ImportanceWhether selective decontamination of the digestive tract (SDD) reduces mortality in critically ill patients remains uncertain.ObjectiveTo determine whether SDD reduces in-hospital mortality in critically ill adults.Design, Setting, and ParticipantsA cluster, crossover, randomized clinical trial that recruited 5982 mechanically ventilated adults from 19 intensive care units (ICUs) in Australia between April 2018 and May 2021 (final follow-up, August 2021). A contemporaneous ecological assessment recruited 8599 patients from participating ICUs between May 2017 and August 2021.InterventionsICUs were randomly assigned to adopt or not adopt a SDD strategy for 2 alternating 12-month periods, separated by a 3-month interperiod gap. Patients in the SDD group (n = 2791) received a 6-hourly application of an oral paste and administration of a gastric suspension containing colistin, tobramycin, and nystatin for the duration of mechanical ventilation, plus a 4-day course of an intravenous antibiotic with a suitable antimicrobial spectrum. Patients in the control group (n = 3191) received standard care.Main Outcomes and MeasuresThe primary outcome was in-hospital mortality within 90 days. There were 8 secondary outcomes, including the proportion of patients with new positive blood cultures, antibiotic-resistant organisms (AROs), and Clostridioides difficile infections. For the ecological assessment, a noninferiority margin of 2% was prespecified for 3 outcomes including new cultures of AROs.ResultsOf 5982 patients (mean age, 58.3 years; 36.8% women) enrolled from 19 ICUs, all patients completed the trial. There were 753/2791 (27.0%) and 928/3191 (29.1%) in-hospital deaths in the SDD and standard care groups, respectively (mean difference, −1.7% [95% CI, −4.8% to 1.3%]; odds ratio, 0.91 [95% CI, 0.82-1.02]; P = .12). Of 8 prespecified secondary outcomes, 6 showed no significant differences. In the SDD vs standard care groups, 23.1% vs 34.6% had new ARO cultures (absolute difference, −11.0%; 95% CI, −14.7% to −7.3%), 5.6% vs 8.1% had new positive blood cultures (absolute difference, −1.95%; 95% CI, −3.5% to −0.4%), and 0.5% vs 0.9% had new C difficile infections (absolute difference, −0.24%; 95% CI, −0.6% to 0.1%). In 8599 patients enrolled in the ecological assessment, use of SDD was not shown to be noninferior with regard to the change in the proportion of patients who developed new AROs (−3.3% vs −1.59%; mean difference, −1.71% [1-sided 97.5% CI, −∞ to 4.31%] and 0.88% vs 0.55%; mean difference, −0.32% [1-sided 97.5% CI, −∞ to 5.47%]) in the first and second periods, respectively.Conclusions and RelevanceAmong critically ill patients receiving mechanical ventilation, SDD, compared with standard care without SDD, did not significantly reduce in-hospital mortality. However, the confidence interval around the effect estimate includes a clinically important benefit.Trial RegistrationClinicalTrials.gov Identifier: NCT02389036

Introduction Evidence indicates HIV oral pre‐exposure prophylaxis (PrEP) is highly efficacious and effective. Substantial early discontinuation rates are reported by many programs, which may be misconstrued as program failure. However, PrEP use may be non‐continuous and still effective, since HIV risk fluctuates. Real‐world PrEP use phenomena, like restarting and cyclical use, and the temporal characteristics of these use patterns are not well described. The objective of our study was to characterize and identify predictors of use patterns observed in large PrEP scale‐up programs in Africa. Methods We analysed demographic and clinical data routinely collected during client visits between 2017 and 2019 in three Jhpiego‐supported programs in Kenya, Lesotho and Tanzania. We characterized duration on/off PrEP and, using ordinal regression, modelled the likelihood of spending additional time off and identified factors associated with increasing cycle number. The Andersen‐Gill model was used to identify predictors of time to PrEP discontinuation. To analyse factors associated with a client's first return following initiation, we used a two‐step Heckman probit. Results Among 47,532 clients initiating PrEP, approximately half returned for follow‐up. With each increase in cycle number, time off PrEP between use cycles decreased. The Heckman first‐step model showed an increased probability of returning versus not by older age groups and among key and vulnerable population groups versus the general population; in the second‐step model older age groups and key and vulnerable populations were less likely in Kenya, but more likely in Lesotho, to return on‐time (refill) versus delayed (restarting). Conclusions PrEP users frequently cycle on and off PrEP. Early discontinuation and delays in obtaining additional prescriptions were common, with broad predictive variability noted. Time off PrEP decreased with cycle number in all countries, suggesting normalization of use with experience. More nuanced measures of use are needed than exist for HIV treatment if effective use of PrEP is to be meaningfully measured. Providers should be equipped with measures and counselling messages that recognize non‐continuous and cyclical use patterns so that clients are supported to align fluctuating risk and use, and can readily restart PrEP after stopping, in effect empowering them further to make their own prevention choices.

