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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. The primary outcome is 30-day all-cause mortality. The secondary outcomes are serious adverse reactions within 30 days; isolation precautions due to resistant bacteria within 30 days; days alive without life support and days alive and out of hospital within 30 and 90 days; 90- and 180-day all-cause mortality and 180-day health-related quality of life. EMPRESS will use Bayesian statistical models with weak to somewhat sceptical neutral priors. Adaptive analyses will be conducted after follow-up of the primary outcome for the first 400 participants concludes and after every 300 subsequent participants, with adaptive stopping for superiority/inferiority and practical equivalence (absolute risk difference <2.5%-points) and response-adaptive randomisation. The expected sample sizes in scenarios with no, small or large differences are 5189, 5859 and 2570 participants, with maximum 14,000 participants and ≥99% probability of conclusiveness across all scenarios., Conclusions: EMPRESS will compare the effects of empirical meropenem against piperacillin/tazobactam in adult, critically ill patients with sepsis. Due to the pragmatic, adaptive design with high probability of conclusiveness, the trial results are expected to directly inform clinical practice., (© 2024 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

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 (3.33/6.67/10 patients/day) under scenarios with no, small, and large differences. Simulations were conducted under a Bayesian framework, with constant stopping thresholds for superiority/inferiority calibrated to keep type-1 error rates at approximately 5%. We assessed multiple performance metrics, including mean sample sizes, event counts/probabilities, probabilities of conclusiveness, root mean squared errors (RMSEs) of the estimated effect in the selected arms, and RMSEs between the analyses at the time of stopping and the final analyses including data from all randomised patients. Performance metrics generally deteriorated when the proportions of randomised patients with available data were smaller due to longer outcome-data lags or faster inclusion, that is, mean sample sizes, event counts/probabilities, and RMSEs were larger, while the probabilities of conclusiveness were lower. Performance metric impairments with outcome-data lags ≤45 days were relatively smaller compared to those occurring with ≥60 days of lag. For most metrics, the effects of different outcome-data lags and lower proportions of randomised patients with available data were larger than those of different design choices, for example, the use of fixed versus response-adaptive randomisation. Increased outcome-data lag substantially affected the performance of adaptive trial designs. Trialists should consider the effects of outcome-data lags when planning adaptive trials., (© 2023 The Authors. Pharmaceutical Statistics published by John Wiley & Sons Ltd.)

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. Therefore, the MELA-PAED trial aims to investigate the efficacy and safety of intraoperative intravenous melatonin for the prevention of emergence agitation in pediatric surgical patients., Methods: MELA-PAED is a randomized, double-blind, parallel two-arm, multi-center, superiority trial comparing intravenous melatonin with placebo. Four hundred participants aged 1-6 years will be randomized 1:1 to either the intervention or placebo. The intervention consists of intravenous melatonin 0.15 mg/kg administered approximately 30 min before the end of surgery. Participants will be monitored in the post-anesthetic care unit (PACU), and the Post Hospitalization Behavior Questionnaire for Ambulatory Surgery (PHBQ-AS) will be performed on days 1, 7, and 14 after the intervention. Serious Adverse Events (SAE) will be assessed up to 30 days after the intervention., Results: The primary outcome is the incidence of emergence agitation, assessed dichotomously as any Watcha score >2 during the participant's stay in the post-anesthetic care unit. Secondary outcomes are opioid consumption in the post-anesthetic care unit and adverse events. Exploratory outcomes include SAEs, postoperative pain, postoperative nausea and vomiting, and time to awakening, to first oral intake, and to discharge readiness., Conclusion: The MELA-PAED trial investigates the efficacy of intravenous intraoperative melatonin for the prevention of emergence agitation in pediatric surgical patients. Results may provide further knowledge concerning the use of melatonin in pediatric perioperative care., (© 2023 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

