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While regular physical activity is a cornerstone of health, wellness, and vitality, the impact of endurance exercise training on molecular signaling within and across tissues remains to be delineated. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to characterize molecular networks underlying the adaptive response to exercise. Here, we describe the endurance exercise training studies undertaken by the Preclinical Animal Sites Studies component of MoTrPAC, in which we sought to develop and implement a standardized endurance exercise protocol in a large cohort of rats. To this end, Adult (6-mo) and Aged (18-mo) female (n = 151) and male (n = 143) Fischer 344 rats were subjected to progressive treadmill training (5 d/wk, ∼70%-75% VO2max) for 1, 2, 4, or 8 wk; sedentary rats were studied as the control group. A total of 18 solid tissues, as well as blood, plasma, and feces, were collected to establish a publicly accessible biorepository and for extensive omics-based analyses by MoTrPAC. Treadmill training was highly effective, with robust improvements in skeletal muscle citrate synthase activity in as little as 1-2 wk and improvements in maximum run speed and maximal oxygen uptake by 4-8 wk. For body mass and composition, notable age- and sex-dependent responses were observed. This work in mature, treadmill-trained rats represents the most comprehensive and publicly accessible tissue biorepository, to date, and provides an unprecedented resource for studying temporal-, sex-, and age-specific responses to endurance exercise training in a preclinical rat model., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Physiological Society.)

Objective: To evaluate the efficacy, safety, and tolerability of inclisiran in participants with atherosclerotic cardiovascular disease (ASCVD) from ORION-10 and ORION-11 stratified by key patient characteristics., Patients and Methods: Participants were randomized 1:1 to receive 300 mg inclisiran sodium (284 mg inclisiran) or placebo on days 1, 90, 270, and 450, alongside background lipid-lowering therapy. This pooled, post hoc analysis stratified participants with ASCVD by sex, age, race, kidney function, body mass index, and glycemic status. Co-primary endpoints were percentage changes in low-density lipoprotein cholesterol (LDL-C) from baseline to day 510, and after day 90 and up to day 540 (time-adjusted). LDL-C goal attainment and safety were also assessed., Results: This analysis of 2975 participants included: female, n=827; Black, n=213; 75 years of age or older, n=458; obese, n=1474; diabetes, n=1182; and moderate-to-severe chronic kidney disease, n=538. Mean baseline LDL-C levels in the total ASCVD population were balanced between treatment arms (inclisiran, 103.4 mg/dL; placebo, 102.0 mg/dL). With inclisiran, mean placebo-corrected percentage changes in LDL-C from baseline were -51.5% (95% CI, -54.0% to -49.0%) and -52.1% (95% CI, -53.9% to -50.4%) to day 510 and day 540 (time-adjusted), respectively; this was consistent across subgroups. LDL-C less than 55 mg/dL at 1 or more visits was reached by 87.6% of participants receiving inclisiran. The inclisiran safety profile was consistent across subgroups., Conclusion: Twice-yearly inclisiran (after initial and 3-month doses) was well-tolerated and provided significant, consistent LDL-C reductions for up to 18 months in participants with ASCVD independent of key patient characteristics (ORION-10 [Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Cholesterol]; NCT03399370 and ORION-11 [Inclisiran for Subjects With ASCVD or ASCVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol]; NCT03400800)., (Copyright © 2024. Published by Elsevier Inc.)

In recent years, wearable electrocardiograms have risen in popularity as a solution for personal monitoring of heart activity. However, this technology has limitations in diagnostic capability and structural function monitoring. Meanwhile, auscultation of the heart remains a fundamental tool for physicians in diagnosis and monitoring of heart disease largely unaddressed in a convenient wearable format. The present work outlines a promising system currently under investigation, allowing user-initiated 10-second chest-sound recordings to be transmitted over Bluetooth-Low-Energy, with an innovative package design providing inherent noise reduction and a high signal-to-noise ratio. The device has been tested on healthy individuals, and system response has been validated against calibrated electrocardiogram recording equipment to analyze signal capture fidelity.

Purpose: This review aims to discuss the role and efficacy of Sacituzumab Govitecan in the management of breast cancer., Summary: Breast cancer is the most prevalent type of cancer among women worldwide. This comprehensive review delves into the advancements brought about by Sacituzumab Govitecan in the treatment of metastatic triple-negative breast cancer (TNBC). With a focus on its mode of action, efficacious role, clinical trials, and comparative advantages over conventional chemotherapy, the review highlights the therapy's precision in targeting cancer cells through monoclonal antibodies. Sacituzumab Govitecan's ability to deliver a chemotherapeutic payload specifically to cancer cells with the Trop-2 receptor sets it apart from traditional chemotherapy, minimizing collateral damage and reducing severe side effects. The impact of Sacituzumab Govitecan on improving progression-free survival, tumor response rates, and, significantly, the quality of life for patients is discussed. This article also sheds light on ongoing trials, FDA recognition, and the therapy's potential to transform breast cancer treatment., Conclusion: In conclusion, Sacituzumab Govitecan shows potential as an innovative therapeutic option for breast cancer, particularly in metastatic breast cancer and triple-negative breast cancer, but it warrants additional research., Competing Interests: The authors declare no conflict of interest.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article, (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Quitting smoking may lead to improvement in substance use, psychiatric symptoms, and pain, especially among high-risk populations who are more likely to experience comorbid conditions. However, causal inferences regarding smoking cessation and its subsequent benefits have been limited., Methods: We emulated a hypothetical open-label randomized control trial of smoking cessation using longitudinal observational data of HIV-positive and HIV-negative US veterans from 2003-2015 in the Veterans Aging Cohort Study. We followed individuals from the first time they self-reported current cigarette smoking (baseline). We categorized participants as quitters or non-quitters at the first follow-up visit (approximately 1 year after baseline). Using inverse probability weighting to adjust for confounding and selection bias, we estimated odds ratios for improvement of co-occurring conditions (unhealthy alcohol use, cannabis use, illicit opioid use, cocaine use, depressive symptoms, anxiety symptoms, and pain symptoms) at second follow-up (approximately 2 years after baseline) for those who quit smoking compared to those who did not, among individuals who had the condition at baseline., Results: Of 4,165 eligible individuals (i.e., current smokers at baseline), 419 reported no current smoking and 2,330 reported current smoking at the first follow-up. Adjusted odds ratios (95% confidence intervals) for associations between quitting smoking and improvement of each condition at second follow-up were: 2.10 (1.01, 4.35) for unhealthy alcohol use, 1.75 (1.00, 3.06) for cannabis use, 1.10 (0.58, 2.08) for illicit opioid use, and 2.25 (1.20, 4.24) for cocaine use, 0.78 (0.44, 1.38) for depressive symptoms, 0.93 (0.58, 1.49) for anxiety symptoms, and 1.31 (0.84, 2.06) for pain symptoms., Conclusions: While a causal interpretation of our findings may not be warranted, we found evidence for decreased substance use among veterans who quit cigarette smoking but none for the resolution of psychiatric conditions or pain symptoms. Findings suggest the need for additional resources combined with smoking cessation to reduce psychiatric and pain symptoms for high-risk populations., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ban et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The minimally invasive repair of pectus excavatum (MIRPE) is associated with significant postoperative pain and opioid use. The objective of this study was to determine the effect of intercostal nerve cryoablation (Cryo) on inpatient and post-hospital opioid prescription practices following MIPRE., Methods: A retrospective review at a single pediatric center was conducted of patients ≤21 years old who underwent MIRPE. Oral morphine equivalents (OME) of inpatient and discharge opioids were compared between Cryo and no-Cryo cohorts., Results: 579 patients were identified (82.8% male, mean age 15.4 ± 2.0 years). Cryo was performed in 73.5% of patients. The total inpatient OME use was less in the Cryo group (0.89 ± 0.68 vs. 1.6 ± 0.5 OME/kg/day; p < 0.001). Patients who underwent Cryo were prescribed significantly less OME at discharge compared to the no-Cryo group (3.9 ± 1.7 vs. 10.0 ± 4.1 OME mg/kg, p < 0.001). There was no statistically significant difference in the proportion of patients who required an opioid prescription refill (Cryo 12.4% vs. no-Cryo 11.5%, p = 0.884) or were readmitted (Cryo 5.3% vs. no-Cryo 4.6%, p = 0.833)., Conclusion: Patients who underwent cryoablation during MIRPE were prescribed significantly less opioid at the time of discharge without increasing the need for opioid refills or hospital readmissions., Level of Evidence: Treatment study; Level III evidence., Competing Interests: Conflicts of interest Dr. Padilla, McMahon, and Notrica are education consultants for Atricure. Dr. Notrica has patents related to pectus repair and receives patent royalties from KLS Martin. The other authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Children with severe neurological impairment (SNI) often receive care in the pediatric intensive care unit (PICU), yet little is known about their parents' experiences. Objective: To examine sources of and changes in stress among parents of children with SNI in the PICU. To compare stressors with "good parent" attributes that describe duties parents aim to uphold for their child. Design/Setting/Subjects: Prospective mixed-methods cohort study at a single U.S. children's hospital. Participants included English-speaking parents/legal guardians of a child with SNI with an expected length of stay >1 week and life expectancy >4 weeks. Measurements: Ten-point stress scale administered at PICU admission and discharge with open-ended response items. A subset of parents completed 1:1 semistructured interviews. Data were integrated to examine differences among participants whose stress increased, stayed the same, or decreased, and themes were compared with "good parent" attributes. Results: Twenty-five parents/legal guardians completed the surveys; 15 completed the interviews. Children were a median of 7 years old (interquartile range [IQR] 4, 9; range 1-21) and had a median PICU length of stay of 10 days (IQR 7, 15; range 3-62). Twenty percent ( n  = 5) of parents were fathers, and 36% ( n  = 9) had a minority racial/ethnic background. Stress was moderate at admission (mean 6.8, standard deviation [SD] ±1.7) and discharge (mean 6, SD ±2); 32% ( n  = 8) reported stress trajectories that stayed the same or increased. Major themes included uncertainty, advocacy, and vulnerability and related closely to "good parent" attributes. Conclusion: Stress among parents of children with SNI related to uncertainty, advocacy, and vulnerability and suggested tensions with "good parent" attributes.

