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Objectives Studies have demonstrated high rates of mortality in people with proximal femoral fracture and SARS-CoV-2, but there is limited published data on the factors that influence mortality for clinicians to make informed treatment decisions. This study aims to report the 30-day mortality associated with perioperative infection of patients undergoing surgery for proximal femoral fractures and to examine the factors that influence mortality in a multivariate analysis.Setting Prospective, international, multicentre, observational cohort study.Participants Patients undergoing any operation for a proximal femoral fracture from 1 February to 30 April 2020 and with perioperative SARS-CoV-2 infection (either 7 days prior or 30-day postoperative).Primary outcome 30-day mortality. Multivariate modelling was performed to identify factors associated with 30-day mortality.Results This study reports included 1063 patients from 174 hospitals in 19 countries. Overall 30-day mortality was 29.4% (313/1063). In an adjusted model, 30-day mortality was associated with male gender (OR 2.29, 95% CI 1.68 to 3.13, p80 years (OR 1.60, 95% CI 1.1 to 2.31, p=0.013), preoperative diagnosis of dementia (OR 1.57, 95% CI 1.15 to 2.16, p=0.005), kidney disease (OR 1.73, 95% CI 1.18 to 2.55, p=0.005) and congestive heart failure (OR 1.62, 95% CI 1.06 to 2.48, p=0.025). Mortality at 30 days was lower in patients with a preoperative diagnosis of SARS-CoV-2 (OR 0.6, 95% CI 0.6 (0.42 to 0.85), p=0.004). There was no difference in mortality in patients with an increase to delay in surgery (p=0.220) or type of anaesthetic given (p=0.787).Conclusions Patients undergoing surgery for a proximal femoral fracture with a perioperative infection of SARS-CoV-2 have a high rate of mortality. This study would support the need for providing these patients with individualised medical and anaesthetic care, including medical optimisation before theatre. Careful preoperative counselling is needed for those with a proximal femoral fracture and SARS-CoV-2, especially those in the highest risk groups.Trial registration number NCT04323644

BackgroundThe COVID-19 pandemic spurred an increase in online information regarding disease spread and symptomatology. ObjectiveOur purpose is to systematically assess the quality and readability of articles resulting from frequently Google-searched COVID-19 terms in the United States. MethodsWe used Google Trends to determine the 25 most commonly searched health-related phrases between February 29 and April 30, 2020. The first 30 search results for each term were collected, and articles were analyzed using the Quality Evaluation Scoring Tool (QUEST). Three raters scored each article in authorship, attribution, conflict of interest, currency, complementarity, and tone. A readability analysis was conducted. ResultsExactly 709 articles were screened, and 195 fulfilled inclusion criteria. The mean article score was 18.4 (SD 2.6) of 28, with 7% (14/189) scoring in the top quartile. National news outlets published the largest share (70/189, 36%) of articles. Peer-reviewed journals attained the highest average QUEST score compared to national/regional news outlets, national/state government sites, and global health organizations (all P

OBJECTIVES/GOALS: Prostate cancer is the 2nd most common cancer among men. 1/3 of these men have a slow-growing disease that can be managed without intervention. Instead of treatment, they can enter an active surveillance program. The goal of this study is to examine if cumulative cancer location can predict one’s disease progression and be used as a clinical marker. METHODS/STUDY POPULATION: This is a retrospective cohort study consisting of men with Gleason Grade 1 prostate cancer enrolled in the Active Surveillance Program at Johns Hopkins. The cohort includes men who were enrolled in the program from 2007 to 2015 before prostate biopsies incorporated multiparametric MRI as of the prostate. We will assess if cumulative cancer location (CCLO), a sum of the total number of histological cancer-positive locations on diagnostic and confirmatory biopsy, can predict grade progression, adverse findings on radical prostatectomy findings, or protocol-based discontinuation. Kaplan Meier survival analyses and multivariable Cox regression will be used to determine if stratifying by CCLO can predict these outcomes. RESULTS/ANTICIPATED RESULTS: We included 1298 men in this study. The study will analyze variables that will be used in multivariable regression. Some variables of interest include age at diagnosis, PSA, PSA density, race/ethnicity, and number of positive cores. We expect that greater variability of tumor location, a higher CCLO score, will lead to more grade progression, protocol-based discontinuation, shorter time on active surveillance and adverse findings after radical prostatectomy. This hypothesis is based on a 2018 study that determined cancer location as a significant predictor of progression at the time of biopsy. Results will be discussed in full at the conference. DISCUSSION/SIGNIFICANCE: Finding a predictive marker of progression at the time of biopsy is clinically significant and can lead to adjusted patient observation and testing while on active surveillance. This will better stratify men on active surveillance, determine who would benefit from genetic testing, and better counsel patients as to how long they will be on surveillance.

