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Geriatric assessment (GA) may identify vulnerabilities and promote risk-stratification in older adults predisposed to toxicities after autologous (auto), allogeneic (allo) hematopoietic cell transplantation (HCT) and chimeric antigen T-cell therapies (CAR T). With increased utilization cellular therapies for older adults the American Society for Transplantation and Cellular Therapy (ASTCT) Committee on Practice Guidelines and its Special Interest Group for Aging (SIG) conducted an online cross-sectional survey between April 2023 and August 2023 to determine transplantation and cellular therapy physicians' practice patterns regarding GA in older patients receiving HCT and CAR T-cell therapies. E-mail surveys were sent to 1168 ASTCT physician members and only 96 (8.2%) respondents completed the survey. Most (86%) were affiliated with university/teaching centers and 70% had a combined HCT and cellular therapy practice. More than 50% of respondents were interested in pursuing GA but 68% described barriers. The top two recognized barriers to GA were lack of time (96%) and clinical support staff (90%). Despite interest, only 15% respondents reported to know the domains of GA 'well'. Among those using GA, the minimum age used for routine GA was 65 years for allo-HCT and CAR T in over 91% respondents. Taken together, we recommend the HCT community leadership and GA experts combine efforts to address the gap in GA uptake and implementation., Competing Interests: Declaration of competing interest none, (Copyright © 2025. Published by Elsevier Inc.)

Immunocompromised individuals are at risk for developing lymphocryptovirus-associated lymphoproliferative diseases, such as Epstein Barr virus (EBV)-associated B cell lymphomas and post-transplant lymphoproliferative disorder (PTLD). We previously reported development of cynomolgus lymphocryptovirus (CyLCV)-associated PTLD in Mauritian cynomolgus macaques (MCMs) undergoing hematopoietic stem cell transplantation (HSCT), which mirrored EBV-PTLD in transplant patients. Here, we sought to develop a MCM model of lymphocryptovirus-associated lymphoproliferative disease in immunosuppressed MCMs without HSCT. Five simian immunodeficiency virus (SIV)-infected, CD8α+ cell-depleted MCMs received an infusion of autologous B-lymphoblastoid cells transformed with CyLCV, followed by varying degrees of immunosuppression. Four of five infused macaques developed masses coincident with increasing CyLCV plasma viremia, and necropsies confirmed the presence of multicentric lymphomas, which most commonly manifested in lymph nodes, gastrointestinal tract, adrenal glands, and pancreas. Affected tissues harbored neoplastic lymphocytes double-positive for CD20 and CyLCV EBNA2 antigen, large frequencies of proliferating B cells, and high levels of cell-associated CyLCV DNA. In addition, longitudinal 18F-fluorodeoxyglucose positron-emission tomography (18F-FDG PET) of one MCM successfully detected lymphoproliferative disease in the adrenal glands prior to clinical signs of disease. These data demonstrate successful induction of lymphocryptovirus-associated PTLD-like disease in 4 of 5 MCMs, and thus support the use of MCMs as a preclinical NHP model of EBV-associated lymphoproliferative disease that could be employed to test novel diagnostic and therapeutic modalities., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Acute encephalopathy, manifesting clinically as delirium, is a common but often unrecognized complication of hematopoietic cell transplantation (HCT). Delirium can occur in patients of any age and is observed after autologous or allogeneic HCT. Although delirium has been studied primarily during initial HCT hospitalizations in recipients of myeloablative conditioning, recent investigations have identified delirium later post-transplantation and in recipients of reduced-intensity conditioning. Acute encephalopathy can be driven by infectious complications, medications, tissue damage, and/or organ dysfunction. Altered consciousness, either mild or profound, is often its only clinical manifestation. Identifying delirium is essential to overall HCT care, because patients who experience delirium have longer hospitalization and recovery times and are at risk for other poor post-HCT outcomes. Given the critical nature of this common complication and the ongoing expansion of HCT for more vulnerable populations, the American Society of Transplantation and Cellular Therapy (ASTCT) recommends intensifying research into post-HCT cognitive changes and establishing standardized definitions that encompass the full spectrum of altered consciousness for clinical care purposes and to provide benchmark endpoints for future research studies. To capture a range of acute neurocognitive changes specifically found in HCT patients (often referred to as acute encephalopathy), the ASTCT proposes a new diagnosis, transplantation-associated altered mentation and encephalopathy (TAME). The TAME diagnosis includes HCT patients who meet Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for delirium and those with acute neurocognitive changes who do not meet all the DSM-5 criteria for delirium (subsyndromal delirium). Early TAME is defined as occurring during conditioning or ≤100 days post-HCT, whereas late TAME occurs >100 days post-HCT in patients with additional HCT-related complications. This manuscript establishes clear diagnostic criteria and discusses factors that can potentially impact the development of TAME, as well as the workup and management of TAME., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Introduction: CMML is a rare neoplasm with overlapping myelodysplastic and myeloproliferative features whose only potential cure is allogeneic hematopoietic cell transplantation (allo-HCT)., Methods: This retrospective study examined 27 CMML patients with high-risk clinical features who underwent first allo-HCT at our institution between 2004 and 2022., Results: Nineteen patients were diagnosed with the proliferative subtype (CMML-MPN) and 8 with the dysplastic subtype (CMML-MDS). Median OS was 15 months post-HCT (95% CI: 5-71); OS at 1, 3, and 5 years was 52%, 35%, and 35%, respectively. Compared to those with CMML-MPN, patients with CMML-MDS had longer OS (median, 8.6 vs. 0.9 years; p = 0.025), RFS (4.4 vs. 0.5 years; p = 0.021), and GVHD-free, relapse-free survival (GRFS, 9.4 vs. 3.4 months; p = 0.033) as well as lower 1-year NRM (13 vs. 47%; p = 0.043), with the statistical significance of this CMML subtype effect maintained in multivariable models. High-risk cytogenetics were associated with shorter GRFS in the univariable (median, 3.1 vs. 6.2 months; p = 0.013) and multivariable (HR = 4.88; p = 0.006) settings., Conclusions: Patients who underwent transplant for CMML-MDS experienced substantially better outcomes than those transplanted for CMML-MPN. Future studies are needed for transplantation optimization in CMML, especially CMML-MPN., (© 2024 S. Karger AG, Basel.)

