Accuracy of frailty instruments in predicting outcomes following perioperative cardiac arrest.

BACKGROUND: Frailty is associated with increased 30-day mortality and non-home discharge following perioperative cardiac arrest. We estimated the predictive accuracy of frailty when added to baseline risk prediction models. METHODS: In this retrospective cohort study using 2015-2020 NSQIP data for 3048 patients aged 50+ undergoing non-cardiac surgery and resuscitation on post-operative day 0 (i.e., intraoperatively or postoperatively on the day of surgery), baseline models including age, sex, ASA physical status, preoperative sepsis or septic shock, and emergent surgery were compared to models that added frailty indices, either RAI or mFI-5, to predict 30-day mortality and non-home discharge. Predictive accuracy was characterized by area under the receiver operating characteristic curve (AUC-ROC), integrated calibration index (ICI), and continuous net reclassification index (NRI). RESULTS: 1786 patients (58.6%) died in the study cohort within 30 days, and 38.6% of eligible patients experienced non-home discharge. The baseline model showed good discrimination (AUC-ROC 0.77 for 30-day mortality and 0.74 for non-home discharge). AUC-ROC and ICI did not significantly change after adding frailty for 30-day mortality or non-home discharge. Adding RAI significantly improved NRI for 30-day mortality and non-home discharge; however, the magnitude was small and difficult to interpret, given other results including false positive and negative rates showing no difference in predictive accuracy. CONCLUSIONS: Incorporating frailty did not significantly improve predictive accuracy of models for 30-day mortality and non-home discharge following perioperative resuscitation. Thus, demonstrated associations between frailty and outcomes of perioperative resuscitation may not translate into improved predictive accuracy. When engaging patients in shared decision-making regarding do-not-resuscitate orders perioperatively, providers should acknowledge uncertainty in anticipating resuscitation outcomes.

COVID-19 Medicaid Continuous Enrollment Provision Yielded Gains In Postpartum Continuity Of Coverage.

The Medicaid continuous enrollment provision mandated by the Families First Coronavirus Response Act of 2020 effectively prohibited the termination of enrollees from Medicaid during the COVID-19 public health emergency, including people enrolled in Medicaid during pregnancy. Using data from the Transformed Medicaid Statistical Information System, we found that the rate of continuous Medicaid enrollment during the twelve months postpartum increased from 59.3 percent for births during March-December 2018 to 90.7 percent for births during March-December 2020, when the public health emergency was in effect. This corresponds to approximately 430,000 fewer people losing Medicaid coverage after pregnancy and an average of more than 2.5 months of additional postpartum enrollment. These findings indicate that states that have extended or that plan to extend pregnancy-related Medicaid eligibility in the postpartum year are likely to experience significant gains in continuity of coverage.

Pycallingcards: an integrated environment for visualizing, analyzing, and interpreting Calling Cards data.

MOTIVATION: Unraveling the transcriptional programs that control how cells divide, differentiate, and respond to their environments requires a precise understanding of transcription factors' (TFs) DNA-binding activities. Calling cards (CC) technology uses transposons to capture transient TF binding events at one instant in time and then read them out at a later time. This methodology can also be used to simultaneously measure TF binding and mRNA expression from single-cell CC and to record and integrate TF binding events across time in any cell type of interest without the need for purification. Despite these advantages, there has been a lack of dedicated bioinformatics tools for the detailed analysis of CC data. RESULTS: We introduce Pycallingcards, a comprehensive Python module specifically designed for the analysis of single-cell and bulk CC data across multiple species. Pycallingcards introduces two innovative peak callers, CCcaller and MACCs, enhancing the accuracy and speed of pinpointing TF binding sites from CC data. Pycallingcards offers a fully integrated environment for data visualization, motif finding, and comparative analysis with RNA-seq and ChIP-seq datasets. To illustrate its practical application, we have reanalyzed previously published mouse cortex and glioblastoma datasets. This analysis revealed novel cell-type-specific binding sites and potential sex-linked TF regulators, furthering our understanding of TF binding and gene expression relationships. Thus, Pycallingcards, with its user-friendly design and seamless interface with the Python data science ecosystem, stands as a critical tool for advancing the analysis of TF functions via CC data. AVAILABILITY AND IMPLEMENTATION: Pycallingcards can be accessed on the GitHub repository: https://github.com/The-Mitra-Lab/pycallingcards.