Background: Inpatient anticholinergic medications have been associated with a higher likelihood of postoperative delirium in older adults. However, it remains unclear whether administering anticholinergic medications after surgery adversely affects long-term cognitive function., Objective: We aimed to evaluate the relationship between in-hospital anticholinergic medications and time to incident dementia in a cohort of older surgical patients. We also sought to determine whether the association between in-hospital anticholinergic drugs and dementia differed by sex and prehospital anticholinergic exposure., Methods: This was a retrospective analysis of electronic health record data from a regional health information exchange. The study population included patients aged 50 years and older who underwent major surgery requiring an inpatient stay between 2014 and 2021. Orders for anticholinergic medications were identified using the anticholinergic cognitive burden (ACB) scale. A Cox proportional hazards model was used to estimate the association between inpatient orders for strong anticholinergics and incident dementia after hospital discharge. Cause-specific hazards were modeled. Stratification and relative excess risk due to interaction (RERI) were used to investigate multiplicative and additive interaction, respectively., Results: In total, 66,420 surgical encounters were analyzed. Approximately 90% of patients received one or more strong anticholinergics during hospitalization, and 3806 patients developed dementia during a median follow-up of 3.4 years. The median time to dementia was 2.2 years. Each one-order increase in inpatient anticholinergic medications was associated with a 0.60% increase in dementia risk (HR 1.006; 95% CI 1.003-1.008). This association was stronger among patients who were prescribed anticholinergics before hospitalization (RERI 0.10; 95% CI 0.08-1.12; p = 0.0122)., Conclusions: Perioperative anticholinergics may increase the risk of dementia after major surgery. Avoiding these medications in hospitalized older adults may improve long-term cognitive outcomes., Competing Interests: Declarations. Conflicts of interest: Z.B.M. has a financial interest in DigiCare Realized and could benefit from the results of this research. M.B. serves as a Chief Scientific Officer and Co-Founder of Blue Agilis, and is the Chief Health Officer of DigiCare Realized. He has equity interest in Blue Agilis, DigiCare Realized, Preferred Population Health Management LLC, and MyShift (previously known as RestUp, LLC). He serves as an advisory board member for Acadia Pharmaceuticals, Eisai, Biogen, and Genentech. These conflicts have been reviewed by Indiana University and have been appropriately managed to maintain objectivity. The remaining authors declare no competing interests. Funding: This study was supported by National Institute on Aging no. K23AG071945. Ethics approval: The protocol for this retrospective cohort study was reviewed and approved by the Indiana University Institutional Review Board (no. 15767) prior to initiation. Consent to participate: Not applicable. Consent for publication: Not applicable. Data availability: The data that support the findings of this study are available from the Regenstrief Institute, but restrictions apply to the availability of these data, which were used under a research agreement for the current study and are therefore not publicly available. Code availability: Not applicable. Author contributions: All authors contributed to the study concept and design. Data analysis was performed by E.H. The first draft of the manuscript was written by E.H. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript., (© 2025. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: The Stop the Bleed campaign gives bystanders an active role in prehospital hemorrhage control. Whether extending bystanders' role to private vehicle transport (PVT) for urban penetrating trauma improves survival is unknown, but past research has found benefit to police and PVT. We hypothesized that for penetrating trauma in an urban environment, where prehospital procedures have been proven harmful, PVT improves outcomes compared to any EMS or advanced life support (ALS) transport. Methods: Post-hoc analysis of an EAST multicenter trial was performed on adult patients with penetrating torso/proximal extremity trauma at 25 urban trauma centers from 5/2019-5/2020. Patients were allocated to PVT and any EMS or ALS transport using nearest neighbor propensity score matching. Univariate analyses included Wilcoxon signed rank or McNemar's Test and logistic regression. Results: Of 1999 penetrating trauma patients in urban settings, 397 (19.9%) had PVT, 1433 (71.7%) ALS transport, and 169 (8.5%) basic life support (BLS) transport. Propensity matching yielded 778 patients, distributed equally into balanced groups. PVT patients were primarily male (90.5%), Black (71.2%), and sustained gunshot wounds (68.9%). ALS transport had significantly higher ED mortality (3.9% vs 1.9%, P = 0.03). There was no difference in in-hospital mortality rate, hospital LOS, or complications for all EMS or ALS only transport patients. Conclusion: Compared to PVT, ALS, which provides more prehospital procedures than BLS, provided no survival benefit for penetrating trauma patients in urban settings. Bystander education incorporating PVT for early arrival of penetrating trauma patients in urban settings to definitive care merits further investigation., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Necrotizing enterocolitis (NEC) is a severe illness with high mortality. Traditional risk factors are prematurity and neonatal stress. Maternal risk factors have also been postulated but are often overlooked. We aimed to define parental and patient factors associated with NEC and their impact on outcomes., Methods: Infants under 1 year old diagnosed with NEC were identified via the Pediatric Health Information System database between 2012 and 2022. The Childhood Opportunity Index (COI) was used to represent each family's household educational, environmental, and socioeconomic conditions. The COI was split into low, middle, and high levels and analyzed across demographics and mortality. Multivariable regression was used to determine