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Identification of specific and therapeutically actionable vulnerabilities, ideally present across multiple mutational backgrounds, is needed to improve acute myeloid leukemia (AML) patients' outcomes. We identify stearoyl-CoA desaturase (SCD), the key enzyme in fatty acid (FA) desaturation, as prognostic of patients' outcomes and, using the clinical-grade inhibitor SSI-4, show that SCD inhibition (SCDi) is a therapeutic vulnerability across multiple AML models in vitro and in vivo. Multiomic analysis demonstrates that SCDi causes lipotoxicity, which induces AML cell death via pleiotropic effects. Sensitivity to SCDi correlates with AML dependency on FA desaturation regardless of mutational profile and is modulated by FA biosynthesis activity. Finally, we show that lipotoxicity increases chemotherapy-induced DNA damage and standard chemotherapy further sensitizes AML cells to SCDi. Our work supports developing FA desaturase inhibitors in AML while stressing the importance of identifying predictive biomarkers of response and biologically validated combination therapies to realize their full therapeutic potential., (© 2024. The Author(s).)

Background: Acute myeloid leukaemia (AML) is a bone marrow malignancy with poor prognosis. One of several treatments for AML is midostaurin combined with intensive chemotherapy (MIC), currently approved for FLT3 mutation-positive (FLT3-MP) AML. However, many patients carrying FLT3 mutations are refractory or experience an early relapse following MIC treatment, and might benefit more from receiving a different treatment. Development of a stratification method that outperforms FLT3 mutational status in predicting MIC response would thus benefit a large number of patients., Methods: We employed mass spectrometry phosphoproteomics to analyse 71 diagnosis samples of 47 patients with FLT3-MP AML who subsequently received MIC. We then used machine learning to identify biomarkers of response to MIC, and validated the resulting predictive model in two independent validation cohorts (n = 20)., Findings: We identified three distinct phosphoproteomic AML subtypes amongst long-term survivors. The subtypes showed similar duration of MIC response, but different modulation of AML-implicated pathways, and exhibited distinct, highly-predictive biomarkers of MIC response. Using these biomarkers, we built a phosphoproteomics-based predictive model of MIC response, which we called MPhos. When applied to two retrospective real-world patient test cohorts (n = 20), MPhos predicted MIC response with 83% sensitivity and 100% specificity (log-rank p < 7∗10 -5 , HR = 0.005 [95% CI: 0-0.31])., Interpretation: In validation, MPhos outperformed the currently-used FLT3-based stratification method. Our findings have the potential to transform clinical decision-making, and highlight the important role that phosphoproteomics is destined to play in precision oncology., Funding: This work was funded by Innovate UK grants (application numbers: 22217 and 10054602) and by Kinomica Ltd., Competing Interests: Declaration of interests WEB—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences, named on a Kinomica patent; LN—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences; SFP—is an employee at Kinomica, owns Kinomica share options; AEC—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences; NN—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences; JAC—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences; DNP—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences; PMC—is an employee at Kinomica, owns Kinomica share options, Kinomica funded attendance and travel to conferences; JK—is an employee at Kinomica, owns Kinomica share options; HRF—no conflict of interest; BP—no conflict of interest; PG—no conflict of interest; AA—no conflict of interest; AJA—received a honorarium for speaking engagements from Astellas; AT—received consultant fees from Kinomica for the role of Programme Director; AW—owns Kinomica share options, funded attendance and travel to conferences; GG—no conflict of interest; MDM—no conflict of interest; JGG—Kinomica co-founder, owns Kinomica share options; DJB—co-founder of Kinomica, owns Kinomica share options, named on Kinomica patents, Kinomica funded attendance and travel to conferences, received honoraria from Kinomica in a consulting role; PRC—co-founder and director of Kinomica, owns Kinomica share options, named on Kinomica patents, Kinomica funded attendance and travel to conferences, received honoraria from Kinomica in a consulting role; ADD—is an employee at Kinomica (CTO), named on Kinomica patents, Kinomica funded attendance and travel to conferences owns Kinomica share options., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Competing Interests: The authors declare no conflict of interest.

Purpose/objectives: The purpose of this article is to inform the reader of the practice of the registered nurse care coordinator (RNCC) within an interprofessional, nurse-led clinic serving uninsured diabetic patients in a large urban city. This clinic serves as a transitional care clinic, providing integrated diabetes management and assisting patients to establish with other primary care doctors in the community once appropriate. The clinic uses an interprofessional collaborative practice (IPCP) model with the RNCC at the center of patient onboarding, integrated responsive care, and clinic transitioning., Primary Practice Setting: Interprofessional, nurse-led clinic for uninsured patients with diabetes., Findings/conclusions: Interprofessional models of care are strengthened using a specialized care coordinator., Implications for Case Management Practice: Care coordination is a key component in case management of a population with chronic disease. The RNCC, having specialized clinical expertise, is an essential member of the interdisciplinary team, contributing a wide range of resources to assist patients in achieving successful outcomes managing diabetes. Transitional care coordination, moving from unmanaged to managed diabetes care, is part of a bundled health care process fundamental to this clinic's IPCP model. In a transitional clinic setting, frequent interaction with patients through onboarding, routine check-ins, and warm handoff helps support and empower the patient to be engaged in their personal health care journey., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

BACKGROUNDCOVID-19 convalescent plasma (CCP) virus-specific antibody levels that translate into recipient posttransfusion antibody levels sufficient to prevent disease progression are not defined.METHODSThis secondary analysis correlated donor and recipient antibody levels to hospitalization risk among unvaccinated, seronegative CCP recipients within the outpatient, double-blind, randomized clinical trial that compared CCP to control plasma. The majority of COVID-19 CCP arm hospitalizations (15/17, 88%) occurred in this unvaccinated, seronegative subgroup. A functional cutoff to delineate recipient high versus low posttransfusion antibody levels was established by 2 methods: (i) analyzing virus neutralization-equivalent anti-Spike receptor-binding domain immunoglobulin G (anti-S-RBD IgG) responses in donors or (ii) receiver operating characteristic (ROC) curve analysis.RESULTSSARS-CoV-2 anti-S-RBD IgG antibody was volume diluted 21.3-fold into posttransfusion seronegative recipients from matched donor units. Virus-specific antibody delivered was approximately 1.2 mg. The high-antibody recipients transfused early (symptom onset within 5 days) had no hospitalizations. A CCP-recipient analysis for antibody thresholds correlated to reduced hospitalizations found a statistical significant association between early transfusion and high antibodies versus all other CCP recipients (or control plasma), with antibody cutoffs established by both methods-donor-based virus neutralization cutoffs in posttransfusion recipients (0/85 [0%] versus 15/276 [5.6%]; P = 0.03) or ROC-based cutoff (0/94 [0%] versus 15/267 [5.4%]; P = 0.01).CONCLUSIONIn unvaccinated, seronegative CCP recipients, early transfusion of plasma units in the upper 30% of study donors' antibody levels reduced outpatient hospitalizations. High antibody level plasma units, given early, should be reserved for therapeutic use.TRIAL REGISTRATIONClinicalTrials.gov NCT04373460.FUNDINGDepartment of Defense (W911QY2090012); Defense Health Agency; Bloomberg Philanthropies; the State of Maryland; NIH (3R01AI152078-01S1, U24TR001609-S3, 1K23HL151826NIH); the Mental Wellness Foundation; the Moriah Fund; Octapharma; the Healthnetwork Foundation; the Shear Family Foundation; the NorthShore Research Institute; and the Rice Foundation.

Background: The WHO defines LBW as "Birth weight less than 2500 grams" regardless of gestational age. Being born with a low birth weight also incurs enormous economic costs, including higher medical expenditures and social service expenses, and decreased productivity in adulthood., Objective: To study distribution of newborns' according to pregnancy related factors and its association with newborns' birth weight., Methods: An institutional based cross-sectional study. New-borns delivered at study institute were considered as study participants. Estimated final sample size was 500. Guardians (mothers) were face-to-face interviewed and also recorded data were collected from the case file and Mother and Child Protection Card., Results: Prevalence of LBW newborns was higher in mothers with late ANC registration, <4 ANC visits, chronic medical conditions, infection during pregnancy, PIH, anemia, consuming tobacco, exposure to second hand smoke, LSCS/Assisted delivery, in female newborns', current pregnancy birth order number more than 2, in pre term newborns' and mothers with bad obstetric history., Conclusion: Create awareness and adoption of suitable family planning methods. Need to do early (within 12 weeks) ANC registration with minimum four ANC visits for better pregnancy outcome. Effective tracking and suitable intervention provided to improve current pregnancy outcome. Health care professional should pay special attention to high-risk pregnancy. Develop social culture in such a way that females are neither addicted nor exposed to any tobacco containing products in their life., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Indian Journal of Community Medicine.)

Background: Extracorporeal membrane oxygenation (ECMO) has extended the survivability of critically ill patients beyond their unsupported prognosis and has widened the timeframe for making an informed decision about the goal of care. However, an extended time window for survival does not necessarily translate into a better outcome and the sustaining treatment is ultimately withdrawn in many patients. Emerging evidence has implicated the determining role of palliative care consult (PCC) in direction of the care that critically ill patients receive. Objective: To evaluate the impact of PCC in withdrawal of life-sustaining treatment (WOLST) among critically ill patients, who were placed on venovenous ECMO (VV-ECMO) at the intensive care unit (ICU) of a tertiary care hospital. Methods: In a retrospective observational study, electronic medical records of 750 patients admitted to the ICU of our hospital between January 1, 2015, and October 31, 2021, were reviewed. Data was collected for patients on VV-ECMO, for whom WOLST was withdrawn during the ICU stay. Clinical characteristics and the underlying reasons for WOLST were compared between those who received PCC (PCC group) and those who did not (non-PCC group). Results: A total of 95 patients were included in our analysis, 63 in the PCC group and 32 in the non-PCC group. The average age of the study population was 48.8 ± 12.6 years, and 64.2% were male. There was no statistically significant difference between the two groups in terms of demographics or clinical characteristics at the time of ICU admission. The average duration of ICU stay and VV-ECMO were 14.1 ± 19.9 days and 9.4 ± 16.6 days, respectively. The number of PCC visits was correlated with the length of ICU stay . The average duration of ICU stay (40.3 ± 33.2 days vs 27.8 ± 19.3 days, P = .05) and ECMO treatment (31.9 ± 27 days vs 18.6 ± 16.1 days, P = .01) were significantly longer in patients receiving PCC than those not receiving PCC. However, the frequency of life sustaining measures or the underlying reasons for WOLST did not significantly differ between the two groups (P > .05). Conclusion: Among ICU patients requiring ECMO support, longer duration of ICU stay and treatment with a higher number of life-sustaining measures seemed to be correlated with the number of PCC visits. The underlying reasons for WOLST seem not to be affected by PCC., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Aims: Diabetes is becoming a major public health problem in the country. One of the most important lifestyle modifications necessary for diabetic patients is maintaining healthy dietary choices. These modifications in dietary practices are supposed to be followed lifelong, along with medication, for better glycemic control. Despite understanding the importance of dietary control and physical activity in the management of diabetes, adherence to these practices is poor. This study aimed to assess the dietary practices of type 2 diabetes mellitus (T2DM) patients and various factors that determine adherence to these healthy dietary practices. The secondary objective was to find the perceptions of participants about the role of diet in controlling diabetes and to find the perception-practice gap among study participants., Methodology: It was a hospital-based cross-sectional study conducted among 450 T2DM patients visiting the non-communicable disease (NCD) clinics of tertiary care hospitals and community health centres (CHCs) of the study district. Dietary practice was assessed using a modified UK Diabetes and Diet Questionnaire (UKDDQ), considering the food patterns in the study area. Statistical tests like chi-square and ordinal logistic regression were applied using Jamovi software for univariate and multivariate analyses., Results: The healthiest food choices were abstinence from alcohol consumption (100%), avoiding processed meat (92.21%), high-fibre breakfast (70.4%), and daily consumption of vegetables (68.2%). Improper dietary practices were regular sugary drinks (38%) and high-glycemic-index food items (22.4%). The mean (SD) of the composite score was 68.02 (8.7) and the median score (interquartile range (IQR)) was 69 (60-76). Tertile analysis of the composite score revealed that with the increase in age, patients were less likely to be in the intermediate or upper tertile score (β = -0.0219, p = 0.016). Being female (odds ratio (OR) =0.603, CI: 0.395-0.917, p = 0.019) and living in a three-generation family made the patients less likely to be in the upper tertile score., Conclusion: Nearly half of the participants had an overall healthy score. Dietary practices were healthy among the participants of lower ages, males, and those living in nuclear and joint families. The highest perception-practice gap was seen for fruit and rice consumption., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Patel et al.)

