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Intersectionality theoretical frameworks have been increasingly incorporated into quantitative research. A range of methods have been applied to describing outcomes and disparities across large numbers of intersections of social identities or positions, with limited evaluation.Using data simulated to reflect plausible epidemiologic data scenarios, we evaluated methods for intercategorical intersectional analysis of continuous outcomes, including cross-classification, regression with interactions, multilevel analysis of individual heterogeneity (MAIHDA), and decision-tree methods (classification and regression trees [CART], conditional inference trees [CTree], random forest). The primary outcome was estimation accuracy of intersection-specific means. We applied each method to an illustrative example using National Health and Nutrition Examination Study (NHANES) systolic blood pressure data.When studying high-dimensional intersections at smaller sample sizes, MAIHDA, CTree, and random forest produced more accurate estimates. In large samples, all methods performed similarly except CART, which produced less accurate estimates. For variable selection, CART performed poorly across sample sizes, although random forest performed best. The NHANES example demonstrated that different methods resulted in meaningful differences in systolic blood pressure estimates, highlighting the importance of selecting appropriate methods.This study evaluates some of a growing toolbox of methods for describing intersectional health outcomes and disparities. We identified more accurate methods for estimating outcomes for high-dimensional intersections across different sample sizes. As estimation is rarely the only objective for epidemiologists, we highlight different outputs each method creates, and suggest the sequential pairing of methods as a strategy for overcoming certain technical challenges.

As cystatin C is increasingly adopted to estimate glomerular filtration rate (eGFR), clinicians will encounter patients in whom cystatin C-based eGFR (eGFRcys) and creatinine-based eGFR (eGFRcr) differ widely. The clinical implications of these differences, eGFRdiffcys-cr, are unknown.To evaluate the associations of eGFRdiffcys-cr with end-stage kidney disease (ESKD) and mortality among individuals with chronic kidney disease (CKD).This is a prospective cohort study of 4956 individuals with mild to moderate CKD from 7 clinical centers in the United States who enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study between 2003 to 2018. Statistical analyses were completed in December 2021.eGFRdiffcys-cr (eGFRcys - eGFRcr) was calculated at baseline and annually thereafter for 3 years. Because 15 mL/min/1.73 m2 represents a clinically meaningful difference in eGFR that also distinguishes CKD stages, eGFRdiffcys-cr was categorized as: less than -15 mL/min/1.73 m2, -15 to 15 mL/min/1.73 m2, and 15 mL/min/1.73 m2 or greater.The outcomes of ESKD, defined as initiation of maintenance dialysis or receipt of a kidney transplant, and all-cause mortality were adjudicated from study entry until administrative censoring in 2018.Among 4956 participants with mean (SD) age of 59.5 (10.5) years, 2152 (43.4%) were Black, 515 (10.4%) were Hispanic, and 2113 (42.6%) were White. There were 2156 (43.5%) women and 2800 (56.5%) men. At baseline, eGFRcys and eGFRcr values differed by more than 15 mL/min/1.73 m2 in one-third of participants (1638 participants [33.1%]). Compared with participants with similar baseline eGFRcys and eGFRcr (eGFRdiffcys-cr -15 to 15 mL/min/1.73 m2), those in whom eGFRcys was substantially lower than eGFRcr (eGFRdiffcys-cr -15 mL/min/1.73 m2) had a higher risk of mortality (hazard ratio [HR], 1.86; 95% CI, 1.40-2.48) while those with eGFRdiffcys-cr of 15 mL/min/1.73 m2 or greater had lower risks of ESKD (subHR [SHR], 0.73; 95% CI, 0.59-0.89) and mortality (HR, 0.68; 95% CI, CI 0.58-0.81). In time-updated analyses, participants with eGFRdiffcys-cr less than -15 mL/min/1.73 m2 had higher risks of ESKD (SHR, 1.83; 95% CI, 1.10-3.04) and mortality (HR, 3.03; 95% CI, 2.19-4.19) compared with participants with similar eGFRcys and eGFRcr. Conversely, participants with eGFRdiffcys-cr of 15 mL/min/1.73 m2 or greater had lower risks of ESKD (SHR, 0.50; 95% CI, 0.35-0.71) and mortality (HR, 0.58; 95% CI, 0.45-0.75). Longitudinal changes in eGFRdiffcys-cr were associated with mortality risk. Compared with participants who had similar slopes by eGFRcys and eGFRcr, those with smaller eGFRcr declines had an 8-fold increased mortality risk (HR, 8.20; 95% CI, 6.37-10.56), and those with larger apparent declines by eGFRcr had a lower mortality risk (HR, 0.14; 95% CI, 0.08-0.24).These findings suggest that large differences between eGFRcys and eGFRcr were common in persons with CKD. These differences and their changes over time may be informative of ESKD and mortality risks, warranting monitoring of both eGFRcys and eGFRcr in this high-risk population.