We used results from an optimization randomized controlled trial which tested five behavioral intervention components to support HIV antiretroviral adherence/HIV viral suppression, grounded in the multiphase optimization strategy and using a fractional factorial design to identify intervention components with cost-effectiveness sufficiently favorable for scalability. Results were incorporated into a validated HIV computer simulation to simulate longer-term effects of combinations of components on health and costs. We simulated the 32 corresponding long-term trajectories for viral load suppression, health related quality of life (HRQoL), and costs. The components were designed to be culturally and structurally salient. They were: motivational interviewing counseling sessions (MI), pre-adherence skill building (SB), peer mentorship (PM), focused support groups (SG), and patient navigation (short version [NS], long version [NL]. All participants also received health education on HIV treatment. We examined four scenarios: one-time intervention with and without discounting and continuous interventions with and without discounting. In all four scenarios, interventions that comprise or include SB and NL (and including health education) were cost effective (< $100,000/quality-adjusted life year). Further, with consideration of HRQoL impact, maximal intervention became cost-effective enough to be scalable. Thus, a fractional factorial experiment coupled with cost-effectiveness analysis is a promising approach to optimize multi-component interventions for scalability. The present study can guide service planning efforts for HIV care settings and health departments., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Recent promotion of new reactor technologies appears to disregard decades-old concerns about nuclear proliferation.

Competing Interests: Declaration of interests R.S.M. is an employee of and has equity in Immusoft Corporation.

Mitochondria have diverse functions critical to whole-body metabolic homeostasis. Endurance training alters mitochondrial activity, but systematic characterization of these adaptations is lacking. Here, the Molecular Transducers of Physical Activity Consortium mapped the temporal, multi-omic changes in mitochondrial analytes across 19 tissues in male and female rats trained for 1, 2, 4, or 8 weeks. Training elicited substantial changes in the adrenal gland, brown adipose, colon, heart, and skeletal muscle. The colon showed non-linear response dynamics, whereas mitochondrial pathways were downregulated in brown adipose and adrenal tissues. Protein acetylation increased in the liver, with a shift in lipid metabolism, whereas oxidative proteins increased in striated muscles. Exercise-upregulated networks were downregulated in human diabetes and cirrhosis. Knockdown of the central network protein 17-beta-hydroxysteroid dehydrogenase 10 (HSD17B10) elevated oxygen consumption, indicative of metabolic stress. We provide a multi-omic, multi-tissue, temporal atlas of the mitochondrial response to exercise training and identify candidates linked to mitochondrial dysfunction., Competing Interests: Declaration of interests S.C.B. has equity in Emmyon, Inc. S.B.M. is a consultant for BioMarin, MyOme, and Tenaya Therapeutics. M.J.W. serves as a consultant for Arch Venture Partners (AVP) and Bristol Myers Squibb, Inc. E.A.A. is a founder of Personalis, Inc, DeepCell, Inc, and Svexa Inc., a founding advisor of Nuevocor, a non-executive director at AstraZeneca, and an advisor to SequenceBio, Novartis, Medical Excellence Capital, and Foresite Capital. D.A. is employed at Insitro, South San Francisco, CA 94080. N.R.G. is employed at 23andMe, Sunnyvale, CA 94086. P.M.J.B. is employed at Pfizer, Cambridge, MA 02139. Insitro, 23andMe, and Pfizer had no involvement in the design or implementation of the work presented here., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Context: Paltusotine is a nonpeptide selective somatostatin receptor 2 agonist in development as once-daily oral treatment for acromegaly., Objective: To evaluate the efficacy and safety of paltusotine in the treatment of patients with acromegaly previously controlled with injected somatostatin receptor ligands (SRLs)., Methods: This phase 3, randomized, double-blind, placebo-controlled trial enrolled adults with acromegaly who had insulin-like growth factor I (IGF-I) ≤1.0 times the upper limit of normal (×ULN) while receiving a stable dose of depot octreotide or lanreotide. Patients were switched from injected SRLs and randomized to receive paltusotine or placebo orally for 36 weeks. The primary endpoint was proportion of patients maintaining IGF-I ≤1.0×ULN. Secondary endpoints were change in IGF-I level, change in Acromegaly Symptom Diary (ASD) score, and maintenance of mean 5-sample growth hormone (GH) <1.0 ng/mL., Results: The primary endpoint was met: 83.3% (25/30) of patients receiving paltusotine and 3.6% (1/28) receiving placebo maintained IGF-I ≤1.0×ULN (odds ratio: 126.53; 95% CI: 13.73, >999.99; P<.0001). Paltusotine was also superior to placebo for all secondary endpoints: mean (±SE) change in IGF-I of 0.04±0.09×ULN versus 0.83±0.1×ULN (P<.0001); mean (±SE) change in ASD score of -0.6±1.5 versus 4.6±1.6 (P=.02); mean GH maintained at <1.0 ng/mL in 20/23 (87.0%) versus 5/18 (27.8%) patients (odds ratio: 16.61; 95% CI: 2.86, 181.36; P=.0003). The most common adverse events were acromegaly symptoms and gastrointestinal effects characteristic of SRLs., Conclusion: Replacement of injected SRLs by once-daily oral paltusotine was effective in maintaining both biochemical and symptom control in patients with acromegaly and was well tolerated., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Purpose: Patients with polyvascular disease (PVD) are at very high cardiovascular risk and require intensive lipid-lowering therapy. This analysis describes the lipid-lowering efficacy and safety of inclisiran versus placebo in patients with and without PVD., Methods: In this post hoc analysis of the ORION-9, ORION-10, and ORION-11 trials, patients were randomized 1:1 to receive 284 mg inclisiran (300 mg inclisiran sodium) or placebo on day 1, day 90, and 6-monthly thereafter. Percentage change in low-density lipoprotein cholesterol (LDL-C) from baseline to day 510 and corresponding time-adjusted change from day 90 and up to day 540 were evaluated per patients' PVD status. Safety was assessed over 540 days., Results: Of 3454 patients, 470 (13.6%) had PVD, and 2984 (86.4%) did not. Baseline characteristics were generally balanced between the treatment arms in both cohorts. A greater proportion of patients with PVD had comorbidities versus those without. The mean (95% confidence interval [CI]) placebo-corrected LDL-C percentage change from baseline to day 510 was -48.9% (-55.6 to -42.2) in patients with PVD and -51.5% (-53.9 to -49.1) in patients without. Proportions of patients with reported treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events were similar between treatment arms, irrespective of PVD status, except for an excess of mild or moderate clinically relevant TEAEs at the injection site with inclisiran., Conclusion: Twice-yearly inclisiran dosing (after the initial and 3-month doses) was well tolerated and provided effective and sustained lipid-lowering in patients, irrespective of PVD status., (© 2022. The Author(s).)

