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Background: Classically, hypertrophic cardiomyopathy (HCM) has been viewed as a single-gene (monogenic) disease caused by pathogenic variants in sarcomere genes. Pathogenic sarcomere variants are individually rare and convey high risk for developing HCM (highly penetrant). Recently, important polygenic contributions have also been characterized. Low penetrance sarcomere variants (LowSVs) at intermediate frequencies and effect sizes have not been systematically investigated. We hypothesize that LowSVs may be common in HCM with substantial influence on disease risk and severity., Methods: Among all sarcomere variants observed in the Sarcomeric Human Cardiomyopathy Registry (SHaRe), we identified putative LowSVs defined by (1) population frequency greater than expected for highly penetrant (monogenic) HCM (allele frequency >5×10 -5 in the Genome Aggregation Database, gnomAD) and (2) moderate enrichment (>2×) in patients with HCM compared with gnomAD. LowSVs were examined for their association with disease severity and clinical outcomes. Functional effects of selected LowSVs were assessed using induced pluripotent stem cell-derived cardiomyocytes. Association of LowSVs with HCM-adjacent traits in the general population was tested using UK Biobank cardiac magnetic resonance imaging data., Results: Among 6045 patients and 1159 unique variants in sarcomere genes, 12 LowSVs were identified. LowSVs were collectively common in the general population (1:350) and moderately enriched in HCM (aggregate odds ratio, 14.9 [95% CI, 12.5-17.9]). Isolated LowSVs were associated with an older age of HCM diagnosis and fewer adverse events. However, LowSVs in combination with a pathogenic sarcomere variant conferred higher morbidity (eg, composite adverse event hazard ratio, 5.4 [95% CI, 3.0-9.8] versus single pathogenic sarcomere variant, 2.0 [95% CI, 1.8-2.2]; P <0.001). An intermediate functional impact was validated for 2 specific LowSVs- MYBPC3 c.442G>A (partial splice gain) and TNNT2 c.832C>T (intermediate effect on contractile mechanics). Cardiac magnetic resonance imaging analysis of the general population revealed 5 of 12 LowSVs were significantly associated with HCM-adjacent traits without overt HCM., Conclusions: This study establishes a new class of low penetrance sarcomere variants that are relatively common in the population. When penetrant, isolated LowSVs cause mild HCM. In combination with pathogenic sarcomere variants, LowSVs markedly increase disease severity, supporting a clinically significant additive effect. Last, LowSVs also contribute to age-related remodeling even in the absence of overt HCM.

Here, we present a bioengineering approach to emulate the human bone marrow in vitro. Our developmentally inspired method uses self-organization of human hematopoietic stem and progenitor cells and vascular endothelial cells cultured in a three-dimensional microphysiological system to create vascularized, perfusable tissue constructs that resemble the hematopoietic vascular niche of the human marrow. The microengineered niche is capable of multilineage hematopoiesis and can generate functionally mature human myeloid cells that can intravasate into perfused blood vessels, providing a means to model the mobilization of innate immune cells from the marrow. We demonstrate the application of this system by presenting a specialized model of ionizing radiation-induced bone marrow injury and a multiorgan model of acute innate immune responses to bacterial lung infection. Furthermore, we introduce an advanced platform that enables large-scale integration and automated experimentation of the engineered hematopoietic tissues for preclinical screening of myelotoxicity due to anti-cancer drugs., Competing Interests: Declaration of interests A.G., J.H.G., T.C., and D.D.H. hold equity in Vivodyne Inc. A.G. and D.D.H. are co-founders, employees, and board directors of Vivodyne Inc. J.H.G., T.C., and P.L.C. are employees of Vivodyne Inc. A.L. is an employee of GSK and holds equity in the company. A patent application describing a technology related to this work is currently under review that includes A.G., G.S.W., and D.D.H. as co-inventors., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Adolescent relationship violence (ARV) is associated with a host of negative health outcomes that can impact individuals across the lifespan. This second article in a two-part series provides clinical context for ARV to assist clinicians who are caring for adolescents and offers practical advice based on current recommendations. Communicating with teens and families about confidentiality and mandated reporting requirements is paramount, and providers must be familiar with documentation and legal nuances. Professional organizations recommend screening women of childbearing age. However, because ARV occurs frequently across all genders and few teens identify or self-report ARV, providing universal education to all teens can overcome barriers associated with delayed disclosure and intervention., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Children with autism spectrum disorder (ASD) experience high rates of atypical eating behaviours, such as food neophobia. Mobile health (mHealth) interventions have been found to improve communication, behaviour and social skills for children with ASD. However, there is limited evidence examining mHealth nutrition interventions among children with ASD., Methods: The present study comprised a qualitative descriptive study that used qualitative content analysis to explore parent and child experiences with a novel mHealth nutrition intervention. Ten parent-child dyads provided user feedback and evaluation of the intervention. Data collection tools included a semistructured interview guide and a quantitative questionnaire with open-ended questions. Data analysis of the interview transcripts and open-ended questionnaire responses was an iterative process that continued until saturation was achieved. Descriptive statistics were used to analyse quantitative questionnaire data., Results: Analysis of the qualitative semistructured interviews led to emergence of three themes: (1) positive intervention outcomes; (2) parent suggestions for improvement; and (3) barriers to engagement. Each theme included subthemes. Questionnaire data revealed the ability to pick rewards and the virtual character that reinforced dietary goals ("Nutrition Ninja") were the most liked components of the application. Sending messages within the application and the Nutrition Ninja game were the least liked components of the application., Conclusions: Collectively, findings indicated that the app served as an interactive tool prompting dietary change and conversations within families. Yet, for some families, the intervention design, resistance to change or child disinterest hindered use and implementation of the intervention., (© 2024 The British Dietetic Association Ltd.)

