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Purpose: This study presents a novel and comprehensive framework for evaluating magnetic resonance guided radiotherapy (MRgRT) workflow by integrating the Failure Modes and Effects Analysis (FMEA) approach with Time-Driven Activity-Based Costing (TDABC). We assess the workflow for safety, quality, and economic implications, providing a holistic understanding of the MRgRT implementation. The aim is to offer valuable insights to healthcare practitioners and administrators, facilitating informed decision-making regarding the 0.35T MRIdian MR-Linac system's clinical workflow., Methods: For FMEA, a multidisciplinary team followed the TG-100 methodology to assess the MRgRT workflow's potential failure modes. Following the mitigation of primary failure modes and workflow optimization, a treatment process was established for TDABC analysis. The TDABC was applied to both MRgRT and computed tomography guided RT (CTgRT) for typical five-fraction stereotactic body RT (SBRT) treatments, assessing total workflow and costs associated between the two treatment workflows., Results: A total of 279 failure modes were identified, with 31 categorized as high-risk, 55 as medium-risk, and the rest as low-risk. The top 20% risk priority numbers (RPN) were determined for each radiation oncology care team member. Total MRgRT and CTgRT costs were assessed. Implementing technological advancements, such as real-time multi leaf collimator (MLC) tracking with volumetric modulated arc therapy (VMAT), auto-segmentation, and increasing the Linac dose rate, led to significant cost savings for MRgRT., Conclusion: In this study, we integrated FMEA with TDABC to comprehensively evaluate the workflow and the associated costs of MRgRT compared to conventional CTgRT for five-fraction SBRT treatments. FMEA analysis identified critical failure modes, offering insights to enhance patient safety. TDABC analysis revealed that while MRgRT provides unique advantages, it may involve higher costs. Our findings underscore the importance of exploring cost-effective strategies and key technological advancements to ensure the widespread adoption and financial sustainability of MRgRT in clinical practice., (© 2024 The Author(s). Journal of Applied Clinical Medical Physics is published by Wiley Periodicals, Inc. on behalf of The American Association of Physicists in Medicine.)

Purpose: Both breast reduction surgery (BRS) in adolescent girls and chest masculinization surgery (CMS) transgender and nonbinary (TGNB) individuals improve physical discomfort and psychological well-being. Nonetheless, CMS in adolescents is highly contested due to concerns regarding safety and capacity for consent. Here, we compare both procedures to quantify trends in incidence, minimum age, and surgical outcomes., Methods: The National Surgical Quality Improvement Program database was queried from 2018 to 2021 for cisgender and TGNB adolescents 18 years or younger who underwent BRS or CMS. Our primary outcome was the incidence of postoperative complications within 30 days of surgery. Multivariate logistic regression was performed to determine if CMS was associated with postoperative complications., Results: Of 2504 adolescents, the majority (n = 2186 [87.3%]) were cisgender female patients who underwent BRS, compared with TGNB adolescents (n = 318 [12.7%]) who underwent CMS. BRS patients were younger at time of surgery (mean [SD] 16.7 [1.2], 17.5 [0.9]; P < 0.001). The minimum age for BRS was consistently 2 to 3 years younger than that for CMS (12.1 to 12.6 years vs 14.0 to 15.1 years). A comparable frequency of BRS and CMS patients developed 1 or more complications within 30 days of surgery (n = 98 [4.5%], n = 13 [4.1%]; P = 0.775)., Conclusion: Cisgender female adolescents undergo breast surgery at a 7-fold rate compared with TGNB adolescents and do so at significantly younger ages. Given the favorable effects of BRS and CMS on psychosocial well-being and their comparable surgical risk of complications, our data help recontextualize the concerns surrounding adolescent CMS., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Syphilis epidemics among women and men-who-have-sex-with-men (MSM) may be connected, but these connections are poorly understood. Using egocentric network data from a U.S. urban MSM cohort, we examined socio-demographics, behaviors, and syphilis positivity among MSM with (1) direct (MSM who report sex with women, MSMW); (2) indirect (MSM who only report male partners, some of whom are MSMW, MSMO/W); and (3) no (MSM who only report male partners and whose partners only have sex with men, MSMO/O) connection to women., Methods: Sexually-active MSM aged 18-45 years were administered behavioral and network interviews (recall period: three months) and syphilis/HIV testing. Syphilis positivity was defined as RPR titer >1:8. Modified Poisson regression was used to test for differences across groups., Results: Among 385 MSM, 14.5% were MSMW and 22.3% were MSMO/W. MSMW and MSMO/W were significantly more likely than MSMO/O to report