Trends and predictors of decompressive craniectomy in acute ischemic stroke, 2011-2020.

INTRODUCTION: Rates of decompressive craniectomy (DC) in acute ischemic stroke (AIS) have been reported to decline over time, attributed to an increase in endovascular therapy (EVT) preventing the development of malignant cerebral edema. We sought to characterize trends in DC in AIS between 2011 and 2020. MATERIAL AND METHODS: We performed a retrospective observational study of U.S. AIS hospitalizations using the National Inpatient Sample, 2011 to 2020. We calculated rates of DC per 10,000 AIS among all AIS hospitalizations, as well as AIS hospitalizations undergoing invasive mechanical ventilation (IMV). A logistic regression to determine predictors of DC was performed. RESULTS: Of ∼4.4 million AIS hospitalizations, 0.5 % underwent DC; of ∼300,000 AIS with IMV, 5.8 % underwent DC. From 2011 to 2020, the rate of DC increased from 37.4 to 59.1 per 10,000 AIS (p < 0.001). The rate of DC in patients undergoing IMV remained stable at ∼550 per 10,000 (p = 0.088). The most important factors predicting DC were age (OR 4.88, 95 % CI 4.53-5.25), hospital stroke volume (OR 2.61, 95 % CI 2.17-3.14), hospital teaching status (OR 1.54, 95 % CI 1.36-1.75), and transfer status (OR 1.53, 95 % CI 1.41-1.66); EVT status did not predict DC. CONCLUSIONS: The rate of DC in AIS has increased between 2011 and 2020. Our findings are contrary to prior reports of decreasing DC rates over time. Increasing EVT rates do not seem to be preventing the occurrence of DC. Future research should focus on the decision-making process for both clinicians and surrogates regarding DC with consideration of long-term outcomes.

Spontaneous Hypothermia As an Indicator of Early Diffuse Anoxic Brain Injury in Post-Cardiac Arrest Patients.

OBJECTIVES: To determine the association between spontaneous hypothermia (SH), defined as initial post-resuscitation core body temperature less than 34°C, and diffuse anoxic brain injury (DABI) on initial CT scan of the head (CTH) in post-cardiac arrest patients. DESIGN SETTING AND PARTICIPANTS: This was a retrospective, observational cohort study. This study was performed at the University of Rochester Medical Center Strong Memorial Hospital. All in-hospital and out-of-hospital cardiac arrest patients with return of spontaneous circulation admitted between January 1, 2022, and October 31, 2022, were included. MAIN OUTCOMES AND MEASURES: The primary outcomes were the odds of DABI on initial CTH for patients with SH compared with patients without SH post-cardiac arrest using a multivariable logistic regression controlling for patient covariates including basic demographics and arrest features. DABI on initial CTH was measured qualitatively and quantitatively using neuroradiologist interpretation and calculated gray-white matter ratio of the basal ganglia, respectively. Secondary outcome measures included length of stay (LOS), inpatient mortality, and those who underwent withdrawal of life-sustaining therapy (WOLST) or progression to brain death. RESULTS: Out of the observed 150 cases of cardiac arrest, 31 patients (21%) had SH. Of the 128 patients who had an initial CTH performed, 27 (21%) had DABI. The adjusted odds ratio of DABI on initial CTH associated with SH was 3.55 (95% CI, 1.08-11.64; p = 0.036) and 2.18 (95% CI, 0.69-6.91; p = 0.182) when DABI was measured qualitatively and quantitatively, respectively, after controlling for multiple covariates. There was a difference observed in LOS between the groups (3 vs. 10 d; p = 0.0005) and this was driven by early WOLST. CONCLUSIONS AND REVELANCE: Patients presenting with SH after cardiac arrest may be at greater risk of early DABI on initial CTH compared with those with higher body temperatures in the post-arrest period. Recognition of early SH may help to risk stratify post-cardiac arrest patients at highest risk of DABI.

Invasive Nodal Staging via Endobronchial Ultrasound and Outcome in Patients Treated with Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer - Results from a Single Institution Study.