Background and Aims: Data on upadacitinib therapy in children with ulcerative colitis (UC) or unclassified inflammatory bowel disease (IBD-U) are scarce. We aimed to evaluate the effectiveness and safety of upadacitinib as an induction therapy in pediatric UC or IBD-U., Methods: In this multicenter retrospective study, children treated with upadacitinib for induction of remission of active UC or IBD-U from 30 centers worldwide were enrolled. Demographic, clinical and laboratory data as well as adverse events (AEs) were recorded at week 8 post induction., Results: One hundred children were included (90 UC and 10 IBD-U, median age 15.6 [interquartile range 13.3-17.1] years). Ninety-eight were previously treated with biologic therapies, and 76 were treated with ≥2 biologics. At the end of the 8-week induction period, clinical response, clinical remission, and corticosteroid-free clinical remission (CFR) were observed in 84%, 62%, and 56% of the children, respectively. Normal C-reactive protein and fecal calprotectin (FC) <150 mcg/g were achieved in 75% and 50%, respectively. Combined CFR and FC remission was observed in 18/46 (39%) children with available data at 8 weeks. AEs were recorded in 37 children, including one serious AE of an appendiceal neuroendocrine tumor. The most frequent AEs were hyperlipidemia (n=13), acne (n=12), and infections (n=10, five of whom with herpes viruses)., Conclusion: Upadacitinib is an effective induction therapy for refractory pediatric UC and IBD-U. Efficacy should be weighed against the potential risks of AEs., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), is an established treatment for heart failure (HF) with reduced left ventricular ejection fraction. It has not been rigorously compared with angiotensin-converting enzyme inhibitors in children. PANORAMA-HF (Prospective Trial to Assess the Angiotensin Receptor Blocker Neprilysin Inhibitor LCZ696 Versus Angiotensin-Converting Enzyme Inhibitor for the Medical Treatment of Pediatric HF) is a randomized, double-blind trial that evaluated the pharmacokinetics and pharmacodynamics (PK/PD), safety, and efficacy of sacubitril/valsartan versus enalapril in children 1 month to <18 years of age with HF attributable to systemic left ventricular systolic dysfunction (LVSD)., Methods: Children with HF attributable to LVSD were randomized to sacubitril/valsartan versus enalapril to assess the efficacy and safety of sacubitril/valsartan at 52 weeks of follow-up. The primary end point of the study was to determine whether sacubitril/valsartan was superior to enalapril for the treatment of pediatric patients with HF attributable to systemic LVSD, assessed using a primary global rank end point consisting of ranking patients from worst to best on the basis of clinical events such as death, listing for urgent heart transplant, mechanical life support requirement, worsening HF, New York Heart Association (NYHA)/Ross class, Patient Global Impression of Severity (PGIS), and Pediatric Quality of Life Inventory physical functioning domain. The change from baseline to 52 weeks in NT-proBNP (N-terminal pro-B-type natriuretic peptide) was an exploratory end point., Results: A total of 375 children (mean age, 8.1±5.6 years; 52% female) were randomized to sacubitril/valsartan (N=187) or enalapril (N=188). At week 52, no significant difference was observed between the 2 treatment arms in the global rank end point (Mann-Whitney probability, 0.52 [95% CI, 0.47-0.58]; Mann-Whitney odds, 0.91 [95% CI, 0.72-1.14]; P =0.42). At week 52, clinically meaningful reductions were observed in both treatment arms in NYHA/Ross, PGIS, Patient Global Impression of Change, and NT-proBNP, without significant differences between groups. Adverse events were similar between treatment arms (incidence: sacubitril/valsartan, 88.8%; enalapril, 87.8%), and the safety profile of sacubitril/valsartan was