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Alcohol is a known teratogen and prenatal alcohol exposure remains a major ongoing public health concern. Fetal alcohol spectrum disorder has become the diagnosis for describing individuals who have been affected by prenatal alcohol exposure. In this Viewpoint, we raise major concerns about its continued use as a diagnostic term in how it perpetuates a misleading and outdated narrative about child development and maternal health. We argue that the term fetal alcohol spectrum disorder has contributed to a culture of racism and discrimination for many who are diagnosed with it. The term fetal alcohol spectrum disorder fails to capture the progress made in our collective understanding of neurodevelopment through advancements in the field of genetics and in understanding the effects of trauma and adversity. We call for urgent international collaborative action to review the use of it as a diagnostic term and, more broadly, to reconsider the practice of diagnosing disabilities as medical illnesses. We suggest that this practice fails to recognise that outcomes of functioning and participation in individuals are not only the results of health conditions, but are also the products of complex interactions and experiences of individuals within the families and societies in which they live., Competing Interests: Declaration of interests ARM has a service contract with the Provincial Health Services Authority of British Columbia to attend conferences and receives support from Sunny Hill Foundation for academic activities. WBG has a contract with Elsevier to edit a book and write a chapter regarding the harms of assessment and diagnosis for neurodevelopmental disorders. He received payment for this work. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

PIK3CA-related overgrowth spectrum (PROS) disorders are caused by somatic mosaic variants that result in constitutive activation of the phosphatidylinositol-3-kinase/AKT/mTOR pathway. Promising responses to molecularly targeted therapy have been reported, although identification of an appropriate agent can be hampered by the mosaic nature and corresponding low variant allele frequency of the causal variant. Moreover, our understanding of the molecular consequences of these variants-for example how they affect gene expression profiles-remains limited. Here we describe in vitro expansion of a human capillary malformation followed by molecular characterization using exome sequencing, single cell gene expression, and targeted long-read single cell RNA-sequencing in a patient with clinical features consistent with Megalencephaly-Capillary Malformation Syndrome (MCAP, a PROS condition). These approaches identified a targetable PIK3CA variant with expression restricted to PAX3+ fibroblast and undifferentiated keratinocyte populations. This study highlights the innovative combination of next-generation single cell sequencing methods to better understand unique transcriptomic profiles and cell types associated with MCAP, revealing molecular intricacies of this genetic syndrome., (© 2024. The Author(s).)

Background: Use of immune checkpoint inhibitors is growing, but clinical trial data may not apply to Indigenous patients or patients living in remote areas., Aims: To provide real-world incidence of immune-related adverse events (irAE) in the Top End of the Northern Territory and compare incidence between demographic subgroups., Methods: This retrospective, observational, cohort study collected data from electronic records of patients living in the Top End with solid organ cancer treated with immunotherapy between January 2016 and December 2021. The primary outcome was cumulative incidence of any-grade and severe irAE. Secondary outcomes were overall survival, treatment duration and reason for treatment discontinuation., Results: Two hundred and twenty-six patients received immunotherapy. Forty-eight (21%) lived in a remote or very remote area, and 36 (16%) were Indigenous. Cumulative incidence of any-grade irAE was 54% (122/226 patients); incidence of severe irAE was 26% (59/226 patients). Rates were similar between Indigenous and non-Indigenous patients of any-grade (42% vs 56%, P = 0.11) and severe (11% vs 18%, P = 0.29) irAE. However, Indigenous patients had shorter treatment duration, more frequently discontinued treatment due to patient preference and appeared to have shorter median overall survival than non-Indigenous patients (17.1 vs 30.4 months; hazard ratio (HR) = 1.5, 95% confidence interval (CI) = 0.92-2.66). There was no difference in mortality between remote and urban patients (median overall survival 27.5 vs 30.2 months; HR = 1.1, 95% CI = 0.7-1.7)., Conclusions: Rates of irAE in our cohort are comparable to those in the published literature. There was no significant difference in any-grade or severe irAE incidence observed between Indigenous and non-Indigenous patients., (© 2024 The Author(s). Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

