Interleukin-6 blocking agents for treating COVID-19: a living systematic review.

BACKGROUND: It has been reported that people with COVID-19 and pre-existing autoantibodies against type I interferons are likely to develop an inflammatory cytokine storm responsible for severe respiratory symptoms. Since interleukin 6 (IL-6) is one of the cytokines released during this inflammatory process, IL-6 blocking agents have been used for treating people with severe COVID-19. OBJECTIVES: To update the evidence on the effectiveness and safety of IL-6 blocking agents compared to standard care alone or to a placebo for people with COVID-19. SEARCH METHODS: We searched the World Health Organization (WHO) International Clinical Trials Registry Platform, the Living OVerview of Evidence (L·OVE) platform, and the Cochrane COVID-19 Study Register to identify studies on 7 June 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) evaluating IL-6 blocking agents compared to standard care alone or to placebo for people with COVID-19, regardless of disease severity. DATA COLLECTION AND ANALYSIS: Pairs of researchers independently conducted study selection, extracted data and assessed risk of bias. We assessed the certainty of evidence using the GRADE approach for all critical and important outcomes. In this update we amended our protocol to update the methods used for grading evidence by establishing minimal important differences for the critical outcomes. MAIN RESULTS: This update includes 22 additional trials, for a total of 32 trials including 12,160 randomized participants all hospitalized for COVID-19 disease. We identified a further 17 registered RCTs evaluating IL-6 blocking agents without results available as of 7 June 2022.  The mean age range varied from 56 to 75 years; 66.2% (8051/12,160) of enrolled participants were men. One-third (11/32) of included trials were placebo-controlled. Twenty-two were published in peer-reviewed journals, three were reported as preprints, two trials had results posted only on registries, and results from five trials were retrieved from another meta-analysis. Eight were funded by pharmaceutical companies.  Twenty-six included studies were multicenter trials; four were multinational and 22 took place in single countries. Recruitment of participants occurred between February 2020 and June 2021, with a mean enrollment duration of 21 weeks (range 1 to 54 weeks). Nineteen trials (60%) had a follow-up of 60 days or more. Disease severity ranged from mild to critical disease. The proportion of participants who were intubated at study inclusion also varied from 5% to 95%. Only six trials reported vaccination status; there were no vaccinated participants included in these trials, and 17 trials were conducted before vaccination was rolled out. We assessed a total of six treatments, each compared to placebo or standard care. Twenty trials assessed tocilizumab, nine assessed sarilumab, and two assessed clazakizumab. Only one trial was included for each of the other IL-6 blocking agents (siltuximab, olokizumab, and levilimab). Two trials assessed more than one treatment. Efficacy and safety of tocilizumab and sarilumab compared to standard care or placebo for treating COVID-19 At day (D) 28, tocilizumab and sarilumab probably result in little or no increase in clinical improvement (tocilizumab: risk ratio (RR) 1.05, 95% confidence interval (CI) 1.00 to 1.11; 15 RCTs, 6116 participants; moderate-certainty evidence; sarilumab: RR 0.99, 95% CI 0.94 to 1.05; 7 RCTs, 2425 participants; moderate-certainty evidence). For clinical improvement at ≥ D60, the certainty of evidence is very low for both tocilizumab (RR 1.10, 95% CI 0.81 to 1.48; 1 RCT, 97 participants; very low-certainty evidence) and sarilumab (RR 1.22, 95% CI 0.91 to 1.63; 2 RCTs, 239 participants; very low-certainty evidence). The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score (WHO-CPS) of level 7 or above remains uncertain at D28 (RR 0.90, 95% CI 0.72 to 1.12; 13 RCTs, 2117 participants; low-certainty evidence) and that for sarilumab very uncertain (RR 1.10, 95% CI 0.90 to 1.33; 5 RCTs, 886 participants; very low-certainty evidence). Tocilizumab reduces all cause-mortality at D28 compared to standard care/placebo (RR 0.88, 95% CI 0.81 to 0.94; 18 RCTs, 7428 participants; high-certainty evidence). The evidence about the effect of sarilumab on this outcome is very uncertain (RR 1.06, 95% CI 0.86 to 1.30; 9 RCTs, 3305 participants; very low-certainty evidence). The evidence is uncertain for all cause-mortality at ≥ D60 for tocilizumab (RR 0.91, 95% CI 0.80 to 1.04; 9 RCTs, 2775 participants; low-certainty evidence) and very uncertain for sarilumab (RR 0.95, 95% CI 0.84 to 1.07; 6 RCTs, 3379 participants; very low-certainty evidence). Tocilizumab probably results in little to no difference in the risk of adverse events (RR 1.03, 95% CI 0.95 to 1.12; 9 RCTs, 1811 participants; moderate-certainty evidence). The evidence about adverse events for sarilumab is uncertain (RR 1.12, 95% CI 0.97 to 1.28; 4 RCT, 860 participants; low-certainty evidence).  The evidence about serious adverse events is very uncertain for tocilizumab (RR 0.93, 95% CI 0.81 to 1.07; 16 RCTs; 2974 participants; very low-certainty evidence) and uncertain for sarilumab (RR 1.09, 95% CI 0.97 to 1.21; 6 RCTs; 2936 participants; low-certainty evidence). Efficacy and safety of clazakizumab, olokizumab, siltuximab and levilimab compared to standard care or placebo for treating COVID-19 The evidence about the effects of clazakizumab, olokizumab, siltuximab, and levilimab comes from only one or two studies for each blocking agent, and is uncertain or very uncertain. AUTHORS' CONCLUSIONS: In hospitalized people with COVID-19, results show a beneficial effect of tocilizumab on all-cause mortality in the short term and probably little or no difference in the risk of adverse events compared to standard care alone or placebo. Nevertheless, both tocilizumab and sarilumab probably result in little or no increase in clinical improvement at D28. Evidence for an effect of sarilumab and the other IL-6 blocking agents on critical outcomes is uncertain or very uncertain. Most of the trials included in our review were done before the waves of different variants of concern and before vaccination was rolled out on a large scale. An additional 17 RCTs of IL-6 blocking agents are currently registered with no results yet reported. The number of pending studies and the number of participants planned is low. Consequently, we will not publish further updates of this review.

