HBS1L deficiency causes retinal dystrophy in a child and a mouse model associated with defective development of photoreceptor cells.

Inherited retinal diseases encompass a genetically diverse group of conditions caused by mutations in genes critical to retinal function, including handful of ribosome-associated genes. This study focuses on HBS1L gene which encodes for HBS1-like translational GTPase crucial for ribosomal rescue. We have reported a female child carrying biallelic HBS1L variants, manifesting with poor growth and neurodevelopmental delay. Here we describe the ophthalmologic findings in the patient and Hbs1ltm1a/tm1a hypomorph mice and describe the associated microscopic and molecular perturbations. The patient has impaired visual function, showing dampened amplitudes of a- and b-waves in both rod- and cone-mediated responses. Hbs1ltm1a/tm1a mice exhibited profound thinning of the entire retina, specifically of the outer photoreceptor layer, due to extensive photoreceptor cell apoptosis. Loss of HBS1L resulted in comprehensive proteomic alterations on mass spectrometry analysis, with 169 proteins increased and 480 decreased including rhodopsin and peripherin 2. GO biological process and GSEA analyses reveal that the downregulated proteins are primarily involved in phototransduction, cilium assembly, and photoreceptor cell development. These findings underscore the importance of ribosomal rescue proteins in maintaining retinal health, particularly in photoreceptor cells.

The solute carrier family 26 member 9 modifies rapidly progressing cystic fibrosis associated with homozygous F508del CFTR mutation.

BACKGROUND AND AIMS: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations to the CF transmembrane conductance regulator (CFTR). Symptoms and severity of the disease can be quite variable suggesting modifier genes play an important role. MATERIALS AND METHODS: Exome sequencing was performed on six individuals carrying homozygous deltaF508 for CFTR genotype but present with rapidly progressing CF (RPCF). Data was analyzed using an unbiased genome-wide genetic burden test against 3076 controls. Single cell RNA sequencing data from LungMAP was utilized to evaluate unique and co-expression of candidate genes, and structural modeling to evaluate the deleterious effects of identified candidate variants. RESULTS: We have identified solute carrier family 26 member 9 (SLC26A9) as a modifier gene to be associated with RPCF. Two rare missense SLC26A9 variants were discovered in three of six individuals deemed to have RPCF: c.229G > A; p.G77S (present in two patients), and c.1885C > T; p.P629S. Co-expression of SLC26A9 and CFTR mRNA is limited across different lung cell types, with the highest level of co-expression seen in human (6.3 %) and mouse (9.0 %) alveolar type 2 (AT2) cells. Structural modeling suggests deleterious effects of these mutations as they are in critical protein domains which might affect the anion transport capability of SLC26A9. CONCLUSION: The enrichment of rare and potentially deleterious SLC26A9 mutations in patients with RPCF suggests SLC26A9 may act as an alternative anion transporter in CF and is a modifier gene associated with this lung phenotype.

WNT2B Deficiency Causes Enhanced Susceptibility to Colitis Due to Increased Inflammatory Cytokine Production.

BACKGROUND & AIMS: Humans with WNT2B deficiency have severe intestinal disease, including significant inflammatory injury, highlighting a critical role for WNT2B. We sought to understand how WNT2B contributes to intestinal homeostasis. METHODS: We investigated the intestinal health of Wnt2b knock out (KO) mice. We assessed the baseline histology and health of the small intestine and colon, and the impact of inflammatory challenge using dextran sodium sulfate (DSS). We also evaluated human intestinal tissue. RESULTS: Mice with WNT2B deficiency had normal baseline histology but enhanced susceptibility to DSS colitis because of an increased early injury response. Although intestinal stem cells markers were decreased, epithelial proliferation was similar to control subjects. Wnt2b KO mice showed an enhanced inflammatory signature after DSS treatment. Wnt2b KO colon and human WNT2B-deficient organoids had increased levels of CXCR4 and IL6, and biopsy tissue from humans showed increased neutrophils. CONCLUSIONS: WNT2B is important for regulation of inflammation in the intestine. Absence of WNT2B leads to increased expression of inflammatory cytokines and increased susceptibility to gastrointestinal inflammation, particularly in the colon.

