Search

Beta-blockers and nondihydropyridine calcium-channel blockers have been standard-of-care (SOC) medications for patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM), even though these agents do not directly affect the underlying pathophysiology of the disease. Cardiac myosin inhibitors act by decreasing the number of myosin heads binding to actin, reducing the pathologic hypercontractility of HCM, and have been shown to improve exercise capacity and alleviate symptoms in oHCM when added to SOC medications. Cardiac myosin inhibitors are currently considered as second-line therapy in the absence of head-to-head comparison studies vs SOC medications. The aim of the ongoing phase 3 study MAPLE-HCM (Metoprolol vs Aficamten in Patients With LVOT Obstruction on Exercise Capacity in HCM) is to fill this evidence gap by evaluating aficamten as both first-line therapy for newly diagnosed oHCM and as a monotherapy alternative for patients currently on SOC drugs. The authors describe the rationale, design, and baseline characteristics of patients in this study. (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol Succinate in Adults With Symptomatic oHCM [MAPLE-HCM]; NCT05767346)., Competing Interests: Funding Support and Author Disclosures The MAPLE-HCM and FOREST-HCM trials are funded by Cytokinetics. Representatives of Cytokinetics have been involved in the design and conduct of the study reported in this paper. Dr Garcia-Pavia has received Speakers Bureau fees from Alnylam Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, BridgeBio, Intellia, Ionis Pharmaceuticals, Novo Nordisk, and Pfizer; has received consulting fees from Alexion, Alnylam Pharmaceuticals, AstraZeneca, Attralus, Bayer, BioMarin, Bristol Myers Squibb, BridgeBio, Cytokinetics, Daiichi-Sankyo, Edgewise, General Electric, Intellia, Idoven, Ionis Pharmaceuticals, Lexeo, Pfizer, Neuroimmune, Novo Nordisk, and Rocket Pharmaceuticals; and has received research and educational support to the institution from Alnylam, AstraZeneca, BridgeBio, Intellia, Novo Nordisk, and Pfizer. Dr Bilen has received consulting fees from Bristol Myers Squibb and Cytokinetics. Dr Burroughs has received consulting fees from Bristol Myers Squibb, Cytokinetics, and Novartis. Dr Costabel has received Speakers Bureau fees from Bristol Myers Squibb and Pfizer; and has received consulting fees from Bristol Myers Squibb, Cytokinetics, and Pfizer. Dr Dybro has received speaker fees from Pfizer and Bristol Myers Squibb. Dr Elliott has received consulting fees from Bristol Myers Squibb, Pfizer, and Cytokinetics; has received speaker fees from Pfizer; and has received an unrestricted grant from Sarepta. Dr Lakdawala has received consulting fees from Pfizer, Bristol Myers Squibb, Cytokinetics, Tenaya, Akros, Neuvocor, and Alexion; and has received unrestricted research support from Pfizer and Bristol Myers Squibb. Ms Mann has received consulting fees from Bristol Myers Squibb and Cytokinetics. Dr Nassif has received research and grant support from AstraZeneca and Cytokinetics; and has received consulting and advisory fees from Vifor and Cytokinetics. Dr Poulsen has received consulting fees from Pfizer and BridgeBio. Dr Reant has received consulting fees from Cytokinetics, Bristol Myers Squibb, Pfizer, Alnylam, Amicus Therapeutics, and Sanofi. Dr Schulze has received honoraria and travel support from Bayer, AstraZeneca, Daiichi-Sankyo, Novartis, Actelion, Roche, Sanofi, Pharmacosmos, Medtronic, Thoratec, Boehringer Ingelheim, HeartWare, Coronus, Abbott, Edwards LifeSciences, Boston Scientific, St. Jude Medical, Abiomed, and the German Cardiac Society; has received research support from the National Institutes of Health, the German Research Foundation, the Else Kröner Fresenius Foundation, the German Heart Foundation, the European Society of Cardiology, Actelion, Medtronic, the Federal Ministry of Education and Research of Germany, Abiomed, Boehringer Ingelheim, and Boston Scientific; and has served on advisory boards for the German Research Council, Cytokinetics, Eurotransplant, Novartis, Bayer, Pharmacosmos, AstraZeneca, Boehringer Ingelheim, the German Cardiac Society, and the European Society of Cardiology. Drs Berhane, Heitner, Jacoby, Kupfer, Malik, Meng, Sohn, and Wohltman are employees of Cytokinetics and hold stock in Cytokinetics. Dr Fifer has received consulting fees from Bristol Myers Squibb, Cytokinetics, Edgewise Therapeutics, and Viz.ai; and has received research grants from Bristol Myers Squibb and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Accurately capturing individuals' experiences with greenspace at ground-level can provide valuable insights into their impact on children's health. However, most previous research has relied on coarse satellite-based measurements., Methods: We utilized CVH and residential address data from Project Viva, a US-based pre-birth cohort, tracking participants from mid-childhood to late adolescence (2007-21). A deep learning segmentation algorithm was applied to street-view images across the US to estimate % street-view trees, grass, and other greenspace (flowers, field, and plants). Exposure estimates were derived by linking street-view greenspace metrics to 500m of participants' residences during mid-childhood, early and late adolescence. CVH scores (range 0-100; higher indicate better CVH) were calculated using the American Heart Association's Life's Essential 8 algorithm at these three time points, incorporating four biomedical components (body weight, blood lipids, blood glucose, blood pressure) and four behavioral components (diet, physical activity, nicotine exposure, sleep). Linear regression models were used to examine cross-sectional and cumulative associations between street-view greenspace metrics and CVH scores. Generalized estimating equations models were used to examine associations between street-view greenspace metrics and changes in CVH scores across three timepoints. All models were adjusted for individual and neighborhood-level confounders., Results: Adjusting for confounders, a one-SD increase in street-view trees within 500m of residence was cross-sectionally associated with a 1.92-point (95%CI: 0.50, 3.35) higher CVH score in late adolescence, but not mid-childhood or early adolescence. Longitudinally, street-view greenspace metrics at baseline (either mid-childhood or early adolescence) were not associated with changes in CVH scores at the same and all subsequent time points. Cumulative street-view greenspace metrics across the three time points were also not associated with CVH scores in late adolescence., Conclusion and Relevance: In this US cohort of children, we observed few evidence of associations between street-level greenspace children's CVH, though the impact may vary with children's growth stage., 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 Elsevier Inc. All rights reserved.)

Cannabis (CB) use and psychological stressors increase oxidative stress in the brain. Glutathione (GSH), the most abundant antioxidant in the brain, protects against oxidative stress. Furthermore, distress intolerance, the inability to tolerate psychological or physiological stress is a risk factor for CB use. The relationship between CB use, brain GSH levels and distress intolerance remains unknown. Therefore, we examined GSH levels in the anterior cingulate cortex (ACC), as a measure of oxidative stress, and its relationship with distress intolerance in adolescent CB users and healthy controls (HC). Sixteen HC and 17 CB-using adolescents were included in the analysis. GSH levels were measured in the ACC using a metabolite-edited proton magnetic resonance spectroscopy sequence on a 3T scanner. Distress intolerance was assessed using the Distress Intolerance Index (DII) and CB use was evaluated using a structured clinical interview. In the CB group, lower CSF-corrected GSH levels in the ACC were correlated with higher DII scores. However, no significant between group differences were observed for ACC CSF-corrected GSH levels or on DII scores. No significant correlations were observed in the HC group between GSH levels and DII. Our findings suggests that the association between lower GSH levels and greater distress intolerance in CB users might reflect alterations in the balance between protective and oxidative stress conditions linked to the ability to tolerate distress. Further examination into this relationship can provide important insights into neurobiological correlates and risk factors associated with CB use to help inform preventive and treatment targets in the future., 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 Elsevier Inc. All rights reserved.)