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. This protocol outlines a simulation study that will gauge if the areas under the HRQoL trajectories could be a viable alternative., Methods: We will gauge the behaviour of the proposed HRQoL operationalisation through Monte Carlo simulations, under clinical scenarios that reflect a broad critical care population eligible for inclusion in a large pragmatic trial. We will simulate 15,360 clinical scenarios based on a full factorial design with the following seven simulation parameters: number of patients per arm, relative mortality reduction in the interventional arm, acceleration of HRQoL improvement in the interventional arm, the relative improvement in final HRQoL in the interventional arm, dampening effect of mortality on HRQoL values at discharge from the ICU, proportion of so-called mortality benefiters in the interventional arm and mortality trajectory shape. For each clinical scenario, we will simulate 100,000 two-arm trials with 1:1 randomisation. HRQoL will be sampled fortnightly after ICU discharge. Outcomes will include HRQoL in survivors and all patients at the end of follow-up; mean areas under the HRQoL trajectories in both arms; and mean difference between areas under the HRQoL trajectories and single-sampled HRQoLs at the end of follow-up., Discussion: In the outlined simulation study, we aim to assess whether the area under the HRQoL trajectory curve could be a candidate for reconciling the seemingly paradoxical effects on improved mortality and reduced HRQoL while remaining sensitive to early or accelerated improvement in patient outcomes. The resultant insights will inform subsequent methodological work on prudent collection and statistical analysis of such data from real critically ill patients., (© 2023 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

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. We thus aimed to assess the associations between DAWOLS and DAOOH and long-term HRQoL., Methods: Secondary analysis of the COVID STEROID 2 trial including adults with COVID-19 and severe hypoxaemia and the Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) trial including adult intensive care unit patients with acute hypoxaemic respiratory failure. Associations between DAWOLS and DAOOH at day 28 and 90 and long-term HRQoL (after 6 or 12 months) using the EuroQol 5-dimension 5-level survey (EQ VAS and EQ-5D-5L index values) were assessed using flexible models and evaluated using measures of fit and prediction adequacy in both datasets (comprising internal performance and external validation), non-parametric correlation coefficients and graphical presentations., Results: We found no strong associations between DAWOLS or DAOOH and HRQoL in survivors at HRQoL-follow-up (615 and 1476 patients, respectively). There was substantial variability in outcomes, and predictions from the best fitted models were poor both internally and externally in the other trial dataset, which also showed inadequate calibration. Moderate associations were found when including non-survivors, although predictions remained uncertain and calibration inadequate., Conclusion: DAWOLS and DAOOH were poorly associated with HRQoL in adult survivors of severe or critical illness included in the COVID STEROID 2 and HOT-ICU trials., (© 2023 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

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. We focused on readily available regression models of increasing complexity (linear, hurdle-negative binomial, zero-one-inflated beta, and cumulative logistic regression models) that allow comparison of multiple treatment arms, adjustment for covariates and interaction terms to assess treatment effect heterogeneity., Results: In general, the simpler models adequately estimated group means despite not fitting the data well enough to mimic the input data. The more complex models better fitted and thus better replicated the input data, although this came with increased complexity and uncertainty of estimates. While the more complex models can model separate components of the outcome distributions (i.e., the probability of having zero DAWOLS), this complexity means that the specification of interpretable priors in a Bayesian setting is difficult. Finally, we present multiple examples of how these outcomes may be visualised to aid assessment and interpretation., Conclusions: This summary of central methodological considerations when using, defining, and analysing DAWOLS and similar outcomes may help researchers choose the definition and analysis method that best fits their planned studies., Trial Registration: COVID STEROID 2 trial, ClinicalTrials.gov: NCT04509973, ctri.nic.in: CTRI/2020/10/028731., (© 2023. The Author(s).)

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. We cover pros and cons of different decisions and provide guidance on using simulation to compare different adaptive trial designs. We focus on Bayesian multi-arm adaptive trials, although the same general considerations apply to frequentist adaptive trials., Results: We provide guidance on 1) interventions and possible common control, 2) outcome selection, follow-up duration and model choice, 3) timing of adaptive analyses, 4) decision rules for adaptive stopping and arm dropping, 5) randomization strategies, 6) performance metrics, their prioritization, and arm selection strategies, and 7) simulations, assessment of performance under different scenarios, and reporting. Finally, we provide an example using a newly developed R simulation engine that may be used to evaluate and compare different adaptive trial designs., Conclusion: This overview may help trialists design better and more transparent adaptive clinical trials and to adequately compare them before initiation., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

