loss as a sequela of bacterial meningitis. Methods: A retrospective cohort study was conducted between 2010 and 2022 of children discharged with bacterial meningitis, using the Pediatric Health Information System's (PHIS) database. Rates of hearing loss and mortality were evaluated over time. Results: A total of 6138 children with a primary diagnosis of bacterial meningitis were identified (3520 male [57.3%], mean age 5.8 months [2.0, 61.2]). Of these, 277 (4.51%) were diagnosed with hearing loss. Children with hearing loss were significantly older (23.6 vs. 5.3 months, p < 0.01), but differences in gender, race, or ethnicity had no association with hearing loss. Streptococcus pneumoniae, Hemophilus influenzae, and Neisseria meningiditis were associated with significantly higher rates of hearing loss than other etiologies (p < 0.01). Children with hearing loss had a higher rate of receiving dexamethasone than children without hearing loss. Overall mortality rate was 2.1%. Hearing loss and mortality demonstrated significant decreases over the study period. Conclusion: Hearing loss remains a common sequela of bacterial meningitis despite widespread uptake of vaccines for preventing S. pneumoniae, H. influenzae, and N. meningitidis. Dexamethasone was not associated with decreased rates of hearing loss in this cohort. From 2010 to 2022, there was a significant decrease in overall rates of mortality and hearing loss for children with bacterial meningitis. Level of Evidence: 3: retrospective case–control series Laryngoscope, 134:3820–3825, 2024 [ABSTRACT FROM AUTHOR]

Heatwaves have significant effects on ecosystems and human health. Human habitability is impacted severely as human exposure to heatwaves is projected to increase, however, the contribution of soil moisture effects to the increased exposure is unknown. We use data from four climate models, in which two experiments are used to isolate soil moisture effects and in this way to examine projected changes of soil moisture contributions to projected increases in heatwave events. Contributions from soil moisture to future population exposure to heatwaves are also investigated. With soil moisture effects combined with global warming, the longest yearly heatwaves are found to increase by up to 20 days, intensify by up to 2°C in mean temperature, with an increasing of frequency by 15% (the percentage relative to the total number of days for a year) over most mid‐latitude land regions by 2040–2070 under the SSP585 high emissions scenario. Furthermore, soil moisture changes are found to have a significant role in projected increases of multiple heatwave characteristics regionally compared with the global land area and contribute to more global population exposed to heatwaves. Plain Language Summary: Heatwaves have great impacts on human health, agriculture, economy, and many other related societal factors. Existing research has not formed a comprehensive understanding of the influences from soil moisture and drought on population exposure to global heatwaves. This study aims to provide a better perception and quantification of soil moisture effects on changes of both heatwaves per se and population exposure to heatwaves, which will help to enhance further insights of climate change impacts on human society. Using outputs from dedicated climate model experiments, it is found detectable contributions from soil moisture changes on exacerbating heatwaves and increasing population exposure to them. This study can inform evidence‐based policies and potential land management techniques such as irrigation, land radiative management, and forestation, for mitigating the impacts of climate extremes. Key Points: We conducted the first global analysis of soil moisture effects on population exposure to heatwavesEffects of projected soil moisture changes constitute a strong component in the exacerbation of heatwaves over most land regionsPopulation exposure to heatwaves rises sharply in Asia, Australia, US, Europe, and central and southern Africa [ABSTRACT FROM AUTHOR]

