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Stephanie H Noh,1– 3 Andrew K Smith,1– 3 Austin R Fox,1– 3 Kevin M Gustafson,1– 3 Changyow C Kwan,1– 3 Ken Y Lin,1,2,4 Sameh Mosaed1,2 1University of California, Irvine School of Medicine, Irvine, CA, 92617, USA; 2Gavin Herbert Eye Institute, Department of Ophthalmology, UC Irvine, Irvine, CA, 92617, USA; 3Tibor Rubin Veteran Affairs Medical Center, Long Beach, CA, 90822, USA; 4Department of Biomedical Engineering, UC Irvine, Irvine, CA, 92617, USACorrespondence: Stephanie H Noh, Gavin Herbert Eye Institute, University of California, Irvine, USA, 850 Health Sciences Road, Irvine, CA, 92617, USA, Tel +1-951-751-7971, Fax +1-949-824-2073, Email shnoh1@hs.uci.eduPurpose: To compare outcomes of ab-interno canaloplasty and trabeculotomy of the superior versus inferior angle.Patients and methods: This was a prospective, non-randomized, interventional comparison study done at the Veteran Affairs Hospital in Long Beach, California. All patients underwent cataract surgery with intraocular lens implantation combined with ab-interno canaloplasty and trabeculotomy with the OMNI Surgical System (SightSciences, Menlo Park, CA, USA), either superiorly or inferiorly. Pre- and post-operative intraocular pressure using Goldmann applanation tonometry and best corrected visual acuity were obtained and compared using paired t-tests. Patients were excluded if they had any prior intraocular surgery or prior laser trabeculoplasty procedures.Results: 38 eyes from 29 patients were analyzed. 19 eyes were included in the superior group and 19 eyes in the inferior group. Mean pre-operative IOP in the superior group was 17.6 ± 5.2 mmHg and in the inferior group was 17.6 ± 4.6 mmHg (p > 0.99). At 12 months, mean postoperative IOP for the superior group decreased 24% to 13.3 ± 2.8 mmHg while the inferior group decreased 26% to 13.1 ± 2.2 mmHg (p = 0.92). Mean preoperative medications in the superior group were 2.2 ± 1.3 and in the inferior group was 2.4 ± 1.3 (p = 0.88). At 12 months, this decreased to 1.3 ± 1.5 post-operatively in the superior group and 2.2 ± 1.6 post-operatively in the inferior group (p = 0.64).Conclusion: There was no statistical difference in efficacy between superior versus inferior canaloplasty/trabeculotomy with OMNI. Therefore, surgeons can perform the procedure in the direction that is most comfortable for them without affecting outcomes.Keywords: OMNI, canaloplasty, trabeculotomy, goniotomy, MIGS

Andrew K Smith,1– 3 Changyow C Kwan,1– 3 Austin Fox,1– 3 Stephanie Noh,1– 3 Kevin Gustafson,1– 3 Ken Y Lin,1,2,4 Sameh Mosaed1,2 1School of Medicine, University of California, Irvine, CA, USA; 2Department of Ophthalmology, Gavin Herbert Eye Institute, Irvine, CA, USA; 3Department of Ophthalmology, Tibor Rubin Veteran Affairs Medical Center, Long Beach, CA, USA; 4Department of Biomedical Engineering, University of California, Irvine, CA, USACorrespondence: Andrew K Smith, Gavin Herbert Eye Institute, University of California, 850 Health Sciences Road, Irvine, CA, 92697-4375, USA, Tel +1-949-824-7944, Fax +1-949-824-2073, Email andrewks@hs.uci.eduPurpose: To evaluate outcomes of new adopters of the OMNI® Surgical System (Sight Sciences, Inc.) by prospectively evaluating intermediate-term outcomes of patients operated by trainees.Patients and Methods: This was a prospective study of surgeries performed by trainees on patients with open angle glaucoma undergoing simultaneous cataract surgery and ab interno canaloplasty and trabeculotomy using the OMNI Surgical System. Pre-operative intraocular pressure (IOP) and number of glaucoma medications were recorded. Only patients with a minimum of 6-month follow up were included. Baseline IOP was used to separate subjects into two groups: Group 1 (IOP ≥ 18 mmHg) and Group 2 (IOP < 18 mmHg). Mean decrease in IOP and medications was calculated and compared with paired t-tests for the overall sample as well as the subgroups. Success was defined as those with a ≥ 20% reduction from pre-operative IOP or with an IOP ≤ 18 mmHg and ≥ 6 mmHg and on the same or fewer number of medications while not requiring additional surgery. Adverse events were also recorded.Results: Forty-two eyes of 31 patients were included. Mean pre-operative IOP was 17.2 ± 4.8 mmHg and mean number of medications was 2.4 ± 1.2. The primary endpoint was reached in 83.3% of patients at 12 months. IOP was reduced by 22.3% to 13.4 ± 2.4 (p< 0.001). Mean number of medications decreased to 1.7 ± 1.6 (p< 0.001). Group 1 mean IOP decreased 35.4% from 22.2 ± 4.6 mmHg to 14.3 ± 2.8 mmHg (p< 0.001). Group 2 mean number of medications decreased from 2.3 ± 1.1 to 1.6 ± 1.5 (p< 0.001).Conclusion: When operated on by the novice MIGS surgeon, the OMNI device provides effective IOP and glaucoma medication reduction with minimal adverse events. Efficacy and safety of the device in the hands of trainees was comparable to experienced glaucoma surgeons suggesting its ease of adoption.Keywords: OMNI, canaloplasty, trabeculotomy, goniotomy, MIGs, minimally invasive glaucoma surgeries

