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Abstract Introduction The United States Advisory Committee on Immunization Practices (ACIP) and the Centers for Disease Control (CDC) recommend COVID-19 vaccines for all immunocompromised individuals. Certain disease groups are at increased risk of comorbidity and death for which disease-specific recommendations should be considered. The objective of the Delphi panel of experts was to summarize expert consensus on COVID-19 vaccinations for patients with rheumatologic disease, renal disease, hematologic malignancy and solid organ transplant (SOT) in the US. Methods A two-stage Delphi panel method was employed, starting with qualitative interviews with key opinion leaders (KOLs) in the four disease areas (n = 4 KOLs, n = 16 total) followed by three rounds of iterative revision of disease-specific COVID-19 vaccine recommendations. Final consensus was rated after the third round. Statements addressed primary and booster dosing (e.g., number and frequency) and other considerations such as vaccine type or heterologous messenger ribonucleic acid (mRNA) vaccination. Following the Delphi Panel, an online survey was conducted to assess physician agreement within the disease areas (n = 50 each, n = 200 total) with the consensus statements. Results Moderate to strong consensus was achieved for all primary series vaccination statements across disease groups, except one in hematology. Similarly, moderate to strong consensus was achieved for all booster series statements in all disease areas. However, statements on antibody titer measurements for re-vaccination considerations and higher dosages for immunocompromised patients did not reach agreement. Overall, approximately 62%–96% of physicians strongly agreed with the primary and booster vaccine recommendations. However, low agreement (29%–69%) was found among physicians for time interval between disease-specific treatment and vaccination, recommendations for mRNA vaccines, heterologous mRNA vaccination, antibody titer measurement and higher vaccine dosage for immunocompromised groups. Conclusion Consensus was achieved for disease-specific COVID-19 vaccine recommendations concerning primary and booster series vaccines and was generally well accepted by practicing physicians.

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or DTRs). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population.

Reza Hajhosseiny,1 Kaivan Khavandi,1 Soudeh Mashayekhi,2 Adam S Greenstein,3 Rayaz A Malik31British Heart Foundation Centre of Cardiovascular Excellence, St Thomas' Hospital, London, UK; 2Department of Primary Care and Public Health, Imperial College London, London, UK; 3Institute of Human Development, University of Manchester, Manchester, UKAbstract: Individuals with type 2 diabetes mellitus are at very substantial risk of cardiovascular disease, and most will succumb to complications from premature coronary artery events. At the same time, the diabetic myocardium undergoes unique phenotypic alterations as a consequence of multiple structural and cellular injuries, which together form "diabetic cardiomyopathy." Attempts to curb risk through intensive modulation of glycemia and blood pressure have proven disappointing in preventing cardiovascular events, and potentially even dangerous. Conversely, prior to development of disease, there appears to be a linear relationship between risk parameters and events. These observations are likely the consequence of widespread vascular damage, which is present at the point that glycemic thresholds meet diagnostic criteria for diabetes. This is particularly true of the microcirculation. Interventions at the prediabetic stage have been consistent with this, where early intensive risk-factor modulation has been successful in preventing events and even regressing existing risk. Upstream, the force driving these pathologies is being overweight and obesity. High-risk individuals can be identified through simple body mass parameters, with confirmation of prediabetes/metabolic syndrome with further assessment of other metabolic parameters such as glucose and lipids. A number of novel pharmacotherapies may prove beneficial at this stage, and incretin-based therapies appear particularly promising in this respect. Similarly, bariatric procedures have shown remarkable improvements in metabolic and cardiovascular outcomes, but are clearly unsuitable as a population-wide strategy. Therapeutic lifestyle change and diet have consistently shown efficacy in reversing dysglycemia, lowering blood pressure, and optimizing cholesterol profiles. However, the longevity of these improvements is often limited, and alternative approaches therefore need to be considered. With an evolving and increasingly sophisticated evidence base for nutritional interventions, there is a clear window of opportunity to rescue these individuals from the clinical sequelae of diabetes and consequent cardiovascular complications.Keywords: hypertension, diabetes, cardiovascular risk