acceptable in children., Conclusions: In this study, sacubitril/valsartan did not show superiority over enalapril in the treatment of children with HF attributable to systemic LVSD using the prespecified global rank end point. However, both treatment arms showed clinically meaningful improvements over 52 weeks., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02678312., Competing Interests: Dr Shaddy is a consultant for Novartis, American Regent Inc., CRI Biotech, and Rocket Pharmaceuticals. S. Solar-Yohay is an employee of US Novartis Pharmaceuticals Corporation and owns stocks in Novartis Pharma AG, Basel, Switzerland. Dr Garito is an employee of Novartis Pharma AG, Basel, Switzerland, and owns its shares. Dr Zhang is an employee of Novartis, Shanghai, China. M. Kocun is an employee of US Novartis Pharmaceuticals Corporation and owns stocks in Novartis Pharma AG, Basel, Switzerland. Dr Canter holds a Data and Safety Monitoring Board chairman position at the Mayo Research Foundation and has participated on an advisory board for CareDx. Dr Rossano reports receiving consulting fees from Bayer, Enzyvant, Merck, AskBio, American Regent, and Bristol Myers Squibb. Dr Halnon reports receiving consulting fees from Novartis and grants or contracts to her institution from Novartis. Dr Daly reports grants or contracts for the TEAMMATE multicenter trial of post–heart transplant immunosuppression (different patient population; Novartis holds the nonexclusive rights to one of the drugs that was studied [everolimus] but Novartis did not provide any support for the TEAMMATE study) and for American Heart Association/Enduring Hearts (ancillary studies to the TEAMMATE study in heart transplant recipients [different drug and patient population]); consulting fees from AstraZeneca (consultation regarding a different pediatric heart failure drug and possible study in children); payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from CareDx (pediatric research board related to the use of Allosure Heart in transplant recipients); leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid in ISHLT program committee 2021–2023 (developed ISHLT scientific sessions program) and AST trainee and young faculty community of practice chair (developed content for fellows and young faculty as part of the AST). Dr Singh is co-chair of the end point adjudication committee at Novartis for PANORAMA-HF. Dr Senni reports receiving consulting fees and payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Novartis, Bayer, Merck, MSD, Abbott, AstraZeneca, Boehringer, Vifor, and Novo Nordisk. Dr Anjos reports an unpaid position as a board member of the pediatric cardiology section of the Portuguese Medical Association. Dr Bonnet reports consulting fees from Novartis paid to his institution for being the steering committee member for the current study and participating in an advisory board for the current study. The other authors declare no competing interests.

DNA replication and RNA transcription processes compete for the same DNA template and, thus, frequently collide. These transcription-replication collisions are thought to lead to genomic instability, which places a selective pressure on organisms to avoid them. Here, we review the predisposing causes, molecular mechanisms, and downstream consequences of transcription-replication collisions (TRCs) with a strong emphasis on prokaryotic model systems, before contrasting prokaryotic findings with cases in eukaryotic systems. Current research points to genomic structure as the primary determinant of steady-state TRC levels and RNA polymerase regulation as the primary inducer of excess TRCs. We review the proposed mechanisms of TRC-induced DNA damage, attempting to clarify their mechanistic requirements. Finally, we discuss what drives genomes to select against TRCs., (© 2024 Federation of European Biochemical Societies.)