INTRODUCTION: Stereotactic body radiation therapy (SBRT) is an effective treatment for medically inoperable early-stage non-small cell lung cancer (NSCLC). The prognostic value of invasive nodal staging (INS) for patients undergoing SRBT has not been studied extensively. Herein, we report the impact of INS in addition to 18F-FDG-PET on treatment outcome for patients with NSCLC undergoing SBRT. MATERIALS AND METHODS: Patients with stage I/ II NSCLC who underwent SBRT were included with IRB approval. Clinical, dosimetric, and radiological data were obtained. Overall survival (OS), regional recurrence free survival (RRFS), local recurrence free survival (LRFS), and distant recurrence free survival (DRFS) were analyzed using Kaplan Meyer method. Univariable analysis (UVA) and multivariable analysis (MVA) were performed to assess the relationship between the variables and the outcomes. RESULTS: A total of 376 patients were included in the analysis. Median follow up was 43 months (IQ 32.6-45.8). Median OS, LRFS, RRFS, DRFS were 40, 32, 32, 33 months, respectively. The 5-year local, regional, and distant failure rates were 13.4%, 23.5% and 25.3%, respectively. The 1-year, 3-year and 5-year OS were 83.8%, 55.6%, and 36.3%, respectively. On MVA, INS was not a predictor of either improved overall or any recurrence free survival endpoints while larger tumor size, age, and adjusted Charleston co-morbidity index (aCCI) were significant for inferior LRFS, RRFS, and DRFS. CONCLUSION: Invasive nodal staging did not improve overall or recurrence free survival among patients with early-stage NSCLC treated with SBRT whereas older age, aCCI, and larger tumor size were significant predictors of LRFS, RRFS, and DRFS.

Black Cohosh Interactions with Prescription Medications Associated with Serotonin Toxicity and Rhabdomyolysis: A Case Report.

BACKGROUND: Serotonin toxicity is a well-described phenomenon that is commonly attributed to a variety of drug-drug combinations. Some unregulated herbal supplements have been implicated in the onset of serotonin toxicity, however, there is currently minimal literature available on the potential for black cohosh to contribute to rhabdomyolysis and serotonin toxicity, in spite of its known serotonergic properties. CASE REPORT: A middle-aged woman presented to the emergency department with serotonin toxicity and rhabdomyolysis shortly after taking black cohosh supplements in the setting of long-term dual antidepressant use. The serotonin toxicity and rhabdomyolysis resolved with IV fluids, benzodiazepines, and discontinuation of the offending drugs. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Patients are sometimes not aware of how over-the-counter supplements might interact with their prescription medications. Female patients taking black cohosh to manage hot flashes and menopausal symptoms could be at risk for developing rhabdomyolysis and serotonin toxicity if they are also taking other serotonergic agents.

Impact of the COVID-19 Pandemic on Inpatient Utilization for Acute Neurologic Disease.

Background and Objective: The initial months of the Corona Virus 2019 (COVID-19) pandemic resulted in decreased hospitalizations. We aimed to describe differences in hospitalizations and related procedures across neurologic disease. Methods: In our retrospective observational study using the California State Inpatient Database and state-wide population-level estimates, we calculated neurologic hospitalization rates for a control period from January 2019 to February 2020 and a COVID-19 pandemic period from March to December 2020. We calculated incident rate ratios (IRR) for neurologic hospitalizations using negative binomial regression and compared relevant procedure rates over time. Results: Population-based neurologic hospitalization rates were 29.1 per 100,000 (95% CI 26.9-31.3) in April 2020 compared to 43.6 per 100,000 (95% CI 40.4-46.7) in January 2020. Overall, the pandemic period had 13% lower incidence of neurologic hospitalizations per month (IRR 0.87, 95% CI 0.86-0.89). The smallest decreases were in neurotrauma (IRR 0.92, 95% CI 0.89-0.95) and neuro-oncologic cases (IRR 0.93, 95% CI 0.87-0.99). Headache admissions experienced the greatest decline (IRR 0.62, 95% CI 0.58-0.66). For ischemic stroke, greater rates of endovascular thrombectomy (5.6% vs 5.0%; P < .001) were observed in the pandemic. Among all neurologic disease, greater rates of gastrostomy (4.0% vs 3.5%; P < .001), intubation/mechanical ventilation (14.3% vs 12.9%, P < .001), and tracheostomy (1.4 vs 1.2%; P < .001) were observed during the pandemic. Conclusions: During the first months of the COVID-19 pandemic there were fewer hospitalizations to varying degrees for all neurologic diagnoses. Rates of procedures indicating severe disease increased. Further study is needed to determine the impact on triage, patient outcomes, and cost consequences.