Background: Selection of central venous catheter (CVC) lock solution impacts catheter mechanical complications and central line–associated bloodstream infections (CLABSIs) in pediatric patients with intestinal failure. Disadvantages of the current clinical standards, heparin and ethanol lock therapy (ELT), led to the discovery of new lock solutions. High‐risk pediatric patients with intestinal failure who lost access to ELT during a recent shortage were offered enrollment in a compassionate use trial with 4% tetrasodium EDTA (T‐EDTA), a lock solution with antimicrobial, antibiofilm, and antithrombotic properties. Methods: We performed a descriptive cohort study including 14 high‐risk pediatric patients with intestinal failure receiving 4% T‐EDTA as a daily catheter lock solution. CVC complications were documented (repairs, occlusions, replacements, and CLABSIs). Complication rates on 4% T‐EDTA were compared with baseline rates, during which patients were receiving either heparin or ELT (designated as heparin/ELT). Results: Patients initiated 4% T‐EDTA at the time they were enrolled in the compassionate use protocol. Use of 4% T‐EDTA resulted in a 50% reduction in CVC complications, compared with baseline rates on heparin/ELT (incidence rate ratio: 0.50; 95% CI, 0.25–1.004; P = 0.051). Conclusion: In a compassionate use protocol for high‐risk pediatric patients with intestinal failure, the use of 4% T‐EDTA reduced composite catheter complications, including those leading to emergency department visits, hospital admissions, additional procedures, and mortality. This outcome suggests 4% T‐EDTA has benefits over currently available lock solutions. [ABSTRACT FROM AUTHOR]

Electron density irregularities in the ionosphere can give rise to scintillations, affecting radio wave phase and amplitude. While scintillations in the cusp and polar cap regions are commonly associated with mesoscale density inhomogeneities and/or shearing, the auroral regions exhibit a strong correlation between scintillation and density structures generated by electron precipitation (arcs). We aim to examine the impact of electron precipitation on the formation of scintillation‐producing density structures using a high‐resolution physics‐based plasma model, the "Geospace Environment Model of Ion‐Neutral Interactions," coupled with a radio propagation model, the "Satellite‐beacon Ionospheric‐scintillation Global Model of the upper Atmosphere." Specifically, we explore the effects of varying spatial and temporal characteristics of the precipitation, including electron total energy flux and their characteristic energies, obtained from the all‐sky‐imagers and Poker Flat Incoherent Scatter Radar observations, on auroral scintillation. To capture small‐scale structures, we incorporate a power‐law turbulence spectrum that induces short wavelength features sensitive to scintillation. Finally, we compare our simulated scintillation results with satellite‐observed scintillations, along with spectral comparisons. Key Points: A physics‐based plasma model and a radio propagation model are used to examine the effects of precipitation on auroral scintillationPrecipitation fluxes with higher energy, a turbulent noise spectrum, and a faster‐moving arc intensify scintillationThe presence of small‐scale precipitation amplifies both phase and amplitude scintillations [ABSTRACT FROM AUTHOR]

A new concept for the regioselective synthesis of Hamilton‐receptor and cyanurate‐functionalized oligo adducts of the fullerene C60 was developed. Based on an in‐situ deprotection and click‐post‐functionalization approach with novel azido precursors, the corresponding fullerene hexakis‐adducts with octahedral addition patterns and up to twelve Hamilton‐receptor/cyanurate moieties surrounding the fullerene sphere were synthesized. The versatility of this approach was further demonstrated by the synthesis of Hamilton‐receptor/cyanurate functionalized fullerene mono‐adducts, which are not accessible by direct cyclopropanation. Several fullerene target compounds were purified by simple washing procedures of the solid crude reaction mixture without the need for chromatography. The resulting fullerene mono‐ and hexakis‐adducts were fully characterized and their supramolecular properties were investigated by NMR‐spectroscopy and isothermal titration calorimetry (ITC). [ABSTRACT FROM AUTHOR]

This article revisits the authorship of and relationship between three mock‐prognostications published pseudonymously in 1591, drawing on contextual, bibliographical, and stylistical analysis to attribute Two Dangerous Comets and A Wonderful Prognostication to Thomas Nashe. The article also considers the significance of these findings for studies of Nashe, satire, and Elizabethan print culture. [ABSTRACT FROM AUTHOR]