the association between COI and in-hospital mortality, adjusting for gestational age, gender, race, primary payor, urban flag, and geographic region., Results: Overall, 10,768 patients with a median gestational age of 29 weeks (IQR 25-34), and a median birthweight of 1,010 g (IQR 660-1,880 g) met inclusion criteria. The cohort was majority male (57 %), and White (46 %), and overall, had a mortality rate of 18 %. Low COI was associated with longer length of stay (56 vs. 53 days) and increased mortality (19 % vs. 15 %) when compared to high COI. On adjusted analysis, high COI was associated with decreased odds of death by time of discharge (OR 0.75, 95 % CI 0.65-0.86, p < 0.001) when compared to low COI., Conclusion: NEC is a disease that disproportionately affects socially disadvantaged infants. The mortality rates of NEC are linked to parental social determinants of health, highlighting this unique population to target for risk assessment and additional prenatal resources., Type of Study: Cross Sectional Study., Level of Evidence: III., Competing Interests: Conflicts of interest The authors have no conflicts of interest., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Background: Postoperative delirium (POD) is a common complication after major surgery and is associated with poor outcomes in older adults. Early identification of patients at high risk of POD can enable targeted prevention efforts. However, existing POD prediction models require inpatient data collected during the hospital stay, which delays predictions and limits scalability., Objective: This study aimed to develop and externally validate a machine learning-based prediction model for POD using routine electronic health record (EHR) data., Methods: We identified all surgical encounters from 2014 to 2021 for patients aged 50 years and older who underwent an operation requiring general anesthesia, with a length of stay of at least 1 day at 3 Indiana hospitals. Patients with preexisting dementia or mild cognitive impairment were excluded. POD was identified using Confusion Assessment Method records and delirium International Classification of Diseases (ICD) codes. Controls without delirium or nurse-documented confusion were matched to cases by age, sex, race, and year of admission. We trained logistic regression, random forest, extreme gradient boosting (XGB), and neural network models to predict POD using 143 features derived from routine EHR data available at the time of hospital admission. Separate models were developed for each hospital using surveillance periods of 3 months, 6 months, and 1 year before admission. Model performance was evaluated using the area under the receiver operating characteristic curve (AUROC). Each model was internally validated using holdout data and externally validated using data from the other 2 hospitals. Calibration was assessed using calibration curves., Results: The study cohort included 7167 delirium cases and 7167 matched controls. XGB outperformed all other classifiers. AUROCs were highest for XGB models trained on 12 months of preadmission data. The best-performing XGB model achieved a mean AUROC of 0.79 (SD 0.01) on the holdout set, which decreased to 0.69-0.74 (SD 0.02) when externally validated on data from other hospitals., Conclusions: Our routine EHR-based POD prediction models demonstrated good predictive ability using a limited set of preadmission and surgical variables, though their generalizability was limited. The proposed models could be used as a scalable, automated screening tool to identify patients at high risk of POD at the time of hospital admission., (©Emma Holler, Christina Ludema, Zina Ben Miled, Molly Rosenberg, Corey Kalbaugh, Malaz Boustani, Sanjay Mohanty. Originally published in JMIR Perioperative Medicine (http://periop.jmir.org), 09.01.2025.)

Background: Anti-inflammatory effects of tranexamic acid (TXA) in reducing trauma endotheliopathy may protect from acute lung injury. Clinical data showing this benefit in trauma patients is lacking. We hypothesized that TXA administration mitigates pulmonary complications in penetrating trauma patients., Materials and Methods: This is a post-hoc analysis of a multicenter, prospective, observational study of adults (18+ years) with penetrating torso and/or proximal extremity injury presenting at 25 urban trauma centers. Tranexamic acid administration in the prehospital setting or within three hours of admission was examined. Participants were propensity matched to compare similarly injured patients. The primary outcome was development of pulmonary complication (ARDS and/or pneumonia)., Results: A total of 2382 patients were included, and 206 (8.6%) received TXA. Of the 206, 93 (45%) received TXA prehospital and 113 (55%) received it within three hours of hospital admission. Age, sex, and incidence of massive transfusion did not differ. The TXA group was more severely injured, more frequently presented in shock (SBP < 90 mmHg), developed more pulmonary complications, and had lower survival ( P < 0.01 for all). After propensity matching, 410 patients remained (205 in each cohort) with no difference in age, sex, or rate of shock. On logistic regression, increased emergency department heart rate was associated with pulmonary complications. Tranexamic acid was not associated with different rate of pulmonary complications or survival on logistic regression. Survival was not different between the groups on logistic regression or propensity score-matched analysis., Conclusions: Tranexamic acid administration is not protective against pulmonary complications in penetrating trauma patients., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The standard treatment for acute graft-vs-host disease (GVHD), a common complication following allogeneic hematopoietic cell transplant, remains prolonged courses of high dose corticosteroids. Previous attempts to decrease corticosteroid exposure during GVHD therapy failed because physicians lack the tools necessary to safely reduce and shorten therapy and fear loss of GVHD control in responding patients. Prior studies have shown that a serum biomarker risk score, the MAGIC algorithm probability (MAP), provided prognostic value within groups with similar clinical severity and that patients with