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Epitopes specific for IgM on peripheral blood lymphocytes from 47 cattle were examined with three class-specific monoclonal antibodies, IL-A30, IL-A50 and B5/4. In all 47 animals tested, mAb IL-A30 detected a similar percentage of peripheral blood lymphocytes as a mAb that recognizes all immunoglobulin classes. However, in some animals mAbs IL-A50 and B5/4 detected a lower percentage of B cells compared with IL-A30 or the mAb against total Ig. They both reacted with a proportion of the serum IgM from these animals, while IL-A30 reacted with all serum IgM. Therefore, it is probable that mAb-A30 recognizes an IgM isotypic determinant and mAbs IL-A50 and B5/4 recognize different IgM allotypic determinants. Using mAb IL-A30 it was found that the percentage of peripheral blood IgM+ lymphocytes varied widely between healthy cattle (4-31%) but remained constant, with only minor variations, within individual animals. [ABSTRACT FROM AUTHOR]

Rationale: Postpartum haemorrhage (PPH) is responsible for around 27% of global maternal deaths. Perineal tears are common in vaginal births and a significant contributor to excessive blood loss. A diversity of perineal techniques are utilised to prevent perineal trauma and reduce the incidence of PPH; however, they lack evidence-based comparisons to understand their effects., Objectives: To assess the effect of perineal techniques during the second stage of labour on the incidence of and morbidity associated with perineal trauma to prevent postpartum complications., Search Methods: We searched four databases and two trial registers up to 16 April 2024. We checked references, searched citations and contacted study authors to identify additional studies., Eligibility Criteria: We included randomised controlled trials (RCTs) of women in the second stage of labour who intended to give birth vaginally, comparing any perineal techniques with control or another perineal technique. We excluded studies that performed perineal techniques outside the second stage of labour., Outcomes: Our critical outcomes were second-, third- and fourth-degree tears measured immediately after birth, and PPH ≥ 500 mL measured within 24 hours after birth., Risk of Bias: We used the Cochrane risk of bias 2 tool to assess bias in the included RCTs., Synthesis Methods: We synthesised results for each outcome within each comparison using meta-analysis where possible. Where this was not possible due to the nature of the data, we synthesised results narratively. We used GRADE to assess the certainty of evidence for each outcome., Included Studies: We included a total of 17 studies with 13,695 participants., Synthesis of Results: Hands off (or poised) versus hands on Hands off (poised) may result in little to no difference in second-degree tears (risk ratio (RR) 0.73, 95% confidence interval (CI) 0.32 to 1.64; 2 studies; low-certainty evidence) and third- or fourth-degree tears when data are combined (RR 1.27, 95% CI 0.81 to 1.99; 2 studies; low-certainty evidence). The evidence is very uncertain about the effect of hands off (poised) on third-degree tears and fourth-degree tears when reported separately (RR 0.50, 95% CI 0.05 to 5.27; 1 study; very low-certainty evidence and RR 3.00, 95% CI 0.13 to 71.22; 1 study; very low-certainty evidence). Hands off (poised) may result in little to no difference in PPH ≥ 500 mL (RR 1.16, 95% CI 0.92 to 1.47; 1 study; low-certainty evidence). Hands off (poised) probably results in little to no difference in breastfeeding two days after birth (RR 1.02, 95% CI 0.99 to 1.06; 1 study; moderate-certainty evidence) and perineal pain (RR 0.98, 95% CI 0.94 to 1.01; 1 study; moderate-certainty evidence). Vocalisation versus control Vocalisation may result in a reduction in second-degree tears (RR 0.56, 95% CI 0.23 to 1.38; 1 study; low-certainty evidence) and third-degree tears (RR 0.13, 95% CI 0.01 to 2.32; 1 study; low-certainty evidence), but the CIs are wide and include the possibility of no effect. No events were reported for fourth-degree tears (low-certainty evidence). Vocalisation may increase maternal satisfaction (RR 1.19, 95% CI 0.93 to 1.51; 1 study; low-certainty evidence). The evidence is very uncertain about the effect of vocalisation on perineal pain (RR 1.44, 95% CI 0.81 to 2.58; 1 study; very low-certainty evidence). Warm compress on the perineum versus control (hands off or no warm compress) Warm compress on the perineum may result in little to no difference in second-degree tears (RR 0.94, 95% CI 0.72 to 1.21; 2 studies; low-certainty evidence), but likely results in a reduction in third- or fourth-degree tears (RR 0.46, 95% CI 0.27 to 0.79; 3 studies; moderate-certainty evidence). Evidence from two smaller studies is very uncertain about the effect of warm compress on the perineum on third-degree tears (RR 0.51, 95% CI 0.04 to 7.05; 2 studies; very low-certainty evidence) or fourth-degree tears (RR 0.11, 95% CI 0.01 to 2.06; 2 studies; very low-certainty evidence) when reported separately. Warm compress likely results in a large reduction in perineal pain (mean difference (MD) -0.81, 95% CI -1.18 to -0.44; 1 study; moderate-certainty evidence). The evidence is very uncertain about the effect of warm compress on the perineum on maternal satisfaction and PPH ≥ 500 mL. Massage of the perineum versus control (hands off or no usual care) Massage of the perineum may have little to no effect on second-degree tears (RR 1.04, 95% CI 0.89 to 1.21; 4 studies; low-certainty evidence). The evidence is very uncertain about the effect of massage of the perineum on third-degree tears (RR 0.57, 95% CI 0.16 to 2.02; 4 studies; very low-certainty evidence). Massage of the perineum may reduce fourth-degree tears but the CIs are wide and include the possibility of no effect (RR 0.26, 95% CI 0.04 to 1.61; 4 studies; low-certainty evidence). The evidence suggests that massage likely results in little to no difference in perineal pain (RR 0.97, 95% CI 0.90, 1.05; 1 study; moderate-certainty evidence). One study reported 10 participants with postpartum haemorrhage across three interventions (warm compress, massage, control). Combined warm compress and massage of the perineum versus control Combined warm compress and massage of the perineum likely results in a reduction in second-degree tears when compared to a control (RR 0.63, 95% CI 0.46 to 0.86; 1 study; moderate-certainty evidence), but the evidence is very uncertain about the effect on third-degree tears (RR 2.92, 95% CI 0.12 to 70.72; 1 study; very low-certainty evidence). The intervention may result in a reduction in PPH ≥ 500 mL but the CIs are wide and include the possibility of no effect (RR 0.43, 95% CI 0.14 to 1.35; 1 study; low-certainty evidence). Combined warm compress and massage likely results in an increase in maternal satisfaction (MD 0.4, 95% CI -0.01 to 0.81; 1 study; moderate-certainty evidence). Combined warm compress and massage of the perineum versus massage alone Combined warm compress and massage of the perineum may result in little to no difference in second-degree tears (RR 0.95, 95% CI 0.86 to 1.06; 1 study; low-certainty evidence) when compared to massage alone, but the evidence is very uncertain about the effect on third- or fourth-degree tears (RR 0.98, 95% CI 0.06 to 15.49; 1 study; very low-certainty evidence). It may also result in little to no difference in PPH ≥ 500 mL (RR 1.10, 95% CI 0.59 to 2.07; 1 study; low-certainty evidence). The evidence suggests that combined warm compress and massage may result in little to no difference in maternal satisfaction (1 study; low-certainty evidence). Other perineal techniques We also assessed evidence on the following comparisons, but since they are used less frequently in global clinical practice to optimise birth outcomes, we have not presented the results summary here: Ritgen's manoeuvre versus standard care; primary delivery of posterior versus anterior shoulder; massage with enriched oil on the perineum versus massage with liquid wax; petroleum jelly on the perineum versus control; and perineal protection device versus control., Authors' Conclusions: Overall, the evidence for the effectiveness of perineal techniques to reduce perineal trauma and postpartum haemorrhage is very uncertain. Very few studies reported rates of postpartum haemorrhage, adverse events, women's or health workers' experience or other important outcomes that allow us to understand the effectiveness and acceptability of perineal techniques to reduce perineal trauma. Prior to any further large trials, research is needed to clarify the types of interventions, including a clear description of the process of development and involvement of relevant stakeholders. There is a need to clarify how the intervention is proposed to achieve its effects. Trials would benefit from process evaluation alongside, to explore context, mechanisms and effects., Funding: This Cochrane review was funded (in part) by WHO (APW 2024/1475460). TF, VL and the CIDG editorial base are funded by UK aid from the UK government for the benefit of low- and middle-income countries (project number 300342-104). The views expressed do not necessarily reflect the UK government's official policies., Registration: Registration and protocol: PROSPERO, CRD42024537252. Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024537252., (Copyright © 2024 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Background: Tuberculosis (TB) remains a significant cause of mortality globally, yet first-line treatment has hardly changed for fifty years. The dose of rifampicin, the most important drug in this regimen, has been historically based on pragmatic cost- and risk-benefit considerations. Evidence suggests the current recommended dose (8-12 mg/kg) may not maximise the potential benefits of this drug. We sought to evaluate the efficacy and safety of higher doses of rifampicin in adults with presumed drug-susceptible TB., Methods: In this systematic review we searched MEDLINE, EMBASE, CENTRAL and Global Health databases for randomised controlled trials up to 31 July 2024 of adults with presumed drug-susceptible TB receiving first-line treatment with an intervention of rifampicin doses higher than currently recommended. Meta-analyses were performed using random effects models where background regimens were the same. Risk ratio was used as the measure for treatment effect. Outcomes of interest related to efficacy and safety., Findings: Of the 5441 total records identified by our searches, nineteen studies (6332 patients, 31.0% female) were eligible for the systematic review and twelve (3763 patients, 31.0% female) for meta-analysis. Rifampicin doses varied from 8 to 35 mg/kg and implementation of the intervention varied between trials. There was no evidence for increased efficacy with higher doses of rifampicin, however the majority of trials investigated minimally increased doses (up to 20 mg/kg). At higher doses (>20 mg/kg), there may be evidence of increased risk of drug-induced liver injury, albeit with no consistent dose-response relationship., Interpretation: Evidence on the efficacy of higher doses of rifampicin in the first-line regimen for TB remains incomplete. While higher doses appear generally safe, the risk of drug-induced liver injury may be increased above doses of 20 mg/kg. Larger clinical trials reporting definitive outcomes are needed to determine whether dosing up to 40 mg/kg could safely improve treatment outcomes or reduce duration of first-line therapy., Funding: WHO, Wellcome Trust., Competing Interests: GD was supported by a consultancy contract from WHO for the initial published version of this review and chaired the Data Safety Monitoring Board for RIFASHORT and the Trial Steering Committee for TRUNCATE-TB. All other authors declare no competing interests., (© 2024 The Author(s).)