Importance: This study examined the role that cytokines may have played in the beneficial outcomes found when outpatient individuals infected with SARS-CoV-2 were transfused with COVID-19 convalescent plasma (CCP) early in their infection. We found that the pro-inflammatory cytokine IL-6 decreased significantly faster in patients treated early with CCP. Participants with COVID-19 treated with CCP later in the infection did not have the same effect. This decrease in IL-6 levels after early CCP treatment suggests a possible role of inflammation in COVID-19 progression. The evidence of IL-6 involvement brings insight into the possible mechanisms involved in CCP treatment mitigating SARS-CoV-2 severity.

KMT2A-rearranged (KMT2A-R) is an aggressive and chemo-refractory acute leukemia which mostly affects children. Transcriptomics-based characterization and chemical interrogation identified kinases as key drivers of survival and drug resistance in KMT2A-R leukemia. In contrast, the contribution and regulation of phosphatases is unknown. In this study we uncover the essential role and underlying mechanisms of SET, the endogenous inhibitor of Ser/Thr phosphatase PP2A, in KMT2A-R-leukemia. Investigation of SET expression in acute myeloid leukemia (AML) samples demonstrated that SET is overexpressed, and elevated expression of SET is correlated with poor prognosis and with the expression of MEIS and HOXA genes in AML patients. Silencing SET specifically abolished the clonogenic ability of KMT2A-R leukemic cells and the transcription of KMT2A targets genes HOXA9 and HOXA10. Subsequent mechanistic investigations showed that SET interacts with both KMT2A wild type and fusion proteins, and it is recruited to the HOXA10 promoter. Pharmacological inhibition of SET by FTY720 disrupted SET-PP2A interaction leading to cell cycle arrest and increased sensitivity to chemotherapy in KMT2A-R-leukemic models. Phospho-proteomic analyses revealed that FTY720 reduced the activity of kinases regulated by PP2A, including ERK1, GSK3β, AURB and PLK1 and led to suppression of MYC, supporting the hypothesis of a feedback loop among PP2A, AURB, PLK1, MYC, and SET. Our findings illustrate that SET is a novel player in KMT2A-R leukemia and they provide evidence that SET antagonism could serve as a novel strategy to treat this aggressive leukemia., (© 2023. The Author(s).)

Background: The diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated multisystem inflammatory syndrome in adults (MIS-A) requires distinguishing it from acute coronavirus disease 2019 (COVID-19) and may affect clinical management., Methods: In this retrospective cohort study, we applied the US Centers for Disease Control and Prevention case definition to identify adults hospitalized with MIS-A at 6 academic medical centers from 1 March 2020 to 31 December 2021. Patients MIS-A were matched by age group, sex, site, and admission date at a 1:2 ratio to patients hospitalized with acute symptomatic COVID-19. Conditional logistic regression was used to compare demographic characteristics, presenting symptoms, laboratory and imaging results, treatments administered, and outcomes between cohorts., Results: Through medical record review of 10 223 patients hospitalized with SARS-CoV-2-associated illness, we identified 53 MIS-A cases. Compared with 106 matched patients with COVID-19, those with MIS-A were more likely to be non-Hispanic black and less likely to be non-Hispanic white. They more likely had laboratory-confirmed COVID-19 ≥14 days before hospitalization, more likely had positive in-hospital SARS-CoV-2 serologic testing, and more often presented with gastrointestinal symptoms and chest pain. They were less likely to have underlying medical conditions and to present with cough and dyspnea. On admission, patients with MIS-A had higher neutrophil-to-lymphocyte ratio and higher levels of C-reactive protein, ferritin, procalcitonin, and D-dimer than patients with COVID-19. They also had longer hospitalization and more likely required intensive care admission, invasive mechanical ventilation, and vasopressors. The mortality rate was 6% in both cohorts., Conclusions: Compared with patients with acute symptomatic COVID-19, adults with MIS-A more often manifest certain symptoms and laboratory findings early during hospitalization. These features may facilitate diagnosis and management., Competing Interests: Potential conflicts of interest. After this work was conducted, S. G. C. became an employee of the University of Utah, where she received funding from the Pediatric Pandemic Network through her institution. A. G. is a copyright holder of the Hidradenitis Suppurativa–Specific Investigator Global Assessment (HS-IGA) and the Hidradenitis Suppurativa Quality of Life score (HiSQOL); received consulting fees (honoraria for advisory role) from AbbVie, Aclaris Therapeutics, AnaptysBio, Aristea Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Incyte, Insmed, Janssen Pharmaceuticals, Novartis, Pfizer, Sonoma Biotherapeutics, UCB, UNION Therapeutics, Ventyx Biosciences, and Viela Bio; and was funded by AbbVie, UCB, the National Psoriasis Foundation, and the CHORD COUSIN Collaboration (C3) through grants to his institution. M. N. received consulting fees from Pfizer for serving on a coronavirus disease 2019 task force. C. J. A. participated on a data safety monitoring board for Abivax. L. M. A. was compensated by Regeneron for work as a coinvestigator in clinical trials, participated on a data safety monitoring board for Ferring Pharmaceuticals, and served on the Infectious Diseases Society of America Board of Directors. L. B. participated on a data safety monitoring board for Gilead Sciences (advisory meeting after the Conference on Retroviruses and Opportunistic Infections on 11 April 2022). R. M. received consulting fees from and is a shareholder in Acolyte Health (Cedars Sinai Accelerator) and reports support for attending meetings and/or travel for the 2023 American Medical Informatics Association Clinical Informatics Conference from Cedars Sinai. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Approximately 20% of individuals infected with SARS-CoV-2 experienced long-term health effects, as defined PCC. However, it is unknown if there are any early biomarkers associated with PCC or whether early intervention treatments may decrease the risk of PCC. In a secondary analysis of a randomized clinical trial, this study demonstrates that among outpatients with SARS-CoV-2, increased IL-6 at time of infection is associated with increased odds of PCC. In addition, among individuals treated early, within 5 days of symptom onset, with COVID-19 convalescent plasma, there was a trend for decreased odds of PCC after adjusting for other demographic and clinical characteristics. Future treatment studies should be considered to evaluate the effect of early treatment and anti-IL-6 therapies on PCC development., Competing Interests: See Acknowledgments for conflicts of interest.

MAS825, a bispecific IL-1β/IL-18 monoclonal antibody, could improve clinical outcomes in COVID-19 pneumonia by reducing inflammasome-mediated inflammation. Hospitalized non-ventilated patients with COVID-19 pneumonia (n = 138) were randomized (1:1) to receive MAS825 (10 mg/kg single i.v.) or placebo in addition to standard of care (SoC). The primary endpoint was the composite Acute Physiology and Chronic Health Evaluation II (APACHE II) score on Day 15 or on the day of discharge (whichever was earlier) with worst-case imputation for death. Other study endpoints included safety, C-reactive protein (CRP), SARS-CoV-2 presence, and inflammatory markers. On Day 15, the APACHE II score was 14.5 ± 1.87 and 13.5 ± 1.8 in the MAS825 and placebo groups, respectively (P = 0.33). MAS825 + SoC led to 33% relative reduction in intensive care unit (ICU) admissions, ~1 day reduction in ICU stay, reduction in mean duration of oxygen support (13.5 versus 14.3 days), and earlier clearance of virus on Day 15 versus placebo + SoC group. On Day 15, compared with placebo group, patients treated with MAS825 + SoC showed a 51% decrease in CRP levels, 42% lower IL-6 levels, 19% decrease in neutrophil levels, and 16% lower interferon-γ levels, indicative of IL-1β and IL-18 pathway engagement. MAS825 + SoC did not improve APACHE II score in hospitalized patients with severe COVID-19 pneumonia; however, it inhibited relevant clinical and inflammatory pathway biomarkers and resulted in faster virus clearance versus placebo + SoC. MAS825 used in conjunction with SoC was well tolerated. None of the adverse events (AEs) or serious AEs were treatment-related., (Published by Oxford University Press on behalf of the British Society for Immunology 2023.)

This study assessed diabetes distress (DD) and glycemic control levels through three time periods during the COVID-19 pandemic in uninsured patients with diabetes. Diabetes Distress Screening Scales 2 and 17 were utilized to identify the prevalence of DD among uninsured patients during multiple stages of the COVID-19 pandemic at the Providing Access to Healthcare (PATH) diabetes clinic at the University of Alabama at Birmingham. For the 328 uninsured diabetic patients who were screened for DD at least once, the mean age was 46 years old with a majority being Black (55.5%), male (56.1%), and non-Hispanic (89.9%). Mean scores reflecting patients' level of DD initially increased in the first 6 months of the pandemic, from 2.86 to 3.44, and then decreased after 12 months of the COVID-19 pandemic to 3.09, while their mean hemoglobin A1c (HbA1c) followed a similar pattern of initial increase (from 11.31 to 12.13) followed by a decline (to 10.79). Addressing patient concerns quickly through early interventions to provide alternative means of care through telehealth and accommodating safe pick-up of diabetes supplies and medications, including insulin, can reduce DD and contribute to better management of glycemic control. Understanding the potential direct correlation of DD with HbA1c in uninsured patients with diabetes is an important factor for clinicians when providing care to this vulnerable population.