Worldwide, there is an increasing uptake of traffic management interventions aimed at reducing the impact of traffic related air pollution on public health. However, the evidence base linking the proposed changes with the resulting improvements in air quality is lacking. In this paper we present data from a micro-network of low-cost PM 10 samplers collected from an isolated urban centre (Auckland, New Zealand). The data was then analysed using a new combination of analytical methods aimed to identify the composition and hence, the source of pollution. Whilst across the three sites mass concentration of PM 10 and black carbon were similar, Raman spectroscopy successfully identified variations in the soot composition at different sites, enabling some particulate matter to be linked to diesel vehicle emissions. A mass reconstruction approach proved useful in determining that the airshed is well-mixed and also highlighted the impacts of urban design on recorded concentrations. The results show that networks of low-cost sensors, combined with the range of analytical techniques used here can help policymakers test the efficacy of interventions and management strategies designed to combat the burden of air pollution on public health., Competing Interests: Declaration of competing interest Hamesh Patel, David Williams and Cherie Tollemache are either employed by Mote Limited or shareholders in Mote Limited. The other 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.)

Objective: To compare perioperative opioid consumption in dogs undergoing pelvic limb surgeries and receiving a lumbosacral plexus block by combining a lumbar [lateral pre-iliac (LPI)] block with a lumbosacral trunk [i.e. parasacral (PS group) or greater ischiatic notch plane (GIN group)] block. Study design Retrospective, descriptive, exploratory, noninferiority cohort study., Methods: Medical records of 37 client-owned dogs were analyzed. Intraoperative (primary outcome) and postoperative (24 hours) opioid use, 24 hour cumulative pain scores and prevalence of complications were compared between the two groups. Opioid use was quantified in morphine equivalents (ME, mg kg -1 ). The noninferiority limit for intraoperative opioid consumption was set at 0.05 ME kg -1 hour -1 . Demographic data, procedure duration, surgery type and perioperative dexmedetomidine and ketamine use were also collected. A t-test or Wilcoxon rank-sum test, a Fisher's exact test and multivariable linear regression were used. Significance was set at p < 0.05., Results: The GIN and PS groups comprised 17 and 20 dogs, respectively. Total intraoperative ME consumption was 0.17 (0.11-0.21) and 0.22 (0.16-0.30) mg kg -1 hour -1 for the GIN and PS groups, respectively (p = 0.077). The noninferiority analysis adjusted by surgery type and body mass revealed that the mean difference between the groups (GIN - PS) was -0.039 (95% CI -0.11-0.03, p = 0.247) ME mg kg -1 hour -1 , indicating that the GIN group was not inferior to the PS group regarding intraoperative ME consumption. Dexmedetomidine and ketamine use, postoperative ME consumption and pain scores were similar between groups., Conclusions and Clinical Relevance: This retrospective study and preliminary observations support the clinical use of the GIN plane block, demonstrating its noninferiority to the PS block when combined with the LPI block for multimodal perioperative analgesia in dogs undergoing pelvic limb surgeries., (Copyright © 2024 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Background: Studies suggest that greater exposure to natural vegetation (i.e., greenness) is associated with better mental health. However, there is limited research on greenness and mental health in the preconception period, a critical window of exposure in the life course. We investigated the associations of residential greenness with perceived stress and depressive symptoms using cross-sectional data from a cohort of pregnancy planners., Methods: From 2013 to 2019, we enrolled female-identified participants aged 21-45 years who were trying to conceive without the use of fertility treatment into a North American preconception cohort study (Pregnancy Study Online [PRESTO]). On the baseline questionnaire, participants completed the 10-item Perceived Stress Scale (PSS) and the Major Depression Inventory (MDI). Using geocoded addresses, we estimated residential greenness exposure via satellite imagery (Normalized Difference Vegetation Index [NDVI]) in a 100m buffer. We estimated mean differences and 95% confidence intervals for the association of greenness with perceived stress and depression scores using linear regression models, adjusting for individual and neighborhood sociodemographic characteristics. We also evaluated the extent to which associations were modified by urbanicity and neighborhood socioeconomic status (SES)., Results: Among 9718 participants, mean age was 29.9 years, 81.5% identified as non-Hispanic White, 25% had household incomes <$50,000, and mean neighborhood income was $61,932. In adjusted models, higher greenness was associated with lower stress and depression scores (mean difference per interquartile range in greenness: -0.20, 95% CI: -0.39, -0.01; and -0.19, 95% CI: -0.48, 0.10, respectively). The association was stronger among residents of lower SES neighborhoods in urban areas (PSS: -0.57, 95% CI: -1.00, -0.15; MDI: -0.72, 95% CI: -1.40, -0.04)., Conclusions: Higher greenness exposure was associated with lower stress and depressive symptoms among pregnancy planners, particularly in lower-SES neighborhoods., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lauren A. Wise reports financial support was provided by National Institutes of Health. Lauren A. Wise reports a relationship with AbbVie Inc that includes: consulting or advisory. Lauren A. Wise reports a relationship with Bill & Melinda Gates Foundation that includes: consulting or advisory. Lauren A. Wise has reported receiving in-kind donations for primary data collection in the Pregnancy Study Online (PRESTO) from Swiss Precision Diagnostics (home pregnancy tests) and Kindara.com (fertility tracking apps). 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., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: Funding Support and Author Disclosures Dr Kaple is a speaker for Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Competing Interests: Conflict of Interest All authors declare no conflicts of interest related to the matter of this statement.

Traffic-related air pollution (TRAP) poses a significant public health risk that is associated with adverse birth outcomes. Large roadway infrastructure projects present a natural experiment to examine how resulting congestion change is associated with adverse birth outcomes for nearby populations. This study is designed to examine the influence of living close to a roadway before, during, and after a construction project using a difference-in-differences design. We integrated data on all large roadway construction projects (defined as widening of existing roads, building new roads, improving bridges, installing intelligent transportation systems, improving intersections, and installing or upgrading traffic signals) in Texas from 2007 to 2016 with Vital Statistic data for all births with residential addresses within 1 km of construction projects. Our outcomes included term low birth weight, term birth weight, preterm birth, and very preterm birth. Using a difference-in-differences design, we included births within 3 years of construction start and 2 years of construction end. In our main model, the exposed group is limited to pregnant individuals residing within 300 m of a construction project, and the control group includes those living within 300-1000 m from a project. We used regression models to estimate the influence of construction on infant health. We included 1,360 large roadway construction projects linked to 408,979 births. During construction, we found that the odds of term low birth weight increased by 19% (95% CI: 1.05, 1.36). However, we saw little evidence of an association for other birth outcomes. Contrary to our hypothesis of decreased TRAP after construction ends, we did not observe consistent improvements post-construction for pregnant individuals living within 300 m. Continued consideration of the influence of traffic congestion programs on birth outcomes is necessary to inform future policy decisions., Competing Interests: Declaration of competing interest All 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 Authors. Published by Elsevier Inc. All rights reserved.)

This case study explores the strategic decision-making and safety considerations in managing a unique scenario where a pacemaker dependent patient, requiring adjuvant radiotherapy for bilateral breast cancer. The conventional pacemaker was located entirely within the treatment target, without the option for transposition because of the bilateral chest treatment, resulting in significant risk of malfunction caused by exposing it to the full prescribed dose. Consequently, the decision was made to replace the conventional pacemaker with a leadless device Micra implanted directly into the heart to mitigate direct device radiation and potential adverse effects of proton therapy on the cardiac device. Following Micra implantation, the patient underwent the proton treatment without complications or serious device malfunctions. This study explores solutions to address the challenges posed by within-the-field cardiac devices and highlights the use of pencil beam proton therapy for individuals with leadless cardiac devices while acknowledging the potential for neutron production and the associated risk of single-event upsets (SEU) in cardiac implantable electronic devices (CIEDs). The findings underscore the significance of strategic decision-making, risk assessment, and continuous monitoring for successful outcomes, particularly in the context of proton therapy for patients with advanced cardiac considerations., Competing Interests: 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., (© 2024 The Authors.)