Objective: Trauma remains the leading cause of death for children over a year old. Motorized recreational conveyances (RCs) adds another potential cause of pediatric trauma. This study aims to determine the impact of adding electric motors to RCs on the severity and frequency of pediatric injuries and craniofacial fractures. Methods: Pediatric trauma information was obtained from the National Electronic Injury Surveillance System (NEISS) database between 2012 and 2021. Demographics, injury cause, diagnoses, and incident narrative were collected. Bivariate and multivariate regression analyses were used to determine injury factors associated with serious injuries. Results: One million five hundred ninety‐six thousand five hundred fifty‐nine encounters were examined; 113,905 (7.1%) were related to pediatric RCs and 5354 (5.4%) of those involved RCs with electric motors. 14.3% of injuries were related to scooters, 18.6% to skateboards, 54.2% to bicycles, and 12.9% to other RCs. There were significant differences in age, sex, race, helmet use, serious injuries, and craniofacial fractures between RC modalities. RC users were more likely to develop facial fractures (OR 2.12; 95%CI 2.01, 2.23; p < .001) and be involved in serious injuries (OR 1.42; 95%CI 1.38, 1.46; p < .001). Compared to their self‐propelled counterparts, motorized scooters (OR 2.24; 95%CI 1.86, 2.69; p < .001) but not motorized skateboards (OR 1.01; 95%CI 0.88, 1.17; p = 0.88) were more likely to cause serious injuries. Helmet use was associated with fewer serious injuries (OR 0.5; 95%CI 0.46, 0.54; p < .001), facial fractures (OR 0.48; 95%CI 0.41, 0.55; p < .001), and skull fractures (OR 0.13; 95%CI 0.09, 0.17; p < .001). Conclusions: The addition of electric motors to RCs significantly increases the risk of pediatric craniofacial fractures and serious injuries. Level of Evidence: 3.The addition of electric motors to common recreational conveyances leads to twice the risk of pediatric serious injuries and craniofacial fractures. Only 30% of children who use these electric recreational conveyances wear helmets, but when they do, they significantly reduce the risks of facial and skull fractures. [ABSTRACT FROM AUTHOR]

Background and purpose: Chronic traumatic encephalopathy (CTE) has gained widespread attention due to its association with multiple concussions and contact sports. However, CTE remains a postmortem diagnosis, and the link between clinical symptoms and CTE pathology is poorly understood. This study aimed to investigate the presence of copathologies and their impact on symptoms in former contact sports athletes. Methods: This was a retrospective case series design of 12 consecutive cases of former contact sports athletes referred for autopsy. Analyses are descriptive and include clinical history as well as the pathological findings of the autopsied brains. Results: All participants had a history of multiple concussions, and all but one had documented progressive cognitive, psychiatric, and/or motor symptoms. The results showed that 11 of the 12 participants had evidence of CTE in the brain, but also other copathologies, including different combinations of tauopathies, and other rare entities. Conclusions: The heterogeneity of symptoms after repetitive head injuries and the diverse pathological combinations accompanying CTE complicate the prediction of CTE in clinical practice. It is prudent to consider the possibility of multiple copathologies when clinically assessing patients with repetitive head injuries, especially as they age, and attributing neurological or cognitive symptoms solely to presumptive CTE in elderly patients should be discouraged. [ABSTRACT FROM AUTHOR]

Persistent infection with high‐risk human papillomavirus (HPV) is recognized as the main cause for the development of anogenital cancers. This study prospectively evaluated the diagnostic performance of the novel Allplex‐HPV28 assay with the Anyplex‐II‐HPV28 to detect and genotype HPV in 234 consecutive swabs and 32 biopsies of the anogenital tract from 265 patients with atypical findings in cytomorphological screening. Agreement in HPV‐DNA detection between the Anyplex‐II and Allplex‐HPV28 assays was 99%. There was a notable diversity in the HPV‐virome, with the most prevalent high‐risk HPV types being 16, 53, 66, and 68. The agreement rates for detecting these genotypes exceeded 93% between the Anyplex‐II and Allplex‐HPV28 assays. Discrepancies in test results were solely noted for Anyplex‐II‐HPV28 results with a low signal intensity of "+", and for Allplex‐HPV28 results with cycle thresholds of ≥36. The semi‐quantitative analysis of HPV‐DNA loads showed significant agreement between the Anyplex‐II‐HPV28 and Allplex‐HPV28 assays (p < 0.001). Furthermore, HPV‐DNA detection rates and mean HPV‐DNA loads significantly correlated with the grade of abnormal changes identified in cytopathological assessment, being highest in cases of HSIL, condyloma accuminatum, and squamous cell carcinoma. Overall agreement rates for detecting specific HPV‐types among the Anyplex‐II and Allplex‐HPV28 assays exceeded 99.5% in cases of atypical squamous cells, condyloma accuminatum, and squamous cell carcinoma. The novel Allplex‐HPV28 assay shows good diagnostic performance in detecting and genotyping HPV commonly associated with anogenital cancers. Consequently, this assay could offer substantial potential for incorporation into future molecular screening programs for anogenital cancers in clinical settings. [ABSTRACT FROM AUTHOR]