Integrated multi-omics approach reveals the role of striated muscle preferentially expressed protein kinase in skeletal muscle including its relationship with myospryn complex.

BACKGROUND: Autosomal-recessive mutations in SPEG (striated muscle preferentially expressed protein kinase) have been linked to centronuclear myopathy with or without dilated cardiomyopathy (CNM5). Loss of SPEG is associated with defective triad formation, abnormal excitation-contraction coupling, calcium mishandling and disruption of the focal adhesion complex in skeletal muscles. To elucidate the underlying molecular pathways, we have utilized multi-omics tools and analysis to obtain a comprehensive view of the complex biological processes and molecular functions. METHODS: Skeletal muscles from 2-month-old SPEG-deficient (Speg-CKO) and wild-type (WT) mice were used for RNA sequencing (n = 4 per genotype) to profile transcriptomics and mass spectrometry (n = 4 for WT; n = 3 for Speg-CKO mice) to profile proteomics and phosphoproteomics. In addition, interactomics was performed using the SPEG antibody on pooled muscle lysates (quadriceps, gastrocnemius and triceps) from WT and Speg-CKO mice. Based on the multi-omics results, we performed quantitative real-time PCR, co-immunoprecipitation and immunoblot to verify the findings. RESULTS: We identified that SPEG interacts with myospryn complex proteins CMYA5, FSD2 and RyR1, which are critical for triad formation, and that SPEG deficiency results in myospryn complex abnormalities (protein levels decreased to 22 ± 3% for CMYA5 [P < 0.05] and 18 ± 3% for FSD2 [P < 0.01]). Furthermore, SPEG phosphorylates RyR1 at S2902 (phosphorylation level decreased to 55 ± 15% at S2902 in Speg-CKO mice; P < 0.05), and its loss affects JPH2 phosphorylation at multiple sites (increased phosphorylation at T161 [1.90 ± 0.24-fold], S162 [1.61 ± 0.37-fold] and S165 [1.66 ± 0.13-fold]; decreased phosphorylation at S228 and S231 [39 ± 6%], S234 [50 ± 12%], S593 [48 ± 3%] and S613 [66 ± 10%]; P < 0.05 for S162 and P < 0.01 for other sites). On analysing the transcriptome, the most dysregulated pathways affected by SPEG deficiency included extracellular matrix-receptor interaction (P < 1e-15) and peroxisome proliferator-activated receptor signalling (P < 9e-14). CONCLUSIONS: We have elucidated the critical role of SPEG in the triad as it works closely with myospryn complex proteins (CMYA5, FSD2 and RyR1), it regulates phosphorylation levels of various residues in JPH2 and S2902 in RyR1, and its deficiency is associated with dysregulation of several pathways. The study identifies unique SPEG-interacting proteins and their phosphorylation functions and emphasizes the importance of using a multi-omics approach to comprehensively evaluate the molecular function of proteins involved in various genetic disorders.

Prevalence of infertility and barriers to family building among male physicians.

BACKGROUND: Fertility declines with increasing age and physicians often delay childbearing beyond prime reproductive years for the sake of medical training. However, the risks of infertility in male physicians compared to the general population remain poorly studied. OBJECTIVES: To characterize rates of infertility among male physicians and identify barriers in access to fertility care and family building. MATERIALS & METHODS: Between June 2022 and December 2022, male physicians were invited to complete a questionnaire regarding fertility and family building. Surveys were disseminated electronically via social media and professional medical societies using Qualtrics (Provo, UT). RESULTS: Two hundred thirty-five responses were included in the final analysis. The mean age of respondents was 36.3 ± 7.4 years. Of 151 respondents with children or currently attempting to have children, 66 (43.7%) delayed family building due to their medical training or career. The most influential factors affecting timing of children were lack of flexibility in schedule, lack of time, stress, and financial strain. Forty-three (18.3.%) respondents had seen a doctor for fertility evaluation; an additional 12 (5.1%) said they considered doing so but did not, mostly due to being too busy. Sixty (25.5%) had undergone semen testing in the past. Thirty-one (13.2%) reported a diagnosis of fertility issues in either themselves or their partner. Twenty-seven (11.5%) endorsed either them or their partner having undergone assistive reproductive technologies or other procedures for infertility. DISCUSSION: A significant proportion of male physicians delayed building their family or seeking fertility evaluation due to their medical career. Around 23.4% of male physicians have either seen or considered seeing a physician for fertility evaluation, suggesting a high prevalence of infertility in this cohort. CONCLUSION: Our results indicate a need for interventions to support family building and fertility evaluation and treatment among male physicians.

