The impact of mosquito sampling strategies on molecular xenomonitoring prevalence for filariasis: a systematic review.

Objective: To explore the impact of mosquito collection methods, sampling intensity and target genus on molecular xenomonitoring detection of parasites causing lymphatic filariasis. Methods: We systematically searched five databases for studies that used two or more collection strategies for sampling wild mosquitoes, and employed molecular methods to assess the molecular xenomonitoring prevalence of parasites responsible for lymphatic filariasis. We performed generic inverse variance meta-analyses and explored sources of heterogeneity using subgroup analyses. We assessed methodological quality and certainty of evidence. Findings: We identified 25 eligible studies, with 172 083 mosquitoes analysed. We observed significantly higher molecular xenomonitoring prevalence with collection methods that target bloodfed mosquitoes compared to methods that target unfed mosquitoes (prevalence ratio: 3.53; 95% confidence interval, CI: 1.52-8.24), but no significant difference compared with gravid collection methods (prevalence ratio: 1.54; 95% CI: 0.46-5.16). Regarding genus, we observed significantly higher molecular xenomonitoring prevalence for anopheline mosquitoes compared to culicine mosquitoes in areas where Anopheles species are the primary vector (prevalence ratio: 6.91; 95% CI: 1.73-27.52). One study provided evidence that reducing the number of sampling sites did not significantly affect molecular xenomonitoring prevalence. Evidence of differences in molecular xenomonitoring prevalence between sampling strategies was considered to be of low certainty, due partly to inherent limitations of observational studies that were not explicitly designed for these comparisons. Conclusion: The choice of sampling strategy can significantly affect molecular xenomonitoring results. Further research is needed to inform the optimum strategy in light of logistical constraints and epidemiological contexts.

How do schools influence the emotional and behavioural health of their pupils? A multi-level analysis of 135 schools in the Born in Bradford inner city multi-ethnic birth cohort.

PURPOSE: To estimate variation in emotional and behavioural problems between primary schools in Bradford, an ethnically diverse and relatively deprived city in the UK. METHODS: We did a cross-sectional analysis of data collected from 2017 to 2021 as part of the 'Born In Bradford' birth cohort study. We used multilevel linear regression in which the dependent variable was the Strengths and Difficulties Questionnaire (SDQ) total score, with a random intercept for schools. We adjusted for pupil-level characteristics including age, ethnicity, socioeconomic status, and parental mental health. RESULTS: The study included 5,036 participants from 135 schools. Participants were aged 7-11 years and 56% were of Pakistani heritage. The mean SDQ score was 8.84 out of a maximum 40. We estimated that the standard deviation in school-level scores was 1.41 (95% CI 1.11-1.74) and 5.49% (95% CI 3.19-9.37%) of variation was explained at school level. After adjusting for pupil characteristics, the standard deviation of school-level scores was 1.04 (95% CI 0.76-1.32) and 3.51% (95% CI 1.75-6.18%) of variation was explained at school level. Simulation suggested that a primary school with 396 pupils at the middle of the distribution has 63 pupils (95% CI 49-78) with a 'raised' SDQ score of 15 + /40; and shifting a school from the lower to the upper quartile would prevent 26 cases (95% CI 5-46). CONCLUSION: The prevalence of emotional and behavioural problems varies between schools. This is partially explained by pupil characteristics; though residual variation in adjusted scores may suggest that schools have a differential impact on mental wellbeing.

Integrated xenosurveillance of Loa loa, Wuchereria bancrofti, Mansonella perstans and Plasmodium falciparum using mosquito carcasses and faeces: A pilot study in Cameroon.

BACKGROUND: Community presence of loiasis must be determined before mass drug administration programmes for lymphatic filariasis and onchocerciasis can be implemented. However, taking human blood samples for loiasis surveillance is invasive and operationally challenging. A xenosurveillance approach based on the molecular screening of mosquitoes and their excreta/feces (E/F) for Loa loa DNA may provide a non-invasive method for detecting the community presence of loiasis. METHODS: We collected 770 wild mosquitoes during a pilot study in a known loiasis transmission area in Mbalmayo, Cameroon. Of these, 376 were preserved immediately while 394 were kept in pools to collect 36-hour E/F samples before processing. Carcasses and E/F were screened for L. loa DNA. To demonstrate this method's potential for integrated disease surveillance, the samples were further tested for Wuchereria bancrofti, Mansonella perstans, and Plasmodium falciparum. RESULTS: Despite limited sample numbers, L. loa DNA was detected in eight immediately-stored mosquitoes (2.13%; 95% CI 1.08 to 4.14), one carcass stored after providing E/F (0.25%; 95% CI 0.04 to 1.42), and three E/F samples (estimated prevalence 0.77%; 95% CI 0.15 to 2.23%). M. perstans and P. falciparum DNA were also detected in carcasses and E/F samples, while W. bancrofti DNA was detected in E/F. None of the carcasses positive for filarial worm DNA came from pools that provided a positive E/F sample, supporting the theory that, in incompetent vectors, ingested parasites undergo a rapid, complete expulsion in E/F. CONCLUSIONS: Mosquito xenosurveillance may provide a useful tool for the surveillance of loiasis alongside other parasitic diseases.