Vasopressin is reported to retain vasoconstrictive activity in the setting of acidemia, but preclinical models are inconsistent and studies have not evaluated the clinical effectiveness of vasopressin based on arterial pH. This study sought to determine the association between arterial pH and blood pressure after vasopressin initiation in septic shock.This retrospective, multicenter, observational cohort study evaluated the association of arterial pH at the time of vasopressin initiation with hemodynamic response to vasopressin and change in catecholamine dose after vasopressin initiation. Hemodynamic response was defined as a catecholamine dose decrease with mean arterial pressure greater than or equal to 65 mm Hg at 6 hours after vasopressin initiation.Patients from eight hospitals in a health system were evaluated.Patients with septic shock initiated on vasopressin as a catecholamine adjunct between January 2012 and November 2017 were screened for inclusion.None.A total of 1,350 patients were included. At the time of vasopressin initiation patients were severely ill with arterial pH 7.28 ± 0.13, Sequential Organ Failure Assessment 14.1 ± 3.5, lactate 5.6 ± 4.6 mmol/L, and norepinephrine-equivalent catecholamine dose 32.3 ± 25.4 µg/min. After adjusting for lactate and Sequential Organ Failure Assessment with multivariable logistic regression, lower arterial pH was independently associated with lower odds of hemodynamic response to vasopressin (for each 0.1 unit arterial pH was below 7.40, response odds ratio 0.79; 95% CI, 0.72-0.87). For each 0.1 unit the pH was below 7.40 at vasopressin initiation, the norepinephrine-equivalent catecholamine dose increased by 1.5 µg/min (95% CI, 0.5-2.5 µg/min) at 1 hour, and increased by 2.5 µg/min (95% CI, 1.4-3.5 µg/min) at 6 hours after vasopressin initiation.Compared with higher arterial pH, patients with septic shock and low arterial pH had lower odds of vasopressin response and higher catecholamine doses after vasopressin initiation. Similar to other vasopressors, the clinical effectiveness of vasopressin appears to be impaired in the setting of acidemia.

The Omicron variant of SARS-CoV-2 is highly transmissible in vaccinated and unvaccinated populations. The dynamics governing its establishment and propensity towards fixation (reaching 100% frequency in the SARS-CoV-2 population) in communities remain unknown. In this work, we describe the dynamics of Omicron at three institutions of higher education (IHEs) in the greater Boston area.We use diagnostic and variant-specifying molecular assays and epidemiological analytical approaches to describe the rapid dominance of Omicron following its introduction to three IHEs with asymptomatic surveillance programs.We show that the establishment of Omicron at IHEs precedes that of the state and region, and that the time to fixation is shorter at IHEs (9.5-12.5 days) than in the state (14.8 days) or region. We show that the trajectory of Omicron fixation among university employees resembles that of students, with a 2-3 day delay. Finally, we compare cycle threshold (Ct) values in Omicron vs. Delta variant cases on college campuses, and identify lower viral loads among college affiliates harboring Omicron infections.We document the rapid takeover of the Omicron variant at IHEs, reaching near-fixation within the span of 9.5-12.5 days despite lower viral loads, on average, than the previously dominant Delta variant. These findings highlight the transmissibility of Omicron, its propensity to rapidly dominate small populations, and the ability of robust asymptomatic surveillance programs to offer early insights into the dynamics of pathogen arrival and spread.

Intracavitary thrombi are an important differential diagnosis of cardiac masses. Cardiac magnetic resonance imaging (CMR) allows their non-invasive characterization. This case highlights extensive cardiac thrombi detected by CMR as solitary presentation of antiphospholipid syndrome.

PurposeCOVID-related stressors associated with loss of income and community are compounded with gender minority stress among trans and non-binary people (TNB) – which may result in mental health burden. The present study examined the effect of COVID-related change in finances and TNB gathering access on anxiety and depression among TNB people.MethodsParticipants were 18 years and older (M age = 30) who completed both pre-pandemic baseline (Fall 2019) and pandemic follow-up (Fall 2020) surveys in the Trans PULSE Canada study. Multivariable regression analyses examined associations between change in (1) finances and (2) access to TNB peers and mental health during the pandemic.ResultsOf 780 participants, 50% reported that COVID had a negative effect on personal income and 58.3% reported loss in access to TNB peer or friend gatherings (in person or online). Depression and anxiety symptoms increased from pre-pandemic to follow-up, and most participants were above measurement cut-offs for clinical levels during the pandemic. Changes in finances and access to peer gatherings were associated with depression symptoms during the pandemic, but effects depended on level of pre-pandemic depression. For participants with high pre-pandemic depression, financial stability was not protective against increased depression at follow-up. Participants experiencing unprecedentedly high levels of depression during COVID may have pursued more TNB gatherings. Neither financial change nor access to TNB gatherings were associated with pandemic anxiety.ConclusionFindings suggest need for a multifaceted approach to mental health programmes and services to address structural barriers, including financial support and meaningful TNB community engagement.