No accurate and rapid diagnostic test exists for tuberculous meningitis (TBM), leading to delayed diagnosis. We leveraged data from multiple studies to improve the predictive performance of diagnostic models across different populations, settings, and subgroups to develop a new predictive tool for TBM diagnosis. We conducted a systematic review to analyze eligible datasets with individual-level participant data (IPD). We imputed missing data and explored three approaches: stepwise logistic regression, classification and regression tree (CART), and random forest regression. We evaluated performance using calibration plots and C-statistics via internal-external cross-validation. We included 3,761 individual participants from 14 studies and nine countries. A total of 1,240 (33%) participants had "definite" (30%) or "probable" (3%) TBM by case definition. Important predictive variables included cerebrospinal fluid (CSF) glucose, blood glucose, CSF white cell count, CSF differential, cryptococcal antigen, HIV status, and fever presence. Internal validation showed that performance varied considerably between IPD datasets with C-statistic values between 0.60 and 0.89. In external validation, CART performed the worst (C = 0.82), and logistic regression and random forest had the same accuracy (C = 0.91). We developed a mobile app for TBM clinical prediction that accounted for heterogeneity and improved diagnostic performance (https://tbmcalc.github.io/tbmcalc). Further external validation is needed.

Objectives: To make inferences regarding the effectiveness of respiratory interventions and case isolation measures in reducing or preventing the transmission of mpox based on synthesis of available literature., Methods: The WHO Clinical Management and Infection Prevention and Control 2022 guideline and droplet precautions in healthcare facilities and home isolation infection prevention control measures for patients with mpox. We conducted a systematic review that included a broad search of five electronic databases. In a two-stage process, we initially sought only randomized controlled trials and observational comparative studies; when the search failed to yield eligible studies, the subsequent search included all study designs including clinical and environmental sampling studies., Results: No studies were identified that directly addressed airborne and droplet precautions and home isolation infection prevention control measures. To inform the review questions the review team synthesized route of transmission data in mpox. There were 2366/4309 (54.9%) cases in which investigators identified mpox infection occurring following transmission through direct physical sexual contact. There were no reported mpox cases in which investigators identified inhalation as a single route of transmission. There were 2/4309 cases in which investigators identified fomite as a single route of transmission. Clinical and environmental sampling studies isolated mpox virus in a minority of saliva, oropharangeal swabs, mpox skin lesions, and hospital room air., Conclusions: Current findings provide compelling evidence that transmission of mpox occurs through direct physical contact. Because investigators have not reported any cases of transmission via inhalation alone, the impact of airborne and droplet infection prevention control measures in reducing transmission will be minimal. Avoiding physical contact with others, covering mpox lesions and wearing a medical mask is likely to reduce onward mpox transmission; there may be minimal reduction in transmission from additionally physically isolating patients with mild disease at home., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kuehn et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Acute otitis media (AOM) is one of the most common childhood infectious diseases. Pain is the key symptom of AOM and central to children's and parents' experience of the illness. Because antibiotics provide only marginal benefits, analgesic treatment including paracetamol (acetaminophen) and non-steroidal anti-inflammatory drugs (NSAIDs) is regarded as the cornerstone of AOM management. This is an update of a review first published in 2016., Objectives: Our primary objective was to assess the effectiveness of paracetamol (acetaminophen) or NSAIDs, alone or combined, compared with placebo or no treatment in relieving pain in children with AOM. Our secondary objective was to assess the effectiveness of NSAIDs as compared with paracetamol in children with AOM., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Issue 5, April 2023; MEDLINE (Ovid, from 1946 to May 2023), Embase (from 1947 to May 2023), CINAHL (from 1981 to May 2023), LILACS (from 1982 to May 2023), and Web of Science Core Collection (from 1955 to May 2023). We searched the WHO ICTRP and ClinicalTrials.gov for completed and ongoing trials (23 May 2023)., Selection Criteria: We included randomised controlled trials comparing the effectiveness of paracetamol or NSAIDs, alone or combined, for pain relief in non-hospitalised children aged six months to 16 years with AOM. We also included trials of paracetamol or NSAIDs, alone or combined, for children with fever or upper respiratory tract infections if we were able to extract subgroup data on pain relief in children with AOM either directly or after obtaining additional data from study authors. We extracted and summarised data for the following comparisons: paracetamol versus placebo, NSAIDs versus placebo, NSAIDs versus paracetamol, and NSAIDs plus paracetamol versus paracetamol alone., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane. We rated the overall certainty of evidence for each outcome of interest using the GRADE approach., Main Results: We included four trials (411 children) which were assessed at low to high risk of bias. Paracetamol versus placebo Data from one trial (148 children) informed this comparison. Paracetamol may be more effective than placebo in relieving pain at 48 hours (proportion of children with pain 10% versus 25%, risk ratio (RR) 0.38, 95% confidence interval (CI) 0.17 to 0.85; number needed to treat for an additional beneficial outcome (NNTB) 7; low-certainty evidence). The evidence is very uncertain about the effects of paracetamol on fever at 48 hours (RR 1.03, 95% CI 0.07 to 16.12; very low-certainty evidence) and adverse events (RR 1.03, 95% CI 0.21 to 4.93; very low-certainty evidence). No data were available for our other outcomes of interest. NSAIDs versus placebo Data from one trial (146 children) informed this comparison. Ibuprofen may be more effective than placebo in relieving pain at 48 hours (proportion of children with pain 7% versus 25%, RR 0.28, 95% CI 0.11 to 0.70; NNTB 6; low-certainty evidence). The evidence is very uncertain about the effect of ibuprofen on fever at 48 hours (RR 1.06, 95% CI 0.07 to 16.57; very low-certainty evidence) and adverse events (RR 1.76, 95% CI 0.44 to 7.10; very low-certainty evidence). No data were available for our other outcomes of interest. NSAIDs versus paracetamol Data from four trials (411 children) informed this comparison. The evidence is very uncertain about the effect of ibuprofen versus paracetamol in relieving ear pain at 24 hours (RR 0.83, 95% CI 0.59 to 1.18; 2 RCTs, 39 children; very low-certainty evidence); 48 to 72 hours (RR 0.91, 95% CI 0.54 to 1.54; 3 RCTs, 183 children; low-certainty evidence); and four to seven days (RR 0.74, 95% CI 0.17 to 3.23; 2 RCTs, 38 children; very low-certainty evidence). The evidence is very uncertain about the effect of ibuprofen versus paracetamol on mean pain score at 24 hours (0.29 lower, 95% CI 0.79 lower to 0.20 higher; 3 RCTs, 111 children; very low-certainty evidence); 48 to 72 hours (0.25 lower, 95% CI 0.66 lower to 0.16 higher; 3 RCTs, 108 children; very low-certainty evidence); and four to seven days (0.30 higher, 95% CI 1.78 lower to 2.38 higher; 2 RCTs, 31 children; very low-certainty evidence). The evidence is very uncertain about the effect of ibuprofen versus paracetamol in resolving fever at 24 hours (RR 0.69, 95% CI 0.24 to 2.00; 2 RCTs, 39 children; very low-certainty evidence); 48 to 72 hours (RR 1.18, 95% CI 0.31 to 4.44; 3 RCTs, 182 children; low-certainty evidence); and four to seven days (RR 2.75, 95% CI 0.12 to 60.70; 2 RCTs, 39 children; very low-certainty evidence). The evidence is very uncertain about the effect of ibuprofen versus paracetamol on adverse events (RR 1.71, 95% CI 0.43 to 6.90; 3 RCTs, 281 children; very low-certainty evidence); reconsultations (RR 1.13, 95% CI 0.92 to 1.40; 1 RCT, 53 children; very low-certainty evidence); and delayed antibiotic prescriptions (RR 1.32, 95% CI 0.74 to 2.35; 1 RCT, 53 children; very low-certainty evidence). No data were available on time to resolution of pain. NSAIDs plus paracetamol versus paracetamol alone Data on the effectiveness of ibuprofen plus paracetamol versus paracetamol alone came from two trials that provided crude subgroup data for 71 children with AOM. The small sample provided imprecise effect estimates, therefore we were unable to draw any firm conclusions (very low-certainty evidence)., Authors' Conclusions: Despite explicit guideline recommendations on the use of analgesics in children with AOM, the current evidence on the effectiveness of paracetamol or NSAIDs, alone or combined, in children with AOM is limited. Paracetamol and ibuprofen as monotherapies may be more effective than placebo in relieving short-term ear pain in children with AOM. The evidence is very uncertain for the effect of ibuprofen versus paracetamol on relieving short-term ear pain in children with AOM, as well as for the effectiveness of ibuprofen plus paracetamol versus paracetamol alone, thereby preventing any firm conclusions. Further research is needed to provide insights into the role of ibuprofen as adjunct to paracetamol, and other analgesics such as anaesthetic eardrops, for children with AOM., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Long COVID occurs in those infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) whose symptoms persist or develop beyond the acute phase. We conducted a systematic review to determine the prevalence of persistent symptoms, functional disability, or pathological changes in adults or children at least 12 weeks postinfection., Methods: We searched key registers and databases from January 1, 2020 to November 2, 2021, limited to publications in English and studies with at least 100 participants. Studies in which all participants were critically ill were excluded. Long COVID was extracted as prevalence of at least 1 symptom or pathology, or prevalence of the most common symptom or pathology, at 12 weeks or later. Heterogeneity was quantified in absolute terms and as a proportion of total variation and explored across predefined subgroups (PROSPERO ID CRD42020218351)., Results: One hundred twenty studies in 130 publications were included. Length of follow-up varied between 12 weeks and 12 months. Few studies had low risk of bias. All complete and subgroup analyses except 1 had I 2 ≥90%, with prevalence of persistent symptoms range of 0%-93% (pooled estimate [PE], 42.1%; 95% prediction interval [PI], 6.8% to 87.9%). Studies using routine healthcare records tended to report lower prevalence (PE, 13.6%; PI, 1.2% to 68%) of persistent symptoms/pathology than self-report (PE, 43.9%; PI, 8.2% to 87.2%). However, studies systematically investigating pathology in all participants at follow up tended to report the highest estimates of all 3 (PE, 51.7%; PI, 12.3% to 89.1%). Studies of hospitalized cases had generally higher estimates than community-based studies., Conclusions: The way in which Long COVID is defined and measured affects prevalence estimation. Given the widespread nature of SARS-CoV-2 infection globally, the burden of chronic illness is likely to be substantial even using the most conservative estimates., Competing Interests: Potential conflicts of interest. DCG is a coinvestigator on the NIHR-funded LOCOMOTION study. NAA has lived experience of Long COVID, is a coinvestigator on the NIHR-funded STIMULATE-ICP and HI-COVE studies, has contributed in an advisory capacity to World Health Organization (WHO) and the European Union Commission's Expert Panel on effective ways of investing in health meetings in relation to post-COVID-19 condition, and has