Introduction: Survivors of SARS-CoV-2 pneumonia often develop persistent respiratory symptom and interstitial lung abnormalities (ILAs) after infection. Risk factors for ILA development and duration of ILA persistence after SARS-CoV-2 infection are not well described in immunocompromised hosts, such as cancer patients., Methods: We conducted a prospective cohort study of 95 patients at a major cancer center and 45 patients at a tertiary referral center. We collected clinical and radiographic data during the index hospitalization for COVID-19 pneumonia and measured pneumonia severity using a semi-quantitative radiographic score, the Radiologic Severity Index (RSI). Patients were evaluated in post-COVID-19 clinics at 3 and 6 months after discharge and underwent comprehensive pulmonary evaluations (symptom assessment, chest computed tomography, pulmonary function tests, 6-min walk test). The association of clinical and radiological factors with ILAs at 3 and 6 months post-discharge was measured using univariable and multivariable logistic regression., Results: Sixty-six (70%) patients of cancer cohort had ILAs at 3 months, of whom 39 had persistent respiratory symptoms. Twenty-four (26%) patients had persistent ILA at 6 months after hospital discharge. In adjusted models, higher peak RSI at admission was associated with ILAs at 3 (OR 1.5 per 5-point increase, 95% CI 1.1-1.9) and 6 months (OR 1.3 per 5-point increase, 95% CI 1.1-1.6) post-discharge. Fibrotic ILAs (reticulation, traction bronchiectasis, and architectural distortion) were more common at 6 months post-discharge., Conclusions: Post-COVID-19 ILAs are common in cancer patients 3 months after hospital discharge, and peak RSI and older age are strong predictors of persistent ILAs., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: COVID-19 convalescent plasma (CCP) is an important therapeutic option for outpatients at high risk of hospitalization from SARS-CoV-2 infection. We assessed the safety of outpatient CCP transfusions administered during clinical trials., Study Design and Methods: We analyzed data pertaining to transfusion-related reactions from two randomized controlled trials in the U.S. that evaluated the efficacy of CCP versus control plasma in various ambulatory settings. Multivariable logistic regression was used to assess whether CCP was associated with transfusion reactions, after adjusting for potential confounders., Results: The combined study reported 79/1351 (5.9%) adverse events during the transfusion visit, with the majority 62/1351 (4.6%) characterized by mild, allergic-type findings of urticaria, and/or pruritus consistent with minor allergic transfusion reactions; the other reported events were attributed to the patients' underlying disease, COVID-19, or vasovagal in nature. We found no difference in the likelihood of allergic transfusion reactions between those receiving CCP versus control plasma (adjusted odds ratio [AOR], 0.75; 95% CI, 0.43-1.31). Risk of urticaria and/or pruritus increased with a pre-existing diagnosis of asthma (AOR, 2.33; 95% CI, 1.16-4.67). We did not observe any CCP-attributed antibody disease enhancement in participants with COVID-19 or increased risk of infection. There were no life-threatening severe transfusion reactions and no patients required hospitalization related to transfusion-associated complications., Discussion: Outpatient plasma administration was safely performed for nearly 1400 participants. CCP is a safe therapeutic option for outpatients at risk of hospitalization from COVID-19., (© 2023 The Authors. Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

Background: Cytokines and chemokines play a critical role in the response to infection and vaccination. We aimed to assess the longitudinal association of COVID-19 vaccination with cytokine and chemokine concentrations and trajectories among people with SARS-CoV-2 infection., Methods: In this longitudinal, prospective cohort study, blood samples were used from participants enrolled in a multi-centre randomised trial assessing the efficacy of convalescent plasma therapy for ambulatory COVID-19. The trial was conducted in 23 outpatient sites in the USA. In this study, participants (aged ≥18 years) were restricted to those with COVID-19 before vaccination or with breakthrough infections who had blood samples and symptom data collected at screening (pre-transfusion), day 14, and day 90 visits. Associations between COVID-19 vaccination status and concentrations of 21 cytokines and chemokines (measured using multiplexed sandwich immunoassays) were examined using multivariate linear mixed-effects regression models, adjusted for age, sex, BMI, hypertension, diabetes, trial group, and COVID-19 waves (pre-alpha or alpha and delta)., Findings: Between June 29, 2020, and Sept 30, 2021, 882 participants recently infected with SARS-CoV-2 were enrolled, of whom 506 (57%) were female and 376 (43%) were male. 688 (78%) of 882 participants were unvaccinated, 55 (6%) were partly vaccinated, and 139 (16%) were fully vaccinated at baseline. After adjusting for confounders, geometric mean concentrations of interleukin (IL)-2RA, IL-7, IL-8, IL-15, IL-29 (interferon-λ), inducible protein-10, monocyte chemoattractant protein-1, and tumour necrosis factor-α were significantly lower among the fully vaccinated group than in the unvaccinated group at screening. On day 90, fully vaccinated participants had approximately 20% lower geometric mean concentrations of IL-7, IL-8, and vascular endothelial growth factor-A than unvaccinated participants. Cytokine and chemokine concentrations decreased over time in the fully and partly vaccinated groups and unvaccinated group. Log 10 cytokine and chemokine concentrations decreased faster among participants in the unvaccinated group than in other groups, but their geometric mean concentrations were generally higher than fully vaccinated participants at 90 days. Days since full vaccination and type of vaccine received were not correlated with cytokine and chemokine concentrations., Interpretation: Initially and during recovery from symptomatic COVID-19, fully vaccinated participants had lower concentrations of inflammatory markers than unvaccinated participants suggesting vaccination is associated with short-term and long-term reduction in inflammation, which could in part explain the reduced disease severity and mortality in vaccinated individuals., Funding: US Department of Defense, National Institutes of Health, Bloomberg Philanthropies, State of Maryland, Mental Wellness Foundation, Moriah Fund, Octapharma, HealthNetwork Foundation, and the Shear Family Foundation., Competing Interests: Declaration of interests KAG reports consultancy work for the Aspen Institute, Teach for America, serving as a non-paid member of a scientific advisory board for Pfizer, and writing COVID-19 management guidelines for UpToDate. AGA reports consultancy work for Implementation Group, Hirslanden Klinik, and Elsevier. ERC reports receiving unrestricted research grants from Gilead and Merck paid to the Regents of the University of California and participating in an advisory board to Theratechnologies for an unrelated topic. JSC reports consultancy work for Merck and Company in 2021. TJG reports employment by Fenwal, a Fresenius Kabi Company. LLH reports research funding to Johns Hopkins Center of American Indian Health from AstraZeneca, US Centers for Disease Control and Prevention, Merck, NIH, and Pfizer. MAH reports contracts from Gilead Sciences, Insmed, and AN2 Therapeutics to the University of Cincinnati. GSM reports research grant support from Teva, Alk-Abello, Genentech, Novartis, GlaxoSmithKline, and Sanofi-Regeneron, serving as an immediate past president of the American Academy of Allergy Asthma and Immunology, and is co-chair of the Continuous Assessment Program Examination for the American Board of Allergy and Immunology. BP reports participating in part of the COVID-19 trials and pulmonary arterial hypertension trials. JHP reports research funding from MindRhythm. JSR is a consultant and advisor with Sanofi Genzyme, and a board of directors member with the American Society for Apheresis. SK reports helping to produce educational materials related to HIV with Integritas Communications and Vindico Medical Education. AC reports serving on the scientific advisory board of SAB Biotherapeutics. EMB reports personal fees and non-financial support from Terumo BCT, Abbott Laboratories, Tegus, and UptoDate, is a member of the US Food and Drug Administration Blood Products Advisory Committee, and served on a convalescent plasma guideline panel. DH reports personal fees from Neurelis, Neurotrope, and medicolegal consulting. DJS is a founder and board member with stock options (macrolide for malaria) for AliquantumRx and reports consulting for Hemex Health and royalties for malaria diagnostic test control standards to Alere. SLH reports serving on the data monitoring committee for Pfizer. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Genomic profiling during the diagnosis of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults is used to guide disease classification, risk stratification, and treatment decisions. Patients for whom diagnostic screening fails to identify disease-defining or risk-stratifying lesions are classified as having B-other ALL. We screened a cohort of 652 BCP-ALL cases enrolled in UKALL14 to identify and perform whole genome sequencing (WGS) of paired tumor-normal samples. For 52 patients with B-other, we compared the WGS findings with data from clinical and research cytogenetics. WGS identified a cancer-associated event in 51 of 52 patients, including an established subtype defining genetic alterations that were previously missed with standard-of-care (SoC) genetics in 5 of them. Of the 47 true B-other ALL, we identified a recurrent driver in 87% (41). A complex karyotype via cytogenetics emerges as a heterogeneous group, including distinct genetic alterations associated with either favorable (DUX4-r) or poor outcomes (MEF2D-r and IGK::BCL2). For a subset of 31 cases, we integrated the findings from RNA sequencing (RNA-seq) analysis to include fusion gene detection and classification based on gene expression. Compared with RNA-seq, WGS was sufficient to detect and resolve recurrent genetic subtypes; however, RNA-seq can provide orthogonal validation of findings. In conclusion, we demonstrated that WGS can identify clinically relevant genetic abnormalities missed with SoC testing as well as identify leukemia driver events in virtually all cases of B-other ALL., (© 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.)

Introduction: Granulocyte-macrophage colony-stimulating factor (GM-CSF), a protein produced in the lung, is essential for pulmonary host defense and alveolar integrity. Prior studies suggest potential benefits in several pulmonary conditions, including acute respiratory distress syndrome and viral infections. This trial evaluated the effect of the addition of inhaled sargramostim (yeast-derived, glycosylated recombinant human GM-CSF) to standard of care (SOC) on oxygenation and clinical outcomes in patients with COVID-19-associated acute hypoxemia., Materials and Methods: A randomized, controlled, open-label trial of hospitalized adults with COVID-19-associated hypoxemia (oxygen saturation <93% on ≥2 L/min oxygen supplementation and/or PaO2/FiO2 <350) randomized 2:1 to inhaled sargramostim (125 mcg twice daily for 5 days) plus SOC versus SOC alone. Institutional SOC before and during the study was not limited. Primary outcomes were change in the alveolar-arterial oxygen gradient (P(A-a)O2) by day 6 and the percentage of patients intubated within 14 days. Safety evaluations included treatment-emergent adverse events. Efficacy analyses were based on the modified intent-to-treat population, the subset of the intent-to-treat population that received ≥1 dose of any study treatment (sargramostim and/or SOC). An analysis of covariance approach was used to analyze changes in oxygenation measures. The intubation rate was analyzed using the chi-squared test. All analyses are considered descriptive. The study was institutional review board approved., Results: In total, 122 patients were treated (sargramostim, n = 78; SOC, n = 44). The sargramostim arm experienced greater improvement in P(A-a)O2 by day 6 compared to SOC alone (least squares [LS] mean change from baseline [SE]: -102.3 [19.4] versus -30.5 [26.9] mmHg; LS mean difference: -71.7 [SE 33.2, 95% CI -137.7 to -5.8]; P = .033; n = 96). By day 14, 11.5% (9/78) of sargramostim and 15.9% (7/44) of SOC arms required intubation (P = .49). The 28-day mortality was 11.5% (9/78) and 13.6% (6/44) in the sargramostim and SOC arms, respectively (hazard ratio 0.85; P = .76). Treatment-emergent adverse events occurred in 67.9% (53/78) and 70.5% (31/44) on the sargramostim and SOC arms, respectively., Conclusions: The addition of inhaled sargramostim to SOC improved P(A-a)O2, a measure of oxygenation, by day 6 in hospitalized patients with COVID-19-associated acute hypoxemia and was well tolerated. Inhaled sargramostim is delivered directly to the lung, minimizing systemic effects, and is simple to administer making it a feasible treatment option in patients in settings where other therapy routes may be difficult. Although proportionally lower rates of intubation and mortality were observed in sargramostim-treated patients, this study was insufficiently powered to demonstrate significant changes in these outcomes. However, the significant improvement in gas exchange with sargramostim shows this inhalational treatment enhances pulmonary efficiency in this severe respiratory illness. These data provide strong support for further evaluation of sargramostim in high-risk patients with COVID-19., (© The Association of Military Surgeons of the United States 2022.)