Efficacy and safety of COVID-19 vaccines.

BACKGROUND: Different forms of vaccines have been developed to prevent the SARS-CoV-2 virus and subsequent COVID-19 disease. Several are in widespread use globally.  OBJECTIVES: To assess the efficacy and safety of COVID-19 vaccines (as a full primary vaccination series or a booster dose) against SARS-CoV-2. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register and the COVID-19 L·OVE platform (last search date 5 November 2021). We also searched the WHO International Clinical Trials Registry Platform, regulatory agency websites, and Retraction Watch. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing COVID-19 vaccines to placebo, no vaccine, other active vaccines, or other vaccine schedules. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We used GRADE to assess the certainty of evidence for all except immunogenicity outcomes.  We synthesized data for each vaccine separately and presented summary effect estimates with 95% confidence intervals (CIs).  MAIN RESULTS: We included and analyzed 41 RCTs assessing 12 different vaccines, including homologous and heterologous vaccine schedules and the effect of booster doses. Thirty-two RCTs were multicentre and five were multinational. The sample sizes of RCTs were 60 to 44,325 participants. Participants were aged: 18 years or older in 36 RCTs; 12 years or older in one RCT; 12 to 17 years in two RCTs; and three to 17 years in two RCTs. Twenty-nine RCTs provided results for individuals aged over 60 years, and three RCTs included immunocompromized patients. No trials included pregnant women. Sixteen RCTs had two-month follow-up or less, 20 RCTs had two to six months, and five RCTs had greater than six to 12 months or less. Eighteen reports were based on preplanned interim analyses. Overall risk of bias was low for all outcomes in eight RCTs, while 33 had concerns for at least one outcome. We identified 343 registered RCTs with results not yet available.  This abstract reports results for the critical outcomes of confirmed symptomatic COVID-19, severe and critical COVID-19, and serious adverse events only for the 10 WHO-approved vaccines. For remaining outcomes and vaccines, see main text. The evidence for mortality was generally sparse and of low or very low certainty for all WHO-approved vaccines, except AD26.COV2.S (Janssen), which probably reduces the risk of all-cause mortality (risk ratio (RR) 0.25, 95% CI 0.09 to 0.67; 1 RCT, 43,783 participants; high-certainty evidence). Confirmed symptomatic COVID-19 High-certainty evidence found that BNT162b2 (BioNtech/Fosun Pharma/Pfizer), mRNA-1273 (ModernaTx), ChAdOx1 (Oxford/AstraZeneca), Ad26.COV2.S, BBIBP-CorV (Sinopharm-Beijing), and BBV152 (Bharat Biotect) reduce the incidence of symptomatic COVID-19 compared to placebo (vaccine efficacy (VE): BNT162b2: 97.84%, 95% CI 44.25% to 99.92%; 2 RCTs, 44,077 participants; mRNA-1273: 93.20%, 95% CI 91.06% to 94.83%; 2 RCTs, 31,632 participants; ChAdOx1: 70.23%, 95% CI 62.10% to 76.62%; 2 RCTs, 43,390 participants; Ad26.COV2.S: 66.90%, 95% CI 59.10% to 73.40%; 1 RCT, 39,058 participants; BBIBP-CorV: 78.10%, 95% CI 64.80% to 86.30%; 1 RCT, 25,463 participants; BBV152: 77.80%, 95% CI 65.20% to 86.40%; 1 RCT, 16,973 participants). Moderate-certainty evidence found that NVX-CoV2373 (Novavax) probably reduces the incidence of symptomatic COVID-19 compared to placebo (VE 82.91%, 95% CI 50.49% to 94.10%; 3 RCTs, 42,175 participants). There is low-certainty evidence for CoronaVac (Sinovac) for this outcome (VE 69.81%, 95% CI 12.27% to 89.61%; 2 RCTs, 19,852 participants). Severe or critical COVID-19 High-certainty evidence found that BNT162b2, mRNA-1273, Ad26.COV2.S, and BBV152 result in a large reduction in incidence of severe or critical disease due to COVID-19 compared to placebo (VE: BNT162b2: 95.70%, 95% CI 73.90% to 99.90%; 1 RCT, 46,077 participants; mRNA-1273: 98.20%, 95% CI 92.80% to 99.60%; 1 RCT, 28,451 participants; AD26.COV2.S: 76.30%, 95% CI 57.90% to 87.50%; 1 RCT, 39,058 participants; BBV152: 93.40%, 95% CI 57.10% to 99.80%; 1 RCT, 16,976 participants). Moderate-certainty evidence found that NVX-CoV2373 probably reduces the incidence of severe or critical COVID-19 (VE 100.00%, 95% CI 86.99% to 100.00%; 1 RCT, 25,452 participants). Two trials reported high efficacy of CoronaVac for severe or critical disease with wide CIs, but these results could not be pooled. Serious adverse events (SAEs) mRNA-1273, ChAdOx1 (Oxford-AstraZeneca)/SII-ChAdOx1 (Serum Institute of India), Ad26.COV2.S, and BBV152 probably result in little or no difference in SAEs compared to placebo (RR: mRNA-1273: 0.92, 95% CI 0.78 to 1.08; 2 RCTs, 34,072 participants; ChAdOx1/SII-ChAdOx1: 0.88, 95% CI 0.72 to 1.07; 7 RCTs, 58,182 participants; Ad26.COV2.S: 0.92, 95% CI 0.69 to 1.22; 1 RCT, 43,783 participants); BBV152: 0.65, 95% CI 0.43 to 0.97; 1 RCT, 25,928 participants). In each of these, the likely absolute difference in effects was fewer than 5/1000 participants. Evidence for SAEs is uncertain for BNT162b2, CoronaVac, BBIBP-CorV, and NVX-CoV2373 compared to placebo (RR: BNT162b2: 1.30, 95% CI 0.55 to 3.07; 2 RCTs, 46,107 participants; CoronaVac: 0.97, 95% CI 0.62 to 1.51; 4 RCTs, 23,139 participants; BBIBP-CorV: 0.76, 95% CI 0.54 to 1.06; 1 RCT, 26,924 participants; NVX-CoV2373: 0.92, 95% CI 0.74 to 1.14; 4 RCTs, 38,802 participants). For the evaluation of heterologous schedules, booster doses, and efficacy against variants of concern, see main text of review. AUTHORS' CONCLUSIONS: Compared to placebo, most vaccines reduce, or likely reduce, the proportion of participants with confirmed symptomatic COVID-19, and for some, there is high-certainty evidence that they reduce severe or critical disease. There is probably little or no difference between most vaccines and placebo for serious adverse events. Over 300 registered RCTs are evaluating the efficacy of COVID-19 vaccines, and this review is updated regularly on the COVID-NMA platform (covid-nma.com). Implications for practice Due to the trial exclusions, these results cannot be generalized to pregnant women, individuals with a history of SARS-CoV-2 infection, or immunocompromized people. Most trials had a short follow-up and were conducted before the emergence of variants of concern. Implications for research Future research should evaluate the long-term effect of vaccines, compare different vaccines and vaccine schedules, assess vaccine efficacy and safety in specific populations, and include outcomes such as preventing long COVID-19. Ongoing evaluation of vaccine efficacy and effectiveness against emerging variants of concern is also vital.