acted as a collaborator on some of the UK's Office for National Statistics outputs on the prevalence of Long COVID. AA has lived experience of Long COVID, is a co-founder of the Patient-Led Research Collaborative, and has contributed in an advisory capacity to National Institutes of Health, Centers for Disease Control and Prevention, and WHO. All authors: No reported conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Mpox was declared a Public Health Emergency of International Concern (PHEIC) by the World Health Organization (WHO) on 23 July 2022, following the identification of thousands of cases in several non-endemic countries in previous months. There are currently no licenced therapeutics for treating mpox; however, some medications may be authorized for use in an outbreak. The efficacy and safety of possible therapeutic options has not been studied in humans with mpox. There is a need to investigate the evidence on safety and effectiveness of treatments for mpox in humans; should any therapeutic option be efficacious and safe, it may be approved for use around the world., Objectives: There are two parts to this Cochrane Review: a review of evidence from randomized controlled trials (RCTs), and a narrative review of safety data from non-randomized studies. Randomized controlled trials review To systematically review the existing evidence on the effectiveness of therapeutics for mpox infection in humans compared to: a) another different therapeutic for mpox, or b) placebo, or c) supportive care, defined as the treatment of physical and psychological symptoms arising from the disease. Non-randomized studies review To assess the safety of therapeutics for mpox infection from non-randomized studies (NRS)., Search Methods: Randomized controlled trials review We searched the following databases up to 25 January 2023: MEDLINE (OVID), Embase (OVID), Biosis previews (Web of Science), CAB Abstracts (Web of science), and Cochrane CENTRAL (Issue 1 2023). We conducted a search of trial registries (Clinicaltrials.gov and International Clinical Trials Registry Platform (ICTRP)) on 25 January 2023. There were no date or language limits placed on the search. We undertook a call to experts in the field for relevant studies or ongoing trials to be considered for inclusion in the review. Non-randomized studies review We searched the following databases on 22 September 2022: Cochrane Central Register of Controlled Trials (CENTRAL; Issue 9 of 12, 2022), published in the Cochrane Library; MEDLINE (Ovid); Embase (Ovid); and Scopus (Elsevier). We also searched the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov for trials in progress., Selection Criteria: For the RCT review and the narrative review, any therapeutic for the treatment of mpox in humans was eligible for inclusion, including tecovirimat, brincidofovir, cidofovir, NIOCH-14, immunomodulators, and vaccine immune globulin. Randomized controlled trials review Studies were eligible for the main review if they were of randomized controlled design and investigated the effectiveness or safety of therapeutics in human mpox infection. Non-randomized studies review Studies were eligible for inclusion in the review of non-randomized studies if they were of non-randomized design and contained data concerning the safety of any therapeutic in human mpox infection., Data Collection and Analysis: Randomized controlled trials review Two review authors independently applied study inclusion criteria to identify eligible studies. If we had identified any eligible studies, we planned to assess the risk of bias, and report results with 95% confidence intervals (CI). The critical outcomes were serious adverse events, development of disease-related complications, admission to hospital for non-hospitalized participants, pain as judged by any visual or numerical pain scale, level of virus detected in clinical samples, time to healing of all skin lesions, and mortality. We planned to perform subgroup analysis to explore whether the effect of the therapeutic on the planned outcomes was modified by disease severity and days from symptom onset to therapeutic administration. We also intended to explore the following subgroups of absolute effects: immunosuppression, age, and pre-existing skin disease. Non-randomized studies review One review author applied study inclusion criteria to identify eligible studies and extracted data. Studies of a non-randomized design containing data on the safety of therapeutics could not be meta-analyzed due to the absence of a comparator; we summarized these data narratively in an appendix., Main Results: Randomized controlled trials review We did not identify any completed RCTs investigating the effectiveness of therapeutics for treating mpox for the main review. We identified five ongoing trials that plan to assess the effectiveness of one therapeutic option, tecovirimat, for treating mpox in adults and children. One of these ongoing trials intends to include populations with, or at greater risk of, severe disease, which will allow an assessment of safety in more vulnerable populations. Non-randomized studies review Three non-randomized studies met the inclusion criteria for the narrative review, concerning data on the safety of therapeutics in mpox. Very low-certainty evidence from non-randomized studies of small numbers of people indicates no serious safety signals emerging for the use of tecovirimat in people with mpox infection, but a possible safety signal for brincidofovir. All three participants who received brincidofovir had raised alanine aminotransferase (ALT), but not bilirubin, suggesting mild liver injury. No study reported severe drug-induced liver injury with brincidofovir., Authors' Conclusions: Randomized controlled trials review This review found no evidence from randomized controlled trials concerning the efficacy and safety of therapeutics in humans with mpox. Non-randomized studies review Very low-certainty evidence from non-randomized studies indicates no serious safety signals emerging for the use of tecovirimat in people with mpox infection. In contrast, very low-certainty evidence raises a safety signal that brincidofovir may cause liver injury. This is also suggested by indirect evidence from brincidofovir use in smallpox. This warrants further investigation and monitoring. This Cochrane Review will be updated as new evidence becomes available to assist policymakers, health professionals, and consumers in making appropriate decisions for the treatment of mpox., (Copyright © 2023 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Background: Human African trypanosomiasis, or sleeping sickness, is a severe disease affecting people in the poorest parts of Africa. It is usually fatal without treatment. Conventional treatments require days of intravenous infusion, but a recently developed drug, fexinidazole, can be given orally. Another oral drug candidate, acoziborole, is undergoing clinical development and will be considered in subsequent editions.   OBJECTIVES: To evaluate the effectiveness and safety of currently used drugs for treating second-stage Trypanosoma brucei gambiense trypanosomiasis (gambiense human African trypanosomiasis, g-HAT)., Search Methods: On 14 May 2021, we searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database, BIOSIS, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform. We also searched reference lists of included studies, contacted researchers working in the field, and contacted relevant organizations., Selection Criteria: Eligible studies were randomized controlled trials that included adults and children with second-stage g-HAT, treated with anti-trypanosomal drugs currently in use., Data Collection and Analysis: Two review authors extracted data and assessed risk of bias; a third review author acted as an arbitrator if needed. The included trial only reported dichotomous outcomes, which we presented as risk ratio (RR) or risk difference (RD) with 95% confidence intervals (CI).   MAIN RESULTS: We included one trial comparing fexinidazole to nifurtimox combined with eflornithine (NECT). This trial was conducted between October 2012 and November 2016 in the Democratic Republic of the Congo and the Central African Republic, and included 394 participants. The study reported on efficacy and safety, with up to 24 months' follow-up.  We judged the study to be at low risk of bias in all domains except blinding;  as the route of administration and dosing regimens differed between treatment groups,  participants and personnel were not blinded, resulting in a high risk of performance bias.   Mortality with fexinidazole may be higher at 24 months compared to NECT. There were 9/264 deaths in the fexinidazole group and 2/130 deaths in the NECT group (RR 2.22, 95% CI 0.49 to 10.11; 394 participants; low-certainty evidence). None of the deaths were related to treatment. Fexinidazole likely results in an increase in the number of people relapsing during follow-up, with 14 participants in the fexinidazole group (14/264) and none in the NECT group (0/130) relapsing at 24 months (RD 0.05, 95% CI 0.02 to 0.08; 394 participants; moderate-certainty evidence).   We are uncertain whether there is any difference between the drugs regarding the incidence of serious adverse events at 24 months. (31/264 with fexinidazole and 13/130 with NECT group at 24 months). Adverse events were common with both drugs (247/264 with fexinidazole versus 121/130 with NECT), with no difference between groups (RR 1.01, 95% CI 0.95 to 1.06; 394 participants; moderate-certainty evidence).  AUTHORS' CONCLUSIONS: Oral treatment with fexinidazole is much easier to administer than conventional treatment, but deaths and relapse appear to be more common. However, the advantages or an oral option are considerable, in terms of convenience, avoiding hospitalisation and multiple intravenous infusions, thus increasing adherence., (Copyright © 2021 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Background: Mycobacterium Tuberculosis (TB) poses a substantial burden in sub-Saharan Africa and is the leading cause of death amongst infectious diseases. Randomised controlled trials (RCTs) are regarded as the gold standard for evaluating the effectiveness of interventions. We aimed to describe published TB treatment trials conducted in Africa., Methods: This is a cross-sectional study of published TB trials conducted in at least one African country. In November 2019, we searched three databases using the validated Africa search filter and Cochrane's sensitive trial string. Published RCTs conducted in at least one African country were included for analysis. Records were screened for eligibility. Co-reviewers assisted with duplicate data extraction. Extracted data included: the country where studies were conducted, publication dates, ethics statement, trial registration number, participant's age range. We used Cochrane's Risk of Bias criteria to assess methodological quality., Results: We identified 10,495 records; 175 trials were eligible for inclusion. RCTs were published between 1952 and 2019. The median sample size was 206 participants (interquartile range: 73-657). Most trials were conducted in South Africa (n = 83) and were drug therapy trials (n = 130). First authors were from 30 countries globally. South Africa had the most first authors (n = 55); followed by the United States of America (USA) (n = 28) and Great Britain (n = 14) with fewer other African countries contributing to the first author tally. Children under 13 years of age eligible to participate in the trials made up 17/175 trials (9.71%). International governments (n = 29) were the most prevalent funders. Ninety-four trials provided CONSORT flow diagrams. Methodological quality such as allocation concealment and blinding were poorly reported or unclear in most trials., Conclusions: By mapping African TB trials, we were able to identify potential research gaps. Many of the global north's researchers were found to be the lead authors in these African trials. Few trials tested behavioural interventions compared to drugs, and far fewer tested interventions on children compared to adults to improve TB outcomes. Lastly, funders and researchers should ensure better methodological quality reporting of trials., Competing Interests: The authors have declared that no competing interests exist.