A Technique to Enable Efficient Adaptive Radiation Therapy: Automated Contouring of Prostate and Adjacent Organs.

Purpose: The purpose of this work was to investigate the use of a segmentation approach that could potentially improve the speed and reproducibility of contouring during magnetic resonance-guided adaptive radiation therapy. Methods and Materials: The segmentation algorithm was based on a hybrid deep neural network and graph optimization approach that also allows rapid user intervention (Deep layered optimal graph image segmentation of multiple objects and surfaces [LOGISMOS] + just enough interaction [JEI]). A total of 115 magnetic resonance-data sets were used for training and quantitative assessment. Expert segmentations were used as the independent standard for the prostate, seminal vesicles, bladder, rectum, and femoral heads for all 115 data sets. In addition, 3 independent radiation oncologists contoured the prostate, seminal vesicles, and rectum for a subset of patients such that the interobserver variability could be quantified. Consensus contours were then generated from these independent contours using a simultaneous truth and performance level estimation approach, and the deviation of Deep LOGISMOS + JEI contours to the consensus contours was evaluated and compared with the interobserver variability. Results: The absolute accuracy of Deep LOGISMOS + JEI generated contours was evaluated using median absolute surface-to-surface distance which ranged from a minimum of 0.20 mm for the bladder to a maximum of 0.93 mm for the prostate compared with the independent standard across all data sets. The median relative surface-to-surface distance was less than 0.17 mm for all organs, indicating that the Deep LOGISMOS + JEI algorithm did not exhibit a systematic under- or oversegmentation. Interobserver variability testing yielded a mean absolute surface-to-surface distance of 0.93, 1.04, and 0.81 mm for the prostate, seminal vesicles, and rectum, respectively. In comparison, the deviation of Deep LOGISMOS + JEI from consensus simultaneous truth and performance level estimation contours was 0.57, 0.64, and 0.55 mm for the same organs. On average, the Deep LOGISMOS algorithm took less than 26 seconds for contour segmentation. Conclusions: Deep LOGISMOS + JEI segmentation efficiently generated clinically acceptable prostate and normal tissue contours, potentially limiting the need for time intensive manual contouring with each fraction.

Association of Do-Not-Resuscitate orders and in-hospital mortality among patients undergoing cranial neurosurgery.

BACKGROUND: Previous studies identified pre-existing DNR orders as a predictor of mortality after surgery. We sought to evaluate mortality of patients receiving cranial neurosurgery with DNR orders placed at the time of, or within 24 h of admission. METHODS: We performed a retrospective cohort study using the California State Inpatient Database, January 2018 to December 2020. We used International Classification of Diseases, 10th Revision (ICD-10) codes to identify emergent hospitalizations with principal diagnosis of brain injury, including traumatic brain injury [TBI], ischemic stroke [IS], intracerebral hemorrhage [ICH], subarachnoid hemorrhage [SAH], or malignant brain tumor [mBT]. We used procedure and Diagnosis Related Group codes to identify cranial neurosurgery. Patients with DNR were one-to-one matched to non-DNR controls based on diagnosis (exact matching), age, sex, Elixhauser comorbidity index, and organ failure (coarsened matching). The primary outcome was inpatient mortality. RESULTS: In California, 30,384 patients underwent cranial neurosurgery, 2018-2020 (n = 3,112, 10% DNR). DNR patients were older, more often female, more often White, with greater comorbidity and organ system dysfunction. There were 2,505 patients with DNR orders 1:1 matched to controls. Patients with DNR had greater inpatient mortality (56% vs. 23%, p < 0.001; Hazard Ratio 3.11, 95% CI 2.50-3.86), received tracheostomy (Odds Ratio [OR] 0.37, 95% CI 0.24-0.57) and gastrostomy less (OR 0.48, 95% CI 0.39-0.58) compared to controls. Multivariable analysis of the unmatched cohort demonstrated similar results. CONCLUSION: Patients undergoing cranial neurosurgery with early or pre-existing DNR have high inpatient mortality compared to clinically similar non-DNR patients; 1 in 2 died during their hospitalization.