Background: Adherence to medication represents a challenge in managing chronic conditions in the geriatric population. This study assessed adherence rates and factors affecting adherence of geriatric patients attending the Helen Joseph Hospital outpatient department. Methods: This was a prospective cross-sectional study of 130 patients aged 65 years and older, with at least two chronic conditions. Participants were administered a survey incorporating the Medication Adherence Rating Scale and the Adherence Barrier Questionnaire to identify medication adherence and patient-specific barriers to adherence, respectively. These instruments are reliable and valid. Results: Descriptive statistics and logistic regression were used for analysis. Most patients were female (63%) with a mean age of 72 (67–78) years. Common comorbidities included type 2 diabetes mellitus (63%), hypertension (98%), dyslipidaemia (92%) and congestive cardiac failure (38%). Polypharmacy was prevalent, affecting 53% of the participants. Despite 96% of participants being adherent, all had at least one barrier to adherence, with the majority (65%) having more than one barrier. The main barriers were forgetfulness (59%), fear of side effects (39%), problems with taking the medications (26%) and believing medications are poisonous (22%). Although most participants accessed the pharmacy easily, only 83% reported consistent medication availability and 11% could not afford to collect their medication. Conclusion: Polypharmacy is common in the population. Despite high adherence rates, barriers such as believing medications are poisonous remain significant. A good patient–doctor relationship improves adherence. Contribution: Understanding the barriers to adherence in older adults with polypharmacy and multimorbidity can assist practitioners improve patient care.

Objective Pain control for hip fractures is often achieved via intravenous opioids. However, opioids can have dangerous adverse effects, including respiratory depression and delirium. Peripheral nerve blockade is an alternative option for pain control that reduces the need for opioid analgesia. The purpose of this study was to compare the use of femoral nerve blocks versus standard pain control for patients with hip fractures. Methods This retrospective study included adult patients presenting to the emergency department with isolated hip fractures between April 2021 and September 2022. The intervention group included all patients who received a femoral nerve block during this time. An equivalent number of patients who received standard pain control during that period was randomly selected to represent the control group. The primary outcome was preoperative opioid requirement, assessed by morphine milligram equivalents (MMEs). Results During the study period, 90 patients were included in each group. Mean preoperative MME was 10.3 (95% confidence interval [CI], 7.4–13.2 MME) for the intervention group and 14.0 (95% CI, 10.2–17.8 MME) for the control group (P=0.13). Patients who received a femoral nerve block also had shorter time from emergency department triage to hospital discharge (7.2 days; 95% CI, 6.2–8.0 days) than patients who received standard care (8.6 days; 95% CI, 7.2–10.0 days). However, this difference was not statistically significant (P=0.09). Conclusion Femoral nerve blockade is a safe and effective alternative to opioids for pain control in patients with hip fractures.

Abstract Introduction Accelerometer-derived physical activity (PA) from cardiac devices are available via remote monitoring platforms yet rarely reviewed in clinical practice. We aimed to investigate the association between PA and clinical measures of frailty and physical functioning. Methods The PATTErn study (A study of Physical Activity paTTerns and major health Events in older people with implantable cardiac devices) enrolled participants aged 60 + undergoing remote cardiac monitoring. Frailty was measured using the Fried criteria and gait speed (m/s), and physical functioning by NYHA class and SF-36 physical functioning score. Activity was reported as mean time active/day across 30-days prior to enrolment (30-day PA). Multivariable regression methods were utilised to estimate associations between PA and frailty/functioning (OR = odds ratio, β = beta coefficient, CI = confidence intervals). Results Data were available for 140 participants (median age 73, 70.7% male). Median 30-day PA across the analysis cohort was 134.9 min/day (IQR 60.8–195.9). PA was not significantly associated with Fried frailty status on multivariate analysis, however was associated with gait speed (β = 0.04, 95% CI 0.01–0.07, p = 0.01) and measures of physical functioning (NYHA class: OR 0.73, 95% CI 0.57–0.92, p = 0.01, SF-36 physical functioning: β = 4.60, 95% CI 1.38–7.83, p = 0.005). Conclusions PA from cardiac devices was associated with physical functioning and gait speed. This highlights the importance of reviewing remote monitoring PA data to identify patients who could benefit from existing interventions. Further research should investigate how to embed this into clinical pathways.