Habitat loss is affecting many species, including the southern mountain caribou (Rangifer tarandus caribou) population in western North America. Over the last half century, this threatened caribou population's range and abundance have dramatically contracted. An integrated population model was used to analyze 51 years (1973-2023) of demographic data from 40 southern mountain caribou subpopulations to assess the effectiveness of population-based recovery actions at increasing population growth. Reducing potential limiting factors on threatened caribou populations offered a rare opportunity to identify the causes of decline and assess methods of recovery. Southern mountain caribou abundance declined by 51% between 1991 and 2023, and 37% of subpopulations were functionally extirpated. Wolf reduction was the only recovery action that consistently increased population growth when applied in isolation, and combinations of wolf reductions with maternal penning or supplemental feeding provided rapid growth but were applied to only four subpopulations. As of 2023, recovery actions have increased the abundance of southern mountain caribou by 52%, compared to a simulation with no interventions. When predation pressure was reduced, rapid population growth was observed, even under contemporary climate change and high levels of habitat loss. Unless predation is reduced, caribou subpopulations will continue to be extirpated well before habitat conservation and restoration can become effective., (© 2024 The Authors. Ecological Applications published by Wiley Periodicals LLC on behalf of The Ecological Society of America.)

Background: People in Connecticut are now more likely to die of a drug-related overdose than a traffic accident. While Connecticut has had some success in slowing the rise in overdose death rates, substantial additional progress is necessary., Methods: We developed, verified, and calibrated a mechanistic simulation of alternative overdose prevention policy options, including scaling up naloxone (NLX) distribution in the community and medications for opioid use disorder (OUD) among people who are incarcerated (MOUD-INC) and in the community (MOUD-COM) in a simulated cohort of people with OUD in Connecticut. We estimated how maximally scaling up each option individually and in combinations would impact 5-year overdose deaths, life-years, and quality-adjusted life-years. All costs were assessed in 2021 USD, employing a health sector perspective in base-case analyses and a societal perspective in sensitivity analyses, using a 3% discount rate and 5-year and lifetime time horizons., Results: Maximally scaling NLX alone reduces overdose deaths 20% in the next 5 years at a favorable incremental cost-effectiveness ratio (ICER); if injectable rather than intranasal NLX was distributed, 240 additional overdose deaths could be prevented. Maximally scaling MOUD-COM and MOUD-INC alone reduce overdose deaths by 14% and 6% respectively at favorable ICERS. Considering all permutations of scaling up policies, scaling NLX and MOUD-COM together is the cost-effective choice, reducing overdose deaths 32% at ICER $19,000/QALY. In sensitivity analyses using a societal perspective, all policy options were cost saving and overdose deaths reduced 33% over 5 years while saving society $338,000 per capita over the simulated cohort lifetime., Conclusions: Maximally scaling access to naloxone and MOUD in the community can reduce 5-year overdose deaths by 32% among people with OUD in Connecticut under realistic budget scenarios. If societal cost savings due to increased productivity and reduced crime costs are considered, one-third of overdose deaths can be reduced by maximally scaling all three policy options, while saving money., (© 2024. The Author(s).)

Aldehyde oxidase (AO) is a molybdenum cofactor-containing cytosolic enzyme that has gained prominence due to its involvement in the developmental failure of several drug candidates in first-in-human trials. Unlike cytochrome P450s (P450) and glucuronosyltransferase, AO substrates have been plagued by poor in vitro to in vivo extrapolation, leading to low systemic exposures and underprediction of human dose. However, apart from measuring a drug's AO clearance rates, it is also important to determine the relative contribution to metabolism by this enzyme (f m,AO ). Although hydralazine is the most well-studied time-dependent inhibitor (TDI) of AO and is frequently employed for AO reaction phenotyping in human hepatocytes to derive f m,AO , multiple studies have expressed concerns pertaining to its utility in providing accurate estimates of f m,AO values due to its propensity to significantly inhibit P450s at the concentrations typically used for reaction phenotyping. In this study, we characterized icotinib, a cyclized analog of erlotinib, as a potent TDI of AO-inactivating human liver cytosolic zoniporide 2-oxidation equipotently with erlotinib with a maximal inactivate rate/inactivator concentration at half maximal inactivation rate ( K I ) ratio of 463 and 501 minute -1 mM -1 , respectively. Moreover, icotinib also exhibits selectivity against P450 and elicits significantly weaker inhibition against human liver microsomal UGT1A1/3 as compared with erlotinib. Finally, we evaluated icotinib as an inhibitor of AO for reaction phenotyping in cryopreserved human hepatocytes and demonstrated that it can yield more accurate prediction of f m,AO compared with hydralazine and induce sustained suppression of AO activity at higher cell densities, which will be important for reaction phenotyping endeavors of low clearance drugs SIGNIFICANCE STATEMENT: In this study, we characterized icotinib as a potent time-dependent inhibitor of AO with ample selectivity margins against the P450s and UGT1A1/3 and demonstrated its utility for reaction phenotyping in human hepatocytes to obtain accurate estimates of fm,AO for victim DDI risk predictions. We envisage the adoption of icotinib in place of hydralazine in AO reaction phenotyping., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Introduction: Emerging data suggests liver disease may be initiated during development when there is high genome plasticity and the molecular pathways supporting liver function are being developed., Methods: Here, we leveraged our Collaborative Cross mouse model of developmental vitamin D deficiency (DVD) to investigate the role of DVD in dysregulating the molecular mechanisms underlying liver disease. We defined the effects on the adult liver transcriptome and metabolome and examined the role of epigenetic dysregulation. Given that the parental origin of the genome (POG) influences response to DVD, we used our established POG model [POG1-(CC011xCC001)F1 and POG2-(CC001xCC011)F1] to identify interindividual differences., Results: We found that DVD altered the adult liver transcriptome, primarily downregulating genes controlling liver development, response to injury/infection (detoxification & inflammation), cholesterol biosynthesis, and energy production. In concordance with these transcriptional changes, we found that DVD decreased liver cell membrane-associated lipids (including cholesterol) and pentose phosphate pathway metabolites. Each POG also exhibited distinct responses. POG1 exhibited almost 2X more differentially expressed genes (DEGs) with effects indicative of increased energy utilization. This included upregulation of lipid and amino acid metabolism genes and increased intermediate lipid and amino acid metabolites, increased energy cofactors, and decreased energy substrates. POG2 exhibited broader downregulation of cholesterol biosynthesis genes with a metabolomics profile indicative of decreased energy utilization. Although DVD primarily caused loss of liver DNA methylation for both POGs, only one epimutation was shared, and POG2 had 6.5X more differentially methylated genes. Differential methylation was detected at DEGs regulating developmental processes such as amino acid transport (POG1) and cell growth & differentiation (e.g., Wnt & cadherin signaling, POG2)., Conclusions: These findings implicate a novel role for maternal vitamin D in programming essential offspring liver functions that are dysregulated in liver disease. Importantly, impairment of these processes was not rescued by vitamin D treatment at weaning, suggesting these effects require preventative measures. Substantial differences in POG response to DVD demonstrate that the parental genomic context of exposure determines offspring susceptibility., Competing Interests: The 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 Knuth, Xue, Elnagheeb, Gharaibeh, Schoenrock, McRitchie, Brouwer, Sumner, Tarantino, Valdar, Rector, Simon and Ideraabdullah.)