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Glycolysis inhibition remains aspirational in cancer therapy. We recently described a promising phosphonate inhibitor of enolase for cancers harboring homozygous deletions of ENO1. Here, we describe the application of a nitroheterocycle phosphonoamidate pro-drug pair to capitalize on tumor hypoxia. This bioreducible prodrug exhibits greater-than 2-fold potency under hypoxic conditions compared to normoxia and exhibits robust stability in biological fluids. Our work provides strong in vitro proof-of-concept for using bioreduction as a pro-drug delivery strategy in the context of enolase inhibition.

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Background Among adult kidney transplant (KT) candidates, 21% are frail and 55% have cognitive impairment, increasing the risk of pre- and post-KT mortality. Centers often assess frailty status and cognitive function during transplant evaluation to help identify appropriate candidate. Yet, there are no ethical guidelines regarding the use of frailty and cognitive function during this evaluation. We seek to develop a clinical consensus on balancing utility and justice in access to KT for frail and cognitively impaired patients. Methods Twenty-seven experts caring for ESRD patients completed a two-round Delphi panel designed to facilitate consensus (> 80% agreement). Results Experts believed that denying patients transplantation based solely on expected patient survival was inequitable to frail or cognitively impaired candidates; 100% agreed that frailty and cognitive impairment are important factors to consider during KT evaluation. There was consensus that health related quality of life and social support are important to consider before waitlisting frail or cognitively impaired patients. Experts identified important factors to consider before waitlisting frail (likely to benefit from KT, frailty reversibility, age, and medical contraindications) and cognitively impaired (degree of impairment and medication adherence) patients. Conclusions Clinical experts believed it was ethically unacceptable to allocate organs solely based on patients’ expected survival; frailty and cognitive impairment should be measured at evaluation when weighed against other clinical factors. Ethical guidelines regarding the use of frailty and cognitive function during KT evaluation ought to be developed.

Cancers harboring homozygous deletion of the glycolytic enzyme enolase 1 (ENO1) are selectively vulnerable to inhibition of the paralogous isoform, enolase 2 (ENO2). A previous work described the sustained tumor regression activities of a substrate-competitive phosphonate inhibitor of ENO2, 1-hydroxy-2-oxopiperidin-3-yl phosphonate (HEX) (5), and its bis-pivaloyoxymethyl prodrug, POMHEX (6), in an ENO1-deleted intracranial orthotopic xenograft model of glioblastoma [Nature Metabolism 2020, 2, 1423−1426]. Due to poor pharmacokinetics of bis-ester prodrugs, this study was undertaken to identify potential non-esterase prodrugs for further development. Whereas phosphonoamidate esters were efficiently bioactivated in ENO1-deleted glioma cells, McGuigan prodrugs were not.Other strategies, including cycloSal and lipid prodrugs of 5, exhibited low micromolar IC 50 values in ENO1-deleted glioma cells and improved stability in human serum over 6. The activity of select prodrugs was also probed using the NCI-60 cell line screen, supporting its use to examine the relationship between prodrugs and cell line-dependent bioactivation.