Abstract The glutamatergic modulator ketamine is associated with changes in sleep, depression, and suicidal ideation (SI). This study sought to evaluate differences in arousal-related sleep metrics between 36 individuals with treatment-resistant major depression (TRD) and 25 healthy volunteers (HVs). It also sought to determine whether ketamine normalizes arousal in individuals with TRD and whether ketamine’s effects on arousal mediate its antidepressant and anti-SI effects. This was a secondary analysis of a biomarker-focused, randomized, double-blind, crossover trial of ketamine (0.5 mg/kg) compared to saline placebo. Polysomnography (PSG) studies were conducted one day before and one day after ketamine/placebo infusions. Sleep arousal was measured using spectral power functions over time including alpha (quiet wakefulness), beta (alert wakefulness), and delta (deep sleep) power, as well as macroarchitecture variables, including wakefulness after sleep onset (WASO), total sleep time (TST), rapid eye movement (REM) latency, and Post-Sleep Onset Sleep Efficiency (PSOSE). At baseline, diagnostic differences in sleep macroarchitecture included lower TST (p = 0.006) and shorter REM latency (p = 0.04) in the TRD versus HV group. Ketamine’s temporal dynamic effects (relative to placebo) in TRD included increased delta power earlier in the night and increased alpha and delta power later in the night. However, there were no significant diagnostic differences in temporal patterns of alpha, beta, or delta power, no ketamine effects on sleep macroarchitecture arousal metrics, and no mediation effects of sleep variables on ketamine’s antidepressant or anti-SI effects. These results highlight the role of sleep-related variables as part of the systemic neurobiological changes initiated after ketamine administration. Clinical Trials Identifier: NCT00088699.

Background: Online physician reviews increase transparency in health care, helping patients make informed decisions about their provider. Language processing techniques can quantify this data and allow providers to better understand patients' experiences, perspectives, and priorities. The objective of this study was to assess patient satisfaction and understand the aspects of care that are valued by patients seeking refractive care using sentiment and word frequency analysis. Methods: Written reviews and Star ratings for members of the Refractive Surgery Alliance Society practicing in the United States were collected from Healthgrades, a popular physician rating website. Surgeons with at least one written review were included in the study. Reviews were scored from -1 (most negative) to +1 (most positive) using Valence Aware Dictionary sEntiment Reasoner (VADER). Reviews were stratified by demographic characteristics, namely gender, region, and years in practice. Word frequency analysis was applied to find the most common words and phrases. Results: A total of 254 specialists and 3104 reviews were analyzed, with an average of 4.4/5 stars and mean 48 ratings each. Most physicians had positive reviews (96%, average VADER ​= ​0.69). Younger physicians (20 years) (P ​

RATIONALE: Acute respiratory failure is a life-threatening clinical outcome in critically ill pediatric patients. In severe cases, patients can require mechanical ventilation (MV) for survival. Early recognition of these patients can potentially help clinicians alter the clinical course and lead to improved outcomes. OBJECTIVES: To build a data-driven model for early prediction of the need for mechanical ventilation in pediatric intensive care unit (PICU) patients. METHODS: The study consists of a single-center retrospective observational study on a cohort of 13,651 PICU patients admitted between 1/01/2010 and 5/15/2018 with a prevalence of 8.06% for MV due to respiratory failure. XGBoost (extreme gradient boosting) and a convolutional neural network (CNN) using medication history were used to develop a prediction model that could yield a time-varying risk-score-a continuous probability of whether a patient will receive MV-and an ideal global threshold was calculated from the receiver operating characteristics (ROC) curve. The early prediction point (EPP) was the first time the risk-score surpassed the optimal threshold, and the interval between the EPP and the start of the MV was the early warning period (EWT). Spectral clustering identified patient groups based on risk-score trajectories after EPP. RESULTS: A clinical and medication history-based model achieved a 0.89 area under the ROC curve (AUROC), 0.6 sensitivity, 0.95 specificity, 0.55 positive predictive value (PPV), and 0.95 negative predictive value (NPV). Early warning time (EWT) median [inter-quartile range] of this model was 9.9[4.2-69.2] hours. Clustering risk-score trajectories within a six-hour window after the early prediction point (EPP) established three patient groups, with the highest risk groups PPV being 0.92. CONCLUSIONS: This study uses a unique method to extract and apply medication history information, such as time-varying variables, to identify patients who may need mechanical ventilation for respiratory failure and provide an early warning period to avert it.