Objective: This study aimed to characterize mobility patterns using wearable inertial sensors and serial assessment across autologous hematopoietic cell transplant (autoHCT) and investigate the relation between mobility and perceived function in patients with hematologic cancer., Design: Prospective longitudinal study., Setting: Hospital adult transplant clinic followed by discharge., Participants: 78 patients with hematological cancer receiving autoHCT., Main Outcome Measures: Mobility was measured across 3 clinical phases (pretransplant, pre-engraftment, and post-engraftment) in using inertial sensors worn during prescribed performance tests in the hospital. Perceived function was assessed using validated provider-reported (Eastern Cooperative Oncology Group [ECOG] Performance Status Scale) and patient-reported [European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ-C30]) measures. Trajectories of 5 selected mobility characteristics (turn duration, gait speed, stride time variability, double support time, and heel strike angle) across the clinical phases were also evaluated using piecewise linear mixed-effects models., Results: Using Principal Components Analysis, 4 mobility patterns were identified pretransplant: Gait Limitation, Sagittal Sway, Coronal Sway, and Balance Control. Gait Limitation measured pretransplant was significantly inversely associated with perceived function reported by the provider- (β = -0.11; 95% CI: -0.19, -0.02) and patient- (β = -4.85; 95% CI: -7.72, -1.99) post-engraftment in age-adjusted linear regression models. Mobility characteristics demonstrated immediate declines early pre-engraftment with stabilization by late pre-engraftment., Conclusion: Patients with hematological cancer experiencing gait limitations pretransplant are likely to have worse perceived function post-engraftment. Mobility declines in early phases post-transplant and may not fully recover, indicating an opportunity for timely rehabilitation referrals. Wearable inertial sensors can be used to identify early mobility problems and patients who may be at risk for future functional decline who may be candidates for early physical rehabilitation., (Copyright © 2024 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Self-replicating RNA derived from the genomes of positive-strand RNA viruses represents a powerful tool for both molecular studies on virus biology and approaches to novel safe and effective vaccines. The following chapter summarizes the principles how such RNAs can be established and used for design of vaccines. Due to the large variety of strategies needed to circumvent specific pitfalls in the design of such constructs the technical details of the experiments are not described here but can be found in the cited literature., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Several studies have shown that microsatellite changes can be profiled in urine for the detection of bladder cancer. The use of microsatellite analysis (MSA) for bladder cancer detection requires a comprehensive analysis of as many as 15 to 20 markers, based on the amplification and interpretations of many individual MSA markers, and it can be technically challenging. Here, to develop fast, more efficient, standardized, and less costly MSA for the detection of bladder cancer, we developed three multiplex-polymerase-chain-reaction-(PCR)-based MSA assays, all of which were analyzed via a genetic analyzer. First, we selected 16 MSA markers based on 9 selected publications. Based on samples from Johns Hopkins University (the JHU sample, the first set sample), we developed an MSA based on triplet, three-tube-based multiplex PCR (a Triplet MSA assay). The discovery, validation, and translation of biomarkers for the early detection of cancer are the primary focuses of the Early Detection Research Network (EDRN), an initiative of the National Cancer Institute (NCI). A prospective study sponsored by the EDRN was undertaken to determine the efficacy of a novel set of MSA markers for the early detection of bladder cancer. This work and data analysis were performed through a collaboration between academics and industry partners. In the current study, we undertook a re-analysis of the primary data from the Compass study to enhance the predictive power of the dataset in bladder cancer diagnosis. Using a four-stage pipeline of modern machine learning techniques, including outlier removal with a nonlinear model, correcting for majority/minority class imbalance, feature engineering, and the use of a model-derived variable importance measure to select predictors, we were able to increase the utility of the original dataset to predict the occurrence of bladder cancer. The results of this analysis showed an increase in accuracy (85%), sensitivity (82%), and specificity (83%) compared to the original analysis. The re-analysis of the EDRN study results using machine learning statistical analysis proved to achieve an appropriate level of accuracy, sensitivity, and specificity to support the use of the MSA for bladder cancer detection and monitoring. This assay can be a significant addition to the tools urologists use to both detect primary bladder cancers and monitor recurrent bladder cancer.

