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Background Mutations in podocyte and basement membrane genes are associated with a growing spectrum of glomerular disease affecting adults and children. Investigation of familial cases has helped to build understanding of both normal physiology and disease. Methods We investigated a consanguineous family with a wide clinical phenotype of glomerular disease using clinical, histological, and new genetic studies. Results We report striking variability in severity of nephropathy within an X-linked Alport syndrome (XLAS) family. Four siblings each carried a mutant COL4A5 allele, p.(Gly953Val) and p.(Gly1033Arg). Two boys had signs limited to hematuria and mild/moderate proteinuria. In striking contrast, a sister presented with end-stage renal disease (ESRD) at 8 years of age and an infant brother presented with nephrotic syndrome, progressing to ESRD by 3 years of age. Both were subsequently found to have homozygous variants in MYO1E , p.(Lys118Glu) and p.(Thr876Arg). MYO1E is a gene implicated in focal segmental glomerulosclerosis and it encodes a podocyte-expressed non-muscle myosin. Bioinformatic modeling demonstrated that the collagen IV-alpha3,4,5 extracellular network connected via known protein–protein interactions to intracellular myosin 1E. Conclusions COL4A5 and MYO1E mutations may summate to perturb common signaling pathways, resulting in more severe disease than anticipated independently. We suggest screening for MYO1E and other non- COL4 ‘podocyte gene’ mutations in XLAS when clinical nephropathy is more severe than expected for an individual’s age and sex.

Background Kidney failure in young people is often unexplained and a significant proportion will have an underlying genetic diagnosis. National Health Service England pioneered a comprehensive genomic testing service for such circumstances accessible to clinicians working outside of genetics. This is the first review of patients using this novel service since October 2021, following its introduction into clinical practice. Methods The ‘Unexplained Young-Onset End-Stage Renal Disease’ (test-code R257) gene panel uses targeted next generation sequencing to analyse 175 genes associated with renal disease in patients under 36 years of age. All tests undertaken between October 2021 and February 2022 were reviewed. Phenotypic data were extracted from request forms and referring clinicians contacted where additional details were required. Results Seventy-one patients underwent R257 testing over the study period. Among them, 23/71 patients (32%) were confirmed to have a genetic diagnosis and 2/71 (3%) had a genetically suggestive variant. Nephronophthisis and Alport syndrome were the most common conditions identified, (4/23 (17%) with pathogenic variants in NPHP1 and 4/23 (17%) with pathogenic variants in COL4A3/COL4A4 ). Positive predictors of a genetic diagnosis included a family history of renal disease (60% of positive cases) and extra-renal disease manifestations (48% of positive cases). Conclusion This is the first study to evaluate the R257 gene panel in unexplained young-onset kidney failure, freely accessible to patients meeting testing criteria in England. A genetic diagnosis was identified in 32% of patients. This study highlights the essential and expanding role that genomic testing has for children and families affected by renal disease today. Graphical abstract

Hepatocyte nuclear factor 1B (HNF1B) encodes a transcription factor expressed in developing human kidney epithelia. Heterozygous HNF1B mutations are the commonest monogenic cause of dysplastic kidney malformations (DKMs). To understand their pathobiology, we generated heterozygous HNF1B mutant kidney organoids from CRISPR-Cas9 gene-edited human ESCs and iPSCs reprogrammed from a family with HNF1B-asscociated DKMs. Mutant organoids contained enlarged malformed tubules and displayed deregulated cell turnover. Numerous genes implicated in Mendelian kidney tubulopathies were downregulated, and mutant tubules resisted the cAMP-mediated dilatation seen in controls. Bioinformatic analyses indicated abnormal WNT, calcium, and glutamatergic pathways, the latter hitherto unstudied in developing kidneys. Glutamate ionotropic receptor kainate type subunit 3 was upregulated in mutant organoids and was detected in their tubules and in fetal human DKM dysplastic epithelia. These results reveal morphological, molecular, and physiological roles for HNF1B in human kidney tubule morphogenesis and functional differentiation. They additionally suggest druggable targets to ameliorate disease.

