Pyronaridine‐artesunate for treating uncomplicated Plasmodium falciparum malaria

Background The World Health Organization (WHO) recommends artemisinin‐based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria. Concerns about artemisinin resistance have led to global initiatives to develop new partner drugs to protect artemisinin derivatives in ACT. Pyronaridine‐artesunate is a novel ACT. Objectives To evaluate the efficacy of pyronaridine‐artesunate compared to alternative ACTs for treating people with uncomplicated P falciparum malaria, and to evaluate the safety of pyronaridine‐artesunate and other pyronaridine treatments compared to alternative treatments. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE; Embase; and LILACS. We also searched ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform, and the ISRCTN registry for ongoing or recently completed trials. The date of the last search was 27 October 2021. Selection criteria For the efficacy analysis, we included randomized controlled trials (RCTs) of pyronaridine‐artesunate for treating uncomplicated P falciparum malaria. For the safety analysis, we included RCTs that used pyronaridine alone or in combination with any other antimalarials. In addition to these analyses, we conducted a separate systematic review summarizing data on safety from non‐randomized studies (NRS) of any patient receiving pyronaridine (NRS safety review). Data collection and analysis Two review authors independently extracted all data and assessed the certainty of the evidence. We meta‐analysed data to calculate risk ratios (RRs) for treatment failures between comparisons, and for safety outcomes between and across comparisons. Main results We included 10 relevant RCTs. Seven RCTs were co‐funded by Shin Poong Pharmaceuticals, and three were funded by government agencies. Efficacy analysis (RCTs) For the efficacy analysis, we identified five RCTs comprising 5711 participants. This included 4465 participants from 13 sites in Africa, and 1246 participants from five sites in Asia. The analysis included 541 children aged less than five years. Overall, pyronaridine‐artesunate had a polymerase chain reaction (PCR)‐adjusted treatment failure rate of less than 5%. We evaluated pyronaridine‐artesunate versus the following. • Artemether‐lumefantrine. Pyronaridine artesunate may perform better for PCR‐adjusted failures at day 28 (RR 0.59, 95% confidence interval (CI) 0.26 to 1.31; 4 RCTs, 3068 participants, low‐certainty evidence); for unadjusted failures at day 28 (RR 0.27, 95% CI 0.13 to 0.58; 4 RCTs, 3149 participants, low‐certainty evidence); and for unadjusted failures at day 42 (RR 0.61, 95% CI 0.46 to 0.82; 4 RCTs, 3080 participants, low‐certainty evidence). For PCR‐adjusted failures at day 42, there may be little or no difference between groups (RR 0.86, 95% CI 0.49 to 1.51; 4 RCTs, 2575 participants, low‐certainty evidence). • Artesunate‐amodiaquine. Pyronaridine artesunate may perform better for PCR‐adjusted failures at day 28 (RR 0.55, 95% CI 0.11 to 2.77; 1 RCT, 1245 participants, low‐certainty evidence); probably performs better for unadjusted failures at day 28 (RR 0.49, 95% CI 0.30 to 0.81; 1 RCT, 1257 participants, moderate‐certainty evidence); may make little or no difference for PCR‐adjusted failures at day 42 (RR 0.98, 95% CI 0.20 to 4.83; 1 RCT, 1091 participants, low‐certainty evidence); and probably makes little or no difference for unadjusted failures at day 42 (RR 0.98, 95% CI 0.78 to 1.23; 1 RCT, 1235 participants, moderate‐certainty evidence). • Mefloquine plus artesunate. Pyronaridine artesunate may perform better for PCR‐adjusted failures at day 28 (RR 0.37, 95% CI 0.13 to 1.05; 1 RCT, 1117 participants, low‐certainty evidence); probably performs better for unadjusted failures at day 28 (RR 0.36, 95% CI 0.17 to 0.78; 1 RCT, 1120 participants, moderate‐certainty evidence); may make little or no difference for unadjusted failures at day 42 (RR 0.84, 95% CI 0.54 to 1.31; 1 RCT, 1059 participants, low‐certainty evidence); but may lead to higher PCR‐adjusted failures at day 42 (RR 1.80, 95% CI 0.90 to 3.57; 1 RCT, 1037 participants, low‐certainty evidence). Safety analysis (RCTs) For the RCT safety analysis, we identified eight RCTs, one of which was delineated by study site, comparing pyronaridine‐artesunate to other antimalarials. Pyronaridine‐artesunate was associated with raised liver enzymes compared to other antimalarials: alanine aminotransferase (ALT) (RR 3.59, 95% CI 1.76 to 7.33; 8 RCTS, 6669 participants, high‐certainty evidence) and aspartate transaminase (AST) (RR 2.22, 95% CI 1.12 to 4.41; 8 RCTs, 6669 participants, moderate‐certainty evidence). No such effect was demonstrated with bilirubin (RR 1.03, 95% CI 0.49 to 2.18; 7 RCTs, 6384 participants, moderate‐certainty evidence). There was one reported case in which raised ALT occurred with raised bilirubin. No study reported severe drug‐induced liver injury. Electrocardiograph (ECG) abnormalities were less common with pyronaridine‐artesunate compared to other antimalarials. We identified no other safety concerns. NRS safety review A review on safety in NRS allowed us to increase the population within which safety was assessed. We included seven studies with 9546 participants: five single‐arm observational studies, one cohort event monitoring study, and one dose‐escalation study. All studies provided data on adverse event frequency, with a small number of participants experiencing serious adverse events and adverse effects related to pyronaridine: serious adverse events average 0.37%; drug‐related 9.0%. In two studies reporting elevations in liver enzymes, small percentages of participants (2.4% and 14.1% respectively) experienced increases in either ALT, AST, or bilirubin on day 7; however, these were small increases that returned to normal by day 42. Authors' conclusions Pyronaridine‐artesunate was efficacious against uncomplicated P falciparum malaria; achieved a PCR‐adjusted treatment failure rate of less than 5% at days 28 and 42; and may be at least as good as, or better than, other marketed ACTs. Pyronaridine‐artesunate increases the risk of episodes of abnormally raised ALT. The observational data did not signal an excess of clinically important adverse effects