In this paper, we discuss surgical palliative care for patients with cancer through the lens of frailty and the preoperative context. Historically, palliative care principles such as complex symptom management, high-risk decision-making and communication have played an important role in preoperative discussions of oncologic surgery for both palliative and curative intent. There is increasing motivation among surgeons to integrate palliative care into the perioperative period in order to more effectively and comprehensively address potential adverse functional and quality of life outcomes. We discuss how the concept of frailty, and various instruments to measure frailty, have impacted perioperative decision-making, review the roots of surgical risk stratification and counseling on acceptable perioperative risk, and explore the preoperative setting as a possible avenue by which primary and specialty palliative care integration may have beneficial impact for patients considering oncologic resections., 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 Inc. All rights reserved.)

Allogeneic hematopoietic stem cell transplantation (alloHSCT) from donors lacking C-C chemokine receptor 5 (CCR5 Δ32/Δ32 ) can cure HIV, yet mechanisms remain speculative. To define how alloHSCT mediates HIV cure, we performed MHC-matched alloHSCT in SIV + , anti-retroviral therapy (ART)-suppressed Mauritian cynomolgus macaques (MCMs) and demonstrated that allogeneic immunity was the major driver of reservoir clearance, occurring first in peripheral blood, then peripheral lymph nodes, and finally in mesenteric lymph nodes draining the gastrointestinal tract. While allogeneic immunity could extirpate the latent viral reservoir and did so in two alloHSCT-recipient MCMs that remained aviremic >2.5 years after stopping ART, in other cases, it was insufficient without protection of engrafting cells afforded by CCR5-deficiency, as CCR5-tropic virus spread to donor CD4 + T cells despite full ART suppression. These data demonstrate the individual contributions of allogeneic immunity and CCR5 deficiency to HIV cure and support defining targets of alloimmunity for curative strategies independent of HSCT., Competing Interests: Declaration of interests J.B.S. has a significant financial interest in and serves on the scientific advisory board of CytoDyn, a company that may have a financial interest in the results of this research and technology. This potential individual conflict of interest has been reviewed and managed by OHSU., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Survivors of child abuse experience high rates of adverse physical and mental health outcomes. Epigenetic alterations in the stress response system, the FKBP5 gene specifically, have been implicated as one mechanism that may link abuse to lifelong health issues. Prior studies primarily included older individuals with a remote history of maltreatment; our objective was to test for differential methylation of FKBP5 in children with abusive vs accidental injuries at the time of diagnosis., Methods: We conducted a cross-sectional pilot study of acutely injured children <4 years old at two children's hospitals (n = 82). Research personnel collected injury histories, buccal swabs (n = 65), and blood samples (n = 25) to measure DNA methylation. An expert panel classified the injuries as abusive, accidental, or indeterminate., Results: Children with abusive as compared to accidental injuries had lower methylation of the FKBP5 promoter in buccal and blood cells, even after controlling for injury severity, socioeconomic status, and psychosocial risk factors., Conclusion: These findings suggest that epigenetic variation in FKBP5 may occur at the earliest indication of abuse and may be associated with delayed resolution of the HPA axis stress response. Additional testing for epigenetic differences in larger sample sizes is needed to further verify these findings., Impact: Children (<4 years old) with abusive compared to accidental injuries showed lower methylation of the FKBP5 promoter in buccal and blood cells at the time of initial diagnosis even after controlling for injury severity, socioeconomic status, and psychosocial risk factors. Early childhood physical abuse may impact the epigenetic regulation of the stress response system, including demethylation within promoters and enhancers of the FKBP5 gene, even at the earliest indication of abuse. The findings are important because unmitigated stress is associated with adverse health outcomes throughout the life-course., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Risk stratification in acute myeloid leukemia (AML) remains principle in survival prognostication and treatment selection. The 2022 European LeukemiaNet (ELN) recommendations were recently published, with notable updates to risk group assignment. The complexity of risk stratification and comparative outcomes between the 2022 and 2017 ELN guidelines remains unknown. This comparative analysis evaluated outcomes between the 2017 and 2022 ELN criteria in patients enrolled within the multicenter Beat AML cohort. Five hundred thirteen patients were included. Most patients had 1 or 2 ELN risk-defining abnormalities. In patients with ≥2 ELN risk-defining mutations, 44% (n = 132) had mutations spanning multiple ELN risk categories. Compared with ELN 2017 criteria, the updated ELN 2022 guidelines changed the assigned risk group in 15% of patients, including 10%, 26%, and 6% of patients categorized as being at ELN 2017 favorable-, intermediate-, and adverse-risk, respectively. The median overall survival across ELN 2022 favorable-, intermediate-, and adverse-risk groups was not reached, 16.8, and 9.7 months, respectively. The ELN 2022 guidelines more accurately stratified survival between patients with intermediate- or adverse-risk AML treated with induction chemotherapy compared with ELN 2017 guidelines. The updated ELN 2022 guidelines better stratify survival between patients with intermediate- or adverse-risk AML treated with induction chemotherapy. The increased complexity of risk stratification with inclusion of additional cytogenetic and molecular aberrations necessitates clinical workflows simplifying risk stratification., (© 2023 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.)