National Cost Estimates of Invasive Mechanical Ventilation and Tracheostomy in Acute Stroke, 2008-2017.

BACKGROUND: Patients with stroke receiving invasive mechanical ventilation (IMV) and tracheostomy incur intense treatment and long hospitalizations. We aimed to evaluate US hospitalization costs for patients with stroke requiring IMV, tracheostomy, or no ventilation. METHODS: We performed a retrospective observational study of US hospitalizations for acute ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage receiving IMV, tracheostomy, or none using the National Inpatient Sample, 2008 to 2017. We calculated hospitalization costs using cost-to-charge ratios adjusted to 2017 US dollars for inpatients with stroke by ventilation status (no IMV, IMV alone, tracheostomy). RESULTS: Of an estimated 5.2 million (95% CI, 5.1-5.3) acute stroke hospitalizations, 2008 to 2017; 9.4% received IMV alone and 1.4% received tracheostomy. Length of stay for patients without IMV was shorter (median, 4 days; interquartile range [IQR], 2-6) compared with IMV alone (median, 6 days; [IQR, 2-13]), and tracheostomy (median, 25 days; [IQR, 18-36]; P<0.001). Mortality for patients without IMV was 3.2% compared with 51.2% for IMV alone and 9.8% for tracheostomy (P<0.001). Median hospitalization costs for patients without IMV was $9503 (IQR, $6544-$14 963), compared with $23 774 (IQR, $10 900-$47 735) for IMV alone and $95 380 (IQR, $63 921-$144 019) for tracheostomy. Tracheostomy placement in ≤7 days had lower costs compared with placement in >7 days (median, $71 470 [IQR, $47 863-$108 250] versus $102 979 [IQR, $69 563-$152 543]; P<0.001). Each day awaiting tracheostomy was associated with a 2.9% cost increase (95% CI, 2.6%-3.1%). US hospitalization costs for patients with acute stroke were $8.7 billion/y (95% CI, $8.5-$8.9 billion). For IMV alone, costs were $1.8 billion/y (95% CI, $1.7-$1.9 billion) and for tracheostomy $824 million/y (95% CI, $789.7-$858.3 million). CONCLUSIONS: Patients with acute stroke who undergo tracheostomy account for 1.4% of stroke admissions and 9.5% of US stroke hospitalization costs. Future research should focus on the added value to society and patients of IMV and tracheostomy, in particular after 7 days for the latter procedure given the increased costs incurred and poor outcomes in stroke.

Association of Postoperative Delirium and Parkinson Disease After Common United States Surgical Procedures.

INTRODUCTION: To determine the association of Parkinson disease (PD) and postoperative delirium following common surgical procedures. METHODS: We performed a retrospective database analysis of the National Inpatient Sample. We used a matched sample of patients with and without PD who underwent any of ten common surgical procedures in the US, 2005-2014. Primary outcome measure was postoperative delirium for patients with and without PD. Secondary measures included disposition, length of stay, and hospital costs. RESULTS: There were 3,235,866 patients receiving any of the ten most common operative procedures, 2005-2014. There were 35,743 patients with and without PD matched based on age, sex, elective admission status, Charlson Comorbidity index, and presence of dementia. Median age was 77 y (interquartile range 72-82), median Charlson Comorbidity index was 1 (standard deviation 0-2), 46.6% were female, and 46.8% were admitted electively. The three most common operative procedures were hip arthroplasty (28.5%), knee arthroplasty (16.1%), and percutaneous coronary angioplasty (14.9%). Postoperative delirium was present in 1519 patients with PD compared to 828 matched patients without PD (4.2% versus 2.3%; P < 0.001). The adjusted odds ratio of postoperative delirium for PD compared to the matched cohort without PD was 1.88 (95% confidence interval 1.73-2.05). Those undergoing spinal fusion (adjusted odds ratio 2.99, 95% confidence interval 2.06-4.38) had the greatest odds of delirium. For patients with PD, adjusted length of stay, adjusted hospital costs, and adjusted odds of postacute care facility discharge were greater compared to the matched cohort without PD. CONCLUSIONS: Patients with PD are more likely to develop postoperative delirium and have a more complicated postoperative course with longer length of stay and greater hospitalization costs.

