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The use of azithromycin reduces maternal infection in women during unplanned cesarean delivery, but its effect on those with planned vaginal delivery is unknown. Data are needed on whether an intrapartum oral dose of azithromycin would reduce maternal and offspring sepsis or death. In this multicountry, placebo-controlled, randomized trial, we assigned women who were in labor at 28 weeks' gestation or more and who were planning a vaginal delivery to receive a single 2-g oral dose of azithromycin or placebo. The two primary outcomes were a composite of maternal sepsis or death and a composite of stillbirth or neonatal death or sepsis. During an interim analysis, the data and safety monitoring committee recommended stopping the trial for maternal benefit. A total of 29,278 women underwent randomization. The incidence of maternal sepsis or death was lower in the azithromycin group than in the placebo group (1.6% vs. 2.4%), with a relative risk of 0.67 (95% confidence interval [CI], 0.56 to 0.79; P<0.001), but the incidence of stillbirth or neonatal death or sepsis was similar (10.5% vs. 10.3%), with a relative risk of 1.02 (95% CI, 0.95 to 1.09; P = 0.56). The difference in the maternal primary outcome appeared to be driven mainly by the incidence of sepsis (1.5% in the azithromycin group and 2.3% in the placebo group), with a relative risk of 0.65 (95% CI, 0.55 to 0.77); the incidence of death from any cause was 0.1% in the two groups (relative risk, 1.23; 95% CI, 0.51 to 2.97). Neonatal sepsis occurred in 9.8% and 9.6% of the infants, respectively (relative risk, 1.03; 95% CI, 0.96 to 1.10). The incidence of stillbirth was 0.4% in the two groups (relative risk, 1.06; 95% CI, 0.74 to 1.53); neonatal death within 4 weeks after birth occurred in 1.5% in both groups (relative risk, 1.03; 95% CI, 0.86 to 1.24). Azithromycin was not associated with a higher incidence in adverse events. Among women planning a vaginal delivery, a single oral dose of azithromycin resulted in a significantly lower risk of maternal sepsis or death than placebo but had little effect on newborn sepsis or death. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; A-PLUS ClinicalTrials.gov number, NCT03871491.).

Observational studies have suggested that accelerated surgery is associated with improved outcomes in patients with a hip fracture. The HIP ATTACK trial assessed whether accelerated surgery could reduce mortality and major complications. HIP ATTACK was an international, randomised, controlled trial done at 69 hospitals in 17 countries. Patients with a hip fracture that required surgery and were aged 45 years or older were eligible. Research personnel randomly assigned patients (1:1) through a central computerised randomisation system using randomly varying block sizes to either accelerated surgery (goal of surgery within 6 h of diagnosis) or standard care. The coprimary outcomes were mortality and a composite of major complications (ie, mortality and non-fatal myocardial infarction, stroke, venous thromboembolism, sepsis, pneumonia, life-threatening bleeding, and major bleeding) at 90 days after randomisation. Patients, health-care providers, and study staff were aware of treatment assignment, but outcome adjudicators were masked to treatment allocation. Patients were analysed according to the intention-to-treat principle. This study is registered at ClinicalTrials.gov (NCT02027896). Between March 14, 2014, and May 24, 2019, 27 701 patients were screened, of whom 7780 were eligible. 2970 of these were enrolled and randomly assigned to receive accelerated surgery (n=1487) or standard care (n=1483). The median time from hip fracture diagnosis to surgery was 6 h (IQR 4–9) in the accelerated-surgery group and 24 h (10–42) in the standard-care group (p<0·0001). 140 (9%) patients assigned to accelerated surgery and 154 (10%) assigned to standard care died, with a hazard ratio (HR) of 0·91 (95% CI 0·72 to 1·14) and absolute risk reduction (ARR) of 1% (−1 to 3; p=0·40). Major complications occurred in 321 (22%) patients assigned to accelerated surgery and 331 (22%) assigned to standard care, with an HR of 0·97 (0·83 to 1·13) and an ARR of 1% (−2 to 4; p=0·71). Among patients with a hip fracture, accelerated surgery did not significantly lower the risk of mortality or a composite of major complications compared with standard care. Canadian Institutes of Health Research.