Sasha E Parets,1 Anna K Knight,2 Alicia K Smith,1,2 1Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA; 2Genetics and Molecular Biology Program, Emory University, Atlanta, GA, USA Abstract: Preterm birth (PTB;

BACKGROUND: As our society ages, improving medical care for an older population will be crucial. Discrimination in healthcare may contribute to substandard experiences with the healthcare system, increasing the burden of poor health in older adults. Few studies have focused on the presence of healthcare discrimination and its effects on older adults. OBJECTIVE: We aimed to examine the relationship between healthcare discrimination and new or worsened disability. DESIGN: This was a longitudinal analysis of data from the nationally representative Health and Retirement Study administered in 2008 with follow-up through 2012. PARTICIPANTS: Six thousand and seventeen adults over the age of 50 years (mean age 67 years, 56.3 % female, 83.1 % white) were included in this study. MAIN MEASURES: Healthcare discrimination assessed by a 2008 report of receiving poorer service or treatment than other people by doctors or hospitals (never, less than a year=infrequent; more than once a year=frequent). Outcome was self-report of new or worsened disability by 2012 (difficulty or dependence in any of six activities of daily living). We used a Cox proportional hazards model adjusting for age, race/ethnicity, gender, net worth, education, depression, high blood pressure, diabetes, cancer, lung disease, heart disease, stroke, and healthcare utilization in the past 2 years. KEY RESULTS: In all, 12.6 % experienced discrimination infrequently and 5.9 % frequently. Almost one-third of participants (29 %) reporting frequent healthcare discrimination developed new or worsened disability over 4 years, compared to 16.8 % of those who infrequently and 14.7 % of those who never experienced healthcare discrimination (p < 0.001). In multivariate analyses, compared to no discrimination, frequent healthcare discrimination was associated with new or worsened disability over 4 years (aHR = 1.63, 95 % CI 1.16–2.27). CONCLUSIONS: One out of five adults over the age of 50 years experiences discrimination in healthcare settings. One in 17 experience frequent healthcare discrimination, and this is associated with new or worsened disability by 4 years. Future research should focus on the mechanisms by which healthcare discrimination influences disability in older adults to promote better health outcomes for an aging population.

© 2015 The Author(s) BACKGROUND: As our society ages, improving medical care for an older population will be crucial. Discrimination in healthcare may contribute to substandard experiences with the healthcare system, increasing the burden of poor health in

Background: Prognosis is critical in individualizing care for older adults with late life disability. Evidence suggests that preferences for prognostic information may be culturally determined. Yet little is known about the preferences of diverse elders for discussing prognosis.Objective: To determine the preferences for discussing prognosis of a diverse sample of older adults with late-life disability.Design& Participants: We interviewed 60 older adults with mean age 78 and mean 2.5 Activities of Daily Living dependencies. Participants were recruited from San Francisco's On Lok program, the first Program of All-inclusive Care for the Elderly (PACE). Participants were interviewed in English, Spanish, and Cantonese, and responded to scenarios in which their doctors estimated they had 5 years and 1 year left to live. Open-ended questions explored the reasons for their responses. Results were analyzed qualitatively using grounded theory.Key Results: Sixty-five percent of participants wanted to discuss the prognosis if their doctor estimated they had <5 years to live and 75% if the estimate was <1 year. Three themes were prominent among patients who wanted to discuss prognosis: to prepare, to make the most of the life they had left, and to make medical or health-related decisions. Those who preferred not to discuss prognosis described emotional difficulty, the uncertainty of prognosis, or that it would not be useful. Nearly all participants said that doctors should not make assumptions based on race or ethnicity, though differences between ethnic groups emerged.Conclusions: Most patients in this diverse sample of disabled elders were interested in discussing prognosis, while a substantial minority was not. Among those participants who preferred to discuss prognosis, many said that prognostic information would be important as they made difficult medical and personal decisions in late-life. Clinicians should inquire about preferences for discussing prognosis before sharing prognostic estimates. [ABSTRACT FROM AUTHOR]