Background and Objectives: The number of GAA repeats in the FXN gene is a major but not sole determinant of the clinical presentation of Friedreich ataxia (FRDA). The objective of this study was to establish whether the length of the GAA repeat tract in the FGF14 gene, which is associated with another neurodegenerative disorder (SCA27B), affects the clinical presentation (age at onset, mFARS score) of patients with FRDA., Methods: The number of GAA repeats in the FXN and FGF14 genes was determined using PCR in a cohort of 221 patients with FRDA. Next, we compared absolute lengths of the FGF14 GAAs with FXN GAAs, followed by correlative analyses to determine potential effects of FGF14 GAA length on age at onset and clinical presentation (mFARS) of FRDA., Results: We found no significant correlation between the size of the GAA repeats in FXN and FGF14 loci in our FRDA cohort. Moreover, the number of GAAs in FGF14 did not affect the clinical presentation of FRDA even in a small number of cases where a long FGF14 allele was present., Discussion: Despite both molecular and clinical similarities between FRDA and SCA27B, the length of the GAA repeats in the FGF14 gene, including potentially pathogenic alleles, did not influence the clinical presentation of FRDA., Competing Interests: The authors report no relevant disclosures. Go to Neurology.org/NG for full disclosures., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Ataxia telangiectasia (A-T) is a DNA repair disorder with cancer predisposition., Objective: We sought to characterize the prevalence and outcomes of hematologic and solid cancers and treatment-associated toxicities in individuals with A-T., Methods: Data were retrospectively analyzed from the Johns Hopkins Ataxia Telangiectasia Clinical Center cohort. Cumulative incidence and standardized incidence ratios of cancer, survival probability after cancer diagnosis, and standardized mortality ratios were calculated. Cox regression estimated risk of death on the basis of chemotherapy (standard vs reduced) dosing, and multivariable logistic regression evaluated cancer risk associations with ataxia telangiectasia mutated (ATM) exons and variants., Results: Eighty-four (16.5%) of 508 individuals were diagnosed with a primary cancer, of whom 62 (74%) were hematologic in origin and 22 (26%) were solid-organ cancers. The cumulative incidence of cancer was 29% by age 35 years. Non-Hodgkin lymphoma occurred most frequently (n = 39), whereas solid cancers disproportionately affected those 18 years and older (n = 22). The standardized mortality ratio was 24.6 (95% CI, 21.1-28.4) overall and 232.9 (95% CI,178.1-299.2) among individuals with cancer. Risk of death was higher when treated with standard/unknown versus modified chemotherapy (hazard ratio, 2.2; 95% CI, 1.1-4.4; P = .024). Chemotherapy-associated toxicities developed in 58% of individuals, predominantly neurologic (n = 14) and gastrointestinal (n = 10) systems. Three exons were enriched for cancer-associated variants., Conclusions: Individuals with A-T experience a wide array of blood and solid-organ malignancies, high mortality rates, and treatment-related toxicities, highlighting need for targeted therapies to mitigate toxicity and optimize survival., Competing Interests: Disclosure statement This work was funded by the National Institutes of Health (grant no. RR00052 to H.L., T.O.C., J.W., M.A.L.G., and S.M.M. and grant no. R21 TR003534 to H.L., T.O.C., J.W., M.A.L.G., S.M.M., and V.N.), the Food and Drug Administration (grant no. RO1 FD007605 to H.L., T.O.C., J.W., M.A.L.G., S.M.M., and V.N.), and the A-T Children’s Project (to H.L., T.O.C., J.W., M.A.L.G., S.M.M., and V.N.). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest., (Published by Elsevier Inc.)

Electroconvulsive therapy (ECT) is a fast-acting, highly effective, and safe treatment for medication-resistant depression. Historically, the clinical benefits of ECT have been attributed to generating a controlled seizure; however, the underlying neurobiology is understudied and remains largely unresolved. Using optical neuroimaging to probe neural activity and hemodynamics in a mouse model of ECT, we demonstrated that a second brain event follows seizure: cortical spreading depolarization (CSD). We further found that ECT stimulation pulse parameters and electrode configuration directly shaped the wave dynamics of seizure and subsequent CSD. To translate these findings to human patients, we tested for the presence of hemodynamic signatures of post-ictal CSD using non-invasive diffuse optical monitoring of cerebral blood flow and oxygenation during routine ECT treatments. We found evidence that humans generate hyperemic waves after ECT seizure which are highly consistent with CSD. These results challenge a long-held assumption that seizure is the primary outcome of ECT and point to new opportunities for optimizing ECT stimulation parameters to precisely modulate brain activity and treatment outcomes., Competing Interests: Competing Interests: No financial conflicts or completing interests to disclose.