Background The United States (US) Expanded Access Program (EAP) to coronavirus disease 2019 (COVID-19) convalescent plasma was initiated in response to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. While randomized clinical trials were in various stages of development and enrollment, there was an urgent need for widespread access to potential therapeutic agents. The objective of this study is to report on the demographic, geographical, and chronological characteristics of patients in the EAP, and key safety metrics following transfusion of COVID-19 convalescent plasma. Methods and findings Mayo Clinic served as the central institutional review board for all participating facilities, and any US physician could participate as a local physician–principal investigator. Eligible patients were hospitalized, were aged 18 years or older, and had—or were at risk of progression to—severe or life-threatening COVID-19; eligible patients were enrolled through the EAP central website. Blood collection facilities rapidly implemented programs to collect convalescent plasma for hospitalized patients with COVID-19. Demographic and clinical characteristics of all enrolled patients in the EAP were summarized. Temporal patterns in access to COVID-19 convalescent plasma were investigated by comparing daily and weekly changes in EAP enrollment in response to changes in infection rate at the state level. Geographical analyses on access to convalescent plasma included assessing EAP enrollment in all national hospital referral regions, as well as assessing enrollment in metropolitan areas and less populated areas that did not have access to COVID-19 clinical trials. From April 3 to August 23, 2020, 105,717 hospitalized patients with severe or life-threatening COVID-19 were enrolled in the EAP. The majority of patients were 60 years of age or older (57.8%), were male (58.4%), and had overweight or obesity (83.8%). There was substantial inclusion of minorities and underserved populations: 46.4% of patients were of a race other than white, and 37.2% of patients were of Hispanic ethnicity. Chronologically and geographically, increases in the number of both enrollments and transfusions in the EAP closely followed confirmed infections across all 50 states. Nearly all national hospital referral regions enrolled and transfused patients in the EAP, including both in metropolitan and in less populated areas. The incidence of serious adverse events was objectively low (, In an observational study of registry data, Jonathon Senefeld and colleagues study factors related to patient enrollment in the Expanded Access Program for use of COVID-19 convalescent plasma in the United States., Author summary Why was this study done? There was a public health need to provide expedited and broad access to convalescent plasma for the treatment of coronavirus disease 2019 (COVID-19) during the early stages of this public health emergency in the United States. Convalescent plasma was initially administered through regulatory pathways that required per-patient approval, resulting in substantial administrative time. The Expanded Access Program (EAP) was initiated to provide broad access to COVID-19 convalescent plasma and to provide a framework for standardized collection of data describing the safety profile of convalescent plasma. What did the researchers do and find? The EAP provided rapid and broad access to convalescent plasma throughout the US and some US territories and was effective at providing therapy for demographic groups that were severely affected by COVID-19. In addition, the data provide evidence supporting that transfusion of convalescent plasma is safe in hospitalized patients with COVID-19. What do these findings mean? The study design of the EAP may serve as an example for future efforts in response to a rapidly developing infectious disease when broad access to a treatment is needed in areas and demographic groups that are often poorly represented in clinical trials.

Background Mobile health (mHealth) apps may provide an efficient way for patients with lower urinary tract symptoms (LUTS) to log and communicate symptoms and medication side effects with their clinicians. Objective The aim of this study was to explore the perceptions of older men with LUTS after using an mHealth app to track their symptoms and tamsulosin side effects. Methods Structured phone interviews were conducted after a 2-week study piloting the daily use of a mobile app to track the severity of patient-selected LUTS and tamsulosin side effects. Quantitative and qualitative data were considered. Results All 19 (100%) pilot study participants completed the poststudy interviews. Most of the men (n=13, 68%) reported that the daily questionnaires were the right length, with 32% (n=6) reporting that the questionnaires were too short. Men with more severe symptoms were less likely to report changes in perception of health or changes in self-management; 47% (n=9) of the men reported improved awareness of symptoms and 5% (n=1) adjusted fluid intake based on the questionnaire. All of the men were willing to share app data with their clinicians. Thematic analysis of qualitative data yielded eight themes: (1) orientation (setting up app, format, symptom selection, and side-effect selection), (2) triggers (routine or habit and symptom timing), (3) daily questionnaire (reporting symptoms, reporting side effects, and tailoring), (4) technology literacy, (5) perceptions (awareness, causation or relevance, data quality, convenience, usefulness, and other apps), (6) self-management, (7) clinician engagement (communication and efficiency), and (8) improvement (reference materials, flexibility, language, management recommendations, and optimize clinician engagement). Conclusions We assessed the perceptions of men using an mHealth app to monitor and improve management of LUTS and medication side effects. LUTS management may be further optimized by tailoring the mobile app experience to meet patients’ individual needs, such as tracking a greater number of symptoms and integrating the app with clinicians’ visits. mHealth apps are likely a scalable modality to monitor symptoms and improve care of older men with LUTS. Further study is required to determine the best ways to tailor the mobile app and to communicate data to clinicians or incorporate data into the electronical medical record meaningfully.