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.

Indoor residual spraying for preventing malaria in communities using insecticide-treated nets.

BACKGROUND: Insecticide-treated nets (ITNs) and indoor residual spraying (IRS) are used to prevent malaria transmission. Both interventions use insecticides to kill mosquitoes that bite and rest indoors. Adding IRS to ITNs may improve malaria control simply because two interventions can be better than one. Furthermore, IRS may improve malaria control where ITNs are failing due to insecticide resistance. Pyrethroid insecticides are the predominant class of insecticide used for ITNs, as they are more safe than other insecticide classes when in prolonged contact with human skin. While many mosquito populations have developed some resistance to pyrethroid insecticides, a wider range of insecticides can be used for IRS. This review is an update of the previous Cochrane 2019 edition. OBJECTIVES: To summarize the effect on malaria of additionally implementing IRS, using non-pyrethroid-like or pyrethroid-like insecticides, in communities currently using ITNs. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; CENTRAL; MEDLINE; and five other databases for records from 1 January 2000 to 8 November 2021, on the basis that ITN programmes did not begin to be implemented as policy before the year 2000. SELECTION CRITERIA: We included cluster-randomized controlled trials (cRCTs), interrupted time series (ITS), or controlled before-after studies (CBAs) comparing IRS plus ITNs with ITNs alone. We included studies with at least 50% ITN ownership (defined as the proportion of households owning one or more ITN) in both study arms. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility, analyzed risk of bias, and extracted data. We used risk ratio (RR) and 95% confidence intervals (CI). We stratified by type of insecticide, 'pyrethroid-like' and 'non-pyrethroid-like'; the latter could improve malaria control better than adding IRS insecticides that have the same way of working as the insecticide on ITNs ('pyrethroid-like'). We used subgroup analysis of ITN usage in the studies to explore heterogeneity. We assessed the certainty of evidence using the GRADE approach. MAIN RESULTS: Eight cRCTs (10 comparisons), one CBA, and one ITS study, all conducted since 2008 in sub-Saharan Africa, met our inclusion criteria. The primary vectors in all sites were mosquitoes belonging to the Anopheles gambiae s.l. complex species; five studies in Benin, Mozambique, Ghana, Sudan, and Tanzania also reported the vector Anopheles funestus. Five cRCTs and both quasi-experimental design studies used insecticides with targets different to pyrethroids (two used bendiocarb, three used pirimiphos-methyl, and one used propoxur. Each of these studies were conducted in areas where the vectors were described as resistant or highly resistant to pyrethroids. Two cRCTs used dichloro-diphenyl-trichlorethane (DDT), an insecticide with the same target as pyrethroids. The remaining cRCT used both types of insecticide (pyrethroid deltamethrin in the first year, switching to bendiocarb for the second year). Indoor residual spraying using 'non-pyrethroid-like' insecticides Six studies were included (four cRCTs, one CBA, and one ITS). Our main analysis for prevalence excluded a study at high risk of bias due to repeated sampling of the same population. This risk did not apply to other outcomes. Overall, the addition of IRS reduced malaria parasite prevalence (RR 0.61, 95% CI 0.42 to 0.88; 4 cRCTs, 16,394 participants; high-certainty evidence). IRS may also reduce malaria incidence on average (rate ratio 0.86, 95% CI 0.61 to 1.23; 4 cRCTs, 323,631 child-years; low-certainty evidence) but the effect was absent in two studies. Subgroup analyses did not explain the qualitative heterogeneity between studies. One cRCT reported no effect on malaria incidence or parasite prevalence in the first year, when a pyrethroid-like insecticide was used for IRS, but showed an effect on both outcomes in the second year, when a non-pyrethroid-like IRS was used. The addition of IRS may also reduce anaemia prevalence (RR 0.71, 95% CI 0.38 to 1.31; 3 cRCTs, 4288 participants; low-certainty evidence). Four cRCTs reported the impact of IRS on entomological inoculation rate (EIR), with variable results; overall, we do not know if IRS had any effect on the EIR in communities using ITNs (very low-certainty evidence). Studies also reported the adult mosquito density and the sporozoite rate, but we could not summarize or pool these entomological outcomes due to differences in the reported data. Three studies measured the prevalence of pyrethroid resistance before and after IRS being introduced: there was no difference detected, but these data are limited. Indoor residual spraying using 'pyrethroid-like' insecticides Adding IRS using a pyrethroid-like insecticide did not appear to markedly alter malaria incidence (rate ratio 1.07, 95% CI 0.80 to 1.43; 2 cRCTs, 15,717 child-years; moderate-certainty evidence), parasite prevalence (RR 1.11, 95% CI 0.86 to 1.44; 3 cRCTs, 10,820 participants; moderate-certainty evidence), or anaemia prevalence (RR 1.12, 95% CI 0.89 to 1.40; 1 cRCT, 4186 participants; low-certainty evidence). Data on EIR were limited so no conclusion was made (very low-certainty evidence). AUTHORS' CONCLUSIONS: in communities using ITNs, the addition of IRS with 'non-pyrethroid-like' insecticides was associated with reduced malaria prevalence. Malaria incidence may also be reduced on average, but there was unexplained qualitative heterogeneity, and the effect may therefore not be observed in all settings. When using 'pyrethroid-like' insecticides, there was no detectable additional benefit of IRS in communities using ITNs.