Prevalence of sexual dysfunction and pursuit of sexual medicine evaluation among male physicians-a survey.

We sought to characterize the prevalence of sexual dysfunction and barriers to treatment among male physicians. Between June and December 2022, male physicians were invited to complete a questionnaire regarding sexual function. Surveys were disseminated electronically via social media and professional medical societies using Qualtrics (Provo, UT). In totla, 235 responses were included in the final analysis. The mean age of respondents was 36.3 ± 7.4 years (range 23-72). 27 (11.5%) reported having seen a doctor for sexual health. Of these 27, 40.7% saw a physician for erectile dysfunction, 29.6% for low libido, 22.2% for premature ejaculation, 7.4% for delayed ejaculation, and 33.3% for other concerns. An additional 29 (12.3%) considered establishing care for sexual issues but didn't, mostly due to being too busy. 46 (19.6%) respondents reported having taken medication to improve erectile function. Therefore, in a cohort of young male physicians, 23.8% had seen or considered seeing a doctor for sexual health concerns, and nearly 1 in 5 had taken medication for erectile dysfunction. Male physicians appear to be at higher risk for sexual dysfunction than the general population and face significant and unique barriers in access to care for sexual dysfunction.

Genetic deficiency of ribosomal rescue factor HBS1L causes retinal dystrophy associated with Pelota and EDF1 depletion.

Inherited retinal diseases (IRDs) encompass a genetically diverse group of conditions in which mutations in genes critical to retinal function lead to progressive loss of photoreceptor cells and subsequent visual impairment. A handful of ribosome-associated genes have been implicated in retinal disorders alongside neurological phenotypes. This study focuses on the HBS1L gene, encoding HBS1 Like Translational GTPase which has been recognized as a critical ribosomal rescue factor. Previously, we have reported a female child carrying biallelic HBS1L mutations, manifesting growth restriction, developmental delay, and hypotonia. In this study, we describe her ophthalmologic findings, compare them with the Hbs1ltm1a/tm1a hypomorph mouse model, and evaluate the underlying microscopic and molecular perturbations. The patient was noted to have impaired visual function observed by electroretinogram (ERG), with dampened amplitudes of a- and b-waves in both rod- and cone-mediated responses. Hbs1ltm1a/tm1a mice exhibited profound retinal thinning of the entire retina, specifically of the outer retinal photoreceptor layer, detected using in vivo imaging of optical coherence tomography (OCT) and retinal cross sections. TUNEL assay revealed retinal degeneration due to extensive photoreceptor cell apoptosis. Loss of HBS1L resulted in comprehensive proteomic alterations in mass spectrometry analysis, with169 proteins increased and 480 proteins decreased including many critical IRD-related proteins. GO biological process and GSEA analyses reveal that these downregulated proteins are primarily involved in photoreceptor cell development, cilium assembly, phototransduction, and aerobic respiration. Furthermore, apart from the diminished level of PELO, a known partner protein, HBS1L depletion was accompanied by reduction in translation machinery associated 7 homolog (Tma7), and Endothelial differentiation-related factor 1(Edf1) proteins, the latter of which coordinates cellular responses to ribosome collisions. This novel connection between HBS1L and ribosome collision sensor (EDF1) further highlights the intricate mechanisms underpinning ribosomal rescue and quality control that are essential to maintain homeostasis of key proteins of retinal health, such as rhodopsin.

Integrated multi-omics approach reveals the role of SPEG in skeletal muscle biology including its relationship with myospryn complex.