Background Continuous α1a-blockade is the first-line treatment for lower urinary tract symptoms (LUTS) among older men with suspected benign prostatic hyperplasia. Variable efficacy and safety for individual men necessitate a more personalized, data-driven approach to prescribing and deprescribing tamsulosin for LUTS in older men. Objective We aim to evaluate the feasibility and usability of the PERSONAL (Placebo–Controlled, Randomized, Patient-Selected Outcomes, N-of-1 Trials) mobile app for tracking daily LUTS severity and medication side effects among older men receiving chronic tamsulosin therapy. Methods We recruited patients from the University of California, San Francisco health care system to participate in a 2-week pilot study. The primary objectives were to assess recruitment feasibility, study completion rates, frequency of symptom tracking, duration of tracking sessions, and app usability rankings measured using a follow-up survey. As secondary outcomes, we evaluated whether daily symptom tracking led to changes in LUTS severity, perceptions of tamsulosin, overall quality of life, medication adherence between baseline and follow-up surveys, and perceived app utility. Results We enrolled 19 men within 23 days, and 100% (19/19) of the participants completed the study. Each participant selected a unique combination of symptoms to track and recorded data in the PERSONAL app, with a median daily completion rate of 79% (11/14 days). The median duration of the app session was 44 (IQR 33) seconds. On a scale of 1 (strongly disagree) to 5 (strongly agree), the participants reported that the PERSONAL app was easy to use (mean 4.3, SD 1.0), that others could learn to use it quickly (mean 4.2, SD 0.9), and that they felt confident using the app (mean 4.4, SD 0.8). LUTS severity, quality of life, and medication adherence remained unchanged after the 2-week study period. Fewer men were satisfied with tamsulosin after using the app (14/19, 74% vs 17/19, 89% at baseline), although the perceived benefit from tamsulosin remained unchanged (18/19, 95% at baseline and at follow-up). In total, 58% (11/19) of the participants agreed that the PERSONAL app could help people like them manage their urinary symptoms. Conclusions This pilot study demonstrated the high feasibility and usability of the PERSONAL mobile app to track patient-selected urinary symptoms and medication side effects among older men taking tamsulosin to manage LUTS. We observed that daily symptom monitoring had no adverse effects on the secondary outcomes. This proof-of-concept study establishes a framework for future mobile app studies, such as digital n-of-1 trials, to collect comprehensive individual-level data for personalized LUTS management in older men.

Mental health comorbidities are frequent in epilepsy. Consequently, psychotherapy is becoming increasingly important. To address the psychological needs of people with epilepsy (PwE) it is essential to understand the subjective experiences of seizures better. There is little research on how people report seizures, and which psychological representations they have. We conducted a thematic analysis based on 42 (micro-phenomenological) interviews with 15 participants on their experiences of seizures. In these interviews, we identified three categories of seizure descriptions: (1) phenomena related to the body and emotions; (2) the moments that are difficult to describe; and (3) the use of figurative language and metaphors. Paroxysmal physical and psychological sensations were often reported spontaneously by the participants. The moments that were difficult to describe were expressed, among other things, through the use of paradoxes or the report of a 'strange' feeling and led participants to use figurative language. As these metaphors can reveal important information about people's subjective experiences, they were analyzed in detail. We identified the three main types of metaphors that the participants used most frequently: (1) perception, (2) nature, and (3) battle. The theme of battle was most frequently used in different forms and was closely related to the metaphors from the fields of perception and nature, thus representing a key point in the personal experience of seizures. These findings can contribute to developing psychotherapeutic approaches for the treatment of seizure disorders.

Dieter R. Bauer / Uwe Lohmann / Volker Trugenberger (Hg.), „Von newen Gebäuen auff alte Stöck“. Archivalische Quellen zur Häusergeschichte, Stuttgart: Kohlhammer 2019. 176 S., Illustrationen, Karten, Pläne. ISBN 978-3-17-037399-0. € 18,–

Importance: Tracheal intubation is one of the most commonly performed and high-risk interventions in critically ill patients. Limited information is available on adverse peri-intubation events. Objective: To evaluate the incidence and nature of adverse peri-intubation events and to assess current practice of intubation in critically ill patients. Design, Setting, and Participants: The International Observational Study to Understand the Impact and Best Practices of Airway Management in Critically Ill Patients (INTUBE) study was an international, multicenter, prospective cohort study involving consecutive critically ill patients undergoing tracheal intubation in the intensive care units (ICUs), emergency departments, and wards, from October 1, 2018, to July 31, 2019 (August 28, 2019, was the final follow-up) in a convenience sample of 197 sites from 29 countries across 5 continents. Exposures: Tracheal intubation. Main Outcomes and Measures: The primary outcome was the incidence of major adverse peri-intubation events defined as at least 1 of the following events occurring within 30 minutes from the start of the intubation procedure: cardiovascular instability (either: systolic pressure 30 minutes, new or increase need of vasopressors or fluid bolus >15 mL/kg), severe hypoxemia (peripheral oxygen saturation