Systems Engineering Approach to Modeling and Analysis of Chronic Obstructive Pulmonary Disease Part II: Extension for Variable Metabolic Rates.

Recently, we developed a systems engineering model of the human cardiorespiratory system [Kurian et al. ACS Omega2023, 8 (23), 20524-20535. DOI: 10.1021/acsomega.3c00854] based on existing models of physiological processes and adapted it for chronic obstructive pulmonary disease (COPD)-an inflammatory lung disease with multiple manifestations and one of the leading causes of death in the world. This control engineering-based model is extended here to allow for variable metabolic rates established at different levels of physical activity. This required several changes to the original model: the model of the controller was enhanced to include the feedforward loop that is responsible for cardiorespiratory control under varying metabolic rates (activity level, characterized as metabolic equivalent of the task-Rm-and normalized to one at rest). In addition, a few refinements were made to the cardiorespiratory mechanics, primarily to introduce physiological processes that were not modeled earlier but became important at high metabolic rates. The extended model is verified by analyzing the impact of exercise (Rm > 1) on the cardiorespiratory system of healthy individuals. We further formally justify our previously proposed adaptation of the model for COPD patients through sensitivity analysis and refine the parameter tuning through the use of a parallel tempering stochastic global optimization method. The extended model successfully replicates experimentally observed abnormalities in COPD-the drop in arterial oxygen tension and dynamic hyperinflation under high metabolic rates-without being explicitly trained on any related data. It also supports the prospects of remote patient monitoring in COPD.

Preferences for virtual versus in-person mental and physical healthcare in Canada: a descriptive study from a cohort of youth and their parents enriched for severe mental illness.

BACKGROUND: Virtual care may improve access to healthcare and may be well suited to digitally connected youth, but experts caution that privacy and technology barriers could perpetuate access inequities. Success of virtual care will depend on its alignment with patient preferences. However, information on preferences for virtual and in-person healthcare is missing, especially for youth. We sought to quantify preferences for and barriers to virtual versus in-person mental and physical healthcare in youth and their parents, including in vulnerable segments of the population such as families with a parent with severe mental illness (SMI). METHODS: Participants were 219 youth and 326 parents from the Families Overcoming Risks and Building Opportunities for Wellbeing cohort from Canada, of which 61% of youth had at least one parent with SMI. Participants were interviewed about healthcare preferences and access to privacy/technology between October 2021 and December 2022. RESULTS: Overall, youth reported a preference for in-person mental (66.6%) and physical healthcare (74.7%) versus virtual care or no preference, and to a somewhat lesser degree, so did their parents (48.0% and 53.9%). Half of participants reported privacy/technology barriers to virtual care, with privacy being the most common barrier. Preferences and barriers varied as a function of parent SMI status, socioeconomic status and rural residence. CONCLUSIONS: The majority of youth and parents in this study prefer in-person healthcare, and the preference is stronger in youth and in vulnerable segments of the population. Lack of privacy may be a greater barrier to virtual care than access to technology.

Degradation of amyloid beta species by multi-copper oxidases.

Reduction of the production of amyloid beta (Aß) species has been intensively investigated as potential therapeutic approaches for Alzheimer's disease (AD). However, the degradation of Aß species, another potential beneficial approach, has been far less explored. In this study, we discovered that ceruloplasmin (CP), an important multi-copper oxidase (MCO) in human blood, could degrade Aß peptides. We also found that the presence of Vitamin C could enhance the degrading effect in a concentration-dependent manner. We then validated the CP-Aß interaction using total internal reflection fluorescence (TIRF) microscopy, fluorescence photometer, and fluorescence polarization measurement. Based on the above discovery, we hypothesized that other MCOs had similar Aß-degrading functions. Indeed, we found that other MCOs could induce Aß degradation as well. Remarkably, we revealed that ascorbate oxidase (AO) had the strongest degrading effect among the tested MCOs. Using induced pluripotent stem (iPS) neuron cells, we observed that AO could rescue neuron toxicity which induced by Aß oligomers. In addition, our electrophysiological analysis with brain slices suggested that AO could prevent an Ab-induced deficit in synaptic transmission in the hippocampus. To the best of our knowledge, our report is the first to demonstrate that MCOs have a degrading function for peptides/proteins. Further investigations are warranted to explore the possible benefits of MCOs for future AD treatment.