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. Vaccination opportunities are missed due to multidose vials not being opened for a few children. We will assess the effect of making BCG available at the first health-facility contact on early infant mortality and morbidity in a rural setting in Guinea-Bissau., Methods and Analysis: In a cluster-randomised crossover trial, we randomise 23 health centres to two different treatment groups. In half of the health centres, BCG is provided as per current practice; in the remaining health centres, we make BCG available everyday to allow opening a vial of BCG if there is just one eligible child present. The randomisation of centres will be crossed over after 12 months and enrolment will continue for another 12 months.We will use logistic regression models with adjustment for village to assess the effect of making BCG available at the first health-facility contact. The main outcome is non-accidental mortality between day 1 and day 42 after birth. We will adjust for sex, health centre, period (before/after crossover) and level of surveillance (level 1 or level 2). Further analyses include assessment of the effect on hospital admission and a cost-effectiveness evaluation., Ethics and Dissemination: If BCG vaccination reduces early infant mortality, missed opportunities and delays of vaccinations expose infants in several low-income countries to unnecessary excess mortality risk. The present trial will provide information on the effect of implementing a feasible intervention, where all children receive BCG at their first health-facility contact. Consent is obtained from all pregnant women registered as part of the trial. The results of the study will be published and communicated to the National Institute of Public Health in Guinea-Bissau., Trial Registration Number: NCT04658680; Clinicaltrials.gov., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Methods: By simulating a multisite trial with 50 sites and 3278 participants, and a presumed six-month all-cause mortality of 60% in the control population, we will investigate the validity of the trial results with different levels of interaction effects on the outcome. The primary simulation outcome of the study is the risks of type-1 and type-2 errors in the simulated scenarios, i.e. at what level of interaction is the desired alpha and beta level exceeded. When keeping the overall risk of type-1 errors ≤ 5% and the risk of type-2 errors ≤ 10%, we will quantify the maximum interaction effect we can accept if the planned sample size is increased by 5% to take into account possible interaction between the trial interventions. Secondly, we will assess how interaction effects influence the minimal detectable difference we may confirm or reject to take into account 5% (small interaction effect), 10% (moderate), or 15% (large) positive interactions in simulations with no 'true' intervention effect (type-1 errors) and small (5%), moderate (10%), or large negative interactions (15%) in simulations with 'true' intervention effects (type-2 errors). Moreover, we will investigate how much the sample size must be increased to account for a small, moderate, or large interaction effects., Discussion: This protocol for a simulation study will inform the design of a 2×2×2 factorial randomised clinical trial of how potential interactions between the assessed interventions might affect conclusions. Protocolising this simulation study is important to ensure valid and unbiased results., Trial Registration: Not relevant., (© 2022. The Author(s).)

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., Setting: Nationwide study of Danish patients from 2000 to 2018., Patients: Male patients with International Classification of Diseases, 10th Revision (ICD-10) codes for ischemic heart disease (IHD), including those who had a continuing prescription for nitrates and a new, filled prescription for PDE5 inhibitors., Measurements: Two composite outcomes were measured: 1) cardiac arrest, shock, myocardial infarction, ischemic stroke, or acute coronary arteriography and 2) syncope, angina pectoris, or drug-related adverse event., Results: From 2000 to 2018, 249 541 male patients with IHD were identified. Of these, 42 073 patients had continuing prescriptions for nitrates. During this period, the prescription rate for PDE5 inhibitors in patients with IHD who were taking nitrates increased from an average of 0.9 prescriptions (95% CI, 0.5 to 1.2 prescriptions) per 100 persons per year in 2000 to 19.5 prescriptions (CI, 18.0 to 21.1 prescriptions) in 2018. No statistically significant association was found between the coprescription of nitrates with PDE5 inhibitors and the risk for either composite outcome (odds ratio [OR], 0.58 [CI, 0.28 to 1.13] for the first outcome and OR, 0.73 [CI, 0.40 to 1.32] for the second outcome)., Limitation: An assumption was made that concurrently filled prescriptions for nitrates and PDE5 inhibitors equaled concomitant use., Conclusion: From 2000 to 2018, the use of PDE5 inhibitors increased 20-fold among Danish patients with IHD who were taking nitrates. A statistically significant association between concomitant use of these medications and cardiovascular adverse events could not be identified., Primary Funding Source: Ib Mogens Kristiansens Almene Fond and Helsefonden.