GVHD that is Minnesota standard risk by clinical symptoms and who have a low MAP at the start of corticosteroid treatment represent a low risk group with good outcomes., Objective: This study tested the hypothesis that serial monitoring of GVHD symptoms and the MAP score in patients with low risk GVHD could provide further risk stratification, and would identify a subset with exceptionally low rates of failure with standard treatment, which we term ultra-low risk (ULR) GVHD who might benefit from reduced corticosteroid treatment., Study Design: Weekly monitoring of clinical symptoms and MAPs from initiation to day 14 of treatment was used to further divide 450 patients with low risk GVHD into groups with different outcomes, such as overall response rates at day 28 and non-relapse mortality at six-months., Results: 310/450 low risk patients (69%) who achieved clinical response by day 14 and had low MAPs at days 7 and 14 constituted an ultra-low risk (ULR) group. that experienced a significantly higher overall response rate at day 28 (93% vs 50%, p<0.001) that was sustained to day 56 (84% vs 45%, p<0.001) and significantly lower six-month NRM (4% vs 13%, p<0.001) compared to the non-ULR patients. Patients who achieved clinical response by day 14 but who developed a high MAP during monitoring (n=20) experienced six-fold higher six-month NRM than the ULR group (25% vs 4%, p<0.001). Among 120 patients who did not achieve a clinical response by day 14, the overwhelming majority (n=112) who maintained low MAPs at both days 7 and 14 of treatment experienced six-fold lower NRM at six months compared to patients with a high MAP at either time point (8% vs 50%, p<0.001). The majority of deaths within the ULR group were due to infections in patients with complete and sustained control of GVHD symptoms while the majority of deaths in the non-ULR group were due to poorly controlled GVHD., Conclusions: Serial monitoring during treatment can identify a large subset of patients by day 14 who achieve excellent GVHD control but remain at risk for treatment complications with standard treatment and who might be suitable candidates for testing abbreviated corticosteroid courses., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Clinical trial success hinges on efficient participant recruitment and retention. However, slow accrual and attrition frequently hinder progress. To address these challenges, a novel dashboard tool with control charts has been developed to provide investigators on the multi-site study of Delirium and Neuropsychological Recovery among Emergency General Surgery Survivors (DANE study) with timely information to improve trial recruitment., Methods: A quality monitoring Excel dashboard with control chart functionality developed by the principal investigator's (PI) group and implemented in a department of a large hospital was re-engineered for research study recruitment purposes. The dashboard provides the PIs and other stakeholders with timely, actionable, and unbiased information on the count of participants who have completed each stage or action within the process, the rates of completion and trends, both for the current week and cumulatively., Results: The DANE dashboard was prototyped using Microsoft Excel for accessibility and rapid development. The tool integrates with a REDCap database, simplifying data import and analysis. By facilitating informed decision-making throughout the recruitment process, the DANE dashboard has significantly enhanced clinical trial efficiency and led to changes in the eligibility criteria and improvements in the approach and consent processes., Conclusions: The DANE dashboard for monitoring participant recruitment and attrition in research studies represents a significant step towards enhancing study management and decision-making processes. It can be adapted to other clinical studies and other staged processes with attrition. The generic version, currently under development, holds promise for evolving into a valuable simulator by incorporating a spreadsheet for generating random data and accounting for resource constraints. This enhancement could further be augmented by integrating forecasting capabilities into the control charts., Trial Registration: The Delirium and Neuropsychological Recovery among Emergency General Surgery Survivors (DANE) study (NCT05373017, 1R01AG076489-01) is a multi-site, two-arm, single-blinded randomized controlled clinical trial to evaluate the efficacy of the Emergency General Surgery (EGS) Delirium Recovery Model to improve the cognitive, physical, and psychological recovery of EGS delirium survivors over 65. The DANE study received approval from the University of Wisconsin-Madison/University of Wisconsin Hospitals and Clinics Institutional Review Board (IRB, no. 2022-0545, approval date September 14, 2022), and Indiana University agreed to cede IRB review to University of Wisconsin-Madison/University of Wisconsin Hospital and Clinics (September 29, 2022)., Competing Interests: Declarations. Ethics approval and consent to participate: The DANE study (NCT05373017, R01AG076489) received approval from the University of Wisconsin-Madison/University of Wisconsin Hospitals and Clinics Institutional Review Board (IRB, no. 2022–0545, approval date September 14, 2022), and Indiana University agreed to cede IRB review to University of Wisconsin-Madison/University of Wisconsin Hospital and Clinics (September 29, 2022). The approval included generating reports to the research team and the funding agency of which this dashboard was part. Consent for publication: Not applicable. Competing interests: Dr. Boustani serves as a chief Scientific Officer and co-Founder of BlueAgilis; the Chief Health Officer of DigiCare Realized, Inc.; and the Chief Health Officer of Mozyne Health, Inc. He has equity interest in Blue Agilis, Inc; DigiCare Realized, Inc; and Mozyne Health Inc.; he sold his equity in Preferred Population Health Management LLC and MyShift, Inc. (previously known as RestUp, LLC). He serves as an advisory board member for Eli Lilly and Co, Eisai, Inc; Merck & Co Inc; Biogen Inc; and Genentech Inc. These conflicts have been reviewed by Indiana University and have been appropriately managed to maintain objectivity., (© 2024. The Author(s).)