The traditional watershed segmentation methods usually suffer from over segmentation for irregularly shaped particles. This is because the distance map of an irregularly shaped particle contains multiple local maxima, and over segmentation would happen if these local maxima were used as seeds for watershed segmentation. In this work, several methods based on morphological reconstruction, including h-dome transform, h-maxima, and area-reconstruction h-dome transform, are introduced to merge, or erase redundant local maxima, and the performance of these methods in avoiding over segmentation is compared. The results show that the area-reconstruction h-dome transform is the most effective method in controlling over segmentation among the evaluated methods. However, the area-reconstruction h-dome transform is achieved by superposition of binary reconstructions at each grayscale level, which is extremely time-consuming and impractical for batch processing. A hybrid pixel-queue algorithm is applied to accelerate the area-reconstruction h-dome transform, and the algorithm is implemented in Cython to further improve the computational efficiency. For a 2592 × 1944 pixel image, on a PC with an Intel Core i5 2.4GHz processor and 8 GB RAM, the processing time of the area-reconstruction h-dome transform after acceleration is about 549 ms, which is 249 times faster than the unaccelerated algorithm and 4 times faster than the reconstruction function in the Scikit-image library (an open-source image processing library for the Python programming language) which performs reconstruction by dilation. The accelerated area-reconstruction h-dome transform algorithm was successfully applied to the segmentation of rubber particles in a thermoplastic polyolefin (TPO) compound. RESEARCH HIGHLIGHTS: Techniques for segmenting particles with irregular shapes based on morphological reconstruction are reviewed. A fast algorithm for area-reconstruction h-dome transform is introduced based on Vincent's first approach combined with the pixel queue algorithm and Cython acceleration. The accelerated reconstruction algorithm is 249 times faster than the unaccelerated algorithm. The fast area-reconstruction h-dome transform algorithm is successfully applied to rubber particle segmentation of a thermal plastic polyolefin., (© 2023 Wiley Periodicals LLC.)

Background Aims: In a previous pilot study of HLA-matched sibling donor hematopoietic cell transplantation (HCT), the authors determined the feasibility of day 4 versus day 5 granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cell (PBSC) collection compared with a historical cohort. Given identified differences in the PBSC product (day 4 cohort with significantly lower infused total nucleated, mononuclear and CD3 cells compared with other collection cohorts), the authors performed a follow-up study to determine long-term post-HCT outcomes, including detailed characterization of chronic graft-versus-host disease (GVHD)., Methods: This was a prospective observational study, and the authors collected data on chronic GVHD, staging, sites of involvement and treatments. Performance status, incidence of relapse, overall survival and duration of immunosuppressive therapy (IST) were also evaluated. Data were examined retrospectively. To account for differences in length of follow-up among cohorts, the authors also determined performance status and chronic GVHD staging, sites and treatment at 2 years post-HCT., Results: At 2 years post-HCT, the overall survival rate was 71.7% in the day 4 cohort compared with 61.5%, 52% and 56% in the day 5, 2-day and historical cohorts, respectively (P = 0.283). The cumulative incidence of chronic GVHD was 65.2% in the day 4 cohort versus 46.4% in the day 5 cohort, 51.1% in the 2-day cohort and 65% in the historical cohort (P = 0.26). There was no significant difference in the maximum overall stage of chronic GVHD (P = 0.513), median number of sites involved (P = 0.401) or cumulative incidence of discontinuation of IST (P = 0.32). Death from chronic GVHD was less common in the day 4 and day 5 cohorts compared with the 2-day and historical cohorts, though this did not reach statistical significance., Conclusions: The authors' preliminary results demonstrated that collection of allogeneic matched sibling donor PBSCs on day 4 of G-CSF was feasible, reduced donor exposure to growth factor and was associated with an initial cost savings. Importantly, the authors now demonstrate that transplantation of day 4 mobilized PBSCs is not associated with any adverse outcomes post-HCT, including late effects such as chronic GVHD. Further investigation of donor G-CSF collection algorithms is merited in other HCT settings, including unrelated and mismatched related donors., Competing Interests: Declaration of Competing Interest RTM reports consultancy for and research funding from Novartis; consultancy and advisory board participation for Incyte; advisory board participation for Kite Pharma/Gilead; research funding from AlloVir; data and safety monitoring board membership with Novartis, Athersys and Vor Pharma; and scientific advisory board participation for Artiva. AG reports advisory board participation for Gamida Cell and Talaris Therapeutics., (Copyright © 2022 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Introduction: For the past 16 years, Military Health System primary care providers have been incentivized to pursue work in a fee-for-service (FFS) model. The system values documentation of productivity to earn as many relative value units as possible. The result is densely packed clinic schedules that often lack the space or flexibility to accommodate patients when sick. Leakage ensues. Furthermore, prevention and patient experience are not directly incentivized., Methods: The Central Texas Market's Accountable Care Organization reformed incentives in its #5 FFS-designed community-based medical homes to value outcomes over productivity. The resulting quality, urgent, internet, and phone care (QUiC) clinics are value-based and, therefore, better structured to achieve the Quad aim (better care, better health/readiness, and low cost). Forsaking deeply ingrained FFS practices, QUiC clinics funnel all routine (information-sharing) appointments into efficient internet or phone appointments. With the time freed by managing common needs in short bursts, QUiC clinics see sick patients with no notice (urgent care). They also focus on prevention and patient experience. We measured the effectiveness of the QUiC clinics in the value-based metrics of (1) patient experience, (2) Healthcare Effectiveness Data and Information Set measures of quality and prevention. (3) access-to-care, (4) leakage, and (5) enrollment., Results: Over a 19 month period, the five community-based medical homes improved significantly in all areas. Specifically, measures of patient satisfaction improved from the mid-80s percent satisfied to the mid-90s percent satisfied. Healthcare Effectiveness Data and Information Set measures increased from average compared to national benchmarks (<50th percentile to 75th percentile) to the 90th percentile in four of five measures of quality and the 75th percentile in the remaining measure. Access to care for routine appointments decreased from 15.4 days to the third next available appointment to 2.8 days. Leakage decreased from 12.2% to 9.6%. These successes were attained without cost or significant reductions in patient enrollments. In changing workflows, the market became the #1 user of virtual video visits in the DOD., Conclusions: This performance improvement project proved the concept that a military market can vastly improve value-based primary care outcomes at no cost and within multiple community-based clinics., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2021. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