Background: Metal allergy following placement of a metal pectus bar for minimally invasive repair of pectus excavatum (MIRPE) is a rare complication with potentially significant morbidity. There is no consensus regarding preoperative metal allergy testing (MAT). This study aims to assess incidence of metal allergy and titanium bar use in tested and untested patients and trends in MAT with different approaches to MAT., Methods: A retrospective chart review was performed on patients who underwent MIRPE from July 2009 to June 2022 at a single institution. During this time, MAT was performed routinely (RT; routine testing) and selectively (ST; selective testing)., Results: The cohort included 741 patients for analysis. Metal bar allergy was documented in 1.3 % of all patients; the incidence was 1.3 % in patients with MAT and 1.4 % without MAT. The incidence of bar allergy was 1.1 % in the RT group and 1.6 % in the ST group. In the RT group, bar allergy occurred in 1.4 % (3/216) of patients with a negative MAT. In the ST group, bar allergy occurred in 1.2 % (2/164) of patients with a negative MAT and in 1.9 % (3/162) of untested patients with a stainless-steel bar. Titanium bar use was not significantly different between the RT and ST groups (18.3 % vs 16.3 %, p > 0.05)., Conclusion: The incidence of metal bar allergy after MIRPE was less than 2 %, and titanium bar use was not significantly different in routine and selective testing groups. MAT was not associated with a reduction in bar allergy, and its use remains unsupported., Level of Evidence: III., Competing Interests: Conflict of interest DMN is a consultant for Atricure and KLS and has patents related to pectus excavatum repair. BEP is a consultant for Atricure. LEM has received honoraria for speaking and teaching with Atricure., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Human error is impossible to eliminate, particularly in systems as complex as healthcare. The extent to which judgment errors in particular impact surgical patient care or lead to harm is unclear., Study Design: The American College of Surgeons NSQIP (2018) procedures from a single institution with 30-day morbidity or mortality were examined. Medical records were reviewed and evaluated for judgment errors. Preoperative variables associated with judgment errors were examined using logistic regression., Results: Of the surgical patients who experienced a morbidity or mortality, 18% (31 of 170) experienced an error in judgment during their hospitalization. Patients with hepatobiliary procedure (odds ratio [OR] 5.4 [95% CI 1.23 to 32.75], p = 0.002), insulin-dependent diabetes (OR 4.8 [95% CI 1.2 to 18.8], p = 0.025), severe COPD (OR 6.0 [95% CI 1.6 to 22.1], p = 0.007), or with infected wounds (OR 8.2 [95% CI 2.6 to 25.8], p < 0.001) were at increased risk for judgment errors., Conclusions: Specific procedure types and patients with certain preoperative variables had higher risk for judgment errors during their hospitalization. Errors in judgment adversely impacted the outcomes of surgical patients who experienced morbidity or mortality in this cohort. Preventing or mitigating errors and closely monitoring patients after an error in judgment is prudent and may improve surgical safety., (Copyright © 2024 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Cardiac abnormalities resulting from chronic epilepsy ("the epileptic heart") constitute a well-recognized comorbidity. However, the association of cardiac alterations with epilepsy duration remains understudied. We sought to evaluate this association using electrocardiogram (ECG)., Methods: We prospectively enrolled children between 1 months and 18 years of age without known cardiac conditions or ion channelopathies during routine clinic visits. ECGs were categorized as abnormal if there were alterations in rhythm; PR, QRS, or corrected QT interval; QRS axis or morphology; ST segment or T wave. An independent association between ECG abnormalities and epilepsy duration was evaluated using multivariable logistic regression modeling., Results: 213 children were enrolled. 100 ECGs (47%) exhibited at least one alteration; most commonly in the ST segment (37, 17%) and T wave (29, 11%). Children with normal ECGs had shorter epilepsy duration as compared to those with ECG abnormalities (46 [18-91] months vs. 73 [32-128 months], p = 0.004). A multivariable logistic regression model demonstrated that increasing epilepsy duration was independently associated with the presence of ECG abnormalities (OR=1.09, 95% CI=1.02-1.16, p = 0.008), adjusted for seizure frequency, generalized tonic-clonic/focal to bilateral tonic-clonic seizures as the predominant seizure type, and number of channel-modifying anti-seizure medications. Increasing epilepsy duration was also independently associated with the presence of ST/T wave abnormalities (OR=1.09, 95% CI=1.01-1.16, p = 0.017), adjusted for the same covariates., Significance: Increasing epilepsy duration is independently associated with the presence of minor ECG abnormalities. Additional studies are needed to evaluate whether this finding may represent a manifestation of the "epileptic heart"., Competing Interests: Declaration of competing interest None of the authors have any conflict of interest to disclose. We confirm that we have read journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objectives: To characterize health-related quality of life (HRQL) and functional recovery trajectories and risk factors for prolonged impairments among critically ill children receiving greater than or equal to 3 days of invasive ventilation., Design: Prospective cohort study., Setting: Quaternary children's hospital PICU., Patients: Children without a preexisting tracheostomy who received greater than or equal to 3 days of invasive ventilation, survived hospitalization, and completed greater than or equal to 1 postdischarge data collection., Interventions: None., Measurements and Main Results: We evaluated 144 children measuring HRQL using proxy-report Pediatric Quality of Life Inventory and functional status using the Functional Status Scale (FSS) reflecting preillness baseline, PICU and hospital discharge, and 1, 3, 6, and 12 months after hospital discharge. They had a median age of 5.3 years (interquartile range, 1.1-13.0 yr), 58 (40%) were female, 45 (31%) had a complex chronic condition, and 110 (76%) had normal preillness FSS scores. Respiratory failure etiologies included lung disease ( n = 49; 34%), neurologic failure ( n = 23; 16%), and septic shock ( n = 22; 15%). At 1-month postdischarge, 68 of 122 (56%) reported worsened HRQL and 35 (29%) had a new functional impairment compared with preillness baseline. This improved at 3 months to 54 (46%) and 24 (20%), respectively, and remained stable through the remaining 9 months of follow-up. We used interaction forests to evaluate relative variable importance including pairwise interactions and found that therapy consultation within 3 days of intubation was associated with better HRQL recovery in older patients and those with better preillness physical HRQL. During the postdischarge year, 76 patients (53%) had an emergency department visit or hospitalization, and 62 (43%) newly received physical, occupational, or speech therapy., Conclusions: Impairments in HRQL and functional status as well as health resource use were common among children with acute respiratory failure. Early therapy consultation was a modifiable characteristic associated with shorter duration of worsened HRQL in older patients., Competing Interests: Dr. Maddux’s institution received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (K23HD096018) and the Francis Family Foundation, Parker B. Francis Award. Drs. Maddux and Mourani received support for article research from the National Institutes of Health (NIH). Dr. Bennett’s institution received funding from the NICHD, the National Heart, Lung, and Blood Institute, and the National Center for Advancing Translational Sciences. Dr. Spear disclosed that a trust with him as beneficiary owns mutual funds that may own stock in pharmaceuticals. Dr. Mourani’s institution received funding from the NIH. 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.)

Cardiovascular disease and heart failure doubles in patients with chronic kidney disease (CKD), but the underlying mechanisms remain obscure. Mitochondria are central to maintaining cellular respiration and modulating cardiomyocyte function. We took advantage of our novel swine model of CKD and left ventricular diastolic dysfunction (CKD-LVDD) to investigate the expression of mitochondria-related genes and potential mechanisms regulating their expression. CKD-LVDD and normal control pigs (n=6/group, 3 males/3 females) were studied for 14 weeks. Renal and cardiac hemodynamics were quantified by multidetector-CT, echocardiography, and pressure-volume loop studies, respectively. Mitochondrial morphology (electron microscopy) and function (Oroboros) were assessed ex vivo. In randomly selected pigs (n=3/group), cardiac mRNA-, MeDIP-, and miRNA-sequencing (seq) were performed to identify mitochondria-related genes and study their pre- and post -transcriptional regulation. CKD-LVDD exhibited cardiac mitochondrial structural abnormalities and elevated mitochondrial H2O2 emission but preserved mitochondrial function. Cardiac mRNA-seq identified 862 mitochondria-related genes, of which 69 were upregulated and 33 downregulated (fold-change ≥2, false discovery rate≤0.05). Functional analysis showed that upregulated genes were primarily implicated in processes associated with oxidative stress, whereas those downregulated mainly participated in respiration and ATP synthesis. Integrated mRNA/miRNA/MeDIP-seq analysis showed that upregulated genes were modulated predominantly by miRNAs, whereas those downregulated were by miRNA and epigenetic mechanisms. CKD-LVDD alters cardiac expression of mitochondria-related genes, associated with mitochondrial structural damage but preserved respiratory function, possibly reflecting intrinsic compensatory mechanisms. Our findings may guide the development of early interventions at stages of cardiac dysfunction in which mitochondrial injury could be prevented, and the development of LVDD ameliorated., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