Hospital Discharge and Readmissions Before and During the COVID-19 Pandemic for California Acute Stroke Inpatients.

BACKGROUND: Acute stroke therapy and rehabilitation declined during the COVID-19 pandemic. We characterized changes in acute stroke disposition and readmissions during the pandemic. METHODS: We used the California State Inpatient Database in this retrospective observational study of ischemic and hemorrhagic stroke. We compared discharge disposition across a pre-pandemic period (January 2019 to February 2020) to a pandemic period (March to December 2020) using cumulative incidence functions (CIF), and re-admission rates using chi-squared. RESULTS: There were 63,120 and 40,003 stroke hospitalizations in the pre-pandemic and pandemic periods, respectively. Pre-pandemic, the most common disposition was home [46%], followed by skilled nursing facility (SNF) [23%], and acute rehabilitation [13%]. During the pandemic, there were more home discharges [51%, subdistribution hazard ratio 1.17, 95% CI 1.15-1.19], decreased SNF discharges [17%, subdistribution hazard ratio 0.70, 95% CI 0.68-0.72], and acute rehabilitation discharges were unchanged [CIF, p<0.001]. Home discharges increased with increasing age, with an increase of 8.2% for those ≥85 years. SNF discharges decreased in a similar distribution by age. Thirty-day readmission rates were 12.7 per 100 hospitalizations pre-pandemic compared to 11.6 per 100 hospitalizations during the pandemic [p<0.001]. Home discharge readmission rates were unchanged between periods. Readmission rates for discharges to SNF (18.4 vs. 16.7 per 100 hospitalizations, p=0.003) and acute rehabilitation decreased (11.3 vs. 10.1 per 100 hospitalizations, p=0.034). CONCLUSIONS: During the pandemic a greater proportion of patients were discharged home, with no change in readmission rates. Research is needed to evaluate the impact on quality and financing of post-hospital stroke care.

Effect of COVID-19 pandemic on outcomes in intracerebral hemorrhage.

OBJECTIVES: Patients with severe intracerebral hemorrhage (ICH) often suffer from impaired capacity and rely on surrogates for decision-making. Restrictions on visitors within healthcare facilities during the pandemic may have impacted care and disposition for patient with ICH. We investigated outcomes of ICH patients during the COVID-19 pandemic compared to a pre-pandemic period. MATERIALS AND METHODS: We conducted a retrospective review of ICH patients from two sources: (1) University of Rochester Get With the Guidelines database and (2) the California State Inpatient Database (SID). Patients were divided into 2019-2020 pre-pandemic and 2020 pandemic groups. We compared mortality, discharge, and comfort care/hospice. Using single-center data, we compared 30-day readmissions and follow-up functional status. RESULTS: The single-center cohort included 230 patients (n = 122 pre-pandemic, n = 108 pandemic group), and the California SID included 17,534 patients (n = 10,537 pre-pandemic, n = 6,997 pandemic group). Inpatient mortality was no different before or during the pandemic in either cohort. Length of stay was unchanged. During the pandemic, more patients were discharged to hospice in the California SID (8.4% vs. 5.9%, p<0.001). Use of comfort care was similar before and during the pandemic in the single center data. Survivors in both datasets were more likely to be discharged home vs. facility during the pandemic. Thirty-day readmissions and follow-up functional status in the single-center cohort were similar between groups. CONCLUSIONS: Using a large database, we identified more ICH patients discharged to hospice during the COVID-19 pandemic and, among survivors, more patients were discharged home rather than healthcare facility discharge during the pandemic.

Manipulation of Redox Metabolism Using Pharmacologic Ascorbate Opens a Therapeutic Window for Radio-Sensitization by ATM Inhibitors in Colorectal Cancer.