Multidrug-resistant bacterial pathogens like vancomycin-resistant Enterococcus faecium (VREfm) are a critical threat to human health 1 . Daptomycin is a last-resort antibiotic for VREfm infections with a novel mode of action 2 , but for which resistance has been widely reported but is unexplained. Here we show that rifaximin, an unrelated antibiotic used prophylactically to prevent hepatic encephalopathy in patients with liver disease 3 , causes cross-resistance to daptomycin in VREfm. Amino acid changes arising within the bacterial RNA polymerase in response to rifaximin exposure cause upregulation of a previously uncharacterized operon (prdRAB) that leads to cell membrane remodelling and cross-resistance to daptomycin through reduced binding of the antibiotic. VREfm with these mutations are spread globally, making this a major mechanism of resistance. Rifaximin has been considered 'low risk' for the development of antibiotic resistance. Our study shows that this assumption is flawed and that widespread rifaximin use, particularly in patients with liver cirrhosis, may be compromising the clinical use of daptomycin, a major last-resort intervention for multidrug-resistant pathogens. These findings demonstrate how unanticipated antibiotic cross-resistance can undermine global strategies designed to preserve the clinical use of critical antibiotics., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Prevention of toilet-to-patient transmission of multidrug-resistant Pseudomonas aeruginosa (MDR PA) poses management-related challenges at many bone marrow transplant units (BMTUs)., Aim: To conduct a longitudinal retrospective analysis of the toilet-to-patient transmission rate for MDR PA under existing infection control (IC) measures at a BMTU with persistent MDR PA toilet colonization., Methods: The local IC bundle comprised: (1) patient education regarding IC; (2) routine patient screening; (3) toilet flushing volume of 9 L; (4) bromination of toilet water tanks, and (5) toilet decontamination using hydrogen peroxide. Toilet water was sampled periodically between 2016 and 2021 (minimum every three months: 26 intervals). Upon MDR PA detection, disinfection and re-sampling were repeated until ≤3 cfu/100 mL was reached. Whole-genome sequencing (WGS) was performed retrospectively on all available MDR PA isolates (90 out of 117 positive environmental samples, 10 out of 14 patients, including nine nosocomial)., Findings: WGS of patient isolates identified six sequence types (STs), with ST235/CT1352/FIM-1 and ST309/CT3049/no-carbapenemase being predominant (three isolates each). Environmental sampling consistently identified MDR PA ST235 (65.5% ST235/CT1352/FIM-1), showing low genetic diversity (difference of ≤29 alleles by core-genome multi-locus sequence typing (cgMLST)). This indicates that direct toilet-to-patient transmission was infrequent although MDR PA was widespread (detection on 79 occasions, detection in every toilet). Only three MDR PA patient isolates can be attributed to the ST235/CT1352/FIM-1 toilet MRD PA population over six years., Conclusion: Stringent targeted toilet disinfection can reduce the potential risk for MDR PA acquisition by patients., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Steroid-refractory acute graft-versus-host disease (aGvHD) is a serious complication after allogeneic hematopoietic stem cell transplantation, associated with significant mortality. Ruxolitinib was the first drug approved for aGvHD, based on results of the REACH2 trial; however, real-world data are limited. We retrospectively analyzed the safety and efficacy of ruxolitinib for treatment of aGvHD at our center from March 2016 to August 2022 and assessed biomarkers of risk. We identified 49 patients receiving ruxolitinib as second- (33/49), third- (11/49), fourth- (3/49), or fifth-line (2/49) treatment. Ruxolitinib was started on median day 11 (range, 7-21) after aGvHD onset; median duration of administration was 37 days (range, 20-86), with 10 patients continuing treatment at last follow-up. Median follow-up period was 501 days (range, 95-905). In the primary analysis at the 1-month assessment, overall response rate was 65%, and failure-free survival was 78%. Infectious complications ≥ CTCAE Grade III were observed in 10/49 patients within 1-month followup. Patients responding to ruxolitinib therapy required fewer steroids and exhibited lower levels of the serum biomarkers regenerating islet-derived protein 3-alpha, suppression of tumorigenicity 2, and the Mount Sinai Acute GVHD International Consortium algorithm probability. A univariate regression model revealed steroid-dependent aGvHD as a significant predictor of better response to ruxolitinib. Within 6-months follow-up, four patients experienced recurrence of underlying malignancy, and eight died due to treatment-related mortality. Overall, ruxolitinib was welltolerated and showed response in heavily pretreated patients, with results comparable to those of the REACH2 trial. Biomarkers may be useful predictors of response to ruxolitinib., (© 2024. The Author(s).)

Abstract: The significance of biomarkers in second-line treatment for acute graft-versus-host disease (GVHD) has not been well characterized. We analyzed clinical data and serum samples at the initiation of second-line systemic treatment of acute GVHD from 167 patients from 17 centers of the Mount Sinai Acute GVHD International Consortium (MAGIC) between 2016 and 2021. Sixty-two patients received ruxolitinib-based therapy, whereas 102 received other systemic agents. In agreement with prospective trials, ruxolitinib resulted in a higher day 28 (D28) overall response Frate than nonruxolitinib therapies (55% vs 31%, P = .003) and patients who received ruxolitinib had significantly lower nonrelapse mortality (NRM) than those who received nonruxolitinib therapies (point estimates at 2-year: 35% vs 61%, P = .002). Biomarker analyses demonstrated that the benefit from ruxolitinib was observed only in patients with low MAGIC algorithm probabilities (MAPs) at the start of second-line treatment. Among patients with a low MAP, those who received ruxolitinib experienced significantly lower NRM than those who received nonruxolitinib therapies (point estimates at 2-year: 12% vs 41%, P = .016). However, patients with high MAP experienced high NRM regardless of treatment with ruxolitinib or nonruxolitinib therapies (point estimates at 2-year: 67% vs 80%, P = .65). A landmark analysis demonstrated that the relationship between the D28 response and NRM largely depends on the MAP level at the initiation of second-line therapy. In conclusion, MAP measured at second-line systemic treatment for acute GVHD predicts treatment response and NRM. The outcomes of patients with high MAP are poor regardless of treatment choice, and ruxolitinib appears to primarily benefit patients with low MAP., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Importance: Older adults with recent injuries can have