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Background: Cluster-randomized trials allow for the evaluation of a community-level or group-/cluster-level intervention. For studies that require a cluster-randomized trial design to evaluate cluster-level interventions aimed at controlling vector-borne diseases, it may be difficult to assess a large number of clusters while performing the additional work needed to monitor participants, vectors, and environmental factors associated with the disease. One such example of a cluster-randomized trial with few clusters was the “efficacy and risk of harms of repeated ivermectin mass drug administrations for control of malaria” trial. Although previous work has provided recommendations for analyzing trials like repeated ivermectin mass drug administrations for control of malaria, additional evaluation of the multiple approaches for analysis is needed for study designs with count outcomes. Methods: Using a simulation study, we applied three analysis frameworks to three cluster-randomized trial designs (single-year, 2-year parallel, and 2-year crossover) in the context of a 2-year parallel follow-up of repeated ivermectin mass drug administrations for control of malaria. Mixed-effects models, generalized estimating equations, and cluster-level analyses were evaluated. Additional 2-year parallel designs with different numbers of clusters and different cluster correlations were also explored. Results: Mixed-effects models with a small sample correction and unweighted cluster-level summaries yielded both high power and control of the Type I error rate. Generalized estimating equation approaches that utilized small sample corrections controlled the Type I error rate but did not confer greater power when compared to a mixed model approach with small sample correction. The crossover design generally yielded higher power relative to the parallel equivalent. Differences in power between analysis methods became less pronounced as the number of clusters increased. The strength of within-cluster correlation impacted the relative differences in power. Conclusion: Regardless of study design, cluster-level analyses as well as individual-level analyses like mixed-effects models or generalized estimating equations with small sample size corrections can both provide reliable results in small cluster settings. For 2-year parallel follow-up of repeated ivermectin mass drug administrations for control of malaria, we recommend a mixed-effects model with a pseudo-likelihood approximation method and Kenward–Roger correction. Similarly designed studies with small sample sizes and count outcomes should consider adjustments for small sample sizes when using a mixed-effects model or generalized estimating equation for analysis. Although the 2-year parallel follow-up of repeated ivermectin mass drug administrations for control of malaria is already underway as a parallel trial, applying the simulation parameters to a crossover design yielded improved power, suggesting that crossover designs may be valuable in settings where the number of available clusters is limited. Finally, the sensitivity of the analysis approach to the strength of within-cluster correlation should be carefully considered when selecting the primary analysis for a cluster-randomized trial.

Residents of long-term care facilities (LTCFs), particularly those in skilled nursing facilities (SNFs), have experienced disproportionately high levels of COVID-19-associated morbidity and mortality and were prioritized for early COVID-19 vaccination (1,2). However, this group was not included in COVID-19 vaccine clinical trials, and limited postauthorization vaccine effectiveness (VE) data are available for this critical population (3). It is not known how well COVID-19 vaccines protect SNF residents, who typically are more medically frail, are older, and have more underlying medical conditions than the general population (1). In addition, immunogenicity of the Pfizer-BioNTech vaccine was found to be lower in adults aged 65-85 years than in younger adults (4). Through the CDC Pharmacy Partnership for Long-Term Care Program, SNF residents and staff members in Connecticut began receiving the Pfizer-BioNTech COVID-19 vaccine on December 18, 2020 (5). Administration of the vaccine was conducted during several on-site pharmacy clinics. In late January 2021, the Connecticut Department of Public Health (CT DPH) identified two SNFs experiencing COVID-19 outbreaks among residents and staff members that occurred after each facility's first vaccination clinic. CT DPH, in partnership with CDC, performed electronic chart review in these facilities to obtain information on resident vaccination status and infection with SARS-CoV-2, the virus that causes COVID-19. Partial vaccination, defined as the period from >14 days after the first dose through 7 days after the second dose, had an estimated effectiveness of 63% (95% confidence interval [CI] = 33%-79%) against SARS-CoV-2 infection (regardless of symptoms) among residents within these SNFs. This is similar to estimated effectiveness for a single dose of the Pfizer-BioNTech COVID-19 vaccine in adults across a range of age groups in noncongregate settings (6) and suggests that to optimize vaccine impact among this population, high coverage with the complete 2-dose series should be recommended for SNF residents and staff members.