BIIB104 (formerly PF-04958242), N -((3 S ,4 S )-4-(4-(5-cyanothiophen-2-yl)phenoxy)tetrahydrofuran-3-yl)propane-2-sulfonamide, is an α -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiator investigated for the treatment of cognitive impairment associated with schizophrenia. Preliminary in vitro metabolism studies with non-radiolabeled BIIB104 in rat, dog, and human liver microsomes (RLM, DLM, and HLM) showed O -dealkylation in all three species, tetrahydrofuran hydroxylation dominating in DLM and HLM, and thiophene hydroxylation prevalent in RLM. However, a subsequent rat mass balance study with [nitrile- 14 C]BIIB104 showed incomplete recovery of administered radioactivity (∼80%) from urine and feces over 7 days following an oral dose, and an exceptionally long plasma total radioactivity half-life. Radiochromatographic metabolite profiling and identification, including chemical derivation, revealed that [ 14 C]cyanide was a major metabolite of [nitrile- 14 C]BIIB104 in RLM, but a minor and trace metabolite in DLM and HLM, respectively. Correspondingly in bile duct-cannulated rats, [ 14 C]thiocyanate accounted for ∼53% of total radioactivity excreted over 48 hours postdose and it, as an endogenous substance, explained the exceptionally long plasma radioactivity half-life. The release of [ 14 C]cyanide from the 2-cyanothiophene moiety is postulated to follow an epoxidation-initiated thiophene-opening based on the detection of non-radiolabeled counterpart metabolites in RLM. This unusual biotransformation serves as a lesson regarding placement of the radioactive label on an aryl nitrile when material will be used for evaluating the metabolism of a new drug candidate. Additionally, the potential cyanide metabolite of nitrile-containing drug molecules may be detected in liver microsomes with liquid chromatography-mass spectrometry following a chemical derivatization. SIGNIFICANCE STATEMENT: Using [nitrile- 14 C]BIIB104, non-intuitive metabolites of BIIB104 were discovered involving a novel cyanide release from the 2-cyanothiophene motif via a postulated epoxidation-initiated thiophene-opening. This unusual biotransformation serves as a lesson regarding placement of the radioactive label on an aryl nitrile when material will be used for evaluating the metabolism of a new drug candidate., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Alzheimer's disease (AD), the most common etiology of dementia in older adults, is projected to double in prevalence over the next few decades. Current treatments for AD manage symptoms or slow progressive decline, but are accompanied by significant inconvenience, risk, and cost. Thus, a better understanding of the risk factors and pathophysiology of AD is needed to develop novel prevention and treatment strategies. Aging is the most important risk factor for AD. Elucidating molecular mechanisms of aging may suggest novel therapeutic targets. While aging is inevitable, it may be accelerated by caloric excess and slowed by caloric restriction (CR) or intermittent fasting. As such, CR may slow aging and reduce the risk of all diseases of aging, including dementia due to AD. The literature on CR, intermittent fasting, and treatment with polyphenols such as resveratrol-a pharmacologic CR-mimetic-supports this hypothesis based on clinical outcomes as well as biomarkers of aging and AD. More studies exploring the role of CR in regulating aging and AD progression in man are needed to fill gaps in our understanding and develop safer and more effective strategies for the prevention and treatment of AD., Competing Interests: RT reports research funding to Georgetown University from Alector, Biogen, Cognition Therapeutics, Eisai, Janssen, Lilly, Roche/Genentech, Vaccinex, and Vivoryon. RT is a consultant to Re: Cognition Health. 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Yap, Hunt and Turner.)

A properly regulated series of developmental and meiotic events must occur to ensure the successful production of gametes. In Drosophila melanogaster ovaries, these early developmental and meiotic events include the production of the 16-cell cyst, meiotic entry, synaptonemal complex (SC) formation, recombination, and oocyte specification. In order to identify additional genes involved in early oocyte development and meiosis, we reanalyzed 3 published single-cell RNA-seq datasets from Drosophila ovaries, using vasa (germline) together with c(3)G, cona, and corolla (SC) as markers. Our analysis generated a list of 2,743 co-expressed genes. Many known SC-related and early oocyte development genes fell within the top 500 genes on this list, as ranked by the abundance and specificity of each gene's expression across individual analyses. We tested 526 available RNAi lines containing shRNA constructs in germline-compatible vectors representing 331 of the top 500 genes. We assessed targeted ovaries for SC formation and maintenance, oocyte specification, cyst development, and double-strand break dynamics. Six uncharacterized genes exhibited early developmental defects. SC and developmental defects were observed for additional genes not well characterized in the early ovary. Interestingly, in some lines with developmental delays, meiotic events could still be completed once oocyte specificity occurred indicating plasticity in meiotic timing. These data indicate that a transcriptomics approach can be used to identify genes involved in functions in a specific cell type in the Drosophila ovary., Competing Interests: Conflicts of interest. The author(s) declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.)

Background and Aims: Inclisiran, an siRNA therapy, consistently reduces low-density lipoprotein cholesterol (LDL-C) with twice-yearly dosing. Potential cardiovascular benefits of implementing inclisiran at a population level, added to statins, were evaluated through simulation., Methods: For each participant in the ORION-10 and ORION-11 trials comparing inclisiran with placebo, baseline 10-year cardiovascular risk was estimated using the SMART equation. The time-adjusted LDL-C difference from baseline observed 90-540 days after baseline was assumed to persist and used to estimate potential reduction in 10-year cardiovascular risk. Impact on 500,000 ORION-like individuals was simulated with Monte-Carlo., Results: Mean baseline LDL-C and predicted 10-year major vascular risk among patients randomized to inclisiran (n = 1288) versus placebo (n = 1264) were 2.66 mmol/L versus 2.60 mmol/L and 24.9% versus 24.6%, respectively. Placebo-corrected time-adjusted absolute reduction in LDL-C with inclisiran was -1.32 mmol/L (95% CI -1.37 to -1.26; p < 0.001), which predicted a 10-year cardiovascular risk of 18.1% with inclisiran versus 24.7% with placebo (absolute difference [95% CI], -6.99% [-7.33 to -6.66]; p < 0.001) NNT 15. Extrapolating to 500,000 inclisiran-treated individuals, the model predicted large population shifts towards lower quintiles of risk with fewer remaining in high-risk categories; 3350 to 471 (≥80% risk), 11,793 to 3332 (60-<80% risk), 52,142 to 22,665 (40-<60% risk), 197,752 to 141,014 (20-<40% risk), and more moving into the lowest risk category (<20%) from 234,963 to 332,518., Conclusions: Meaningful gains in population health might be achieved over 10 years by implementing at-scale approaches capable of providing substantial and sustained reductions in LDL-C beyond those achievable with statins., Competing Interests: Declaration of competing interest Kausik K. Ray reports unrestricted research grants to Imperial College London from Amgen, Daiichi Sankyo, Regeneron, Sanofi, and SC, EC or advisory board honoraria from Novartis, Esperion, Daiichi Sankyo, Abbott, Bayer, Eli Lilly, Silence Therapeutics, CSL Behring, New Amsterdam Pharma, Sanofi, Amgen, Novo Nordisk, BI, Scribe, Vaxxinity, CRISPR, AZ, Kowa, and Cargene, honoraria for CME and non-CME from Novartis, Novo Nordisk, BI, AZ, Viatris, Daiichi Sankyo, Amgen, and Sanofi, and stock options from PEMI-31; Laura H. Gunn has no conflict of interests to declare; Lorena Garcia Conde is an employee of Novartis; Frederick J. Raal reports receiving advisory board fees and lecture fees from Amgen, Sanofi-Aventis, Regeneron Pharmaceuticals, The Medicines Company, and Novartis; R. Scott Wright reports receiving advisory board fees from Boehringer Ingelheim and past fees for consulting on lipid issues with The Medicines Company; Nathalie H. Gosselin is an employee of Certara, consulting division; Lawrence A. Leiter reports grant support paid to his institution, advisory board fees, and fees for CME from Amgen and Novartis, fees for serving on a steering committee, and advisory board fees from Esperion, grant support paid to his institution, and fees for serving on a steering committee from Kowa, The Medicines Company, and Novartis; advisory board fees and fees for CME from Amarin, Astra Zeneca, HLS, Merck, Pfizer, and Sanofi; Wolfgang Koenig reports receiving consulting fees and lecture fees from AstraZeneca, Novartis, and Amgen, consulting fees from Pfizer, The Medicines Company, Novartis, DalCor Pharmaceuticals, Kowa, Corvidia Therapeutics, Esperion, Genentech, OMEICOS, Novo Nordisk, LIB Therapeutics, New Amsterdam Pharma, TenSixteen Bio, and Daiichi Sankyo, lecture fees from Berlin-Chemie, Bristol-Myers Squibb, and Sanofi, and grant support and provision of reagents from Singulex, Abbott, Roche Diagnostics, and Dr Beckmann Pharma; Gregory G. Schwartz reports receiving research support, paid to his institution from AstraZeneca, Resverlogix, Sanofi, Silence Therapeutics, and The Medicines Company, and a patent (62/806313) on a method for reducing cardiovascular risk assigned in full to the University of Colorado; Ulf Landmesser reports receiving lecture fees and advisory fees from AstraZeneca, Amgen, Sanofi, Berlin Chemie, and Abbott, advisory fees from The Medicines Company, and grant support, lecture fees, and advisory fees from Bayer and Novartis., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) is characterized by excess lipid accumulation that can progress to inflammation (nonalcoholic steatohepatitis, NASH), and fibrosis. Serum β-hydroxybutyrate (β-HB), a product of the ketogenic pathway, is commonly used as a surrogate marker for hepatic fatty acid oxidation (FAO). However, it remains uncertain whether this relationship holds true in the context of NAFLD in humans. We compared fasting serum β-HB levels with direct measurement of liver mitochondrial palmitate oxidation in humans stratified based on NAFLD severity ( n = 142). Patients were stratified based on NAFLD activity score (NAS): NAS = 0 (no disease), NAS = 1-2 (mild), NAS = 3-4 (moderate), and NAS ≥ 5 (advanced). Moderate and advanced NAFLD is associated with reductions in liver 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), serum β-HB, but not 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) mRNA, relative to no disease. Worsening liver mitochondrial complete palmitate oxidation corresponded with lower H MGCS2 mRNA but not total (complete + incomplete) palmitate oxidation. Interestingly, we found that liver HMGCS2 mRNA and serum β-HB correlated with liver mitochondrial β-hydroxyacyl-CoA dehydrogenase (β-HAD) activity and CPT1A mRNA. Also, lower mitochondrial mass and markers of mitochondrial turnover positively correlated with lower HMGCS2 in the liver. These data suggest that liver ketogenesis and FAO occur at comparable rates in individuals with NAFLD. Our findings support the utility of serum β-HB to serve as a marker of liver injury and hepatic FAO in the context of NAFLD. NEW & NOTEWORTHY Serum β-hydroxybutyrate (β-HB) is frequently utilized as a surrogate marker for hepatic fatty acid oxidation; however, few studies have investigated this relationship during states of liver disease. We found that the progression of nonalcoholic fatty liver disease (NAFLD) is associated with reductions in circulating β-HB and liver 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2). As well, decreased rates of hepatic fatty acid oxidation correlated with liver HMGCS2 mRNA and serum β-HB. Our work supports serum β-HB as a potential marker for hepatic fatty acid oxidation and liver injury during NAFLD.