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. HRQoL was assessed using EuroQol 5 dimensions 5 levels (EQ-5D-5L) questionnaire and EQ visual analogue scale score (EQ-VAS), and analyses were conducted in both survivors only and the intention-to-treat population with assignment of the worst scores to deceased patients., Results: We obtained 1-year vital status for 2887/2928 (98.6%), and HRQoL for 2600/2928 (88.8%) of the trial population. One year after randomisation, 707/1442 patients (49%) in the lower oxygenation group vs. 704/1445 (48.7%) in the higher oxygenation group had died (adjusted risk ratio 1.00; 95% confidence interval 0.93-1.08, p = 0.92). In total, 1189/1476 (80.4%) 1-year survivors participated in HRQoL interviews: median EQ-VAS scores were 65 (interquartile range 50-80) in the lower oxygenation group versus 67 (50-80) in the higher oxygenation group (p = 0.98). None of the five EQ-5D-5L dimensions differed between groups., Conclusion: Among adult ICU patients with severe hypoxaemia, a lower oxygenation target (8 kPa) did not improve survival or HRQoL at 1 year as compared to a higher oxygenation target (12 kPa)., (© 2022. Springer-Verlag GmbH Germany, part of Springer Nature.)

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. However, the associations between DAWOLS-DAAOOH and HRQoL are uncertain., Methods: We will assess associations between DAWOLS-DAAOOH at day 28 and 90 (independent variables/predictors) and HRQoL assessed using the EuroQol EQ-5D-5L questionnaire (EQ-VAS and EQ-5D-5L index values) at 6 or 12 months (dependent variables) in two RCTs: the COVID STEROID 2 RCT conducted in adult patients with COVID-19 and severe hypoxaemia and the Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) RCT conducted in adult intensive care patients with acute hypoxaemic respiratory failure. We will describe associations using best-fitting fractional polynomial transformations separately in each dataset, with the resulting models presented and assessed in both datasets graphically and using measures of fit and prediction adequacy (i.e., internal performance and external validation). We will use multiple imputation if missingness exceeds 5%., Discussion: The outlined study will provide important knowledge on the associations between DAWOLS-DAAOOH and HRQoL in adult critically ill patients, which may help researchers and clinical trialists prioritise and select outcomes in future RCTs conducted in this population., (© 2021 The Acta Anaesthesiologica Scandinavica Foundation.)

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. We will search 10 selected general and speciality journals for RCTs conducted in adult ICU patients from 2018 and onwards reporting at least 1 patient-important outcome other than mortality (including days alive without life support/days alive and out of hospital-type outcomes, health-related quality of life, functional/cognitive/neurological outcomes, and other general patient-important outcomes). We will summarise data on outcome measures and definitions, assessment time points, proportions and handling of death, proportions and handling of missing data, and effect measures and statistical methods used for analysis., Discussion: The outlined scoping review will provide an overview of choices, definitions and handling of patient-important outcomes other than mortality in contemporary RCTs conducted in adult ICU patients. This may guide discussions with patients and relatives, the design of future RCTs, and research on optimal outcome choices and handling., (© 2021 Acta Anaesthesiologica Scandinavica Foundation.)

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. Controlling for background factors using Cox proportional hazards models, survival was analyzed between 9 and 24 months of age. We measured the mortality rate ratio (MRR) to compare vaccination groups. Oral polio vaccine (OPV) campaigns, which started in 1995, reduced the mortality rate and reduced the difference between vaccination groups. In the main analysis, we therefore censored for OPV campaigns; there were 151 nonaccident deaths before the OPV campaigns., Results: Compared with MV administered alone (MV-only), DTP administered with or after MV had MRR 2.20 (1.31-3.70), and DTP-only had MRR 1.78 (1.01-3.11). Compared with MV-only, DTP administered with MV had a female-male MRR 0.56 (0.13-2.38), significantly different to DTP administered after MV, which had MRR 14.83 (1.88-117.1), test of interaction P = .011. Compared with having DTP (no MV) as most recent vaccination, MV-only had a nonaccident MRR of 0.56 (0.32-0.99)., Conclusion: The negative effects of non-live DTP with or after live MV are not explained merely by selection bias. These observations support a live-vaccine-last policy where DTP should not be given with or after MV., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