Context: Despite increased focus on improving palliative care in the emergency department (ED), there is little research on how to best address the specific needs of this patient population.Objectives: To better understand the experiences of acutely symptomatic patients seen in the ED.Methods: Using in-person semi-structured interviews, we explored the attitudes, experiences, and beliefs of 14 patients and seven family caregivers on the inpatient palliative care consult service, who had been admitted through the ED at two academic medical centers. We used a grounded theory approach to code responses. Transcripts were coded by a palliative medicine physician, an emergency medicine physician, and a general internist. Discrepancies were resolved by consensus. Coded sections were iteratively reviewed for interpretation, and concepts were collapsed into themes.Results: Five distinct themes emerged: 1) unprepared for managing symptoms at home; 2) uncertainty and anxiety; 3) communication is essential; 4) mixed experiences with symptom management; and 5) conflicting perspectives about the purpose of palliative care clinicians in the ED.Conclusion: Patients and caregivers identified systems, communication, and clinical issues in ED care that should be a focus for future research. [ABSTRACT FROM AUTHOR]

Background: Incorporating genomic data into risk prediction has become an increasingly popular approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not., Methods: Elastic Net was used to develop three risk score models using a discovery dataset (n = 1226; 314 cases, 912 controls) comprised of 5 diverse cohorts with available blood-derived DNA methylation (DNAm) measured on the Illumina Epic BeadChip. The first risk score, exposure and methylation risk score (eMRS) used cumulative and childhood trauma exposure and DNAm variables; the second, methylation-only risk score (MoRS) was based solely on DNAm data; the third, methylation-only risk scores with adjusted exposure variables (MoRSAE) utilized DNAm data adjusted for the two exposure variables. The potential of these risk scores to predict future PTSD based on pre-deployment data was also assessed. External validation of risk scores was conducted in four independent cohorts., Results: The eMRS model showed the highest accuracy (92%), precision (91%), recall (87%), and f1-score (89%) in classifying PTSD using 3730 features. While still highly accurate, the MoRS (accuracy = 89%) using 3728 features and MoRSAE (accuracy = 84%) using 4150 features showed a decline in classification power. eMRS significantly predicted PTSD in one of the four independent cohorts, the BEAR cohort (beta = 0.6839, p=0.006), but not in the remaining three cohorts. Pre-deployment risk scores from all models (eMRS, beta = 1.92; MoRS, beta = 1.99 and MoRSAE, beta = 1.77) displayed a significant (p < 0.001) predictive power for post-deployment PTSD., Conclusion: The inclusion of exposure variables adds to the predictive power of MRS. Classification-based MRS may be useful in predicting risk of future PTSD in populations with anticipated trauma exposure. As more data become available, including additional molecular, environmental, and psychosocial factors in these scores may enhance their accuracy in predicting PTSD and, relatedly, improve their performance in independent cohorts., (© 2024. The Author(s).)

Importance: The widowhood effect, in which mortality increases and function decreases in the period following spousal death, may be heightened in older adults with functional impairment and serious illnesses, such as cancer, dementia, or organ failure, who are highly reliant on others, particularly spouses, for support. Yet there are limited data on widowhood among people with these conditions., Objective: To determine the association of widowhood with function and mortality among older adults with dementia, cancer, or organ failure., Design, Setting, and Participants: This longitudinal cohort study used population-based, nationally representative data from the Health and Retirement Study database linked to Medicare claims from 2008 to 2018. Participants were married or partnered community-dwelling adults aged 65 years and older with and without cancer, organ failure, or dementia and functional impairment (function score <9 of 11 points), matched on widowhood event and with follow-up until death or disenrollment. Analyses were conducted from September 2021 to May 2024., Exposure: Widowhood., Main Outcomes and Measures: Function score (range 0-11 points; 1 point for independence with each activity of daily living [ADL] or instrumental activity of daily living [IADL]; higher score indicates better function) and 1-year mortality., Results: Among 13 824 participants (mean [SD] age, 70.1 [5.5] years; 6416 [46.4%] female; mean [SD] baseline function score, 10.2 [1.6] points; 1-year mortality: 0.4%) included, 5732 experienced widowhood. There were 319 matched pairs of people with dementia, 1738 matched pairs without dementia, 95 matched pairs with cancer, 2637 matched pairs without cancer, 85 matched pairs with organ failure, and 2705 matched pairs without organ failure. Compared with participants without these illnesses, widowhood was associated with a decline in function immediately following widowhood for people with cancer (change, -1.17 [95% CI, -2.10 to -0.23] points) or dementia (change, -1.00 [95% CI, -1.52 to -0.48] points) but not organ failure (change, -0.84 [95% CI, -1.69 to 0.00] points). Widowhood was also associated with increased 1-year mortality among people with cancer (hazard ratio [HR], 1.08 [95% CI, 1.04 to 1.13]) or dementia (HR, 1.14 [95% CI, 1.02 to 1.27]) but not organ failure (HR, 1.02 [95% CI, 0.98 to 1.06])., Conclusions and Relevance: This cohort study found that widowhood was associated with increased functional decline and increased mortality in older adults with functional impairment and dementia or cancer. These findings suggest that persons with these conditions with high caregiver burden may experience a greater widowhood effect.

