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KCNQ2 variants in children with neurodevelopmental impairment are difficult to assess due to their heterogeneity and unclear pathogenic mechanisms. We describe a child with neonatal-onset epilepsy, developmental impairment of intermediate severity, and KCNQ2 G256W heterozygosity. Analyzing prior KCNQ2 channel cryoelectron microscopy models revealed G256 as a node of an arch-shaped non-covalent bond network linking S5, the pore turret, and the ion path. Co-expression with G256W dominantly suppressed conduction by wild-type subunits in heterologous cells. Ezogabine partly reversed this suppression. Kcnq2G256W/+ mice have epilepsy leading to premature deaths. Hippocampal CA1 pyramidal cells from G256W/+ brain slices showed hyperexcitability. G256W/+ pyramidal cell KCNQ2 and KCNQ3 immunolabeling was significantly shifted from axon initial segments to neuronal somata. Despite normal mRNA levels, G256W/+ mouse KCNQ2 protein levels were reduced by about 50%. Our findings indicate that G256W pathogenicity results from multiplicative effects, including reductions in intrinsic conduction, subcellular targeting, and protein stability. These studies provide evidence for an unexpected and novel role for the KCNQ2 pore turret and introduce a valid animal model of KCNQ2 encephalopathy. Our results, spanning structure to behavior, may be broadly applicable because the majority of KCNQ2 encephalopathy patients share variants near the selectivity filter.

Objective: Differential disease control may contribute to racial disparities in outcomes of childhood‐onset systemic lupus erythematosus (cSLE). We evaluated associations of race and individual‐ or neighborhood‐level social determinants of health (SDoH) with achievement of low lupus disease activity state (LLDAS), a clinically relevant treatment target. Methods: In this cSLE cohort study using the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry, the primary exposure was self‐reported race and ethnicity, and collected SDoH included insurance status and area deprivation index (ADI). Outcomes included LLDAS, disease activity, and time‐averaged prednisone exposure. Associations among race and ethnicity, SDoH, and disease activity were estimated with multivariable regression models, adjusting for disease‐related and demographic factors. Results: Among 540 children with cSLE, 27% identified as Black, 25% identified as White, 23% identified as Latino/a, 11% identified as Asian, 9% identified as more than one race, and 5% identified as other. More Black children (41%) lived in neighborhoods of highest ADI compared to White children (16%). Black race was associated with lower LLDAS achievement (adjusted odds ratio 0.56, 95% confidence interval [CI] 0.38–0.82) and higher disease activity (adjusted β 0.94, 95% CI 0.11–1.78). The highest ADI was not associated with lower LLDAS achievement on adjustment for renal disease and insurance. However, renal disease was found to be a significant mediator (P = 0.04) of the association between ADI and prednisone exposure. Conclusions: Children with cSLE who identified as Black are less likely to achieve LLDAS and have a higher disease activity. Living in areas of higher ADI may relate to renal disease and subsequent prednisone exposure. Strategies to address root causes will be important to design interventions mitigating cSLE racial disparities. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the antimicrobial effectiveness of a novel 5-(1,3-benzothiazol-2-yl)-4-[(E)-(phenylmethylidene)amino]-4H-1,2,4-triazole-3-thiol derivatives. Methods: Starting from 2-aminothiophenol, a series of novel benzothiazole tethered triazole compounds were synthesized using conventional multi-step reactions. The reaction conditions were optimized for yield. Characterization was performed using 1H, 13C NMR, IR, and mass spectrometry. To determine the antimicrobial activity, both the agar well diffusion method and micro broth dilution method were employed. Molecular docking was conducted with AutoDock Vina, and ADME analysis was performed using SwissADME. The evaluation of toxicity was carried out using ADMETlab 2.0. Results and Discussion: Compound with a 2-NO2 substitution showed potent antibacterial activity against E. coli, with an inhibition of 50 µg/mL, similar to the standard drug chloramphenicol. The derivatives containing 3-Br and thiophene substitutions exhibited excellent activity against P. aeruginosa, with an inhibition concentration of 50 µg/mL. Moreover, the compounds with substitutions of 4-Br, 2,4-F, 4-F, and thiophene showed notable antifungal activity against C. albicans at a concentration of 250 µg/mL, surpassing the effectiveness of the standard drug griseofulvin. The results of molecular docking indicated that the compounds possessing 2-NO2, 3-Br, and 2,4-F substitutions displayed the most potent binding affinities towards their target proteins. The ADMET properties of these compounds were thoroughly evaluated and confirmed their drug-like characteristics and pharmacokinetic viability. Conclusions: The results of the antimicrobial activity assays and molecular docking studies indicate that several of the synthesized compounds demonstrated potency equal to or exceeding that of standard drugs. Furthermore, the ADMET profiles of these compounds were favourable, suggesting good pharmacokinetic properties. These findings highlight the potential of the synthesized compounds as effective antimicrobial agents, warranting further investigation and development. [ABSTRACT FROM AUTHOR]