impaired long-term biopsychosocial function and may benefit from interventions adapted to their needs., Objective: To determine if a collaborative care intervention, Trauma Medical Home (TMH), improved the biopsychosocial function of older patients in the year after injury., Design, Setting, and Participants: This was a single-blinded, randomized clinical trial conducted at 4 level I trauma centers in Indianapolis, Indiana, and Madison, Wisconsin. Between October 2017 and October 2021, patients aged 50 years and older with an Injury Severity Score (ISS) of 9 or greater and without traumatic brain or spinal cord injury were enrolled. Exclusions were significant brain injury or a spinal cord injury with a persistent neurologic deficit at the time of enrollment, extensive burns, pregnancy, incarceration, neurodegenerative disease, visual or auditory impairment that would preclude study participation, a life expectancy of less than 1 year, significant alcohol or drug use history, and acute stroke during admission. Of 10 276 patients screened, 430 were randomized and 299 completed 12-month follow-up. Data were analyzed from March to July 2023., Intervention: Intervention patients received 6 months of TMH delivered by a nurse care coordinator guided by an interdisciplinary team (trauma surgeon, pulmonary critical care and geriatrician physicians, nurses, and psychologist) in partnership with primary care. The care coordinator used standard protocols to monitor and treat biopsychosocial symptoms., Main Outcomes and Measures: Primary outcomes were Medical Outcome Study Short Form-36 (SF-36) score and Short Physical Performance Battery (SPPB) score at 12 months. Secondary outcomes were Patient Health Questionnaire-9 (PHQ-9) score, the Generalized Anxiety Disorder scale-7 (GAD-7) score, and health care utilization., Results: A total of 429 participants (228 [53.1%] female; mean [SD] age, 69.3 [10.8] years; mean [SD] ISS, 12.3 [4.6]) completed baseline assessments and were randomized. Follow-up was 76% (n = 324) at 6 months and 70% (n = 299) at 12 months. There were no differences between the TMH and usual care groups at 12 months in SF-36 Physical Component Summary score (mean [SD], 40.42 [12.82] vs 39.18 [12.43]), SF-36 Mental Component Summary score (mean [SD], 53.92 [10.02] vs 53.21 [10.82]), or SPPB score (mean [SD], 8.00 [3.60] vs 8.28 [3.88]). Secondary outcomes were also no different. Planned subgroup analysis revealed patients with baseline symptoms of anxiety or depression (high GAD-7 and PHQ-9 scores) experienced improvement in the Mental Component Summary score when randomized to the TMH intervention., Conclusions and Relevance: The TMH intervention did not significantly influence quality of life, depressive and anxiety symptoms, or physical function of older adults with injury at 12 months. Subgroup analysis showed positive impact in patients with a high burden of anxiety and depression symptoms at enrollment. Collaborative care interventions may improve long-term outcomes of select patients, but further research is needed., Trial Registration: ClinicalTrials.gov Identifier: NCT03108820.

Abstract: Graft-versus-host disease (GVHD) is a major cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation. Algorithms containing either the gastrointestinal (GI) GVHD biomarker amphiregulin (AREG) or a combination of 2 GI GVHD biomarkers (suppressor of tumorigenicity-2 [ST2] + regenerating family member 3 alpha [REG3α]) when measured at GVHD diagnosis are validated predictors of NRM risk but have never been assessed in the same patients using identical statistical methods. We measured the serum concentrations of ST2, REG3α, and AREG by enzyme-linked immunosorbent assay at the time of GVHD diagnosis in 715 patients divided by the date of transplantation into training (2004-2015) and validation (2015-2017) cohorts. The training cohort (n = 341) was used to develop algorithms for predicting the probability of 12-month NRM that contained all possible combinations of 1 to 3 biomarkers and a threshold corresponding to the concordance probability was used to stratify patients for the risk of NRM. Algorithms were compared with each other based on several metrics, including the area under the receiver operating characteristics curve, proportion of patients correctly classified, sensitivity, and specificity using only the validation cohort (n = 374). All algorithms were strong discriminators of 12-month NRM, whether or not patients were systemically treated (n = 321). An algorithm containing only ST2 + REG3α had the highest area under the receiver operating characteristics curve (0.757), correctly classified the most patients (75%), and more accurately risk-stratified those who developed Minnesota standard-risk GVHD and for patients who received posttransplant cyclophosphamide-based prophylaxis. An algorithm containing only AREG more accurately risk-stratified patients with Minnesota high-risk GVHD. Combining ST2, REG3α, and AREG into a single algorithm did not improve performance., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Acute graft versus host disease (GVHD) is a common and serious complication of allogeneic hematopoietic cell transplantation (HCT) in children but overall clinical grade at onset only modestly predicts response to treatment and survival outcomes. Two tools to assess risk at initiation of treatment were recently developed. The Minnesota risk system stratifies children for risk of nonrelapse mortality (NRM) according to the pattern of GVHD target organ severity. The Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm of 2 serum biomarkers (ST2 and REG3α) predicts NRM in adult patients but has not been validated in a pediatric population. We aimed to develop and validate a system that stratifies children at the onset of GVHD for risk of 6-month NRM. We determined the MAGIC algorithm probabilities (MAPs) and Minnesota risk for a multicenter cohort of 315 pediatric patients who developed GVHD requiring treatment with systemic corticosteroids. MAPs created 3 risk groups with distinct outcomes at the start of treatment and were more accurate than Minnesota risk stratification for prediction of NRM (area under the receiver operating curve (AUC), .79 versus .62, P = .001). A novel model that combined Minnesota risk and biomarker scores created from a training cohort was more accurate than either biomarkers or clinical systems in a validation cohort (AUC .87) and stratified patients into 2 groups with highly different 6-month NRM (5% versus 38%, P < .001). In summary, we validated the MAP as a prognostic biomarker in pediatric patients with GVHD, and a novel risk stratification that combines Minnesota risk and biomarker risk performed best. Biomarker-based risk stratification can be used in clinical trials to develop more tailored approaches for children who require treatment for GVHD., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Introduction: Anticholinergic medications are