Hoarding disorder (HD) is a debilitating neuropsychiatric condition that affects 2%-6% of the population and increases in incidence with age. Major depressive disorder (MDD) co-occurs with HD in approximately 50% of cases and leads to increased functional impairment and disability. However, only one study to date has examined the rate and trajectory of hoarding symptoms in older individuals with a lifetime history of MDD, including those with current active depression (late-life depression; LLD). We therefore sought to characterize this potentially distinct phenotype. We determined the incidence of HD in two separate cohorts of participants with LLD (n = 73) or lifetime history of MDD (n = 580) and examined the reliability and stability of hoarding symptoms using the Saving Inventory-Revised (SI-R) and Hoarding Rating Scale-Self Report (HRS), as well as the co-variance of hoarding and depression scores over time. HD was present in 12% to 33% of participants with MDD, with higher rates found in those with active depressive symptoms. Hoarding severity was stable across timepoints in both samples (all correlations >0.75), and fewer than 30% of participants in each sample experienced significant changes in severity between any two timepoints. Change in depression symptoms over time did not co-vary with change in hoarding symptoms. These findings indicate that hoarding is a more common comorbidity in LLD than previously suggested, and should be considered in screening and management of LLD. Future studies should further characterize the interaction of these conditions and their impact on outcomes, particularly functional impairment in this vulnerable population., (Copyright © 2023 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate for associations between a child's neighborhood, as categorized by Child Opportunity Index (COI 2.0), and 1) PICU mortality, 2) severity of illness at PICU admission, and 3) PICU length of stay (LOS)., Design: Retrospective cohort study., Setting: Fifteen PICUs in the United States., Patients: Children younger than 18 years admitted from 2019 to 2020, excluding those after cardiac procedures. Nationally-normed COI category (very low, low, moderate, high, very high) was determined for each admission by census tract, and clinical features were obtained from the Virtual Pediatric Systems LLC (Los Angeles, CA) data from each site., Interventions: None., Measurements and Main Results: Among 33,901 index PICU admissions during the time period, median patient age was 4.9 years and PICU mortality was 2.1%. There was a higher percentage of admissions from the very low COI category (27.3%) than other COI categories (17.2-19.5%, p < 0.0001). Patient admissions from the high and very high COI categories had a lower median Pediatric Index of Mortality 3 risk of mortality (0.70) than those from the very low, low, and moderate COI groups (0.71) ( p < 0.001). PICU mortality was lowest in the very high (1.7%) and high (1.9%) COI groups and highest in the moderate group (2.5%), followed by very low (2.3%) and low (2.2%) ( p = 0.001 across categories). Median PICU LOS was between 1.37 and 1.50 days in all COI categories. Multivariable regression revealed adjusted odds of PICU mortality of 1.30 (95% CI, 0.94-1.79; p = 0.11) for children from a very low versus very high COI neighborhood, with an odds ratio [OR] of 0.996 (95% CI, 0.993-1.00; p = 0.05) for mortality for COI as an ordinal value from 0 to 100. Children without insurance coverage had an OR for mortality of 3.58 (95% CI, 2.46-5.20; p < 0.0001) as compared with those with commercial insurance., Conclusions: Children admitted to a cohort of U.S. PICUs were often from very low COI neighborhoods. Children from very high COI neighborhoods had the lowest risk of mortality and observed mortality; however, odds of mortality were not statistically different by COI category in a multivariable model. Children without insurance coverage had significantly higher odds of PICU mortality regardless of neighborhood., Competing Interests: Dr. McCrory received funding from the Wake Forest Department of Anesthesiology. Dr. Maddux’s institution received funding from the National Institute of Child Health and Human Development (K23HD096018) and the Francis Family Foundation. 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 the World Federation of Pediatric Intensive and Critical Care Societies.)

Background and Objectives: Parents and family caregivers of children with severe neurologic impairment (SNI) experience many stressors, especially during their child's critical illness. This study aimed to examine parent experiences around the time of their child's PICU care to explore ways parents make meaning in relation to these stressors., Methods: This qualitative study of data from a single center in the United States followed Consolidated Criteria for Reporting Qualitative Research guidelines. One to one semistructured interviews queried parents' psychosocial well-being around the time of their child's PICU care. Eligible participants had a child with an SNI condition for >3 months admitted to the PICU for >24 hours with an expected length of stay >1 week., Results: Data were analyzed by a research team with expertise in palliative care, psychology, critical care, and qualitative methods. Fifteen family caregivers of 15 children participated. Children were a median of 8 years old (interquartile range 4-11.5) and 80% (n = 12) had congenital/genetic conditions. Parent/family caregivers were a median age of 39 years old (interquartile range 36-42.5); 20% (n = 3) self-identified as fathers and 47% (n = 7) as having to a minority racial background. Parents discussed ongoing meaning-making that occurred through domains of comprehension and purpose, and themes of understanding of other people and the world around them. Subthemes focused on appreciation/acceptance, adaptability/accountability, valuing all lives, and learning/teaching about their child., Conclusions: Meaning-making may be an opportunity for support in the PICU among parents/family caregivers of children with SNI., (Copyright © 2024 by the American Academy of Pediatrics.)

Globally ≈10% of adults have diabetes, with 80% in disadvantaged regions, hence low-cost renoprotective agents are desirable. Fenofibrate demonstrated microvascular benefits in several cardiovascular end-point diabetes trials, but knowledge of effects in late-stage kidney disease is limited. We report new FIELD substudy data and call for further kidney outcomes data., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Cannabinoids are lipophilic substances derived from Cannabis sativa that can exert a variety of effects in the human body. They have been studied in cellular and animal models as well as in human clinical trials for their therapeutic benefits in several human diseases. Some of these include central nervous system (CNS) diseases and dysfunctions such as forms of epilepsy, multiple sclerosis, Parkinson's disease, pain and neuropsychiatric disorders. In addition, the endogenously produced cannabinoid lipids, endocannabinoids, are critical for normal CNS function, and if controlled or modified, may represent an additional therapeutic avenue for CNS diseases. This review discusses in vitro cellular, ex vivo tissue and in vivo animal model studies on cannabinoids and their utility as therapeutics in multiple CNS pathologies. In addition, the review provides an overview on the use of cannabinoids in human clinical trials for a variety of CNS diseases. Cannabinoids and endocannabinoids hold promise for use as disease modifiers and therapeutic agents for the prevention or treatment of neurodegenerative diseases and neurological disorders.

A novel class of nonpeptide melanocortin type 2 receptor (MC2R) antagonists was discovered through modification of known nonpeptide MC4R ligands. Structure-activity relationship (SAR) studies led to the discovery of 17h (CRN04894), a highly potent and subtype-selective first-in-class MC2R antagonist, which demonstrated remarkable efficacy in a rat model of adrenocorticotrophic hormone (ACTH)-stimulated corticosterone secretion. Oral administration of 17h suppressed ACTH-stimulated corticosterone secretion in a dose-dependent manner at doses ≥3 mg/kg. With its satisfactory pharmaceutical properties, 17h was advanced to Phase 1 human clinical trials in healthy volunteers with the goal of moving into patient trials to evaluate CRN04894 for the treatment of ACTH-dependent diseases, including congenital adrenal hyperplasia (CAH) and Cushing's disease (CD)., Competing Interests: The authors declare the following competing financial interest(s): All authors are employees of Crinetics Pharmaceuticals, Inc., except S.H. and G.R. who were previous employees and A.K.K. and Y.Z. who were also previous employees and are currently consultants for Crinetics., (© 2024 American Chemical Society.)