Autosomal-recessive mutations in SPEG (striated muscle preferentially expressed protein kinase) have been linked to centronuclear myopathy. Loss of SPEG is associated with defective triad formation, abnormal excitation-contraction coupling, and calcium mishandling in skeletal muscles. To elucidate the underlying molecular pathways, we have utilized multi-omics tools and analysis to obtain a comprehensive view of the complex biological processes. We identified that SPEG interacts with myospryn complex proteins (CMYA5, FSD2, RyR1), and SPEG deficiency results in myospryn complex abnormalities. In addition, transcriptional and protein profiles of SPEG-deficient muscle revealed defective mitochondrial function including aberrant accumulation of enlarged mitochondria on electron microscopy. Furthermore, SPEG regulates RyR1 phosphorylation at S2902, and its loss affects JPH2 phosphorylation at multiple sites. On analyzing the transcriptome, the most dysregulated pathways affected by SPEG deficiency included extracellular matrix-receptor interaction and peroxisome proliferator-activated receptors signaling, which may be due to defective triad and mitochondrial abnormalities. In summary, we have elucidated the critical role of SPEG in triad as it works closely with myospryn complex, phosphorylates JPH2 and RyR1, and demonstrated that its deficiency is associated with mitochondrial abnormalities. This study emphasizes the importance of using multi-omics techniques to comprehensively analyze the molecular anomalies of rare diseases. Synopsis: We have previously linked mutations in SPEG (striated preferentially expressed protein) with a recessive form of centronuclear myopathy and/or dilated cardiomyopathy and have characterized a striated muscle-specific SPEG-deficient mouse model that recapitulates human disease with disruption of the triad structure and calcium homeostasis in skeletal muscles. In this study, we applied multi-omics approaches (interactomic, proteomic, phosphoproteomic, and transcriptomic analyses) in the skeletal muscles of SPEG-deficient mice to assess the underlying pathways associated with the pathological and molecular abnormalities. SPEG interacts with myospryn complex proteins (CMYA5, FSD2, RyR1), and its deficiency results in myospryn complex abnormalities.SPEG regulates RyR1 phosphorylation at S2902, and its loss affects JPH2 phosphorylation at multiple sites.SPEGα and SPEGß have different interacting partners suggestive of differential function.Transcriptome analysis indicates dysregulated pathways of ECM-receptor interaction and peroxisome proliferator-activated receptor signaling.Mitochondrial defects on the transcriptome, proteome, and electron microscopy, may be a consequence of defective calcium signaling.

WNT2B Deficiency Causes Increased Susceptibility to Colitis in Mice and Impairs Intestinal Epithelial Development in Humans.

Background and aims: WNT2B is a canonical Wnt ligand previously thought to be fully redundant with other Wnts in the intestinal epithelium. However, humans with WNT2B deficiency have severe intestinal disease, highlighting a critical role for WNT2B. We sought to understand how WNT2B contributes to intestinal homeostasis. Methods: We investigated the intestinal health of Wnt2b knock out (KO) mice. We assessed the impact of inflammatory challenge to the small intestine, using anti-CD3χ antibody, and to the colon, using dextran sodium sulfate (DSS). In addition, we generated human intestinal organoids (HIOs) from WNT2B-deficient human iPSCs for transcriptional and histological analyses. Results: Mice with WNT2B deficiency had significantly decreased Lgr5 expression in the small intestine and profoundly decreased expression in the colon, but normal baseline histology. The small intestinal response to anti-CD3χ antibody was similar in Wnt2b KO and wild type (WT) mice. In contrast, the colonic response to DSS in Wnt2b KO mice showed an accelerated rate of injury, featuring earlier immune cell infiltration and loss of differentiated epithelium compared to WT. WNT2B-deficient HIOs showed abnormal epithelial organization and an increased mesenchymal gene signature. Conclusion: WNT2B contributes to maintenance of the intestinal stem cell pool in mice and humans. WNT2B deficient mice, which do not have a developmental phenotype, show increased susceptibility to colonic injury but not small intestinal injury, potentially due to a higher reliance on WNT2B in the colon compared to the small intestine.WNT2B deficiency causes a developmental phenotype in human intestine with HIOs showing a decrease in their mesenchymal component and WNT2B-deficient patients showing epithelial disorganization. Data Transparency Statement: All RNA-Seq data will be available through online repository as indicated in Transcript profiling. Any other data will be made available upon request by emailing the study authors.

Optimizing detection of clinically significant prostate cancer through nomograms incorporating mri, clinical features, and advanced serum biomarkers in biopsy naïve men.