BACKGROUND Plant-based diets are associated with multiple health benefits and a favorable environmental impact. For prostate cancer, previous studies suggest a beneficial role of specific plant-based foods (e.g., tomatoes) and a potentially harmful role of specific animal-based foods (e.g., meat, dairy). However, less is known about plant-based dietary patterns. OBJECTIVE To examine the relationship between Plant-based Diet Indices and prostate cancer risk, including clinically relevant disease. DESIGN This was a prospective cohort study including 47,239 men in the Health Professionals Follow-up Study (1986-2014). Overall and healthful Plant-based Diet Indices were calculated from food frequency questionnaires. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) to examine the risk of incident prostate cancer (total and by clinical category), among men ages

A multidisciplinary approach provided safe and feasible cancer treatment in a patient with advanced pancreatic cancer and coexisting active substance use disorder.

Key Points Question Is frailty associated with increased risk of progression of benign prostatic hyperplasia (BPH) symptoms and serious adverse events among men receiving drug therapy? Findings In a cohort study of 3047 men with moderate-to-severe lower urinary tract symptoms due to suspected BPH, higher deficit accumulation frailty index was associated with a higher risk of clinical BPH progression, particularly among men receiving doxazosin with finasteride, and serious adverse events. Meaning These findings suggest that frail men with lower urinary tract symptoms due to suspected BPH are more likely to have progression of symptoms, despite drug therapy, as well as serious adverse events., This cohort study examines the association between a deficit accumulation frailty index and clinical progression or serious adverse events among men using drug therapy for benign prostatic hyperplasia (BPH)., Importance Benign prostatic hyperplasia (BPH) in older men can cause lower urinary tract symptoms (LUTS), which are increasingly managed with medications. Frailty may contribute to both symptom progression and serious adverse events (SAEs), shifting the balance of benefits and harms of drug therapy. Objective To assess the association between a deficit accumulation frailty index and clinical BPH progression or SAE. Design, Setting, and Participants This cohort study used data from the Medical Therapy of Prostatic Symptoms trial, which compared placebo, doxazosin, finasteride, and combination therapy in men with moderate-to-severe LUTS, reduced urinary flow rate, and no prior BPH interventions, hypotension, or elevated prostate-specific antigen. Enrollment was from 1995 to 1998, and follow-up was through 2001. Data were assessed in February 2021. Exposures A frailty index (score range, 0-1) using 68 potential deficits collected at baseline was used to categorized men as robust (score ≤0.1), prefrail (score 0.1 to

Background Pulmonary vascular and right ventricular myocardial remodelling are unique phenomena in PH progression. Both processes are accompanied by an abundant re-expression of the extra-domain A of fibronectin (ED-A+ Fn) therefore qualifying as promising biomarker or even therapeutic target. Nevertheless, its functional role in PH pathogenesis remains unclear until now. Objective: The purpose of our study was to analyse the development of PH and RHF in a mouse model of monocrotaline (MCT)-induced PH comparing C57BL/6 ED-A+ Fn knockout (KO) and wild-type (WT) mice. Methods PH was induced by subcutaneous injection of a single dose of MCT (60 mg/kg body weight). Subgroups were additionally treated with the dual endothelin receptor antagonist Macitentan (MAC, 15mg/kg body weight per day from day 14 to 28). There were 6 experimental groups: sham-treated control WT mice (WTco, n=4); MCT induced PH WT mice (WTPH, n=6); MCT induced PH WT mice treated with MAC (WTPH_MAC, n=6); sham-treated control KO mice (KOco, n=4); MCT induced PH KO mice (KOPH, n=6); MCT induced PH KO mice treated with MAC (KOPH_MAC, n=6). Between day 26 and 28, transthoracic echocardiography and right heart catheterization were performed. Both, lung and cardiac tissue samples were subjected to histological analyses. Results Right heart catheterization revealed significantly increased RVPsys values in WTPH (87.0±16.4mmHg) compared to WTco (36.1±9.4mmHg; p=0.034) animals, which showed, at least in trend, a diminution in the WTPH_MAC group (67.1±20.9mmHg; p=n.s.). There was a non-significant increase in RVPsys in the KOPH (55.6±14.9mmHg) compared to KOco mice (37.2±5.6mmHg; p=n.s.) without any differences compared to the KOPH_MAC group (60.9±14.0mmHg; p=n.s.). When comparing the WTPH and the KOPH group, RVPsys was significantly lower in the KO animals (p=0.014), while there were no differences between the WTPH_MAC and the KOPH_MAC group (p=n.s.). Echocardiographic evaluation including surrogate parameters of right ventricular (RV) overload and failure were significantly altered in WTPH compared to WTco animals (p Conclusions The findings of the current study underline the hypothesis that ED-A+ Fn is a key player in the pathogenesis of PH and associated RHF. Thus, it might represent a promising therapeutic target, e.g., by the administration of neutralizing antibodies. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): University Hospital Jena