Background and Objectives: Recent studies suggest that the choroid plexus (CP) may function as a site of access of inflammatory cells into the CNS in multiple sclerosis (MS). Pediatric-onset MS (POMS) is characterized by a high inflammatory burden, as evidenced by a high relapse rate and volume of T2 lesions, making patients with POMS an informative population to evaluate choroid plexus volume (CPV). The objectives of the study were (1) to evaluate CPV at symptom onset in participants with POMS compared with healthy controls (HCs); (2) to evaluate changes in CPV in the first year of disease in participants with POMS; and (3) to evaluate associations between CPV, brain volumes, relapse activity, and disability in participants with POMS., Methods: Baseline 1.5T MRI scans were acquired from 23 participants with POMS and 23 age-matched and sex-matched HCs; 18 participants with POMS also had 12-month follow-up MRI scans. The CP of the lateral ventricles was segmented manually. CP and brain structure volumes were normalized for total intracranial volume. The number of relapses, T2 and gadolinium-enhancing T1 lesion counts, and Expanded Disability Status Scale (EDSS) scores at 12 months were also analyzed. Baseline CPVs were compared between groups using the Wilcoxon exact test, and CPV change from baseline to 12 months in participants with POMS was compared using the Wilcoxon signed-rank test. The relationship between CPV and brain volumetric measures, T2 lesion volumes, lesion count, number of relapses, and EDSS scores was assessed through Spearman correlation., Results: The median normalized CPV was 1.51 × 10 -3 (interquartile range [IQR]: 1.32-1.76) in POMS baseline scans and 1.21 × 10 -3 (IQR: 1.1-1.47) in HC scans ( p = 0.001). CPV did not significantly change at 12 months in the 18 participants with POMS with follow-up scans ( p = 0.352). CPV in participants with POMS and HCs correlated with lateral ventricular volume ( p = 0.012 for both groups) but did not correlate with brain and T2 lesion volumes or lesion count at baseline, nor with relapse activity or EDSS scores at 12 months in participants with POMS., Discussion: CPV measured at baseline is greater in participants with POMS than in HCs. Baseline CPV did not predict higher disease activity or worse neurologic outcomes over 1 year. While higher CPV may be an early feature of inflammation in MS, its strong correlation with ventricular volumes could also reflect enlargement secondary to the mechanical attachment of CP to the ventricular wall.

Background: The electrocardiogram (ECG) is routinely performed in children with the limb electrodes positioned on the torso, but few studies have investigated the effects of this modification on the pediatric ECG. Our objective was to assess the agreement between the standard limb lead configuration and a modified torso electrode configuration in normal, healthy children, and to assess the effect of height on that agreement., Methods: 185 children aged 5-18 years underwent two consecutive 12‑lead ECGs, one with standard distal limb lead placement and one with the limb leads placed on the torso. Agreement was assessed for 17 ECG parameters (intervals, axes, and amplitudes) using Bland-Altman plots, height-dependent mean error, and false positive rates., Results: The torso configuration systematically biased the QRS and P wave axes rightwards (towards aVF). Adequate agreement was observed for PR interval and QRS duration, but QTc limits of agreement (±40 ms) were wide. The torso configuration overestimated left-precordial Q, R, and S wave amplitudes and underestimated right-precordial R and S wave amplitudes compared to the distal limb placement. Mean measurement errors increased with the magnitude of the ECG parameter. Mean and variance of measurement errors were more pronounced in shorter children. False positive rates did not differ between the torso and distal limb configurations., Conclusion: Modified placement of the limb electrodes onto the torso resulted in multiple differences in the pediatric ECG signals. This may lead to misclassification of electrocardiographic abnormalities, particularly in children with measurement values at the upper limits of normal., Competing Interests: Declaration of competing interest There were no potential conflicts of interest relevant to this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: We aimed to (1) determine the association between