PURPOSE: To develop nomograms that predict the detection of clinically significant prostate cancer (csPCa, defined as ≥GG2 [Grade Group 2]) at diagnostic biopsy based on multiparametric prostate MRI (mpMRI), serum biomarkers, and patient clinicodemographic features. MATERIALS AND METHODS: Nomograms were developed from a cohort of biopsy-naïve men presenting to our 11-hospital system with prostate specific antigen (PSA) of 2-20 ng/mL who underwent pre-biopsy mpMRI from March 2018-June 2021 (n = 1494). The outcomes were the presence of csPCa and high-grade prostate cancer (defined as ≥GG3 prostate cancer). Using significant variables on multivariable logistic regression, individual nomograms were developed for men with total PSA, % free PSA, or prostate health index (PHI) when available. The nomograms were both internally validated and evaluated in an independent cohort of 366 men presenting to our hospital system from July 2021-February 2022. RESULTS: 1031 of 1494 men (69%) underwent biopsy after initial evaluation with mpMRI, 493 (47.8%) of whom were found to have ≥GG2 PCa, and 271 (26.3%) were found to have ≥GG3 PCa. Age, race, highest PIRADS score, prostate health index when available, % free PSA when available, and PSA density were significant predictors of ≥GG2 and ≥GG3 PCa on multivariable analysis and were used for nomogram generation. Accuracy of nomograms in both the training cohort and independent cohort were high, with areas under the curves (AUC) of ≥0.885 in the training cohort and ≥0.896 in the independent validation cohort. In our independent validation cohort, our model for ≥GG2 prostate cancer with PHI saved 39.1% of biopsies (143/366) while only missing 0.8% of csPCa (1/124) with a biopsy threshold of 20% probability of csPCa. CONCLUSIONS: Here we developed nomograms combining serum testing and mpMRI to help clinicians risk stratify patients with elevated PSA of 2-20 ng/mL who are being considered for biopsy. Our nomograms are available at https://rossnm1.shinyapps.io/MynMRIskCalculator/ to aid with biopsy decisions.

Compensated Hypospermatogenesis: Elevated Follicle-stimulating Hormone Predicts Decline in Semen Parameters Among Men With Normal Index Semen Analysis.

OBJECTIVE: To determine whether men with elevated follicle-stimulating hormone (FSH) and normal semen analysis (SA) are more likely to experience a decline in semen parameters over time compared to men with normal FSH. METHODS: Men presenting for fertility evaluation between 2002 and 2020 with normal initial SA were dichotomized according to baseline FSH as normal (<7.6 IU/mL) vs elevated (≥7.6 IU/mL). Primary outcomes included the development of abnormal sperm concentration (<15 million/mL) and total motile sperm count <9 million. Secondary outcomes included abnormal sperm motility (<40%), morphology (<4%), and total number of SA abnormalities. RESULTS: The final sample consisted of 858 men; 776 had normal FSH, and 82 had elevated FSH at presentation. Compared to men with normal FSH, men with elevated FSH had lower total motile sperm count (64.1 vs 107.3, P < .001) and higher testosterone levels (339 ng/dL vs 309 ng/dL, P = .03). At each follow-up timepoint, more men with elevated FSH had oligospermia compared to men with normal FSH. Men with elevated FSH were more likely to experience a decline in total motile sperm count below the intrauterine insemination threshold of 9 million and more likely to develop SA abnormalities over time. CONCLUSION: In men presenting for fertility evaluation with normal index SA, elevated FSH was associated with subsequent decline in semen parameters over time. Men with elevated FSH and normal SA, a condition we have termed compensated hypospermatogenesis, represent an at-risk population for whom close follow-up is warranted.

Diversity in Orthopaedic Surgery Medical Device Clinical Trials: An Analysis of the Food and Drug Administration Safety and Innovation Act.