The lack of extreme water level fluctuations in managed, non-peat forming wetland ecosystems can result in decreased productivity through the loss of heterogeneity of these ecosystems. Stochastic disruption, such as a water level drawdown, can effectively reverse this effect and return the wetland to a more productive state, associated with higher biodiversity through new vegetation development. Yet, aside from the effect on vegetation dynamics, little is known about longer-term effects (30 years) of a water level drawdown, hereafter referred to as legacy effects, and how this may impact future water level drawdowns. Here, we aim to unravel the legacy effects of a water level drawdown, stand alone and along a water level gradient, on seed bank properties and nutrient availability in a eutrophic clay wetland. To identify these, we studied the hydrologically managed nature reserve Oostvaardersplassen in the Netherlands. Here, one section was subjected to a multi-year water level drawdown and another section was kept inundated. We determined seed bank properties in both areas, spatially and along a soil elevation gradient (20 cm). Nutrient availability was measured by taking sediment samples along the water level gradient and through experimental manipulation of the water level in an indoor mesocosm experiment. Germination was higher in locations with a water level drawdown history, especially at relatively high elevations. Additionally, the proportion of pioneer species in the seed bank was higher in the water level drawdown area. Overall, nutrient concentrations were higher compared to other aquatic systems. Nutrient availability was higher in the inundated area and did not respond to the water level gradient. We conclude that 30 years after an induced water level drawdown there is no depletion of nutrients, while we still observe a legacy effect in the number of viable seeds in the seed bank., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kerstin Bouma reports financial support was provided by Vereniging van Bos- en Natuurterreineigenaren. 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., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

A paraganglioma is a neuroendocrine tumor that may secrete catecholamines and present with symptoms of sympathetic overload such as hypertension and diaphoresis. It is important that paragangliomas are identified, as they must often be treated by surgical excision. IgG4-related retroperitoneal fibrosis (IgG4-RPF) is a systemic inflammatory disease that results in the infiltration of IgG4-positive plasma cells in the retroperitoneum. Such fibrosis may adversely affect nearby organs and tissues. Here, we describe a case of combined paraganglioma and IgG4-RPF in a 47-year-old female patient. This case demonstrates the deleterious effect of these two conditions when they occur simultaneously., (© 2024 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

Immune checkpoint inhibition, with or without chemotherapy, is an established standard of care for metastatic non-small cell lung cancer (NSCLC). For locally advanced NSCLC treated with chemoradiotherapy, consolidation immunotherapy has dramatically improved outcomes. Recently, immunotherapy has also been established as a valuable component of treatment for resectable NSCLC with pembrolizumab, atezolizumab, and nivolumab all approved for use in this setting. As more results read out from ongoing perioperative clinical trials, navigating treatment options will likely become increasingly complex for the practicing oncologist. In this paper, we distill key outcomes from major perioperative trials and highlight current knowledge gaps. In addition, we provide practical considerations for incorporating perioperative immunotherapy into the clinical management of operable NSCLC., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Spontaneous abortion (SAB), defined as a pregnancy loss before 20 weeks of gestation, affects up to 30% of conceptions, yet few modifiable risk factors have been identified. We estimated the effect of ambient air pollution exposure on SAB incidence in Pregnancy Study Online (PRESTO), a preconception cohort study of North American couples who were trying to conceive. Participants completed questionnaires at baseline, every 8 weeks during preconception follow-up, and in early and late pregnancy. We analyzed data on 4643 United States (U.S.) participants and 851 Canadian participants who enrolled during 2013-2019 and conceived during 12 months of follow-up. We used country-specific national spatiotemporal models to estimate concentrations of particulate matter <2.5 μm (PM 2.5 ), nitrogen dioxide (NO 2 ), and ozone (O 3 ) during the preconception and prenatal periods at each participant's residential address. On follow-up and pregnancy questionnaires, participants reported information on pregnancy status, including SAB incidence and timing. We fit Cox proportional hazards regression models with gestational weeks as the time scale to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of time-varying prenatal concentrations of PM 2.5 , NO 2 , and O 3 with rate of SAB, adjusting for individual- and neighborhood-level factors. Nineteen percent of pregnancies ended in SAB. Greater PM 2.5 concentrations were associated with a higher incidence of SAB in Canada, but not in the U.S. (HRs for a 5 μg/m 3 increase = 1.29, 95% CI: 0.99, 1.68 and 0.94, 95% CI: 0.83, 1.08, respectively). NO 2 and O 3 concentrations were not appreciably associated with SAB incidence. Results did not vary substantially by gestational weeks or season at risk. In summary, we found little evidence for an effect of residential ambient PM 2.5 , NO 2 , and O 3 concentrations on SAB incidence in the U.S., but a moderate positive association of PM 2.5 with SAB incidence in Canada., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Lauren A. Wise and Elizabeth E. Hatch reports financial support was provided by National Institute of Environmental Health Sciences. Lauren A. Wise reports a relationship with AbbVie Inc that includes: consulting or advisory. Dr. Lauren Wise serves as a consultant for AbbVie, Inc. and the Gates Foundation. She also receives in-kind donations for primary data collection in Pregnancy Study Online (PRESTO) from Swiss Precision Diagnostics (home pregnancy tests) and Kindara.com (fertility apps). All of these relationships are for work unrelated to this manuscript. The remaining authors report no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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.

Organophosphate ester flame retardants and plasticizers (OPEs) are common exposures in modern built environments. Toxicological models report that some OPEs reduce dopamine and serotonin in the brain. Deficiencies in these neurotransmitters are associated with anxiety and depression. We hypothesized that exposure to higher concentrations of OPEs in house dust would be associated with a greater risk of depression and stress in mothers across the prenatal and postpartum periods. We conducted a nested prospective cohort study using data collected on mothers (n = 718) in the CHILD Cohort Study, a longitudinal multi-city Canadian birth cohort (2008-2012). OPEs were measured in house dust sampled at 3-4 months postpartum. Maternal depression and stress were measured at 18 and 36 weeks gestation and 6 months and 1 year postpartum using the Centre for Epidemiologic Studies for Depression Scale (CES-D) and Perceived Stress Scale (PSS). We used linear mixed models to examine the association between a summed Z-Score OPE index and continuous depression and stress scores. In adjusted models, one standard deviation increase in the OPE Z-score index was associated with a 0.07-point (95% CI: 0.01, 0.13) increase in PSS score. OPEs were not associated with log-transformed CES-D (β: 0.63%, 95% CI: -0.18%, 1.46%). The effect of OPEs on PSS score was strongest at 36 weeks gestation and weakest at 1 year postpartum. We observed small increases in maternal perceived stress levels, but not depression, with increasing OPEs measured in house dust during the prenatal and early postpartum period in this cohort of Canadian women. Given the prevalence of prenatal and postpartum anxiety and the ubiquity of OPE exposures, additional research is warranted to understand if these chemicals affect maternal mental health., 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 © 2023 Elsevier Inc. All rights reserved.)