Background: Outpatient monoclonal antibodies are no longer effective and antiviral treatments for coronavirus disease 2019 (COVID-19) disease remain largely unavailable in many countries worldwide. Although treatment with COVID-19 convalescent plasma (CCP) is promising, clinical trials among outpatients have shown mixed results., Methods: We conducted an individual participant data meta-analysis from outpatient trials to assess the overall risk reduction for all-cause hospitalizations by day 28 in transfused participants. Relevant trials were identified by searching Medline, Embase, medRxiv, World Health Organization COVID-19 Research Database, Cochrane Library, and Web of Science from January 2020 to September 2022., Results: Five included studies from 4 countries enrolled and transfused 2620 adult patients. Comorbidities were present in 1795 (69%). The virus neutralizing antibody dilutional titer levels ranged from 8 to 14 580 in diverse assays. One hundred sixty of 1315 (12.2%) control patients were hospitalized, versus 111 of 1305 (8.5%) CCP-treated patients, yielding a 3.7% (95% confidence interval [CI], 1.3%-6.0%; P = .001) absolute risk reduction and 30.1% relative risk reduction for all-cause hospitalization. The hospitalization reduction was greatest in those with both early transfusion and high titer with a 7.6% absolute risk reduction (95% CI, 4.0%-11.1%; P = .0001) accompanied by at 51.4% relative risk reduction. No significant reduction in hospitalization was seen with treatment >5 days after symptom onset or in those receiving CCP with antibody titers below the median titer., Conclusions: Among outpatients with COVID-19, treatment with CCP reduced the rate of all-cause hospitalization and may be most effective when given within 5 days of symptom onset and when antibody titer is higher., Competing Interests: Potential conflicts of interest. R. L. has received fees from Pfizer for serving as subinvestigator of a COVID vaccine trial. F. P. has received fees from Pfizer for serving as a principal investigator for a COVID vaccine trial. D. J. S. is a founder and board member of AliquantumRx with stock options; Hemex Health malaria diagnostics consulting; royalties for malaria diagnostic test control standards from Alere (Binax Inc/D/B/A Inverness Medical); consulting fees for legal malaria case from Mabrey Firm (2019); the following grants or contracts: NIH/NIAID R01AI150763, NIH R21TR001737, NIH R01AI111962, DOD TB210115 (CDMRP Tick-Borne Disease Research Program); the following patents: USP 9642865 (issued 9 May 2017, New angiogenesis inhibitors), USP 7270948 (issued 18 September 2007, Detection of malaria parasites by laser desorption mass spectrometry), Salts and polymorphs of cethromycin for the treatment of disease (pending, application 20210163522), and Macrolide compounds and their use in liver stage malaria and related disease (pending, application PCT/US2015/046665); and participation on 2018 NIAID Safety Monitoring Committee/Independent Safety Monitor Intramural, all outside the submitted work. B. J. A. R. reports advisory board membership for Roche and AstraZeneca on a COVID-19 therapy; membership on a data and safety monitoring board (DSMB) for Exevir; consulting fees from Roche and AstraZeneca; grants or contracts and payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from Gilead Sciences; and support for attending meetings and/or travel from Pfizer. J. J. Z. reports consulting fees from City of Hope; cell therapy consultant; participation on DSMB for the PACER trial; DSMB for the Tolerant trial; and advisory boards for Sanofi and Sobi. L. J. D. reports the following grants or contracts: 75A50120C00094 (BARDA), Collection, testing, and provision of COVID-19 convalescent plasma for NHLBI/NIH (C3PO) through America's Blood Centers; US Veterans Health Administration, Pittsburgh (contract number 36C24E20D0027, VA CURES-1); and Vanderbilt University (Collection, testing, and provision of COVID-19 convalescent plasma for Association of Convalescent Plasma Treatment with Mortality and Clinical Trajectory in Patients Hospitalized with COVID-19 in the Community Setting). B. P. reports the following grants or contracts: COVID Trials, Incyte, Parexel, Novartis Pharmaceuticals, Partner Therapeutics, Fulcrum Therapeutics (to University Health Science Center), and Pulmonary Hypertension Trials, United Therapeutics, GlaxoSmithKline, Insmed, Merck Sharp & Dohme (to University of Texas Health Center). C. W. C. reports consulting honorarium for participation on NHLBI ACTIV4 CONNECTS Steering Committee. I. E. reports support for attending meetings and/or travel for 50 Congreso Argentino de Medicina Respiratoria 2022, Abstract Scholarship, American Thoracic Society, International Conference in Philadelphia, 2020 Assembly on Pediatrics. G. P. M. reports grants or contracts from Pfizer, Moderna, Medicago, and Merck for clinical research (as principal investigator), and payment for presentations from Moderna. D. O. reports consulting fees paid to author from the Fight Infectious Diseases Foundation and the Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol. B. R. M. reports the following grants or contracts: NIH/NIAID R01AI150763, NIH R21TR001737, NIH R01AI111962, and DOD TB210115 (CDMRP Tick-Borne Disease Research Program). D. W. reports payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from AstraZeneca, and support for attending meetings and/or travel from Laboratorios Raffo. C. R. reports grants or contracts from Gilead Sciences, ViiV Healthcare, Janssen-Cilag, AIDSfonds, and Health∼Holland; participation on a DSMB or advisory board as well as support for attending meetings and/or travel from Gilead Sciences and ViiV Healthcare; and gifts for the #awarehivukraine foundation. M. A. H. reports grants or contracts from Gilead, Insmed, and AN2 Therapeutics, as well as participation on the AIDS Clinical Trials Group Tuberculosis Transformative Science Group Study Monitoring Committee. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) reduces hospitalizations among outpatients treated early after symptom onset. It is unknown whether CCP reduces time to symptom resolution among outpatients., Methods: We evaluated symptom resolution at day 14 by trial arm using an adjusted subdistribution hazard model, with hospitalization as a competing risk. We also assessed the prevalence of symptom clusters at day 14 between treatments. Clusters were defined based on biologic clustering, impact on ability to work, and an algorithm., Results: Among 1070 outpatients followed up after transfusion, 381 of 538 (70.8%) receiving CCP and 381 of 532 (71.6%) receiving control plasma were still symptomatic (P = .78) at day 14. Associations between CCP and symptom resolution by day 14 did not differ significantly from those in controls after adjustment for baseline characteristics (adjusted subdistribution hazard ratio, 0.99; P = .62). The most common cluster consisted of cough, fatigue, shortness of breath, and headache and was found in 308 (57.2%) and 325 (61.1%) of CCP and control plasma recipients, respectively (P = .16)., Conclusions: In this trial of outpatients with early COVID-19, CCP was not associated with faster resolution of symptoms compared with control. Overall, there were no differences by treatment in the prevalence of each symptom or symptom clusters at day 14., Clinical Trials Registration: NCT04373460., Competing Interests: Potential conflicts of interest. E. M. B. is a member of the Food and Drug Administration's Blood Products Advisory Committee. (All opinions in this manuscript are of the authors and do not reflect the Blood Products Advisory Committee or the position of the Food and Drug Administration; this arrangement has been reviewed and approved by Johns Hopkins University in accordance with its conflict-of-interest policies.) A. C. serves on the Scientific Advisory Board of Sabtherapeutics, which is developing cow-derived human immunoglobulins for the treatment of coronavirus disease 2019 and other infectious diseases. K. A. G. is a paid consultant for UpToDate, Teach for America, and the Aspen Institute. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Whilst bone marrow adipocytes (BMAd) have long been appreciated by clinical haemato-pathologists, it is only relatively recently, in the face of emerging data, that the adipocytic niche has come under the watchful eye of biologists. There is now mounting evidence to suggest that BMAds are not just a simple structural entity of bone marrow microenvironments but a bona fide driver of physio- and pathophysiological processes relevant to multiple aspects of health and disease. Whilst the truly multifaceted nature of BMAds has only just begun to emerge, paradigms have shifted already for normal, malignant and non-malignant haemopoiesis incorporating a view of adipocyte regulation. Major efforts are ongoing, to delineate the routes by which BMAds participate in health and disease with a final aim of achieving clinical tractability. This review summarises the emerging role of BMAds across the spectrum of normal and pathological haematological conditions with a particular focus on its impact on cancer therapy., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Patients hospitalized with COVID-19 have an increased incidence of thromboembolism. The role of extended thromboprophylaxis after hospital discharge is unclear., Objective: To determine whether anticoagulation is superior to placebo in reducing death and thromboembolic complications among patients discharged after COVID-19 hospitalization., Design: Prospective, randomized, double-blind, placebo-controlled clinical trial. (ClinicalTrials.gov: NCT04650087)., Setting: Done during 2021 to 2022 among 127 U.S. hospitals., Participants: Adults aged 18 years or older hospitalized with COVID-19 for 48 hours or more and ready for discharge, excluding those with a requirement for, or contraindication to, anticoagulation., Intervention: 2.5 mg of apixaban versus placebo twice daily for 30 days., Measurements: The primary efficacy end point was a 30-day composite of death, arterial thromboembolism, and venous thromboembolism. The primary safety end points were 30-day major bleeding and clinically relevant nonmajor bleeding., Results: Enrollment was terminated early, after 1217 participants were randomly assigned, because of a lower than anticipated event rate and a declining rate of COVID-19 hospitalizations. Median age was 54 years, 50.4% were women, 26.5% were Black, and 16.7% were Hispanic; 30.7% had a World Health Organization severity score of 5 or greater, and 11.0% had an International Medical Prevention Registry on Venous Thromboembolism risk prediction score of greater than 4. Incidence of the primary end point was 2.13% (95% CI, 1.14 to 3.62) in the apixaban group and 2.31% (CI, 1.27 to 3.84) in the placebo group. Major bleeding occurred in 2 (0.4%) and 1 (0.2%) and clinically relevant nonmajor bleeding occurred in 3 (0.6%) and 6 (1.1%) apixaban-treated and placebo-treated participants, respectively. By day 30, thirty-six (3.0%) participants were lost to follow-up, and 8.5% of apixaban and 11.9% of placebo participants permanently discontinued the study drug treatment., Limitations: The introduction of SARS-CoV-2 vaccines decreased the risk for hospitalization and death. Study enrollment spanned the peaks of the Delta and Omicron variants in the United States, which influenced illness severity., Conclusion: The incidence of death or thromboembolism was low in this cohort of patients discharged after hospitalization with COVID-19. Because of early enrollment termination, the results were imprecise and the study was inconclusive., Primary Funding Source: National Institutes of Health.

