Empirical meropenem versus piperacillin/tazobactam for adult patients with sepsis (EMPRESS) trial: Protocol.

Background: Piperacillin/tazobactam may be associated with less favourable outcomes than carbapenems in patients with severe bacterial infections, but the certainty of evidence is low.

Methods: The Empirical Meropenem versus Piperacillin/Tazobactam for Adult Patients with Sepsis (EMPRESS) trial is an investigator-initiated, international, parallel-group, randomised, open-label, adaptive clinical trial with an integrated feasibility phase. We will randomise adult, critically ill patients with sepsis to empirical treatment with meropenem or piperacillin/tazobactam for up to 30 days.

Intravenous MELAtonin for prevention of Postoperative Agitation and Emergence Delirium in children (MELA-PAED): A protocol and statistical analysis plan for a randomized clinical trial.

Background: Emergence agitation and delirium in children remain a common clinical challenge in the post-anesthetic care unit. Preoperative oral melatonin has been suggested as an effective preventive drug with a favorable safety profile. The oral bioavailability of melatonin, however, is low.

Effects of duration of follow-up and lag in data collection on the performance of adaptive clinical trials.

Different combined outcome-data lags (follow-up durations plus data-collection lags) may affect the performance of adaptive clinical trial designs. We assessed the influence of different outcome-data lags (0-105 days) on the performance of various multi-stage, adaptive trial designs (2/4 arms, with/without a common control, fixed/response-adaptive randomisation) with undesirable binary outcomes according to different inclusion rates (3.33/6.

Health-related quality of life trajectories in critical illness: Protocol for a Monte Carlo simulation study.

Background: Health-related quality of life (HRQoL) is a patient-centred outcome increasingly used as a secondary outcome in critical care research. It may cover several important dimensions of clinical status in intensive care unit (ICU) patients that arguably elude other more easily quantified outcomes such as mortality. Poor associations with harder outcomes, conflicting data on HRQoL in critically ill compared to the background population, and paradoxical effects on HRQoL and mortality complicate the current operationalisation in critical care trials.

Use of days alive without life support and similar count outcomes in randomised clinical trials - an overview and comparison of methodological choices and analysis methods.

Background: Days alive without life support (DAWOLS) and similar outcomes that seek to summarise mortality and non-mortality experiences are increasingly used in critical care research. The use of these outcomes is challenged by different definitions and non-normal outcome distributions that complicate statistical analysis decisions.

Methods: We scrutinized the central methodological considerations when using DAWOLS and similar outcomes and provide a description and overview of the pros and cons of various statistical methods for analysis supplemented with a comparison of these methods using data from the COVID STEROID 2 randomised clinical trial.

Association between days alive without life support/out of hospital and health-related quality of life.

Background: Trials in critically ill patients increasingly focus on days alive without life support (DAWOLS) or days alive out of hospital (DAOOH) and health-related quality of life (HRQoL). DAWOLS and DAOOH convey more information than mortality and are simpler and faster to collect than HRQoL. However, whether these outcomes are associated with HRQoL is uncertain.

Can BCG vaccination at first health-facility contact reduce early infant mortality? Study protocol for a cluster-randomised trial (CS-BCG).

Introduction: Increasing evidence suggests that the BCG vaccine has non-specific effects, altering the susceptibility to non-tuberculous infections. Thus, early BCG vaccination may reduce mortality. BCG is recommended at birth but is often delayed.

An overview of methodological considerations regarding adaptive stopping, arm dropping, and randomization in clinical trials.

Background And Objectives: Adaptive features may increase flexibility and efficiency of clinical trials, and improve participants' chances of being allocated to better interventions. Our objective is to provide thorough guidance on key methodological considerations for adaptive clinical trials.

Methods: We provide an overview of key methodological considerations for clinical trials employing adaptive stopping, adaptive arm dropping, and response-adaptive randomization.

Interactions in the 2×2×2 factorial randomised clinical STEPCARE trial and the potential effects on conclusions: a protocol for a simulation study.