Background: Atrial fibrillation (AF) is common in patients with hypertrophic cardiomyopathy (HCM) and can be challenging to manage. Atrioventricular nodal (AVN) ablation may be an effective management strategy for AF in these patients., Objective: The purpose of this study was to assess the efficacy of AVN ablation in HCM patients who have failed medical therapy and/or catheter ablation for AF., Methods: A multicenter study with retrospective analysis of a prospectively collated HCM registry was performed. AVN ablation patients were identified. Baseline characteristics and device and procedural indications were collected. Symptoms defined by New York Heart Association and European Heart Rhythm Association classification and echocardiographic findings during follow-up were assessed., Results: Fifty-nine patients were included in the study. Indications for AVN ablation were 6 (10.2%) inappropriate implantable cardioverter-defibrillator shock, 35 (59.3%) ineffective rate control, and 18 (30.5%) to regularize rhythm for symptom improvement. During post-AVN ablation follow-up of 79.4 ± 61.1 months, left ventricular ejection fraction (LVEF) remained stable (pre-LVEF 48.9% ± 12.6% vs post-LVEF 50.1% ± 10.1%; P = .29), even in those without a cardiac resynchronization therapy (CRT) device (pre-LVEF 54.3% ± 8.0% vs post-LVEF 53.8% ± 8.0%; P = .65). Forty-nine patients (83.1%) reported an improvement in symptoms regardless of AF type (17/21 [81.0%] paroxysmal vs 32/38 [84.2%] persistent; P = 1.00), presence of baseline left ventricular impairment (22/26 [84.6%] LVEF ≤50% vs 27/33 [81.8%] LVEF ≥50%; P = 1.00) or CRT device (27/32 [84.4%] CRT vs 22/27 [81.5%] no CRT; P = 1.00). Symptoms improved in 16 patients (89.0%) who underwent AVN ablation to regularize rhythm., Conclusion: AVN ablation improved symptoms without impacting left ventricular function in the majority of patients. The data suggest that AVN ablation is an effective and safe management approach for AF in HCM and should be further evaluated in larger prospective studies., (Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Biliary complications after orthotopic liver transplant (OLT) remain one of the primary causes of morbidity and mortality in liver transplant recipients with an approximate incidence between 5% and 32%. Given the limited supply of hepatic grafts, one of the most feared outcomes as a result of biliary complications is acute and or chronic graft failure. Biliary complications include leaks, biliary stasis, and stone formation, sphincter of Oddi dysfunction, recurrence of biliary disease (primary sclerosing cholangitis and primary biliary cirrhosis), and biliary strictures/obstruction. Overwhelmingly, the most common complication in hepatic transplantation is biliary stricture formation accounting for more than 50%. Currently, the mainstay of therapy as it pertains to biliary strictures/obstruction includes endoscopic retrograde cholangiography-guided therapy, percutaneous transhepatic cholangiography-guided therapy, or surgical revision/retransplantation. We present a case of biliary obstruction in a patient with a second liver transplant complicated by Cocoon Syndrome managed via sharp recanalization of CBD occlusion and placement of an endoscopic biliary Viabil stent., (© 2023 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

Traffic-related air pollution (TRAP) is an established health hazard, and roadway construction has the potential to affect TRAP by relieving congestion. The relationship between roadway construction and congestion is of policy importance, but few studies examine it using large samples of construction projects and detailed traffic and air pollution data. We create a dataset of construction projects in Texas and link them to data on air pollution and three variables operationalizing congestion: average annual daily traffic (AADT), AADT per lane, and delay in hours. We use difference-in-difference methods to estimate the effect of widening and intersection improvements on congestion and air pollution. On average over the period during construction, we find that widening increases delay by 42% (95% CI: 30, 56%), but intersection projects do not affect delay. On average and over the first three years post-construction, we find that widening reduces delay by 33% (95% CI: -41, -24%) and reduces NO 2 levels within 500 m by 13% (95% CI: -22, -2%), and intersection projects reduce delay by 52% (95% CI: -65, -35%) and reduce NO 2 levels within 500 m by 12% (95% CI: -18, -5%). These short-term impacts are relevant for understanding the impact of roadway construction on human health., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Perry Hystad reports financial support was provided by Health Effects Institute., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Ambulatory spinal surgery is a care delivery model meant to improve patient outcomes and reduce in-hospital length of stay (LOS). We reviewed the experience of implementing an outpatient spine surgery program in Manitoba, Canada and highlight elements that can be used to reduce LOS and re-presentation to hospital., Methods: This is a retrospective cohort study using data from the Canadian Spine Outcomes and Research Network and independent chart review of adult patients undergoing outpatient spinal surgery between 2015 and 2018. Patient demographics, comorbidities, perioperative course, LOS, and readmissions were analyzed., Results: We included 217 patients in this analysis. The mean LOS was 36.2 hours; 71.98% of patients had a LOS <24 hours. A Kruskal-Wallis test by ranks analysis was conducted and identified 7 elements that correlated with prolonged length of stay (>1 day): age older than 55 (P = 0.027), body mass index >25 (P = 0.045), uncontrolled diabetes (P = 0.015), preoperative use of opioid medication (P = 0.024), American Society of Anesthesiologists classification of 3 (P = 0.023), non-minimally invasive surgical approach, and multilevel procedures. Most (94.1%) of the patients with none of these elements (i.e., age <55, low body mass index, normal/controlled diabetes, minimal preoperative opioid use, American Society of Anesthesiologist classification <3, minimally invasive surgical procedure) had a favorable LOS, <24 hours, compared with 84.8% with 1 risk factor, 80.4% of those with two, 69.8% with three, 53.1% with four, and 31.2% with 5 or more. A small number of patients (14.98%) presented to an emergency department within 90 days of their operation, and there was a 6.28% readmission rate., Conclusions: We identified several patient and surgical criteria that correlate with prolonged length of stays following planned ambulatory spine surgery. Our work provides some empiric evidence to help guide surgeons on which patients and approaches are ideal for ambulatory surgery., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To describe the gross and ultrasound anatomy of the parasacral region and an ultrasound-guided greater ischiatic notch (GIN) plane approach aimed at staining the lumbosacral trunk (LST) in canine cadavers. To evaluate if the ultrasound-guided GIN plane approach is non-inferior to the previously described ultrasound-guided parasacral approach at staining the LST., Study Design: Prospective, randomized, non-inferiority experimental anatomic study., Animals: A total of 17 (23.9 ± 5.2 kg) mesocephalic canine cadavers., Methods: Anatomic and echographic landmarks, and the feasibility of performing a GIN plane technique were evaluated using two canine cadavers. The remaining 15 cadavers had each hemipelvis randomly assigned to be administered either parasacral or GIN plane injection of 0.15 mL kg -1 dye solution. The parasacral region was dissected after injections to assess the staining of LST, cranial gluteal nerve, pararectal fossa and pelvic cavity. The stained LST were removed and processed for histological evaluation of intraneural injections. A one-sided z-test for non-inferiority (non-inferiority margin -14%) was used to statistically evaluate the success of the GIN plane versus the parasacral approach. Data were considered statistically significant when p < 0.05., Results: The GIN plane and parasacral approach stained the LST in 100% and 93.3% of the injections, respectively. The success rate difference between treatments was 6.7% [95% confidence interval, -0.6 to 19.0%; p < 0.001 for non-inferiority]. The GIN plane and parasacral injections stained the LST for 32.7 ± 16.8 mm and 43.1 ± 24.3 mm, respectively (p = 0.18). No evidence of intraneural injection was found., Conclusions and Clinical Relevance: The ultrasound-guided GIN plane technique resulted in nerve staining that was non-inferior to the parasacral technique and may be considered an alternative to the parasacral approach to block the LST in dogs., (Copyright © 2023 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Dual-mobility total hip arthroplasties were developed to decrease the risk of dislocation and instability seen with traditional fixed-bearing total hip arthroplasties. However, dual-mobility constructs, notably the first-generation design, come with a risk of intraprosthetic dislocation (IPD). These dislocations occur when the polyethylene femoral head component is dislodged, causing direct articulation between the inner ceramic femoral head and the metal acetabular shell. This is different than a polyethylene liner dislocation in a standard total hip arthroplasty. Causes of IPD include polyethylene wear and iatrogenic dislocation from closed reduction attempts. Timely identification is essential to reduce the risk of soft tissue metallosis, raised cobalt and chromium levels, and the need for major revisions. This complication can be seen on imaging, but radiologists must be aware of the various components and mechanisms of failure to recognize this unique complication. We present a case of a dual-mobility construct with IPD between the femoral head components, illustrated on radiographs and CT and subsequently confirmed at the time of surgery., (© 2023 The Authors.)