Background and Aim: Atrophic gastritis (AG) and gastric intestinal metaplasia (GIM) are early changes in the stepwise progression to gastric adenocarcinoma. There is heterogeneity in international guidelines regarding the endoscopic diagnosis and surveillance of AG and GIM. This study aims to determine the prevalence of GIM in an Australian center and assess the approach of Australian endoscopists for these two conditions. Methods: We conducted a single‐center retrospective study of adult patients between January 2015 and December 2020 diagnosed with GIM on gastric biopsy following upper gastric endoscopy. A web‐based, 25‐question, investigator‐designed, multiple‐choice survey was distributed among all registered endoscopists in Australia. Results: The overall prevalence of GIM within a single Australian center was 11.7% over 5 years. Of the 1026 patients identified, only 58.7% underwent mapping biopsies using the modified Sydney protocol. Among the cohort, 1.6% had low‐grade dysplasia, 0.9% had high‐grade dysplasia, and 1.8% had malignancy on initial gastroscopy. Two hundred and sixty‐seven (7.2%) endoscopists completed the survey, 44.2% indicated they would perform mapping for all patients, and 36% only for high‐risk patients. Only 1.5% (n = 4) of respondents were able to correctly identify all six endoscopic photos of GIM/AG. Conclusion: This study demonstrates that in a large tertiary center, GIM is a prevalent endoscopic finding, but the associated rates of dysplasia and cancer were low. Additionally, among a small proportion of surveyed Australian endoscopists, there is notable variability in the endoscopic approach for AG and GIM and significant knowledge gaps. More training is required to increase the recognition of GIM and compliance with histological mapping. [ABSTRACT FROM AUTHOR]

Aims: The 2022 WHO classification for kidney tumours recently downgraded clear cell tubulopapillary (also known as clear cell papillary) renal cell carcinoma (RCC) to a benign neoplasm (i.e. clear cell tubulopapillary renal cell tumour) based on the overwhelmingly banal nature of this neoplasm. However, it has been recognized that some clear cell tubulopapillary renal cell tumours demonstrate vascular, adipose or pelvicalyceal invasion, raising the possibility of more aggressive behaviour. The goal of this study was to determine if these 'high stage' features have an effect on tumour prognosis, warranting a carcinoma designation. Methods and Results: After excluding cases with tissue artefact (i.e. prior core biopsy track changes) and other RCC subtypes with next‐generation sequencing, nine clear cell tubulopapillary renal cell tumours with these so‐called 'high stage' features, and otherwise classic morphologic and immunophenotypic findings, including low‐grade cytology and 'cup‐like' CA9 expression, were evaluated. Median tumour size was 2.2 cm with a range of 0.8 to 6.7 cm. Eight cases (89%) demonstrated perinephric or hilar adipose tissue invasion, although most of these cases showed a bulging (in contrast to an infiltrative) growth pattern. One case demonstrated renal vascular invasion in addition to hilar adipose tissue invasion, and one case demonstrated extension into the pelvicalyceal system. There were no recurrences or evidence of metastatic disease. Conclusion: These overall findings continue to support the benign designation for clear cell tubulopapillary renal cell tumours, despite morphologic features that might raise the possibility of a 'higher stage' neoplasm. [ABSTRACT FROM AUTHOR]