Summary: Background: Adults with chronic low back pain (CLBP) suffer impaired sleep. Medications for CLBP can impact sleep which in turn may influence treatment outcomes. This systematic review and meta-analysis examined the effects of pharmacotherapy (any type) on sleep in adults with CLBP. Methods: In this systematic review and meta-analysis, we searched PubMed, CINAHL, SPORTDiscus, PsycINFO, EMBASE, and CENTRAL from inception to 10 July 2022. Randomised controlled trials that investigated the effects of pharmacotherapy on sleep in adults with CLBP were included. Manual citation search of relevant systematic reviews and included studies were also conducted. Mean change from baseline for sleep outcomes (e.g., sleep quality, total sleep time, wake after sleep onset) was the effect of interest. Pairwise inverse-variance random effect meta-analysis was performed to impute pooled estimates (Hedges’ g or risk ratios). The Hartung-Knapp-Sidik-Jonkman method was used where there were ≤5 studies. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used for evaluating the certainty of evidence. This study was registered with PROSPERO (CRD42022309419). Findings: Assessment of 3959 records resulted in nine studies (n = 2927) being included. Pharmacotherapy for CLBP management had a small, yet unlikely clinically significant, effect on improving sleep in adults with CLBP, when compared to placebo (g [95% CI]: −0.23 [−0.37, −0.09], p = .0009; I2 = 30.1%; n = 1433; studies: n = 8; GRADE: low). Notably, no eligible studies investigated the effect of sleep medications in this population, despite being within the scope of this review. Interpretation: Pharmacotherapy used to manage CLBP provided improvements in sleep in adults with CLBP. Given that these effects were small and unlikely clinically significant, clinicians could consider alternative treatments (e.g., non-pharmacological interventions) for managing sleep in adults with CLBP. However, low to very low certainty of evidence precluded strong conclusions. To improve certainty of evidence and confidence in the effect estimates, future research needs to use robust method to minimise bias. Additional research evaluating multiple sleep characteristics, using both validated objective and subjective measures, is also warranted to further investigate the influence of distinct sleep parameters. Funding: The Summer Research Scholarship from the Appleton Institute, Central Queensland University, Australia.