PURPOSE: Ataxia telangiectasia mutated kinase (ATM) inhibitors are potent radiosensitizers that regulate DNA damage responses and redox metabolism, but they have not been translated clinically because of the potential for excess normal tissue toxicity. Pharmacologic ascorbate (P-AscH-; intravenous administration achieving mM plasma concentrations) selectively enhances H2O2-induced oxidative stress and radiosensitization in tumors while acting as an antioxidant and mitigating radiation damage in normal tissues including the bowel. We hypothesized that P-AscH- could enhance the therapeutic index of ATM inhibitor-based chemoradiation by simultaneously enhancing the intended effects of ATM inhibitors in tumors and mitigating off-target effects in adjacent normal tissues. METHODS AND MATERIALS: Clonogenic survival was assessed in human (human colon tumor [HCT]116, SW480, HT29) and murine (CT26, MC38) colorectal tumor lines and normal cells (human umbilical vein endothelial cell, FHs74) after radiation ± DNA repair inhibitors ± P-AscH-. Tumor growth delay was assessed in mice with HCT116 or MC38 tumors after fractionated radiation (5 Gy × 3) ± the ATM inhibitor KU60019 ± P-AscH-. Intestinal injury, oxidative damage, and transforming growth factor ß immunoreactivity were quantified using immunohistochemistry after whole abdominal radiation (10 Gy) ± KU60019 ± P-AscH-. Cell cycle distribution and ATM subcellular localization were assessed using flow cytometry and immunohistochemistry. The role of intracellular H2O2 fluxes was assessed using a stably expressed doxycycline-inducible catalase transgene. RESULTS: KU60019 with P-AscH- enhanced radiosensitization in colorectal cancer models in vitro and in vivo by H2O2-dependent oxidative damage to proteins and enhanced DNA damage, abrogation of the postradiation G2 cell cycle checkpoint, and inhibition of ATM nuclear localization. In contrast, concurrent P-AscH- markedly reduced intestinal toxicity and oxidative damage with KU60019. CONCLUSIONS: We provide evidence that redox modulating drugs, such as P-AscH-, may facilitate the clinical translation of ATM inhibitors by enhancing tumor radiosensitization while simultaneously protecting normal tissues.

Complications and outcomes of hospitalizations for patients with and without Parkinson disease.

Objective: To examine complications and outcomes of hospitalizations for common indications for hospitalization among patients with Parkinson disease (PD). Methods: We identified and selected the ten most common indications for hospitalization among individuals ≥65 years of age using principal diagnoses from the California State Inpatient Database, 2018-2020. Patients with comorbid PD were identified using secondary diagnosis codes and matched one-to-one to patients without PD based on principal diagnosis (exact matching), age, gender, race and ethnicity, and Elixhauser comorbidity index (coarsened exact matching). We identified potentially preventable complications based on the absence of present on admission indicators among secondary diagnoses. In the matched cohort, we compared inpatient complications, early Do-Not-Resuscitate (DNR) orders (placed within 24 h of admission), use of life-sustaining therapies, new nursing facility requirement on discharge, and death or hospice discharge for patients with and without PD. Results: We identified 35,457 patients with PD among the ten leading indications for hospitalization in older adults who were matched one-to-one to patients without PD (n = 70,914 in total). Comorbid PD was associated with an increased odds of developing aspiration pneumonia (OR 1.17 95% CI 1.02-1.35) and delirium (OR 1.11 95% CI 1.02-1.22) during admission. Patients with PD had greater odds of early DNR orders [placed within 24 h of admission] (OR 1.34 95% CI 1.29-1.39). While there was no difference in the odds of mechanical ventilation (OR 1.04 95% CI 0.98-1.11), patients with PD demonstrated greater odds of tracheostomy (OR 1.41 95% CI 1.12-1.77) and gastrostomy placement (OR 2.00 95% CI 1.82-2.20). PD was associated with greater odds of new nursing facility requirement upon discharge (OR 1.58 95% CI 1.53-1.64). Patients with PD were more likely to die as a result of their hospitalization (OR 1.11 95% CI 1.06-1.16). Conclusion: Patients with PD are at greater risk of developing aspiration pneumonia and delirium as a complication of their hospitalization. While patients with PD more often have early DNR orders, they have greater utilization of life-sustaining therapies and experience worse outcomes of their hospitalization including new nursing facility requirement upon discharge and greater mortality.