It is widely accepted that the gut microbiota plays a significant role in modulating inflammatory and immune responses of their host. In recent years, the host-microbiota interface has gained relevance in understanding the development of many non-communicable chronic conditions, including cardiovascular disease, cancer, autoimmunity and neurodegeneration. Importantly, dietary fibre (DF) and associated compounds digested by the microbiota and their resulting metabolites, especially short-chain fatty acids (SCFA), were significantly associated with health beneficial effects, such as via proposed anti-inflammatory mechanisms. However, SCFA metabolic pathways are not fully understood. Major steps include production of SCFA by microbiota, uptake in the colonic epithelium, first-pass effects at the liver, followed by biodistribution and metabolism at the host's cellular level. As dietary patterns do not affect all individuals equally, the host genetic makeup may play a role in the metabolic fate of these metabolites, in addition to other factors that might influence the microbiota, such as age, birth through caesarean, medication intake, alcohol and tobacco consumption, pathogen exposure and physical activity. In this article, we review the metabolic pathways of DF, from intake to the intracellular metabolism of fibre-derived products, and identify possible sources of inter-individual variability related to genetic variation. Such variability may be indicative of the phenotypic flexibility in response to diet, and may be predictive of long-term adaptations to dietary factors, including maladaptation and tissue damage, which may develop into disease in individuals with specific predispositions, thus allowing for a better prediction of potential health effects following personalized intervention with DF.

The sudden and dramatic advent of the COVID-19 pandemic led to urgent demands for timely, relevant, yet rigorous research. This paper discusses the origin, design, and execution of the SolPan research commons, a large-scale, international, comparative, qualitative research project that sought to respond to the need for knowledge among researchers and policymakers in times of crisis. The form of organization as a research commons is characterized by an underlying solidaristic attitude of its members and its intrinsic organizational features in which research data and knowledge in the study is shared and jointly owned. As such, the project is peer-governed, rooted in (idealist) social values of academia, and aims at providing tools and benefits for its members. In this paper, we discuss challenges and solutions for qualitative studies that seek to operate as research commons., Competing Interests: 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., (© 2022 The Authors.)

Data for outcomes after autologous hematopoietic cell transplantation (auto-HCT) in diffuse large B-cell lymphoma (DLBCL) patients ≥70 years are limited. Auto-HCT is feasible in older DLBCL patients. Using the Center for International Blood and Marrow Transplant Research database, we compared outcomes of auto-HCT in DLBCL patients aged 60 to 69 years (n = 363) versus ≥70 years (n = 103) between 2008 and 2019. Non-relapse mortality (NRM), relapse/progression (REL), progression-free survival (PFS), and overall survival (OS) were modeled using Cox proportional hazards models. All patients received BEAM conditioning (carmustine, etoposide, cytosine arabinoside and melphalan). On univariate analysis, in the 60 to 69 years versus ≥70 years cohorts, 100-day NRM was 3% versus 4%, 5-year REL was 47% versus 45%, 5-year PFS 40% versus 38% and 5-year OS 55% versus 41%, respectively. On multivariate analysis, patients ≥70 had no significant difference in NRM (hazard ratio [HR] 1.43, 95% confidence interval [CI] 0.85-2.39), REL (HR 1.11, 95% CI 0.79-1.56), PFS (HR 1.23, 95% CI 0.92-1.63) compared to patients 60 to 69 years. Patients ≥70 years had a higher mortality (HR 1.39, 95% CI 1.05-1.85, p=0.02), likely because of inferior post-relapse OS in this cohort (HR 1.82, 95% CI 1.27-2.61, P = .001). DLBCL was the major cause of death in both cohorts (62% versus 59%). Older patients should not be denied auto-HCT solely on the basis of chronological age., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The coronavirus disease 2019 (COVID-19) pandemic forced American medical systems to adapt to high patient loads of respiratory disease. Its disruption of normal routines also brought opportunities for broader reform. The purpose of this article is to describe how the Carl R. Darnall Army Medical Center (CRDAMC), a medium-sized Army hospital, capitalized on opportunities to advance its strategic aims during the pandemic. Specifically, the hospital sequentially adopted virtual video visits, surged on preventative screenings, and made-over its image to appeal to patients seeking urgent care. These campaigns supported COVID-19 efforts and larger strategic goals simultaneously, and they will endure for years to come. Predictably, CRDAMC encountered obstacles in the course of its transformation. These obstacles and their follow-on lessons are provided to assist future medical leaders seeking quantum change in the opportunities made available by health crises.