Background: Randomised clinical trials with a factorial design may assess the effects of multiple interventions in the same population. Factorial trials are carried out under the assumption that the trial interventions have no interactions on outcomes. Here, we present a protocol for a simulation study investigating the consequences of different levels of interactions between the trial interventions on outcomes for the future 2×2×2 factorial designed randomised clinical Sedation, TEmperature, and Pressure after Cardiac Arrest and REsuscitation (STEPCARE) trial in comatose patients after out-of-hospital cardiac arrest.

Long-term mortality and health-related quality of life of lower versus higher oxygenation targets in ICU patients with severe hypoxaemia.

Purpose: We assessed outcomes after 1 year of lower versus higher oxygenation targets in intensive care unit (ICU) patients with severe hypoxaemia.

Methods: Pre-planned analyses evaluating 1-year mortality and health-related quality-of-life (HRQoL) outcomes in the previously published Handling Oxygenation Targets in the ICU trial which randomised 2928 adults with acute hypoxaemia to targets of arterial oxygen of 8 kPa or 12 kPa throughout the ICU stay up to 90 days. One-year all-cause mortality was assessed in the intention-to-treat population.

Adverse Events Associated With Coprescription of Phosphodiesterase Type 5 Inhibitors and Oral Organic Nitrates in Male Patients With Ischemic Heart Disease : A Case-Crossover Study.

Background: Concomitant use of oral organic nitrates (nitrates) and phosphodiesterase type 5 (PDE5) inhibitors is contraindicated.

Objective: To measure temporal trends in the coprescription of nitrates and PDE5 inhibitors and to measure the association between cardiovascular outcomes and the coprescription of nitrates with PDE5 inhibitors.

Design: Case-crossover design.

Health-related quality of life and days alive without life support or out of hospital: Protocol.

Background: Mortality is often the primary outcome in randomised clinical trials (RCTs) conducted in critically ill patients. Due to increased awareness on survivors after critical illness and outcomes other than mortality, health-related quality of life (HRQoL) and days alive without life support (DAWOLS) or days alive and out of hospital (DAAOOH) are increasingly being used. DAWOLS and DAAOOH convey more information than mortality, are easier to collect than HRQoL, and are usually assessed at earlier time points, which may be preferable in some situations.

Patient-important outcomes other than mortality in recent ICU trials: Protocol for a scoping review.

Background: Randomised clinical trials (RCTs) conducted in intensive care units (ICUs) frequently focus on all-cause mortality, but other patient-important outcomes are increasingly used and recommended. Their use, however, is not straightforward: choices and definitions, operationalisation of death, handling of missing data, choice of effect measures, and statistical analyses for these outcomes vary greatly.

Methods: We will conduct a scoping review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews.

Timeliness of DTaP-IPV-Hib Vaccination and Development of Atopic Dermatitis Between 4 Months and 1 Year of Age-Register-Based Cohort Study.

Background: An Australian study including 4433 children found that delayed Diphtheria-Tetanus-acellular Pertussis-containing vaccination was associated with reduced risk of developing atopic dermatitis (AD) before age 1 year.

Objective: We assessed whether delayed vaccination against diphtheria, tetanus, acellular pertussis, polio, and Haemophilus influenzae type b (Diphtheria, Tetanus, acellular Pertussis - Inactivated Polio vaccine - Haemophilus influenzae type b [DTaP]) was associated with a reduced risk of new cases of AD before age 1 year in Denmark.

Methods: We used nationwide registers to follow 883,160 children born in Denmark from 1997 to 2012.

Using BCG vaccine to enhance non-specific protection of health care workers during the COVID-19 pandemic: A structured summary of a study protocol for a randomised controlled trial in Denmark.

Objectives: The Bacille Calmette-Guérin (BCG) vaccine against tuberculosis is associated with non- specific protective effects against other infections, and significant reductions in all-cause morbidity and mortality have been reported. We aim to test whether BCG vaccination may reduce susceptibility to and/or the severity of COVID-19 and other infectious diseases in health care workers (HCW) and thus prevent work absenteeism.The primary objective is to reduce absenteeism due to illness among HCW during the COVID-19 pandemic.

Reduction in Short-term Outpatient Consultations After a Campaign With Measles Vaccine in Children Aged 9-59 Months: Substudy Within a Cluster-Randomized Trial.

Background: We assessed a measles vaccination campaign's potential short-term adverse events.