Psychological or educational eHealth interventions on depression, anxiety or stress following preterm birth: a systematic review.

Objective: To determine the efficacy and characteristics of psychological or educational eHealth interventions on reducing symptoms of mental illness in parents of preterm or low birthweight infants. Background: Many parents suffer psychological disorders after preterm birth. Computer or mobile application-based interventions are a promising alternative. Methods: We searched seven electronic databases up to January 2020 and included randomised and quasi-randomised controlled trials assessing psychological or educational eHealth interventions in parents of infants born very preterm <32 weeks or with very low birthweight <1500g (primary question), or preterm <37 weeks or with low birthweight <2500g (secondary question). Primary outcomes were measures of depression, anxiety, acute stress disorder or post-traumatic stress disorder. Secondary outcomes included other indicators of mental health, quality of life and intervention characteristics. We had planned random-effects meta-analysis in our protocol (CRD42018105731). Results: Of 9768 records, no study reported our primary outcomes. Three studies showed potential benefits for parental self-efficacy, discharge preparedness, parental satisfaction and family satisfaction with the neonatal intensive care unit. Conclusions: We found scarce evidence on the efficacy of psychological or educational eHealth interventions on reducing mental illness in parents of preterm or low birthweight infants, highlighting the need for more research.

Vaginal birth vs caesarean section for extremely preterm vertex infants: a systematic review and meta-analyses.

PURPOSE: To synthesize evidence of mode of birth in extremely preterm vertex infants. METHODS: We searched MEDLINE, EMBASE, CINAHL, Cochrane CENTRAL, Web of Science, and ClinicalTrials.gov (January 1995-July 2019). We included studies comparing outcomes by vaginal birth or caesarean section in vertex infants born < 28 weeks or with birthweight < 1500 g. Two reviewers independently performed all steps. Primary outcomes were death and/or severe brain injury. We synthesised the data using random-effects meta-analyses (PROSPERO CRD42017074145). RESULTS: We included 14 studies with 129,475 infants. In vertex singletons < 28 weeks, caesarean section was associated with reduced adjusted odds of death (aOR 0.62, 95% confidence interval [CI] 0.39-0.99, 3 studies, 10,331 infants). For severe brain injury or a composite of death or severe brain injury, adjusted data were lacking. In infants with very low birth weight overall (< 1500 g) we found no significant benefit for our primary outcomes (e.g., death, aOR 0.77, 0.55-1.07, 2 studies, 105,439 infants), although there were some benefits associated with caesarean section in smaller weight subgroups (e.g., death aOR 500-700 g: 0.53, 0.49-0.57 [1 study, 5989 infants] and 1000-1250 g: 0.78, 0.65-0.93 [1 study, 14,906 infants]), but not larger weights (1250-1500 g: 1.38, 1.15-1.65 [1 study, 17,715 infants]). CONCLUSION: Caesarean section was associated with a significant decrease in the adjusted odds of death in extremely preterm vertex infants < 28 weeks. Smaller birth weight subgroups supported these results. The absence of randomized trials warrants judicious interpretation of these results, which are the currently available highest level of evidence. This study will inform further research.

Pregnancy outcomes in women taking probiotics or prebiotics: a systematic review and meta-analysis.