Background: Tuberculous meningitis (TBM) is the most lethal and disabling form of tuberculosis. Delayed diagnosis and treatment, which is a risk factor for poor outcome, is caused in part by lack of availability of diagnostic tests that are both rapid and accurate. Several attempts have been made to develop clinical scoring systems to fill this gap, but none have performed sufficiently well to be broadly implemented. We aim to identify and validate a set of clinical predictors that accurately classify TBM using individual patient data (IPD) from published studies. Methods: We will perform a systematic review and obtain IPD from studies published from the year 1990 which undertook diagnostic testing for TBM in adolescents or adults using at least one of, microscopy for acid-fast bacilli, commercial nucleic acid amplification test for Mycobacterium tuberculosis or mycobacterial culture of cerebrospinal fluid.  Clinical data that have previously been shown to be associated with TBM, and can inform the final diagnosis, will be requested. The data-set will be divided into training and test/validation data-sets for model building. A predictive logistic model will be built using a training set with patients with definite TBM and no TBM. Should it be warranted, factor analysis may be employed, depending on evidence for multicollinearity or the case for including latent variables in the model. Discussion: We will systematically identify and extract key clinical parameters associated with TBM from published studies and use a 'big data' approach to develop and validate a clinical prediction model with enhanced generalisability. The final model will be made available through a smartphone application. Further work will be external validation of the model and test of efficacy in a randomised controlled trial., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Boyles T et al.)