Systems Engineering Approach to Modeling and Analysis of Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by airflow limitation. This study develops a systems engineering framework for representing important mechanistic details of COPD in a model of the cardiorespiratory system. In this model, we present the cardiorespiratory system as an integrated biological control system responsible for regulating breathing. Four engineering control system components are considered: sensor, controller, actuator, and the process itself. Knowledge of human anatomy and physiology is used to develop appropriate mechanistic mathematical models for each component. Following a systematic analysis of the computational model, we identify three physiological parameters associated with reproducing clinical manifestations of COPD: changes in the forced expiratory volume, lung volumes, and pulmonary hypertension. We quantify the changes in these parameters (airway resistance, lung elastance, and pulmonary resistance) as the ones that result in a systemic response that is diagnostic of COPD. A multivariate analysis of the simulation results reveals that the changes in airway resistance have a broad impact on the human cardiorespiratory system and that the pulmonary circuit is stressed beyond normal under hypoxic environments in most COPD patients.

Empirical progression criteria thresholds for feasibility outcomes in HIV clinical trials: a methodological study.

INTRODUCTION: Pilot and feasibility trials use predetermined thresholds for feasibility outcomes to decide if a larger trial is feasible. These thresholds may be derived from the literature, observational data, or clinical experience. The aim of this study was to determine empirical estimates for feasibility outcomes to inform future HIV pilot randomized trials. METHODS: We conducted a methodological study of HIV clinical trials indexed in the past 5 years (2017-2021) in the PubMed database. We included trials of people living with HIV individually randomized to any type of intervention and excluded pilot trials and cluster randomized trials. Screening and data extraction were conducted in duplicate. We computed estimates for recruitment, randomization, non-compliance, lost to follow-up, discontinuation, and the proportion analyzed using a random effects meta-analysis of proportions and reported these estimates according to the following subgroups: use of medication, intervention type, trial design, income level, WHO region, participant type, comorbidities, and source of funding. We report estimates with 95% confidence intervals. RESULTS: We identified 2122 studies in our search, of which 701 full texts were deemed relevant, but only 394 met our inclusion criteria. We found the following estimates: recruitment (64.1%; 95% CI 57.7 to 70.3; 156 trials); randomization (97.1%; 95% CI 95.8 to 98.3; 187 trials); non-compliance (3.8%; 95% CI 2.8 to 4.9; 216 trials); lost to follow-up (5.8%; 95% CI 4.9 to 6.8; 251 trials); discontinuation (6.5%; 95% CI 5.5 to 7.5; 215 trials); analyzed (94.2%; 95% CI 92.9 to 95.3; 367 trials). There were differences in estimates across most subgroups. CONCLUSION: These estimates may be used to inform the design of HIV pilot randomized trials with careful consideration of variations due to some of the subgroups investigated.

Fragility of statistically significant outcomes in randomized trials comparing bariatric surgeries.