Purpose: Due to stay-at-home orders during COVID-19, we transitioned supervised, group, in-person resistance training interventions in two clinical trials in cancer survivors to live, online delivery using video-conferencing technology. We describe the feasibility, preliminary efficacy, and safety of live online group training and compare to in-person training., Methods: Adherence (% sessions attended), retention (% participants completing intervention), and safety (# adverse events) data of resistance training groups from two randomized controlled trials in cancer survivors that participated before or during the COVID-19 pandemic were collated. Participants were post-treatment breast cancer survivors and their spouses (n = 62) and prostate cancer survivors (n = 32) (age range: 38-82 years). During COVID-19, delivery of supervised, group resistance exercise sessions was delivered live online via video-conference. Preliminary evidence for training efficacy was assessed by chair stand performance over the 6-month intervention., Results: Feasibility of online resistance training was better than in-person for both studies (adherence: 86% vs 82% and 91% vs. 81% and retention 95% vs. 80% and 92% vs. 84% for online and in-person classes). Improvements in chair stand time were similar in prostate cancer and spouse groups that trained online vs. in-person, except for breast cancer survivors who improved more with in-person training (7% vs. 14% for online vs. in-person). Safety was similar between formats (12 vs. 11 adverse events for online vs. in-person)., Conclusion: Supervised, in-person group resistance training can be feasibly adapted for live, online delivery and could help broaden approaches to exercise delivery in cancer survivors, including older adults., Trial Registration: The studies described in this commentary were registered on ClinicalTrials.gov on August 3, 2018 (NCT03630354) and on October 30, 2018 (NCT03741335)., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Acute graft-versus-host disease (GVHD) is a common and life-threatening complication of allogeneic haematopoietic stem cell transplantation (HSCT); there is an urgent unmet need for effective therapies. We aimed to evaluate the Janus kinase 1 inhibitor itacitinib versus placebo, both in combination with corticosteroids, for initial treatment of acute GVHD., Methods: GRAVITAS-301 was an international, double-blind, adaptive (group sequential design) phase 3 study conducted at 129 hospitals and community practices in 19 countries. Eligible patients were aged 18 years or older, had previously received allogeneic HSCT for a haematological malignancy, developed grades II-IV acute GVHD, and received up to 2 days of systemic corticosteroids. Patients were stratified by clinical standard-risk or high-risk acute GVHD and randomly assigned (1:1), via a centralised interactive voice response system, to receive either oral itacitinib (200 mg) or placebo once daily, both in addition to corticosteroids. The primary endpoint was overall response rate (ORR) at day 28 (defined as the proportion of patients with complete response, very good partial response, or partial response 28 days after the start of treatment). For sample size determination, an absolute improvement in ORR at day 28 over standard therapy of 16% was considered clinically meaningful. Efficacy analyses were performed in the intention-to-treat population; safety analyses included patients who received at least one dose of study drug. GRAVITAS-301 is registered with ClinicalTrials.gov (NCT03139604) and is complete., Findings: Between July 19, 2017, and Oct 3, 2019, 439 patients were randomly assigned to receive either itacitinib plus corticosteroids (n=219; itacitinib group) or placebo plus corticosteroids (n=220; placebo group). 173 (39%) patients were female and 390 (89%) were White. At baseline, 107 (24%) of 439 patients (itacitinib 51 [23%] of 219; placebo 56 [25%] of 220) had clinical high-risk acute GVHD. The ORR at day 28 was 74% (95% CI 67·6-79·7; 162 of 219; complete response 53% [116 of 219]) for itacitinib and 66% (59·7-72·6; 146 of 220; complete response, 40% [89 of 220]) for placebo (odds ratio for ORR 1·45, 95% CI 0·96-2·20; two-sided p=0·078). Grade 3 or worse adverse events occurred in 185 (86%) of 215 itacitinib recipients and 178 (82%) of 216 placebo recipients, and most commonly included thrombocytopenia or platelet count decreased (78 [36%] vs 68 [31%]), neutropenia or neutrophil count decreased (49 [23%] vs 45 [21%]), anaemia (42 [20%] vs 26 [12%]), and hyperglycaemia (26 [12%] vs 28 [13%]). Treatment-related deaths occurred in three of 215 patients (1%) in the itacitinib group and four of 216 (2%) in the placebo group., Interpretation: The observed improvement in ORR at day 28 with the addition of itacitinib versus placebo to corticosteroids did not reach the prespecified significance level. Further studies might provide additional insight into the utility of selective JAK1 inhibition for the treatment of acute GVHD., Funding: Incyte., Competing Interests: Declaration of interests All authors report researching funding from Incyte. RZ reports honoraria from Incyte, Novartis, and Mallinckcrodt. GS reports lecture fees from Incyte and honoraria from Novartis. MAS reports research funding from Genentech, Cellect Biotechnology, Fortis, Seattle Genetics, Amgen, Celgene, PBD, Genzyme Sanofi, and Jansen; advisory board participation and honoraria or consultancy fees from Amgen, Astellas, Dova Pharmaceuticals, FlatIron, Incyte, Partners Therapeutics, Pfizer, and Sanofi Genzyme; and speakers bureau participation and honoraria for consulting work from AbbVie, Merck, and Takeda. SA reports speakers bureau participation for Incyte. CPV reports honoraria from Incyte. JC reports honoraria from Incyte. SG reports honoraria for lectures and presentations from Novartis, Merck Sharp & Dohme, and Gilead, and honoraria for serving on advisory boards from Pfizer, Novartis, and Gilead. DD reports honoraria for serving on advisory boards from Alexion, Amgen, Janssen, Roche, Sunesis, and Takeda, and research support from Sanofi. RM-Z, MA, ML, and AMB are employees and shareholders of Incyte. Y-BC reports consultancy fees from Incyte, Takeda, and Magenta, and serving on independent adjudication committees for AbbVie, Daiichi, and Equillium. MK, LV, MJC, GM, MG, and JS declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