Background: Prior to introducing pneumococcal conjugate vaccines (PCVs), Streptococcus pneumoniae was most commonly isolated from the middle ear fluid of children with acute otitis media (AOM). Reducing nasopharyngeal colonisation of this bacterium by PCVs may lead to a decline in AOM. The effects of PCVs deserve ongoing monitoring since studies from the post-PCV era report a shift in causative otopathogens towards non-vaccine serotypes and other bacteria. This updated Cochrane Review was first published in 2002 and updated in 2004, 2009, 2014, and 2019., Objectives: To assess the effect of PCVs in preventing AOM in children up to 12 years of age., Search Methods: We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, Web of Science, and two trials registers, ClinicalTrials.gov and WHO ICTRP, to 11 June 2020., Selection Criteria: Randomised controlled trials of PCV versus placebo or control vaccine., Data Collection and Analysis: We used the standard methodological procedures expected by Cochrane. The primary outcomes were frequency of all-cause AOM and adverse effects. Secondary outcomes included frequency of pneumococcal AOM and frequency of recurrent AOM (defined as three or more AOM episodes in six months or four or more in one year). We used GRADE to assess the certainty of the evidence., Main Results: We included 15 publications of 11 trials (60,733 children, range 74 to 37,868 per trial) of 7- to 11-valent PCVs versus control vaccines (meningococcus type C vaccine in three trials, and hepatitis A or B vaccine in eight trials). We included one additional publication of a previously included trial for this 2020 update. We did not find any relevant trials with the newer 13-valent PCV. Most studies were funded by pharmaceutical companies. Overall, risk of bias was low. In seven trials (59,415 children), PCVs were administered in early infancy, whilst four trials (1318 children) included children aged one year and over who were either healthy or had a history of respiratory illness. There was considerable clinical heterogeneity across studies, therefore we reported results from individual studies. PCV administered in early infancy PCV7 The licenced 7-valent PCV with CRM197 as carrier protein (CRM197-PCV7) was associated with a 6% (95% confidence interval (CI) -4% to 16%; 1 trial; 1662 children) and 6% (95% CI 4% to 9%; 1 trial; 37,868 children) relative risk reduction (RRR) in low-risk infants (moderate-certainty evidence), but was not associated with a reduction in all-cause AOM in high-risk infants (RRR -5%, 95% CI -25% to 12%). PCV7 with the outer membrane protein complex of Neisseria meningitidis serogroup B as carrier protein (OMPC-PCV7) was not associated with a reduction in all-cause AOM (RRR -1%, 95% CI -12% to 10%; 1 trial; 1666 children; low-certainty evidence). CRM197-PCV7 and OMPC-PCV7 were associated with 20% (95% CI 7% to 31%) and 25% (95% CI 11% to 37%) RRR in pneumococcal AOM, respectively (2 trials; 3328 children; high-certainty evidence), and CRM197-PCV7 with 9% (95% CI -12% to 27%) and 10% (95% CI 7% to 13%) RRR in recurrent AOM (2 trials; 39,530 children; moderate-certainty evidence). PHiD-CV10/11 The effect of a licenced 10-valent PCV conjugated to protein D, a surface lipoprotein of Haemophilus influenzae, (PHiD-CV10) on all-cause AOM in healthy infants varied from 6% (95% CI -6% to 17%; 1 trial; 5095 children) to 15% (95% CI -1% to 28%; 1 trial; 7359 children) RRR (low-certainty evidence). PHiD-CV11 was associated with 34% (95% CI 21% to 44%) RRR in all-cause AOM (1 trial; 4968 children; moderate-certainty evidence). PHiD-CV10 and PHiD-CV11 were associated with 53% (95% CI 16% to 74%) and 52% (95% CI 37% to 63%) RRR in pneumococcal AOM (2 trials; 12,327 children; high-certainty evidence), and PHiD-CV11 with 56% (95% CI -2% to 80%) RRR in recurrent AOM (1 trial; 4968 children; low-certainty evidence). PCV administered at a later age PCV7 We found no evidence of a beneficial effect on all-cause AOM of administering CRM197-PCV7 in children aged 1 to 7 years with a history of respiratory illness or frequent AOM (2 trials; 457 children; moderate-certainty evidence) and CRM197-PCV7 combined with a trivalent influenza vaccine in children aged 18 to 72 months with a history of respiratory tract infections (1 trial; 597 children; moderate-certainty evidence). CRM197-PCV9 In 1 trial including 264 healthy daycare attendees aged 1 to 3 years, CRM197-PCV9 was associated with 17% (95% CI -2% to 33%) RRR in parent-reported all-cause otitis media (very low-certainty evidence). Adverse events Nine trials reported on adverse effects (77,389 children; high-certainty evidence). Mild local reactions and fever were common in both groups, and occurred more frequently in PCV than in control vaccine groups: redness (< 2.5 cm): 5% to 20% versus 0% to 16%; swelling (< 2.5 cm): 5% to 12% versus 0% to 8%; and fever (< 39 °C): 15% to 44% versus 8% to 25%. More severe redness (> 2.5 cm), swelling (> 2.5 cm), and fever (> 39 °C) occurred less frequently (0% to 0.9%, 0.1% to 1.3%, and 0.4% to 2.5%, respectively) in children receiving PCV, and did not differ significantly between PCV and control vaccine groups. Pain or tenderness, or both, was reported more frequently in PCV than in control vaccine groups: 3% to 38% versus 0% to 8%. Serious adverse events judged to be causally related to vaccination were rare and did not differ significantly between groups, and no fatal serious adverse event judged causally related to vaccination was reported., Authors' Conclusions: Administration of the licenced CRM197-PCV7 and PHiD-CV10 during early infancy is associated with large relative risk reductions in pneumococcal AOM. However, the effects of these vaccines on all-cause AOM is far more uncertain based on low- to moderate-certainty evidence. We found no evidence of a beneficial effect on all-cause AOM of administering PCVs in high-risk infants, after early infancy, and in older children with a history of respiratory illness. Compared to control vaccines, PCVs were associated with an increase in mild local reactions (redness, swelling), fever, and pain and/or tenderness. There was no evidence of a difference in more severe local reactions, fever, or serious adverse events judged to be causally related to vaccination., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Uptake of human papillomavirus (HPV) vaccine remains low in many countries, although the bivalent and quadrivalent HPV vaccines given as a three-dose schedule are effective in the prevention of precancerous lesions of the cervix in women. Simpler immunisation schedules, such as those with fewer doses, might reduce barriers to vaccination, as may programmes that include males., Objectives: To evaluate the efficacy, immunogenicity, and harms of different dose schedules and different types of HPV vaccines in females and males., Search Methods: We conducted electronic searches on 27 September 2018 in Ovid MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL) (in the Cochrane Library), and Ovid Embase. We also searched the WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov (both 27 September 2018), vaccine manufacturer websites, and checked reference lists from an index of HPV studies and other relevant systematic reviews., Selection Criteria: We included randomised controlled trials (RCTs) with no language restriction. We considered studies if they enrolled HIV-negative males or females aged 9 to 26 years, or HIV-positive males or females of any age., Data Collection and Analysis: We used methods recommended by Cochrane. We use the term 'control' to refer to comparator products containing an adjuvant or active vaccine and 'placebo' to refer to products that contain no adjuvant or active vaccine. Most primary outcomes in this review were clinical outcomes. However, for comparisons comparing dose schedules, the included RCTs were designed to measure antibody responses (i.e. immunogenicity) as the primary outcome, rather than clinical outcomes, since it is unethical to collect cervical samples from girls under 16 years of age. We analysed immunogenicity outcomes (i.e. geometric mean titres) with ratios of means, clinical outcomes (e.g. cancer and intraepithelial neoplasia) with risk ratios or rate ratios and, for serious adverse events and deaths, we calculated odds ratios. We rated the certainty of evidence with GRADE., Main Results: We included 20 RCTs with 31,940 participants. The length of follow-up in the included studies ranged from seven months to five years. Two doses versus three doses of HPV vaccine in 9- to 15-year-old females Antibody responses after two-dose and three-dose HPV vaccine schedules were similar after up to five years of follow-up (4 RCTs, moderate- to high-certainty evidence). No RCTs collected clinical outcome data. Evidence about serious adverse events in studies comparing dose schedules was of very low-certainty owing to imprecision and indirectness (three doses 35/1159; two doses 36/1158; 4 RCTs). One death was reported in the three-dose group (1/898) and none in the two-dose group (0/899) (low-certainty evidence). Interval between doses of HPV vaccine in 9- to 14-year-old females and males Antibody responses were stronger with a longer interval (6 or 12 months) between the first two doses of HPV vaccine than a shorter interval (2 or 6 months) at up to three years of follow-up (4 RCTs, moderate- to high-certainty evidence). No RCTs collected data about clinical outcomes. Evidence about serious adverse events in studies comparing intervals was of very low-certainty, owing to imprecision and indirectness. No deaths were reported in any of the studies (0/1898, 3 RCTs, low-certainty evidence). HPV vaccination of 10- to 26-year-old males In one RCT there was moderate-certainty evidence that quadrivalent HPV vaccine, compared with control, reduced the incidence of external genital lesions (control 36 per 3081 person-years; quadrivalent 6 per 3173 person-years; rate ratio 0.16, 95% CI 0.07 to 0.38; 6254 person-years) and anogenital warts (control 28 per 2814 person-years; quadrivalent 3 per 2831 person-years; rate ratio 0.11, 95% CI 0.03 to 0.38; 5645 person-years). The quadrivalent vaccine resulted in more injection-site adverse events, such as pain or redness, than control (537 versus 601 per 1000; risk ratio (RR) 1.12, 95% CI 1.06 to 1.18, 3895 participants, high-certainty evidence). There was very low-certainty evidence from two RCTs about serious adverse events with quadrivalent vaccine (control 12/2588; quadrivalent 8/2574), and about deaths (control 11/2591; quadrivalent 3/2582), owing to imprecision and indirectness. Nonavalent versus quadrivalent vaccine in 9- to 26-year-old females and males Three RCTs were included; one in females aged 9- to 15-years (n = 600), one in females aged 16- to 26-years (n = 14,215), and one in males aged 16- to 26-years (n = 500). The RCT in 16- to 26-year-old females reported clinical outcomes. There was little to no difference in the incidence of the combined outcome of high-grade cervical epithelial neoplasia, adenocarcinoma in situ, or cervical cancer between the HPV vaccines (quadrivalent 325/6882, nonavalent 326/6871; OR 1.00, 95% CI 0.85 to 1.16; 13,753 participants; high-certainty evidence). The other two RCTs did not collect data about clinical outcomes. There were slightly more local adverse events with the nonavalent vaccine (905 per 1000) than the quadrivalent vaccine (846 per 1000) (RR 1.07, 95% CI 1.05 to 1.08; 3 RCTs, 15,863 participants; high-certainty evidence). Comparative evidence about serious adverse events in the three RCTs (nonavalent 243/8234, quadrivalent 192/7629; OR 0.60, 95% CI 0.14 to 2.61) was of low certainty, owing to imprecision and indirectness. HPV vaccination for people living with HIV Seven RCTs reported on HPV vaccines in people with HIV, with two small trials that collected data about clinical outcomes. Antibody responses were higher following vaccination with either bivalent or quadrivalent HPV vaccine than with control, and these responses could be demonstrated to have been maintained for up to 24 months in children living with HIV (low-certainty evidence). The evidence about clinical outcomes and harms for HPV vaccines in people with HIV is very uncertain (low- to very low-certainty evidence), owing to imprecision and indirectness., Authors' Conclusions: The immunogenicity of two-dose and three-dose HPV vaccine schedules, measured using antibody responses in young females, is comparable. The quadrivalent vaccine probably reduces external genital lesions and anogenital warts in males compared with control. The nonavalent and quadrivalent vaccines offer similar protection against a combined outcome of cervical, vaginal, and vulval precancer lesions or cancer. In people living with HIV, both the bivalent and quadrivalent HPV vaccines result in high antibody responses. For all comparisons of alternative HPV vaccine schedules, the certainty of the body of evidence about serious adverse events reported during the study periods was low or very low, either because the number of events was low, or the evidence was indirect, or both. Post-marketing surveillance is needed to continue monitoring harms that might be associated with HPV vaccines in the population, and this evidence will be incorporated in future updates of this review. Long-term observational studies are needed to determine the effectiveness of reduced-dose schedules against HPV-related cancer endpoints, and whether adopting these schedules improves vaccine coverage rates., (Copyright © 2019 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Background: Tuberculous meningitis (TBM) is the most lethal and disabling form of tuberculosis. Delayed diagnosis and treatment, which is a risk factor for poor outcome, is caused in part by lack of availability of diagnostic tests that are both rapid and accurate. Several attempts have been made to develop clinical scoring systems to fill this gap, but none have performed sufficiently well to be broadly implemented. We aim to identify and validate a set of clinical predictors that accurately classify TBM using individual patient data (IPD) from published studies. Methods: We will perform a systematic review and obtain IPD from studies published from the year 1990 which undertook diagnostic testing for TBM in adolescents or adults using at least one of, microscopy for acid-fast bacilli, commercial nucleic acid amplification test for Mycobacterium tuberculosis or mycobacterial culture of cerebrospinal fluid.  Clinical data that have previously been shown to be associated with TBM, and can inform the final diagnosis, will be requested. The data-set will be divided into training and test/validation data-sets for model building. A predictive logistic model will be built using a training set with patients with definite TBM and no TBM. Should it be warranted, factor analysis may be employed, depending on evidence for multicollinearity or the case for including latent variables in the model. Discussion: We will systematically identify and extract key clinical parameters associated with TBM from published studies and use a 'big data' approach to develop and validate a clinical prediction model with enhanced generalisability. The final model will be made available through a smartphone application. Further work will be external validation of the model and test of efficacy in a randomised controlled trial., Competing Interests: No competing interests were disclosed., (Copyright: © 2019 Boyles T et al.)