Community views on mass drug administration for soil-transmitted helminths: a qualitative evidence synthesis

This is a protocol for a Cochrane Review (qualitative). The objectives are as follows: To synthesize qualitative research evidence about community experience with, and perception of, mass drug administration (MDA) programmes for soil‐transmitted helminths (STHs). To assess how findings confirm, extend, enrich, or conflict with those previously identified for MDA programmes for lymphatic filariasis

Challenging the current hypothesis that thrombosis is responsible for the post-COVID-19 condition

People with the post-COVID-19 condition suffer symptoms that persist beyond 12 weeks following acute COVID-19 infection. Fatigue, shortness of breath, and cognitive dysfunction (“brain fog”) are common. Scientists, clinicians, and patients debate the pathophysiology. One pathophysiological hypothesis is that prothrombotic changes associated with acute COVID-19 persist, causing clots that lead to symptoms. This theory, arising from a research team in South Africa and supported by a paper in Nature Medicine, has been widely disseminated on social media and entered the public narrative as a cause of the post-COVID-19 condition.We describe the development of this theory, examine the findings of a Cochrane review that critically appraises the “microclot” beliefs, and critically appraise the influential study relating clotting biomarkers to cognitive deficits. We conclude the inferences for the hypothesis are not based on evidence, unlicensed use of antithrombotic medication is not justified, and apheresis should not be considered outside of a well-designed clinical trial

Infection prevention and control measures to reduce the transmission of mpox: A systematic review