Background: Partial cystectomy (PC) offers potential benefits for select patients with muscle-invasive bladder cancer (MIBC). However, the oncologic efficacy of PC may be compromised due to the underutilization of standard-of-care modalities, such as neoadjuvant chemotherapy (NAC) and pelvic lymph node dissection (PLND). We aimed to assess factors influencing the incorporation of NAC and PLND with PC and evaluate their impact on overall survival (OS)., Methods: We identified 2,832 patients with cT2-4N0M0 bladder cancer (BCa) who underwent PC between 2004 and 2019 using the National Cancer Database (NCDB). The primary endpoint was OS. Kaplan-Meier analysis compared OS in treatment modalities in PC patients. Multivariate Cox Proportional Hazards (CPH) model assessed the impact of age, sex, race, insurance, income, Charlson-Deyo Index (CDI), clinical T-stage, facility type, histology, surgical margins, NAC, PLND adequacy [≥10 lymph node (LN) yield], and adjuvant radiation treatment on OS. Multivariate logistic regressions were performed to examine predictors of NAC and PLND receipt in PC patients., Results: Two hundred and thirty-one patients received multi-agent NAC with PC. NAC treatment with PLND was associated with significantly improved OS (P<0.001). Median OS was 43.9 months in patients treated with PC alone, while median OS was not reached in PC patients treated with NAC & PLND. Furthermore, patients who received NAC without any PLND had a median OS of 50.6 months, while those treated with PLND without NAC had a median OS of 76.5 months. This persisted in the adjusted CPH model, where private insurance, NAC, and PLND significantly improved OS, especially when PLND yielded ≥10 LN. Conversely, age >80 years old, CDI >2, cT3-4, positive margins, and adjuvant radiation all increased adjusted mortality risk. After controlling for clinicopathologic variables, females were less likely to receive PLND [odds ratio (OR) 0.719, P=0.005], while NAC was more likely administered to PC patients diagnosed from 2016-2019 (OR 5.295, P<0.001). PC patients who received NAC were more likely to have PLND performed as part of their treatment regimen (OR 2.189, P<0.001). Additionally, patients treated at academic centers were more likely to have NAC administered and PLND performed (OR 1.745, P=0.003; OR 2.465, P<0.001, respectively)., Conclusions: Despite guideline recommendations, the utilization of NAC and PLND with PC remains insufficient. Our analysis underscores the significant OS benefit of these recommended treatments as part of MIBC care. Importantly, we highlight a gradual increase in NAC and PLND receipt in recent years, centered largely at academic facilities. Notably, gender disparities exist in PLND receipt, emphasizing the need for further investigation., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-24-165/coif). The authors have no conflicts of interest to declare., (2024 Translational Andrology and Urology. All rights reserved.)

Background: Children from families with low socioeconomic status (SES), as determined by income, experience several negative outcomes, such as higher rates of newborn mortality and behavioral issues. Moreover, associations between DNA methylation and low income or poverty status are evident beginning at birth, suggesting prenatal influences on offspring development. Recent evidence suggests neighborhood opportunities may protect against some of the health consequences of living in low income households. The goal of this study was to assess whether neighborhood opportunities moderate associations between household income (HI) and neonate developmental maturity as measured with DNA methylation., Methods: Umbilical cord blood DNA methylation data was available in 198 mother-neonate pairs from the larger CANDLE cohort. Gestational age acceleration was calculated using an epigenetic clock designed for neonates. Prenatal HI and neighborhood opportunities measured with the Childhood Opportunity Index (COI) were regressed on gestational age acceleration controlling for sex, race, and cellular composition., Results: Higher HI was associated with higher gestational age acceleration (B = .145, t = 4.969, p = 1.56x10-6, 95% CI [.087, .202]). Contrary to expectation, an interaction emerged showing higher neighborhood educational opportunity was associated with lower gestational age acceleration at birth for neonates with mothers living in moderate to high HI (B = -.048, t = -2.08, p = .03, 95% CI [-.092, -.002]). Female neonates showed higher gestational age acceleration at birth compared to males. However, within males, being born into neighborhoods with higher social and economic opportunity was associated with higher gestational age acceleration., Conclusion: Prenatal HI and neighborhood qualities may affect gestational age acceleration at birth. Therefore, policy makers should consider neighborhood qualities as one opportunity to mitigate prenatal developmental effects of HI., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Pilkay 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.)