Background: The efficacy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescent plasma (CCP) for preventing infection in exposed, uninfected individuals is unknown. CCP might prevent infection when administered before symptoms or laboratory evidence of infection., Methods: This double-blinded, phase 2 randomized, controlled trial (RCT) compared the efficacy and safety of prophylactic high titer (≥1:320 by Euroimmun ELISA) CCP with standard plasma. Asymptomatic participants aged ≥18 years with close contact exposure to a person with confirmed coronavirus disease 2019 (COVID-19) in the previous 120 hours and negative SARS-CoV-2 test within 24 hours before transfusion were eligible. The primary outcome was new SARS-CoV-2 infection., Results: In total, 180 participants were enrolled; 87 were assigned to CCP and 93 to control plasma, and 170 transfused at 19 sites across the United States from June 2020 to March 2021. Two were excluded for screening SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) positivity. Of the remaining 168 participants, 12/81 (14.8%) CCP and 13/87 (14.9%) control recipients developed SARS-CoV-2 infection; 6 (7.4%) CCP and 7 (8%) control recipients developed COVID-19 (infection with symptoms). There were no COVID-19-related hospitalizations in CCP and 2 in control recipients. Efficacy by restricted mean infection free time (RMIFT) by 28 days for all SARS-CoV-2 infections (25.3 vs 25.2 days; P = .49) and COVID-19 (26.3 vs 25.9 days; P = .35) was similar for both groups., Conclusions: Administration of high-titer CCP as post-exposure prophylaxis, although appearing safe, did not prevent SARS-CoV-2 infection., Clinical Trials Registration: NCT04323800., Competing Interests: Potential conflicts of interests . The authors report the following: K. G.reports grants or contracts unrelated to this work and paid to institution from NIHI, personal fees from Aspen Institute, Teach for America and UpToDate. T. G. reports paid consultant for Fresenius Kabi USA and reports <$5000 of JNJ stock. A. C. reports Scientific Advisory Board of Sabtherapeutics (cow-derived human immunoglobulins COVID-19 treatment and other infectious diseases) and Ortho Diagnostics Speakers Bureau, and consulting fees from Ortho Diagnostics and Pfizer, and payment for expert testimony from King & Spalding LLP, and leadership or fiduciary role with American Society for Microbiology, and part owner of Melatech. E. B.’s time is funded in part by National Heart Lung and Blood Institute (NHLBI) through grant number 1K23HL151826, is a member of the FDA Blood Products Advisory Committee, Abbot Laboratories, Grifols Diagnostic Solutions, personal fee for invited educational presentations for Terumo BCT (honoraria for educational webinar), and advisor for California Institute for Regenerative Medicine (convalescent plasma program), and unpaid participation as invited member for a Data Safety Monitoring Board for the following trial: ‘Assessment of safety and efficacy of COVID-19 Convalescent Plasma for treatment of COVID-19 in adults in Uganda; A Phase III randomized controlled trial. S. S. reports research grants from Ansun, Astellas, Cidara, Emergent Biosolutions, F2G, Gilead, Merck, Scynexis, Zeteo, Shionogi and Shire, personal fees from Adagio, Adamis, Celltrion, Immunome, Intermountain Health and Karyopharm (consultant, advisory board and data safety monitoring board member), participation on a Data Safety Monitoring Board or Advisory Board for Adagio, Adamis, Amplyx, Immunome, Intermountain Health, Janssen, Karyopharm, Reviral, and stock options from Immunome. D. Su. reports grants or contracts unrelated to this work from NIH/NIAID (R01AI150763 Dual artemisinin action combats resistance; NIH R21TR001737 Quantum model repurposing of cethromycin for liver stage malaria; NIH R01AI111962 Optimized Combination Antimalarial Drug Therapy), founder, board member, and stock options from AliquantumRx, DSMB member NIAID SMC/ISM Intramural 2018, medical royalties for malaria test (Binax Inc/D/B/A Inverness), consultant on malaria diagnosis for Masimo and Hemex Health and consulting fees for legal malaria case (Mabrey Firm 2019 and Ressler and Ressler 2018), and patents (Issued-USP 9,642,865 9 May 2017 New angiogenesis inhibitors; Issued-USP 9,568,471 14 February 2017 Malaria Diagnosis in Urine; Issued-USP 7,270,948 18 September 2007 Detection of malaria parasites by laser desorption mass spectrometry; Pending SALTS AND POLYMORPHS OF CETHROMYCIN FOR THE TREATMENT OF DISEASE Patent Application (Application number 20210163522); and Pending- Macrolide compounds and their use in liver stage malaria and related disease (Application number PCT/US2015/046665). E. C. reports research grants from Gilead Sciences and Merck Sharp and Dohme (funds paid to UC Regents), payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Gilead Sciences, and advisory board member for Gilead Sciences. J. C. is aconsultant for Merck and Co. and Resverlogix. S. Ka. reports educational product development for Integritas Communications Group. G. M. reports research grants from Teva, Sanofi Regeneron, Astra Zeneca, Alk Abello, Genentech, Propeller Health, GlaxoSmithKline, and Novartis, and honoraria paid to author for HCPLive educational presentation, and position as Secretary/Treasurer (March 2019 to February 2020), President-Elect (March 2020 to February 2021), President (March 2021 to February 2022) of the American Academy of Allergy, Asthma, and Immunology (payments made to institution during term as President), and Director of American Board of Allergy and Immunology (2020–2025), Co-Chair of American Board of Allergy and Immunology Continuous Assessment Program Examination Committee (2020–2022) (honoraria paid to author). C. S. reports research grants from Centers for Disease Control and Prevention, Merck and Pfizer. D. J. reports grants or contracts unrelated to this work from National Eye Institute, National Institutes of Health, and National Center for Advancing Translational Research, National Institutes of Health; Board of Directors of the American Uveitis Society, speaking honoraria from Retina Society, Controversies in Ophthalmology, University of Rochester, Wills Eye Hospital, LSU School of Medicine and Icahn School of Medicine at Mt. Sinai, and participation on a Data Safety Monitoring Board or Advisory Board for National Eye Institute Intramural Branch. D. Sh. reports numerous grants supporting ongoing and completed research unrelated to this article from the NIH; and is a member of DSMB for the Pelvic Floor Disorders Network (stipend support for meeting activities 4/year). D. H. reports consulting fees from Neurotrope. M. H. reports grants or contracts unrelated to this work from NIH National Center of Advancing Translational Sciences (NCATS) (grant number KL2TR001426), NIH National Institute of Allergy and Infectious Diseases (NIAID) (grant number UM1AI069501), and Insmed Inc, and is a member of the AIDS Clinical Trials Group (ACTG) Tuberculosis Transformative Science Group (TB TSG) Study Monitoring Committee. O. L. reports grants or contracts unrelated to this work from Division of Intramural Research, NIAID, NIH. V. C. reports stock/stock options from spouse’s employer and under spouse’s name from Pfizer. D. T. reports board membership with Excision Bio and board membership (DSMB) with Merck and Co (paid to author); employment with JHU; various expert testimony paid to author; honoraria for CME programs only, paid to author (no service on corporate speaker’s bureau); royalties from UpToDate; and stock/stock options with Excision Bio. N. M. reports participation as HyazOUT and UtahONE combined DSMB member for NIH National Center for Advancing Translational Sciences (NCATS) U24TR001609-S3.All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Severe COVID-19 illness can lead to thrombotic complications, organ failure, and death. Antithrombin (AT) regulates thromboinflammation and is a key component of chemical thromboprophylaxis. Our goal was to examine the link between AT activity and responsiveness to thromboprophylaxis, markers of hypercoagulability, and inflammation among severe COVID-19 patients., Methods: This was a single-center, prospective observational study enrolling SARS-CoV-2-positive patients admitted to the intensive care unit on prophylactic enoxaparin. Blood was collected daily for 7 days to assess AT activity and anti-factor Xa levels. Patient demographics, outcomes, and hospital laboratory results were collected. Continuous variables were compared using Mann-Whitney tests, and categorical variables were compared using χ2 tests. Multivariable logistic regression was used to determine the association between AT activity and mortality., Results: In 36 patients, 3 thromboembolic events occurred, and 18 (50%) patients died. Patients who died had higher fibrinogen, D-dimer, and C-reactive protein (CRP) levels and lower AT activity. Reduced AT activity was independently associated with mortality and correlated with both markers of hypercoagulability (D-dimer) and inflammation (CRP)., Conclusion: Low AT activity is associated with mortality and persistent hypercoagulable and proinflammatory states in severe COVID-19 patients. The anti-thromboinflammatory properties of AT make it an appealing therapeutic target for future studies., (© 2022 S. Karger AG, Basel.)

Despite being predominantly a childhood disease, the incidence of acute lymphoblastic leukemia (ALL) has a second peak in adults aged 60 years and over. These older adults fare extremely poorly with existing treatment strategies and very few studies have undertaken a comprehensive genetic and genomic characterization to improve prognosis in this age group. We performed cytogenetic, single nucleotide polymorphism (SNP) array and next-generation sequencing (NGS) analyses on samples from 210 patients aged ≥60 years from the UKALL14 and UKALL60+ clinical trials. BCR-ABL1-positive disease was present in 26% (55/210) of patients, followed by low hypodiploidy/near triploidy in 13% (28/210). Cytogenetically cryptic rearrangements in CRLF2, ZNF384 and MEF2D were detected in 5%, 1% and <1% of patients, respectively. Copy number abnormalities were common and deletions in ALL driver genes were seen in 77% of cases. IKZF1 deletion was present in 51% (40/78) of samples tested and the IKZF1plus profile was identified in over a third (28/77) of cases of B-cell precursor ALL. The genetic good-risk abnormalities high hyperdiploidy (n=2), ETV6-RUNX1 (no cases) and ERG deletion (no cases) were exceptionally rare in this cohort. RAS pathway mutations were seen in 17% (4/23) of screened samples. KDM6A abnormalities, including biallelic deletions, were discovered in 5% (4/78) of SNP arrays and 9% (2/23) of NGS samples, and represent novel, potentially therapeutically actionable lesions using EZH2 inhibitors. Outcome remained poor with 5-year event-free and overall survival rates of 17% and 24%, respectively, across the cohort, indicating a need for novel therapeutic strategies.