Background Motor competence and executive functions co-develop throughout childhood and adolescence, and there is emerging evidence that improvements in motor competence may have cognitive benefits in these populations. There is a need to provide a quantitative synthesis of the cross-sectional, longitudinal and experimental studies that have examined the association between motor competence and executive functions in school-aged youth. Objectives The primary aim of our systematic review was to synthesise evidence of the association between motor competence and executive functions in school-aged children and adolescents (5–18 years). Our secondary aim was to examine key moderators of this association. Methods We searched the PubMed, PsycINFO, Scopus, Ovid MEDLINE, SPORTDiscus and EMBASE databases from inception up to 27 June 2023. We included cross-sectional, longitudinal and experimental studies that assessed the association between motor competence (e.g., general motor competence, locomotor skills, object control skills and stability skills) and executive functions (e.g., general executive functions, inhibition, working memory and cognitive flexibility) in children and adolescents aged 5–18 years. Results In total, 12,117 records were screened for eligibility, and 44 studies were included. From the 44 included studies, we meta-analysed 37 studies with 251 effect sizes using a structural equation modelling approach in the statistical program R. We found a small positive association (r = 0.18, [95% confidence interval (CI) 0.13–0.22]) between motor competence and executive functions. The positive associations were observed in cross-sectional (r = 0.17, [95% CI 0.13–0.22]), longitudinal ( r  = 0.15, [95% CI 0.03–0.28]) and experimental studies ( r  = 0.25, [95% CI 0.01–0.45]). We also found that general motor competence ( r  = 0.25, [95% CI 0.18–0.33]), locomotor ( r  = 0.15, [95% CI 0.09–0.21]), object control ( r  = 0.14, [95% CI 0.08–0.20]) and stability ( r  = 0.14, [95% CI 0.08–0.20]) skills were associated with executive functions. We did not find any moderating effects for participants’ age on the associations between motor competence and executive functions. Conclusions Our findings suggest a small-to-moderate positive association between motor competence and executive functions in children and adolescents. The small number of experimental studies included in this review support the assertion that interventions targeting children’s motor competence may be a promising strategy to improve their executive functions; however, more research is needed to confirm these findings. Future studies should explore the underlying mechanisms linking motor competence and executive functions as their comprehension may be used to optimise future intervention design and delivery. PROSPERO Registration CRD42021285134.

Bruce R. Gerratt University of California, Los Angeles Katherine Verdolini Abbott University of Pittsburgh, Pittsburgh, PA Julie Barkmeier-Kraemer University of Arizona, Tucson Robert E. Hillman Massachusetts General Hospital, Boston Contact author: Gail B. Kempster, Department of Communication Disorders and Sciences, Rush University Medical Center, 1653 W. Congress Parkway, 203 Senn, Chicago, IL 60612. E-mail: gail_b_kempster{at}rush.edu . Purpose: This article presents the development of the Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V) following a consensus conference on perceptual voice quality measurement sponsored by the American Speech-Language-Hearing Association's Special Interest Division 3, Voice and Voice Disorders. The CAPE-V protocol and recording form were designed to promote a standardized approach to evaluating and documenting auditory-perceptual judgments of vocal quality. Method: A summary of the consensus conference proceedings and the factors considered by the authors in developing this instrument are included. Conclusion: The CAPE-V form and instructions, included as appendices to this article, enable clinicians to document perceived voice quality deviations following a standard (i.e., consistent and specified) protocol. Key Words: Consensus Auditory-Perceptual Evaluation of Voice, voice, voice assessment CiteULike     Connotea     Del.icio.us     Digg     Facebook     Reddit     Technorati     Twitter     What's this?