Background: Chronic anterior uveitis (CAU) carries a significant risk for eye complications and vision loss. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) introduced consensus treatment plans (CTPs) to standardize treatment for CAU and facilitate future comparative effectiveness studies. Two CTPs were developed to address: 1) initiation of methotrexate (MTX) in patients with CAU naïve to steroid-sparing therapy, and 2) initiation of a TNF inhibitor (TNFi) in patients with severe uveitis or uveitis refractory to MTX. We evaluated implementation of the uveitis CTPs using existing CARRA Registry infrastructure and assessed feasibility of the CTPs for comparative effectiveness research. Methods: This prospective observational cohort study was conducted at nine pilot sites between February 2020 and August 2022. Patients with JIA-associated CAU (JIA-U) were treated according to either the MTX or TNFi CTP. Uveitis activity and medication use were recorded at 0, 3, and 6 months. We assessed patient enrollment rates, CTP arm selection, uveitis control, and quality of data collection. We also evaluated CTP arm selection in a retrospective cohort of similar JIA-U patients enrolled in the CARRA Registry during the same study period. Results: Seventeen patients were included in the pilot cohort. Eight were treated with the MTX CTP (4 oral MTX, 4 subcutaneous MTX), and 9 with the TNFi CTP (9 received standard-dose adalimumab, none selected high-dose adalimumab or infliximab). Uveitis was controlled in 13 of 17 patients by 6 months. Query of the CARRA-wide Registry identified 42 patients with JIA-U who were treated according to the MTX or TNFi CTPs. Among these, 26 were treated with MTX (8 oral, 18 subcutaneous) and 16 with TNFi (12 standard dose adalimumab, 2 high dose adalimumab, and 2 infliximab). Conclusion: Both the MTX and TNFi uveitis CTPs can practically be implemented in clinical settings and are currently being utilized across Registry sites. However, in patients starting TNFi therapy, all pilot study participants and most patients across the CARRA Registry were treated with a standard dose of adalimumab. This consensus on the treatment approach underscores its broad acceptance but also limits the applicability of the uveitis TNFi CTP for comparative effectiveness research. [ABSTRACT FROM AUTHOR]

Introduction The Notch pathway is a highly conserved cell-cell signaling mechanism that functions in virtually all tissues to regulate multiple aspects of cell fate and homeostasis. Dysregulation of Notch signaling [...], Notch signaling is a highly conserved intercellular pathway with tightly regulated and pleiotropic roles in normal tissue development and homeostasis. Dysregulated Notch signaling has also been implicated in human disease, including multiple forms of cancer, and represents an emerging therapeutic target. Successful development of such therapeutics requires a detailed understanding of potential on-target toxicities. Here, we identify autosomal dominant mutations of the canonical Notch ligand Jagged1 (or JAG1) as a cause of peripheral nerve disease in 2 unrelated families with the hereditary axonal neuropathy Charcot-Marie-Tooth disease type 2 (CMT2). Affected individuals in both families exhibited severe vocal fold paresis, a rare feature of peripheral nerve disease that can be life- threatening. Our studies of mutant protein posttranslational modification and localization indicated that the mutations (p.Ser577Arg, p.Ser650Pro) impair protein glycosylation and reduce JAG1 cell surface expression. Mice harboring heterozygous CMT2-associated mutations exhibited mild peripheral neuropathy, and homozygous expression resulted in embryonic lethality by midgestation. Together, our findings highlight a critical role for JAG1 in maintaining peripheral nerve integrity, particularly in the recurrent laryngeal nerve, and provide a basis for the evaluation of peripheral neuropathy as part of the clinical development of Notch pathway-modulating therapeutics.

Objective: The purpose of this research was to investigate the prevalence of lifestyle behaviors and suicide-related behaviors and the association between them using a nationally representative sample of adolescents from the USA.Methods: 13,677 high school students aged 14-18 years were included in this cross-sectional study. The research data were retrieved from the Youth Risk Behavior Surveillance System Survey in 2019. All data on age, sex, grade, race, physical activity, television time, fruit intake, and suicide-related behavior were self-reported by students. Logistic regression models were adopted to examine the association between lifestyle behaviors and the suicide-related behaviors.Results: Students who played video/computer games for ≥2 h had higher risk of suicide attempt (OR = 1.55, 95%CI: 1.30-1.85). Daily sleep duration of ≤8 h was positively associated with considering a suicide attempt (OR = 1.99, 95%CI: 1.62-2.43). In addition, participants who did not engage in any sport team were more likely to report considering a suicide attempt (OR = 1.50, 95%CI: 1.24-1.81).Conclusion: This research suggests that some lifestyle behaviors (e.g., time for video or computer use, sleep duration, sports team participation, regular breakfast intake, and substance use) are associated with increased risk of suicidal behavior and ideation in high school students. To identify the specific effect of multiple lifestyle factors in influencing the risk of suicide-related behaviors in high school students, longitudinal studies are warranted in future.