Institutional Variability in Representation of Women and Racial and Ethnic Minority Groups Among Medical School Faculty.

Importance: Bolstering the ranks of women and underrepresented groups in medicine (URM) among medical faculty can help address ongoing health care disparities and therefore constitutes a critical public health need. There are increasing proportions of URM faculty, but comparisons of these changes with shifts in regional populations are lacking. Objective: To quantify the representation of women and URM and assess changes and variability in representation by individual US medical schools. Design, Setting, and Participants: This retrospective cross-sectional study assessed US medical school faculty rosters for women and URM, including American Indian and Alaska Native, Black, Hispanic, and Native Hawaiian or other Pacific Islander faculty. US allopathic medical schools participating in the Association of American Medical Colleges (AAMC) Faculty Administrative Management Online User System from 1990 to 2019 (updated December 31 for each year), were included. Faculty data were analyzed from yearly cross-sections updated as of December 31 for each year from 1990 to 2019. For census data, decennial census data were used for years 1990, 2000, and 2010. Intercensal estimates were used for all other years from 1990 to 2019. Main Outcomes and Measures: Trends and variability in representation quotient (RQ), defined as representation of a group within an institution's faculty compared to its respective US county. Results: There were 121 AAMC member institutions (72 076 faculty) in 1990, which increased to 144 institutions (184 577 faculty) in 2019. The median RQ of women faculty increased from 0.42 (IQR, 0.37-0.46) to 0.80 (IQR, 0.74-0.89) (slope, +1.4% per year; P < .001). The median RQ of Black faculty increased from 0.10 (IQR, 0.06-0.22) to 0.22 (IQR, 0.14-0.41) (slope, +0.5% per year; P < .001), but remained low. In contrast, the median RQ of Hispanic faculty decreased from 0.44 (IQR, 0.19-1.22) to 0.34 (IQR, 0.23-0.62) (slope, -1.7% per year; P < .001) between 1990 and 2019. Absolute total change in RQ of URM showed an increase; however, the 30-year slope did not differ from zero (+0.1% per year; P = .052). Although RQ of women faculty increased for most institutions (127 [88.2%]), large variability in URM faculty trends were observed (57 institutions [39.6%] with increased RQ and 10 institutions [6.9%] with decreased RQ). Nearly one-quarter of institutions shifted from the top to bottom 50th percentile institutional ranking by URM RQ with county vs national comparisons. Conclusions and Relevance: The findings of this cross-sectional study suggest that representation of women in academic medicine improved with time, while URM overall experienced only modest increases with wide variability across institutions. Among URM, the Hispanic population has lost representational ground. County-based population comparisons provide new insights into institutional variation in representation among medical school faculty.

Reversal of Advanced Directives in Neurologic Emergencies.

Objective: Patients with advanced directives or Medical Orders for Life-Sustaining Treatment (MOLST), including "Do Not Resuscitate" (DNR) and/or "Do Not Intubate" (DNI), may be candidates for procedural interventions when presenting with acute neurologic emergencies. Such interventions may limit morbidity and mortality, but typically they require MOLST reversal. We investigated outcomes of patients with MOLST reversal for treatment of neurologic emergencies. Methods: We conducted a retrospective chart review from July 1, 2019 to April 30, 2021 of patients with MOLST reversal treated in our NeuroMedicine Intensive Care Unit. Variables collected include neurologic disease, MOLST reversal decision maker, procedural interventions, and outcomes. Results: Twenty-seven patients (18 female, median age 78 years (IQR 73-85 years), median baseline modified Rankin score 1 [IQR 0-2.5] were identified with MOLST reversal. The most common pre-procedural MOLST was DNR/DNI (n=22, 81%), and 93% (n=25) pre-procedural MOLSTs were completed by the patient. MOLSTs were reversed by surrogates in n=23 cases (85%). The median time from MOLST completion to MOLST reversal was 603 days (IQR 45 days to 4 years). The most common neurologic emergency was ischemic stroke (n=14, 52%). Most patients died (n=14, 52%), 26% (n=7) were discharged to skilled nursing, and 22% (n=6) returned to home or assisted living. Conclusions: In neurologic emergencies, urgent shared decision making is needed to ensure goal-concordant care, which may result in reversal of existing advanced directives. Outcomes of patients with MOLST reversal were heterogeneous, emphasizing the importance of deliberate patient-centered care weighing the risks and benefits of each intervention.