Importance: Disasters experienced by an entire community provide opportunities to understand individual differences in risk for adverse health outcomes over time. DNA methylation (DNAm) differences may help to distinguish individuals at increased risk following large-scale disasters., Objective: To examine the association of epigenetic age acceleration with probable posttraumatic stress disorder (PTSD) and PTSD symptom severity in women., Design, Setting, and Participants: This prospective cohort study examined data from participants in the Women and Their Children's Health cohort, who were characterized longitudinally following the Deepwater Horizon oil spill (DHOS) in 2010 and through numerous hurricanes in the Gulf Coast region of the US. Wave 1 occurred August 6, 2012, through June 26, 2014, and wave 2 occurred September 2, 2014, through May 27, 2016. Data were analyzed between August 18 and November 4, 2023. Address-based sampling was used to recruit women aged 18 to 80 years and residing in 1 of the 7 Louisiana parishes surrounding the DHOS-affected region. Recruitment consisted of 2-stage sampling that (1) undersampled the 2 more urban parishes to maximize probability of participant oil exposure and (2) proportionally recruited participants across census tracts in the 5 other parishes closest to the spill., Exposure: Posttraumatic stress subsequent to the DHOS., Main Outcome and Measures: Epigenetic age acceleration was measured by DNAm assayed from survey wave 1 blood samples. Posttraumatic stress disorder was assessed using the PTSD Checklist for DSM-5 at survey wave 2, and lifetime trauma exposure was assessed using the Life Events Checklist for DSM-5. General linear models were used to examine the association between wave 1 DNAm age and wave 2 probable PTSD diagnosis and symptom severity., Results: A total of 864 women (mean [SD] age, 47.1 [12.0] years; 328 Black [38.0%], 19 American Indian [2.2%], 486 White [56.3%], and 30 of other racial groups, including uknown or unreported [3.5%]) were included. Black and American Indian participants had a higher age acceleration at wave 1 compared with White participants (β = 1.64 [95% CI, 1.02-2.45] and 2.34 [95% CI, 0.33-4.34], respectively), and they had higher PTSD symptom severity at wave 2 (β = 7.10 [95% CI, 4.62-9.58] and 13.08 [95% CI, 4.97-21.18], respectively). Epigenetic age acceleration at wave 1 was associated with PTSD symptom severity at wave 2 after adjusting for race, smoking, body mass index, and household income (β = 0.38; 95% CI, 0.11-0.65)., Conclusions and Relevance: In this cohort study, epigenetic age acceleration was higher in minoritized racial groups and associated with future PTSD diagnosis and severity. These findings support the need for psychoeducation about traumatic responses to increase the likelihood that treatment is sought before years of distress and entrenchment of symptoms and comorbidities occur.

Importance: The Palliative Performance Scale (PPS) is one of the most widely used prognostic tools for patients with serious illness. However, current prognostic estimates associated with PPS scores are based on data that are over a decade old., Objective: To generate updated prognostic estimates by PPS score, care setting, and illness category, and examine how well PPS predicts short- and longer-term survival., Design, Setting, and Participants: This prognostic study was conducted at a large academic medical center with robust inpatient and outpatient palliative care practices using electronic health record data linked with data from California Vital Records. Eligible participants included patients who received a palliative care consultation between January 1, 2018, and December 31, 2020. Data analysis was conducted from November 2022 to February 2024., Exposure: Palliative care consultation with a PPS score documented., Main Outcomes and Measures: The primary outcomes were predicted 1-, 6-, and 12-month mortality and median survival of patients by PPS score in the inpatient and outpatient settings, and performance of the PPS across a range of survival times. In subgroup analyses, mortality risk by PPS score was estimated in patients with cancer vs noncancer illnesses and those seen in-person vs by video telemedicine in the outpatient setting., Results: Overall, 4779 patients (mean [SD] age, 63.5 [14.8] years; 2437 female [51.0%] and 2342 male [49.0%]) had a palliative care consultation with a PPS score documented. Of these patients, 2276 were seen in the inpatient setting and 3080 were seen in the outpatient setting. In both the inpatient and outpatient settings, 1-, 6-, and 12-month mortality were higher and median survival was shorter for patients with lower PPS scores. Prognostic estimates associated with PPS scores were substantially longer (2.3- to 11.7-fold) than previous estimates commonly used by clinicians. The PPS had good ability to discriminate between patients who lived and those who died in the inpatient setting (integrated time-dependent area under the curve [iAUC], 0.74) but its discriminative ability was lower in the outpatient setting (iAUC, 0.67). The PPS better predicted 1-month survival than longer-term survival. Mortality rates were higher for patients with cancer than other serious illnesses at most PPS levels., Conclusions and Relevance: In this prognostic study, prognostic estimates associated with PPS scores were substantially longer than previous estimates commonly used by clinicians. Based on these findings, an online calculator was updated to assist clinicians in reaching prognostic estimates that are more consistent with modern palliative care practice and specific to the patient's setting and diagnosis group.

Introduction: Transurethral resection of bladder tumour (TURBT) is one of the more common procedures performed by urologists. It is often described as an 'incision-free' and 'well-tolerated' operation. However, many patients experience distress and discomfort with the procedure. Substantial opportunity exists to improve the TURBT experience. An enhanced recovery after surgery (ERAS) protocol designed by patients with bladder cancer and their providers has been developed., Methods and Analysis: This is a single-centre, randomised controlled trial to investigate the effectiveness of an ERAS protocol compared with usual care in patients with bladder cancer undergoing ambulatory TURBT. The ERAS protocol is composed of preoperative, intraoperative and postoperative components designed to optimise each phase of perioperative care. 100 patients with suspected or known bladder cancer aged ≥18 years undergoing initial or repeat ambulatory TURBT will be enrolled. The change in Quality of Recovery 15 score, a measure of the quality of recovery, between the day of surgery and postoperative day 1 will be compared between the ERAS and control groups., Ethics and Dissemination: The trial has been approved by the Johns Hopkins Institutional Review Board #00392063. Participants will provide informed consent to participate before taking part in the study. Results will be reported in a separate publication., Trial Registration Number: NCT05905276., 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.)