Objective: The objective of this study was to compare the effectiveness of a second tumor necrosis factor inhibitor (TNFi) versus a non‐TNFi biologic following discontinuation of a TNFi for patients with polyarticular‐course juvenile idiopathic arthritis (pJIA). Methods: Using the Childhood Arthritis and Rheumatology Research Alliance Registry, patients with pJIA who started receiving a second biologic following a first TNFi were identified. Patients were required to have no active uveitis on the index date and a visit six months after the index date. Outcome measures included Clinical Juvenile Arthritis Disease Activity Score with a maximum of 10 active joints (cJADAS10), cJADAS10 inactive disease (ID; ≤2.5) and cJADAS10 minimal disease activity (MiDA; ≤5). Multiple imputation was used to account for missing data. Adjusted odds ratios (aORs) were calculated using propensity score quintiles to compare outcomes at six months following second biologic initiation. Results: There were 216 patients included, 84% initially received etanercept, and most patients stopped receiving it because of its ineffectiveness (74%). A total of 183 (85%) started receiving a second TNFi, and 33 (15%) started receiving a non‐TNFi. Adalimumab was the most common second biologic received (71% overall, 84% of second TNFi), and tocilizumab was the most common non‐TNFi second biologic received (9% overall, 58% of non‐TNFi). There was no difference between receiving TNFi versus non‐TNFi in cJADAS10 ID (29% vs 25%; aOR 1.23, 95% confidence interval [CI] 0.47–3.20) or at least MiDA (43% vs 39%; aOR 1.11, 95% CI 0.47–2.62) at six months. Conclusion: Most patients with pJIA started receiving TNFi rather than non‐TNFi as their second biologic, and there were no differences in disease activity at six months. [ABSTRACT FROM AUTHOR]

N-Glycanase 1 (NGLY1) is a cytoplasmic deglycosylating enzyme. Loss-of-function mutations in the NGLY1 gene cause NGLY1 deficiency, which is characterized by developmental delay, seizures, and a lack of sweat and tears. To model the phenotypic variability observed among patients, we crossed a Drosophila model of NGLY1 deficiency onto a panel of genetically diverse strains. The resulting progeny showed a phenotypic spectrum from 0 to 100% lethality. Association analysis on the lethality phenotype, as well as an evolutionary rate covariation analysis, generated lists of modifying genes, providing insight into NGLY1 function and disease. The top association hit was Ncc69 (human NKCC1/2), a conserved ion transporter. Analyses in NGLY1-/- mouse cells demonstrated that NKCC1 has an altered average molecular weight and reduced function. The misregulation of this ion transporter may explain the observed defects in secretory epithelium function in NGLY1 deficiency patients.

Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin (FXN). Most FRDA patients are homozygous for large expansions of GAA repeat sequences in intron 1 of FXN, whereas a fraction of patients are compound heterozygotes, with a missense or nonsense mutation in one FXN allele and expanded GAAs in the other. A prevalent missense mutation among FRDA patients changes a glycine at position 130 to valine (G130V). Herein, we report generation of the first mouse model harboring an Fxn point mutation. Changing the evolutionarily conserved glycine 127 in mouse Fxn to valine results in a failure-to-thrive phenotype in homozygous animals and a substantially reduced number of offspring. Like G130V in FRDA, the G127V mutation results in a dramatic decrease of Fxn protein without affecting transcript synthesis or splicing. FxnG127V mouse embryonic fibroblasts exhibit significantly reduced proliferation and increased cell senescence. These defects are evident in early passage cells and are exacerbated at later passages. Furthermore, increased frequency of mitochondrial DNA lesions and fragmentation are accompanied by marked amplification of mitochondrial DNA in FxnG127V cells. Bioenergetics analyses demonstrate higher sensitivity and reduced cellular respiration of FxnG127V cells upon alteration of fatty acid availability. Importantly, substitution of FxnWT with FxnG127V is compatible with life, and cellular proliferation defects can be rescued by mitigation of oxidative stress via hypoxia or induction of the NRF2 pathway. We propose FxnG127V cells as a simple and robust model for testing therapeutic approaches for FRDA.