Background: Infectious disease epidemics are a constant threat, and while we can strengthen preparedness in advance, inevitably, we will sometimes be caught unaware by novel outbreaks. To address the challenge of rapidly identifying clinical research priorities in those circumstances, we developed and piloted a protocol for carrying out a systematic, rapid research needs appraisal (RRNA) of existing evidence within 5 days in response to outbreaks globally, with the aim to inform clinical research prioritization., Methods: The protocol was derived from rapid review methodologies and optimized through effective use of pre-defined templates and global time zones. It was piloted using a Lassa fever (LF) outbreak scenario. Databases were searched from 1969 to July 2017. Systematic reviewers based in Canada, the UK, and the Philippines screened and extracted data using a systematic review software. The pilot was evaluated through internal analysis and by comparing the research priorities identified from the data, with those identified by an external LF expert panel., Results: The RRNA pilot was completed within 5 days. To accommodate the high number of articles identified, data extraction was prioritized by study design and year, and the clinical research prioritization done post-day 5. Of 118 potentially eligible articles, 52 met the data extraction criteria, of which 46 were extracted within the 5-day time frame. The RRNA team identified 19 clinical research priorities; the expert panel independently identified 21, of which 11 priorities overlapped. Each method identified a unique set of priorities, showing that combining both methods for clinical research prioritization is more robust than using either method alone., Conclusions: This pilot study shows that it is feasible to carry out a systematic RRNA within 5 days in response to a (re-) emerging outbreak to identify gaps in existing evidence, as long as sufficient resources are identified, and reviewers are experienced and trained in advance. Use of an online systematic review software and global time zones effectively optimized resources. Another 3 to 5 days are recommended for review of the extracted data and to formulate clinical research priorities. The RRNA can be used for a "Disease X" scenario and should optimally be combined with an expert panel to ensure breadth and depth of coverage of clinical research priorities.

Norovirus (NoV) is the commonest cause of gastrointestinal disease in the United Kingdom and in many developed countries, causing diarrhea and vomiting in millions of cases worldwide annually. Transmission is most often mediated from person to person. NoV infection has, however, additionally been associated with the consumption of food, either through the consumption of food contaminated at source such as seafood, berries, and salad, or as a consequence of the foodstuff being contaminated in some way by a food handler during processing or serving. A systematic review of outbreaks attributed to NoV between January 2003 and July 2017 was conducted to assess the contribution of food handlers to the burden of NoV, and to identify foods commonly associated with NoV outbreaks. A total of 3021 articles were screened, of which 27 met the definition of confirmed foodborne outbreaks and 47 met the criteria for definite food-handler NoV outbreaks. Of all food types, shellfish were implicated in the greatest number of definite foodborne outbreaks. Food handlers contributed to definite food-handler outbreaks involving a diverse range of foodstuffs and in a wide variety of settings, including weddings and military establishments. More genotypes of NoV were found in people who were ill than in samples from food and food handlers. The potential for both food products and food handlers to contribute to the burden of NoV infection is demonstrated conclusively.

Background: Lone parents in high-income countries have high rates of poverty (including in-work poverty) and poor health. Employment requirements for these parents are increasingly common. 'Welfare-to-work' (WtW) interventions involving financial sanctions and incentives, training, childcare subsidies and lifetime limits on benefit receipt have been used to support or mandate employment among lone parents. These and other interventions that affect employment and income may also affect people's health, and it is important to understand the available evidence on these effects in lone parents., Objectives: To assess the effects of WtW interventions on mental and physical health in lone parents and their children living in high-income countries. The secondary objective is to assess the effects of welfare-to-work interventions on employment and income., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Ovid, Embase Ovid, PsycINFO EBSCO, ERIC EBSCO, SocINDEX EBSCO, CINAHL EBSCO, Econlit EBSCO, Web of Science ISI, Applied Social Sciences Index and Abstracts (ASSIA) via Proquest, International Bibliography of the Social Sciences (IBSS) via ProQuest, Social Services Abstracts via Proquest, Sociological Abstracts via Proquest, Campbell Library, NHS Economic Evaluation Database (NHS EED) (CRD York), Turning Research into Practice (TRIP), OpenGrey and Planex. We also searched bibliographies of included publications and relevant reviews, in addition to many relevant websites. We identified many included publications by handsearching. We performed the searches in 2011, 2013 and April 2016., Selection Criteria: Randomised controlled trials (RCTs) of mandatory or voluntary WtW interventions for lone parents in high-income countries, reporting impacts on parental mental health, parental physical health, child mental health or child physical health., Data Collection and Analysis: One review author extracted data using a standardised extraction form, and another checked them. Two authors independently assessed risk of bias and the quality of the evidence. We contacted study authors to obtain measures of variance and conducted meta-analyses where possible. We synthesised data at three time points: 18 to 24 months (T1), 25 to 48 months (T2) and 49 to 72 months (T3)., Main Results: Twelve studies involving 27,482 participants met the inclusion criteria. Interventions were either mandatory or voluntary and included up to 10 discrete components in varying combinations. All but one study took place in North America. Although we searched for parental health outcomes, the vast majority of the sample in all included studies were female. Therefore, we describe adult health outcomes as 'maternal' throughout the results section. We downgraded the quality of all evidence at least one level because outcome assessors were not blinded. Follow-up ranged from 18 months to six years. The effects of welfare-to-work interventions on health were generally positive but of a magnitude unlikely to have any tangible effects.At T1 there was moderate-quality evidence of a very small negative impact on maternal mental health (standardised mean difference (SMD) 0.07, 95% Confidence Interval (CI) 0.00 to 0.14; N = 3352; studies = 2)); at T2, moderate-quality evidence of no effect (SMD 0.00, 95% CI 0.05 to 0.05; N = 7091; studies = 3); and at T3, low-quality evidence of a very small positive effect (SMD -0.07, 95% CI -0.15 to 0.00; N = 8873; studies = 4). There was evidence of very small positive effects on maternal physical health at T1 (risk ratio (RR) 0.85, 95% CI 0.54 to 1.36; N = 311; 1 study, low quality) and T2 (RR 1.06, 95% CI 0.95 to 1.18; N = 2551; 2 studies, moderate quality), and of a very small negative effect at T3 (RR 0.97, 95% CI 0.91 to 1.04; N = 1854; 1 study, low quality).At T1, there was moderate-quality evidence of a very small negative impact on child mental health (SMD 0.01, 95% CI -0.06 to 0.09; N = 2762; studies = 1); at T2, of a very small positive effect (SMD -0.04, 95% CI -0.08 to 0.01; N = 7560; studies = 5), and at T3, there was low-quality evidence of a very small positive effect (SMD -0.05, 95% CI -0.16 to 0.05; N = 3643; studies = 3). Moderate-quality evidence for effects on child physical health showed a very small negative effect at T1 (SMD -0.05, 95% CI -0.12 to 0.03; N = 2762; studies = 1), a very small positive effect at T2 (SMD 0.07, 95% CI 0.01 to 0.12; N = 7195; studies = 3), and a very small positive effect at T3 (SMD 0.01, 95% CI -0.04 to 0.06; N = 8083; studies = 5). There was some evidence of larger negative effects on health, but this was of low or very low quality.There were small positive effects on employment and income at 18 to 48 months (moderate-quality evidence), but these were largely absent at 49 to 72 months (very low to moderate-quality evidence), often due to control group members moving into work independently. Since the majority of the studies were conducted in North America before the year 2000, generalisabilty may be limited. However, all study sites were similar in that they were high-income countries with developed social welfare systems., Authors' Conclusions: The effects of WtW on health are largely of a magnitude that is unlikely to have tangible impacts. Since income and employment are hypothesised to mediate effects on health, it is possible that these negligible health impacts result from the small effects on economic outcomes. Even where employment and income were higher for the lone parents in WtW, poverty was still high for the majority of the lone parents in many of the studies. Perhaps because of this, depression also remained very high for lone parents whether they were in WtW or not. There is a lack of robust evidence on the health effects of WtW for lone parents outside North America.