B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common childhood cancer. Despite a high overall cure rate, relapsed B-cell ALL remains a leading cause of cancer-related death among children. The addition of the bispecific T-cell engager molecule blinatumomab (an anti-CD19 and anti-CD3 single-chain molecule) to therapy for newly diagnosed standard-risk (as defined by the National Cancer Institute) B-cell ALL in children may improve outcomes. We conducted a phase 3 trial involving children with newly diagnosed standard-risk B-cell ALL who had an average or higher risk of relapse. Patients were randomly assigned to receive chemotherapy alone or chemotherapy plus two nonsequential 28-day cycles of blinatumomab. The primary end point was disease-free survival. The data and safety monitoring committee reviewed the results from the first interim efficacy analysis, which included 1440 patients who had undergone randomization (722 to chemotherapy alone and 718 to blinatumomab and chemotherapy) and recommended early termination of randomization. At a median follow-up of 2.5 years, the estimated 3-year disease-free survival (±SE) was 96.0±1.2% with blinatumomab and chemotherapy and 87.9±2.1% with chemotherapy alone (difference in restricted mean survival time, 72 days; 95% confidence interval, 36 to 108; P<0.001 by stratified log-rank test). The estimated 3-year disease-free survival among patients with an average relapse risk was 97.5±1.3% with blinatumomab and chemotherapy and 90.2±2.3% with chemotherapy alone; among those with a higher relapse risk, the corresponding values were 94.1±2.5% and 84.8±3.8%. Cytokine release syndrome, seizures, and sepsis of grade 3 or higher were rare during blinatumomab cycles, but the overall incidence of nonfatal sepsis and catheter-related infections was significantly higher among patients with an average relapse risk who had been assigned to receive blinatumomab and chemotherapy than among those assigned to receive chemotherapy alone. Adding blinatumomab to combination chemotherapy in patients with newly diagnosed childhood standard-risk B-cell ALL of average or higher risk of relapse significantly improved disease-free survival. (Funded by the National Institutes of Health and others; AALL1731 ClinicalTrials.gov number, NCT03914625.).

Sepsis is present in many hospitalizations that culminate in death. The contribution of sepsis to these deaths, and the extent to which they are preventable, is unknown. To estimate the prevalence, underlying causes, and preventability of sepsis-associated mortality in acute care hospitals. Cohort study in which a retrospective medical record review was conducted of 568 randomly selected adults admitted to 6 US academic and community hospitals from January 1, 2014, to December 31, 2015, who died in the hospital or were discharged to hospice and not readmitted. Medical records were reviewed from January 1, 2017, to March 31, 2018. Clinicians reviewed cases for sepsis during hospitalization using Sepsis-3 criteria, hospice-qualifying criteria on admission, immediate and underlying causes of death, and suboptimal sepsis-related care such as inappropriate or delayed antibiotics, inadequate source control, or other medical errors. The preventability of each sepsis-associated death was rated on a 6-point Likert scale. The study cohort included 568 patients (289 [50.9%] men; mean [SD] age, 70.5 [16.1] years) who died in the hospital or were discharged to hospice. Sepsis was present in 300 hospitalizations (52.8%; 95% CI, 48.6%-57.0%) and was the immediate cause of death in 198 cases (34.9%; 95% CI, 30.9%-38.9%). The next most common immediate causes of death were progressive cancer (92 [16.2%]) and heart failure (39 [6.9%]). The most common underlying causes of death in patients with sepsis were solid cancer (63 of 300 [21.0%]), chronic heart disease (46 of 300 [15.3%]), hematologic cancer (31 of 300 [10.3%]), dementia (29 of 300 [9.7%]), and chronic lung disease (27 of 300 [9.0%]). Hospice-qualifying conditions were present on admission in 121 of 300 sepsis-associated deaths (40.3%; 95% CI 34.7%-46.1%), most commonly end-stage cancer. Suboptimal care, most commonly delays in antibiotics, was identified in 68 of 300 sepsis-associated deaths (22.7%). However, only 11 sepsis-associated deaths (3.7%) were judged definitely or moderately likely preventable; another 25 sepsis-associated deaths (8.3%) were considered possibly preventable. In this cohort from 6 US hospitals, sepsis was the most common immediate cause of death. However, most underlying causes of death were related to severe chronic comorbidities and most sepsis-associated deaths were unlikely to be preventable through better hospital-based care. Further innovations in the prevention and care of underlying conditions may be necessary before a major reduction in sepsis-associated deaths can be achieved.