BACKGROUND: Randomized controlled trials (RCTs) are regarded as high-level evidence, but the strength of their P values can be difficult to ascertain. The Fragility Index (FI) is a novel metric that evaluates the frailty of trial findings. It is defined as the minimum number of patients required to change from a non-event to event for the findings to lose statistical significance. This study aims to characterize the robustness of bariatric surgery RCTs by examining their FIs. METHODS: A search was conducted in MEDLINE, EMBASE, and CENTRAL from January 2000 to February 2022 for RCTs comparing two bariatric surgeries with statistically significant dichotomous outcomes. Bivariate correlation was conducted to identify associations between FI and trial characteristics. RESULTS: A total of 35 RCTs were included with a median sample size of 80 patients (Interquartile range [IQR] 58-109). The median FI was 2 (IQR 0-5), indicating that altering the status of two patients in one treatment arm would overturn the statistical significance of results. Subgroup analyses of RCTs evaluating diabetes-related outcomes produced a FI of 4 (IQR 2-6.5), while RCTs comparing Roux-en-Y gastric bypass and sleeve gastrectomy had an FI of 2 (IQR 0.5-5). Increasing FI was found to be correlated with decreasing P value, increasing sample size, increasing number of events, and increasing journal impact factor. CONCLUSION: Bariatric surgery RCTs are fragile, with only a few patients required to change from non-events to events to reverse the statistical significance of most trials. Future research should examine the use of FI in trial design.

Fragility of statistically significant findings from randomized trials in comparing laparoscopic versus robotic abdominopelvic surgeries.

BACKGROUND: Utility of robotic over laparoscopic approach has been an area of debate across all surgical specialties over the past decade. The fragility index (FI) is a metric that evaluates the frailty of randomized controlled trials (RCTs) findings by altering the status of patients from an event to non-event until significance is lost. This study aims to evaluate the robustness of RCTs comparing laparoscopic and robotic abdominopelvic surgeries through the FI. METHODS: A search was conducted in MEDLINE and EMBASE for RCTs with dichotomous outcomes comparing laparoscopic and robot-assisted surgery in general surgery, gynecology, and urology. The FI and reverse fragility Index (RFI) metrics were used to assess the strength of findings reported by RCTs, and bivariate correlation was conducted to analyze relationships between FI and trial characteristics. RESULTS: A total of 21 RCTs were included, with a median sample size of 89 participants (Interquartile range [IQR] 62-126). The median FI was 2 (IQR 0-15) and median RFI 5.5 (IQR 4-8.5). The median FI was 3 (IQR 1-15) for general surgery (n = 7), 2 (0.5-3.5) for gynecology (n = 4), and 0 (IQR 0-8.5) for urology RCTs (n = 4). Correlation was found between increasing FI and decreasing p-value, but not sample size, number of outcome events, journal impact factor, loss to follow-up, or risk of bias. CONCLUSION: RCTs comparing laparoscopic and robotic abdominal surgery did not prove to be very robust. While possible advantages of robotic surgery may be emphasized, it remains novel and requires further concrete RCT data.

Performance on Patient Experience Measures of Former Chief Medical Residents as Physician Exemplars Chosen by the Profession.

Importance: Physicians' knowledge about each other's quality is central to clinical decision-making, but such information is not well understood and is rarely harnessed to identify exemplars for disseminating best practices or quality improvement. One exception is chief medical resident selection, which is typically based on interpersonal, teaching, and clinical skills. Objective: To compare care for patients of primary care physicians (PCPs) who were former chiefs with care for patients of nonchief PCPs. Design, Setting, and Participants: Using 2010 to 2018 Medicare Fee-For-Service Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey data (response rate, 47.6%), Medicare claims for random 20% samples of fee-for-service beneficiaries, and medical board data from 4 large US states, we compared care for patients of former chief PCPs with care for patients of nonchief PCPs in the same practice using linear regression. Data were analyzed from August 2020 to January 2023. Exposures: Receiving the plurality of primary care office visits from a former chief PCP. Main Outcomes and Measures: Composite of 12 patient experience items as primary outcome and 4 spending and utilization measures as secondary outcomes. Results: The CAHPS samples included 4493 patients with former chief PCPs and 41 278 patients with nonchief PCPs. The 2 groups were similar in age (mean [SD], 73.1 [10.3] years vs 73.2 [10.3] years), sex (56.8% vs 56.8% female), race and ethnicity (1.2% vs 1.0% American Indian or Alaska Native, 1.3% vs 1.9% Asian or Pacific Islander, 4.8% vs. 5.6% Hispanic, 7.3% vs 6.6% non-Hispanic Black, and 81.5% vs. 80.0% non-Hispanic White), and other characteristics. The Medicare claims for random 20% samples included 289 728 patients with former chief PCPs and 2 954 120 patients with nonchief PCPs. Patients of former chief PCPs rated their care experiences significantly better than patients of nonchief PCPs (adjusted difference in composite, 1.6 percentage points; 95% CI, 0.4-2.8; effect size of 0.30 standard deviations (SD) of the physician-level distribution of performance; P = .01), including markedly higher ratings of physician-specific communication and interpersonal skills typically emphasized in chief selection. Differences were large for patients of racial and ethnic minority groups (1.16 SD), dual-eligible patients (0.81 SD), and those with less education (0.44 SD) but did not vary significantly across groups. Differences in spending and utilization were minimal overall. Conclusions and Relevance: In this study, patients of PCPs who were former chief medical residents reported better care experiences than patients of other PCPs in the same practice, especially for physician-specific items. The study results suggest that the profession possesses information about physician quality, motivating the development and study of strategies for harnessing such information to select and repurpose exemplars for quality improvement.