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. Binary regression models adjusting for potential confounding factors were applied to estimate relative risks (adjusted relative risks [aRRs]) of developing AD among children with delayed DTaP vaccination (defined as given 1 month or more after the recommended age) compared with timely vaccinated children., Results: Among 143,429 children with a delayed first dose of DTaP, 4,847 (3.4%) developed AD between age 4 months and 1 year, compared with 27,628 (3.7%) among 739,731 children not having delayed DTaP (aRR 0.94; 95% CI, 0.91-0.97). The aRR was 0.94 (95% CI, 0.90-0.99) for children with a delayed second dose, and the aRR was 0.88 (95% CI, 0.82-0.93) when comparing children with delayed first and second doses with all timely vaccinated children., Conclusions: The results support the hypothesis that delayed vaccination with DTaP is associated with reduced risk of developing new cases of AD after age 4 months. The dose-dependent relationship strengthens the evidence of a causal relationship. Some countries are introducing maternal pertussis vaccination and delaying the first dose of DTaP, providing a possibility for further testing the hypothesis., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

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- Haemophilus influenzae type b) . We therefore investigated whether Penta vaccinations were associated with excess female deaths in rural Bangladesh. Between June 29, 2011 and April 20, 2016, we examined the mortality rates of 7644 children followed between 6 weeks and 9 months of age. We analyzed mortality using crude mortality rate ratio (MRR) and age-adjusted MRR (aMRR) from a Cox proportional hazards model. Mortality was analyzed according to sex, number of doses of Penta, and the order in which BCG and Penta were administered. During follow-up, 43 children died. For children who were only BCG vaccinated (BCG-only), the adjusted F/M MRR was 0.47 (0.09-2.48). However, among children who had Penta as their most recent vaccination, the adjusted F/M MRR was 9.91 (1.16-84.44). Hence, the adjusted F/M MRR differed significantly for BCG-only and for Penta as the most recent administered vaccination. Although the mortality rate was low in rural Bangladesh, there was a marked difference between adjusted F/M MRR's for children vaccinated with BCG-only compared with children where Penta was the most recent administered vaccination. Although usually ascribed to differential treatment and access to care, DTP-containing vaccines may be part of the explanation for the excessive female mortality reported in some regions.