In contrast to wild type bovine viral diarhea virus (BVDV) specific double deletion mutants are not able to establish persistent infection upon infection of a pregnant heifer. Our data shows that this finding results from a defect in transfer of the virus from the mother animal to the fetus. Pregnant heifers were inoculated with such a double deletion mutant or the parental wild type virus and slaughtered pairwise on days 6, 9, 10 and 13 post infection. Viral RNA was detected via qRT-PCR and RNAscope analyses in maternal tissues for both viruses from day 6 p.i. on. However, the double deletion mutant was not detected in placenta and was only found in samples from animals infected with the wild type virus. Similarly, high levels of wild type viral RNA were present in fetal tissues whereas the genome of the double deletion mutant was not detected supporting the hypothesis of a specific inhibition of mutant virus replication in the placenta. We compared the induction of gene expression upon infection of placenta derived cell lines with wild type and mutant virus via gene array analysis. Genes important for the innate immune response were strongly upregulated by the mutant virus compared to the wild type in caruncle epithelial cells that establish the cell layer on the maternal side at the maternal-fetal interface in the placenta. Also, trophoblasts which can be found on the fetal side of the interface showed significant induction of gene expression upon infection with the mutant virus although with lower complexity. Growth curves recorded in both cell lines revealed a general reduction of virus replication in caruncular epithelial cells compared to the trophoblasts. Compared to the wild type virus this effect was dramtic for the mutant virus that reached only a TCID50 of 1.0 at 72 hours post infection., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: GM holds a patent on the use of double deletion mutants of pestiviruses as vaccines.

The pestivirus classical swine fever virus (CSFV) represents one of the most important pathogens of swine. Its virulence is dependent on the RNase activity of the essential structural glycoprotein E rns that uses an amphipathic helix as a membrane anchor and forms homodimers via disulfide bonds employing cysteine 171. Dimerization is not necessary for CSFV viability but for its virulence. Mutant E rns proteins lacking cysteine 171 are still able to interact transiently as shown in crosslink experiments. Deletion analysis did not reveal the presence of a primary sequence-defined contact surface essential for dimerization, but indicated a general importance of an intact ectodomain for efficient establishment of dimers. Pseudoreverted viruses reisolated in earlier experiments from pigs with mutations Cys171Ser/Ser209Cys exhibited partially restored virulence and restoration of the ability to form E rns homodimers. Dimer formation was also observed for experimentally mutated proteins, in which other amino acids at different positions of the membrane anchor region of E rns were replaced by cysteine. However, with one exception of two very closely located residues, the formation of disulfide-linked dimers was only observed for cysteine residues located at the same position of the helix.

Clonal hematopoiesis of indeterminate potential (CHIP) is an age-associated condition defined by the presence of a somatic mutation in a leukemia-associated gene in individuals who otherwise have no evidence of a hematologic malignancy. In the allogeneic hematopoietic cell transplantation (HCT) setting, clonal hematopoiesis (CH) mutations present in donor stem cells can be transferred to recipients at the time of HCT. Given that the consequences of donor-derived CH in HCT recipients are not entirely clear, we sought to investigate clinical outcomes in patients with engrafted donor-derived CH using a matched cohort analysis of both related and unrelated donors. Of 209 patients with next-generation sequencing performed before and after HCT, donor-derived CH mutations were detected in 15 (5.2%). DNMT3A was the most commonly mutated gene (9 of 15; 60%); mutations in SF3B1, CSF3R, STAT3, CBLB, TET2, and ASXL1 were also identified. Donor-derived CH was not associated with delayed neutrophil or platelet engraftment, and there was no impact on conversion to full donor chimerism. No patients with donor-derived CH experienced relapse, in contrast to 15.6% (7 of 45) in the matched control cohort without CH (P = .176). Donor-derived CH was not associated with worse overall survival; however, patients with donor-derived CH were more likely to develop chronic graft-versus-host disease (GVHD) necessitating systemic immunosuppressive therapy (IST) (P = .045) and less likely to discontinue IST (P = .03) compared with controls without donor-derived CH. We conclude that donor-derived CH does not have an adverse impact on relapse, survival, or engraftment outcomes but may potentiate a graft-versus-leukemia effect, as reflected by increased chronic GVHD necessitating IST., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The TRDC-locus encodes the T cell receptor delta constant region, one component of the γδ T cell receptor which is essential for development of γδ T cells. In contrast to peptide recognition by αβ T cells, antigens activating γδ T cells are mostly MHC independent and not well characterized. Therefore, the function of γδ T cells and their contribution to protection against infections is still unclear. Higher numbers of circulating γδ T cells compared to mice, render the pig a suitable animal model to study γδ T cells. Knocking-out the porcine TRDC-locus by intracytoplasmic microinjection and somatic cell nuclear transfer resulted in healthy living γδ T cell deficient offspring. Flow cytometric analysis revealed that TRDC-KO pigs lack γδ T cells in peripheral blood mononuclear cells (PBMC) and spleen cells. The composition of the remaining leucocyte subpopulations was not affected by the depletion of γδ T cells. Genome-wide transcriptome analyses in PBMC revealed a pattern of changes reflecting the impairment of known or expected γδ T cell dependent pathways. Histopathology did not reveal developmental abnormalities of secondary lymphoid tissues. However, in a vaccination experiment the KO pigs stayed healthy but had a significantly lower neutralizing antibody titer as the syngenic controls., (© 2021. The Author(s).)