Objectives To determine the association of catecholamine dose, lactate concentration, and timing from shock onset at vasopressin initiation with in-hospital mortality. Design Retrospective, observational study using segmented and multivariable logistic regression to evaluate the associations of catecholamine dose, lactate concentration, and timing from shock onset at vasopressin initiation with in-hospital mortality. Setting Multiple hospitals within the Cleveland Clinic Health System. Patients Adult patients who met criteria for septic shock based on the U.S. Centers for Disease Control and Prevention Adult Sepsis Event definition. Interventions All patients received continuous infusion vasopressin as an adjunct to catecholamine vasopressors. Measurements and main results In total, 1,610 patients were included with a mean Acute Physiology and Chronic Health Evaluation III 109.0 ± 35.1 and Sequential Organ Failure Assessment 14.0 ± 3.5; 41% of patients survived the hospital admission. At the time of vasopressin initiation, patients had median (interquartile range) lactate concentration 3.9 mmol/L (2.3-7.2 mmol/L), norepinephrine-equivalent dose 25 µg/min (18-40 µg/min), and 5.3 hours (2.1-12.2 hr) elapsed since shock onset. The odds of in-hospital mortality increased 20.7% for every 10 µg/min increase in norepinephrine-equivalent dose up to 60 µg/min at the time of vasopressin initiation (adjusted odds ratio, 1.21 [95% CI, 1.09-1.34]), but no association was detected when the norepinephrine-equivalent dose exceeded 60 µg/min (adjusted odds ratio, 0.96 [95% CI, 0.84-1.10]). There was a significant interaction between timing of vasopressin initiation and lactate concentration (p = 0.02) for the association with in-hospital mortality. A linear association between increasing in-hospital mortality was detected for increasing lactate concentration at the time of vasopressin initiation, but no association was detected for time elapsed from shock onset. Conclusions Higher norepinephrine-equivalent dose at vasopressin initiation and higher lactate concentration at vasopressin initiation were each associated higher in-hospital mortality in patients with septic shock who received vasopressin.

Successful clinical translation of mesenchymal stromal cell (MSC) products has not been achieved in the United States and may be in large part due to MSC functional heterogeneity. Efforts have been made to identify 'priming' conditions that produce MSCs with consistent immunomodulatory function; however, challenges remain with predicting and understanding how priming impacts MSC behavior. The purpose of this study was to develop a high throughput, image-based approach to assess MSC morphology in response to combinatorial priming treatments and establish morphological profiling as an effective approach to screen the effect of manufacturing changes (i.e. priming) on MSC immunomodulation. We characterized the morphological response of multiple MSC lines/passages to an array of Interferon-gamma (IFN-γ) and Tumor Necrosis Factor alpha (TNF-⍺) priming conditions, as well as the effects of priming on MSC modulation of activated T cells and MSC secretome. Although considerable functional heterogeneity, in terms of T cell suppression, was observed between different MSC lines and at different passages, this heterogeneity was significantly reduced with combined IFN-γ/TNF-⍺ priming. The magnitude of this change correlated strongly with multiple morphological features and was also reflected by MSC secretion of immunomodulatory factors e.g. PGE2, ICAM-1, and CXCL16. Overall, this study further demonstrates the ability of priming to enhance MSC function, as well as the ability of morphology to better understand MSC heterogeneity and predict changes in function due to manufacturing. This article is protected by copyright. All rights reserved.

Robust polyclonal humoral immune responses have the potential to generate a diverse set of antibodies to neutralize and eliminate viruses such as SARS-CoV-2 and protect against transmission, re-infection and the evolution of variants that evade immunity. CD73 is present on subsets of human B and T cells where it plays a role in lymphocyte activation and migration. CD73 also functions as an ectoenzyme that converts AMP into immunosuppressive adenosine. We have developed a humanized anti-CD73 antibody, mupadolimab (CPI-006), that blocks CD73 enzymatic activity and activates CD73POSB cells, thereby inducing differentiation into plasmablasts, immunoglobulin class switching, and antibody secretion independent of the adenosine modulatory activity. These effects suggest mupadolimab may enhance the magnitude, diversity, and duration of anti-viral responses in patients with COVID-19. This hypothesis was tested in a dose escalation phase 1 trial in 29 hospitalized patients with COVID-19. Single doses of 0.3 mg/kg – 5 mg/kg mupadolimab were well tolerated with no drug related adverse events. Doses greater than 0.3 mg/kg resulted in rapid generation of IgG and IgM to SARS-CoV-2 significantly above titers measured in convalescent controls, with elevated IgG titers sustained for more than 6 months beyond presentation of symptoms. Based on these findings, a randomized double-blind, placebo-controlled Phase 3 study in hospitalized patients was initiated. The primary endpoint was proportion of patients alive and free from respiratory failure within 28 days. This trial was discontinued early during the period of waning COVID-19 incidence after enrolling 40 patients. Although underpowered, results from this trial suggest improvement in the primary and key secondary endpoints in patients treated with single doses of 2 mg/kg and 1 mg/kg compared to placebo. The presumed mechanism of action, stimulation of B cells, may represent a novel approach to immunotherapy of COVID-19 and other viral infections.