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. In log-binomial models, we estimated the relative risk (RR) of nonaccidental outpatient consultations., Results: Among 8319 children (4437 intervention/3882 control), 652 nonaccidental outpatient consultations occurred (322 intervention/330 control). The measles vaccination campaign tended to reduce nonaccidental outpatient consultations by 16% (RR, 0.84 [95% confidence interval {CI}, .65-1.11]), especially if caused by respiratory symptoms (RR, 0.68 [95% CI, .42-1.11]). The reduction tended to be larger in children who prior to trial enrollment had a pentavalent vaccination (diphtheria, tetanus, pertussis, hepatitis B, and Haemophilus influenzae type b) as the most recent vaccination (RR, 0.61 [95% CI, .42-.89]) than in children who prior to trial enrollment had a routine measles vaccination as the most recent vaccination (RR, 0.93 [95% CI, .68-1.26]) (P = .04 for interaction)., Conclusions: In the short term, a measles vaccination campaign seems not to increase nonaccidental outpatient consultations but may reduce them., Clinical Trials Registration: NCT03460002., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., Methods: In a randomized controlled trial (RCT) of early MV in children aged 4.5 months, the BCG-scar status of the children and their mother were registered at enrollment at 4.5 months of age. The children were followed up until they were 36 months of age. Using a Cox proportional hazards model, we compared mortality rate ratios according to maternal and child BCG-scar status after adjusting for where the BCG vaccine was given (the national hospital or elsewhere). We censored for other interventions that have immunomodulating effects on child survival, including neonatal vitamin A supplementation and early MV., Results: A total of 2213 children had not received neonatal vitamin A supplementation and early MV; 83% of these children and 44% of the mothers had a BCG scar. Children whose mother had a BCG scar were not more likely to have a BCG scar than those whose mother did not have a BCG scar (risk ratio, 1.01 [95% confidence interval (CI), 0.98-1.05]). Among the children, having a BCG scar was associated with a 41% (95% CI, 5%-64%) lower mortality between the ages of 4.5 and 36 months. The reduction in mortality was 66% (95% CI, 33%-83%) if the mother also had a BCG scar but only 8% (95% CI, -83% to 53%) if the mother had no BCG scar (test of interaction, P = .04)., Conclusions: Maternal BCG priming might be important for the effect of BCG vaccination on child survival. Ensuring better BCG vaccine scarring among mothers and children could have a considerable effect on child mortality levels., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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 4.5 + 9 months or MV at 9 months as recommended. At enrolment and 9 months children had their mid-upper-arm-circumference (MUAC) and weight measured. Consultations (out/inpatient) were registered at monthly home visits. Weight-for-age and MUAC-for-age Z-scores were obtained using the WHO growth reference and compared by group in linear regression models. Consultation rates between enrolment and 9 months were compared in Cox proportional hazards models, providing consultation Hazard Ratios (HRs) for early MV versus no early MV. We tested whether the effect of early MV was modified by OPV campaigns by splitting observation time at exposure to OPV campaigns., Results: Among 3548 children enrolled between 2012 and 2015, early MV had no effect on MUAC-for-age (mean difference comparing early MV vs. no MV -0.01, 95% CI -0.06-0.04), weight-for-age (mean difference -0.03, 95% CI -0.07-0.02) or rates of consultations (HR = 1.03, 95% CI 0.92-1.16). The rate of consultations for children enrolled was lower after exposure to OPV campaigns (HR = 0.81, 95% CI 0.71-0.92). The effect of MV differed before exposure to OPV campaigns (HR = 1.12, 95% CI 0.98-1.29) and after OPV campaigns (HR = 0.83, 95% CI 0.67-1.03) (test for interaction: p = 0.03). Associations did not differ by sex., Conclusion: Early MV had no overall effect on consultation rates and growth between enrolment and 9 months of age. However, early MV tended to have beneficial effects for children subsequently exposed to OPV campaigns. As beneficial effects were observed in subgroups, the results should be interpreted with caution., Clinical Trials Registration: NCT01644721., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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. We assessed discrimination, calibration and overall performance of the SMS-ICU and compared discrimination with the commonly used and more complex SAPS II and SOFA scores., Results: Mortality at day 90 was 30.7%. The discrimination (area under the receiver operating characteristic curve) for the SMS-ICU was 0.67 (95% CI: 0.65-0.69), as compared with 0.68 (95% CI: 0.66-0.70, P = 0.35) for SAPS II and 0.63 (95% CI: 0.61-0.65, P < 0.001) for the SOFA score. Calibration (intercept and slope) was 0.001 and 0.786, respectively, and Nagelkerke's R 2 (overall performance) was 0.06. The proportions of missing data for the SMS-ICU, SAPS II and SOFA scores were 0.2%, 8.5% and 6.8%, respectively., Conclusions: Discrimination for 90-day mortality of the SMS-ICU in this cohort was poor, but similar to SAPS II and better than that of the SOFA score with markedly less missing data., (© 2019 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