Blood-CNS barrier disruption is a hallmark of numerous neurological disorders, yet whether barrier breakdown is sufficient to trigger neurodegenerative disease remains unresolved. Therapeutic strategies to mitigate barrier hyperpermeability are also limited. Dominant missense mutations of the cation channel transient receptor potential vanilloid 4 (TRPV4) cause forms of hereditary motor neuron disease. To gain insights into the cellular basis of these disorders, we generated knock-in mouse models of TRPV4 channelopathy by introducing two disease-causing mutations (R269C and R232C) into the endogenous mouse Trpv4 gene. TRPV4 mutant mice exhibited weakness, early lethality, and regional motor neuron loss. Genetic deletion of the mutant Trpv4 allele from endothelial cells (but not neurons, glia, or muscle) rescued these phenotypes. Symptomatic mutant mice exhibited focal disruptions of blood–spinal cord barrier (BSCB) integrity, associated with a gain of function of mutant TRPV4 channel activity in neural vascular endothelial cells (NVECs) and alterations of NVEC tight junction structure. Systemic administration of a TRPV4-specific antagonist abrogated channel-mediated BSCB impairments and provided a marked phenotypic rescue of symptomatic mutant mice. Together, our findings show that mutant TRPV4 channels can drive motor neuron degeneration in a non–cell autonomous manner by precipitating focal breakdown of the BSCB. Further, these data highlight the reversibility of TRPV4-mediated BSCB impairments and identify a potential therapeutic strategy for patients with TRPV4 mutations. Editor's summary: TRPV4 (transient receptor potential vanilloid 4) is a mechanosensitive cation channel important for vascular function. TRPV4 mutations have been identified in patients with motor neuropathies, but it is unknown how functional alternations in this channel drive neurodegeneration. Sullivan et al. show that mice with gain-of-function mutations in Trpv4 developed progressive neurological symptoms that were associated with blood–spinal cord barrier breakdown and focal loss of motor neurons. Removal of Trpv4 from endothelial cells (but not other cell types) or treatment with a small molecule antagonist reversed pathology. These findings reveal a cascade of events that potentially drives neurodegeneration in TRPV4 channelopathies. —Daniela Neuhofer [ABSTRACT FROM AUTHOR]

Background: To date, no citation analysis has been conducted in the physical activity field, which can contribute to assess the impact of this research field and identify knowledge gaps. Therefore, this study aimed to identify the 500 most cited physical activity publications and report their bibliometric characteristics. Methods: The Web of Science database (all database indexes) was searched, and bibliometric characteristics were imported and calculated. Results: A total of 520 publications were ranked as the top 500. The sum of the citations was 326,258, and the average citation density was 41.0 (45.1) citations per year. Original research articles constituted the major portion of included publications (53.7%; 170,774 citations). Papers reporting relationship of physical activity with health were the most prevalent type of publication included (43.7%; 141,027 citations). Journal impact factor had a weak but significant positive correlation with citation density (r =.12; P =.006). The United States was ranked first in terms of the contributions from institutions and authors contributing to the most cited physical activity papers. Conclusions: Top physical activity publications are well cited compared with other health behavior fields. Original research reporting on the associations between physical activity and health has a higher citation impact compared with other types of original research within the physical activity field. The physical activity research field continues to expand rapidly as newer publications attract more citations in a shorter time span compared with older publications. [ABSTRACT FROM AUTHOR]