BACKGROUND: Probiotics are living microorganisms that, when administered in adequate amounts, confer a health benefit. It has been speculated that probiotics might help prevent preterm birth, but in two previous systematic reviews possible major increases in this risk have been suggested. Our objective was to perform a systematic review and meta-analysis of the risk of preterm birth and other adverse pregnancy outcomes in pregnant women taking probiotics, prebiotics or synbiotics. METHODS: We searched six electronic databases (MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, Web of Science's Core collection and BIOSIS Preview) up to September 2016 and contacted authors for additional data. We included randomized controlled trials in which women with a singleton pregnancy received a probiotic, prebiotic or synbiotic intervention. Two independent reviewers extracted data using a piloted form and assessed the risk of bias using the Cochrane risk of bias tool. We used random-effects meta-analyses to pool the results. RESULTS: We identified 2574 publications, screened 1449 non-duplicate titles and abstracts and read 160 full text articles. The 49 publications that met our inclusion criteria represented 27 studies. No study used synbiotics, one used prebiotics and the rest used probiotics. Being randomized to take probiotics during pregnancy neither increased nor decreased the risk of preterm birth < 34 weeks (RR 1.03, 95% CI 0.29-3.64, I2 0%, 1017 women in 5 studies), preterm birth < 37 weeks (RR 1.08, 95% CI 0.71-1.63, I2 0%, 2484 women in 11 studies), or most of our secondary outcomes, including gestational diabetes mellitus. CONCLUSIONS: We found no evidence that taking probiotics or prebiotics during pregnancy either increases or decreases the risk of preterm birth or other infant and maternal adverse pregnancy outcomes. TRIAL REGISTRATION: We prospectively published the protocol for this study in the PROSPERO database ( CRD42016048129 ).

What Interventions Are Being Used to Prevent Preterm Birth and When?

OBJECTIVE: This study sought to determine the proportions of women at risk of preterm birth who received progesterone, elective and rescue cerclage, or pessary to prevent preterm birth, by using medical records. The authors also sought to determine whether these proportions differed among primary-, secondary-, and tertiary-level centres. METHODS: The authors conducted a retrospective cohort study and extracted data from consecutive medical charts of women with an estimated date of confinement over 3 months in primary-, secondary-, and tertiary-level centres in Southern Ontario. The study identified women with a previous spontaneous preterm birth or a short cervix and determined whether they were offered and whether they received a preventive intervention for preterm birth. Descriptive statistics and Fisher exact tests were calculated. RESULTS: The authors reviewed 1024 consecutive charts at primary, secondary, and tertiary centres and identified 31 women with a previous spontaneous preterm birth or a short cervix. Of these women, less than one half (42%) received progesterone or cerclage for prevention of preterm birth, and none received pessary. One in four women (26%) were not referred to an obstetrician or maternal-fetal medicine specialist in time for an intervention, and among those referred before 24 weeks of gestation, an intervention was offered to 57% of the women. CONCLUSION: Less than half of women at risk of spontaneous preterm birth received progesterone, cerclage, or pessary, attesting to the importance of improving knowledge translation methods to encourage timely referral and use of progesterone for the prevention of preterm birth.

The More, the Better? Combining Interventions to Prevent Preterm Birth in Women at Risk: a Systematic Review and Meta-Analysis.

OBJECTIVES: To systematically examine the evidence around the combination of interventions to prevent preterm birth. METHODS: Without language restrictions, we searched clinicaltrials.gov and five electronic databases (Medline, EMBASE, CINAHL, Cochrane CENTRAL, and Web of Science) up to July 7, 2016. We included randomized and non-randomized studies where asymptomatic women at risk of preterm birth received any combination of progesterone, cerclage, or pessary compared with either one or no intervention. Primary outcomes were preterm birth <34 and <37 weeks and neonatal death. Two independent reviewers extracted data using a piloted form and assessed risk and direction of bias. We pooled data with unlikely or unclear bias using random-effects meta-analyses. Comparisons with likely bias (e.g., confounding by indication) were not pooled. RESULTS: We screened 1335 results and assessed 154 full texts, including seven studies. In singletons, we found no differences in preterm birth <34 weeks when comparing pessary & progesterone with pessary alone (RR 1.30, 95% CI 0.70-2.42) or progesterone alone (RR 1.16, 95% CI 0.79-1.72). Similarly, we found no differences in preterm birth <37 weeks when comparing cerclage & progesterone with cerclage alone (RR 1.04, 95% CI 0.56-1.93) or with progesterone alone (RR 0.82, 95% CI 0.57-1.19) nor between pessary & progesterone and pessary alone (RR 1.04, 95% CI 0.62-1.74). No data were available for neonatal death in singletons. CONCLUSIONS: Despite being a common clinical practice, evidence to support the combined use of multiple versus single interventions for preventing preterm birth is scarce.

Is Tobacco Use Associated With Risk of Recurrence and Mortality Among People With TB?: A Systematic Review and Meta-Analysis.

BACKGROUND: Associations between tobacco use and poor TB treatment outcomes are well documented. However, for important outcomes such as TB recurrence or relapse and mortality during treatment, as well as for associations with smokeless tobacco (ST), the evidence is not summarized systematically. RESEARCH QUESTION: Is tobacco use associated with risk of poor treatment outcomes among people with TB? STUDY DESIGN AND METHODS: The MEDLINE, Embase, and Cumulative Index of Nursing and Allied Health Literature databases were searched on November 22, 2021. Epidemiologic studies reporting associations between tobacco use and at least one TB treatment outcome were eligible. Independent double-screening, extractions, and quality assessments were undertaken. Random effects meta-analyses were conducted for the two primary review outcomes (TB recurrence or relapse and mortality during treatment), and heterogeneity was explored using subgroups. Other outcomes were synthesized narratively. RESULTS: Our searches identified 1,249 records, of which 28 were included in the meta-analyses. Based on 15 studies, higher risk of TB recurrence or relapse was found with ever using tobacco vs never using tobacco (risk ratio [RR], 1.78; 95% CI, 1.31-2.43; I2 = 85%), current tobacco use vs no tobacco use (RR, 1.95; 95% CI, 1.59-2.40; I2 = 72%), and former tobacco use vs never using tobacco (RR, 1.84; 95% CI, 1.21-2.80; I2 = 4%); heterogeneity arose from differences in study quality, design, and participant characteristics. Thirty-eight studies were identified for mortality, of which 13 reported mortality during treatment. Ever tobacco use (RR, 1.55; 95% CI, 1.32-1.81; I2 = 0%) and current tobacco use (RR, 1.51; 95% CI, 1.09-2.10; I2 = 87%) significantly increased the likelihood of mortality during treatment among people with TB compared with never using tobacco and not currently using tobacco, respectively; heterogeneity was explained largely by differences in study design. Almost all studies in the meta-analyses scored high or moderate on quality assessments. Narrative synthesis showed that tobacco use was a risk factor for other unfavorable TB treatment outcomes, as previously documented. Evidence on ST was limited, but identified studies suggested an increased risk for poor outcomes with its use compared with not using it. INTERPRETATION: Tobacco use significantly increases the risk of TB recurrence or relapse and mortality during treatment among people with TB, highlighting the need to address tobacco use to improve TB outcomes. TRIAL REGISTRY: PROSPERO; No.: CRD42017060821; URL: https://www.crd.york.ac.uk/prospero/.