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. Infants are enrolled at a home visit before 72 hours of life. In intervention clusters, children are vaccinated with BCG and oral polio vaccine (OPV). In control clusters, the caregivers are informed about vaccination opportunities. Using Cox-proportional hazards models, we will test whether BCG and OPV provided at a single home visit can reduce early infant mortality up to 60 days.The trial was initiated with a pilot study in Biombo region in June 2015. The trial was scaled up to full study including Oio and Cacheu regions in July 2016. The trial was expanded to include the urban study area in July 2017., Ethics and Dissemination: BCG vaccination is delayed in many low-income settings. WHO-recommended home visits are resource demanding and vaccines are not part of the recommendation. Utilising the home visits to provide BCG and OPV may provide countries with a further incentive to introduce a single home visit. In countries, where home visits are already in place, vaccines can easily be added to reduce early infant mortality. The trial is approved by the Guinean Ethical Committee (Reference number: 0016/CNES/INASA/2015) and the Danish Ethics Committee has given its consultative approval. The results of the trial will be published in international peer-reviewed journals., Trial Registration Number: NCT02504203; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Areas Covered: We discuss the limitations of using RCTs only as a tool to evaluate NSEs of vaccines. Such RCTs can be ethically problematic, they are time consuming and expensive. Furthermore, they only assess the NSEs in a given context, but it is inherent in the concept of NSEs that the NSEs of a given vaccine are modified by other immunomodulatory conditions. As an alternative, we propose that triangulation of RCTs and observational studies, merging multiple lines of evidence with different underlying bias structures, can build a strong argument for causality. We examine two examples related to measles vaccine and oral polio vaccine., Expert Commentary: Using RCTs alone to evaluate NSEs of vaccines severely limits the possibilities for studying NSEs. Results from both RCTs and non-RCT studies should be triangulated to strengthen causal interpretation.

Background: Recurrent wheeze (RW) is frequent in childhood. Studies have suggested that BCG vaccination can have nonspecific effects, reducing general nontuberculosis morbidity, including respiratory tract infections and atopic diseases. The mechanisms behind these nonspecific effects of BCG are not fully understood, but a shift from a T H 2 to a T H 1 response has been suggested as a possible explanation., Objective: We hypothesized that BCG at birth would reduce the cumulative incidence of RW during the first year of life., Methods: The Danish Calmette Study is a multicenter randomized trial conducted from 2012-2015 at 3 Danish hospitals. The 4262 newborns of 4184 included mothers were randomized 1:1 to BCG (SSI strain 1331) or to a no-intervention control group within 7 days of birth; siblings were randomized together as one randomization unit. Exclusion criteria were gestational age of less than 32 weeks, birth weight of less than 1000 g, known immunodeficiency, or no Danish-speaking parent. Information was collected through telephone interviews and clinical examinations at 3 and 13 months of age; data collectors were blind to randomization group. RW was defined in several ways, with the main definition being physician-diagnosed and medically treated RW up to 13 months of age., Results: By 13 months, 211 (10.0%) of 2100 children in the BCG group and 195 (9.4%) of 2071 children in the control group had received a diagnosis of RW from a medical doctor and received antiasthma treatment (relative risk, 1.07; 95% CI, 0.89-1.28). Supplementary analyses were made, including an analysis of baseline risk factors for development of RW., Conclusion: Neonatal BCG had no effect on the development of RW before 13 months of age., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Vaccination with Bacillus Calmette-Guérin (BCG) is used in many countries as protection against tuberculosis. Studies have suggested that BCG may also have non-specific effects, reducing non-tuberculosis mortality, morbidity, and atopic manifestations. In this study, we evaluated the effect of neonatal BCG vaccination on allergic sensitization and suspected food allergy at 13 months of age., Methods: The Danish Calmette Study was conducted from 2012 to 2015 at three Danish hospitals. Within 7 days of birth, the 4262 newborns of 4184 included mothers were randomized 1:1 to BCG or to a no-intervention control group. Exclusion criteria were gestational age <32 weeks, birth weight <1000 g, known immunodeficiency, or no Danish-speaking parent. Follow-up information was collected through telephone interviews at 3 and 13 months of age. Subgroups of participants were offered blood sampling at 13 months of age., Results: By 13 months of age, the parents and/or general practitioners of 5.6% (117/2089) of the children in the BCG group and 6.1% (126/2061) of the control group suspected food allergy, resulting in a risk ratio comparing BCG-vaccinated children with control children of 0.91 (95% CI 0.71-1.16). Among 1370 blood samples, sensitization (Phadiatop Infant >0.35 kUA/L) was found in 55 of 743 (7.4%) children in the BCG group and 50 of 627 (8.0%) of the control group (risk ratio 0.94 [0.65-1.36])., Conclusion: In this randomized clinical trial, neonatal BCG had no significant effect on suspected food allergy or on sensitization at 13 months of age., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Measles vaccine (MV) may have non-specific beneficial effects for child health and particularly seems to prevent respiratory infections. Streptococcus pneumoniae is the leading cause of bacterial pneumonia among children worldwide, and nasopharyngeal colonization precedes infection., Objective: We investigated whether providing early MV at 18 weeks of age reduced pneumococcal colonization and/or density up to 9 months of age., Method: The study was conducted in 2013-2014 in Guinea-Bissau. Pneumococcal vaccine was not part of the vaccination program. Infants aged 18 weeks were block-randomized 2:1 to early or no early MV; at age 9 months, all children were offered MV as per current policy. Nasopharyngeal swabs were taken at baseline, age 6.5 months, and age 9 months. Pneumococcal density was determined by q-PCR. Prevalence ratios of pneumococcal colonization and recent antibiotic treatment (yes/no) by age 6.5 months (PR6.5) and age 9 months (PR9) were estimated using Poisson regression with robust variance estimates while the pneumococcal geometric mean ratio (GMR6.5 and GMR9) was obtained using OLS regression., Results: Analyses included 512 children; 346 early MV-children and 166 controls. At enrolment, the pneumococcal colonization prevalence was 80% (411/512). Comparing early MV-children with controls, the PR6.5 was 1.02 (95%CI = 0.94-1.10), and the PR9 was 1.04 (0.96-1.12). The GMR6.5 was 1.02 (0.55-1.89), and the GMR9 was 0.69 (0.39-1.21). Early MV-children tended to be less frequently treated with antibiotics prior to follow up (PR6.5 0.60 (0.34-1.05) and PR9 0.87 (0.50-1.53)). Antibiotic treatment was associated with considerably lower colonization rates, PR6.5 0.85 (0.71-1.01) and PR9 0.66 (0.52-0.84), as well as lower pneumococcal density, GMR6.5 0.32 (0.12-0.86) and GMR9 0.52 (0.18-1.52)., Conclusion: Early MV at age 18 weeks had no measurable effect on pneumococcal colonization prevalence or density. Higher consumption of antibiotics among controls may have blurred an effect of early MV., Trial Registration: clinicaltrials.gov NCT01486355.