The conformational features of α-halopropiophenones were investigated to understand the influence of α-halogens on conformation through hyperconjugative interactions, electrostatics, and steric factors. Using NMR, C-H scalar coupling constants were measured in different solvents, revealing a pattern in the conformational equilibria, which we validated by computational means. This behavior arises largely from hyperconjugative effects with the exception of the fluoro-derivatives, which are also influenced by steric and electrostatic interactions. In all cases, the contribution to hyperconjugation of the α-halo ketones is driven by the oxygen lone pair (rather than the C-X bond), which donates electron density to the adjacent C-C bonds. Additionally, C-C α bond rotation generates distortions in the side chain, responsible for destabilization, thus affecting system conjugation. These structural features identified for the α-halo ketones are also reflected in their reactivity, which is distinct from that expected for nucleophilic addition.

The genus Acacia is a large group of woody legumes containing an enormous amount of morphological diversity in leaf shape. This diversity is at least in part the result of an innovation in leaf development where many Acacia species are capable of developing leaves of both bifacial and unifacial morphologies. While not unique in the plant kingdom, unifaciality is most commonly associated with monocots, and its developmental genetic mechanisms have yet to be explored beyond this group. In this study, we identify an accession of Acacia crassicarpa with high regeneration rates and isolate a clone for genome sequencing. We generate a chromosome-level assembly of this readily transformable clone, and using comparative analyses, confirm a whole-genome duplication unique to Caesalpinoid legumes. This resource will be important for future work examining genome evolution in legumes and the unique developmental genetic mechanisms underlying unifacial morphogenesis in Acacia., Competing Interests: Conflicts of interest The author(s) declare no conflicts of interest., (Published by Oxford University Press on behalf of The Genetics Society of America 2023.)

We report the morphological characteristics of oocysts of Eimeria lancasterensisJoseph, 1969, collected from 6 of 6 (100%) eastern gray squirrels, Sciurus carolinensis, collected in Arkansas (n = 3) and Oklahoma (n = 3), and Eimeria ontarioensisLee and Dorney, 1971, recovered from an individual of S. carolinensis from Arkansas. Oocysts of E. lancasterensis were ovoidal to ellipsoidal, measuring (L × W) 24.0 × 14.6 (18-29 × 12-16) µm; shape index (L/W) was 1.6 (1.3-1.8). A micropyle and an oocyst residuum were absent, but up to 2 polar granules were present. Oocysts of E. ontarioensis were piriform and measured 40.6 × 26.0 (37-44 × 23-28); L/W was 1.6 (1.5-1.7). These oocysts possessed a distinct micropyle and rarely a polar granule but lacked an oocyst residuum. The DNA was isolated from both eimerians, and the 18S rDNA genetic markers were PCR-amplified, cloned, sequenced, and analyzed. To our knowledge, this study represents the first time 18S DNA sequence data have been generated from E. lancasterensis and E. ontarioensis found in North American sciurid hosts, as well as new geographic distribution records for these coccidians. In addition, we also include a tabular summary of these 2 species of Eimeria from Sciurus spp. worldwide, with information on their hosts, distribution, and taxonomically important morphological characteristics, including key measurements of oocysts and sporocysts., (© American Society of Parasitologists 2024.)

Introduction: Minimally invasive repair of pectus excavatum (MIRPE) with intercostal nerve cryoablation (Cryo) decreases length of hospitalization and opioid use, but long-term recovery of sensation has been poorly described. The purpose of this study was to quantify long-term hypoesthesia and neuropathic pain after MIRPE with Cryo., Methods: A prospective cohort study was conducted single-institution of patients ≤21 years who presented for bar removal. Consented patients underwent chest wall sensory testing and completed neuropathic pain screening. Chest wall hypoesthesia to cold, soft touch, and pinprick were measured as the percent of the treated anterior chest wall surface area (TACWSA); neuropathic pain was evaluated by questionnaire., Results: The study enrolled 47 patients; 87% male; median age 18.4 years. The median bar dwell time was 2.9 years. A median of 2 bars were placed; 80.9% were secured with pericostal sutures. At enrollment, 46.8% of patients had identifiable chest wall hypoesthesia. The mean percentage of TACWSA with hypoesthesia was 4.7 ± 9.3% (cold), 3.9 ± 7.7% (soft touch), and 5.9 ± 11.8% (pinprick). Hypoesthesia to cold was found in 0 dermatomes in 62%, 1 dermatome in 11%, 2 dermatomes in 17% and ≥3 dermatomes in 11%. T5 was the most common dermatome with hypoesthesia. Neuropathic symptoms were identified by 13% of patients; none required treatment., Conclusion: In long-term follow up after MIRPE with Cryo, 46.8% of patients experienced some chest wall hypoesthesia; the average TACWSA with hypoesthesia was 4-6%. Hypoesthesia was mostly limited to 1-2 dermatomes, most commonly T5. Chronic symptomatic neuropathic pain was rare., Level of Evidence: Level IV., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: To describe rates and associated risk factors for functional decline 6 months after critical bronchiolitis in a large, multicenter dataset., Design: Nonprespecified secondary analysis of existing 6-month follow-up data of patients in the Randomized Evaluation of Sedation Titration for Respiratory Failure trial ( RESTORE , NCT00814099)., Setting: Patients recruited to RESTORE in any of 31 PICUs in the United States, 2009-2013., Patients: Mechanically ventilated PICU patients under 2 years at admission with a primary diagnosis of bronchiolitis., Interventions: There were no interventions in this secondary analysis; in the RESTORE trial, PICUs were randomized to protocolized sedation versus usual care., Measurements and Main Results: "Functional decline," defined as worsened Pediatric Overall Performance Category and/or Pediatric Cerebral Performance Category (PCPC) scores at 6 months post-PICU discharge as compared with preillness baseline. Quality of life was assessed using Infant Toddler Quality of Life Questionnaire (ITQOL; children < 2 yr old at follow-up) or Pediatric Quality of Life Inventory (PedsQL) at 6 months post-PICU discharge. In a cohort of 232 bronchiolitis patients, 28 (12%) had functional decline 6 months postdischarge, which was associated with unfavorable quality of life in several ITQOL and PedsQL domains. Among 209 patients with normal baseline functional status, 19 (9%) had functional decline. In a multivariable model including all subjects, decline was associated with greater odds of worse baseline PCPC score and longer PICU length of stay (LOS). In patients with normal baseline status, decline was also associated with greater odds of longer PICU LOS., Conclusions: In a random sampling of RESTORE subjects, 12% of bronchiolitis patients had functional decline at 6 months. Given the high volume of mechanically ventilated patients with bronchiolitis, this observation suggests many young children may be at risk of new morbidities after PICU admission, including functional and/or cognitive morbidity and reduced quality of life., Competing Interests: Dr. Watson’s institution received funding from the National Institutes of Health (NIH); he received support for article research from the NIH. Dr. Shein received funding from Ceribell and Hill Ward Henderson. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Introduction: Alzheimer's Prevention Initiative Generation Study 1 evaluated amyloid beta (Aβ) active immunotherapy (vaccine) CAD106 and BACE-1 inhibitor umibecestat in cognitively unimpaired 60- to 75-year-old participants at genetic risk for Alzheimer's disease (AD). The study was reduced in size and terminated early. Results from the CAD106 cohort are presented., Methods: Sixty-five apolipoprotein E ε4 homozygotes with/without amyloid deposition received intramuscular CAD106 450 μg (n = 42) or placebo (n = 23) at baseline; Weeks 1, 7, 13; and quarterly; 51 of them had follow-up Aβ positron emission tomography (PET) scans at 18 to 24 months., Results: CAD106 induced measurable serum Aβ immunoglobulin G titers in 41/42 participants, slower rates of Aβ plaque accumulation (mean [standard deviation] annualized change from baseline in amyloid PET Centiloid: -0.91[5.65] for CAD106 versus 8.36 [6.68] for placebo; P < 0.001), and three amyloid-related imaging abnormality cases (one symptomatic)., Discussion: Despite early termination, these findings support the potential value of conducting larger prevention trials of Aβ active immunotherapies in individuals at risk for AD., Highlights: This was the first amyloid-lowering prevention trial in persons at genetic risk of late-onset Alzheimer's disease (AD). Active immunotherapy targeting amyloid (CAD106) was tested in this prevention trial. CAD106 significantly slowed down amyloid plaque deposition in apolipoprotein E homozygotes. CAD106 was generally safe and well tolerated, with only three amyloid-related imaging abnormality cases (one symptomatic). Such an approach deserves further evaluation in larger AD prevention trials., (© 2023 Novartis. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Importance: Sepsis is a leading cause of death among children worldwide. Current pediatric-specific criteria for sepsis were published in 2005 based on expert opinion. In 2016, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection, but it excluded children., Objective: To update and evaluate criteria for sepsis and septic shock in children., Evidence Review: The Society of Critical Care Medicine (SCCM) convened a task force of 35 pediatric experts in critical care, emergency medicine, infectious diseases, general pediatrics, nursing, public health, and neonatology from 6 continents. Using evidence from an international survey, systematic review and meta-analysis, and a new organ dysfunction score developed based on more than 3 million electronic health record encounters from 10 sites on 4 continents, a modified Delphi consensus process was employed to develop criteria., Findings: Based on survey data, most pediatric clinicians used sepsis to refer to infection with life-threatening organ dysfunction, which differed from prior pediatric sepsis criteria that used systemic inflammatory response syndrome (SIRS) criteria, which have poor predictive properties, and included the redundant term, severe sepsis. The SCCM task force recommends that sepsis in children be identified by a Phoenix Sepsis Score of at least 2 points in children with suspected infection, which indicates potentially life-threatening dysfunction of the respiratory, cardiovascular, coagulation, and/or neurological systems. Children with a Phoenix Sepsis Score of at least 2 points had in-hospital mortality of 7.1% in higher-resource settings and 28.5% in lower-resource settings, more than 8 times that of children with suspected infection not meeting these criteria. Mortality was higher in children who had organ dysfunction in at least 1 of 4-respiratory, cardiovascular, coagulation, and/or neurological-organ systems that was not the primary site of infection. Septic shock was defined as children with sepsis who had cardiovascular dysfunction, indicated by at least 1 cardiovascular point in the Phoenix Sepsis Score, which included severe hypotension for age, blood lactate exceeding 5 mmol/L, or need for vasoactive medication. Children with septic shock had an in-hospital mortality rate of 10.8% and 33.5% in higher- and lower-resource settings, respectively., Conclusions and Relevance: The Phoenix sepsis criteria for sepsis and septic shock in children were derived and validated by the international SCCM Pediatric Sepsis Definition Task Force using a large international database and survey, systematic review and meta-analysis, and modified Delphi consensus approach. A Phoenix Sepsis Score of at least 2 identified potentially life-threatening organ dysfunction in children younger than 18 years with infection, and its use has the potential to improve clinical care, epidemiological assessment, and research in pediatric sepsis and septic shock around the world.