Importance: Racial discrimination increases the risk of adverse brain health outcomes, potentially via neuroplastic changes in emotion processing networks. The involvement of deep brain regions (brainstem and midbrain) in these responses is unknown. Potential associations of racial discrimination with alterations in deep brain functional connectivity and accelerated epigenetic aging, a process that substantially increases vulnerability to health problems, are also unknown., Objective: To examine associations of racial discrimination with brainstem and midbrain resting-state functional connectivity (RSFC) and DNA methylation age acceleration (DMAA) among Black women in the US., Design, Setting, and Participants: This cohort study was conducted between January 1, 2012, and February 28, 2015, and included a community-based sample of Black women (aged ≥18 years) recruited as part of the Grady Trauma Project. Self-reported racial discrimination was examined in association with seed-to-voxel brain connectivity, including the locus coeruleus (LC), periaqueductal gray (PAG), and superior colliculus (SC); an index of DMAA (Horvath clock) was also evaluated. Posttraumatic stress disorder (PTSD), trauma exposure, and age were used as covariates in statistical models to isolate racial discrimination-related variance. Data analysis was conducted between January 10 and October 30, 2023., Exposure: Varying levels of racial discrimination exposure, other trauma exposure, and posttraumatic stress disorder (PTSD)., Main Outcomes and Measures: Racial discrimination frequency was assessed with the Experiences of Discrimination Scale, other trauma exposure was evaluated with the Traumatic Events Inventory, and current PTSD was evaluated with the PTSD Symptom Scale. Seed-to-voxel functional connectivity analyses were conducted with LC, PAG, and SC seeds. To assess DMAA, the Methylation EPIC BeadChip assay (Illumina) was conducted with whole-blood samples from a subset of 49 participants., Results: This study included 90 Black women, with a mean (SD) age of 38.5 (11.3) years. Greater racial discrimination was associated with greater left LC RSFC to the bilateral precuneus (a region within the default mode network implicated in rumination and reliving of past events; cluster size k = 228; t85 = 4.78; P < .001, false discovery rate-corrected). Significant indirect effects were observed for the left LC-precuneus RSFC on the association between racial discrimination and DMAA (β [SE] = 0.45 [0.16]; 95% CI, 0.12-0.77)., Conclusions and Relevance: In this study, more frequent racial discrimination was associated with proportionately greater RSFC of the LC to the precuneus, and these connectivity alterations were associated with DMAA. These findings suggest that racial discrimination contributes to accelerated biological aging via altered connectivity between the LC and default mode network, increasing vulnerability for brain health problems.