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

House modifications for preventing malaria

Background Malaria remains an important public health problem. Research in 1900 suggested house modifications may reduce malaria transmission. A previous version of this review concluded that house screening may be effective in reducing malaria. This update includes data from five new studies. Objectives To assess the effects of house modifications that aim to reduce exposure to mosquitoes on malaria disease and transmission. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register; Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE (PubMed); Embase (OVID); Centre for Agriculture and Bioscience International (CAB) Abstracts (Web of Science); and the Latin American and Caribbean Health Science Information database (LILACS) up to 25 May 2022. We also searched the World Health Organization International Clinical Trials Registry Platform, ClinicalTrials.gov, and the ISRCTN registry to identify ongoing trials up to 25 May 2022. Selection criteria Randomized controlled trials, including cluster‐randomized controlled trials (cRCTs), cross‐over studies, and stepped‐wedge designs were eligible, as were quasi‐experimental trials, including controlled before‐and‐after studies, controlled interrupted time series, and non‐randomized cross‐over studies. We sought studies investigating primary construction and house modifications to existing homes reporting epidemiological outcomes (malaria case incidence, malaria infection incidence or parasite prevalence). We extracted any entomological outcomes that were also reported in these studies. Data collection and analysis Two review authors independently selected eligible studies, extracted data, and assessed the risk of bias. We used risk ratios (RR) to compare the effect of the intervention with the control for dichotomous data. For continuous data, we presented the mean difference; and for count and rate data, we used rate ratios. We presented all results with 95% confidence intervals (CIs). We assessed the certainty of evidence using the GRADE approach. Main results One RCT and six cRCTs met our inclusion criteria, with an additional six ongoing RCTs. We did not identify any eligible non‐randomized studies. All included trials were conducted in sub‐Saharan Africa since 2009; two randomized by household and four at the block or village level. All trials assessed screening of windows, doors, eaves, ceilings, or any combination of these; this was either alone, or in combination with roof modification or eave tube installation (an insecticidal "lure and kill" device that reduces mosquito entry whilst maintaining some airflow). In one trial, the screening material was treated with 2% permethrin insecticide. In five trials, the researchers implemented the interventions. A community‐based approach was adopted in the other trial. Overall, the implementation of house modifications probably reduced malaria parasite prevalence (RR 0.68, 95% CI 0.57 to 0.82; 5 trials, 5183 participants; moderate‐certainty evidence), although an inconsistent effect was observed in a subpopulation of children in one study. House modifications reduced moderate to severe anaemia prevalence (RR 0.70, 95% CI 0.55 to 0.89; 3 trials, 3643 participants; high‐certainty evidence). There was no consistent effect on clinical malaria incidence, with rate ratios ranging from 0.38 to 1.62 (3 trials, 3365 participants, 4126.6 person‐years). House modifications may reduce indoor mosquito density (rate ratio 0.63, 95% CI 0.30 to 1.30; 4 trials, 9894 household‐nights; low‐certainty evidence), although two studies showed little effect on this parameter. Authors' conclusions House modifications – largely screening, sometimes combined with insecticide and lure and kill devices – were associated with a reduction in malaria parasite prevalence and a reduction in people with anaemia. Findings on malaria incidence were mixed. Modifications were also associated with lower indoor adult mosquito density, but this effect was not present in some studies

Prevalence, risk factors, and antimicrobial resistance of endemic healthcare-associated infections in Africa: a systematic review and meta-analysis

Background Healthcare-associated infections (HCAI) place a significant burden on healthcare systems globally. This systematic review and meta-analysis aimed to investigate the prevalence, risk factors, and aetiologic agents of endemic HCAI in Africa. Methods MEDLINE/PubMed, CINAHL, and Global Health databases (EBSCOhost interface) were searched for studies published in English and French describing HCAI in Africa from 2010 to 2022. We extracted data on prevalence of HCAI, risk factors, aetiologic agents, and associated antimicrobial resistance patterns. We used random-effects models to estimate parameter values with 95% confidence intervals for risk factors associated with HCAI. This study was registered in PROSPERO (CRD42022374559) and followed PRISMA 2020 guidelines. Results Of 2541 records screened, 92 were included, comprising data from 81,968 patients. Prevalence of HCAI varied between 1.6 and 90.2% with a median of 15% across studies. Heterogeneity (I2) varied from 93 to 99%. Contaminated wound (OR: 1.75, 95% CI: 1.31–2.19), long hospital stay (OR: 1.39, 95% CI: 0.92–1.80), urinary catheter (OR: 1.57, 95% CI: 0.35–2.78), intubation and ventilation (OR: 1.53, 95% CI: 0.85–2.22), vascular catheters (OR: 1.49, 95% CI: 0.52–2.45) were among risk factors associated with HCAI. Bacteria reported from included studies comprised 6463 isolates, with E. coli (18.3%, n = 1182), S. aureus (17.3%, n = 1118), Klebsiella spp. (17.2%, n = 1115), Pseudomonas spp. (10.3%, n = 671), and Acinetobacter spp. (6.8%, n = 438) being most common. Resistance to multiple antibiotics was common; 70.3% (IQR: 50–100) of Enterobacterales were 3rd -generation cephalosporin resistant, 70.5% (IQR: 58.8–80.3) of S. aureus were methicillin resistant and 55% (IQR: 27.3–81.3) Pseudomonas spp. were resistant to all agents tested. Conclusions HCAI is a greater problem in Africa than other regions, however, there remains a paucity of data to guide local action. There is a clear need to develop and validate sustainable HCAI definitions in Africa to support the implementation of routine HCAI surveillance and inform implementation of context appropriate infection prevention and control strategies