Background: The primary aim of our systematic review and meta-analysis was to investigate the effect of resistance training on academic outcomes in school-aged youth. Methods: We conducted a systematic search of six electronic databases (CINAHL Complete, PsycINFO, SCOPUS, Ovid MEDLINE, SPORTDiscus and EMBASE) with no date restrictions. Studies were eligible if they: (a) included school-aged youth (5-18 years), and (b) examined the effect of resistance training on academic outcomes (i.e., cognitive function, academic achievement, and/or on-task behaviour in the classroom). Risk of bias was assessed using the appropriate Cochrane Risk of Bias Tools, funnel plots and Egger's regression asymmetry tests. A structural equation modelling approach was used to conduct the meta-analysis. Results: Fifty-three studies were included in our systematic review. Participation in resistance training (ten studies with 53 effect sizes) had a small positive effect on the overall cognitive, academic and on-task behaviours in school-aged youth (standardized mean difference (SMD) 0.19, 95% confidence interval (CI) 0.05-0.32). Resistance training was more effective (SMD 0.26, 95% CI 0.10-0.42) than concurrent training, i.e., the combination of resistance training and aerobic training (SMD 0.11, 95% CI - 0.05-0.28). An additional 43 studies (including 211 effect sizes) examined the association between muscular fitness and cognition or academic achievement, also yielding a positive relationship (SMD 0.13, 95% CI 0.10-0.16). Conclusion: This review provides preliminary evidence that resistance training may improve cognitive function, academic performance, and on-task behaviours in school-aged youth. (Autor).

The identification of prognostic markers in patients receiving neoadjuvant therapy is crucial for treatment optimization in HER2-positive breast cancer, with the immune microenvironment being a key factor. Here, we investigate the complexity of B and T cell receptor (BCR and TCR) repertoires in the context of two phase III trials, NeoALTTO and CALGB 40601, evaluating neoadjuvant paclitaxel with trastuzumab and/or lapatinib in women with HER2-positive breast cancer. BCR features, particularly the number of reads and clones, evenness and Gini index, are heterogeneous according to hormone receptor status and PAM50 subtypes. Moreover, BCR measures describing clonal expansion, namely evenness and Gini index, are independent prognostic factors. We present a model developed in NeoALTTO and validated in CALGB 40601 that can predict event-free survival (EFS) by integrating hormone receptor and clinical nodal status, breast pathological complete response (pCR), stromal tumor-infiltrating lymphocyte levels (%) and BCR repertoire evenness. A prognostic score derived from the model and including those variables, HER2-EveNT, allows the identification of patients with 5-year EFS > 90%, and, in those not achieving pCR, of a subgroup of immune-enriched tumors with an excellent outcome despite residual disease. Neoadjuvant therapies with dual anti-HER2 blockade have proven effective in HER2 + breast cancer treatment. Here, the authors develop a score that integrates antigen receptor repertoire features and clinical parameters to predict prognosis after anti-HER2 neoadjuvant treatments.

ObjectiveTo determine post-discharge patient-reported symptoms before and after implementation of restrictive opioid prescribing among women undergoing minimally invasive gynecologic surgery.MethodsWe compared clinical outcomes and symptom burden among a cohort of 389 women undergoing minimally invasive gynecologic surgery at a single institution before and after implementation of a restrictive opioid prescribing quality improvement initiative in July 2018. Post-discharge symptom burdens were collected up to 42 days after discharge using the MD Anderson Symptom Inventory and analyzed using linear mixed effects models.ResultsThe majority of women included in this study were white non-smokers and the median age was 55 (range 23–83). Most women underwent hysterectomy (64%), had surgery for malignancy (71%), and were discharged from the hospital on the day of surgery (65%). Women in the restrictive opioid prescribing group had a median reduction in morphine equivalent dose prescribed at discharge of 83%, corresponding to a median reduction in 25 tablets of 5 mg oxycodone per person. There was no difference between opioid prescribing groups in either the rate of refill requests (P=1) or hospital re-admission (P=1) up to 30 days after discharge. After adjustment for co-variates, there was no statistically significant difference in post-discharge symptom burden including patient-reported pain (P=0.08), sleep (P=0.30), walking interference (P=0.64), activity interference (P=0.12), or affective interference (P=0.67). There was a trend toward less reported constiptation in the restrictive opioid prescribing group that did not reach statistical significance (P=0.05).ConclusionWe found that restrictive post-operative opioid prescribing was not associated with differences in longitudinal symptom burden among women undergoing minimally invasive gynecologic surgery. These results provide the most comprehensive picture to date of post-operative symptom recovery under different opioid prescribing approaches, lending additional support for existing recommendations to reduce opioid prescribing following gynecologic surgery.