In a previous study, we observed decreased 1,25-dihydroxyvitamin D levels, secondary hyperparathyroidism, and increased bone turnover markers in living kidney donors (LKDs) at 3 months and 36 months after kidney donation. In our recent survey-based study, we found no increased risk of fractures of all types but observed significantly more vertebral fractures in LKDs compared with matched controls. To elucidate the long-term effects of kidney donation on bone health, we recruited 139 LKDs and 139 age and sex matched controls from the survey-based participants for further mechanistic analyses. Specifically, we assessed whether LKDs had persistent abnormalities in calcium- and phosphorus-regulating hormones and related factors, in bone formation and resorption markers, and in density and microstructure of bone compared with controls. We measured serum markers, bone mineral density (BMD), bone microstructure and strength (via high-resolution peripheral quantitative computed tomography and micro-finite element analysis [HRpQCT]), and advanced glycation end-products in donors and controls. LKDs had decreased 1,25-dihydroxyvitamin D concentrations (donors mean 33.89 pg/mL vs. controls 38.79 pg/mL, percent difference = -12.6%; P  < .001), increases in both parathyroid hormone (when corrected for ionized calcium; donors mean 52.98 pg/mL vs. controls 46.89 pg/mL,% difference 13%; P  = .03) and ionized calcium levels (donors mean 5.13 mg/dL vs. controls 5.04 mg/dL; P  < .001), and increases in several bone resorption and formation markers versus controls. LKDs and controls had similar measures of BMD; however, HRpQCT suggested that LKDs have a statistically insignificant tendency toward thinner cortical bone and lower failure loads as measured by micro-finite element analysis. Our findings suggest that changes in the hormonal mileu after kidney donation and the long-term cumulative effects of these changes on bone health persist for decades after kidney donation and may explain later-life increased rates of vertebral fractures., Competing Interests: R.K. reported receiving grants from Mayo Clinic Rochester during the conduct of the study and nonfinancial support from Bridge Bio outside the submitted work. No other disclosures were reported. The current clinical investigation is an original full-length submission., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Objective: Automated surgical step recognition (SSR) using AI has been a catalyst in the "digitization" of surgery. However, progress has been limited to laparoscopy, with relatively few SSR tools in endoscopic surgery. This study aimed to create a SSR model for transurethral resection of bladder tumors (TURBT), leveraging a novel application of transfer learning to reduce video dataset requirements., Materials and Methods: Retrospective surgical videos of TURBT were manually annotated with the following steps of surgery: primary endoscopic evaluation, resection of bladder tumor, and surface coagulation. Manually annotated videos were then utilized to train a novel AI computer vision algorithm to perform automated video annotation of TURBT surgical video, utilizing a transfer-learning technique to pre-train on laparoscopic procedures. Accuracy of AI SSR was determined by comparison to human annotations as the reference standard., Results: A total of 300 full-length TURBT videos (median 23.96 min; IQR 14.13-41.31 min) were manually annotated with sequential steps of surgery. One hundred and seventy-nine videos served as a training dataset for algorithm development, 44 for internal validation, and 77 as a separate test cohort for evaluating algorithm accuracy. Overall accuracy of AI video analysis was 89.6%. Model accuracy was highest for the primary endoscopic evaluation step (98.2%) and lowest for the surface coagulation step (82.7%)., Conclusion: We developed a fully automated computer vision algorithm for high-accuracy annotation of TURBT surgical videos. This represents the first application of transfer-learning from laparoscopy-based computer vision models into surgical endoscopy, demonstrating the promise of this approach in adapting to new procedure types., Competing Interests: AA, MZ, OB, TW, and DA were employed by Theator Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Deol, Tollefson, Antolin, Zohar, Bar, Ben-Ayoun, Mynderse, Lomas, Avant, Miller, Elliott, Boorjian, Wolf, Asselmann and Khanna.)

Purpose: This article summarizes emerging nontraditional therapies administered via the nebulization route for use in the emergency department (ED)., Summary: Although traditional routes of medication administration (eg, intravenous) have been the mainstay of administration modalities for decades, these routes may not be appropriate for all patients. Nowhere is this more readily apparent than in the ED setting, where patients with a variety of presentations receive care. One unique route for medication administration that has increasingly gained popularity in the ED is that of aerosolized drug delivery. This route holds promise as direct delivery of medications to the site of action could yield a more rapid and effective therapeutic response while also minimizing systemic adverse effects by utilizing a fraction of the systemic dose. Medication administration via nebulization also provides an alternative that is conducive to rapid, less invasive access, which is advantageous in the emergent setting of the ED. This review is intended to analyze the existing literature regarding this route of administration, including the nuances that can impact drug efficacy, as well as the available literature regarding novel, noncommercial nebulized medication therapy given in the ED., Conclusion: Multiple medications have been investigated for administration via this route, and when implementing any of these therapies several practical considerations must be taken into account, from medication preparation to administration, to ensure optimal efficacy while minimizing adverse effects. The pharmacist is an essential bedside team member in these scenarios to assist with navigating unique and complex nuances of this therapy as they develop., (© American Society of Health-System Pharmacists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Cancers exhibit complex transcriptomes with aberrant splicing that induces isoform-level differential expression compared to non-diseased tissues. Transcriptomic profiling using short-read sequencing has utility in providing a cost-effective approach for evaluating isoform expression, although short-read assembly displays limitations in the accurate inference of full-length transcripts. Long-read RNA sequencing (Iso-Seq), using the Pacific Biosciences (PacBio) platform, can overcome such limitations by providing full-length isoform sequence resolution which requires no read assembly and represents native expressed transcripts. A constraint of the Iso-Seq protocol is due to fewer reads output per instrument run, which, as an example, can consequently affect the detection of lowly expressed transcripts. To address these deficiencies, we developed a concatenation workflow, PacBio Full-Length Isoform Concatemer Sequencing (PB&#95;FLIC-Seq), designed to increase the number of unique, sequenced PacBio long-reads thereby improving overall detection of unique isoforms. In addition, we anticipate that the increase in read depth will help improve the detection of moderate to low-level expressed isoforms., Results: In sequencing a commercial reference (Spike-In RNA Variants; SIRV) with known isoform complexity we demonstrated a 3.4-fold increase in read output per run and improved SIRV recall when using the PB&#95;FLIC-Seq method compared to the same samples processed with the Iso-Seq protocol. We applied this protocol to a translational cancer case, also demonstrating the utility of the PB&#95;FLIC-Seq method for identifying differential full-length isoform expression in a pediatric diffuse midline glioma compared to its adjacent non-malignant tissue. Our data analysis revealed increased expression of extracellular matrix (ECM) genes within the tumor sample, including an isoform of the Secreted Protein Acidic and Cysteine Rich (SPARC) gene that was expressed 11,676-fold higher than in the adjacent non-malignant tissue. Finally, by using the PB&#95;FLIC-Seq method, we detected several cancer-specific novel isoforms., Conclusion: This work describes a concatenation-based methodology for increasing the number of sequenced full-length isoform reads on the PacBio platform, yielding improved discovery of expressed isoforms. We applied this workflow to profile the transcriptome of a pediatric diffuse midline glioma and adjacent non-malignant tissue. Our findings of cancer-specific novel isoform expression further highlight the importance of long-read sequencing for characterization of complex tumor transcriptomes., (© 2024. The Author(s).)