Importance: The Society of Critical Care Medicine Pediatric Sepsis Definition Task Force sought to develop and validate new clinical criteria for pediatric sepsis and septic shock using measures of organ dysfunction through a data-driven approach., Objective: To derive and validate novel criteria for pediatric sepsis and septic shock across differently resourced settings., Design, Setting, and Participants: Multicenter, international, retrospective cohort study in 10 health systems in the US, Colombia, Bangladesh, China, and Kenya, 3 of which were used as external validation sites. Data were collected from emergency and inpatient encounters for children (aged <18 years) from 2010 to 2019: 3 049 699 in the development (including derivation and internal validation) set and 581 317 in the external validation set., Exposure: Stacked regression models to predict mortality in children with suspected infection were derived and validated using the best-performing organ dysfunction subscores from 8 existing scores. The final model was then translated into an integer-based score used to establish binary criteria for sepsis and septic shock., Main Outcomes and Measures: The primary outcome for all analyses was in-hospital mortality. Model- and integer-based score performance measures included the area under the precision recall curve (AUPRC; primary) and area under the receiver operating characteristic curve (AUROC; secondary). For binary criteria, primary performance measures were positive predictive value and sensitivity., Results: Among the 172 984 children with suspected infection in the first 24 hours (development set; 1.2% mortality), a 4-organ-system model performed best. The integer version of that model, the Phoenix Sepsis Score, had AUPRCs of 0.23 to 0.38 (95% CI range, 0.20-0.39) and AUROCs of 0.71 to 0.92 (95% CI range, 0.70-0.92) to predict mortality in the validation sets. Using a Phoenix Sepsis Score of 2 points or higher in children with suspected infection as criteria for sepsis and sepsis plus 1 or more cardiovascular point as criteria for septic shock resulted in a higher positive predictive value and higher or similar sensitivity compared with the 2005 International Pediatric Sepsis Consensus Conference (IPSCC) criteria across differently resourced settings., Conclusions and Relevance: The novel Phoenix sepsis criteria, which were derived and validated using data from higher- and lower-resource settings, had improved performance for the diagnosis of pediatric sepsis and septic shock compared with the existing IPSCC criteria.

In vitro time-dependent inhibition (TDI) kinetic parameters for cytochrome P450 (CYP) 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6, were determined in pooled human liver microsomes for 19 drugs (and 2 metabolites) for which clinical drug-drug interactions (DDI) are known. In vitro TDI data were incorporated into the projection of the magnitude of DDIs using mechanistic static models and Simcyp®. Results suggest that for the mechanistic static model, use of estimated average unbound exit concentration of the inhibitor from the liver resulted in a successful prediction of observed magnitude of clinical DDIs and was similar to Simcyp®. Overall, predictions of DDI magnitude (i.e., fold increase in AUC of a CYP-specific marker substrate) were within 2-fold of actual values. Geometric mean-fold errors were 1.7 and 1.6 for static and dynamic models, respectively. Projections of DDI from both models were also highly correlated to each other (r2 = 0.92). This investigation demonstrates that DDI can be reliably predicted from in vitro TDI data generated in HLM for several CYP enzymes. Simple mechanistic static model equations as well as more complex dynamic PBPK models can be employed in this process. Significance Statement Cytochrome P450 time-dependent inhibitors (TDI) can cause drug-drug interactions (DDI). An ability to reliably assess the potential for a new drug candidate to cause DDI is essential during drug development. In this report, TDI data for 19 drugs (and 2 metabolites) were measured and used in static and dynamic models to reliably project the magnitude of DDI resulting from inhibition of CYP1A2, 2B6, 2C8, 2C9, 2C19, and 2D6., (Copyright © 2024 American Society for Pharmacology and Experimental Therapeutics.)

Introduction: As paediatric intensive care unit (PICU) mortality declines, there is growing recognition of the morbidity experienced by children surviving critical illness and their families. A comprehensive understanding of the adverse physical, cognitive, emotional and social sequelae common to PICU survivors is limited, however, and the trajectory of recovery and risk factors for morbidity remain unknown., Methods and Analysis: The Post-Intensive Care Syndrome - paediatrics Longitudinal Cohort Study will evaluate child and family outcomes over 2 years following PICU discharge and identify child and clinical factors associated with impaired outcomes. We will enrol 750 children from 30 US PICUs during their first PICU hospitalisation, including 500 case participants experiencing ≥3 days of intensive care that include critical care therapies (eg, mechanical ventilation, vasoactive infusions) and 250 age-matched, sex-matched and medical complexity-matched control participants experiencing a single night in the PICU with no intensive care therapies. Children, parents and siblings will complete surveys about health-related quality of life, physical function, cognitive status, emotional health and peer and family relationships at multiple time points from baseline recall through 2 years post-PICU discharge. We will compare outcomes and recovery trajectories of case participants to control participants, identify risk factors associated with poor outcomes and determine the emotional and social health consequences of paediatric critical illness on parents and siblings., Ethics and Dissemination: This study has received ethical approval from the University of Pennsylvania Institutional Review Board (protocol #843844). Our overall objective is to characterise the ongoing impact of paediatric critical illness to guide development of interventions that optimise outcomes among children surviving critical illness and their families. Findings will be presented at key disciplinary meetings and in peer-reviewed publications at fixed data points. Published manuscripts will be added to our public study website to ensure findings are available to families, clinicians and researchers., Trials Registration Number: NCT04967365., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Superior mesenteric artery syndrome (SMAS) is a rare and potentially life-threatening cause of small bowel obstruction in which the superior mesenteric artery impinges on the third portion of the duodenum. SMAS is typically encountered in patients with low body fat and a history of rapid weight loss and is often diagnosed as a chronic or subacute condition. Here, we describe a case of a healthy adolescent boy without typical SMAS prodromal symptoms presenting with a severe, hyperacute proximal small bowel obstruction due to SMAS. Complications arising from massive gastric and duodenal distension, including gastric, pancreatic and renal ischaemia, necessitated emergent surgical intervention consisting of the duodenojejunostomy bypass with partial gastric resection. The patient recovered without significant lasting consequences., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)