Correction: Addressing TB multimorbidity in policy and practice: An exploratory survey of TB providers in 27 high-TB burden countries.

[This corrects the article DOI: 10.1371/journal.pgph.0001205.].

Invasive bacterial disease in young infants in rural Gambia: Population-based surveillance.

Background: Invasive bacterial diseases (IBD) cause significant mortality in young infants. There are limited population-based data on IBD in young infants in Sub-Saharan Africa. Methods: We conducted population-based surveillance for IBD among infants aged 0-90 days in a demographic surveillance area in rural Gambia between 1 March 2011 and 31 December 2017. Infants admitted to health facilities within the study area had standardised clinical evaluation plus conventional microbiological investigation. We defined IBD as isolation of pathogenic bacteria from blood, cerebrospinal fluid, lung, or pleural aspirate. We determined incidence, aetiology and case-fatality of IBD. Results: A total of 3794 infants were admitted and 3605 (95%) had at least one sample collected for culture. We detected 254 (8.0%) episodes of IBD (bacteraemia 241; meningitis 14; pneumonia seven). The incidence of IBD in infants aged 0-90 days was 25 episodes/1000 person-years (95% confidence interval (CI) = 22-28), the incidence in neonates was 50 episodes/1000 person-years (95% CI = 43-58) and the incidence in infants aged 29-90 days was 12 episodes/1000 person-years (95% CI = 9-15). The most common pathogens causing IBD were Staphylococcus aureus (n = 102, 40%), Escherichia coli (n = 37, 15%), Streptococcus pneumoniae (n = 24, 9%) and Klebsiella pneumoniae (n = 12, 5%). Case-fatality was 29% (95% CI = 23-37) in neonates and 19% (95% CI = 11-29) in infants aged 29-90 days. A minimum of 7.3% of all young infant deaths in the population were caused by IBD. Conclusions: IBD are common in young infants in rural Gambia and have a high case-fatality. Strategies are needed to prevent IBD in young infants. Overcoming barriers to widespread implementation of existing vaccines and developing new vaccines against the most common pathogens causing IBD should be among top priorities for reducing the high mortality rate in young infants.

Prevalence and risks of tuberculosis multimorbidity in low-income and middle-income countries: a meta-review.

OBJECTIVES: Co-occurrence of tuberculosis (TB) with other chronic conditions (TB multimorbidity) increases complexity of management and adversely affects health outcomes. We aimed to map the prevalence of the co-occurrence of one or more chronic conditions in people with TB and associated health risks by systematically reviewing previously published systematic reviews. DESIGN: Systematic review of systematic reviews (meta-review). SETTING: Low-income and middle-income countries (LMICs). PAPERS: We searched in Medline, Embase, PsycINFO, Social Sciences Citation Index, Science Citation Index, Emerging Sources Citation Index and Conference Proceedings Citation Index, and the WHO Global Index Medicus from inception to 23 October 2020, contacted authors and reviewed reference lists. Pairs of independent reviewers screened titles, abstracts and full texts, extracted data and assessed the included reviews' quality (AMSTAR2). We included systematic reviews reporting data for people in LMICs with TB multimorbidity and synthesised them narratively. We excluded reviews focused on children or specific subgroups (eg, incarcerated people). PRIMARY AND SECONDARY OUTCOME MEASURES: Prevalence or risk of TB multimorbidity (primary); any measure of burden of disease (secondary). RESULTS: From the 7557 search results, 54 were included, representing >6 296 000 people with TB. We found that the most prevalent conditions in people with TB were depression (45.19%, 95% CI: 38.04% to 52.55%, 25 studies, 4903 participants, I2=96.28%, high quality), HIV (31.81%, 95% CI: 27.83% to 36.07%, 68 studies, 62 696 participants, I2=98%, high quality) and diabetes mellitus (17.7%, 95% CI: 15.1% to 20.0.5%, 48 studies, 48,036 participants, I2=98.3%, critically low quality). CONCLUSIONS: We identified several chronic conditions that co-occur in a significant proportion of people with TB. Although limited by varying quality and gaps in the literature, this first meta-review of TB multimorbidity highlights the magnitude of additional ill health burden due to chronic conditions on people with TB. PROSPERO REGISTRATION NUMBER: CRD42020209012.

Effectiveness of interventions to address obesity and health risk behaviours among people with severe mental illness in low- and middle-income countries (LMICs): a systematic review and meta analysis.