In 2015, the oncolytic herpes simplex virus 1 (HSV‐1) T‐VEC (talimogene laherparepvec) was approved for intratumoral injection in non‐resectable malignant melanoma. To determine whether viral replication is required for oncolytic activity, we compared replication‐deficient HSV‐1 d106S with replication‐competent T‐VEC. High infectious doses of HSV‐1 d106S killed melanoma (n = 10), head‐and‐neck squamous cell carcinoma (n = 11), and chondrosarcoma cell lines (n = 2) significantly faster than T‐VEC as measured by MTT metabolic activity, while low doses of T‐VEC were more effective over time. HSV‐1 d106S and, to a lesser extent T‐VEC, triggered caspase‐dependent early apoptosis as shown by pan‐caspase inhibition and specific induction of caspases 3/7, 8, and 9. HSV‐1 d106S induced a higher ratio of apoptosis‐inducing infected cell protein (ICP) 0 to apoptosis‐blocking ICP6 than T‐VEC. T‐VEC was oncolytic for an extended period of time as viral replication continued, which could be partially blocked by the antiviral drug aciclovir. High doses of T‐VEC, but not HSV‐1 d106S, increased interferon‐β mRNA as part of the intrinsic immune response. When markers of immunogenic cell death were assessed, ATP was released more efficiently in the context of T‐VEC than HSV‐1 d106S infection, whereas HMGB1 was induced comparatively well. Overall, the early oncolytic effect on three different tumour entities was stronger with the non‐replicative strain, while the replication‐competent virus elicited a stronger innate immune response and more pronounced immunogenic cell death. [ABSTRACT FROM AUTHOR]

Space‐based observations of the signatures associated with STEVE show how this phenomenon might be closely related to an extreme version of a SAID channel. Measurements show high velocities (>4 km/s), high temperatures (>4,000 K), and very large current density drivers (up to 1 μA/m2). This phenomena happens in a small range of latitudes, less than a degree, but with a large longitudinal span. In this study, we utilize the GEMINI model to simulate an extreme SAID/STEVE. We assume a FAC density coming from the magnetosphere as the main driver, allowing all other parameters to adjust accordingly. We have two main objectives with this work: show how an extreme SAID can have velocity values comparable or larger than the ones measured under STEVE, and to display the limitations and missing physics that arise due to the extreme values of temperature and velocity. Changes had to be made to GEMINI due to the extreme conditions, particularly some neutral‐collision frequencies. The importance of the temperature threshold at which some collision frequencies go outside their respective bounds, as well as significance of the energies that would cause inelastic collisions and impact ionization are displayed and discussed. We illustrate complex structures and behaviors, emphasizing the importance of 3D simulations in capturing these phenomena. Longitudinal structure is emphasized, as the channel develops differently depending on MLT. However, these simulations should be viewed as approximations due to the limited observations available to constrain the model inputs and the assumptions made to achieve sensible results. Key Points: We present a full 4D (3D + time) simulation of an extreme SAIDWe utilize the GEMINI model for the simulation due to the practicality and easiness to set arbitrary input files. Though challenges remainWe highlight the importance of inelastic collisions and impact ionization on damping the channel velocity, physics not included in GEMINI [ABSTRACT FROM AUTHOR]

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The natural product chlorotonil displays high potency against multidrug‐resistant Gram‐positive bacteria and Plasmodium falciparum. Yet, its scaffold is characterized by low solubility and oral bioavailability, but progress was recently made to enhance these properties. Applying late‐stage functionalization, we aimed to further optimize the molecule. Previously unknown reactions including a sulfur‐mediated dehalogenation were revealed. Dehalogenil, the product of this reaction, was identified as the most promising compound so far, as this new derivative displayed improved solubility and in vivo efficacy while retaining excellent antimicrobial activity. We confirmed superb activity against multidrug‐resistant clinical isolates of Staphylococcus aureus and Enterococcus spp. and mature transmission stages of Plasmodium falciparum. We also demonstrated favorable in vivo toxicity, pharmacokinetics and efficacy in infection models with S. aureus. Taken together, these results identify dehalogenil as an advanced lead molecule. [ABSTRACT FROM AUTHOR]