Background: Studies of the early months of the coronavirus disease 2019 (COVID-19) pandemic indicate that patient outcomes may be adversely affected by surges. However, the impact on in-hospital mortality during the largest surge to date, September 2020-March 2021, has not been studied. This study aimed to determine whether in-hospital mortality was impacted by the community surge of COVID-19., Methods: This is a retrospective cohort study of 416 962 adult COVID-19 patients admitted immediately before or during the surge at 229 US academic and 432 community hospitals in the Vizient Clinical Database. The odds ratios (ORs) of death among hospitalized patients during each phase of the surge was compared with the corresponding odds before the surge and adjusted for demographic, comorbidity, hospital characteristic, length of stay, and complication variables., Results: The unadjusted proportion of deaths among discharged patients was 9% in both the presurge and rising surge stages but rose to 12% during both the peak and declining surge intervals. With the presurge phase defined as the referent, the risk-adjusted ORs (aORs) for the surge periods were rising, 1.14 (1.10-1.19), peak 1.37 (1.32-1.43), and declining, 1.30 (1.25-1.35). The surge rise in-hospital mortality was present in 7 of 9 geographic divisions and greater for community hospitals than for academic centers., Conclusions: These data support public policies aimed at containing pandemic surges and supporting healthcare delivery during surges., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objective: Sepsis is a major public health problem. Understanding the epidemiology of sepsis subtypes is important to quantify the magnitude of the problem and identify targets for system wide treatment strategies. We sought to describe the current national epidemiology of community-acquired (CAS), hospital-acquired (HAS) and healthcare-associated sepsis (HCAS) hospitalizations among academic medical centers in the United States using current discharge diagnosis taxonomies., Methods: Retrospective analysis of patient discharge data from the Vizient Clinical Data Base/Resource Manager. We identified sepsis hospitalizations using four ICD-10 coding strategies: (1) "Martin" sepsis codes (21 ICD-10 codes), (2) "Angus" sepsis codes (ICD-10 infection + ICD-10 organ dysfunction), (3) Medicare "SEP-1" codes (28 ICD-10 codes), and (4) "explicit sepsis" codes (ICD-10 R65.20 and R65.21). Using present-on-admission flags for each diagnosis, we also distinguished: (1) community-acquired sepsis (CAS), (2) hospital-acquired sepsis (HAS), and (3) healthcare associated sepsis (HCAS)., Results: Among 22,655,240 hospitalizations, the number and incidence of sepsis hospitalizations were: (1) Martin (n = 1,718,257, 75.8 per 1000 hospitalizations), (2) Angus (n = 2,749,163, 121.3 per 1000), (3) SEP-1 (n = 1,624,909, 71.7 per 1000), and (4) explicit sepsis (n = 655,853, 28.9 per 1000). CAS was the most common sepsis subtype. HAS exhibited higher adjusted mortality than CAS. ICU admission was highest for HAS (Martin, 1.5%; Angus, 1.5%; SEP-1, 1.6%; Explicit, 1.9%)., Conclusions: These results illustrate the prevalence of sepsis at US academic medical centers using the most current sepsis classification taxonomies and discharge diagnosis codes. These results highlight important considerations when using hospital discharge data to characterize the epidemiology of sepsis., Competing Interests: The authors declare no conflicts of interests., (© 2022 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

The ongoing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants severely limits available effective monoclonal antibody therapies. Effective drugs are also supply limited. COVID-19 convalescent plasma (CCP) qualified for high antibody levels effectively reduces immunocompetent outpatient hospitalization. The Food and Drug Administration currently allows outpatient CCP for the immunosuppressed. Viral-specific antibody levels in CCP can range 10- to 100-fold between donors, unlike the uniform viral-specific monoclonal antibody dosing. Limited data are available on the efficacy of polyclonal CCP to neutralize variants. We examined 108 pre-δ/pre-ο donor units obtained before March 2021, 20 post-δ COVID-19/postvaccination units, and 1 pre-δ/pre-ο hyperimmunoglobulin preparation for variant-specific virus (vaccine-related isolate [WA-1], δ, and ο) neutralization correlated to Euroimmun S1 immunoglobulin G antibody levels. We observed a two- to fourfold and 20- to 40-fold drop in virus neutralization from SARS-CoV-2 WA-1 to δ or ο, respectively. CCP antibody levels in the upper 10% of the 108 donations as well as 100% of the post-δ COVID-19/postvaccination units and the hyperimmunoglobulin effectively neutralized all 3 variants. High-titer CCP neutralizes SARS-CoV-2 variants despite no previous donor exposure to the variants., (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.)

Objective: The Coronavirus Disease 2019 (COVID-19) pandemic has overwhelmed the capacity of healthcare resources and posed a challenge for worldwide hospitals. The ability to distinguish potentially deteriorating patients from the rest helps facilitate reasonable allocation of medical resources, such as ventilators, hospital beds, and human resources. The real-time accurate prediction of a patient's risk scores could also help physicians to provide earlier respiratory support for the patient and reduce the risk of mortality., Methods: We propose a robust real-time prediction model for the in-hospital COVID-19 patients' probability of requiring mechanical ventilation (MV). The end-to-end neural network model incorporates the Multi-task Gaussian Process to handle the irregular sampling rate in observational data together with a self-attention neural network for the prediction task., Results: We evaluate our model on a large database with 9,532 nationwide in-hospital patients with COVID-19. The model demonstrates significant robustness and consistency improvements compared to conventional machine learning models. The proposed prediction model also shows performance improvements in terms of area under the receiver operating characteristic curve (AUROC) and area under the precision-recall curve (AUPRC) compared to various deep learning models, especially at early times after a patient's hospital admission., Conclusion: The availability of large and real-time clinical data calls for new methods to make the best use of them for real-time patient risk prediction. It is not ideal for simplifying the data for traditional methods or for making unrealistic assumptions that deviate from observation's true dynamics. We demonstrate a pilot effort to harmonize cross-sectional and longitudinal information for mechanical ventilation needing prediction., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Polyclonal convalescent plasma may be obtained from donors who have recovered from coronavirus disease 2019 (Covid-19). The efficacy of this plasma in preventing serious complications in outpatients with recent-onset Covid-19 is uncertain., Methods: In this multicenter, double-blind, randomized, controlled trial, we evaluated the efficacy and safety of Covid-19 convalescent plasma, as compared with control plasma, in symptomatic adults (≥18 years of age) who had tested positive for severe acute respiratory syndrome coronavirus 2, regardless of their risk factors for disease progression or vaccination status. Participants were enrolled within 8 days after symptom onset and received a transfusion within 1 day after randomization. The primary outcome was Covid-19-related hospitalization within 28 days after transfusion., Results: Participants were enrolled from June 3, 2020, through October 1, 2021. A total of 1225 participants underwent randomization, and 1181 received a transfusion. In the prespecified modified intention-to-treat analysis that included only participants who received a transfusion, the primary outcome occurred in 17 of 592 participants (2.9%) who received convalescent plasma and 37 of 589 participants (6.3%) who received control plasma (absolute risk reduction, 3.4 percentage points; 95% confidence interval, 1.0 to 5.8; P = 0.005), which corresponded to a relative risk reduction of 54%. Evidence of efficacy in vaccinated participants cannot be inferred from these data because 53 of the 54 participants with Covid-19 who were hospitalized were unvaccinated and 1 participant was partially vaccinated. A total of 16 grade 3 or 4 adverse events (7 in the convalescent-plasma group and 9 in the control-plasma group) occurred in participants who were not hospitalized., Conclusions: In participants with Covid-19, most of whom were unvaccinated, the administration of convalescent plasma within 9 days after the onset of symptoms reduced the risk of disease progression leading to hospitalization. (Funded by the Department of Defense and others; CSSC-004 ClinicalTrials.gov number, NCT04373460.)., (Copyright © 2022 Massachusetts Medical Society.)

Convalescent plasma, collected from donors who have recovered from a pathogen of interest, has been used to treat infectious diseases, particularly in times of outbreak, when alternative therapies were unavailable. The COVID-19 pandemic revived interest in the use of convalescent plasma. Large observational studies and clinical trials that were executed during the pandemic provided insight into how to use convalescent plasma, whereby high levels of antibodies against the pathogen of interest and administration early within the time course of the disease are critical for optimal therapeutic effect. Several studies have shown outpatient administration of COVID-19 convalescent plasma (CCP) to be both safe and effective, preventing clinical progression in patients when administered within the first week of COVID-19. The United States Food and Drug Administration expanded its emergency use authorization (EUA) to allow for the administration of CCP in an outpatient setting in December 2021, at least for immunocompromised patients or those on immunosuppressive therapy. Outpatient transfusion of CCP and infusion of monoclonal antibody therapies for a highly transmissible infectious disease introduces nuanced challenges related to infection prevention. Drawing on our experiences with the clinical and research use of CCP, we describe the logistical considerations and workflow spanning procurement of qualified products, infrastructure, staffing, transfusion, and associated management of adverse events. The purpose of this description is to facilitate the efforts of others intent on establishing outpatient transfusion programs for CCP and other antibody-based therapies., (© 2022 AABB.)