Long noncoding RNA GATA2-AS1 augments endothelial hypoxia inducible factor 1-α induction and regulates hypoxic signaling.

Vascular endothelial cells form the inner cellular lining of blood vessels and have myriad physiologic functions including angiogenesis and response to hypoxia. We recently identified a set of endothelial cell (EC)-enriched long noncoding RNAs (lncRNAs) in differentiated human primary cell types and described the role of the STEEL lncRNA in angiogenic patterning. We sought to further understand the role of EC-enriched lncRNAs in physiologic adaptation of the vascular endothelium. In this work, we describe an abundant, cytoplasmic, and EC-enriched lncRNA, GATA2-AS1, that is divergently transcribed from the EC-enriched developmental regulator, GATA2. While GATA2-AS1 is largely coexpressed with GATA2 in ECs, GATA2-AS1 and GATA2 appear to be complementary rather than synergistic as they have mostly distinct target genes. Common single nucleotide variants in GATA2-AS1 exons are associated with early-onset coronary artery disease and decreased expression of GATA2-AS1 in endothelial cell lines. In most cells, HIF1-α is central to the transcriptional response to hypoxia, while in ECs, both HIF1-α and HIF2-α are required to coordinate an acute and chronic response, respectively. In this setting, GATA2-AS1 contributes to the "HIF switch" and augments HIF1-α induction in acute hypoxia to regulate HIF1-α/HIF2-α balance. In hypoxia, GATA2-AS1 orchestrates HIF1-α-dependent induction of the glycolytic pathway and HIF1-α-independent maintenance of mitochondrial biogenesis. Similarly, GATA2-AS1 coordinates both metabolism and "tip/stalk" cell signaling to regulate angiogenesis in hypoxic ECs. Furthermore, we find that GATA2-AS1 expression patterns are perturbed in atherosclerotic disease. Together, these results define a role for GATA2-AS1 in the EC-specific response to hypoxia.

Highly synchronized cortical circuit dynamics mediate spontaneous pain in mice.

Cortical neural dynamics mediate information processing for the cerebral cortex, which is implicated in fundamental biological processes such as vision and olfaction, in addition to neurological and psychiatric diseases. Spontaneous pain is a key feature of human neuropathic pain. Whether spontaneous pain pushes the cortical network into an aberrant state and, if so, whether it can be brought back to a "normal" operating range to ameliorate pain are unknown. Using a clinically relevant mouse model of neuropathic pain with spontaneous pain-like behavior, we report that orofacial spontaneous pain activated a specific area within the primary somatosensory cortex (S1), displaying synchronized neural dynamics revealed by intravital two-photon calcium imaging. This synchronization was underpinned by local GABAergic interneuron hypoactivity. Pain-induced cortical synchronization could be attenuated by manipulating local S1 networks or clinically effective pain therapies. Specifically, both chemogenetic inhibition of pain-related c-Fos-expressing neurons and selective activation of GABAergic interneurons significantly attenuated S1 synchronization. Clinically effective pain therapies including carbamazepine and nerve root decompression could also dampen S1 synchronization. More important, restoring a "normal" range of neural dynamics through attenuation of pain-induced S1 synchronization alleviated pain-like behavior. These results suggest that spontaneous pain pushed the S1 regional network into a synchronized state, whereas reversal of this synchronization alleviated pain.