Higher levels of inflammatory biomarkers are associated with an increased risk of perioperative atrial fibrillation and myocardial injury after non-cardiac surgery (MINS). Colchicine is an anti-inflammatory drug that might reduce the incidence of these complications. COP-AF was a randomised trial conducted at 45 sites in 11 countries. Patients aged 55 years or older and undergoing major non-cardiac thoracic surgery were randomly assigned (1:1) to receive oral colchicine 0·5 mg twice daily or matching placebo, starting within 4 h before surgery and continuing for 10 days. Randomisation was done with use of a computerised, web-based system, and was stratified by centre. Health-care providers, patients, data collectors, and adjudicators were masked to treatment assignment. The coprimary outcomes were clinically important perioperative atrial fibrillation and MINS during 14 days of follow-up. The main safety outcomes were a composite of sepsis or infection, and non-infectious diarrhoea. The intention-to-treat principle was used for all analyses. This trial is registered with ClinicalTrials.gov, NCT03310125. Between Feb 14, 2018, and June 27, 2023, we enrolled 3209 patients (mean age 68 years [SD 7], 1656 [51·6%] male). Clinically important atrial fibrillation occurred in 103 (6·4%) of 1608 patients assigned to colchicine, and 120 (7·5%) of 1601 patients assigned to placebo (hazard ratio [HR] 0·85, 95% CI 0·65 to 1·10; absolute risk reduction [ARR] 1·1%, 95% CI –0·7 to 2·8; p=0·22). MINS occurred in 295 (18·3%) patients assigned to colchicine and 325 (20·3%) patients assigned to placebo (HR 0·89, 0·76 to 1·05; ARR 2·0%, –0·8 to 4·7; p=0·16). The composite outcome of sepsis or infection occurred in 103 (6·4%) patients in the colchicine group and 83 (5·2%) patients in the placebo group (HR 1·24, 0·93–1·66). Non-infectious diarrhoea was more common in the colchicine group (134 [8·3%] events) than the placebo group (38 [2·4%]; HR 3·64, 2·54–5·22). In patients undergoing major non-cardiac thoracic surgery, administration of colchicine did not significantly reduce the incidence of clinically important atrial fibrillation or MINS but increased the risk of mostly benign non-infectious diarrhoea. Canadian Institutes of Health Research, Accelerating Clinical Trials Consortium, Innovation Fund of the Alternative Funding Plan for the Academic Health Sciences Centres of Ontario, Population Health Research Institute, Hamilton Health Sciences, Division of Cardiology at McMaster University, Canada; Hanela Foundation, Switzerland; and General Research Fund, Research Grants Council, Hong Kong.