Background: Mefloquine is recommended in international health guidelines for preventing malaria in travellers. Reports of psychosis and suicide are often alluded to but are not clearly established., Methods: We carried out a systematic review of the literature to identify and critically appraise any reported death or parasuicide associated with mefloquine prophylaxis. We developed a comprehensive search that included publications up to 11 July 2017. We included case studies but excluded newspaper reports. Two authors independently appraised each death or parasuicide against a standardised causality assessment tool. The protocol was registered on PROSPERO (CRD42016041988)., Results: We identified 527 articles that required full-text retrieval; of these 17 were unique publications that reported deaths or parasuicide. Eight unique publications had sufficient detail to be included in causality assessment. We identified 2 deaths with a probable association that appeared to be idiosyncratic drug reactions; we categorised the remaining 8 deaths as "unlikely" to be related to mefloquine, or "unclassifiable". There was one parasuicide with a possible causal association. There were 9 additional publications that searched spontaneous drug reporting databases; none provided sufficient detail to perform a causality assessment., Conclusions: Overall, the number of deaths that we could reliably attribute to the prophylactic use of mefloquine is very low., (Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Lone parents in high-income countries have high rates of poverty (including in-work poverty) and poor health. Employment requirements for these parents are increasingly common. 'Welfare-to-work' (WtW) interventions involving financial sanctions and incentives, training, childcare subsidies and lifetime limits on benefit receipt have been used to support or mandate employment among lone parents. These and other interventions that affect employment and income may also affect people's health, and it is important to understand the available evidence on these effects in lone parents., Objectives: To assess the effects of WtW interventions on mental and physical health in lone parents and their children living in high-income countries. The secondary objective is to assess the effects of welfare-to-work interventions on employment and income., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Ovid, Embase Ovid, PsycINFO EBSCO, ERIC EBSCO, SocINDEX EBSCO, CINAHL EBSCO, Econlit EBSCO, Web of Science ISI, Applied Social Sciences Index and Abstracts (ASSIA) via Proquest, International Bibliography of the Social Sciences (IBSS) via ProQuest, Social Services Abstracts via Proquest, Sociological Abstracts via Proquest, Campbell Library, NHS Economic Evaluation Database (NHS EED) (CRD York), Turning Research into Practice (TRIP), OpenGrey and Planex. We also searched bibliographies of included publications and relevant reviews, in addition to many relevant websites. We identified many included publications by handsearching. We performed the searches in 2011, 2013 and April 2016., Selection Criteria: Randomised controlled trials (RCTs) of mandatory or voluntary WtW interventions for lone parents in high-income countries, reporting impacts on parental mental health, parental physical health, child mental health or child physical health., Data Collection and Analysis: One review author extracted data using a standardised extraction form, and another checked them. Two authors independently assessed risk of bias and the quality of the evidence. We contacted study authors to obtain measures of variance and conducted meta-analyses where possible. We synthesised data at three time points: 18 to 24 months (T1), 25 to 48 months (T2) and 49 to 72 months (T3)., Main Results: Twelve studies involving 27,482 participants met the inclusion criteria. Interventions were either mandatory or voluntary and included up to 10 discrete components in varying combinations. All but one study took place in North America. Although we searched for parental health outcomes, the vast majority of the sample in all included studies were female. Therefore, we describe adult health outcomes as 'maternal' throughout the results section. We downgraded the quality of all evidence at least one level because outcome assessors were not blinded. Follow-up ranged from 18 months to six years. The effects of welfare-to-work interventions on health were generally positive but of a magnitude unlikely to have any tangible effects.At T1 there was moderate-quality evidence of a very small negative impact on maternal mental health (standardised mean difference (SMD) 0.07, 95% Confidence Interval (CI) 0.00 to 0.14; N = 3352; studies = 2)); at T2, moderate-quality evidence of no effect (SMD 0.00, 95% CI 0.05 to 0.05; N = 7091; studies = 3); and at T3, low-quality evidence of a very small positive effect (SMD -0.07, 95% CI -0.15 to 0.00; N = 8873; studies = 4). There was evidence of very small positive effects on maternal physical health at T1 (risk ratio (RR) 0.85, 95% CI 0.54 to 1.36; N = 311; 1 study, low quality) and T2 (RR 1.06, 95% CI 0.95 to 1.18; N = 2551; 2 studies, moderate quality), and of a very small negative effect at T3 (RR 0.97, 95% CI 0.91 to 1.04; N = 1854; 1 study, low quality).At T1, there was moderate-quality evidence of a very small negative impact on child mental health (SMD 0.01, 95% CI -0.06 to 0.09; N = 2762; studies = 1); at T2, of a very small positive effect (SMD -0.04, 95% CI -0.08 to 0.01; N = 7560; studies = 5), and at T3, there was low-quality evidence of a very small positive effect (SMD -0.05, 95% CI -0.16 to 0.05; N = 3643; studies = 3). Moderate-quality evidence for effects on child physical health showed a very small negative effect at T1 (SMD -0.05, 95% CI -0.12 to 0.03; N = 2762; studies = 1), a very small positive effect at T2 (SMD 0.07, 95% CI 0.01 to 0.12; N = 7195; studies = 3), and a very small positive effect at T3 (SMD 0.01, 95% CI -0.04 to 0.06; N = 8083; studies = 5). There was some evidence of larger negative effects on health, but this was of low or very low quality.There were small positive effects on employment and income at 18 to 48 months (moderate-quality evidence), but these were largely absent at 49 to 72 months (very low to moderate-quality evidence), often due to control group members moving into work independently. Since the majority of the studies were conducted in North America before the year 2000, generalisabilty may be limited. However, all study sites were similar in that they were high-income countries with developed social welfare systems., Authors' Conclusions: The effects of WtW on health are largely of a magnitude that is unlikely to have tangible impacts. Since income and employment are hypothesised to mediate effects on health, it is possible that these negligible health impacts result from the small effects on economic outcomes. Even where employment and income were higher for the lone parents in WtW, poverty was still high for the majority of the lone parents in many of the studies. Perhaps because of this, depression also remained very high for lone parents whether they were in WtW or not. There is a lack of robust evidence on the health effects of WtW for lone parents outside North America.

Background: Human African trypanosomiasis, or sleeping sickness, is a painful and protracted disease affecting people in the poorest parts of Africa and is fatal without treatment. Few drugs are currently available for second-stage sleeping sickness, with considerable adverse events and variable efficacy., Objectives: To evaluate the effectiveness and safety of drugs for treating second-stage human African trypanosomiasis., Search Methods: We searched the Cochrane Infectious Diseases Group Specialized Register (January 2013), CENTRAL (The Cochrane Library Issue 12 2012) , MEDLINE (1966 to January 2013), EMBASE (1974 to January 2013), LILACS (1982 to January 2013 ), BIOSIS (1926-January 2013), mRCT (January 2013) and reference lists. We contacted researchers working in the field and organizations., Selection Criteria: Randomized and quasi-randomized controlled trials including adults and children with second-stage HAT, treated with anti-trypanosomal drugs., Data Collection and Analysis: Two authors (VL and AK) extracted data and assessed methodological quality; a third author (JS) acted as an arbitrator. Included trials only reported dichotomous outcomes, and we present these as risk ratio (RR) with 95% confidence intervals (CI)., Main Results: Nine trials with 2577 participants, all with Trypansoma brucei gambiense HAT, were included. Seven trials tested currently available drugs: melarsoprol, eflornithine, nifurtimox, alone or in combination; one trial tested pentamidine, and one trial assessed the addition of prednisolone to melarsoprol. The frequency of death and number of adverse events were similar between patients treated with fixed 10-day regimens of melarsoprol or 26-days regimens. Melarsoprol monotherapy gave fewer relapses than pentamidine or nifurtimox, but resulted in more adverse events.Later trials evaluate nifurtimox combined with eflornithine (NECT), showing this gives few relapses and is well tolerated. It also has practical advantages in reducing the frequency and number of eflornithine slow infusions to twice a day, thus easing the burden on health personnel and patients., Authors' Conclusions: Choice of therapy for second stage Gambiense HAT will continue to be determined by what is locally available, but eflornithine and NECT are likely to replace melarsoprol, with careful parasite resistance monitoring. We need research on reducing adverse effects of currently used drugs, testing different regimens, and experimental and clinical studies of new compounds, effective for both stages of the disease.

Background: Roma and Sinti in Italy are excluded from the rest of society, often live in precarious housing conditions and have poor access to health services. In Italy, the Roma and Sinti minority (.3% of the overall population) is scarcely represented if compared with other European countries., Methods: To establish what is known and how Roma and Sinti health is studied in Italy, we conducted a review of the scientific literature, including articles published between 2000 and 2010, found in Medline, Embase and Web of Science., Results: We analyzed 15 relevant articles out of 32 references. Four papers describe rare autosomal recessive disorders. Four illustrate outbreaks of measles. The remaining papers describe health conditions suffered by this minority. All but two, however, are based on data collected at health services., Conclusions: The lack of prevalence data and analysis of determinants is a detriment to the health of the Roma and Sinti populations in Italy. Participatory research and evidence-based interventions are needed to improve health outcomes and living conditions of the Roma and Sinti people.

The objective of this study was to analyse interventions for the prevention of overweight and obesity in children under 5 years of age. We carried out a systematic review focusing exclusively on randomized controlled trials (RCTs). Data sources include Medline, Cochrane Library, EMBASE, CINHAL, PsychInfo and Web of Science. Data were extracted from seventeen articles describing seven RCTs identified through electronic search, screening of references in systematic reviews, own files and contact with authors. RCTs were assessed with the Jadad scale. Four trials were carried out in preschool settings, one with an exclusive educational component, two with an exclusive physical activity component and one with both. Two trials were family-based, with education and counselling for parents and children. The remaining trial was carried out in maternity hospitals, with a training intervention on breastfeeding. None of the interventions had an effect in preventing overweight and obesity. The failure to show an effect may be due to the choice of outcomes, the quality of the RCTs, the suboptimal implementation of the interventions, the lack of focus on social and environmental determinants. More rigorous research is needed on interventions and on social and environmental factors that could impact on lifestyle., (© 2010 The Authors. obesity reviews © 2010 International Association for the Study of Obesity.)