Interleukin-1 (IL-1)-family cytokines are potent modulators of inflammation, coordinating a vast array of immunological responses across innate and adaptive immune systems. Dysregulated IL-1-family cytokine signaling, however, is involved in a multitude of adverse health effects, such as chronic inflammatory conditions, autoimmune diseases, and cancer. Within the IL-1 family of cytokines, six-IL-1α, IL-1β, IL-33, IL-36α, IL-36β, and IL-36γ-require the IL-1 receptor accessory protein (IL-1RAcP) as their shared co-receptor. Common features of cytokine signaling include redundancy of signaling pathways, sharing of cytokines and receptors, pleiotropy of the cytokines themselves, and multifaceted immune responses. Accordingly, targeting multiple cytokines simultaneously is an emerging therapeutic strategy and can provide advantages over targeting a single cytokine pathway. Here, we show that two monoclonal antibodies, CAN10 and 3G5, which target IL-1RAcP for broad blockade of all associated cytokines, do so through distinct mechanisms and provide therapeutic opportunities for the treatment of inflammatory diseases., Competing Interests: Declaration of interests E.J.G., G.S.B., C.G., S.R., and D.L. are employees of Cantargia AB (Medicon Village, Lund, Sweden). K.S. is an employee of Innovagen AB (Lund, Sweden). E.J.G, G.S.B., K.S., C.G., S.R., T.F., and D.L. are shareholders of Cantargia AB. Cantargia AB is the owner of the intellectual property rights for CAN10 and 3G5 for use in the treatment of autoinflammatory and autoimmune diseases., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The adult mammalian heart harbors minute levels of cycling cardiomyocytes (CMs). Large numbers of images are needed to accurately quantify cycling events using microscopy-based methods. CardioCount is a new deep learning-based pipeline to rigorously score nuclei in microscopic images. When applied to a repository of 368,434 human microscopic images, we found evidence of coupled growth between CMs and cardiac endothelial cells in the adult human heart. Additionally, we found that vascular rarefaction and CM hypertrophy are interrelated in end-stage heart failure. CardioCount is available for use via GitHub and via Google Colab for users with minimal machine learning experience., Competing Interests: This work was funded by a Stead Society Grant (Dr Karra), a Duke University Strong Start Physician Scientist Award (Dr Karra), and NHLBI grant R01 HL15777 (Dr Karra). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Observational studies suggest that posttraumatic stress disorder (PTSD) increases risk for various autoimmune diseases. Insights into shared biology and causal relationships between these diseases may inform intervention approaches to PTSD and co-morbid autoimmune conditions. We investigated the shared genetic contributions and causal relationships between PTSD, 18 autoimmune diseases, and 3 immune/inflammatory biomarkers. Univariate MiXeR was used to contrast the genetic architectures of phenotypes. Genetic correlations were estimated using linkage disequilibrium score regression. Bi-directional, two-sample Mendelian randomization (MR) was performed using independent, genome-wide significant single nucleotide polymorphisms; inverse variance weighted and weighted median MR estimates were evaluated. Sensitivity analyses for uncorrelated (MR PRESSO) and correlated horizontal pleiotropy (CAUSE) were also performed. PTSD was considerably more polygenic (10,863 influential variants) than autoimmune diseases (median 255 influential variants). However, PTSD evidenced significant genetic correlation with nine autoimmune diseases and three inflammatory biomarkers. PTSD had putative causal effects on autoimmune thyroid disease (p = 0.00009) and C-reactive protein (CRP) (p = 4.3 × 10 -7 ). Inferences were not substantially altered by sensitivity analyses. Additionally, the PTSD-autoimmune thyroid disease association remained significant in multivariable MR analysis adjusted for genetically predicted inflammatory biomarkers as potential mechanistic pathway variables. No autoimmune disease had a significant causal effect on PTSD (all p values > 0.05). Although causal effect models were supported for associations of PTSD with CRP, shared pleiotropy was adequate to explain a putative causal effect of CRP on PTSD (p = 0.18). In summary, our results suggest a significant genetic overlap between PTSD, autoimmune diseases, and biomarkers of inflammation. PTSD has a putative causal effect on autoimmune thyroid disease, consistent with existing epidemiologic evidence. A previously reported causal effect of CRP on PTSD is potentially confounded by shared genetics. Together, results highlight the nuanced links between PTSD, autoimmune disorders, and associated inflammatory signatures, and suggest the importance of targeting related pathways to protect against disease and disability., (© 2024. The Author(s).)

Smoking exposure during adulthood can disrupt oocyte development in women, contributing to infertility and possibly adverse birth outcomes. Some of these effects may be reflected in epigenome profiles in granulosa cells (GCs) in human follicular fluid. We compared the epigenetic modifications throughout the genome in GCs from women who were former (N = 15) versus never smokers (N = 44) undergoing assisted reproductive technologies (ART). This study included 59 women undergoing ART. Smoking history including time since quitting was determined by questionnaire. GCs were collected during oocyte retrieval and DNA methylation (DNAm) levels were profiled using the Infinium MethylationEPIC BeadChip. We performed an epigenome-wide association study with robust linear models, regressing DNAm level at individual loci on smoking status, adjusting for age, ovarian stimulation protocol, and three surrogate variables. We performed differentially methylated regions (DMRs) analysis and over-representation analysis of the identified CpGs and corresponding gene set. 81 CpGs were differentially methylated among former smokers compared to never smokers (FDR < 0.05). We identified 2 significant DMRs (KCNQ1 and RHBDD2). The former smoking-associated genes were enriched in oxytocin signaling, adrenergic signaling in cardiomyocytes, platelet activation, axon guidance, and chemokine signaling pathway. These epigenetic variations have been associated with inflammatory responses, reproductive outcomes, cancer development, neurodevelopmental disorder, and cardiometabolic health. Secondarily, we examined the relationships between time since quitting and DNAm at significant CpGs. We observed three CpGs in negative associations with the length of quitting smoking (p < 0.05), which were cg04254052 (KCNIP1), cg22875371 (OGDHL), and cg27289628 (LOC148145), while one in positive association, which was cg13487862 (PLXNB1). As a pilot study, we demonstrated epigenetic modifications associated with former smoking in GCs. The study is informative to potential biological pathways underlying the documented association between smoking and female infertility and biomarker discovery for smoking-associated reproductive outcomes., (© 2024. The Author(s).)

People with ovaries experience reproductive aging as their reproductive function and system declines. This has significant implications for both fertility and long-term health, with people experiencing an increased risk of cardiometabolic disorders after menopause. Reproductive aging can be assessed through markers of ovarian reserve, response to fertility treatment or molecular biomarkers, including DNA methylation. Changes in DNA methylation with age associate with poorer reproductive outcomes, and epigenome-wide studies can provide insight into genes and pathways involved. DNA methylation-based epigenetic clocks can quantify biological age in reproductive tissues and systemically. This review provides an overview of hallmarks and theories of aging in the context of the reproductive system, and then focuses on studies of DNA methylation in reproductive tissues.