known to cause adverse cognitive effects in community-dwelling older adults and medical inpatients, including dementia. The prevalence with which such medications are prescribed in older adults undergoing major surgery is not well described nor is their mediating relationship with delirium and dementia. We sought to determine the prevalence of high-risk medication use in major surgery patients and their relationship with the subsequent development of dementia., Methods: This was a retrospective cohort study which used data between January 2013 and December 2019, in a large midwestern health system, including sixteen hospitals. All patients over age 50 undergoing surgery requiring an inpatient stay were included. The primary exposure was the number of doses of anticholinergic medications delivered during the hospital stay. The primary outcome was a new diagnosis of Alzheimer's disease and related dementias at 1-y postsurgery. Regression methods and a mediation analysis were used to explore relationships between anticholinergic medication usage, delirium, and dementia., Results: There were 39,665 patients included, with a median age of 66. Most patients were exposed to anticholinergic medications (35,957/39,665; 91%), and 7588/39,665 (19.1%) patients received six or more doses during their hospital stay. Patients with at least six doses of these medications were more likely to be female, black, and with a lower American Society of Anesthesiologists class. Upon adjusted analysis, high doses of anticholinergic medications were associated with increased odds of dementia at 1 y relative to those with no exposure (odds ratio 2.7; 95% confidence interval 2.2-3.3). On mediation analysis, postoperative delirium mediated the effect of anticholinergic medications on dementia, explaining an estimated 57.6% of their association., Conclusions: High doses of anticholinergic medications are common in major surgery patients and, in part via a mediating relationship with postoperative delirium, are associated with the development of dementia 1 y following surgery. Strategies to decrease the use of these medications and encourage the use of alternatives may improve long-term cognitive recovery., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The overall response rate (ORR) 28 days after treatment has been adopted as the primary endpoint for clinical trials of acute graft versus host disease (GVHD). However, physicians often need to modify immunosuppression earlier than day (D) 28, and non-relapse mortality (NRM) does not always correlate with ORR at D28. We studied 1144 patients that received systemic treatment for GVHD in the Mount Sinai Acute GVHD International Consortium (MAGIC) and divided them into a training set (n=764) and a validation set (n=380). We used a recursive partitioning algorithm to create a Mount Sinai model that classifies patients into favorable or unfavorable groups that predicted 12 month NRM according to overall GVHD grade at both onset and D14. In the Mount Sinai model grade II GVHD at D14 was unfavorable for grade III/IV GVHD at onset and predicted NRM as well as the D28 standard response model. The MAGIC algorithm probability (MAP) is a validated score that combines the serum concentrations of suppression of tumorigenicity 2 (ST2) and regenerating islet-derived 3-alpha (REG3α) to predict NRM. Inclusion of the D14 MAP biomarker score with the D14 Mount Sinai model created three distinct groups (good, intermediate, poor) with strikingly different NRM (8%, 35%, 76% respectively). This D14 MAGIC model displayed better AUC, sensitivity, positive and negative predictive value, and net benefit in decision curve analysis compared to the D28 standard response model. We conclude that this D14 MAGIC model could be useful in therapeutic decisions and may offer an improved endpoint for clinical trials of acute GVHD treatment., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Acute graft-versus-host disease (GvHD) is a major and sometimes lethal complication following allogeneic stem cell transplantation (aSCT). In the last 10 years, a massive loss of microbiota diversity with suppression of commensal bacteria and their protective metabolites has been identified as a major risk factor of GvHD., Summary: Since 2018, several studies have been published showing some efficacy of fecal microbiota transfer (FMT) in aSCT patients. FMT was used (1) to eliminate antibiotic resistant bacteria, (2) to restore microbiota diversity after hematopoietic recovery, or (3) in most cases to treat steroid-resistant GvHD. Overall response rates between 30 and 50% have been reported, but randomized trials are still pending. Newer approaches try to evaluate the role of prophylactic FMT in order to prevent GvHD and other complications. Although aSCT patients are heavily immunosuppressed, no major safety concerns regarding FMT have been reported so far., Key Message: FMT is a promising approach for modulation of GvHD after aSCT and should be further explored in randomized trials., Competing Interests: E. Holler is member of the Scientific Advisory Board of Maat Pharma, Lyon, and Pharmabiome, Zürich., (© 2024 S. Karger AG, Basel.)

Vitamin D3 regulates a variety of biological processes irrespective of its well-known importance for calcium metabolism. Epidemiological and animal studies indicate a role in immune regulation, intestinal barrier function and microbiome diversity. Here, we analyzed the impact of different vitamin D3- containing diets on C57BL/6 and BALB/c mice, with a particular focus on gut homeostasis and also investigated effects on immune cells in vitro . Weak regulatory effects were detected on murine T cells. By trend, the active vitamin D3 metabolite 1,25-dihydroxyvitamin D3 suppressed IFN, GM-CSF and IL-10 cytokine secretion in T cells of C57BL/6 but not BALB/c mice, respectively. Using different vitamin D3-fortified diets, we found a tissue-specific enrichment of mainly CD11b+ myeloid cells but not T cells in both mouse strains e.g. in spleen and Peyer's Patches. Mucin Reg3γ and Batf expression, as well as important proteins for gut homeostasis, were significantly suppressed in the small intestine of C57BL76 but not BALB/c mice fed with a high-vitamin D3 containing diet. Differences between both mouse stains were not completely explained by differences in vitamin D3 receptor expression which was strongly expressed in epithelial cells of both strains. Finally, we analyzed gut microbiome and again an impact of vitamin D3 was detected in C57BL76 but not BALB/c. Our data suggest strain-specific differences in vitamin D3 responsiveness under steady state conditions which may have important implications when choosing a murine disease model to study vitamin D3 effects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Schreiber, Ghimire, Hiergeist, Renner, Althammer, Babl, Peuker, Schoenhammer, Hippe, Gessner, Albrecht, Pielmeier, Büttner-Herold, Bruns, Hoffmann, Herr, Holler, Peter, Kreutz and Matos.)