cumulative PaO 2 and PaCO 2 exposure 24 h post-return of circulation and survival with favorable neurologic outcome. And (2) to assess adherence to American Heart Association post-cardiac arrest care treatment goals (PaO 2 75-100 mmHg and PaCO 2 35-45 mmHg)., Design and Setting: Prospectively collected data were analysed from five Pediatric Resuscitation Quality collaborative sites supplemented with retrospective PaO 2 and PaCO 2 data., Patients: Children aged 1 day-17 years with return of circulation after cardiac arrest, admitted 2019-2022, with ≥ 4 arterial blood gasses spanning at least 12 h within 24 h post-return of ciculation, were eligible. Congenital cyanotic heart disease events were excluded., Measurements: Area under the curve calculation provided hourly cumulative PaO 2 and PaCO 2 exposures per child and similarly guideline recommended cumulative ranges. The primary outcome was survival to hospital discharge with favorable neurologic outcome defined as a Pediatric Cerebral Performance Category 1-3, or no pre-arrest baseline difference., Main Results: Among 292 included children (median age 2.6 years (IQR 0.4-10.9)), 57 % survived to discharge and 48 % had favorable neurologic outcome (88 % of survivors). Cumulative PaO 2 and PaCO 2 exposure 0-24 h post-return of circulation were not significantly associated with favorable neurologic outcome in multivariable analysis (OR 1.0, 95 %CI 0.98-1.02 and OR 0.97, 95 %CI 0.87-1.09 respectively). Cumulative PaO 2 and PaCO 2 remained within guideline recommended ranges for 24 % and 58 % of children respectively with median areas under the curve over 0 - 24 h of 2664 mmHg (2151 - 3249 mmHg) for PaO 2 and 948 mmHg (853 - 1051 mmHg) for PaCO 2 . AHA post-cardiac arrest care guideline recommendations for PaO 2 (1800-2400 mmHg) and PaCO 2 (840-1080 mmHg) were recalculated as area under the curve ranges. Achieving both normoxia and normocapnia was observed in 12 % of children., Conclusions: Cumulative PaO 2 and PaCO 2 exposure in the first 24 h post-return of circulation was not associated with survival with favorable neurologic outcome. Pediatric AHA post-cardiac arrest care guideline normoxia and normocapnia goals were often not met. Larger cohort studies are necessary to improve the accuracy of cumulative exposure calculations, assess the long-term effects of PaO 2 and PaCO 2 exposure, and explore the influence of other post-cardiac arrest care therapeutic strategies., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Marijn Albrecht reports a relationship with ZOLL Medical Corporation that includes: funding grants. Vinay Nadkarni MD receives unrestricted grant funding to his institution from the National Institutes of Health, US Department of Defense, ZOLL Medical, Laerdal Foundation, RQI Partners, Philips Medical, and Nihon-Kohden. All are unrelated to this study. He serves as Editorial Board Member for Resuscitation and Pediatric Critical Care Medicine and was not involved in the editorial review or the decision to publish this article. Lastly, he serves on the Executive Committee for the Society of Critical Care Medicine (SCCM). The views expressed as an author in this manuscript are his, and are not intended to represent the views of the SCCM. Dana Niles was an employee of Children’s Hospital of Philadelphia at the time of data collection and analysis and is currently an employee of Philips Medical. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper]., (© 2024 The Author(s).)

Background: Septal reduction therapy (SRT) provides substantial symptomatic improvement in patients with obstructive hypertrophic cardiomyopathy (HCM). However, long-term disease course after SRT and predictors of adverse outcomes have not been systematically examined., Methods: Data from 13 high clinical volume HCM centers from the international SHARE (Sarcomeric Human Cardiomyopathy Registry) were analyzed. Patients were followed from the time of SRT until last follow-up or occurrence of heart failure (HF) composite outcome (cardiac transplantation, implantation of a left ventricular assist device, left ventricular ejection fraction <35%, development of New York Heart Association class III or IV symptoms), ventricular arrhythmias composite outcome (sudden cardiac death, resuscitated cardiac arrest, or appropriate implantable cardioverter defibrillator therapy), or HCM-related death. Cox proportional hazards models were used to identify