Methods: In a cluster-randomized trial assessing a measles vaccination campaign's effect on all-cause mortality and hospital admission among children aged 9-59 months in Guinea-Bissau, children received a measles vaccination (intervention) or a health check-up (control). One month to 2 months later, we visited a subgroup of children to ask mothers/guardians about outpatient consultations since enrollment.

Penta is associated with an increased female-male mortality ratio: cohort study from Bangladesh.

Diphtheria-tetanus-pertussis (DTP) vaccine may be associated with excess female deaths. There are few studies of possible nonspecific effects of the DTP-containing vaccine Penta (DTP-hepatitis B- influenzae type . We therefore investigated whether Penta vaccinations were associated with excess female deaths in rural Bangladesh.

Out-of-Sequence Vaccinations With Measles Vaccine and Diphtheria-Tetanus-Pertussis Vaccine: A Reanalysis of Demographic Surveillance Data From Rural Bangladesh.

Background: Due to delays in vaccinations, diphtheria-tetanus-whole-cell-pertussis (DTP) is often given with or after measles vaccine (MV)-out of sequence. We reanalyzed data from Matlab, Bangladesh, to examine how administration of MV and DTP out-of-sequence was associated with child survival.

Methods: In sum, 36 650 children born between 1986 and 1999 were followed with registration of vaccinations and survival.

The effect of early measles vaccination on morbidity and growth: A randomised trial from Guinea-Bissau.

Background: Measles vaccine (MV) has beneficial non-specific effects protecting against non-measles infections in some situations. Within a trial of the effect of MV on mortality, we assessed effects of early MV on the secondary outcomes consultations and growth, overall, and by sex and exposure to campaigns with oral polio vaccine (OPV).

Materials And Methods: Children were randomly assigned to MV at 4.

Correction: Effect of early measles vaccine on pneumococcal colonization: A randomized trial from Guinea-Bissau.

[This corrects the article DOI: 10.1371/journal.pone.

Can earlier BCG vaccination reduce early infant mortality? Study protocol for a cluster randomised trial in Guinea-Bissau.

Introduction: The BCG vaccine is designed to protect against tuberculosis, but the vaccine may have broader effects. In 2014, the Strategic Advisory Group of Experts on Immunization reviewed the literature on non-specific effects of BCG, and concluded that the evidence was consistent with beneficial non-specific effects and requested further randomised trials.

Methods And Analyses: Within the Bandim Health Project's urban and rural health and demographic surveillance systems, we will conduct a cluster-randomised trial in six suburban districts and 55 rural villages.

External validation of the Simplified Mortality Score for the Intensive Care Unit (SMS-ICU).

Background: The Simplified Mortality Score for the Intensive Care Unit (SMS-ICU) is a clinical prediction model, which estimates the risk of 90-day mortality in acutely ill adult ICU patients using 7 readily available variables. We aimed to externally validate the SMS-ICU and compare its discrimination with existing prediction models used with 90-day mortality as the outcome.

Methods: We externally validated the SMS-ICU using data from 3282 patients included in the Stress Ulcer Prophylaxis in the Intensive Care Unit trial, which randomised acutely ill adult ICU patients with risk factors for gastrointestinal bleeding to prophylactic pantoprazole or placebo in 33 ICUs in Europe.

Maternal Priming: Bacillus Calmette-Guérin (BCG) Vaccine Scarring in Mothers Enhances the Survival of Their Child With a BCG Vaccine Scar.

Background And Hypothesis: Maternal priming might enhance the beneficial nonspecific effects (NSEs) of live measles vaccination (MV). Children with a bacillus Calmette-Guérin (BCG) vaccine scar have a lower mortality rate than those without a scar that is not explained by protection against tuberculosis. We examined the hypothesis that BCG scarring would have a stronger effect on a child if the mother also had a BCG scar.

How to evaluate potential non-specific effects of vaccines: the quest for randomized trials or time for triangulation?

Introduction: Emerging evidence suggests that vaccines, in addition to their disease-specific effects, have important non-specific effects (NSEs), which contribute to their overall effect on mortality and morbidity. Immunological studies have shown that NSEs are biologically plausible. Many advocate that randomized controlled trials (RCTs) with overall mortality or morbidity as the outcome are the only way forward to confirm or refute NSEs.