Aims: To study the effects of a bridging dose of U‐100 glargine (U‐100G) with the first dose of degludec in type 1 diabetes (T1D) patients transitioning from glargine to degludec, by comparing the glucose metrics 48 h before and after the transition. Materials and Methods: Patients with T1D on a stable U‐100G regimen and with glycated haemoglobin concentration <75 mmol/mol were randomized (double‐blind) to one dose of placebo or U‐100G with first dose of degludec, administered at 9:00 pm. Patients on once‐daily U‐100G at baseline received 50% of total U‐100G dose (bridging dose), while patients on twice‐daily U‐100G received 50% of the evening U‐100G dose. Participants wore a continuous glucose monitor during the study. Results: Forty participants were randomized, of whom 37 completed the study. The cohort was 65% male, the mean age was 47 years, duration of T1D 22 years, BMI 26 kg/m2, HbA1c 51 mmol/mol and total daily insulin dose 0.7 units/kg body weight. The bridging group included 19 participants (once‐daily U‐100G: n = 12; twice‐daily U‐100G: n = 7) and the placebo group included 18 participants (once‐daily U‐100G: n = 12; twice‐daily U‐100G: n = 6). Change in time in range (TIR) was not significantly different between the two treatment groups. In secondary analyses, among twice‐daily U‐100G users, TIR (3.9‐10 mmol/L) increased 8% in the bridging group in the 48 h after first dose of degludec compared to the preceding 48 h, while participants in the placebo group had a 9.5% decrease (p = 0.027). Conclusions: A subgroup of well‐controlled twice‐daily U‐100G users transitioning to degludec benefited from a 50% bridging dose of evening U‐100G with the first dose of degludec in a small pilot study. [ABSTRACT FROM AUTHOR]

At a given exercise intensity, blood flow restriction (BFR) reduces the volume of exercise required to impair post‐exercise neuromuscular function. Compared to traditional exercise, the time course of recovery is less clear. After strenuous exercise, force output assessed with electrical muscle stimulation is impaired to a greater extent at low versus high stimulation frequencies, a condition known as prolonged low‐frequency force depression (PLFFD). It is unclear if BFR increases PLFFD after exercise. This study tested if BFR during exercise increases PLFFD and slows recovery of neuromuscular function compared to regular exercise. Fifteen physically active participants performed six low‐load sets of knee‐extensions across four conditions: resistance exercise to task failure (RETF), resistance exercise to task failure with BFR applied continuously (BFRCONT) or intermittently (BFRINT), and resistance exercise matched to the lowest exercise volume condition (REVM). Maximal voluntary contraction (MVC) force output, voluntary activation and a force–frequency (1–100 Hz) curve were measured before and 0, 1, 2, 3, 4 and 24 h after exercise. Exercise to task failure caused similar reductions at 0 h for voluntary activation (RETF = 81.0 ± 14.2%, BFRINT = 80.9 ± 12.4% and BFRCONT = 78.6 ± 10.7%) and MVC force output (RETF = 482 ± 168 N, BFRINT = 432 ± 174 N, and BFRCONT = 443 ± 196 N), which recovered to baseline values between 4 and 24 h. PLFFD occurred only after RETF at 1 h supported by a higher frequency to evoke 50% of the force production at 100 Hz (1 h: 17.5 ± 4.4 vs. baseline: 15 ± 4.1 Hz, P = 0.0023), BFRINT (15.5 ± 4.0 Hz; P = 0.03), and REVM (14.9 ± 3.1 Hz; P = 0.002), with a trend versus BFRCONT (15.7 ± 3.5 Hz; P = 0.063). These findings indicate that, in physically active individuals, using BFR during exercise does not impair the recovery of neuromuscular function by 24 h post‐exercise. What is the central question of this study?Does the addition of blood flow restriction (BFR) during resistance exercise impaired recovery of neuromuscular function in physically active individuals?What is the main finding and its importance?While BFR during exercise increased fatiguability compared to exercise without BFR, it did not further impair the 24‐h recovery in neuromuscular function compared to exercise without BFR. These findings are relevant for applying BFR exercise in the training and/or rehabilitation of physically active populations such that it does not appear to further exacerbate muscle contractile function compared to regular strenuous exercise. [ABSTRACT FROM AUTHOR]