Preterm pre-labour ruptured membranes close to term is associated with increased risk of neonatal infection, but immediate delivery is associated with risks of prematurity. The balance of risks is unclear. We aimed to establish whether immediate birth in singleton pregnancies with ruptured membranes close to term reduces neonatal infection without increasing other morbidity. The PPROMT trial was a multicentre randomised controlled trial done at 65 centres across 11 countries. Women aged over 16 years with singleton pregnancies and ruptured membranes before the onset of labour between 34 weeks and 36 weeks and 6 days weeks who had no signs of infection were included. Women were randomly assigned (1:1) by a computer-generated randomisation schedule with variable block sizes, stratified by centre, to immediate delivery or expectant management. The primary outcome was the incidence of neonatal sepsis. Secondary infant outcomes included a composite neonatal morbidity and mortality indicator (ie, sepsis, mechanical ventilation ≥24 h, stillbirth, or neonatal death); respiratory distress syndrome; any mechanical ventilation; and duration of stay in a neonatal intensive or special care unit. Secondary maternal outcomes included antepartum or intrapartum haemorrhage, intrapartum fever, postpartum treatment with antibiotics, and mode of delivery. Women and caregivers could not be masked, but those adjudicating on the primary outcome were masked to group allocation. Analyses were by intention to treat. This trial is registered with the International Clinical Trials Registry, number ISRCTN44485060. Between May 28, 2004, and June 30, 2013, 1839 women were recruited and randomly assigned: 924 to the immediate birth group and 915 to the expectant management group. One woman in the immediate birth group and three in the expectant group were excluded from the primary analyses. Neonatal sepsis occurred in 23 (2%) of 923 neonates whose mothers were assigned to immediate birth and 29 (3%) of 912 neonates of mothers assigned to expectant management (relative risk [RR] 0·8, 95% CI 0·5–1·3; p=0·37). The composite secondary outcome of neonatal morbidity and mortality occurred in 73 (8%) of 923 neonates of mothers assigned to immediate delivery and 61 (7%) of 911 neonates of mothers assigned to expectant management (RR 1·2, 95% CI 0·9–1·6; p=0·32). However, neonates born to mothers in the immediate delivery group had increased rates of respiratory distress (76 [8%] of 919 vs 47 [5%] of 910, RR 1·6, 95% CI 1·1–2·30; p=0·008) and any mechanical ventilation (114 [12%] of 923 vs 83 [9%] of 912, RR 1·4, 95% CI 1·0–1·8; p=0·02) and spent more time in intensive care (median 4·0 days [IQR 0·0–10·0] vs 2·0 days [0·0–7·0]; p<0·0001) compared with neonates born to mothers in the expectant management group. Compared with women assigned to the immediate delivery group, those assigned to the expectant management group had higher risks of antepartum or intrapartum haemorrhage (RR 0·6, 95% CI 0·4–0·9), intrapartum fever (0·4, 0·2–0·9), and use of postpartum antibiotics (0·8, 0·7–1·0), and longer hospital stay (p<0·0001), but a lower risk of caesarean delivery (RR 1·4, 95% CI 1·2–1·7). In the absence of overt signs of infection or fetal compromise, a policy of expectant management with appropriate surveillance of maternal and fetal wellbeing should be followed in pregnant women who present with ruptured membranes close to term. Australian National Health and Medical Research Council, the Women's and Children's Hospital Foundation, and The University of Sydney.

This study aimed to investigate incidence, risk factors, and outcomes for sepsis-associated delirium (SAD) in mechanically ventilated patients. We performed a retrospective post-hoc analysis of the DExmedetomidine for Sepsis in Intensive care unit Randomized Evaluation (DESIRE) trial. Outcomes included 28-day mortality, ventilator-free days, length of ICU stay, self-extubation, and re-intubation. Multivariable analysis was performed to identify variables independently associated with SAD. We retrospectively divided the patients into two groups: delirium group (n = 89) and non-delirium group (n = 98). There were no significant differences between the groups in 28-day mortality, self-extubation, and re-intubation. The number of ventilator-free days was significantly less in the delirium vs. non-delirium group (17 vs. 22 days, p = .006), and the length of ICU stay was significantly longer in the delirium group (10 vs. 5 days, p = .04). Multivariable analyses revealed that emergency surgery, more doses of midazolam, and fentanyl were independent predictors for SAD. SAD was associated with a less number of ventilator-free days and longer length of ICU stay. Emergency surgery, more doses of midazolam, and fentanyl may be independent risk factors for SAD in mechanically ventilated patients with sepsis. •Sepsis-associated delirium (SAD) was not associated with a higher 28-day mortality.•SAD were associated with shorter ventilator-free days and a longer length of ICU stay.•Emergency surgery, more doses of midazolam and fentanyl were independent predictors for SAD.