Background: The outcome of chemotherapy in patients older than 40 years with acute lymphoblastic leukaemia is poor and myeloablative allogeneic haematopoietic stem-cell transplantation (HSCT) has a high transplant-related mortality (TRM) in this age cohort. The aim of this study was to assess the activity and safety of reduced-intensity conditioned allogeneic HSCT in this patient population., Methods: This was a single-arm, prospective study within the UKALL14 trial done in 46 centres in the UK, which recruited patients to the transplantation substudy. Participants in UKALL14 had B-cell or T-cell acute lymphoblastic leukaemia, were aged 25-65 years (BCR-ABL1-negative) or 18-65 years (BCR-ABL1-positive), and for this subcohort had a fit, matched sibling donor or an 8 out of 8 allelic matched unrelated donor (HLA-A, HLA-B, HLA-C, and HLA-DR). On June 20, 2014, the protocol was amended to allow 7 out of 8 matched unrelated donors if the patient had high risk cytogenetics or was minimal residual disease (MRD)-positive after the second induction course. Patients were given fludarabine, melphalan, and alemtuzumab (FMA; intravenous fludarabine 30 mg/m 2 on days -6 to -2, melphalan 140 mg/m 2 on day -2, and alemtuzumab 30 mg on day -1 [sibling donor] and days -2 and -1 [unrelated donor]) before allogeneic HSCT (aged ≥41 years patient pathway). Donor lymphocyte infusions were given from 6 months for mixed chimerism or MRD. The primary endpoint was event-free survival and secondary and transplantation-specific endpoints included overall survival, relapse incidence, TRM, and acute and chronic graft-versus-host disease (GVHD). This study is registered with ClinicalTrials.gov, NCT01085617., Findings: From Feb 22, 2011, to July 26, 2018, 249 patients (236 aged ≥41 years and 13 younger than 41 years) considered unfit for a myeloablative allograft received an FMA reduced-intensity conditioned HSCT. 138 (55%) patients were male and 111 (45%) were female. 88 (35%) participants received transplantations from a sibling donor and 160 (64%) received transplantations from unrelated donors. 211 (85%) participants had B-precursor acute lymphoblastic leukaemia. High-risk cytogenetics were present in 43 (22%) and another 63 (25%) participants were BCR-ABL1-positive. At median follow-up of 49 months (IQR 36-70), 4-year event-free survival was 46·8% (95% CI 40·1-53·2) and 4-year overall survival was 54·8% (48·0-61·2). 4-year cumulative incidence of relapse was 33·6% (27·9-40·2) and 4-year TRM was 19·6% (15·1-25·3). 27 (56%) of 48 patients with TRM had infection as the named cause of death. Seven (15%) of 48 patients had fungal infections, 13 (27%) patients had bacterial infections (six gram-negative), and 11 (23%) had viral infections (three cytomegalovirus and two Epstein-Barr virus). Acute GVHD grade 2-4 occurred in 29 (12%) of 247 patients and grade 3-4 occurred in 12 (5%) patients. Chronic GVHD incidence was 84 (37%) of 228 patients (50 [22%] had extensive chronic GVHD). 49 (30%) of 162 patients had detectable end-of-induction MRD, which portended worse outcomes with event-free survival (HR 2·40 [95% CI 1·46-3·93]) and time-to-relapse (HR 2·41 [1·29-4·48])., Interpretation: FMA reduced-intensity conditioned allogeneic HSCT in older patients with acute lymphoblastic leukaemia in first complete remission provided good disease control with moderate GVHD, resulting in better-than-expected event-free survival and overall survival in this high-risk population. Strategies to reduce infection-related TRM will further improve outcomes., Funding: Cancer Research UK., Competing Interests: Declaration of interests DIM reports educational events, consulting, and advisory boards for Pfizer, Amgen, Kite, and Novartis. MC declares grants or contracts with Incyte and Cyclacel; speakers bureau or honoraria for Incyte, Novartis, Pfizer, Astellas, Jazz, and Gilead; and advisory boards for Novartis, Pfizer, Jazz, and Daiichi-Sankyo. AM received educational honoraria and payments for advisory boards and travel sponsorship from Roche; advisory board honoraria from Amgen; educational and travel payments from BMS and Celgene; and advisory board honoraria from AbbVie. TFM declares travel grants from Amgen, Jazz, Pfizer, Bayer, Kyowa Kirin, Celgene, Kite/Gilead, Janssen, and Takeda; advisory board honoraria from Kite/Gilead, Amgen, Novartis, Pfizer, Celgene, Daiichi Sankyo, Atara, and Roche; lecture honoraria from Kite/Gilead, Takeda, Janssen, Roche, Servier, Novartis, and Celgene; and research funding from Janssen, AstraZeneca, and Novartis. AVM received honoraria for an educational event for Amgen. MNP received honoraria and meeting support from Kite. NM received speaker fees from Amgen, Janssen, and AbbVie; attended advisory boards of AbbVie and Kite; and had conference support from AbbVie and Takeda. CJR reports paid educational events for Kite and Incyte; and advisory boards for Kite, Novartis, Amgen, and Pfizer. AKF reports consulting for Amgen. BP received honoraria from Pfizer and Amgen. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: The use of an innovative approach for mental health interviews met unprecedented needs during the coronavirus disease 2019 pandemic for patients and staff at a community health clinic and provided nursing students with a telehealth activity that met patient care education requirements while practicing essential skills., Method: The nursing students and instructors worked collaboratively with the clinical team to call patients using an algorithm that incorporates screeners for depression, anxiety, and chronic disease distress., Results: Reports during daily debriefings and feedback obtained from evaluations were summarized by faculty and used to improve the activity. These reports indicated the experience was beneficial to students and clinic staff., Conclusion: Providers were able to follow up on vulnerable patients more quickly, students were able to practice essential nursing skills during a time when safety concerns limited direct patient interaction, and patients continued to feel connected to health care providers during a global pandemic. [ J Nurs Educ . 2022;61(4):205-207.] .

Background: Treatment for adults with acute lymphoblastic leukaemia requires improvement. UKALL14 was a UK National Cancer Research Institute Adult ALL group study that aimed to determine the benefit of adding the anti-CD20 monoclonal antibody, rituximab, to the therapy of adults with de novo B-precursor acute lymphoblastic leukaemia., Methods: This was an investigator-initiated, phase 3, randomised controlled trial done in all UK National Health Service Centres treating patients with acute lymphoblastic leukaemia (65 centres). Patients were aged 25-65 years with de-novo BCR-ABL1-negative acute lymphoblastic leukaemia. Patients with de-novo BCR-ABL1-positive acute lymphoblastic leukaemia were eligible if they were aged 19-65 years. Participants were randomly assigned (1:1) to standard-of-care induction therapy or standard-of-care induction therapy plus four doses of intravenous rituximab (375 mg/m 2 on days 3, 10, 17, and 24). Randomisation used minimisation and was stratified by sex, age, and white blood cell count. No masking was used for patients, clinicians, or staff (including the trial statistician), although the central laboratory analysing minimal residual disease and CD20 was masked to treatment allocation. The primary endpoint was event-free survival in the intention-to-treat population. Safety was assessed in all participants who started trial treatment. This study is registered with ClincialTrials.gov, NCT01085617., Findings: Between April 19, 2012, and July 10, 2017, 586 patients were randomly assigned to standard of care (n=292) or standard of care plus rituximab (n=294). Nine patients were excluded from the final analysis due to misdiagnosis (standard of care n=4, standard of care plus rituximab n=5). In the standard-of-care group, median age was 45 years (IQR 22-65), 159 (55%) of 292 participants were male, 128 (44%) were female, one (<1%) was intersex, and 143 (59%) of 244 participants had high-risk cytogenetics. In the standard-of-care plus rituximab group, median age was 46 years (IQR 23-65), 159 (55%) of 294 participants were male, 130 (45%) were female, and 140 (60%) of 235 participants had high-risk cytogenetics. After a median follow-up of 53·7 months (IQR 40·3-70·4), 3-year event-free survival was 43·7% (95% CI 37·8-49·5) for standard of care versus 51·4% (45·4-57·1) for standard of care plus rituximab (hazard ratio [HR] 0·85 [95% CI 0·69-1·06]; p=0·14). The most common adverse events were infections and cytopenias, with no difference between the groups in the rates of adverse events. There were 11 (4%) fatal (grade 5) events in induction phases 1 and 2 in the standard-of-care group and 13 (5%) events in the standard-of-care plus rituximab group). 3-year non-relapse mortality was 23·7% (95% CI 19·0-29·4) in the standard-of-care group versus 20·6% (16·2-25·9) in the standard-of-care plus rituximab group (HR 0·88 [95% CI 0·62-1·26]; p=0·49)., Interpretation: Standard of care plus four doses of rituximab did not significantly improve event-free survival over standard of care. Rituximab is beneficial in acute lymphoblastic leukaemia but four doses during induction is likely to be insufficient., Funding: Cancer Research UK and Blood Cancer UK., Competing Interests: Declaration of interests AKF received institutional peer-reviewed grant funding from Cancer Research UK, the Medical Research Council, and Servier; received consulting fees from Amgen; has a leadership/fiduciary role for the British Society of Haematology (unpaid); and is on a data safety and monitoring board for Novartis. AAK has received honoraria from Kite and Gilead; has received institutional peer-reviewed grant funding from Millennium pharmaceutics, Bristol Myers Squibb, Amgen, Celgene, Merck Sharp and Dohme, Janssen-Cilag, Pfizer, and Cancer Research UK; and is on a data safety and monitoring board or advisory committee for the University of Birmingham. AKM has received honoraria form Amgen, Roche, Abbvie, and Celgene; has received institutional peer-reviewed grant funding from Janssen and AstraZeneca; has received meeting support from Roche, Celgene, and Abbvie; and is on a data safety and monitoring board or advisory committee for Novartis. AVM has received institutional peer-reviewed grant funding from Cancer Research UK, Blood Cancer UK, the EU Innovative Medicines Initiative, and North East Children's Cancer Fund; has a leadership/fiduciary role for the ALLTogther Consortium Board and the Genetics Committee and Science Committee (unpaid); and has received honoraria from Amgen. AZC has received honoraria from Pfizer, Amgen, and Hartley Taylor; and is on a data safety and monitoring board or advisory committee for Pfizer. BB has received institutional peer-reviewed grant funding from Novartis/Haematology Society of Australia and New Zealand (New Investigator Scholarship). CJR has received honoraria from Kite; is on a data safety and monitoring board or advisory committee for Incyte, Gilead, and Pfizer; and has a leadership/fiduciary role as the National Cancer Research Institute Adult ALL Group Chair (unpaid). DIM has received consulting fees from Amgen, Pfizer, Kite, and Novartis; and honoraria from Amgen, Pfizer, and Kite. DY has received meetings support from Amgen, Servier, and Jazz; and is on a data safety and monitoring board or advisory committee for the University of Birmingham, Gilead, and Pfizer. KEB has received research grant support from Blood Cancer UK. LC-H has received institutional peer-reviewed grant funding from Millennium pharmaceutics, Bristol Myers Squibb, Amgen, Celgene., Merck Sharp and Dohme, Janssen-Cilag, Pfizer, and Cancer Research UK. MC has received institutional peer-reviewed grant funding from Cure Leukaemia, Blood Cancer UK, Cyclacel, and Incyte; has received consulting fees from Pfizer, Novartis, and Jazz; has received payment or honoraria from Pfizer, Novartis, Jazz, and Astellias; and has received meeting support from Novartis. PS has received institutional peer-reviewed grant funding from Cancer Research UK, Blood Cancer UK, and Servier. RK has received honoraria from Amgen and Pfizer; and is on a data safety and monitoring board or advisory committee for Amgen. TFM has received honoraria from Amgen, Pfizer, Kite, Gilead, Janssen, Roche, Servier, Novartis, and Celgene; has received institutional peer-reviewed grant funding from Janssen and AstraZeneca; and has received meeting support from Novartis, Amgen, Pfizer, Kite, Gilead, Celgene, Daiichi Sankyo, and Atara. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Benchmarks for protective immunity from infection or severe disease after SARS-CoV-2 vaccination are still being defined. Here, we characterized virus neutralizing and ELISA antibody levels, cellular immune responses, and viral variants in 4 separate groups: healthy controls (HCs) weeks (early) or months (late) following vaccination in comparison with symptomatic patients with SARS-CoV-2 after partial or full mRNA vaccination. During the period of the study, most symptomatic breakthrough infections were caused by the SARS-CoV-2 Alpha variant. Neutralizing antibody levels in the HCs were sustained over time against the vaccine parent virus but decreased against the Alpha variant, whereas IgG titers and T cell responses against the parent virus and Alpha variant declined over time. Both partially and fully vaccinated patients with symptomatic infections had lower virus neutralizing antibody levels against the parent virus than the HCs, similar IgG antibody titers, and similar virus-specific T cell responses measured by IFN-γ. Compared with HCs, neutralization activity against the Alpha variant was lower in the partially vaccinated infected patients and tended to be lower in the fully vaccinated infected patients. In this cohort of breakthrough infections, parent virus neutralization was the superior predictor of breakthrough infections with the Alpha variant of SARS-CoV-2.