Evaluating the diagnostic test accuracy of molecular xenomonitoring methods for characterising the community burden of Onchocerciasis.

BACKGROUND: Molecular xenomonitoring (MX), the detection of parasite nucleic acid in the vector population, is recommended for onchocerciasis surveillance in elimination settings. However, the sensitivity of MX for detecting onchocerciasis-positive communities has not previously been evaluated. MX may have additional applications for control programmes but its utility is restricted by a limited understanding of the relationship between MX results and human prevalence. METHODS: We conducted a systematic review of studies reporting the prevalence of Onchocerca volvulus DNA in wild-caught Simulium spp. flies (MX rate) and corresponding prevalence of microfilaria (mf) in humans. We evaluated the sensitivity of MX for detecting onchocerciasis-positive communities and describe the characteristics of studies with reduced sensitivity. We conducted a linear regression to evaluate the relationship between mf prevalence and MX rate. RESULTS: We identified 15 relevant studies, with 13 studies comprising 34 study communities included in the quantitative analyses. Most communities were at advanced stages towards elimination and had no or extremely low human prevalence. MX detected positive flies in every study area with >1% mf prevalence, with the exception of one study conducted in the Venezuelan Amazonian focus. We identified a significant relationship between the two measurements, with mf prevalence accounting for half of the variation in MX rate (R2 0.50, p<0.001). CONCLUSION: MX is sensitive to communities with ongoing onchocerciasis transmission. It has potential to predict human mf prevalence, but further data is required to understand this relationship, particularly from MX surveys conducted earlier in control programmes before transmission has been interrupted.

Evaluating the Diagnostic Test Accuracy of Molecular Xenomonitoring Methods for Characterizing Community Burden of Lymphatic Filariasis.

BACKGROUND: Molecular xenomonitoring (MX), the detection of pathogen DNA in mosquitoes, is a recommended approach to support lymphatic filariasis (LF) elimination efforts. Potential roles of MX include detecting presence of LF in communities and quantifying progress towards elimination of the disease. However, the relationship between MX results and human prevalence is poorly understood. METHODS: We conducted a systematic review and meta-analysis from all previously conducted studies that reported the prevalence of filarial DNA in wild-caught mosquitoes (MX rate) and the corresponding prevalence of microfilaria (mf) in humans. We calculated a pooled estimate of MX sensitivity for detecting positive communities at a range of mf prevalence values and mosquito sample sizes. We conducted a linear regression to evaluate the relationship between mf prevalence and MX rate. RESULTS: We identified 24 studies comprising 144 study communities. MX had an overall sensitivity of 98.3% (95% confidence interval, 41.5-99.9%) and identified 28 positive communities that were negative in the mf survey. Low sensitivity in some studies was attributed to small mosquito sample sizes (<1000) and very low mf prevalence (<0.25%). Human mf prevalence and mass drug administration status accounted for approximately half of the variation in MX rate (R2 = 0.49, P < .001). Data from longitudinal studies showed that, within a given study area, there is a strong linear relationship between MX rate and mf prevalence (R2 = 0.78, P < .001). CONCLUSIONS: MX shows clear potential as tool for detecting communities where LF is present and as a predictor of human mf prevalence.