Several pieces of evidence suggest immune dysregulation could trigger the onset and modulate sequelae of new onset refractory status epilepticus (NORSE), including its subtype with prior fever known as febrile infection‐related epilepsy syndrome (FIRES). Consensus‐driven recommendations have been established to guide the initiation of first‐ and second‐line immunotherapies in these patients. Here, we review the literature to date on second‐line immunotherapy for NORSE/FIRES, presenting results from 28 case reports and series describing the use of anakinra, tocilizumab, or intrathecal dexamethasone in 75 patients with NORSE. Among them, 52 patients were managed with anakinra, 21 with tocilizumab, and eight with intrathecal dexamethasone. Most had elevated serum or cerebrospinal fluid cytokine levels at treatment initiation. Treatments were predominantly initiated during the acute phase of the disease (92%) and resulted, within the first 2 weeks, in seizure control for up to 73% of patients with anakinra, 70% with tocilizumab, and 50% with intrathecal dexamethasone. Cytokine levels decreased after treatment for most patients. Anakinra and intrathecal dexamethasone were mainly initiated in children with FIRES, whereas tocilizumab was more frequently prescribed for adults, with or without a prior febrile infection. There was no clear correlation between the response to treatment and the time to initiate the treatment. Most patients experienced long‐term disability and drug‐resistant post‐NORSE epilepsy. Initiation of second‐line immunotherapies during status epilepticus (SE) had no clear effect on the emergence of post‐NORSE epilepsy or long‐term functional outcomes. In a small number of cases, the initiation of anakinra or tocilizumab several years after SE onset resulted in a reduction of seizure frequency for 67% of patients. These data highlight the potential utility of anakinra, tocilizumab, and intrathecal dexamethasone in patients with NORSE. There continues to be interest in the utilization of early cytokine measurements to guide treatment selection and response. Prospective studies are necessary to understand the role of early immunomodulation and its associations with epilepsy and functional outcomes. [ABSTRACT FROM AUTHOR]

Macrophages expressing group V phospholipase A2 (Pla2g5) release the free fatty acid (FFA) linoleic acid (LA), potentiating lung type 2 inflammation. Although Pla2g5 and LA increase in viral infections, their role remains obscure. We generated Pla2g5flox/flox mice, deleted Pla2g5 by using the Cx3cr1cre transgene, and activated bone marrow‐derived macrophages (BM‐Macs) with poly:IC, a synthetic double‐stranded RNA that triggers a viral‐like immune response, known Pla2g5‐dependent stimuli (IL‐4, LPS + IFNγ, IL‐33 + IL‐4 + GM‐CSF) and poly:IC + LA followed by lipidomic and transcriptomic analysis. Poly:IC‐activated Pla2g5flox/flox;Cx3cr1cre/+ BM‐Macs had downregulation of major bioactive lipids and critical enzymes producing those bioactive lipids. In addition, AKT phosphorylation was lower in poly:IC‐stimulated Pla2g5flox/flox;Cx3cr1cre/+ BM‐Macs, which was not restored by adding LA to poly:IC‐stimulated BM‐Macs. Consistently, Pla2g5flox/flox;Cx3cr1cre/+ mice had diminished poly:IC‐induced lung inflammation, including inflammatory macrophage proliferation, while challenging Pla2g5flox/flox;Cx3cr1cre/+ mice with poly:IC + LA partially restored lung inflammation and inflammatory macrophage proliferation. Finally, mice lacking FFA receptor‐1 (Ffar1)‐null mice had reduced poly:IC‐induced lung cell recruitment and tissue macrophage proliferation, not corrected by LA. Thus, Pla2g5 contributes to poly:IC‐induced lung inflammation by regulating inflammatory macrophage proliferation and LA/Ffar1‐mediated lung cell recruitment and tissue macrophage proliferation. [ABSTRACT FROM AUTHOR]