Bisphenol A (BPA) is a synthetic chemical to which humans are exposed through a variety of environmental sources. We have conducted a comprehensive, systematic review of 29 epidemiology studies and 27 experimental animal studies, published through May 2022, evaluating the potential carcinogenicity of BPA to contribute to the understanding of whether BPA is carcinogenic in humans. We conducted this review according to best practices for systematic reviews and incorporating established frameworks for study quality evaluation and evidence integration. The epidemiology studies have many limitations that increase the risk of biased results, but overall, the studies do not provide clear and consistent evidence for an association between BPA exposure and the development of any type of cancer. The experimental animal studies also do not provide strong and consistent evidence that BPA is associated with the induction of any malignant tumor type. Some of the proposed mechanisms for BPA carcinogenicity are biologically plausible, but the relevance to human exposures is not clear. We conclude that there is inadequate evidence to support a causal relationship between BPA exposure and human carcinogenicity, based on inadequate evidence in humans, as well as evidence from experimental animal studies that suggests a causal relationship is not likely., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All of the authors are employees of Gradient, an independent environmental and risk science consulting firm. The work reported in this paper was conducted during the normal course of employment. Two of the authors (JEG and RLP) have previously provided consulting on BPA-related issues and have given testimony on topics related to BPA at meetings with regulatory agencies, with funding provided by the American Chemistry Council (ACC). All other authors declare that they have not been involved in any regulatory activities related to the contents of this paper. This manuscript is the professional work product of the authors, and the opinions and conclusions offered within are not necessarily those of their employers or the financial sponsor of the work., (Copyright © 2023 Gradient. Published by Elsevier Inc. All rights reserved.)