Indoor residual spraying for preventing malaria in communities using insecticide-treated nets.

BACKGROUND: Insecticide-treated nets (ITNs) and indoor residual spraying (IRS) are used to control malaria vectors. Both strategies use insecticides to kill mosquitoes that bite and rest indoors. For ITNs, the World Health Organization (WHO) only recommended pyrethroids until 2018, but mosquito vectors are becoming resistant to this insecticide. For IRS, a range of insecticides are recommended. Adding IRS to ITNs may improve control, simply because two interventions may be better than one; it may improve malaria control where ITNs are failing due to pyrethroid resistance; and it may slow the emergence and spread of pyrethroid resistance. OBJECTIVES: To summarize the effect on malaria of additionally implementing IRS, using non-pyrethroid-like or pyrethroid-like insecticides, in communities currently using ITNs. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; Embase; LILACS; the WHO International Clinical Trials Registry Platform; ClinicalTrials.gov; and the ISRCTN registry up to 18 March 2019. SELECTION CRITERIA: Cluster-randomized controlled trials (cRCTs), interrupted time series (ITS), or controlled before-and-after studies (CBAs) comparing IRS plus ITNs with ITNs alone. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for eligibility, analyzed risk of bias, and extracted data. We used risk ratio (RR) and 95% confidence intervals (CI). We stratified by type of insecticide: 'non-pyrethroid-like', as this could improve malaria control better than adding IRS insecticides that have the same way of working as the insecticide on ITNs ('pyrethroid-like'). We used subgroup analysis of ITN usage in the trials to explore heterogeneity. We assessed the certainty of evidence using the GRADE approach. MAIN RESULTS: Six cRCTs (eight comparisons) met our inclusion criteria conducted since 2008 in sub-Saharan Africa. Malaria transmission in all sites was from mosquitoes belonging to the Anopheles gambiae s.l. complex species; two trials in Benin and Tanzania also reported the vector Anopheles funestus. Three trials used insecticide with targets different to pyrethroids (two used bendiocarb and one used pirimiphos-methyl); two trials used dichloro-diphenyl-trichlorethane (DDT), an insecticide with the same target as pyrethroids; and one trial used both types of insecticide (pyrethroid deltamethrin in the first year, switching to bendiocarb for the second-year). ITN usage was greater than 50% in three trials, and less than 50% in the remainder.Indoor residual spraying using 'non-pyrethroid-like' insecticides Adding IRS with a non-pyrethroid-like insecticide had mixed results. Overall, we do not know if the addition of IRS impacted on malaria incidence (rate ratio 0.93, 95% CI 0.46 to 1.86; 2 cRCTs, 566 child-years; very low-certainty evidence); it may have reduced malaria parasite prevalence (0.67, 95% CI 0.35 to 1.28; 5 comparisons from 4 cRCTs, 10,440 participants; low-certainty evidence); and it may have reduced the prevalence of anaemia (RR CI 0.46, 95% 0.18 to 1.20; 3 comparisons from 2 cRCTs, 2026 participants; low-certainty evidence). Three trials reported the impact on EIR, with variable results; overall, we do not know if IRS had any effect on the EIR in communities using ITNs (very low-certainty evidence). Trials also reported the adult mosquito density and the sporozoite rate, but we could not summarize or pool these entomological outcomes due to unreported data. ITN usage did not explain the variation in malaria outcomes between different studies. One trial reported no effect on malaria incidence or parasite prevalence in the first year, when the insecticide used for IRS had the same target as pyrethroids, but showed an effect on both outcomes in the second year, when the insecticide was replaced by one with a different target.Two trials measured the prevalence of pyrethroid resistance before and after IRS being introduced: no difference was detected, but these data are limited.Indoor residual spraying using 'pyrethroid-like' insecticidesAdding IRS using a pyrethroid-like insecticide did not appear to markedly alter malaria incidence (rate ratio 1.07, 95% CI 0.80 to 1.43; 2 cRCTs, 15,717 child-years; moderate-certainty evidence), parasite prevalence (RR 1.11, 95% CI 0.86 to 1.44; 3 cRCTs, 10,820 participants; moderate-certainty evidence), or anaemia prevalence (RR 1.12, 95% CI 0.89 to 1.40; 1 cRCT, 4186 participants; low-certainty evidence). Data on the entomological inoculation rate (EIR) were limited, and therefore we do not know if IRS had any effect on the EIR in communities using ITNs (very low-certainty evidence). AUTHORS' CONCLUSIONS: Four trials have evaluated adding IRS using 'non-pyrethroid-like' insecticides in communities using ITNs. Some of these trials showed effects, and others did not. Three trials have evaluated adding IRS using 'pyrethroid-like' insecticides in communities using ITNs, and these studies did not detect an additional effect of the IRS. Given the wide geographical variety of malaria endemicities, transmission patterns, and insecticide resistance, we need to be cautious with inferences to policy from the limited number of trials conducted to date, and to develop relevant further research to inform decisions.