Plasmapheresis to remove amyloid fibrin(ogen) particles for treating the post‐COVID‐19 condition

Background The post‐COVID‐19 condition (PCC) consists of a wide array of symptoms including fatigue and impaired daily living. People seek a wide variety of approaches to help them recover. A new belief, arising from a few laboratory studies, is that 'microclots' cause the symptoms of PCC. This belief has been extended outside these studies, suggesting that to recover people need plasmapheresis (an expensive process where blood is filtered outside the body). We appraised the laboratory studies, and it was clear that the term 'microclots' is incorrect to describe the phenomenon being described. The particles are amyloid and include fibrin(ogen); amyloid is not a part of a thrombus which is a mix of fibrin mesh and platelets. Initial acute COVID‐19 infection is associated with clotting abnormalities; this review concerns amyloid fibrin(ogen) particles in PCC only. We have reported here our appraisal of laboratory studies investigating the presence of amyloid fibrin(ogen) particles in PCC, and of evidence that plasmapheresis may be an effective therapy to remove amyloid fibrin(ogen) particles for treating PCC. Objectives Laboratory studies review To summarize and appraise the research reports on amyloid fibrin(ogen) particles related to PCC. Randomized controlled trials review To assess the evidence of the safety and efficacy of plasmapheresis to remove amyloid fibrin(ogen) particles in individuals with PCC from randomized controlled trials. Search methods Laboratory studies review We searched for all relevant laboratory studies up to 27 October 2022 using a comprehensive search strategy which included the search terms ‘COVID’, ‘amyloid’, ‘fibrin’, ‘fibrinogen’. Randomized controlled trials review We searched the following databases on 21 October 2022: Cochrane COVID‐19 Study Register; MEDLINE (Ovid); Embase (Ovid); and BIOSIS Previews (Web of Science). We also searched the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov for trials in progress. Selection criteria Laboratory studies review Laboratory studies that investigate the presence of amyloid fibrin(ogen) particles in plasma samples from patients with PCC were eligible. This included studies with or without controls. Randomized controlled trials review Studies were eligible if they were of randomized controlled design and investigated the effectiveness or safety of plasmapheresis for removing amyloid fibrin(ogen) particles for treating PCC. Data collection and analysis Two review authors applied study inclusion criteria to identify eligible studies and extracted data. Laboratory studies review We assessed the risk of bias of included studies using pre‐developed methods for laboratory studies. We planned to perform synthesis without meta‐analysis (SWiM) as described in our protocol. Randomized controlled trials review We planned that if we identified any eligible studies, we would assess risk of bias and report results with 95% confidence intervals. The primary outcome was recovery, measured using the Post‐COVID‐19 Functional Status Scale (absence of symptoms related to the illness, ability to do usual daily activities, and a return to a previous state of health and mind). Main results Laboratory studies review We identified five laboratory studies. Amyloid fibrin(ogen) particles were identified in participants across all studies, including those with PCC, healthy individuals, and those with diabetes. The results of three studies were based on visual images of amyloid fibrin(ogen) particles, which did not quantify the amount or size of the particles identified. Formal risk of bias assessment showed concerns in how the studies were conducted and reported. This means the results were insufficient to support the belief that amyloid fibrin(ogen) particles are associated with PCC, or to determine whether there is a difference in the amount or size of amyloid fibrin(ogen) particles in the plasma of people with PCC compared to healthy controls. Randomized controlled trials review We identified no trials meeting our inclusion criteria. Authors' conclusions In the absence of reliable research showing that amyloid fibrin(ogen) particles contribute to the pathophysiology of PCC, there is no rationale for plasmapheresis to remove amyloid fibrin(ogen) particles in PCC. Plasmapheresis for this indication should not be used outside the context of a well‐conducted randomized controlled trial

Is routine Vitamin A supplementation still justified for children in Nepal? Trial synthesis findings applied to Nepal national mortality estimates