Interpersonal synchrony refers to the temporal coordination of actions between individuals and is a common feature of social behaviors, from team sport to ensemble music performance. Interpersonal synchrony of many rhythmic (periodic) behaviors displays dynamics of coupled biological oscillators. The current study addresses oscillatory dynamics on the levels of brain and behavior between music duet partners performing at spontaneous (uncued) rates. Wireless EEG was measured from N = 20 pairs of pianists as they performed a melody first in Solo performance (at their spontaneous rate of performance), and then in Duet performances at each partner’s spontaneous rate. Influences of partners’ spontaneous rates on interpersonal synchrony were assessed by correlating differences in partners’ spontaneous rates of Solo performance with Duet tone onset asynchronies. Coupling between partners’ neural oscillations was assessed by correlating amplitude envelope fluctuations of cortical oscillations at the Duet performance frequency between observed partners and between surrogate (re-paired) partners, who performed the same melody but at different times. Duet synchronization was influenced by partners’ spontaneous rates in Solo performance. The size and direction of the difference in partners’ spontaneous rates were mirrored in the size and direction of the Duet asynchronies. Moreover, observed Duet partners showed greater inter-brain correlations of oscillatory amplitude fluctuations than did surrogate partners, suggesting that performing in synchrony with a musical partner is reflected in coupled cortical dynamics at the performance frequency. The current study provides evidence that dynamics of oscillator coupling are reflected in both behavioral and neural measures of temporal coordination during musical joint action.

GATA2 deficiency was described in 2011, and shortly thereafter allogeneic hematopoietic stem cell transplantation (HSCT) was shown to reverse the hematologic disease phenotype. However, there remain major unanswered questions regarding the type of conditioning regimen, type of donors, and graft-versus-host disease (GVHD) prophylaxis. We report 59 patients with GATA2 mutations undergoing HSCT at National Institutes of Health between 2013 and 2020. Primary endpoints were engraftment, reverse of the clinical phenotype, secondary endpoints were overall survival (OS), event-free survival (EFS), and the incidence of acute and chronic GVHD. The OS and EFS at 4 years were 85·1% and 82·1% respectively. Ninety-six percent of surviving patients had reversal of the hematologic disease phenotype by one-year post-transplant. Incidence of grade III-IV aGVHD in matched related donor (MRD) and matched unrelated donor recipients (URD) patients receiving Tacrolimus/Methotrexate for GVHD prophylaxis was 32%. In contrast, in the MRD and URD who received post-transplant cyclophosphamide (PT/Cy), no patient developed grade III-IV aGVHD. Six percent of haploidentical related donor (HRD) recipients developed grade III-IV aGVHD. In summary, a busulfan-based HSCT regimen in GATA2 deficiency reverses the hematologic disease phenotype, and the use of PT/Cy reduced the risk of both aGVHD and cGVHD.

INTRODUCTION AND OBJECTIVE:Plant-based diets are associated with multiple health benefits as well as a favorable environmental impact. For prostate cancer, previous studies suggest a beneficial rol...

INTRODUCTION AND OBJECTIVE:Central sensitization (CS) is an impairment in the processing of sensory information that results in ongoing hypersensitivity to nociceptive and other somatic signals. CS...

Initial fluid resuscitation volume for sepsis is controversial, particularly in patients at high baseline risk for complications. This study was designed to assess the association between 30 mL/kg crystalloids and intubation in patients with sepsis or septic shock and heart failure, end-stage renal disease, or cirrhosis.This propensity score-matched retrospective cohort study included patients with sepsis or septic shock admitted to a large medical ICU. Primary exposure was IV fluid volume in the first 6 h following sepsis diagnosis, divided into two cohorts: ≥ 30 mL/kg (standard group) and 30 mL/kg (restricted group). The primary outcome was need for mechanical ventilation within 72 h following initiation of fluid resuscitation. Secondary outcomes were length of stay, ventilator days, and time to intubation.A total of 208 patients were included, with 104 (50%) in the restricted group ( 30 mL/kg) and 104 in the standard group (≥ 30 mL/kg). No difference in intubation incidence was detected between the two groups, with 36 patients (35%) in the restricted group and 33 (32%) in the standard group (adjusted OR, 0.75; 95% CI, 0.41-1.36; P = .34) intubated. There was no difference between standard and restricted groups in alive ICU-free days (17 ± 11 days vs 17 ± 10 days; P = .64), duration of mechanical ventilation (10 ± 12 days vs 11 ± 16 days; P = .96), or hours to intubation (16 ± 19 h vs 14 ± 15; P = .55).No differences were detected in the incidence of intubation in patients with sepsis and cirrhosis, end-stage renal disease, or heart failure who received guideline-recommended fluid resuscitation with 30 mL/kg compared with patients initially resuscitated with a lower fluid volume.