Importance: Living kidney donors may have an increased risk of fractures due to reductions in kidney mass, lower concentrations of serum 1,25-dihydroxyvitamin D, and secondary increases in serum parathyroid hormone., Objective: To compare the overall and site-specific risk of fractures among living kidney donors with strictly matched controls from the general population who would have been eligible to donate a kidney but did not do so., Design, Setting, and Participants: This survey study was conducted between December 1, 2021, and July 31, 2023. A total of 5065 living kidney donors from 3 large transplant centers in Minnesota were invited to complete a survey about their bone health and history of fractures, and 16 156 population-based nondonor controls without a history of comorbidities that would have precluded kidney donation were identified from the Rochester Epidemiology Project and completed the same survey. A total of 2132 living kidney donors and 2014 nondonor controls responded to the survey. Statistical analyses were performed from May to August 2023., Exposure: Living kidney donation., Main Outcomes and Measures: The rates of overall and site-specific fractures were compared between living kidney donors and controls using standardized incidence ratios (SIRs)., Results: At the time of survey, the 2132 living kidney donors had a mean (SD) age of 67.1 (8.9) years and included 1245 women (58.4%), and the 2014 controls had a mean (SD) age of 68.6 (7.9) years and included 1140 women (56.6%). The mean (SD) time between donation or index date and survey date was 24.2 (10.4) years for donors and 27.6 (10.7) years for controls. The overall rate of fractures among living kidney donors was significantly lower than among controls (SIR, 0.89; 95% CI, 0.81-0.97). However, there were significantly more vertebral fractures among living kidney donors than among controls (SIR, 1.42; 95% CI, 1.05-1.83)., Conclusions and Relevance: This survey study found a reduced rate of overall fractures but an excess of vertebral fractures among living kidney donors compared with controls after a mean follow-up of 25 years. Treatment of excess vertebral fractures with dietary supplements such as vitamin D3 may reduce the numbers of vertebral fractures and patient morbidity.

Background: A significant factor for the high prevalence of traumatic brain injury (TBI) among U.S. service members is their exposure to explosive munitions leading to blast-related TBI. Our understanding of the specific clinical effects of mild TBI having a component of blast mechanism remains limited compared to pure blunt mechanisms., Objective: The purpose of this review is to provide a synopsis of clinical research findings on the long-term effects of blast-related mild TBI derived to date from the Long-Term Impact of Military-Relevant Brain Injury Consortium - Chronic Effects of Neurotrauma Consortium (LIMBIC-CENC)., Methods: Publications on blast-related mild TBI from LIMBIC-CENC and the LIMBIC-CENC prospective longitudinal study (PLS) cohort were reviewed and their findings summarized. Findings from the broader literature on blast-related mild TBI that evaluate similar outcomes are additionally reviewed for a perspective on the state of the literature., Results: The most consistent and compelling evidence for long-term effects of blast-related TBI is for poorer psychological health, greater healthcare utilization and disability levels, neuroimaging impacts on brain structure and function, and greater headache impact on daily life. To date, evidence for chronic cognitive performance deficits from blast-related mild TBI is limited, but futher research including crucial longitudinal data is needed., Conclusion: Commentary is provided on: how LIMBIC-CENC findings assimilate with the broader literature; ongoing research gaps alongside future research needs and priorities; how the scientific community can utilize the LIMBIC-CENC database for independent or collaborative research; and how the evidence from the clinical research should be assimilated into clinical practice.