Background The World Health Organization has recommended Vitamin A supplementation for children in low- and middle-income countries for many years to reduce child mortality. Nepal still practices routine Vitamin A supplementation. We examined the potential current impact of these programs using national data in Nepal combined with an update of the mortality effect estimate from a meta-analysis of randomized controlled trials. Methods We used the 2017 Cochrane review as a template for an updated meta-analysis. We conducted fresh searches, re-applied the inclusion criteria, re-extracted the data for mortality and constructed a summary of findings table using GRADE. We applied the best estimate of the effect obtained from the trials to the national statistics of the country to estimate the impact of supplementation on under-five mortality in Nepal. Results The effect estimates from well-concealed trials gave a 9% reduction in mortality (Risk Ratio: 0.91, 95% CI 0.85 to 0.97, 6 trials; 1,046,829 participants; low certainty evidence). The funnel plot suggested publication bias, and a meta-analysis of trials published since 2000 gave a smaller effect estimate (Risk Ratio: 0.96, 95% CI 0.89 to 1.03, 2 trials, 1,007,587 participants), with the DEVTA trial contributing 55.1 per cent to this estimate. Applying the estimate from well-concealed trials to Nepal’s under-five mortality rate, there may be a reduction in mortality, and this is small from 28 to 25 per 1000 live births; 3 fewer deaths (95% CI 1 to 4 fewer) for every 1000 children supplemented. Conclusions Vitamin A supplementation may only result in a quantitatively unimportant reduction in child mortality. Stopping blanket supplementation seems reasonable given these data

Should all pregnant women take calcium supplements in Nepal? GRADE evidence to policy assessment

Background The WHO recommends oral calcium supplementation (1.5–2.0 g) in pregnant women to reduce the risk of pre-eclampsia living in areas with low dietary calcium intake. Although maternal mortality is high in Nepal and eclampsia causes at least 20% of maternal deaths, implementing WHO recommendations would be a major undertaking. Objective This review aimed to assess whether the current evidence supports the blanket supplementation of calcium to prevent pre-eclampsia among pregnant women in Nepal. Methods We used a structured approach to appraise the evidence for calcium supplementation in Nepal. We identified what may influence the impact of calcium supplementation in Nepal and conducted a situation analysis in the country covering maternal mortality, pre-eclampsia occurrence, and existing government policy provisions for supplementation. We also consulted with experts and government officials to explore their perspectives and experience on supplementation. We then used AMSTAR (A MeaSurement Tool to Assess Systematic Reviews) to appraise the Cochrane Systematic Review of calcium supplementation. Finally, we used these data in a GRADE (Grading of Recommendations Assessment, Development and Evaluation)–Evidence to Decision framework to reach a policy recommendation. Results Our assessment of the Cochrane Review showed that the recommendation made by the WHO is based on weak evidence and trial findings that are not consistent between studies. The Cochrane Review found low certainty of the evidence for benefit (reduction in pre-eclampsia and maternal mortality). Conversely, there is a high certainty of the evidence of undesirable effects (HELLP [haemolysis, elevated liver enzymes and low platelets] syndrome) although this is uncommon. The likely absolute reduction in maternal deaths projected to Nepal was estimated to be low, while the implementation costs were high. Stakeholders also raised several concerns regarding feasibility, acceptability, appropriate dosing, and risk communication. Conclusions This review concludes that the blanket supplementation of calcium cannot be recommended in Nepal. A better approach may be to identify high-risk pregnant women and manage their antenatal visits and delivery to prevent mortality from pre-eclampsia

State-building, war and violence : evidence from Latin America

In European history, war has played a major role in state‐building and the state monopoly on violence. But war is a very specific form of organized political violence, and it is decreasing on a global scale. Other patterns of armed violence now dominate, ones that seem to undermine state‐building, thus preventing the replication of European experiences. As a consequence, the main focus of the current state‐building debate is on fragility and a lack of violence control inside these states. Evidence from Latin American history shows that the specific patterns of the termination of both war and violence are more important than the specific patterns of their organization. Hence these patterns can be conceptualized as a critical juncture for state‐building. While military victories in war, the subordination of competing armed actors and the prosecution of perpetrators are conducive for state‐building, negotiated settlements, coexistence, and impunity produce instability due to competing patterns of authority, legitimacy, and social cohesion