Low haemoglobin (Hb) concentrations and anaemia in children have adverse effects on development and functioning, some of which may have consequences in later life. Exposure to ambient air pollution is reported to be associated with anaemia, but there is little evidence specific to low- and middle-income countries (LMICs), where childhood anaemia prevalence is greatest. We aimed to determine if long-term ambient fine particulate matter (≤2.5 μm in aerodynamic diameter [PM 2.5 ]) exposure was associated with Hb levels and the prevalence of anaemia in children aged <5 years living in 36 LMICs. We used Demographic and Health Survey data, collected between 2010 and 2019, which included blood Hb measurements. Satellite-derived estimates of annual average PM 2.5 was the main exposure variable, which was linked to children's area of residence. Anaemia was defined according to standard World Health Organization guidelines (Hb < 11 g/dL). The association of PM 2.5 with Hb levels and anaemia prevalence was examined using multivariable linear and logistic regression models, respectively. We examined whether the effects of ambient PM 2.5 were modified by a child's sex and age, household wealth index, and urban/rural place of residence. Models were adjusted for relevant covariates, including other outdoor pollutants and household cooking fuel. The study included 154,443 children, of which 89,904 (58.2%) were anaemic. The country-level prevalence of anaemia ranged from 15.8% to 87.9%. Mean PM 2.5 exposure was 33.0 (±21.6) μg/m 3 . The adjusted model showed that a 10 μg/m 3 increase in annual PM 2.5 concentration was associated with greater odds of anaemia (OR = 1.098 95% CI: 1.087, 1.109). The same increase in PM 2.5 was associated with a decrease in average Hb levels of 0.075 g/dL (95% CI: 0.081, 0.068). There was evidence of effect modification by household wealth index and place of residence, with greater adverse effects in children from lower wealth quintiles and children in rural areas. Exposure to annual PM 2.5 was cross-sectionally associated with decreased blood Hb levels, and greater risk of anaemia, in children aged <5 years living in 36 LMICs., 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 © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: This study seeks to estimate the potential societal economic impact of treating patients with heart valve disease (HVD) in China with surgical tissue valve replacement versus mechanical valves., Methods: This societal economic cost-benefit evaluation is based on an individual simulation model for subgroups of patients with HVD that is also aggregated to a macrosocietal model. The individual simulation model was developed to estimate the likely economic impact of surgical aortic valve replacement (SAVR) with tissue versus mechanical valves for different subgroups among all eligible patients with HVD over their remaining lifetimes. Clinical inputs were informed by health claims database analysis, expert clinical opinion, and published literature. Epidemiological inputs and demographic inputs were sourced from the published literature and the China Statistical Yearbook 2020. Health gains were valued at 3 times the average national income., Results: Projected total lifetime economic gains were greater for patients receiving tissue valves. Costs were reported in 2021 US dollars. The average lifetime net economic gain for tissue valve patients was $51 736 (20.0% more than for mechanical valve patients). Increasing the use of tissue valves to 50% among all eligible patients with HVD would provide aggregate long-term economic gains of $167 billion during their remaining lifetimes. The economic gains from greater tissue valve use were due to avoiding anticoagulation monitoring costs, improved quality of life, and greater post-SAVR labor force participation., Conclusion: Increased use of tissue valves versus mechanical values in SAVR procedures in China would be likely to generate a substantial societal economic gain., (Copyright © 2023 International Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Background: The microbiome-gut-brain-axis (MGBA) is emerging as an important mechanistic link between diet and mental health. The role of significant modifiers of the MGBA, including gut microbial metabolites and systemic inflammation, in individuals comorbid with obesity and mental disorders, is under-investigated., Objectives: This exploratory analysis examined associations among microbial metabolites-fecal SCFAs, plasma inflammatory cytokines, and diet with depression and anxiety scores in adults comorbid with obesity and depression., Methods: Stool and blood were obtained from a subsample (n = 34) of participants enrolled in an integrated behavioral intervention for weight loss and depression. Pearson partial correlation and multivariate analyses determined associations among changes in fecal SCFAs (propionic, butyric, acetic, and isovaleric acids), plasma cytokines [C-reactive protein, interleukin 1 beta, interleukin 1 receptor antagonist (IL-1RA), interleukin 6, and TNF-α], and 35 dietary markers over 2 mo, and changes in SCL-20 (Depression Symptom Checklist 20-item) and GAD-7 (Generalized Anxiety Disorder 7-Item) scores over 6 mo., Results: Changes in the SCFAs and TNF-α at 2 mo were positively associated (standardized coefficients: 0.06-0.40; 0.03-0.34) with changes in depression and anxiety scores at 6 mo, whereas changes in IL-1RA at 2 mo were inversely associated (standardized coefficients: -0.24; -0.05). After 2 mo, changes in 12 dietary markers, including animal protein, were associated with changes in SCFAs, TNF-α, or IL-1RA at 2 mo (standardized coefficients: -0.27 to 0.20). Changes in 11 dietary markers, including animal protein, at 2 mo were associated with changes in depression or anxiety symptom scores at 6 mo (standardized coefficients: -0.24 to 0.20; -0.16 to 0.15)., Conclusions: Gut microbial metabolites and systemic inflammation may be biomarkers of importance within the MGBA, linking dietary markers, such as animal protein intake, to depression and anxiety for individuals with comorbid obesity. These findings are exploratory and warrant replication., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Objective: Transpulmonary ultrasound dilution (TPUD) is a minimally invasive technique to measure cardiac output (CO) using a 1 mL kg -1 isotonic 37 °C saline injectate indicator. The objective was to evaluate the performance of TPUD using a room temperature saline injectate., Study Design: Prospective experimental trial., Animals: A total of seven anesthetized male Yorkshire piglets., Methods: Piglets aged 1 month and weighing 7.7-9.0 kg were anesthetized with detomidine-ketamine-hydromorphone-isoflurane and a pulmonary artery flow probe (PAFP) placed via a median sternotomy. The thoracic cavity remained open during measurement of CO by PAFP and TPUD. The TPUD indicators of 1 mL kg -1 0.9% saline at 37 °C and 20 °C were compared during infusions of phenylephrine and dobutamine, blood withdrawal and replacement. Bias, limits of agreement (LoAs) and percentage error (PE) between each iteration of PAFP and TPUD were measured with Bland-Altman plots. Trending ability via concordance, angular bias and radial LoA were compared., Results: Bland-Altman plots showed negligible bias with varying LoAs. PEs of 22% and 38% were found for 37 °C and 20 °C saline injectates, respectively. In the four-quadrant plots, the concordance rate was 94% and 100% for measurements obtained with 37 °C and 20 °C saline injectates, respectively. Angular bias for both were < ±5 °, with radial LoA < ±7 °., Conclusions: TPUD was accurate when using 1 mL kg -1 of isotonic saline at 37 °C in a range of CO within 0.2-0.8 L minute -1 , and it reliably tracked positive and negative changes in CO. Room temperature (20 °C) indicator was less accurate but equally able to track direction of changes in CO., Clinical Relevance: The use of room temperature injectates allows an easy, readily available clinical application of TPUD CO monitoring while preserving the trending ability of the monitor., (Copyright © 2022 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Background: Considering diversity, equity, and inclusion (DEI) in clinical trials ensures that data collected for investigational treatments reflect the populations most likely to benefit from those therapies. Resources and recommendations regarding DEI were assembled by the trial sponsor to assist clinical trial development., Methods: A cross-disciplinary team from the sponsoring organization was assembled to inform trial planning and collate resources that promote DEI throughout the clinical trial life cycle., Results: Representatives from clinical operations, health economic outcomes research, medical affairs, patient advocacy, procurement, and research and development functional groups united together to implement DEI strategies in clinical trials. Planning strategies focus on eligibility, participant/patient engagement, feedback through patient advocacy organizations, and community interactions. Informed site, investigator, and vendor selection at trial startup supports efforts to recruit diverse target trial populations and engage underrepresented businesses; establishing relationships and demographic target-goal tracking should be maintained throughout trial management. Continued communication during trial closeout consolidates learnings and enhances partnerships with trial participants and patient advocacy organizations. The sponsoring organization continuously updates an internal library of resources to facilitate implementation of outlined strategies., Conclusions: This first iteration of guidance intends to improve the representation of target populations who will ultimately benefit from investigational therapies; to assist sponsor clinical trial teams in developing recruitment and retention plans; and to ensure compliance with federal granting agencies. The sponsoring organization anticipates data from future clinical trials will help characterize the impact of these initiatives to ensure evidence-based practices are used in future clinical trials to enhance DEI., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors are employees of Cerevel Therapeutics and may hold stock or stock options in the company., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Infective endocarditis and cardiac implantable electronic device infection (CIEDI) have witnessed an increasing incidence in clinical practice and associated with increasing health care expenditure. Expanding indications of CIED in various cardiovascular conditions have also contributed to the surge of these infections. Early diagnosis of these infections is associated with a favorable prognosis. Given the lack of a single definitive diagnostic method and the limitations of echocardiography, which is considered a central diagnostic imaging modality, additional imaging modalities are required. Recent studies have highlighted the diagnostic utility of FDG PET and CT. In this review article, we discuss the existing limitations of echocardiography, acquisition protocols of PET/CT, and indications of these advanced imaging modalities in infective endocarditis and CIEDI diagnosis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: DNA cytosine nucleotide methylation (epigenomics and epigenetics) is an important mechanism for controlling gene expression in cardiac development. Combined artificial intelligence and whole-genome epigenomic analysis of circulating cell-free DNA in maternal blood has the potential for the detection of fetal congenital heart defects., Objective: This study aimed to use genome-wide DNA cytosine methylation and artificial intelligence analyses of circulating cell-free DNA for the minimally invasive detection of fetal congenital heart defects., Study Design: In this prospective study, whole-genome cytosine nucleotide methylation analysis was performed on circulating cell-free DNA using the Illumina Infinium MethylationEPIC BeadChip array. Multiple artificial intelligence approaches were evaluated for the detection of congenital hearts. The Ingenuity Pathway Analysis program was used to identify gene pathways that were epigenetically altered and important in congenital heart defect pathogenesis to further elucidate the pathogenesis of isolated congenital heart defects., Results: There were 12 cases of isolated nonsyndromic congenital heart defects and 26 matched controls. A total of 5918 cytosine nucleotides involving 4976 genes had significantly altered methylation, that is, a P value of <.05 along with ≥5% whole-genome cytosine nucleotide methylation difference, in congenital heart defect cases vs controls. Artificial intelligence analysis of the methylation data achieved excellent congenital heart defect predictive accuracy (areas under the receiver operating characteristic curve, ≥0.92). For example, an artificial intelligence model using a combination of 5 whole-genome cytosine nucleotide markers achieved an area under the receiver operating characteristic curve of 0.97 (95% confidence interval, 0.87-1.0) with 98% sensitivity and 94% specificity. We found epigenetic changes in genes and gene pathways involved in the following important cardiac developmental processes: "cardiovascular system development and function," "cardiac hypertrophy," "congenital heart anomaly," and "cardiovascular disease." This lends biologic plausibility to our findings., Conclusion: This study reported the feasibility of minimally invasive detection of fetal congenital heart defect using artificial intelligence and DNA methylation analysis of circulating cell-free DNA for the prediction of fetal congenital heart defect. Furthermore, the findings supported an important role of epigenetic changes in congenital heart defect development., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: When treating esophageal cancer with radiation therapy, it is critical to limit the dose to surrounding structures, such as the lung and/or heart, as much as possible. Proton radiation therapy allows a reduced radiation dose to both the heart and lungs, potentially reducing the risk of cardiopulmonary toxicity. Here, we report disease control, survival, and toxicity outcomes among patients with esophageal cancer treated with proton radiation therapy and concurrent chemotherapy (chemoradiation therapy; CRT) with or without surgery., Materials and Methods: We enrolled 17 patients with thoracic esophageal carcinoma on a prospective registry between 2010 and 2021. Patients received proton therapy to a median dose of 50.4-GyRBE (range, 50.4-64.8) in 1.8-Gy fractions.Acute and late toxicities were graded per the Common Terminology Criteria for Adverse Events, version 4.0 (US National Cancer Institute, Bethesda, Maryland). In addition, disease control, patterns of failure, and survival outcomes were collected., Results: Nine patients received preoperative CRT, and 8 received definitive CRT. Overall, 88% of patients had adenocarcinoma, and 12% had squamous cell carcinoma. With a median follow-up of 2.1 years (range, 0.5-9.4), the 3-year local progression-free, disease-free, and overall survival rates were 85%, 66%, and 55%, respectively. Two patients (1 with adenocarcinoma and 1 with squamous cell carcinoma) recurred at the primary site after refusing surgery after a complete clinical response to CRT. The most common acute nonhematologic and hematologic toxicities, respectively, were grades 1 to 3 esophagitis and grades 1 to 4 leukopenia, both affecting 82% of patients. No acute cardiopulmonary toxicities were observed in the absence of surgical resection. Reagarding surgical complications, 3 postoperative cardiopulmonary complications occurred as follows: 1 grade 1 pleural effusion, 1 grade 3 pleural effusion, and 1 grade 2 anastomotic leak. Two severe late CRT toxicities occurred: 1 grade 5 tracheoesophageal fistula and 1 grade 3 esophageal stenosis requiring a feeding tube., Conclusion: Proton radiation therapy is a safe, effective treatment for esophageal cancer with increasing evidence supporting its role in reducing cardiopulmonary toxicity., Competing Interests: Conflicts of Interest: Bradford Hoppe, MD, MPH, and Perry Johnson, PhD, are Associate Editors of the International Journal of Particle Therapy. All other authors have no relevant conflicts of interest to disclose., (©Copyright 2022 The Author(s).)