An IQ consortium working group (WG) conducted a survey across multiple biopharmaceutical companies to gain information about the level of blinding commonly utilized for early clinical development trials. The main objectives were: (1) to understand blinding practices between healthy volunteer (HV) and early explorative patient trials in all therapeutic areas except oncology where early clinical trials are commonly open-label; (2) to understand the rationale for blinding/unblinding practices; (3) to understand the groups and personnel involved in unblinding; and (4) strategic considerations around blinding/unblinding options in early clinical development trials-risk of bias vs. potential for acceleration. A survey containing 31 main questions with additional sub-clarifying questions was conducted. Sixteen large and mid-size pharmaceutical companies responded. Responses were aligned across functions within each participating company. Additional information was gathered at an American Association of Pharmaceutical Scientists (AAPS) webinar with polling options to roughly 550 registered attendees to evaluate the reason for the unblinding decisions. The results revealed divergence across companies in the blinding approaches most commonly applied but with some study types, there were clearly favored options. Based on these results, the WG developed strategic considerations for first-in-human HV trials and nonpivotal explorative trials in patients. This paper should facilitate discussions among various clinical development functions, such as Clinical Pharmacology, Statistics, Clinical, Bioanalytics, and Regulatory Functions. Such discussions on study design and operations are warranted to allow implementation of more flexible blinding approaches to accelerate data driven decisions in drug development and allow earlier access of patients to needful medicines., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Chromosomal abnormalities are established prognostic markers in adult ALL. We assessed the prognostic impact of established chromosomal abnormalities and key copy number alterations (CNA) among 652 patients with B-cell precursor ALL treated on a modern MRD driven protocol. Patients with KMT2A-AFF1, complex karyotype (CK) and low hypodiploidy/near-triploidy (HoTr) had high relapse rates 50%, 60% & 53% and correspondingly poor survival. Patients with BCR-ABL1 had an outcome similar to other patients. JAK-STAT abnormalities (CRLF2, JAK2) occurred in 6% patients and were associated with a high relapse rate (56%). Patients with ABL-class fusions were rare (1%). A small group of patients with ZNF384 fusions (n = 12) had very good survival. CNA affecting IKZF1, CDKN2A/B, PAX5, BTG1, ETV6, EBF1, RB1 and PAR1 were assessed in 436 patients. None of the individual deletions or profiles were associated with survival, either in the cohort overall or within key subgroups. Collectively these data indicate that primary genetic abnormalities are stronger prognostic markers than secondary deletions. We propose a revised UKALL genetic risk classification based on key established chromosomal abnormalities: (1) very high risk: CK, HoTr or JAK-STAT abnormalities; (2) high risk: KMT2A fusions; (3) Tyrosine kinase activating: BCR-ABL1 and ABL-class fusions; (4) standard risk: all other patients., (© 2021. The Author(s).)

Importance: There is clinical equipoise for COVID-19 convalescent plasma (CCP) use in patients hospitalized with COVID-19., Objective: To determine the safety and efficacy of CCP compared with placebo in hospitalized patients with COVID-19 receiving noninvasive supplemental oxygen., Design, Setting, and Participants: CONTAIN COVID-19, a randomized, double-blind, placebo-controlled trial of CCP in hospitalized adults with COVID-19, was conducted at 21 US hospitals from April 17, 2020, to March 15, 2021. The trial enrolled 941 participants who were hospitalized for 3 or less days or presented 7 or less days after symptom onset and required noninvasive oxygen supplementation., Interventions: A unit of approximately 250 mL of CCP or equivalent volume of placebo (normal saline)., Main Outcomes and Measures: The primary outcome was participant scores on the 11-point World Health Organization (WHO) Ordinal Scale for Clinical Improvement on day 14 after randomization; the secondary outcome was WHO scores determined on day 28. Subgroups were analyzed with respect to age, baseline WHO score, concomitant medications, symptom duration, CCP SARS-CoV-2 titer, baseline SARS-CoV-2 serostatus, and enrollment quarter. Outcomes were analyzed using a bayesian proportional cumulative odds model. Efficacy of CCP was defined as a cumulative adjusted odds ratio (cOR) less than 1 and a clinically meaningful effect as cOR less than 0.8., Results: Of 941 participants randomized (473 to placebo and 468 to CCP), 556 were men (59.1%); median age was 63 years (IQR, 52-73); 373 (39.6%) were Hispanic and 132 (14.0%) were non-Hispanic Black. The cOR for the primary outcome adjusted for site, baseline risk, WHO score, age, sex, and symptom duration was 0.94 (95% credible interval [CrI], 0.75-1.18) with posterior probability (P[cOR<1] = 72%); the cOR for the secondary adjusted outcome was 0.92 (95% CrI, 0.74-1.16; P[cOR<1] = 76%). Exploratory subgroup analyses suggested heterogeneity of treatment effect: at day 28, cORs were 0.72 (95% CrI, 0.46-1.13; P[cOR<1] = 93%) for participants enrolled in April-June 2020 and 0.65 (95% CrI, 0.41 to 1.02; P[cOR<1] = 97%) for those not receiving remdesivir and not receiving corticosteroids at randomization. Median CCP SARS-CoV-2 neutralizing titer used in April to June 2020 was 1:175 (IQR, 76-379). Any adverse events (excluding transfusion reactions) were reported for 39 (8.2%) placebo recipients and 44 (9.4%) CCP recipients (P = .57). Transfusion reactions occurred in 2 (0.4) placebo recipients and 8 (1.7) CCP recipients (P = .06)., Conclusions and Relevance: In this trial, CCP did not meet the prespecified primary and secondary outcomes for CCP efficacy. However, high-titer CCP may have benefited participants early in the pandemic when remdesivir and corticosteroids were not in use., Trial Registration: ClinicalTrials.gov Identifier: NCT04364737.

Genomic classification has improved risk assignment of pediatric, but not adult B-lineage acute lymphoblastic leukemia (B-ALL). The international UKALLXII/ECOG-ACRIN E2993 (#NCT00002514) trial accrued 1229 adolescent/adult patients with BCR-ABL1- B-ALL (aged 14 to 65 years). Although 93% of patients achieved remission, 41% relapsed at a median of 13 months (range, 28 days to 12 years). Five-year overall survival (OS) was 42% (95% confidence interval, 39, 44). Transcriptome sequencing, gene expression profiling, cytogenetics, and fusion polymerase chain reaction enabled genomic subtyping of 282 patient samples, of which 264 were eligible for trial, accounting for 64.5% of E2993 patients. Among patients with outcome data, 29.5% with favorable outcomes (5-year OS 65% to 80%) were deemed standard risk (DUX4-rearranged [9.2%], ETV6-RUNX1/-like [2.3%], TCF3-PBX1 [6.9%], PAX5 P80R [4.1%], high-hyperdiploid [6.9%]); 50.2% had high-risk genotypes with 5-year OS of 0% to 27% (Ph-like [21.2%], KMT2A-AFF1 [12%], low-hypodiploid/near-haploid [14.3%], BCL2/MYC-rearranged [2.8%]); 20.3% had intermediate-risk genotypes with 5-year OS of 33% to 45% (PAX5alt [12.4%], ZNF384/-like [5.1%], MEF2D-rearranged [2.8%]). IKZF1 alterations occurred in 86% of Ph-like, and TP53 mutations in patients who were low-hypodiploid (54%) and BCL2/MYC-rearranged (33%) but were not independently associated with outcome. Of patients considered high risk based on presenting age and white blood cell count, 40% harbored subtype-defining genetic alterations associated with standard- or intermediate-risk outcomes. We identified distinct immunophenotypic features for DUX4-rearranged, PAX5 P80R, ZNF384-R/-like, and Ph-like genotypes. These data in a large adult B-ALL cohort treated with a non-risk-adapted approach on a single trial show the prognostic importance of genomic analyses, which may translate into future therapeutic benefits., (© 2021 by The American Society of Hematology.)

IKZF1 deletions (ΔIKZF1) are commonly detected in B-precursor acute lymphoblastic leukemia (ALL; B-ALL) and are widely assumed to have a significant impact on outcome. We compared the ability of multiplex ligand-dependent probe amplification (MLPA) and polymerase chain reaction (PCR) to detect ΔIKZF1 and to determine the impact on event-free survival of patients with precursor B-ALL aged 23 to 65 years recruited to the completed trial UKALL14 (ISRCTN 66541317). From 655 recruits with BCR-ABL1+ and BCR-ABL1- B-ALL, all available diagnostic DNA samples (76% of the recruited population) were screened by multiplex end point PCR covering 4 deletions: dominant-negative (DN) Δ4-7 or the loss of function Δ2-7, Δ4-8, and Δ2-8 (n = 498), MLPA (n = 436), or by both (n = 420). Although patients with BCR-ABL1- ΔIKZF1 were more likely to have minimal residual disease at the end of induction, we did not find any impact of ΔIKZF1 (including subgroup analysis for DN or loss-of-function lesions) or the IKZF1plus genotype on event-free, overall survival, or relapse risk by univariable or multivariable analyses. Consistent with the technical approach, MLPA not only detected a wider range of deletions than PCR but also failed to detect some PCR-detected lesions. The main difference between our study and others reporting an association between ΔIKZF1 and outcome is the older age of participants in our population. The impact of ΔIKZF1 in ALL may be less marked in an older population of patients. Our study underscores the need for analyses in large, harmonized data sets. This trial was registered at www.clinicaltrials.gov as #NCT01085617., (© 2021 by The American Society of Hematology.)

Objectives: Early tracheostomy (fewer than eight days after intubation) is associated with shorter length of stay in the intensive care unit and shorter duration of mechanical ventilation. Studies assessing the association between early tracheostomy and incidence of delirium, however, are lacking. This investigation sought to fill this gap., Design: Retrospective cross-sectional study., Setting: Multi-institutional acute care facilities in the United States., Participants: Data were derived from the National Inpatient Sample data from 2010 to 2014. Included patients were 65 or older and underwent both intubation and tracheostomy during the hospitalization. The authors excluded patients who underwent multiple intubations or tracheostomy procedures., Interventions: Early tracheostomy versus non-early tracheostomy., Results: In total, 23,310 patients were included, of whom 24.8% underwent early tracheostomy. From multivariate logistic regression, early tracheostomy was associated with lower odds of having a delirium diagnosis (odds ratio [OR] 0.77, p < 0.00001) across all admission classifications. Upon subgroup analysis, early tracheostomy was associated significantly with lower odds of having delirium for patients admitted with medical (OR 0.74, p < 0.00001) and nonsurgical injury admissions (OR 0.74, p = 0.00116)., Conclusions: Early tracheostomy was associated significantly with lower odds of delirium among all patients studied. This association held true across medical and nonsurgical subgroups., Competing Interests: Conflict of Interest None., (Published by Elsevier Inc.)

The SARS-CoV2 pandemic has created extreme shortages of N95 mask necessitating the need for rapid development of reuse and reprocessing plans. Our aim was to create a process to recapture, reprocess, and redistribute N95 masks using hydrogen peroxide vapor as a real time disinfection method within a large hospital system. We were able to recapture and reprocess 29, 706 N95 masks using hydrogen peroxide vapor with approximately 25% loss due to damage., (Copyright © 2020 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)