Hepatocyte Specific gp130 Signalling Underlies APAP Induced Liver Injury.

N-acetyl-p-aminophenol (APAP)-induced liver damage is associated with upregulation of Interleukin-11 (IL11), which is thought to stimulate IL6ST (gp130)-mediated STAT3 activity in hepatocytes, as a compensatory response. However, recent studies have found IL11/IL11RA/gp130 signaling to be hepatotoxic. To investigate further the role of IL11 and gp130 in APAP liver injury, we generated two new mouse strains with conditional knockout (CKO) of either Il11 (CKOIl11) or gp130 (CKOgp130) in adult hepatocytes. Following APAP, as compared to controls, CKOgp130 mice had lesser liver damage with lower serum Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST), greatly reduced serum IL11 levels (90% lower), and lesser centrilobular necrosis. Livers from APAP-injured CKOgp130 mice had lesser ERK, JNK, NOX4 activation and increased markers of regeneration (PCNA, Cyclin D1, Ki67). Experiments were repeated in CKOIl11 mice that, as compared to wild-type mice, had lower APAP-induced ALT/AST, reduced centrilobular necrosis and undetectable IL11 in serum. As seen with CKOgp130 mice, APAP-treated CKOIl11 mice had lesser ERK/JNK/NOX4 activation and greater features of regeneration. Both CKOgp130 and CKOIl11 mice had normal APAP metabolism. After APAP, CKOgp130 and CKOIl11 mice had reduced Il6, Ccl2, Ccl5, Il1ß, and Tnfα expression. These studies exclude IL11 upregulation as compensatory and establish autocrine, self-amplifying, gp130-dependent IL11 secretion from damaged hepatocytes as toxic and anti-regenerative.

Retinal arterial pulsation as an indicator of raised intraocular pressure.

Ophthalmic emergencies are invariably challenging for the non-specialist to identify and evaluate, and may be complicated by occult but vision threatening raised intraocular pressure. We present a case of hypertensive uveitis accompanied by the finding of retinal arterial pulsation, which when visualised by direct ophthalmoscopy allows the non-specialist to identify significantly raised intraocular pressure requiring urgent evaluation by an ophthalmologist.

Molecular Dissection of Pro-Fibrotic IL11 Signaling in Cardiac and Pulmonary Fibroblasts.

In fibroblasts, TGFß1 stimulates IL11 upregulation that leads to an autocrine loop of IL11-dependent pro-fibrotic protein translation. The signaling pathways downstream of IL11, which acts via IL6ST, are contentious with both STAT3 and ERK implicated. Here we dissect IL11 signaling in fibroblasts and study IL11-dependent protein synthesis pathways in the context of approved anti-fibrotic drug mechanisms of action. We show that IL11-induced ERK activation drives fibrogenesis and while STAT3 phosphorylation (pSTAT3) is also seen, this appears unrelated to fibroblast activation. Ironically, recombinant human IL11, which has been used extensively in mouse experiments to infer STAT3 activity downstream of IL11, increases pSTAT3 in Il11ra1 null mouse fibroblasts. Unexpectedly, inhibition of STAT3 was found to induce severe proteotoxic ER stress, generalized fibroblast dysfunction and cell death. In contrast, inhibition of ERK prevented fibroblast activation in the absence of ER stress. IL11 stimulated an axis of ERK/mTOR/P70RSK protein translation and its selectivity for Collagen 1 synthesis was ascribed to an EPRS-regulated, ribosome stalling mechanism. Surprisingly, the anti-fibrotic drug nintedanib caused dose-dependent ER stress and lesser pSTAT3 expression. Pirfenidone had no effect on ER stress whereas anti-IL11 specifically inhibited the ERK/mTOR axis while reducing ER stress. These studies define the translation-specific signaling pathways downstream of IL11, intersect immune and metabolic signaling and reveal unappreciated effects of nintedanib.