predictors of outcome., Results: Of the 10 225 patients in SHARE, 1832 (18%; 968 [53%] male) underwent SRT, including 455 (25%) with alcohol septal ablation and 1377 (75%) with septal myectomy. The periprocedural 30-day mortality rate was 0.4% (8 of 1832) and 1499 of 1565 (92%) had a maximal left ventricular outflow tract gradient <50 mm Hg at 1 year. After 6.8 years (range, 3.4-9.8 years; 12 565 person-years) from SRT, 77 (4%) experienced HCM-related death (0.6% per year), 236 (13%) a composite HF outcome (1.9% per year), and 87 (5%) a composite ventricular arrhythmia outcome (0.7% per year). Among adults, older age at SRT was associated with a higher incidence of HCM death (hazard ratio, 1.22 [95 CI, 1.1-1.3]; P <0.01) and the HF composite (hazard ratio, 1.14 [95 CI, 1.1-1.2] per 5-year increase; P <0.01) in a multivariable model. Female patients also had a higher risk of the HF composite after SRT (hazard ratio, 1.4 [95 CI, 1.1-1.8]; P <0.01). De novo atrial fibrillation occurred after SRT in 387 patients (21%). Among pediatric patients followed for a median of 13 years after SRT, 26 of 343 (16%) developed the HF composite outcome, despite 96% being free of recurrent left ventricular outflow tract obstruction., Conclusions: Successful short- and long-term relief of outflow tract obstruction was observed in experienced multidisciplinary HCM centers. A subset of patients progressed to develop HF, but event-free survival at 10 years was 83% and ventricular arrhythmias were rare. Older age, female sex, and SRT during childhood were associated with a greater risk of developing HF., Competing Interests: Dr Ho is supported by funding from the National Institutes of Health (National Heart, Lung, and Blood Institute grant R01HL155568). Dr Day is supported by funding from the National Institutes of Health (National Heart, Lung, and Blood Institute grants R01 HL167524, R01 HL168841, and R61/R33 HL164376), Lexicon Pharmaceuticals, and the American Heart Association. Dr Ware is supported by the Wellcome Trust (grant 107469/Z/15/Z) and the UK Medical Research Council. Dr Scemsarian is the recipient of a National Health and Medical Research Council investigator grant (grant 2016822) and a New South Wales Health cardiovascular disease clinician scientist grant. Dr Ingles is the recipient of a National Heart Foundation of Australia future leader fellowship grant (grant 106732) and receives research grant support from Bristol Myers Squibb. Dr Reza is supported by funding from the National Institutes of Health (National Heart, Lung, and Blood Institute grant K23HL166961). Dr I. Olivotto has received grants from Bristol Myers Squibb, Cytokinetics, Amicus, Genzyme, Shire, Bayer, Boston Scientific, and Menarini International; fees (honoraria or consulting) from Bristol Myers Squibb, Cytokinetics, Amicus, Genzyme, Shire, and Boston Scientific; and served or is serving as principal investigator for EXPLORER‐HCM (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy), MAVA‐LTE (A Long-Term Safety Extension Study of Mavacamten in Adults Who Have Completed EXPLORER-HCM), REDWOOD‐HCM (Randomized Evaluation of Dosing With CK-3773274 in Obstructive Outflow Disease in HCM), REDWOOD‐OLE (REDWOOD‐HCM Open Label Extension), and SEQUOIA‐HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM). Dr Maurizi has received fees (honoraria or consulting) from Bristol Myers Squibb. Dr Ho receives research funding from the National Institutes of Health and has received unrestricted research funding or consulting fees from Bristol Myers Squibb, Cytokinetics, Pfizer, Tenaya, Biomarin, viz.AI, and Lexicon Pharmaceuticals. Dr Lakdawala receives research funding from BMS and Pfizer and modest consulting incomes from BMS, Pfizer, Alexion, Tenaya, Akros, Neuvocor, and Cytokinetics. Dr Stendahl serves or has served as site principal investigator for MAVA-LTE, PIONEER-OLE (Phase 2 Open-label Pilot Study Evaluating Mavacamten in Subjects With Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction Open-Label Extension), and VALOR-HCM (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy), and serves or has served as site subinvestigator for ACACIA-HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic nHCM), FOREST-HCM (Follow-Up, Open-Label, Research Evaluation of Sustained Treatment with Aficamten in HCM), MAPLE-HCM (Metoprolol vs Aficamten in Patients with LVOT Obstruction on Exercise Capacity in HCM), and SEQUOIA-HCM.