Acute graft-versus-host disease (aGVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT), for which therapeutic options are limited. Strategies to promote intestinal tissue tolerance during aGVHD may improve patient outcomes. Using single-cell RNA sequencing, we identified a lipocalin-2 (LCN2)-expressing neutrophil population in mice with intestinal aGVHD. Transfer of LCN2-overexpressing neutrophils or treatment with recombinant LCN2 reduced aGVHD severity, whereas the lack of epithelial or hematopoietic LCN2 enhanced aGVHD severity and caused microbiome alterations. Mechanistically, LCN2 induced insulin-like growth factor 1 receptor (IGF-1R) signaling in macrophages through the LCN2 receptor SLC22A17, which increased interleukin-10 (IL-10) production and reduced major histocompatibility complex class II (MHCII) expression. Transfer of LCN2-pretreated macrophages reduced aGVHD severity but did not reduce graft-versus-leukemia effects. Furthermore, LCN2 expression correlated with IL-10 expression in intestinal biopsies in multiple cohorts of patients with aGVHD, and LCN2 induced IGF-1R signaling in human macrophages. Collectively, we identified a LCN2-expressing intestinal neutrophil population that reduced aGVHD severity by decreasing MHCII expression and increasing IL-10 production in macrophages. This work provides the foundation for administration of LCN2 as a therapeutic approach for aGVHD.

Introduction: Data on genomic susceptibility for adverse outcomes after hematopoietic stem cell transplantation (HSCT) for recipients are scarce., Methods: We performed a genome wide association study (GWAS) to identify genes associated with survival/mortality, relapse, and severe graft-versus-host disease (sGvHD), fitting proportional hazard and subdistributional models to data of n=1,392 recipients of European ancestry from three centres., Results: The single nucleotide polymorphism (SNP) rs17154454, intronic to the neuronal growth guidant semaphorin 3C gene ( SEMA3C) , was genome-wide significantly associated with event-free survival (p=7.0x10 -8 ) and sGvHD (p=7.5x10 -8 ). Further associations were detected for SNPs in the Paxillin gene ( PXN) with death without prior relapse or sGvHD, as well as for SNPs of the Plasmacytoma Variant Translocation 1 gene (PVT1 , a long non-coding RNA gene ) , the Melanocortin 5 Receptor (MC5R) gene and the WW Domain Containing Oxidoreductase gene ( WWOX) , all associated with the occurrence of sGvHD. Functional considerations support the observed associations., Discussion: Thus, new genes were identified, potentially influencing the outcome of HSCT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Rosenberger, Crossland, Dressel, Kube, Wolff, Wulf, Bickeböller, Dickinson and Holler.)

Objective: To identify and critically evaluate models predicting insomnia treatment response in adult populations., Methods: Pubmed, EMBASE, and PsychInfo databases were searched from January 2000 to January 2023 to identify studies reporting the development or validation of multivariable models predicting insomnia treatment outcomes in adults. Data were extracted according to CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies (CHARMS) guidelines and study quality was assessed using the Prediction model study Risk Of Bias Assessment Tool (PROBAST)., Results: Eleven studies describing 53 prediction models were included and appraised. Treatment response was most frequently assessed using wake after sleep onset (n = 10; 18.9%), insomnia severity index (n = 10; 18.9%), and sleep onset latency (n = 9, 17%). Dysfunctional Beliefs About Sleep (DBAS) score was the most common predictor in final models (n = 33). R 2 values ranged from 0.06 to 0.80 for models predicting continuous response and area under the curve (AUC) ranged from 0.73 to 0.87 for classification models. Only two models were internally validated, and none were externally validated. All models were rated as having a high risk of bias according to PROBAST, which was largely driven by the analysis domain., Conclusion: Prediction models may be a useful tool to assist clinicians in selecting the optimal treatment strategy for patients with insomnia. However, no externally validated models currently exist. These results highlight an important gap in the literature and underscore the need for the development and validation of modern, methodologically rigorous models., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The microbiome is a predictor of clinical outcome in patients receiving allogeneic hematopoietic stem cell transplantation (allo-SCT). Microbiota-derived metabolites can modulate these outcomes. How bacteria, fungi and viruses contribute to the production of intestinal metabolites is still unclear. We combined amplicon sequencing, viral metagenomics and targeted metabolomics from stool samples of patients receiving allo-SCT (n = 78) and uncovered a microbiome signature of Lachnospiraceae and Oscillospiraceae and their associated bacteriophages, correlating with the production of immunomodulatory metabolites (IMMs). Moreover, we established the IMM risk index (IMM-RI), which was associated with improved survival and reduced relapse. A high abundance of short-chain fatty acid-biosynthesis pathways, specifically butyric acid via butyryl-coenzyme A (CoA):acetate CoA-transferase (BCoAT, which catalyzes EC 2.8.3.8) was detected in IMM-RI low-risk patients, and virome genome assembly identified two bacteriophages encoding BCoAT as an auxiliary metabolic gene. In conclusion, our study identifies a microbiome signature associated with protective IMMs and provides a rationale for considering metabolite-producing consortia and metabolite formulations as microbiome-based therapies., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)