sex behaviors associated with increased syphilis acquisition/transmission risk, including: > 2 sex partners [MSMW aPR:1.28 (0.98-1.68); MSMO/W aPR:1.35 (1.09-1.69)], concurrent sex partners [MSMW aPR:1.50 (1.17-1.92); MSMO/W aPR:1.39 (1.11-1.74)], and for MSMW only, transactional sex [aPR:2.07 (1.11-3.88)]. Syphilis positivity was 16.4% and was lower among MSMW (9.4%) and MSMO/W (14.1%) than MSMO/O (18.5%), but differences were not significant., Conclusions: There may be considerable connectivity between MSM and female sex partners that could facilitate syphilis transmission, and behaviors that increase acquisition/transmission risk among MSMW and MSMO/W may be distinct from MSMO/O. Future work should focus on examining the context and temporal patterns of sex partnerships among MSMW and MSMO/W., Competing Interests: Conflicts of Interest and Sources of Support: This work was supported by the Centers for Disease Control and Prevention [1U01PS005171-01], and the Johns Hopkins University Center for AIDS Research [P30AI094189]., (Copyright © 2024 American Sexually Transmitted Diseases Association. All rights reserved.)

The spatial organization of a neuronal circuit is critically important for its function since the location of neurons is often associated with function. In the cerebellum, the major output of the cerebellar cortex are synapses made from Purkinje cells onto neurons in the cerebellar nuclei, yet little has been known about the spatial organization of these synapses. We explored this question using whole-cell electrophysiology and optogenetics in acute sagittal cerebellar slices to produce spatial connectivity maps of cerebellar cortical output in mice. We observed non-random connectivity where Purkinje cell inputs clustered in cerebellar transverse zones: while many nuclear neurons received inputs from a single zone, several multi-zonal connectivity motifs were also observed. Single neurons receiving input from all four zones were overrepresented in our data. These findings reveal that the output of the cerebellar cortex is spatially structured and represents a locus for multimodal integration in the cerebellum., (© 2024. The Author(s).)

Objectives: To define consensus entrustable professional activities (EPAs) for neurocritical care (NCC) advanced practice providers (APPs), establish validity evidence for the EPAs, and evaluate factors that inform entrustment expectations of NCC APP supervisors., Design: A three-round modified Delphi consensus process followed by application of the EQual rubric and assessment of generalizability by clinicians not affiliated with academic medical centers., Setting: Electronic surveys., Subjects: NCC APPs ( n = 18) and physicians ( n = 12) in the United States with experience in education scholarship or APP program leadership., Interventions: None., Measurements and Main Results: The steering committee generated an initial list of 61 possible EPAs. The panel proposed 30 additional EPAs. A total of 47 unique nested EPAs were retained by consensus opinion. The steering committee defined six core EPAs addressing medical knowledge, procedural competencies, and communication proficiency which encompassed the nested EPAs. All core EPAs were retained and subsequently met the previously described cut score for quality and structure using the EQual rubric. Most clinicians who were not affiliated with academic medical centers rated each of the six core EPAs as very important or mandatory. Entrustment expectations did not vary by prespecified groups., Conclusions: Expert consensus was used to create EPAs for NCC APPs that reached a predefined quality standard and were important to most clinicians in different practice settings. We did not identify variables that significantly predicted entrustment expectations. These EPAs may aid in curricular design for an EPA-based assessment of new NCC APPs and may inform the development of EPAs for APPs in other critical care subspecialties., Competing Interests: Dr. Sigman received funding from the Journal of Clinical Neuroscience and the American Academy of Neuroscience. Dr. Sarwal’s institution received funding from Butterfly, ImageMonitoring, and Stimdia; she disclosed she is a member of the Board of Directors Neurocritical Care Society (NCS). Dr. Greer’s institution received funding from Becton, Dickinson and Company; he received funding from Thieme Publishers for medical-legal consultations. Dr. Morris’ institution received funding from the National Institute of Neurological Disorders and Stroke and the National Center for Advancing Translational Sciences. Dr. Zafar received funding from Marinus and Corticare. Dr. Livesay received funding from Stroke Challenges/Lombardi Hill LLC; she disclosed she is an officer for the NCS. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Purpose: To investigate whether gynecologic and radiation oncologists document discussions of chemoradiation treatment's gonadotoxicity for patients with cervical cancer and what patient and physician factors make discussions more likely., Methods and Materials: Women with LACC treated with definitive CRT between 2009 and 2022 were included. Visit notes with gynecologic and radiation oncologists were reviewed for sexual health discussions. Fertility and premature menopause discussions were only evaluated among premenopausal patients. Variables of interest including demographics and staging were collected. Univariate and multivariate analyses were conducted using Rv4.2.1., Results: A total of 93 women were included (22-91 years old). Most were Stage IIB (32%) or IIIB (34%). Sexual health discussions occurred among 74.2% of patients and did not have a significant relationship with any patient factors. Fertility discussions occurred with 17.5% of the 57 premenopausal patients and were more likely among younger patients (≤31.9, p < 0.001) with fewer children (≤1, p < 0.001). Premature menopause discussions occurred among 73.7% of premenopausal patients and were more likely among younger patients (≤39.0, p = 0.015)., Conclusions: It is promising to see that oncologists are discussing sexual health and premature menopause with most patients. The limited fertility discussions suggest that oncologists are less likely to discuss fertility as women approach the age of menopause or already have children. Involvement of reproductive endocrinologists and psychologists may provide patients with a more comprehensive understanding of long-term quality of life., (Copyright © 2024 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Homozygous plakophilin-2 ( PKP2 ) variants have been identified as a cause of a lethal form of dilated cardiomyopathy with excessive trabeculations (DCM-ET) in three cases. We report three more cases from two families with homozygous pathogenic PKP2 variants and perinatal-onset, lethal DCM-ET. Identification of the genetic abnormalities played a key role in decision-making and family counselling in these cases. This case series supports the published evidence that biallelic loss of function PKP2 variants cause a lethal, perinatal-onset cardiomyopathy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Sickle haemoglobin (HbS) polymerisation perturbs red blood cell (RBC) rheology and drives sickle cell disease (SCD) pathophysiology. Voxelotor is an HbS polymerisation inhibitor that increases haemoglobin (Hb)-oxygen affinity., Methods/results: In this 48-week, prospective, single-centre translational study, 10 children aged 4-11 years with SCD were treated with voxelotor. Improvements in RBC deformability were observed using osmotic/oxygen gradient ektacytometry, with increases in minimal and maximal elongation index and reductions in point of sickling. Increased Hb and reduced markers of haemolysis were also observed., Conclusion: These findings suggest that voxelotor treatment is associated with reduced RBC sickling and haemolysis in children with SCD., Competing Interests: Satheesh Chonat: consultant, research funding: Agios, Alexion, Daichi Sankyo, Forma Therapeutics, Genentech/Roche, Pfizer, Novartis, Novo Nordisk, Takeda Pharmaceuticals. Earl Fields, Hannah Baratz and Amanda Watt: nothing to disclose. Mira Pochron and Sandy Dixon: currently employed with Pfizer. Margaret Tonda: former employee of Pfizer. Clark Brown: employee: Pfizer; consultant: Imara, Novo Nordisk; research support: Novartis Pharmaceuticals, Imara, Forma Therapeutics. David Archer: consultant, research funding: Pfizer, Forma Therapeutics., (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease that manifests in midlife and progressively worsens with age. SCA6 is rare, and many patients are not diagnosed until long after disease onset. Whether disease-causing cellular alterations differ at different disease stages is currently unknown, but it is important to answer this question in order to identify appropriate therapeutic targets across disease duration. We used transcriptomics to identify changes in gene expression at disease onset in a well-established mouse model of SCA6 that recapitulates key disease features. We observed both up- and down-regulated genes with the major down-regulated gene ontology terms suggesting mitochondrial dysfunction. We explored mitochondrial function and structure and observed that changes in mitochondrial structure preceded changes in function, and that mitochondrial function was not significantly altered at disease onset but was impaired later during disease progression. We also detected elevated oxidative stress in cells at the same disease stage. In addition, we observed impairment in mitophagy that exacerbates mitochondrial dysfunction at late disease stages. In post-mortem SCA6 patient cerebellar tissue, we observed metabolic changes that are consistent with mitochondrial impairments, supporting our results from animal models being translatable to human disease. Our study reveals that mitochondrial dysfunction and impaired mitochondrial degradation likely contribute to disease progression in SCA6 and suggests that these could be promising targets for therapeutic interventions in particular for patients diagnosed after disease onset., (© 2024. The Author(s).)