Introduction: People with severe mental illness (SMI) are more likely to have obesity and engage in health risk behaviours than the general population. The aims of this study are (1) evaluate the effectiveness of interventions that focus on body weight, smoking cessation, improving sleeping patterns, and alcohol and illicit substance abuse; (2) Compare the number of interventions addressing body weight and health risk behaviours in low- and middle-income countries (LMICs) v. those reported in published systematic reviews focusing on high-income countries (HICs). Methods: Intervention studies published up to December 2020 were identified through a structured search in the following database; OVID MEDLINE (1946-December 2020), EMBASE (1974-December 2020), CINAHL (1975-2020), APA PsychoINFO (1806-2020). Two authors independently selected studies, extracted study characteristics and data and assessed the risk of bias. and risk of bias was assessed using the Cochrane risk of bias tool V2. We conducted a narrative synthesis and, in the studies evaluating the effectiveness of interventions to address body weight, we conducted random-effects meta-analysis of mean differences in weight gain. We did a systematic search of systematic reviews looking at cardiometabolic and health risk behaviours in people with SMI. We compared the number of available studies of LMICs with those of HICs. Results: We assessed 15 657 records, of which 9 met the study inclusion criteria. Six focused on healthy weight management, one on sleeping patterns and two tested a physical activity intervention to improve quality of life. Interventions to reduce weight in people with SMI are effective, with a pooled mean difference of -4.2 kg (95% CI -6.25 to -2.18, 9 studies, 459 participants, I 2 = 37.8%). The quality and sample size of the studies was not optimal, most were small studies, with inadequate power to evaluate the primary outcome. Only two were assessed as high quality (i.e. scored 'low' in the overall risk of bias assessment). We found 5 reviews assessing the effectiveness of interventions to reduce weight, perform physical activity and address smoking in people with SMI. From the five systematic reviews, we identified 84 unique studies, of which only 6 were performed in LMICs. Conclusion: Pharmacological and activity-based interventions are effective to maintain and reduce body weight in people with SMI. There was a very limited number of interventions addressing sleep and physical activity and no interventions addressing smoking, alcohol or harmful drug use. There is a need to test the feasibility and cost-effectiveness of context-appropriate interventions to address health risk behaviours that might help reduce the mortality gap in people with SMI in LMICs.

Addressing TB multimorbidity in policy and practice: An exploratory survey of TB providers in 27 high-TB burden countries.

In people with TB, co-existence of long-term conditions (e.g., depression, diabetes and HIV) and risk factors (e.g.,alcohol misuse, malnutrition, and smoking) are associated with increased mortality and poor treatment outcomes including delayed recovery, TB treatment failure and relapse. However, it is unclear as to what extent these comorbidities are addressed in TB policy and practice. Between August and October 2021, we conducted an online cross-sectional survey in high-TB burden countries. We recruited a purposive sample of TB health workers, managers, policy makers, advisors and advocates from these countries. The survey enquired about the extent to which various comorbid conditions are: (a) mentioned in TB policies, plans, and guidelines; (b) screened, diagnosed, treated or referred to specialist services by TB healthcare workers. We summarised using descriptive analysis. Of the 1100 potential respondents contacted in 33 countries, 543 responded but only 446 (41%) from 27 countries provided sufficient data for inclusion in the study. We found no notable differences between these providing insufficient data and those completing the survey. HIV, diabetes mellitus, depression and tobacco and alcohol use disorders were identified as the most common and concerning comorbid conditions in TB. HIV was screened for and managed by TB services in most countries. Screening for diabetes and/or tobacco and alcohol use disorders was offered by almost half of all TB services but only a few offered relevant treatments. Depression was rarely screened for, almost never treated, and only infrequently referred to specialist services. Most respondents felt confident in screening/diagnosing these comorbid conditions but not in treating these conditions. With the exception of HIV, chronic comorbid conditions are only partially screened for and rarely managed within TB services. Mental health conditions are for the most part neglected. Given their adverse impact on TB outcomes, integrating screening and management of these comorbidities within TB programmes offers a significant opportunity to meet TB targets, address non-communicable diseases and improve patient well-being.

Risk factors of infant mortality in rural The Gambia: a retrospective cohort study.

Objective: The main objective was to assess the risk factors for infant mortality among children living in the Health and Demographic Surveillance System (HDSS) in Farafenni, The Gambia. Our secondary objective was to assess these risks separately in the neonatal and postneonatal (>28 days) period. Design: Retrospective cohort study. Setting: HDSS in an urban centre and surrounding area in The Gambia. Patients: 7365 infants (47% female) born between 2014 and 2018, of which 126 (1.71%) died in the first year. Main outcome measures: Infant mortality. Results: Risk factors for mortality were death of any sibling (HR 2.78, 95% CI 1.54 to 5.00), having a twin (HR 1.96, 95% CI 1.01 to 3.80), being born in the harvest season (HR 1.55, 95% CI 1.07 to 2.24), living in a rural village (HR 4.34, 95% CI 2.03 to 9.29) and longer distance to the nearest village with a public health centre (HR 1.33, 95% CI 1.11 to 1.59). In addition, no breast feeding (HR 10.73, 95% CI 6.83 to 16.86) and no BCG vaccination in the first week of life (HR 3.47, 95% CI 1.07 to 11.24) were associated with infant mortality. Similar risk factors were found in the neonatal and postneonatal periods. Conclusion: Most risk factors associated with infant mortality (neonatal and postneonatal) are not easily modifiable at the individual level and would require programmatic approaches to target vulnerable infants and facilitate access to health services.

Deploying Machine Learning Models Using Progressive Web Applications: Implementation Using a Neural Network Prediction Model for Pneumonia Related Child Mortality in The Gambia.