INTRODUCTION: Demographic factors contribute markedly to orthopaedic surgery outcomes. However, women and minorities have been historically excluded from clinical trials. The United States passed the Safety and Innovation Act (Food and Drug Administration Safety and Innovation Act [FDA-SIA]) in 2012 to increase study diversity and mandate reporting of certain demographics. The purpose of this study was to investigate demographic reporting and analysis among high-risk orthopaedic medical device trials and evaluate the effectiveness of the FDA-SIA in increasing diversity of study enrollment. METHODS: The premarket approval database was queried for all original submissions approved by the Orthopedic Advisory Committee from January 1, 2003, to July 1, 2022. Study demographics were recorded. Weighted means of race, ethnicity, and sex were compared before and after FDA-SIA implementation with the US population. RESULTS: We identified 51 orthopaedic trials with unique study data. Most Food and Drug Administration device trials reported age (98.0%) and sex (96.1%), but only 49.0% and 37.3% reported race and ethnicity, respectively. Only 23 studies analyzed sex, six analyzed race, and two analyzed ethnicity. Compared with the US population, participants were overwhelmingly White (91.36% vs. 61.63%, P < 0.001) with a significant underrepresentation of Black (3.65% vs. 12.41%, P = 0.008), Asian (0.86% vs. 4.8%, P = 0.030), and Hispanic participants (3.02% vs. 18.73%, P < 0.001) before 2013. The FDA-SIA increased female patient enrollment (58.99% vs. 47.96%, P = 0.021) but did not increase the enrollment of racial or ethnic minorities. CONCLUSION: Despite efforts to increase the generalizability of studies within the FDA-SIA, orthopaedic medical devices still fail to enroll diverse populations and provide demographic subgroup analysis. The study populations within these trials do not represent the populations for whom these devices will be indicated in the community. The federal government must play a stronger role in mandating study diversity, enforcing appropriate statistical analysis of the demographic subgroups, and executing measures to ensure compliance. LEVEL OF EVIDENCE: I.

Unique Capabilities of Genome Sequencing for Rare Disease Diagnosis.

Background: Causal variants underlying rare disorders may remain elusive even after expansive gene panels or exome sequencing (ES). Clinicians and researchers may then turn to genome sequencing (GS), though the added value of this technique and its optimal use remain poorly defined. We therefore investigated the advantages of GS within a phenotypically diverse cohort. Methods: GS was performed for 744 individuals with rare disease who were genetically undiagnosed. Analysis included review of single nucleotide, indel, structural, and mitochondrial variants. Results: We successfully solved 218/744 (29.3%) cases using GS, with most solves involving established disease genes (157/218, 72.0%). Of all solved cases, 148 (67.9%) had previously had non-diagnostic ES. We systematically evaluated the 218 causal variants for features requiring GS to identify and 61/218 (28.0%) met these criteria, representing 8.2% of the entire cohort. These included small structural variants (13), copy neutral inversions and complex rearrangements (8), tandem repeat expansions (6), deep intronic variants (15), and coding variants that may be more easily found using GS related to uniformity of coverage (19). Conclusion: We describe the diagnostic yield of GS in a large and diverse cohort, illustrating several types of pathogenic variation eluding ES or other techniques. Our results reveal a higher diagnostic yield of GS, supporting the utility of a genome-first approach, with consideration of GS as a secondary or tertiary test when higher-resolution structural variant analysis is needed or there is a strong clinical suspicion for a condition and prior targeted genetic testing has been negative.

Comparing the severity of chronic rhinosinusitis symptoms before versus during the COVID-19 pandemic.

Background: COVID-19 measures such as masking, social distancing, and staying indoors may mitigate chronic rhinosinusitis (CRS) symptoms. We evaluate whether these measures correlated with improved symptoms in patients with CRS. Methods: This retrospective study compared SNOT-22 survey data from the Northwestern CRS Registry at the time of enrollment and at years 1-5 of follow-up. The final sample consisted of 1826 SNOT-22 surveys for 598 patients. April 10, 2020 to December 31, 2021 was considered "during the pandemic" and prior to March 11, 2020 was considered "pre-pandemic." Wilcoxon test was used to compare SNOT22 at enrollment pre-pandemic versus during pandemic. Separate linear mixed models were performed to estimate SNOT22 at 1 to 5 years after enrollment pre-pandemic versus during pandemic. Results: Subjects enrolled during the pandemic had worse SNOT22 scores than those enrolled pre-pandemic (53 vs. 42, p = .0024). Total SNOT-22 scores were improved during the pandemic than before the pandemic at 1 year follow-up (18.17 vs. 12.22, p = .001). This effect persists when evaluating the nasal (7.33 vs. 5.13, p = .003), sleep (2.63 vs. 1.39, p = .008), function (1.40 vs. 0.72, p = .015), and emotion (0.77 vs. 0.17, p < .001) domains individually. There was no statistically significant difference in total SNOT-22 score at Years 2-5 of follow-up. Conclusions: Patients with CRS experience a greater reduction in symptom severity in their first year of treatment during the pandemic than before the pandemic, plausibly from measures such as masking and staying indoors. Level of Evidence: 4.