Machine learning (ML) models are commonly used to generate predictions, but these models can also support the discovery of new science. Generating accurate predictions necessitates that a model captures the structure of the underlying data. If the structure is properly extracted, ML could be a useful exploratory and evidential tool. In this paper, we present a case study that demonstrates the use of ML for exploratory data analysis (EDA) in the climate space. We apply the ML explainability method of spatiotemporal zeroed feature importance (stZFI) to understand how climate-variable associations evolve over space and time. Our analyses focus on data from ensembles of Earth system models (ESMs) which provide data on different climate states and conditions. We elect to work with ESM ensembles since they allow us to compare feature importance across alternative scenarios not available with observed data. The ensembles also account for natural variability so that we can distinguish between signal and noise due to natural climate variability when computing feature importance. The use of perturbed initial condition ensembles introduces variability mimicking the natural variability in the atmosphere; thus the signals emerging using feature importance (FI) can be evaluated against the natural variability in the climate system. For our analyses, we consider the 1991 volcanic eruption of Mount Pinatubo, which was a large stratospheric aerosol injection. We explore the climate pathway associated with the eruption from aerosols to radiation to temperature at both the near-surface and stratospheric levels. In addition to applying the method to data generated from two different ESMs, we apply stZFI to reanalysis data to compare the associations identified by stZFI. We show how stZFI tracks the importance of aerosol optical depth over time on forecasting temperatures. This case study illustrates usefulness of an ML tool (stZFI) for EDA on a well-studied climate exemplar.

Purpose: Previous work using ambulatory voice recordings has shown no differences in average vocal behavior between patients with phonotraumatic vocal hyperfunction and matched controls. This study used larger groups to replicate these results and expanded the analysis to include distributional characteristics of ambulatory voice use and measures indicative of glottal closure. Method: Subjects included 180 adult women: 90 diagnosed with vocal fold nodules or polyps and 90 age-, sex-, and occupation-matched controls with no history of voice disorders. Weeklong summary statistics (average, variability, skewness, kurtosis) of voice use were computed from neck-surface acceleration recorded using an ambulatory voice monitor. Voice measures included estimates of sound pressure level (SPL), fundamental frequency (f[subscript o]), cepstral peak prominence, and the difference between the first and second harmonic magnitudes (H1-H2). Results: Statistical comparisons resulted in medium-large differences (Cohen's d = 0.5) between groups for SPL skewness, f[subscript o] variability, and H1-H2 variability. Two logistic regressions (theory-based and stepwise) found SPL skewness and H1-H2 variability to classify patients and controls based on their weekly voice data, with an area under the receiver operating characteristic curve of 0.85 and 0.82 on training and test sets, respectively. Conclusion: Compared to controls, the weekly voice use of patients with phonotraumatic vocal hyperfunction reflected higher SPL tendencies (negatively skewed SPL) with more abrupt glottal closure (reduced H1-H2 variability, especially toward higher values). Further work could examine posttreatment data (e.g., after surgery and/or therapy) to determine the extent to which these differences are associated with the etiology and pathophysiology of phonotraumatic vocal fold lesions.