Background: Emraclidine is a novel, brain-penetrant, highly selective M4 receptor positive allosteric modulator in development for the treatment of schizophrenia. We aimed to evaluate the safety and tolerability of multiple ascending doses of emraclidine in patients with schizophrenia., Methods: We conducted a two-part, randomised, phase 1b trial in the USA. Eligible participants were aged 18-50 years (part A) or 18-55 years (part B) with a primary diagnosis of schizophrenia per the Diagnostic and Statistical Manual of Mental Disorders 5th edition, as confirmed by the Mini International Neuropsychiatric Interview, and extrapyramidal symptom assessments indicating normal to mild symptoms at screening. Part A evaluated the safety and tolerability of emraclidine in five cohorts of participants with stable schizophrenia who received ascending oral doses of emraclidine 5-40 mg (40 mg was administered as 20 mg twice daily) or placebo at a single US site. Part B was a double-blind, randomised, placebo-controlled study that enrolled adults with acute schizophrenia across five US sites; participants were randomly assigned (1:1:1) to receive emraclidine 30 mg once daily, emraclidine 20 mg twice daily, or placebo for 6 weeks (doses established in part A). The primary endpoint was safety and tolerability, assessed in the safety population (participants who received at least one dose of emraclidine or placebo). This trial is now complete and is registered with ClinicalTrials.gov, NCT04136873., Findings: Between Sept 23, 2019, and Sept 17, 2020, 118 patients were assessed for eligibility and 49 were randomly assigned across five cohorts in part A. 44 participants completed the study, with 36 participants receiving emraclidine and eight receiving placebo. The two highest doses tested were selected for part B. Between Oct 12, 2020, and May 7, 2021, 148 patients were assessed for eligibility and 81 were randomly assigned to emraclidine 30 mg once daily (n=27), emraclidine 20 mg twice daily (n=27), or placebo (n=27) in part B. Incidence of adverse events (14 [52%] of 27 participants in the emraclidine 30 mg once daily group, 15 [56%] of 27 in the emraclidine 20 mg twice daily group, and 14 [52%] of 27 in the placebo group), clinical assessments, and weight changes were similar across groups. The most common adverse event was headache (15 [28%] of 54 participants in the emraclidine groups, seven [26%] of 27 in the placebo group). Modest, transient increases in blood pressure and heart rate in emraclidine groups observed at treatment initiation diminished over time and were not considered clinically meaningful by week 6., Interpretation: These data support further investigation of emraclidine as a once-daily treatment for schizophrenia without need for titration and with a potentially favourable side-effect profile., Funding: Cerevel Therapeutics., Competing Interests: Declaration of interests JHK reports consulting agreements with Aptinyx, Atai Life Sciences, AstraZeneca, Biogen Idec, Biomedisyn Corporation, Bionomics, Boehringer Ingelheim International, Cadent Therapeutics, Clexio Bioscience, COMPASS Pathways, Concert Pharmaceuticals, Eisai, Epiodyne, EpiVario, Greenwich Biosciences, Heptares Therapeutics, Janssen Research & Development, Jazz Pharmaceuticals, Lohocla Research Corporation, Novartis, Otsuka America Pharmaceutical, Perception Neuroscience Holdings, PsychoGenics, RBNC Therapeutics, Spring Care, Sunovion Pharmaceuticals, Taisho Pharmaceutical Holdings, Takeda Industries, Tempero Bio, and Terran Biosciences; serves on the scientific advisory boards of Biohaven Pharmaceuticals, BioXcel Therapeutics (Clinical Advisory Board), Cadent Therapeutics (Clinical Advisory Board), and Cerevel Therapeutics; holds consulting agreements with EpiVario, Eisai, Jazz Pharmaceuticals, Lohocla Research Corporation, Novartis, PsychoGenics, RBNC Therapeutics, Tempero Bio, and Terran Biosciences; serves on the Board of Directors for Freedom Biosciences and holds stock or stock options in Biohaven Pharmaceuticals, Sage Pharmaceuticals, Spring Care, Biohaven Pharmaceuticals Medical Sciences, EpiVario, RBNC Therapeutics, Terran Biosciences, and Tempero Bio; has received research support from AstraZeneca, Novartis, and Cerevel Therapeutics; and serves as Editor of Biological Psychiatry and is a named inventor on a number of patents and patent applications—most recently, US Provisional Patent Application 63/125,181, filed on Dec 14, 2020. JMK has been a consultant or adviser to or has received honoraria from Acadia, Alkermes, Allergan, Cerevel Therapeutics, IntraCellular Therapies, Janssen or Johnson & Johnson, Karuna, LB Pharma, Lundbeck, Lyndra, Medscape, Merck, Neurocrine, Otsuka, Reviva, Roche, Sumitomo Dainippon, Saladex, Sunovion, Takeda, and Teva; has received grant support from Janssen, Lundbeck, Otsuka, and Sunovion; and is a shareholder of LB Pharma and a shareholder in Vanguard Research Group. CUC has been a consultant or adviser to or has received honoraria from AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Axsome Therapeutics, Cerevel Therapeutics, Compass, Damitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen or Johnson & Johnson, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Medscape, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Segirus, Servier, SK Life Science, Sumitomo Dainippon, Sunovion, Supernus, Takeda, Teva, and Viatris; has provided expert testimony for Janssen and Otsuka; has served on a Data Safety Monitoring Board for Lundbeck, Rovi, Supernus, and Teva; has received grant support from Janssen and Takeda; and has received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, and LB Pharma. DPW reports grants and research support from AbbVie, Acadia, Alkermes, Allergan, Avanir, Biogen, Boehringer Ingelheim, Cerevel, Indivior, IntraCellular, Janssen, Johnson & Johnson Research and Development, Lundbeck, Lupin, Lyndra, Novartis, Noven, Otsuka, Pfizer, Roche, Sunovion, and Takeda; has been a consultant for Biogen, Boehringer Ingelheim, Janssen, Lyndra, and Otsuka; and served as principal investigator on this trial. ML, SD, SP, IC, PI, LF, SV, PP, RS, and JR are employees of Cerevel Therapeutics and might hold stock or stock options in the company., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Competing Interests: Declaration of interests We declare no competing interests.