Abstract Background Social behavior and social organization have major influences on individual health and fitness. Yet, biomedical research focuses on studying a few genotypes under impoverished social conditions. Understanding how lab conditions have modified social organizations of model organisms, such as lab mice, relative to natural populations is a missing link between socioecology and biomedical science. Results Using a common garden design, we describe the formation of social structure in the well-studied laboratory mouse strain, C57BL/6J, in replicated mixed-sex populations over 10-day trials compared to control trials with wild-derived outbred house mice in outdoor field enclosures. We focus on three key features of mouse social systems: (i) territory establishment in males, (ii) female social relationships, and (iii) the social networks formed by the populations. Male territorial behaviors were similar but muted in C57 compared to wild-derived mice. Female C57 sharply differed from wild-derived females, showing little social bias toward cage mates and exploring substantially more of the enclosures compared to all other groups. Female behavior consistently generated denser social networks in C57 than in wild-derived mice. Conclusions C57 and wild-derived mice individually vary in their social and spatial behaviors which scale to shape overall social organization. The repeatable societies formed under field conditions highlights opportunities to experimentally study the interplay between society and individual biology using model organisms.

Case presentation. A 16-year-old female presented to the emergency department with a four-day history of right lower quadrant abdominal pain for several hours. The patient was afebrile and physical examination was notable for isolated tenderness in the right lower quadrant. Ultrasound and computed tomography demonstrated an adnexal cystic structure. Pelvic magnetic resonance imaging was ordered to better characterize the pathology. Discussion. Isolated fallopian tube torsion is an uncommon entity requiring prompt surgical intervention. Recognition and appropriate management are essential.

During academic activities, adolescents must manage both the internal distraction of mind-wandering and the external distraction of digital media. Attention training has emerged as a promising strategy for minimizing these distractions, but scalable interventions that can deliver effective attention training in high schools are still needed. The present investigation used a one-group pre-post design to examine the feasibility and outcomes of a digital attention training course at a public high school. The intervention was delivered with reasonably strong fidelity of implementation, with students completing 92% of the lessons and 79% of the daily exercises. At baseline, students reported mind-wandering more frequently during class than they multitasked, and mind-wandering was more negatively correlated with classroom focus. From pre-test to post-test (n = 229), students reported improved emotional regulation and reduced mind-wandering during daily life. Among the 76% of students who felt they paid attention in class less than they should, classroom focus improved significantly. During class, these students reported significantly less mind-wandering but slightly greater digital multitasking. During homework, they reported significantly less digital multitasking but only marginally reduced mind-wandering. Collectively, these results suggest that online interventions could be a scalable way of providing attention training in high schools, but that future work must consider the role of both mind-wandering and digital multitasking.

Heterochromatin spreading, the expansion of repressive chromatin structure from sequence-specific nucleation sites, is critical for stable gene silencing. Spreading re-establishes gene-poor constitutive heterochromatin across cell cycles but can also invade gene-rich euchromatin de novo to steer cell fate decisions. How chromatin context (i.e. euchromatic, heterochromatic) or different nucleation pathways influence heterochromatin spreading remains poorly understood. Previously, we developed a single-cell sensor in fission yeast that can separately record heterochromatic gene silencing at nucleation sequences and distal sites. Here we couple our quantitative assay to a genetic screen to identify genes encoding nuclear factors linked to the regulation of heterochromatin nucleation and the distal spreading of gene silencing. We find that mechanisms underlying gene silencing distal to a nucleation site differ by chromatin context. For example, Clr6 histone deacetylase complexes containing the Fkh2 transcription factor are specifically required for heterochromatin spreading at constitutive sites. Fkh2 recruits Clr6 to nucleation-distal chromatin sites in such contexts. In addition, we find that a number of chromatin remodeling complexes antagonize nucleation-distal gene silencing. Our results separate the regulation of heterochromatic gene silencing at nucleation versus distal sites and show that it is controlled by context-dependent mechanisms. The results of our genetic analysis constitute a broad community resource that will support further analysis of the mechanisms underlying the spread of epigenetic silencing along chromatin.