Hao‐Fountain syndrome (HAFOUS, OMIM: #616863) is a neurodevelopmental disorder caused by pathogenic variants in the gene USP7 coding for USP7, a protein involved in several crucial cellular homeostatic mechanisms and the recently described MUST complex. The phenotype of HAFOUS is insufficiently understood, yet there is a great need to better understand the spectrum of disease, genotype–phenotype correlations, and disease trajectories. We now present a larger cohort of 32 additional individuals and provide further clinical information about six previously reported individuals. A questionnaire‐based study was performed to characterize the phenotype of Hao‐Fountain syndrome more clearly, to highlight new traits, and to better distinguish the disease from related neurodevelopmental disorders. In addition to confirming previously described features, we report hyperphagia and increased body weight in a subset of individuals. HAFOUS patients present an increased rate of birth complications, congenital anomalies, and abnormal pain thresholds. Speech impairment emerges as a potential hallmark of Hao‐Fountain syndrome. Cognitive testing reports reveal borderline intellectual functioning on average, although some individuals score in the range of intellectual disability. Finally, we created a syndrome‐specific severity score. This score neither indicates a sex‐ nor age‐specific difference of clinical severity, yet highlights a more severe outcome when amino acid changes colocalize to the catalytic domain of the USP7 protein. [ABSTRACT FROM AUTHOR]

Lynch syndrome (LS) predisposes to cancer in adulthood and is caused by heterozygous germline variants in a mismatch repair (MMR) gene. Recent studies show an increased prevalence of LS among children with cancer, suggesting a causal relationship. For LS‐spectrum (LSS) cancers, including high‐grade gliomas and colorectal cancer, causality has been supported by typical MMR‐related tumor characteristics, but for non‐LSS cancers, causality is unclear. We characterized 20 malignant tumors of 18 children with LS, including 16 non‐LSS tumors. We investigated second hits, tumor mutational load, mutational signatures and MMR protein expression. In all LSS tumors and three non‐LSS tumors, we detected MMR deficiency caused by second hit somatic alterations. Furthermore, these MMR‐deficient tumors carried driver variants that likely originated as a consequence of MMR deficiency. However, in 13 non‐LSS tumors (81%), a second hit and MMR deficiency were absent, thus a causal link between LS and cancer development in these children is lacking. These findings demonstrate that causality of LS in children with cancer, which can be determined by molecular tumor characterization, seems to be restricted to specific tumor types. Large molecular and epidemiological studies are needed to further refine the tumor spectrum in children with LS. [ABSTRACT FROM AUTHOR]

Background and purpose: Diagnosing small fiber neuropathies can be challenging. To address this issue, whether serum neurofilament light chain (sNfL) could serve as a potential biomarker of damage to epidermal Aδ‐ and C‐fibers was tested. Methods: Serum NfL levels were assessed in 30 patients diagnosed with small fiber neuropathy and were compared to a control group of 19 healthy individuals. Electrophysiological studies, quantitative sensory testing and quantification of intraepidermal nerve fiber density after skin biopsy were performed in both the proximal and distal leg. Results: Serum NfL levels were not increased in patients with small fiber neuropathy compared to healthy controls (9.1 ± 3.9 and 9.4 ± 3.8, p = 0.83) and did not correlate with intraepidermal nerve fiber density at the lateral calf or lateral thigh or with other parameters of small fiber impairment. Conclusion: Serum NfL levels cannot serve as a biomarker for small fiber damage. [ABSTRACT FROM AUTHOR]