Severe ovarian hyperstimulation syndrome requiring recurrent large-volume paracenteses until 21 weeks' gestation: a case report.

Objective: To report a case of severe ovarian hyperstimulation syndrome (OHSS) persisting into the late second trimester of a singleton pregnancy. Design: Case report. Setting: Academic tertiary care center. Patients: A 29-year-old woman with severe OHSS after fresh embryo transfer after controlled ovarian hyperstimulation requiring intervention until 21 weeks' gestation in a singleton pregnancy. Interventions: Thorough evaluation of an unusual case of severe OHSS and medical/procedural management of its sequelae in the setting of ongoing pregnancy. Main Outcome Measuress: The clinical development of severe OHSS during pregnancy and its effect on pregnancy outcomes. Results: Severe OHSS persisted until 21 weeks' gestation with reaccumulating ascitic fluid, which impacted pregnancy outcomes. Conclusions: Clinicians should be aware of the risk of severe OHSS and its possible effect on pregnancy outcomes beyond the first trimester.

Trends in postpartum mental health care before and during COVID-19.

OBJECTIVE: To assess the impact of COVID-19 on trends in postpartum mental health diagnoses and utilization of psychotherapy and prescription drug treatment. DATA SOURCES: Data were obtained from a large, national health insurance claims database that tracks individuals longitudinally. STUDY DESIGN: We used interrupted time series models to examine changes in trends of postpartum mental health diagnoses before and during the COVID-19 pandemic and t-tests to examine differences in treatment. DATA EXTRACTION METHODS: We used billing codes to identify individuals who received mental health-related diagnoses and treatment in the first 90 days after a birth hospitalization. We excluded individuals diagnosed with schizophrenia or bipolar disorder and those with an unknown payer at delivery. PRINCIPAL FINDINGS: Compared to the pre-pandemic period, the trend in new postpartum mental health diagnoses increased significantly in the post-COVID-19 period (0.06 percentage points [95%CI 0.01, 0.11]). Over 12 months, the percentage of new diagnoses was 5.0% greater relative to what would be expected in absence of COVID-19. The percentage of diagnosed individuals who did not receive treatment increased from 50.4% to 52.7% (p = 0.003). CONCLUSIONS: Findings point to an urgent need to improve screening and treatment pathways for perinatal individuals in the wake of COVID-19.

Electroacupuncture attenuates surgical pain-induced delirium-like behavior in mice via remodeling gut microbiota and dendritic spine.

Surgical pain is associated with delirium in patients, and acupuncture can treat pain. However, whether electroacupuncture can attenuate the surgical pain-associated delirium via the gut-brain axis remains unknown. Leveraging a mouse model of foot incision-induced surgical pain and delirium-like behavior, we found that electroacupuncture stimulation at specific acupoints (e.g., DU20+KI1) attenuated both surgical pain and delirium-like behavior in mice. Mechanistically, mice with incision-induced surgical pain and delirium-like behavior showed gut microbiota imbalance, microglia activation in the spinal cord, somatosensory cortex, and hippocampus, as well as an enhanced dendritic spine elimination in cortex revealed by two-photon imaging. The electroacupuncture regimen that alleviated surgical pain and delirium-like behavior in mice also effectively restored the gut microbiota balance, prevented the microglia activation, and reversed the dendritic spine elimination. These data demonstrated a potentially important gut-brain interactive mechanism underlying the surgical pain-induced delirium in mice. Pending further studies, these findings revealed a possible therapeutic approach in preventing and/or treating postoperative delirium by using perioperative electroacupuncture stimulation in patients.