Case Presentation: A 16-year-old female presented to the emergency department with acute onset of right lower quadrant abdominal pain for several hours. The patient was afebrile and physical examination was notable for isolated tenderness in the right lower quadrant. Ultrasound and computed tomography demonstrated an adnexal cystic structure. Pelvic magnetic resonance imaging was ordered to better characterize the pathology.Discussion: Isolated fallopian tube torsion is an uncommon entity requiring prompt surgical intervention. Recognition and appropriate management are essential.

Learning Objectives: To survey graduating EM residents on their perceptions of the EM job market and its effect on their desire to pursue fellowship training.Background: The COVID-19 pandemic has resulted in changes to the emergency medicine (EM) workforce which pose challenges to residents graduating from EM training programs. New graduates face increasing uncertainty in the search for their first job. EM graduates in 2020 and 2021 saw a notable decrease in opportunities compared to years prior. ACEP’s Workforce Study (April 2021) predicts a surplus of emergency physicians by 2030. Objectives: To survey graduating EM residents on their perceptions of the EM job market and its effect on their desire to pursue fellowship training.Methods: We surveyed senior residents (PGY2 and above) at three- and four-year EM residency programs in the greater NYC area. Paper surveys were mailed out to each of the programs with a return envelope; a virtual link to complete the survey was also made available. Surveys were distributed from August 2021 to November 2021 to 22 EM residency programs (695 residents). Participation was voluntary and anonymous. The only demographic information gathered was program name and PGY level.Results: A total of 412 senior residents from the 22 EM residency programs completed the survey. Of the 412 seniors, 183 were PGY2s, 174 were PGY3s, and 55 were PGY4s and 5s (we included responses from residents in combined EM/IM programs). Survey questions and results are summarized in Table 1. Compared to colleagues in previous years, graduating EM residents anticipated broadening their job search. 58% of those considering fellowship after residency stated that their interest in fellowship has increased due to anticipated challenges in the job market (difficulty securing a full-time attending position).Conclusions: The majority of senior residents expressed concern about the current and future EM job market. How and where EM graduates apply for jobs may be impacted as a result. These data may prove valuable to residency programs, institutions, physician groups, and EM-bound medical students.

This study examines the adoption and implementation of an information system in a mandatory context focusing on an Israeli governmental organization. The system referred to as “Slot” is an online platform for managing educational activities within this organization. The research investigates the impact of the system on its functionality users and the results of its usage. Additionally, the study explores factors that influence the acceptance and utilization of information systems, including whether the willingness to use the system under instruction depends on other variables. The key findings of this study are: perceived ease of use significantly and positively influences perceived usefulness; perceived usefulness significantly and positively affects symbolic adoption; and supervisor influence significantly and positively impacts perceived usefulness. Moreover, the relationship between perceived ease of use and symbolic adoption is entirely mediated by perceived usefulness as is the relationship between supervisor influence and symbolic adoption. The study’s limitations include the relatively small sample size and the specific context of the research, which may limit the generalizability of the findings. Future research could explore similar models in different organizational settings to validate and extend the applicability of the results. The findings suggest that enhancing the perceived ease of use and usefulness of mandatory systems can significantly impact their symbolic adoption, with supervisory influence playing a crucial role in shaping user perceptions. These insights can inform strategies for more effective implementation and management of information systems in mandatory settings.