We have previously shown that the thermolabile, cavity-creating p53 cancer mutant Y220C can be reactivated by small-molecule stabilizers. In our ongoing efforts to unearth druggable variants of the p53 mutome, we have now analyzed the effects of other cancer-associated mutations at codon 220 on the structure, stability, and dynamics of the p53 DNA-binding domain (DBD). We found that the oncogenic Y220H, Y220N, and Y220S mutations are also highly destabilizing, suggesting that they are largely unfolded under physiological conditions. A high-resolution crystal structure of the Y220S mutant DBD revealed a mutation-induced surface crevice similar to that of Y220C, whereas the corresponding pocket's accessibility to small molecules was blocked in the structure of the Y220H mutant. Accordingly, a series of carbazole-based small molecules, designed for stabilizing the Y220C mutant, also bound to and stabilized the folded state of the Y220S mutant, albeit with varying affinities due to structural differences in the binding pocket of the two mutants. Some of the compounds also bound to and stabilized the Y220N mutant, but not the Y220H mutant. Our data validate the Y220S and Y220N mutants as druggable targets and provide a framework for the design of Y220S or Y220N-specific compounds as well as compounds with dual Y220C/Y220S specificity for use in personalized cancer therapy.

Magnetic resonance imaging (MRI) has long been contraindicated in patients with implanted pacemakers, defibrillators, and cardiac resynchronisation therapy (CRT) devices due to the risk of adverse effects through electromagnetic interference. Since many recipients of these devices will have a lifetime indication for an MRI scan, the implantable systems should be developed as ‘MRI-conditional’ (be safe for the MRI environment under predefined conditions). We evaluated the clinical safety of several Biotronik ProMRI (‘MRI-conditional’) defibrillator and CRT systems during head and lower lumbar MRI scans at 1.5 Tesla. The study enrolled 194 patients at 22 sites in Australia, Canada, and Europe. At ≥9 weeks after device implantation, predefined, non-diagnostic, specific absorption rate (SAR)-intensive head and lower lumbar MRI scans (total ≈30 minutes per patient) were performed in 146 patients that fulfilled pre-procedure criteria. Three primary endpoints were evaluated: freedom from serious adverse device effects (SADEs) related to MRI and defibrillator/CRT (leading to death, hospitalisation, life-threatening condition, or potentially requiring implanted system revision or replacement), pacing threshold increase, and sensing amplitude decrease, all at the 1-month post-MRI clinical visit. No MRI-related SADE occurred. Lead values remained stable, measured in clinic and monitored daily by the manufacturer home monitoring technology.

Background: No previous studies exist examining 2 inhaled epoprostenol formulations in an acute respiratory distress syndrome (ARDS) patient population. Objective: The study aim was to evaluate a formulary conversion from inhaled Flolan to Veletri to determine the impact on effectiveness, safety, and cost in patients with ARDS. Methods: This was a single-center, retrospective, matched cohort observational study at a tertiary care academic medical center. Patients included were mechanically ventilated, adult patients with ARDS receiving inhaled Flolan or Veletri for ≥1 hour in the intensive care unit. Results: A total of 132 patients were included in the matched cohort. There was no difference detected in change in partial pressure of arterial O2/fraction of inspired O2(PaO2/FiO2) ratio after 1 hour of therapy between the inhaled Flolan and Veletri groups (27.2 ± 46.2 vs 30 ± 68 mm Hg, P = 0.78). Significant differences in secondary outcomes included incidence of hypotension (83% vs 95.5%, P = 0.04) and thrombocytopenia (9.1% vs 29.5%, P < 0.01) in the inhaled Flolan and Veletri groups, respectively, with no difference in cost per duration of therapy ( P = 0.29). Conclusions and Relevance: There was no difference in the change in PaO2/FiO2ratio after 1 hour of therapy between inhaled Flolan and Veletri in an ARDS patient population. The formulary conversion from inhaled Flolan to Veletri was likely justified.

Thrombotic thrombocytopenic purpura (TTP) is fatal in 90% of patients if left untreated and must be diagnosed early to optimize patient outcomes. However, the very low incidence of TTP is an obstacle to the development of evidence-based clinical practice recommendations, and the very wide variability in survival rates across centers may be partly ascribable to differences in management strategies due to insufficient guidance. We therefore developed an expert statement to provide trustworthy guidance about the management of critically ill patients with TTP. As strong evidence was difficult to find in the literature, consensus building among experts could not be reported for most of the items. This expert statement is timely given the recent advances in the treatment of TTP, such as the use of rituximab and of the recently licensed drug caplacizumab, whose benefits will be maximized if the other components of the management strategy follow a standardized pattern. Finally, unanswered questions are identified as topics of future research on TTP.