Greenspace may benefit sleep by enhancing physical activity, reducing stress or air pollution exposure. Studies on greenspace and children's sleep are limited, and most use satellite-derived measures that do not capture ground-level exposures that may be important for sleep. We examined associations of street view imagery (SVI)-based greenspace with sleep in Project Viva, a Massachusetts pre-birth cohort. We used deep learning algorithms to derive novel metrics of greenspace (e.g., %trees, %grass) from SVI within 250m of participant residential addresses during 2007-2010 (mid-childhood, mean age 7.9 years) and 2012-2016 (early adolescence, 13.2y) (N = 533). In early adolescence, participants completed >5 days of wrist actigraphy. Sleep duration, efficiency, and time awake after sleep onset (WASO) were derived from actigraph data. We used linear regression to examine cross-sectional and prospective associations of mid-childhood and early adolescence greenspace exposure with early adolescence sleep, adjusting for confounders. We compared associations with satellite-based greenspace (Normalized Difference Vegetation Index, NDVI). In unadjusted models, mid-childhood SVI-based total greenspace and %trees (per interquartile range) were associated with longer sleep duration at early adolescence (9.4 min/day; 95%CI:3.2,15.7; 8.1; 95%CI:1.7,14.6 respectively). However, in fully adjusted models, only the association between %grass at mid-childhood and WASO was observed (4.1; 95%CI:0.2,7.9). No associations were observed between greenspace and sleep efficiency, nor in cross-sectional early adolescence models. The association between greenspace and sleep differed by racial and socioeconomic subgroups. For example, among Black participants, higher NDVI was associated with better sleep, in neighborhoods with low socio-economic status (SES), higher %grass was associated with worse sleep, and in neighborhoods with high SES, higher total greenspace and %grass were associated with better sleep time. SVI metrics may have the potential to identify specific features of greenspace that affect sleep., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Gallbladder cancer (GBC) is an aggressive malignancy associated with a high risk of recurrence and mortality. We used a machine-based learning approach to stratify patients into distinct prognostic groups using preperative variables., Methods: Patients undergoing curative-intent resection of GBC were identified using a multi-institutional database. A classification and regression tree (CART) was used to stratify patients relative to overall survival (OS) based on preoperative clinical factors., Results: CART analysis identified tumor size, biliary drainage, carbohydrate antigen 19-9 (CA19-9) levels, and neutrophil-lymphocyte ratio (NLR) as the factors most strongly associated with OS. Machine learning cohorted patients into four prognostic groups: Group 1 (n = 109): NLR ≤1.5, CA19-9 ≤20, no drainage, tumor size <5.0 cm; Group 2 (n = 88): NLR >1.5, CA19-9 ≤20, no drainage, tumor size <5.0 cm; Group 3 (n = 46): CA19-9 >20, no drainage, tumor size <5.0 cm; Group 4 (n = 77): tumor size <5.0 cm with drainage OR tumor size ≥5.0 cm. Median OS decreased incrementally with CART group designation (59.5, 27.6, 20.6, and 12.1 months; p < 0.0001)., Conclusions: A machine-based model was able to stratify GBC patients into four distinct prognostic groups based only on preoperative characteristics. Characterizing patient prognosis with machine learning tools may help physicians provide more patient-centered care., (Copyright © 2022 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Pregnancy is a sensitive time for maternal cardiovascular functioning and exposures to arsenic or manganese may adversely affect blood pressure (BP)., Objectives: This study examined the associations between arsenic and manganese exposures and maternal BP measured during pregnancy. Effect modification by pre-pregnancy body mass index (BMI) was evaluated., Methods: Pregnant women (N = 1522) were recruited for a prospective cohort study in Bangladesh (2008-2011). Exposure to arsenic and manganese was measured in drinking water at <16 weeks gestation and toenails at one-month postpartum. Systolic and diastolic BP were measured monthly. Linear mixed models estimated mean BP and differences in mean BP over gestation for arsenic or manganese exposures and adjusted for covariates., Results: Arsenic levels had an increasing dose-response association with maternal BP after 25 weeks gestation. Effect modification was observed for BMI. Participants with lower BMI (<23 kg/m 2 ) exposed to 50 μg/L arsenic had 2.83 mmHg (95% CI:1.74-3.92) greater mean systolic and 1.96 mmHg (95% CI: 1.02-2.91 mmHg) diastolic BP compared to those exposed to ≤ 1 μg/L arsenic at 40 weeks gestation. Participants with higher BMI (≥23 kg/m 2 ) showed a greater mean systolic BP of 5.72 mmHg (95% CI: 3.18-8.27 mmHg) and diastolic BP change of 6.09 mmHg (95% CI: 4.02-8.16 mmHg) at 40 weeks gestation when exposed to 50 μg/L compared to ≤ 1 μg/L arsenic. Participants with lower BMI exposed to drinking water manganese in the 2nd quartile (181-573 μg/L) had 1.04 mmHg higher mean diastolic BP (95% CI: 0.01-2.07 mmHg) at 40 weeks gestation compared to those in the 1st quartile (0.5-180 μg/L)., Conclusion: Arsenic exposures during pregnancy were consistently associated with increased average maternal systolic and diastolic BP. The effect of manganese on BP was less consistent., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Household air pollution (HAP) from cooking with solid fuels has been associated with adverse respiratory effects, but most studies use surveys of fuel use to define HAP exposure, rather than on actual air pollution exposure measurements., Objective: To examine associations between household and personal fine particulate matter (PM 2.5 ) and black carbon (BC) measures and respiratory symptoms., Methods: As part of the Prospective Urban and Rural Epidemiology Air Pollution study, we analyzed 48-h household and personal PM 2.5 and BC measurements for 870 individuals using different cooking fuels from 62 communities in 8 countries (Bangladesh, Chile, China, Colombia, India, Pakistan, Tanzania, and Zimbabwe). Self-reported respiratory symptoms were collected after monitoring. Associations between PM 2.5 and BC exposures and respiratory symptoms were examined using logistic regression models, controlling for individual, household, and community covariates., Results: The median (interquartile range) of household and personal PM 2.5 was 73.5 (119.1) and 65.3 (91.5) μg/m 3 , and for household and personal BC was 3.4 (8.3) and 2.5 (4.9) x10 -5  m -1 , respectively. We observed associations between household PM 2.5 and wheeze (OR: 1.25; 95%CI: 1.07, 1.46), cough (OR: 1.22; 95%CI: 1.06, 1.39), and sputum (OR: 1.26; 95%CI: 1.10, 1.44), as well as exposure to household BC and wheeze (OR: 1.20; 95%CI: 1.03, 1.39) and sputum (OR: 1.20; 95%CI: 1.05, 1.36), per IQR increase. We observed associations between personal PM 2.5 and wheeze (OR: 1.23; 95%CI: 1.00, 1.50) and sputum (OR: 1.19; 95%CI: 1.00, 1.41). For household PM 2.5 and BC, associations were generally stronger for females compared to males. Models using an indicator variable of solid versus clean fuels resulted in larger OR estimates with less precision., Conclusions: We used measurements of household and personal air pollution for individuals using different cooking fuels and documented strong associations with respiratory symptoms., (Copyright © 2022. Published by Elsevier Inc.)

Background: Primary laterality of colorectal cancer is thought to be associated with differences in outcomes. Liver metastasis is the most common site of solitary colorectal cancer spread. However, how primary colorectal cancer laterality affects outcomes in colorectal liver metastasis remains unclear., Methods: The Colorectal Liver Operative Metastasis International Collaborative (COLOMIC) of operative hepatectomy cases for colorectal liver metastasis was compiled from five participating institutions. This included consecutive cases from 2000 to 2018 at all sites. A total of 884 patients were included in this study. Univariate, multivariate, and Kaplan-Meier analyses were performed., Results: Patients with left-sided versus right-sided cancers had significantly better overall survival: 49.4 vs. 41.8 months (p < 0.05). Patients with KRAS mutations had significantly worse median overall survival compared to KRAS wild-type (43.6 vs 56.1 months; p < 0.001). In left-sided cancers, KRAS mutations were associated with significantly worse median overall survival compared to KRAS wild-type cancers (43.6 vs 56.6 months; p < 0.01). This association was absent in patients with right-sided primary tumors. Multivariate Cox regression analysis revealed different variable sets (non-overlapping) were associated with overall survival, when comparing left-sided and right-sided cancers., Conclusion: Understanding how primary tumor laterality and related biological aspects affect long-term outcomes can potentially inform treatment decisions for patients with colorectal liver metastases., (Copyright © 2022 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Lipid monitoring is recommended by treatment guidelines to assess efficacy and adherence to lipid lowering therapy, but the available data is mostly limited to integrated health delivery systems with less diverse populations., Objective: To determine the proportion of patients that completed appropriate lipid monitoring at an urban academic medical center and whether lipid monitoring is associated with treatment intensification., Methods: Adults prescribed ≥1 LDL-C lowering therapy and with ≥1 outpatient encounter during 2018 and 2019 were included. Appropriate lipid monitoring was defined as ≥1 lipid panel obtained during the 12 month follow up period. Treatment intensification was defined as a dose increase, change to a higher intensity statin, or addition of a new LDL-C lowering therapy. The association between lipid monitoring and treatment intensification were assessed using regression models., Results: Of the 12,332 patients on LDL-C lowering therapy, 88% had ≥1 lipid panel. The average patient was 60 years of age, 50% were female, and 50% identified as black or African American. On regression analysis (odds ratio [OR], 95% confidence interval [CI]), lipid monitoring occurred less frequently in adults >75 years of age (0.63, 0.44 to 0.90), black or African American individuals (0.78, 0.69 to 0.89), and those insured by Medicaid (0.72, 0.61 to 0.86). The odds of treatment intensification steadily increased with the number of lipid panels compared to those without lipid monitoring., Conclusion: Lipid monitoring is associated with treatment intensification but occurs less frequently in adults >75 years of age, black or African American individuals, and those insured by Medicaid., (Copyright © 2022. Published by Elsevier Inc.)