Trends in the Surgical Management of Thoracic Outlet Syndrome.

BACKGROUND: The operative treatment for thoracic outlet syndrome (TOS) varies in the United States. This may be due to differences in specialty training of the provider. We sought to identify which procedures are primarily performed by specialty, identify patient characteristics presenting for different neurogenic TOS surgical interventions, and describe the safety of TOS surgery. METHODS: Patients treated for neurogenic TOS between 2016 and 2018 were identified from the American College of Surgeons National Surgical Quality Improvement Program (NSQIP). Patient characteristics, surgeon details, intraoperative variables, and complication outcomes were abstracted. Patient cohorts were stratified by type of operative intervention and by treating specialty. RESULTS: Transthoracic first rib resection was the most common procedure performed for TOS relief (46.1%), followed by division of the scalene muscles with rib resection (23.9%) and brachial plexus exploration with decompression (19.4%). Vascular surgeons performed 87% of TOS repairs. Thirty-day complication rate was 3.5%. Addition of scalenectomy to first rib resection was common and resulted in increased operative time but did not increase early complication rate or readmission rate. CONCLUSION: Patient characteristics and dispositions are similar between the various TOS operative approaches. All major surgical treatments for TOS have low complication rates. Transthoracic first rib resection performed by vascular surgeons remains the most common surgical treatment for patients with TOS in the United States. Despite neurogenic symptoms representing most cases, less than 10% of operations are performed by peripheral nerve specialists, highlighting a potential need for greater incorporation of TOS release into peripheral nerve practices.

The broad reach and inaccuracy of men's health information on social media: analysis of TikTok and Instagram.

Social media (SoMe) offers great potential to expand access to health information, but a significant proportion of users consume its content instead of consulting a physician. We sought to quantify the volume and characterize the accuracy of men's health-related content on TikTok and Instagram. We searched TikTok and Instagram for the terms: testosterone, erectile dysfunction, male infertility, semen retention, Peyronie's disease, and vasectomy. The top 10 hashtags for each term were used to estimate the total impressions for each term on each platform, and posts were then characterized by creator type, content type, and accuracy (1 to 5 scale). TikTok had 2,312,407,100 impressions and Instagram had 3,107,300 posts across all topics. Semen retention had the most impressions on TikTok (1,216,074,000) and posts on Instagram (1,077,000). Physicians created only a small portion of total TikTok and Instagram posts (10.3% and 12.9%, respectively). Across all topics, the accuracy of content was poor (2.6 ± 1.7), however, physician posts were more accurate than non-physician posts (mean 4.2 ± 1.2 vs 2.3 ± 1.6, p < 0.001, respectively). Men's health content is popular on TikTok and Instagram but is not accurate. We recommend that physicians actively engage in SoMe to address misinformation.

A neurodevelopmental disorder caused by a novel de novo SVA insertion in exon 13 of the SRCAP gene.

Pathogenic variants in the SRCAP (SNF2-related CREBBP activator protein) gene, which encodes a chromatin-remodeling ATPase, cause neurodevelopmental disorders including Floating Harbor syndrome (FLHS). Here, we report the discovery of a de novo transposon insertion in SRCAP exon 13 from trio genome sequencing in a 28-year-old female with failure to thrive, developmental delay, mood disorder and seizure disorder. The insertion was a full-length (~2.8 kb), antisense-oriented SVA insertion relative to the SRCAP transcript, bearing a 5' transduction and hallmarks of target-primed reverse transcription. The 20-bp 5' transduction allowed us to trace the source SVA element to an intron of a long non-coding RNA on chromosome 12, which is highly expressed in testis. RNA sequencing and qRT-PCR confirmed significant depletion of SRCAP expression and low-level exon skipping in the proband. This case highlights a novel disease-causing structural variant and the importance of transposon analysis in a clinical diagnostic setting.