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 (P 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 Search Portal, and the International Standard Randomized Controlled Trial Number (ISRCTN) registry for ongoing or recently completed trials. The date of the last search was 8 May 2018. SELECTION CRITERIA: Efficacy analysis: randomized controlled trials (RCTs) of pyronaridine-artesunate for treating uncomplicated P falciparum malaria.Safety analysis: RCTs of pyronaridine-artesunate or pyronaridine for treating P falciparum or P vivax malaria. DATA COLLECTION AND ANALYSIS: For this update, two review authors independently re-extracted all data and assessed certainty of 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 studies. Seven studies were co-funded by Shin Poong Pharmaceuticals which manufactures the drug. Three studies were funded by government agencies.For efficacy analysis we identified five RCTs with 5711 participants. This included 4465 participants from 13 sites in Africa, and 1246 participants from five sites in Asia. It included 541 children aged less than five years.For polymerase chain reaction (PCR)-adjusted failures at day 28, pyronaridine-artesunate may have fewer failures compared to artemether-lumefantrine (RR 0.59, 95% confidence interval (CI) 0.26 to 1.31; 4 RCTs, 3068 participants, low-certainty evidence), artesunate-amodiaquine (RR 0.55, 95% CI 0.11 to 2.77; 1 RCT, 1245 participants, low-certainty evidence), and mefloquine plus artesunate (RR 0.37, 95% CI 0.13 to 1.05; 1 RCT, 1117 participants, low-certainty evidence).For unadjusted failures at day 28, pyronaridine-artesunate may have fewer failures compared to artemether-lumefantrine (RR 0.27, 95% CI 0.13 to 0.58; 4 RCTs, 3149 participants, low-certainty evidence), and probably has fewer failures compared to artesunate-amodiaquine (RR 0.49, 95% CI 0.30 to 0.81; 1 RCT, 1257 participants, moderate-certainty evidence) and mefloquine plus artesunate (RR 0.36, 95% CI 0.17 to 0.78; 1 RCT, 1120 participants, moderate-certainty evidence).For PCR-adjusted failures at day 42, pyronaridine-artesunate may make little or no difference compared to artemether-lumefantrine (RR 0.86, 95% CI 0.49 to 1.51; 4 RCTs, 2575 participants, low-certainty evidence) and artesunate-amodiaquine (RR 0.98, 95% CI 0.20 to 4.83; 1 RCT, 1091 participants, low-certainty evidence), but may have higher failures than mefloquine plus artesunate (RR 1.80, 95% CI 0.90 to 3.57; 1 RCT, 1037 participants, low-certainty evidence). Overall, pyronaridine-artesunate had a PCR-adjusted treatment failure rate of less than 5%.For unadjusted failures at day 42, pyronaridine-artesunate may have fewer failures compared to artemether-lumefantrine (RR 0.61, 95% CI 0.46 to 0.82; 4 RCTs, 3080 participants, low-certainty evidence), may make little or no difference compared to mefloquine plus artesunate (RR 0.84, 95% CI 0.54 to 1.31; 1 RCT, 1059 participants, low-certainty evidence), and probably makes little or no difference compared to artesunate-amodiaquine (RR 0.98, 95% CI 0.78 to 1.23; 1 RCT, 1235 participants, moderate-certainty evidence).For the safety analysis of severe adverse events and liver function, we identified eight RCTs with 6614 participants comparing pyronaridine-artesunate to other antimalarials, four of which were not in the previous version of this review. A further two RCTs, comparing pyronaridine alone to other treatments, contributed to the synthesis of all adverse events.Raised alanine aminotransferase (ALT) greater than five times the upper limit of normal (> 5 x ULN) is more frequent with pyronaridine-artesunate compared to other antimalarials (RR 3.34, 95% CI 1.63 to 6.84; 8 RCTS, 6581 participants, high-certainty evidence). There is probably little or no difference for raised bilirubin > 2.5 x ULN between pyronaridine-artesunate and other antimalarials (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, meeting criteria for moderate drug-induced liver injury. 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. 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 raised ALT > 5 x ULN. This meets criteria for mild drug-induced liver injury. On one instance this was linked to raised bilirubin, indicating moderate drug-induced liver injury. No episodes of severe drug-induced liver injury were reported. The findings of this review cannot fully inform a risk-benefit assessment for an unselected population. Readers should remain aware of this uncertainty when considering use of pyronaridine-artesunate in patients with known or suspected pre-existing liver dysfunction, and when co-administering with other medications which may cause liver dysfunction.