BACKGROUND: Translating research outputs into practical tools for medical practitioners is a neglected area and could have a substantial impact. One of the barriers to implementing artificial intelligence (AI) and machine learning (ML) applications is their practical deployment in the field. Traditional web-based (i.e., server sided) applications are dependent on reliable internet connections, which may not be readily available in rural areas. Native mobile apps require device specific programming skills as well as contemporary hardware and software, with often rapid and unpredictable platform specific changes. This is a major challenge for using AI/ML tools in resource-limited settings. METHODS: An emerging technology, progressive web applications (PWAs), first introduced by Google in 2015, offers an opportunity to overcome the challenges of deploying bespoke AI/ML systems. The same PWA code can be implemented across all desktop platforms, iOS and Android phones and tablets. In addition to platform independence, a PWA can be designed to be primarily offline. RESULTS: We demonstrate how a neural network-based pneumonia mortality prediction triage tool was migrated from a typical academic framework (paper and web-based prototype) to a tool that can be used offline on any mobile phone-the most convenient deployment vehicle. After an initial online connection to download the software, the application runs entirely offline, reading data from cached memory, and running code via JavaScript. On mobile devices the application is installed as a native app, without the inconvenience of platform specific code through manufacturer code stores. DISCUSSION: We show that an ML application can be deployed as a platform independent offline PWA using a pneumonia-related child mortality prediction tool as an example. The aim of this tool was to assist clinical staff in triaging children for hospital admission, by predicting their risk of death. PWAs function seamlessly when their host devices lose internet connectivity, making them ideal for e-health apps that can help improve health and save lives in resource-limited settings in line with the UN Sustainable Development Goal 3 (SDG3).

Pregnancy-related interventions in mothers at risk for gestational diabetes in Asian India and low and middle-income countries (PRIMORDIAL study): protocol for a randomised controlled trial.

INTRODUCTION: Lifestyle modification is the mainstay of gestational diabetes mellitus (GDM) prevention. However, clinical trials evaluating the safety and efficacy of diet or physical activity (PA) in low-income and middle-income settings such as Africa and India are lacking. This trial aims to evaluate the efficacy of yoghurt consumption and increased PA (daily walking) in reducing GDM incidence in high-risk pregnant women. METHODS AND ANALYSIS: The study is a 2×2 factorial, open-labelled, multicentre randomised controlled trial to be conducted in Vellore, South India and The Gambia, West Africa. 'High-risk' pregnant women (n=1856) aged ≥18 years and ≤16 weeks of gestational age, with at least one risk factor for developing GDM, will be randomised to either (1) yoghurt (2) PA (3) yoghurt +PA or (4) standard antenatal care. Participants will be followed until 32 weeks of gestation with total active intervention lasting for a minimum of 16 weeks. The primary endpoint is GDM incidence at 26-28 weeks diagnosed using International Association of the Diabetes and Pregnancy Study Groups criteria or elevated fasting glucose (≥5.1 mmol/L) at 32 weeks. Secondary endpoints include absolute values of fasting plasma glucose concentration at 32 weeks gestation, maternal blood pressure, gestational weight gain, intrapartum and neonatal outcomes. Analysis will be both by intention to treat and per-protocol. Continuous outcome measurements will be analysed using multiple linear regression and binary variables by logistic regression. ETHICS AND DISSEMINATION: The study is approved by Oxford Tropical Research Ethics Committee (44-18), ethics committees of the Christian Medical College, Vellore (IRB 11367) and MRCG Scientific Coordinating Committee (SCC 1645) and The Gambia Government/MRCG joint ethics committee (L2020.E15). Findings of the study will be published in peer-reviewed scientific journals and presented in conferences. TRIAL REGISTRATION NUMBER: ISRCTN18467720.

Safety of Administering Live Vaccines During Pregnancy: A Systematic Review and Meta-Analysis of Pregnancy Outcomes.

Live-attenuated vaccines (LAV) are currently contraindicated during pregnancy, given uncertain safety records for the mother-infant pair. LAV might, however, play an important role to protect them against serious emerging diseases, such as Ebola and Lassa fever. For this systematic review we searched relevant databases to identify studies published up to November 2019. Controlled observational studies reporting pregnancy outcomes after maternal immunization with LAV were included. The ROBINS-I tool was used to assess risk of bias. Pooled odds ratios (OR) were obtained under a random-effects model. Of 2831 studies identified, fifteen fulfilled inclusion criteria. Smallpox, rubella, poliovirus, yellow fever and dengue vaccines were assessed in these studies. No association was found between vaccination and miscarriage (OR 0.98, 95% CI 0.87-1.10), stillbirth (OR 1.04, 95% CI 0.74-1.48), malformations (OR 1.09, 95% CI 0.98-1.21), prematurity (OR 0.99, 95% CI 0.90-1.08) or neonatal death (OR 1.06, 95% CI 0.68-1.65) overall. However, increased odds of malformations (OR 1.24; 95% CI 1.03-1.49) and miscarriage after first trimester immunization (OR 4.82; 95% CI 2.38-9.77) was found for smallpox vaccine. Thus, we did not find evidence of harm related to LAV other than smallpox with regards to pregnancy outcomes, but quality of evidence was very low. Overall risks appear to be small and have to be balanced against potential benefits for the mother-infant pair.

Aetiology of invasive bacterial infection and antimicrobial resistance in neonates in sub-Saharan Africa: a systematic review and meta-analysis in line with the STROBE-NI reporting guidelines.