Aim: The epigenome influences gene regulation and phenotypes in response to exposures. Epigenome assessment can determine exposure history aiding in diagnosis. Materials & methods: Here we developed and implemented a machine learning algorithm, the exposure signature discovery algorithm (ESDA), to identify the most important features present in multiple epigenomic and transcriptomic datasets to produce an integrated exposure signature (ES). Results: Signatures were developed for seven exposures including Staphylococcus aureus , human immunodeficiency virus, SARS-CoV-2, influenza A (H3N2) virus and Bacillus anthracis vaccinations. ESs differed in the assays and features selected and predictive value. Conclusion: Integrated ESs can potentially be utilized for diagnosis or forensic attribution. The ESDA identifies the most distinguishing features enabling diagnostic panel development for future precision health deployment.

Pregnancy can exacerbate or prompt the onset of stress-related disorders, such as post-traumatic stress disorder (PTSD). PTSD is associated with heightened stress responsivity and emotional dysregulation, as well as increased risk of chronic disorders and mortality. Further, maternal PTSD is associated with gestational epigenetic age acceleration in newborns, implicating the prenatal period as a developmental time period for the transmission of effects across generations. Here, we evaluated the associations between PTSD symptoms, maternal epigenetic age acceleration, and infant gestational epigenetic age acceleration in 89 maternal-neonatal dyads. Trauma-related experiences and PTSD symptoms in mothers were assessed during the third trimester of pregnancy. The MethylationEPIC array was used to generate DNA methylation data from maternal and neonatal saliva samples collected within 24 h of infant birth. Maternal epigenetic age acceleration was calculated using Horvath's multi-tissue clock, PhenoAge and GrimAge. Gestational epigenetic age was estimated using the Haftorn clock. Maternal cumulative past-year stress (GrimAge: p  = 3.23e-04, PhenoAge: p  = 9.92e-03), PTSD symptoms (GrimAge: p  = 0.019), and difficulties in emotion regulation (GrimAge: p  = 0.028) were associated with accelerated epigenetic age in mothers. Maternal PTSD symptoms were associated with lower gestational epigenetic age acceleration in neonates ( p  = 0.032). Overall, our results suggest that maternal cumulative past-year stress exposure and trauma-related symptoms may increase the risk for age-related problems in mothers and developmental problems in their newborns.

Differentially methylated regions (DMRs) are genomic regions with methylation patterns across multiple CpG sites that are associated with a phenotype. In this study, we proposed a Principal Component (PC) based DMR analysis method for use with data generated using the Illumina Infinium MethylationEPIC BeadChip (EPIC) array. We obtained methylation residuals by regressing the M-values of CpGs within a region on covariates, extracted PCs of the residuals, and then combined association information across PCs to obtain regional significance. Simulation-based genome-wide false positive (GFP) rates and true positive rates were estimated under a variety of conditions before determining the final version of our method, which we have named DMR PC . Then, DMR PC and another DMR method, coMethDMR, were used to perform epigenome-wide analyses of several phenotypes known to have multiple associated methylation loci (age, sex, and smoking) in a discovery and a replication cohort. Among regions that were analysed by both methods, DMR PC identified 50% more genome-wide significant age-associated DMRs than coMethDMR. The replication rate for the loci that were identified by only DMR PC was higher than the rate for those that were identified by only coMethDMR (90% for DMRPC vs. 76% for coMethDMR). Furthermore, DMR PC identified replicable associations in regions of moderate between-CpG correlation which are typically not analysed by coMethDMR. For the analyses of sex and smoking, the advantage of DMR PC was less clear. In conclusion, DMR PC is a new powerful DMR discovery tool that retains power in genomic regions with moderate correlation across CpGs.

Background: Diabetic neovascular glaucoma is a secondary glaucoma that may require immediate correction of elevated intraocular pressure to control pain and protect the optic nerve. While there is a seasonal trend to glucose levels, it is unknown if a seasonal trend exists for diabetic neovascular glaucoma., Objective: This study evaluates the incidence of urgent glaucoma tube shunt implantation in diabetic neovascular glaucoma in a tertiary academic referral center in Southern California., Methods: Electronic medical records were queried for urgent glaucoma tube shunt surgery from 2014 to 2021. The number of cases were separated by month of occurrence, and average hemoglobin A1c values were calculated per month. Data were analyzed via ANOVA tests and one-tailed t-tests., Results: A total of 127 cases were identified. The months of March and April contained the most cases averaging 3 and 2.75 cases, respectively. April had statistically significant higher case numbers than that of other months ( P  = .041). ANOVA tests excluding April showed no statistically significant difference between the remaining months ( P  = .901). Average hemoglobin A1c values were highest in the months of April and March at 9.8 and 9.6%, respectively., Conclusion: Emergency glaucoma tube shunt surgery for diabetic neovascular glaucoma occurs most frequently in April. This observation may provide insight into disease prevention through diabetes management and help improve surgical operations such that staffing and resources are allocated accordingly., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)