Laboratory evaluation of molecular xenomonitoring using mosquito and tsetse fly excreta/feces to amplify Plasmodium, Brugia, and Trypanosoma DNA.

Background:  Results from an increasing number of studies suggest that mosquito excreta/feces (E/F) testing has considerable potential to serve as a supplement for traditional molecular xenomonitoring techniques. However, as the catalogue of possible use-cases for this methodology expands, and the list of amenable pathogens grows, a number of fundamental methods-based questions remain. Answering these questions is critical to maximizing the utility of this approach and to facilitating its successful implementation as an effective tool for molecular xenomonitoring. Methods:  Utilizing E/F produced by mosquitoes or tsetse flies experimentally exposed to Brugia malayi, Plasmodium falciparum, or Trypanosoma brucei brucei, factors such as limits of detection, throughput of testing, adaptability to use with competent- and incompetent-vector species, and effects of additional blood feedings post parasite-exposure were evaluated.  Two platforms for the detection of pathogen signal (quantitative real-time PCR and digital PCR [dPCR]) were also compared, with strengths and weaknesses examined for each.       Results:  Experimental results indicated that high throughput testing is possible when evaluating mosquito E/F for the presence of either B. malayi or P. falciparum from both competent- and incompetent-vector mosquito species.  Furthermore, following exposure to pathogen, providing mosquitoes with a second, uninfected bloodmeal did not expand the temporal window for E/F collection during which pathogen detection was possible.  However, this collection window did appear longer in E/F collected from tsetse flies following exposure to T. b. brucei.  Testing also suggested that dPCR may facilitate detection through its increased sensitivity.  Unfortunately, logistical obstacles will likely make the large-scale use of dPCR impractical for this purpose. Conclusions:  By examining many E/F testing variables, expansion of this technology to a field-ready platform has become increasingly feasible.  However, translation of this methodology from the lab to the field will first require the completion of field-based pilot studies aimed at assessing the efficacy of E/F screening.

Insecticide space spraying for preventing malaria transmission.