This study aimed to identify when and how eye movements change across the human lifespan to benchmark developmental biomarkers. The sample size comprised 45,696 participants, ranging in age from 6 to 80 years old (M = 30.39; SD = 17.46). Participants completed six eye movement tests: Circular Smooth Pursuit, Horizontal Smooth Pursuit, Vertical Smooth Pursuit, Horizontal Saccades, Vertical Saccades, and Fixation Stability. These tests examined all four major eye movements (fixations, saccades, pursuits, and vergence) using 89 eye-tracking algorithms. A semi-supervised, self-training, machine learning classifier was used to group the data into age ranges. This classifier resulted in 12 age groups: 6–7, 8–11, 12–14, 15–25, 26–31, 32–38, 39–45, 46–53, 54–60, 61–68, 69–76, and 77–80 years. To provide a descriptive indication of the strength of the self-training classifier, a series of multiple analyses of variance (MANOVA) were conducted on the multivariate effect of the age groups by test set. Each MANOVA revealed a significant multivariate effect on age groups (p < 0.001). Developmental changes in eye movements across age categories were identified. Specifically, similarities were observed between very young and elderly individuals. Middle-aged individuals (30s) generally showed the best eye movement metrics. Clinicians and researchers may use the findings from this study to inform decision-making on patients’ health and wellness and guide effective research methodologies.

Heterochromatin formation requires three distinct steps: nucleation, self-propagation (spreading) along the chromosome, and faithful maintenance after each replication cycle. Impeding any of those steps induces heterochromatin defects and improper gene expression. The essential histone chaperone FACT (facilitates chromatin transcription) has been implicated in heterochromatin silencing, but the mechanisms by which FACT engages in this process remain opaque. Here, we pinpoint its function to the heterochromatin spreading process in fission yeast. FACT impairment reduces nucleation-distal H3K9me3 and HP1/Swi6 accumulation at subtelomeres and derepresses genes in the vicinity of heterochromatin boundaries. FACT promotes spreading by repressing heterochromatic histone turnover, which is crucial for the H3K9me2 to me3 transition that enables spreading. FACT mutant spreading defects are suppressed by removal of the H3K9 methylation antagonist Epe1. Together, our study identifies FACT as a histone chaperone that promotes heterochromatin spreading and lends support to the model that regulated histone turnover controls the propagation of repressive methylation marks.

Background: Micronutrient deficiencies may occur after restorative proctocolectomy (RPC) with ileal pouch-anal anastomosis (IPAA) in patients with ulcerative colitis (UC), largely due to malabsorption and/or pouch inflammation. Objectives: The objective of this study was to report the frequency of iron deficiency in patients with UC who underwent RPC with IPAA and identify associated risk factors. Methods: We conducted a retrospective chart review of patients with UC or IBD-unclassified who underwent RPC with IPAA at Mount Sinai Hospital between 2008 and 2017. Patients younger than 18 years of age at the time of colectomy were excluded. Descriptive statistics were used to analyze baseline characteristics. Medians with interquartile range (IQR) were reported for continuous variables, and proportions were reported for categorical variables. Iron deficiency was defined by ferritin

Abstract Background When lengthening the tibia segment using motorized internal lengthening nails (MILN), undesired distal migration of the proximal fibula segment is prevented by tibiofibular stabilization, traditionally using a screw. A tightened cortical suspensory fixation rope (tether) is an alternative option, but its appropriateness has never been studied. The primary outcome was comparing the amount of proximal fibular migration between patients who were stabilized with either a tether or a screw. The secondary outcome was to evaluate the effect of fibular migration on the clinical outcome between both groups. Methods A retrospective study was conducted on patients who underwent tibial lengthening with MILN between April 2016 and June 2022. Two cohorts were compared: 18 limbs with tether fixation versus 29 limbs with screw fixation. Data on the patient's age, sex, etiologies, and clinical outcomes were collected. Radiographic measurements included the lengthening distance and the amount of proximal fibular migration. Results In total, 47 limbs from 41 patients, with average age 35.01 ± 13.72 years old. There were 28 males (68.29%) and 13 females (31.71%). The tether group demonstrated a statistically significant greater distance of migration than the screw group (p