BACKGROUND: Aetiological data for neonatal infections are essential to inform policies and programme strategies, but such data are scarce from sub-Saharan Africa. We therefore completed a systematic review and meta-analysis of available data from the African continent since 1980, with a focus on regional differences in aetiology and antimicrobial resistance (AMR) in the past decade (2008-18). METHODS: We included data for microbiologically confirmed invasive bacterial infection including meningitis and AMR among neonates in sub-Saharan Africa and assessed the quality of scientific reporting according to Strengthening the Reporting of Observational Studies in Epidemiology for Newborn Infection (STROBE-NI) checklist. We calculated pooled proportions for reported bacterial isolates and AMR. FINDINGS: We included 151 studies comprising data from 84 534 neonates from 26 countries, almost all of which were hospital-based. Of the 82 studies published between 2008 and 2018, insufficient details were reported regarding most STROBE-NI items. Regarding culture positive bacteraemia or sepsis, Staphylococcus aureus, Klebsiella spp, and Escherichia coli accounted for 25% (95% CI 21-29), 21% (16-27), and 10% (8-10) respectively. For meningitis, the predominant identified causes were group B streptococcus 25% (16-33), Streptococcus pneumoniae 17% (9-6), and S aureus 12% (3-25). Resistance to WHO recommended ß-lactams was reported in 614 (68%) of 904 cases and resistance to aminoglycosides in 317 (27%) of 1176 cases. INTERPRETATION: Hospital-acquired neonatal infections and AMR are a major burden in Africa. More population-based neonatal infection studies and improved routine surveillance are needed to improve clinical care, plan health systems approaches, and address AMR. Future studies should be reported according to standardised reporting guidelines, such as STROBE-NI, to aid comparability and reduce research waste. FUNDING: Uduak Okomo was supported by a Medical Research Council PhD Studentship.

A clinical carepath for obese pregnant women: a pragmatic pilot cluster randomized controlled trial.

Objectives: Obese women are at increased risks for complications during pregnancy, birth, and in their infants. Although guidelines have been established for the clinical care of obese pregnant women, management is sometimes suboptimal. Our goal was to determine the feasibility of implementing and testing a clinical carepath for obese pregnant women compared to standard care, in a pilot cluster randomized controlled trial (RCT). Methods: A pragmatic pilot cluster RCT was conducted, randomly allocating eight clinics to the carepath or standard care for obese pregnant women. Women were eligible if they had a pre-pregnancy body mass index (BMI) of ≥30 kg/m2 and a viable singleton <21 weeks. The primary outcomes were the feasibility of conducting a full-scale cluster RCT (defined as >80%: randomization of clinics, use in eligible women, and completeness of follow-up) and of the intervention (defined as >80%: compliance with each step in the carepath and recommendation of the carepath by clinicians to a colleague). Results: All eight approached clinics agreed to participate and were randomized. Half of the intervention clinics used the carepath, resulting in <80% uptake of eligible women. High follow-up (99.5%) was achieved, in 188 of 189 women. The carepath was feasible for numerous guideline-directed recommendations for screening, but less so for counseling topics. When the carepath was used in the majority of women, all clinicians, most of whom were midwives, reported they would recommend it to a colleague. The intervention group had significantly higher overall adherence to the guideline recommendations compared to control (relative risk: 1.71, 95% confidence interval: 1.57-1.87). Conclusions: In this pragmatic pilot cluster RCT, a guideline-directed clinical carepath improved some aspects of care of obese pregnant women and was recommended by clinicians, particularly midwives. A cluster RCT may not be feasible in a mix of obstetric and midwifery clinics, but may be feasible in midwifery clinics.

Neonatal Outcomes in Women With Untreated Antenatal Depression Compared With Women Without Depression: A Systematic Review and Meta-analysis.

IMPORTANCE: Despite the prevalence of antenatal depression and the fact that only one-third of pregnant women with depression consider it acceptable to take antidepressants, the effect of untreated depression on neonatal outcomes remains to be addressed thoroughly. OBJECTIVE: To undertake a systematic review and meta-analysis to understand the effect of untreated depression on neonatal outcomes. DATA SOURCES: We executed our search strategy, with emphasis on its exhaustiveness, in MEDLINE, EMBASE, PsycINFO, Cumulative Index to Nursing and Allied Health, Cochrane Central Register of Controlled Trials, and Web of Science. The search was conducted in July, 2015. STUDY SELECTION: We included randomized and nonrandomized studies that examined neonatal outcomes in women with depression receiving neither pharmacological nor nonpharmacological treatment compared with women without depression. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently screened titles and abstracts, assessed full-text articles, extracted data, and assessed their quality using a modified version of the Newcastle-Ottawa Scale. We pooled data using random-effects meta-analyses, quantified heterogeneity using the I2 statistic, and explored it with subgroup analyses by type of assessment of depression, severity, reported conflicts of interest, and study quality. MAIN OUTCOMES AND MEASURES: Primary outcomes were preterm birth before 37 weeks and before 32 weeks, small and large for gestational age, low birth weight, and neonatal intensive care unit admission. RESULTS: Of the 6646 titles initially identified, 23 studies met inclusion criteria, all observational, with a total of 25 663 women. Untreated depression was associated with significantly increased risks of preterm birth (odds ratio [OR], 1.56; 95% CI, 1.25-1.94; 14 studies; I2, 39%) and low birth weight (OR, 1.96; 95% CI, 1.24-3.10; 8 studies; I2, 48%), with a trend toward higher risks for exposure to more severe depression. While the odds of preterm birth more than doubled in studies reporting conflicts of interest (OR, 2.50; 95% CI, 1.70-3.67; 5 studies; I2, 0%), studies not reporting such conflicts showed more moderate results (OR, 1.34; 95% CI, 1.08-1.66; 9 studies; I2, 30%). CONCLUSIONS AND RELEVANCE: Our results contrast with what is, to our knowledge, the only previous systematic review that examined the question of untreated depression because we found significant risks of 2 key perinatal outcomes, preterm birth and low birth weight. These are important results for pregnant women and clinicians to take into account in the decision-making process around depression treatment.