Background: Nine out of ten deaths from malaria occur in sub-Saharan Africa. Various control measures have achieved some progress in the control of the disease, but malaria is still a major public health problem in Africa. Randomized controlled trials (RCTs) are universally considered the best study type to rigorously assess whether an intervention is effective. The study reported here provides a descriptive analysis of RCTs reporting interventions for the prevention and treatment of malaria conducted in Africa, with the aim of providing detailed information on their main clinical and methodological characteristics, that could be used by researchers and policy makers to help plan future research., Methods: Systematic searches for malaria RCTs were conducted using electronic databases (Medline, Embase, the Cochrane Library), and an African geographic search filter to identify RCTs conducted in Africa was applied. Results were exported to the statistical package STATA 8 to obtain a random sample from the overall data set. Final analysis of trial characteristics was done in a double blinded fashion by two authors using a standardized data extraction form., Results: A random sample of 92 confirmed RCTs (from a total of 943 reports obtained between 1948 and 2007) was prepared. Most trials investigated drug treatment in children with uncomplicated malaria. Few trials reported on treatment of severe malaria or on interventions in pregnant women. Most trials were of medium size (100-500 participants), individually randomized and based in a single centre. Reporting of trial quality was variable. Although three-quarter of trials provided information on participants' informed consent and ethics approval, more details are needed., Conclusions: The majority of malaria RCT conducted in Africa report on drug treatment and prevention in children; there is need for more research done in pregnant women. Sources of funding, informed consent and trial quality were often poorly reported. Overall, clearer reporting of trials is needed.

Background: Human African trypanosomiasis, or sleeping sickness, is a painful and protracted disease affecting people in the poorest parts of Africa and is fatal without treatment. Few drugs are currently available for second-stage sleeping sickness, with considerable adverse events and variable efficacy., Objectives: To evaluate the effectiveness and safety of drugs for treating second-stage human African trypanosomiasis., Search Strategy: We searched the Cochrane Infectious Diseases Group Specialized Register (May 2010), CENTRAL (The Cochrane Library Issue 3 2010) , MEDLINE (1966 to May 2010), EMBASE (1974 to May 2010), LILACS (1982 to May 2010 ), BIOSIS (1926-May 2010), mRCT (May 2010) and reference lists. We contacted researchers working in the field and organizations., Selection Criteria: Randomized and quasi-randomized controlled trials., Data Collection and Analysis: Two authors (VL and AK) extracted data and assessed methodological quality; a third author (JS) acted as an arbitrator. Included trials only reported dichotomous outcomes, and we present these as risk ratio (RR) with 95% confidence intervals (CI)., Main Results: Nine trials with 2577 participants, all with Trypansoma brucei gambiense HAT, were included. Seven trials tested currently available drugs: melarsoprol, eflornithine, nifurtimox, alone or in combination; one trial tested pentamidine, and one trial assessed the addition of prednisolone to melarsoprol. Fixed 10-day regimens of melarsoprol were found to be as effective as those of 26 days, with similar numbers of adverse events. Melarsoprol monotherapy gave fewer relapses than pentamidine or nifurtimox, but resulted in more adverse events.Later trials evaluate nifurtimox combined with eflornithine (NECT), showing this gives few relapses and is well tolerated. It also has practical advantages in reducing the burden on health personnel and patients, when compared to eflornithine monotherapy., Authors' Conclusions: Choice of therapy for second stage Gambiense HAT will continue to be determined by what is locally available, but eflornithine and NECT are likely to replace melarsoprol, with careful parasite resistance monitoring. We need research on reducing adverse effects of currently used drugs, testing different regimens, and experimental and clinical studies of new compounds, effective for both stages of the disease.

Cattle in Africa are a genetically diverse population that has resulted from successive introduction of Asian Bos indicus and European B. taurus cattle. However, analysis of mitochondrial genetic diversity in African cattle identified three lineages, one associated with Asian B. indicus, one with European B. taurus, and a third ascribed to an indigenous African sub-species of cattle. Due to their extended coevolution, indigenous African herbivores are generally tolerant to endemic African pathogens. We are interested in identifying alleles derived from the indigenous African cattle that may be associated with tolerance to African pathogens. An analysis of the locus which encodes the abundant plasma membrane-associated tyrosine phosphatase, CD45, identified three highly divergent allelic families in Kenya Boran cattle. Analysis of allelic distribution in a diverse range of cattle populations suggests a European B. taurus, an Asian B. indicus, and an African origin. This demonstrates not only significant allelic polymorphism at the CD45 locus in cattle but also convincing autosomal evidence for a distinct African sub-species of cattle. Furthermore, maximum-likelihood analysis of selection pressures revealed that the CD45 locus is subject to exceptionally strong natural selection which we suggest may be pathogen driven.

The mechanisms whereby trypanotolerant N'Dama cattle control infection with Trypanosoma congolense are unknown. Previous studies have suggested that the monocytes of N'Dama cattle are more highly activated during infection than those of trypanosusceptible Boran cattle. However, we have recently reported that the monocytes of Boran cattle have a reduced capacity to secrete nitric oxide during trypanosome infection. We therefore evaluated the production of nitric oxide by monocytes of trypanotolerant N'Dama cattle infected with T. congolense in response to interferon-gamma, bacterial lipopolysaccharide or trypanosome antigens. Interferon-gamma-induced nitric oxide production was decreased between days 25 and 76 of infection, while lipopolysaccharide-induced secretion of nitric oxide was increased at days 13 and again at day 76 post-infection. Trypanosome antigens did not elicit nitric oxide production. Analysis of interleukin-10 mRNA transcription in peripheral blood leucocytes revealed an increase at time points that coincided with decreased interferon-gamma-induced nitric oxide synthesis. In contrast, interferon-gamma mRNA expression was not changed during infection while tumour necrosis factor-alpha was slightly reduced at day 32 post-infection. Recombinant interleukin-10 suppressed interferon-gamma-induced nitric oxide and tumour necrosis factor-alpha secretion, but not lipopolysaccharide-induced nitric oxide secretion in cultures of peripheral blood mononuclear cells and monocytes of uninfected cattle. These results suggest that the nitric oxide response of monocytes to IFN-gamma but not lipopolysaccharide, is suppressed during infection. The kinetics of the upregulation of interleukin-10 and its biological activity indicate a possible association with the depression of nitric oxide production and control of tumour necrosis factor-alpha.

A comparison of T-cell-mediated immune responses in trypanotolerant N'Dama and susceptible Boran cattle during primary infection with tsetse-transmitted Trypanosoma congolense was conducted to assess whether different patterns of T-cell activation occurred during trypanosome infection. Proliferation and IFN-gamma synthesis in response to trypanosome antigens and to the mitogen Con A were measured in LNC before infection and 10 and 35 days postinfection. Phenotypic analysis of LNC was also carried out. No significant differences in the in vitro proliferation of LNC to VSG, to hsp70/BiP, or to Con A were detected between the breeds. In contrast, IFN-gamma production in response to Con A was higher in Boran cattle at 35 days p.i. A reduction in the number of CD2+ and CD4+ T-cells and an increase in the percentage of B-cells, CD8+ T-cells, and gamma delta T-cells during infection in both N'Dama and Boran was revealed by cytofluorimetric analysis of lymph node cells.

Trypanosomiasis is a serious constraint to livestock production in sub-Saharan Africa. Some breeds of cattle are genetically more resistant to the pathogenic effects of trypanosome infection. We measured B-cell activation and the quantity and isotype of antibody produced at the cellular level in six trypanotolerant N'Dama and five trypanosusceptible Boran cattle. The frequencies of spleen cells secreting total and parasite-specific IgM and IgG were measured prior to and 16, 28, and 35 days after a primary challenge with Trypanosoma congolense. Boran cattle had higher frequencies of splenic cells secreting IgM specific for trypanosome-derived variable surface glycoprotein (VSG), cysteine protease (congopain, CP), and heat shock protein (hsp 70/BiP) and the nonparasite antigen, ovalbumin, than did N'Dama cattle. In contrast, the number of VSG-specific IgG-secreting cells was significantly greater in N'Dama than in Boran cattle. During infection, low titers of anti-VSG IgM were detected transiently in the serum of all animals. However, N'Dama had significantly more VSG-specific IgG in blood than Boran during infection. The peripheral blood mononuclear cell population of N'Dama cattle contained a higher percentage of surface IgM-positive B-cells prior to and throughout infection than were found in the blood of Boran. In addition, during infection N'Dama cattle had more circulating lymphocytes that could be activated in vitro to undergo differentiation into IgM- and IgG-secreting cells. These findings demonstrate differences in the frequency of trypanosome-specific antibody-secreting cells in the spleen and in the activation state of B-cells in the blood between N'Dama and Boran cattle during a primary infection with T. congolense.

We examined the contribution of MHC class II-restricted T cells (CD4+), MHC class I-restricted T cells (CD8+), gamma/delta T cell receptor (TCR)+ T cells, B cells and macrophages to the development and control of in vitro proliferative responses of bovine lymphocytes to ovalbumin (OA). Cell populations for in vitro assay were obtained from peripheral blood (peripheral blood leukocytes, PBL) of OA-primed cattle. Specific cell populations were depleted or purified from PBL by staining with monoclonal antibodies (MAbs) against the appropriate differentiation antigens and sorting on a Fluorescence Activated Cell Sorter (FACS). OA-specific in vitro responses of in vivo primed PBL were dependent on the presence of CD4+ T cells. Their presence could not be replaced by the inclusion of T cell growth factor (TCGF) in the culture system, indicating that CD4+ T cells probably actively proliferate in response to antigenic stimulation. Bovine CD8+ T cells and gamma/delta TCR+ T cells appeared to exert a suppressive effect on proliferative responses. No proliferation was observed in PBL after the depletion of MHC class II+ cells. In this case, the response could be restored by the addition of macrophages or LPS-activated B cells to the MHC class II- population.