Introduction: Mortality prediction scores are widely used in intensive care units (ICUs) and in research, but their predictive value deteriorates as scores age. Existing mortality prediction scores are imprecise and complex, which increases the risk of missing data and decreases the applicability bedside in daily clinical practice. We propose the development and validation of a new, simple and updated clinical prediction rule: the Simplified Mortality Score for use in the Intensive Care Unit (SMS-ICU)., Methods and Analysis: During the first phase of the study, we will develop and internally validate a clinical prediction rule that predicts 90-day mortality on ICU admission. The development sample will comprise 4247 adult critically ill patients acutely admitted to the ICU, enrolled in 5 contemporary high-quality ICU studies/trials. The score will be developed using binary logistic regression analysis with backward stepwise elimination of candidate variables, and subsequently be converted into a point-based clinical prediction rule. The general performance, discrimination and calibration of the score will be evaluated, and the score will be internally validated using bootstrapping. During the second phase of the study, the score will be externally validated in a fully independent sample consisting of 3350 patients included in the ongoing Stress Ulcer Prophylaxis in the Intensive Care Unit trial. We will compare the performance of the SMS-ICU to that of existing scores., Ethics and Dissemination: We will use data from patients enrolled in studies/trials already approved by the relevant ethical committees and this study requires no further permissions. The results will be reported in accordance with the Transparent Reporting of multivariate prediction models for Individual Prognosis Or Diagnosis (TRIPOD) statement, and submitted to a peer-reviewed journal., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

The case-time-control design is an extension of the case-crossover design capable of handling time trends in the exposure of the general population. Time-invariant confounders are controlled for by the design itself. The idea is to compare the exposure status of a person in one or several reference periods during which no event occurred with the exposure status of the same person in the index period where the event occurred. By comparing case-crossover results in cases to case-crossover results in controls, the exposure-outcome association can be estimated by conditional logistic regression. We review the mathematical assumptions underlying the case-time-control design and examine sensitivity to deviations from the assumed independence of within-individual exposure history. Results from simulating various scenarios suggest that the design is quite robust to deviations from this model assumption. In addition, we show that changes in exposure probability over time can be modeled in a flexible way using splines.