Introduction: Sub-Saharan Africa has the world's highest rates of neonatal mortality. Mothers are critical to the survival of these at-risk newborns. The aim of this integrative review is to appraise the published literature on the experiences, cultural values, and perceptions of mothers of hospitalized newborns in Malawi to inform future research., Methods: This integrative review utilizes Whittemore and Knafl's review model. CINAHL, PubMed, and Academic Search Elite databases were searched., Results: Five summarizing themes were identified across ten articles relating to the mother as a caregiver, experiences of mother as a caregiver, cultural observations and perceptions of the mother, influence of others on the mother, and discrimination and stigma., Discussion: Mothers' experiences of having a newborn requiring hospitalization in Malawi are complex. Results indicate a need for more studies to understand the experiences of mothers of newborns requiring hospitalization in Malawi in order to provide culturally congruent newborn care., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Left ventricular global longitudinal strain (LV GLS) on echocardiography is a sensitive yet clinically significant marker of myocardial dysfunction. Reduced LV GLS is prevalent in adults with chronic kidney disease and hypertension and is associated with adverse cardiovascular outcomes. It may be a biomarker of chronic kidney disease-associated myocardial dysfunction in children, but data are limited. Our objective was to describe LV GLS in the CKiD study (Chronic Kidney Disease in Children) and to examine the association between blood pressure (BP) and reduced LV GLS., Methods: A single apical 4-chamber view was used to estimate LV GLS. Our main analyses examined the association of clinic BP with the absolute value of LV GLS and LV GLS dichotomized at 16. Sensitivity analyses using 24-hour ambulatory BP monitoring data were also performed. Generalized estimating equations were used to account for within-person correlation and to estimate robust SEs for 95% CIs. Covariates in adjusted models included: age, sex, race, estimated glomerular filtration rate, urine protein, hemoglobin, left ventricular hypertrophy, and the use of renin-angiotensin system inhibitors., Results: LV GLS was measured in 962 person-visits. A total of 77 assessments had an LV GLS <16. In adjusted models, both clinic systolic BP (odds ratio, 1.02 [95% CI, 1.01-1.03]) and diastolic BP (odds ratio, 1.02 [95% CI, 1.00-1.03]) percentiles were associated with LV GLS <16. Having awake or nighttime diastolic BP hypertension on ambulatory BP monitoring was significantly associated with a lower absolute value of LV GLS., Conclusions: Office systolic and diastolic hypertension was associated with diminished LV GLS. Only diastolic hypertension detected on ambulatory BP monitoring was associated with lower LV GLS., Competing Interests: None.

Purpose: Klinefelter syndrome, a sex chromosome aneuploidy (SCA), is associated with a 47,XXY chromosomal complement and is diagnosed in ∼1:600 live male births. Individuals with a 46,XX cell line, in addition to 47,XXY, are less common with a limited number of published case reports., Methodology: To better understand the implications of a 47,XXY/46,XX karyotype, we conducted a retrospective, multicenter analysis of the cytogenetic findings and associated clinical records of 34 patients diagnosed with this SCA across 14 institutions., Results: Presence of the XX cell line ranged from 5% to 98% in patient specimens. Phenotypes also exhibited significant heterogeneity with some reporting a single reason for referral and others presenting with a constellation of symptoms, including ambiguous genitalia and ovotestes. Ovotestes were present in 12% of individuals in this cohort, who had a significantly higher percentage of XX cells. Notably, 2 patients were assigned female sex at birth., Conclusion: These findings highlight the variability of the clinical phenotypes associated with this SCA, as well as the challenges of clinical management for this population. Karyotype or fluorescence in situ hybridization analysis, which offer single-cell resolution, rather than chromosomal microarray or molecular testing, is the ideal test strategy in these instances as mosaicism can occur at low levels., Competing Interests: Conflict of Interest The authors have no conflicts of interest to declare., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Progress in genetic diagnosis and orphan drug legislation has opened doors to new therapies in rare neurogenetic diseases (RNDs). Innovative therapies such as gene therapy can improve patients' quality of life but come with academic, regulatory, and financial challenges. Registries can play a pivotal role in generating evidence to tackle these, but their development requires multidisciplinary knowledge and expertise. This study aims to develop a practical framework for creating and implementing patient registries addressing common challenges and maximizing their impact on care, research, drug development, and regulatory decision making with a focus on RNDs. A comprehensive 3-step literature and qualitative research approach was used to develop the framework. A qualitative systematic literature review was conducted, extracting guidance and practices leading to the draft framework. Subsequently, we interviewed representatives of 5 established international RND registries to add learnings from hands-on experiences to the framework. Expert input on the draft framework was sought in digital multistakeholder focus groups to refine the framework. The literature search; interviews with 5 registries; and focus groups with patient representatives (n = 4), clinicians (n = 6), regulators, health technology assessment (HTA) bodies and payers (n = 7), industry representatives (n = 7), and data/information technology (IT) specialists (n = 5) informed development of the framework. It covers the interests of different stakeholders, purposes for data utilization, data aspects, IT infrastructure, governance, and financing of rare disease registries. Key principles include that data should be rapidly accessible, independent, and trustworthy. Governance should involve multiple stakeholders. In addition, data should be highly descriptive, machine-readable, and accessible through a shared infrastructure and not spread over multiple isolated repositories. Sustainable and independent financing of registries is deemed important but remains challenging because of a lack of widely supported funding models. The proposed framework will guide stakeholders in establishing or improving rare disease registries that fulfill requirements of academics and patients as well as regulators, HTA bodies, and commercial parties. There is a need for more clarity regarding quality requirements for registries in regulatory and HTA context. In addition, independent financing models for registries should be developed, as well as well-defined policies on technical uniformity in health data.