In this trial involving women who received standard antibiotic prophylaxis for nonelective cesarean section, the risk of infection after surgery was lower with the addition of azithromycin than with placebo. Globally, pregnancy-associated infection is a major cause of maternal death and is the fourth most common cause in the United States. 1 Maternal infection is also associated with a prolonged hospital stay and increased health care costs. 2 , 3 Cesarean delivery is the most common major surgical procedure 4 and is associated with a rate of surgical-site infection (including endometritis and wound infection) that is 5 to 10 times the rate for vaginal delivery. 5 Despite routine use of antibiotic prophylaxis (commonly, a cephalosporin given before skin incision 6 ), infection after cesarean section remains an important concern, particularly among women who undergo nonelective procedures . . .

Sepsis remains a significant cause of neonatal morbidity and mortality in China. A better understanding of neonatal sepsis in China as compared with other industrialized and non-industrialized countries may help optimize neonatal health care both regionally and globally. Literature cited in this review was retrieved from PubMed using the keywords \"neonatal sepsis,\" \"early-onset (EOS)\" and \"late-onset (LOS)\" in English, with the focus set on population-based studies. This review provides an updated summary regarding the epidemiology, pathogen profile, infectious work-up, and empirical treatment of neonatal sepsis within and beyond China. The incidence of neonatal EOS and the proportion of Group B Streptococcus (GBS) within pathogens causing EOS in China seem to differ from those in developed countries, possibly due to different population characteristics and intrapartum/postnatal health care strategies. Whether to adopt GBS screening and intrapartum antibiotic prophylaxis in China remains highly debatable. The pathogen profile of LOS in China was shown to be similar to other countries. However, viruses as potential pathogens of neonatal LOS have been underappreciated. Growing antimicrobial resistance in China reflects limitations in adapting antibiotic regimen to local microbial profile and timely cessation of treatment in non-proven bacterial infections. This review stresses that the local epidemiology of neonatal sepsis should be closely monitored in each institution. A prompt and adequate infectious work-up is critically important in diagnosing neonatal sepsis. Adequate and appropriate antibiotic strategies must be overemphasized to prevent the emergence of multi-resistant bacteria in China.

•Most cases of invasive meningococcal disease in Europe are caused by serogroup B.•The notification rate of serogroup B is highest among infants.•Routine MCC vaccination was the driving force behind the decreasing trend in SgC.•The notification rates of serogroups Y and W are increasing in some countries. Invasive meningococcal disease (IMD) is a major cause of bacterial meningitis and septicaemia although infection by some serogroups may be prevented through vaccination. We aimed to describe the epidemiology of IMD in EU/EEA countries during 2004–2014 to monitor serogroup- and age-specific trends, and compare country trends by the period of meningococcal C conjugate (MCC) vaccine introduction. We analysed IMD surveillance data by age, gender, serogroup, country and outcome. We estimated the percentage change in annual notification rate (NR), using linear regression analysis of the log of the annual NR. We grouped countries by the year they introduced MCC vaccination into their routine immunisation programmes. The overall NR was 0.9/100 000 population, and decreased 6.6% (95%CI: −8.0%;−5.1%) annually. Infants had the highest NR (16.0/100 000), and there were decreasing trends in all age groups <50years. Serogroup B (SgB) caused 74% of all cases, and the majority of cases in all age groups. There were decreasing trends in SgB and serogroup C (SgC) and an increasing trend in serogroup Y. Countries that introduced MCC vaccination before, and between 2004 and 2014, had decreasing trends in NR of SgC, but not countries without routine MCC vaccination. Our findings support evidence that routine MCC vaccination was the driving force behind the decreasing SgC trend. Vaccinating against SgB in the first year of life could help reduce the burden of IMD due to this serogroup. Changing serogroup-specific NR trends highlight the need for high-quality surveillance data to accurately assess the changing epidemiology of IMD, the effectiveness and impact of implemented vaccines, and the need for future vaccines.