Dynamin-2 reduction rescues the skeletal myopathy of a SPEG-deficient mouse model.

Striated preferentially expressed protein kinase (SPEG), a myosin light chain kinase, is mutated in centronuclear myopathy (CNM) and/or dilated cardiomyopathy. No precise therapies are available for this disorder, and gene replacement therapy is not a feasible option due to the large size of SPEG. We evaluated the potential of dynamin-2 (DNM2) reduction as a potential therapeutic strategy because it has been shown to revert muscle phenotypes in mouse models of CNM caused by MTM1, DNM2, and BIN1 mutations. We determined that SPEG-ß interacted with DNM2, and SPEG deficiency caused an increase in DNM2 levels. The DNM2 reduction strategy in Speg-KO mice was associated with an increase in life span, body weight, and motor performance. Additionally, it normalized the distribution of triadic proteins, triad ultrastructure, and triad number and restored phosphatidylinositol-3-phosphate levels in SPEG-deficient skeletal muscles. Although DNM2 reduction rescued the myopathy phenotype, it did not improve cardiac dysfunction, indicating a differential tissue-specific function. Combining DNM2 reduction with other strategies may be needed to target both the cardiac and skeletal defects associated with SPEG deficiency. DNM2 reduction should be explored as a therapeutic strategy against other genetic myopathies (and dystrophies) associated with a high level of DNM2.

Reanalysis of Exome Data Identifies Novel SLC25A46 Variants Associated with Leigh Syndrome.

SLC25A46 (solute carrier family 25 member 46) mutations have been linked to various neurological diseases with recessive inheritance, including Leigh syndrome, optic atrophy, and lethal congenital pontocerebellar hypoplasia. SLC25A46 is expressed in the outer membrane of mitochondria, where it plays a critical role in mitochondrial dynamics. A deceased 7-month-old female infant was suspected to have Leigh syndrome. Clinical exome sequencing was non-diagnostic, but research reanalysis of the sequencing data identified two novel variants in SLC25A46: a missense (c.1039C>T, p.Arg347Cys; NM_138773, hg19) and a donor splice region variant (c.283+5G>A) in intron 1. Both variants were predicted to be damaging. Sanger sequencing of cDNA detected a single missense allele in the patient compared to control, and the SLC25A46 transcript levels were also reduced due to the splice region variant. Additionally, Western blot analysis of whole-cell lysate showed a decrease of SLC25A46 expression in proband fibroblasts, relative to control cells. Further, analysis of mitochondrial morphology revealed evidence of increased fragmentation of the mitochondrial network in proband fibroblasts, compared to control cells. Collectively, our findings suggest that these novel variants in SLC24A46, the donor splice one and the missense variant, are the cause of the neurological phenotype in this proband.

Motion Analytics of Trapezius Muscle Activity in an 18-Year-Old Female with Extended Upper Brachial Plexus Birth Palsy.

Background The trapezius muscle is often utilized as a muscle or nerve donor for repairing shoulder function in those with brachial plexus birth palsy (BPBP). To evaluate the native role of the trapezius in the affected limb, we demonstrate use of the Motion Browser, a novel visual analytics system to assess an adolescent with BPBP. Method An 18-year-old female with extended upper trunk (C5-6-7) BPBP underwent bilateral upper extremity three-dimensional motion analysis with Motion Browser. Surface electromyography (EMG) from eight muscles in each limb which was recorded during six upper extremity movements, distinguishing between upper trapezius (UT) and lower trapezius (LT). The Motion Browser calculated active range of motion (AROM), compiled the EMG data into measures of muscle activity, and displayed the results in charts. Results All movements, excluding shoulder abduction, had similar AROM in affected and unaffected limbs. In the unaffected limb, LT was more active in proximal movements of shoulder abduction, and shoulder external and internal rotations. In the affected limb, LT was more active in distal movements of forearm pronation and supination; UT was more active in shoulder abduction. Conclusion In this female with BPBP, Motion Browser demonstrated that the native LT in the affected limb contributed to distal movements. Her results suggest that sacrificing her trapezius as a muscle or nerve donor may affect her distal functionality. Clinicians should exercise caution when considering nerve transfers in children with BPBP and consider individualized assessment of functionality before pursuing surgery.