BACKGROUND: Space spraying is the dispersal of a liquid fog of insecticide into an outdoor area to kill adult insects. It has been regularly used in public health and pest control programmes, including use as an emergency response to malaria epidemics. This Cochrane Review aims to assist the decision-making of malaria vector control programmes by summarizing the evidence of the impact of space spraying on malaria transmission. OBJECTIVES: The review's primary objective was to evaluate the impact of space spraying on malaria transmission, or the incremental impact when applied in combination with other malaria control methods, in comparison to equivalent conditions with no space spraying intervention.To guide future evaluations of space spraying, a secondary objective was to identify and summarize the range of space spraying strategies that have been trialled, those which were promising and warrant further evaluation, and those which appear unlikely to warrant further evaluation (for example, if they were not feasible to implement, or were unacceptable to the population). SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; PubMed (MEDLINE); Embase (OVID), CAB Abstracts (Web of Science), LILACS (BIREME), the World Health Organization (WHO) International Clinical Trials Registry Platform, and ClinicalTrials.gov up to 18 April 2018. We contacted organizations for ongoing and unpublished trials, and checked the reference lists of all included studies for relevant studies. SELECTION CRITERIA: We included cluster-randomized controlled trials, interrupted time series (ITS) studies, randomized cross-over studies, and controlled before-and-after (CBA) studies comparing space spraying with no space spraying that met the inclusion criteria for the review. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for eligibility and risk of bias, and extracted the data. For ITS studies, we present findings graphically, and estimated the effect of space spraying on the step change and the slope change. We assessed the certainty of evidence using the GRADE approach. MAIN RESULTS: Two ITS studies, conducted between 1972 and 1984, met our inclusion criteria for the primary objective, and one study contributed to the quantitative analysis. This study was conducted in India, reported the incidence of malaria in four separate sites, and covered a total population of 18,460 people. In the pooled analysis across sites, there was no step effect for the incidence of uncomplicated malaria (step rate ratio 1.00, 95% confidence interval (CI) 0.51 to 1.92). There was an effect on the slope: the number of cases was reduced by 15% per month (slope rate ratio 0.85, 95% CI 0.79 to 0.91). Using these ratios, we estimated the effect of 12 months of space spraying on malaria incidence to be a reduction from 6 cases to 1 case per month per 1000 population (95% CI 0 to 2 cases, very low-certainty evidence). The second study reported the impact of space spraying on malaria incidence and adult mosquito density in a population of 15,106 in Haiti, but it did not provide data from previous years. Thus, we could not estimate an effect of space spraying that was independent from temporal trends.For the review's secondary objective, we identified a further two studies in addition to the two ITS studies; both used a CBA design and were conducted between 1973 and 2000. The four studies used a range of delivery methods including handheld, vehicle-mounted, and aircraft-mounted spraying equipment. A variety of insecticides, doses, and spraying times were also used, with methods typically determined based on environmental factors and vector profiles. AUTHORS' CONCLUSIONS: Evidence from one state in India conducted over 30 years ago suggests an effect of space spraying on the incidence of malaria, but the certainty of the evidence is very low. Reliable research in a variety of settings will help establish whether and when this intervention may be worthwhile.

Insecticide-treated nets for preventing malaria.