Pestiviruses are members of the family Flaviviridae , a group of enveloped viruses that bud at intracellular membranes. Pestivirus particles contain three glycosylated envelope proteins, E rns , E1, and E2. Among them, E1 is the least characterized concerning both biochemical features and function. E1 from bovine viral diarrhea virus (BVDV) strain CP7 was analyzed with regard to its intracellular localization and membrane topology. Here, it is shown that even in the absence of other viral proteins, E1 is not secreted or expressed at the cell surface but localizes predominantly in the endoplasmic reticulum (ER). Using engineered chimeric transmembrane domains with sequences from E1 and vesicular stomatitis virus G protein, the E1 ER-retention signal could be narrowed down to six fully conserved polar residues in the middle part of the transmembrane domain of E1. Retention was observed even when several of these polar residues were exchanged for alanine. Mutations with a strong impact on E1 retention prevented recovery of infectious viruses when tested in the viral context. Analysis of the membrane topology of E1 before and after the signal peptide cleavage via a selective permeabilization and an in vivo labeling approach revealed that mature E1 is a typical type I transmembrane protein with a single span transmembrane anchor at its C terminus, whereas it adopts a hairpin-like structure with the C terminus located in the ER lumen when the precleavage situation is mimicked by blocking the cleavage site between E1 and E2. IMPORTANCE The shortage of specific antibodies against E1, making detection and further analysis of E1 difficult, resulted in a lack of knowledge on E1 compared to E rns and E2 with regard to biosynthesis, structure, and function. It is known that pestiviruses bud intracellularly. Here, we show that E1 contains its own ER retention signal: six fully conserved polar residues in the middle part of the transmembrane domain are shown to be the determinants for ER retention of E1. Moreover, those six polar residues could serve as a functional group that intensely affect the generation of infectious viral particles. In addition, the membrane topology of E1 has been determined. In this context, we also identified dynamic changes in membrane topology of E1 with the carboxy terminus located on the luminal side of the ER in the precleavage state and relocation of this sequence upon signal peptidase cleavage. Our work provides the first systematic analysis of the pestiviral E1 protein with regard to its biochemical and functional characteristics.

Pestiviruses contain three envelope proteins: E rns , E1, and E2. Expression of HA-tagged E1 or mutants thereof showed that E1 forms homodimers and -trimers. C123 and, to a lesser extent, C171, affected the oligomerization of E1 with a double mutant C123S/C171S preventing oligomerization completely. E1 also establishes disulfide linked heterodimers with E2, which are crucial for the recovery of infectious viruses. Co-expression analyses with the HA-tagged E1 wt/E1 mutants and E2 wt/E2 mutants demonstrated that C123 in E1 and C295 in E2 are the critical sites for E1/E2 heterodimer formation. Introduction of mutations preventing E1/E2 heterodimer formation into the full-length infectious clone of BVDV CP7 prevented the recovery of infectious viruses, proving that C123 in E1 and C295 in E2 play an essential role in the BVDV life cycle, and further support the conclusion that heterodimer formation is the crucial step. Interestingly, we found that the retention signal of E1 is mandatory for intracellular localization of the heterodimer, so that absence of the E1 retention signal directs the heterodimer to the cell surface even though the E2 retention signal is still present. The covalent linkage between E1 and E2 plays an essential role for this process.

Pestiviruses express the unique essential envelope protein E rns , which exhibits RNase activity, is attached to membranes by a long amphipathic helix, and is partially secreted from infected cells. The RNase activity of E rns is directly connected with pestivirus virulence. Formation of homodimers and secretion of the protein are hypothesized to be important for its role as a virulence factor, which impairs the host's innate immune response to pestivirus infection. The unusual membrane anchor of E rns raises questions with regard to proteolytic processing of the viral polyprotein at the E rns carboxy-terminus. Moreover, the membrane anchor is crucial for establishing the critical equilibrium between retention and secretion and ensures intracellular accumulation of the protein at the site of virus budding so that it is available to serve both as structural component of the virion and factor controlling host immune reactions. In the present manuscript, we summarize published as well as new data on the molecular features of E rns including aspects of its interplay with the other two envelope proteins with a special focus on the biochemistry of the E rns membrane anchor.