BACKGROUND: A previous version of this Cochrane Review identified that insecticide-treated nets (ITNs) are effective at reducing child mortality, parasite prevalence, and uncomplicated and severe malaria episodes. Insecticide-treated nets have since become a core intervention for malaria control and have contributed greatly to the dramatic decline in disease incidence and malaria-related deaths seen since the turn of the millennium. However, this time period has also seen a rise in resistance to pyrethroids (the insecticide used in ITNs), raising questions over whether the evidence from trials conducted before resistance became widespread can be applied to estimate the impact of ITNs on malaria transmission today. OBJECTIVES: The primary objective of this review was to assess the impact of ITNs on mortality and malaria morbidity, incorporating any evidence published since the previous update into new and existing analyses, and assessing the certainty of the resulting evidence using GRADE. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) published in the Cochrane Library, MEDLINE, Embase, LILACS, the World Health Organization (WHO) International Clinical Trials Registry Platform, ClinicalTrials.gov, and the ISRCTN registry for new trials published since 2004 and up to 18 April 2018. SELECTION CRITERIA: We included individual randomized controlled trials (RCTs) and cluster RCTs comparing bed nets or curtains treated with a synthetic pyrethroid insecticide at a minimum target impregnation dose recommended by the WHO with no nets or untreated nets. DATA COLLECTION AND ANALYSIS: One review author assessed the identified trials for eligibility and risk of bias, and extracted data. We compared intervention and control data using risk ratios (RRs), rate ratios, and mean differences, and presented all results with their associated 95% confidence intervals (CIs). We assessed the certainty of evidence using the GRADE approach. We drew on evidence from a meta-analysis of entomological outcomes stratified by insecticide resistance from 2014 to inform the GRADE assessments. MAIN RESULTS: Our updated search identified three new trials. A total of 23 trials met the inclusion criteria, enrolling more than 275,793 adults and children. The included studies were conducted between 1987 and 2001.ITN versus no netsInsecticide-treated nets reduce child mortality from all causes by 17% compared to no nets (rate ratio 0.83, 95% CI 0.77 to 0.89; 5 trials, 200,833 participants, high-certainty evidence). This corresponds to a saving of 5.6 lives (95% CI 3.6 to 7.6) each year for every 1000 children protected with ITNs. Insecticide-treated nets also reduce the incidence of uncomplicated episodes of Plasmodium falciparum malaria by almost a half (rate ratio 0.55, 95% CI 0.48 to 0.64; 5 trials, 35,551 participants, high-certainty evidence) and probably reduce the incidence of uncomplicated episodes of Plasmodium vivax malaria (risk ratio (RR) 0.61, 95% CI 0.48 to 0.77; 2 trials, 10,967 participants, moderate-certainty evidence).Insecticide-treated nets were also shown to reduce the prevalence of P falciparum malaria by 17% compared to no nets (RR 0.83, 95% CI 0.71 to 0.98; 6 trials, 18,809 participants, high-certainty evidence) but may have little or no effect on the prevalence of P vivax malaria (RR 1.00, 95% CI 0.75 to 1.34; 2 trials, 10,967 participants, low-certainty evidence). A 44% reduction in the incidence of severe malaria episodes was seen in the ITN group (rate ratio 0.56, 95% CI 0.38 to 0.82; 2 trials, 31,173 participants, high-certainty evidence), as well as an increase in mean haemoglobin (expressed as mean packed cell volume) compared to the no-net group (mean difference 1.29, 95% CI 0.42 to 2.16; 5 trials, 11,489 participants, high-certainty evidence).ITN versus untreated netsInsecticide-treated nets probably reduce child mortality from all causes by a third compared to untreated nets (rate ratio 0.67, 95% CI 0.36 to 1.23; 2 trials, 25,389 participants, moderate-certainty evidence). This corresponds to a saving of 3.5 lives (95% CI -2.4 to 6.8) each year for every 1000 children protected with ITNs. Insecticide-treated nets also reduce the incidence of uncomplicated P falciparum malaria episodes (rate ratio 0.58, 95% CI 0.44 to 0.78; 5 trials, 2036 participants, high-certainty evidence) and may also reduce the incidence of uncomplicated P vixax malaria episodes (rate ratio 0.73, 95% CI 0.51 to 1.05; 3 trials, 1535 participants, low-certainty evidence).Use of an ITN probably reduces P falciparum prevalence by one-tenth in comparison to use of untreated nets (RR 0.91, 95% CI 0.78 to 1.05; 3 trials, 2,259 participants, moderate-certainty evidence). However, based on the current evidence it is unclear whether or not ITNs impact on P vivax prevalence (1 trial, 350 participants, very low certainty evidence) or mean packed cell volume (2 trials, 1,909 participants, low certainty evidence). AUTHORS' CONCLUSIONS: Although there is some evidence that insecticide resistance frequency has some effects on mosquito mortality, it is unclear how quantitatively important this is. It appeared insufficient to downgrade the strong evidence of benefit on mortality and malaria illness from the trials conducted earlier.

Assessing the feasibility of integration of self-care for filarial lymphoedema into existing community leprosy self-help groups in Nepal.

BACKGROUND: Lymphatic filariasis (LF) and leprosy are disabling infectious diseases endemic in Nepal. LF infection can lead to lymphoedema and hydrocoele, while secondary effects of leprosy infection include impairments to hands, eyes and feet. The disabling effects of both conditions can be managed through self-care and the supportive effects of self-help groups (SHGs). A network of SHGs exists for people affected by leprosy in four districts in Nepal's Central Development Region, however no such service exists for people affected by LF. The aim of this study was to determine the feasibility of integrating LF affected people into existing leprosy SHGs in this area. METHODS: A survey was conducted using a semi-structured questionnaire to elicit information on: (i) participant characteristics, clinical manifestation and disease burden; (ii) participants' knowledge of management of their condition and access to services; and (iii) participants' knowledge and perceptions of the alternate condition (LF affected participants' knowledge of leprosy and vice versa) and attitudes towards integration. RESULTS: A total of 52 LF affected and 53 leprosy affected participants were interviewed from 14 SHGs. On average, leprosy affected participants were shown to have 1.8 times greater knowledge of self-care techniques, and practiced 2.5 times more frequently than LF affected participants. Only a quarter of LF affected participants had accessed a health service for their condition, compared with 94.3% of leprosy affected people accessing a service (including SHGs), at least once a week. High levels of stigma were perceived by both groups towards the alternate condition, however, the majority of LF (79%) and leprosy (94.3%) affected participants stated that they would consider attending an integrated SHG. CONCLUSIONS: LF affected participants need to increase their knowledge of self-care and access to health services. Despite stigma being a potential barrier, attitudes towards integration were positive, suggesting that the SHGs may be a good platform for LF affected people to start self-care in this area. TRIAL REGISTRATION: This is not a registered trial.