Nursing homes house populations that are highly vulnerable to coronavirus disease. Point prevalence surveys (PPSs) provide information on the severe acute respiratory syndrome coronavirus 2 infection status of staff and residents in nursing homes and enable isolation of infectious persons to halt disease spread. We collected 16 weeks of public health surveillance data on a subset of nursing homes (34/212) in Connecticut, USA. We fit a Poisson regression model to evaluate the association between incidence and time since serial PPS onset, adjusting for decreasing community incidence and other factors. Nursing homes conducted a combined total of 205 PPSs in staff and 232 PPSs in residents. PPS was associated with 41%–80% reduction in incidence rate in nursing homes. Our findings provide support for the use of repeated PPSs in nursing home staff and residents, combined with strong infection prevention measures such as cohorting, in contributing to outbreak control.

Background Bordetella bronchiseptica is a gram-negative, obligate aerobic coccobacillus known to cause disease in domesticated animals and pets. In humans, B. bronchiseptica commonly leads to respiratory infections like pneumonia or bronchitis, and animal contact usually precedes the onset of symptoms. Case presentation We report a case of post-traumatic B. bronchiseptica meningitis without recent surgery in the setting of immunosuppression with a monoclonal antibody. Our case concerns a 77-year-old male with ulcerative colitis on infliximab who sustained a mechanical fall and developed a traumatic cerebrospinal fluid leak complicated by meningitis. He received meropenem then ceftazidime during his hospital course, and temporary neurosurgical drain placement was required. His clinical condition improved, and he was discharged at his baseline neurological status. Conclusions B. bronchiseptica is an unusual cause of meningitis that may warrant consideration in immunocompromised hosts with known or suspected animal exposures. To better characterize this rare cause of meningitis, we performed a systematic literature review and summarized all previously reported cases.

Background: Malaria in pregnancy affects both the mother and the fetus. However, evidence supporting treatment guidelines for uncomplicated (including asymptomatic) falciparum malaria in pregnant women is scarce and assessed in varied ways. We did a systematic literature review and individual patient data (IPD) meta-analysis to compare the efficacy and tolerability of different artemisinin-based or quinine-based treatments for malaria in pregnant women. Methods: We did a systematic review of interventional or observational cohort studies assessing the efficacy of artemisinin-based or quinine-based treatments in pregnancy. Seven databases (MEDLINE, Embase, Global Health, Cochrane Library, Scopus, Web of Science, and Literatura Latino Americana em Ciencias da Saude) and two clinical trial registries (International Clinical Trials Registry Platform and ClinicalTrials.gov) were searched. The final search was done on April 26, 2019. Studies that assessed PCR-corrected treatment efficacy in pregnancy with follow-up of 28 days or more were included. Investigators of identified studies were invited to share data from individual patients. The outcomes assessed included PCR-corrected efficacy, PCR-uncorrected efficacy, parasite clearance, fever clearance, gametocyte development, and acute adverse events. One-stage IPD meta-analysis using Cox and logistic regression with random-effects was done to estimate the risk factors associated with PCR-corrected treatment failure, using artemether-lumefantrine as the reference. This study is registered with PROSPERO, CRD42018104013. Findings: Of the 30 studies assessed, 19 were included, representing 92% of patients in the literature (4968 of 5360 episodes). Risk of PCR-corrected treatment failure was higher for the quinine monotherapy (n=244, adjusted hazard ratio [aHR] 6·11, 95% CI 2·57–14·54, p Interpretation: Efficacy and tolerability of artemisinin-based combination therapies (ACTs) in pregnant women are better than quinine. The lower efficacy of artemether-lumefantrine compared with other ACTs might require dose optimisation.

Background The choice of malaria treatment for HIV-infected pregnant women receiving efavirenz-based antiretroviral therapy must consider the potential impact of drug interactions on antimalarial exposure and clinical response. The aim of this study was to investigate the effects of efavirenz on artemether-lumefantrine (AL) because no studies have isolated the impact of efavirenz for HIV-infected pregnant women. Methods A prospective clinical pharmacokinetic (PK) study compared HIV-infected, efavirenz-treated pregnant women with HIV-uninfected pregnant women in Tororo, Uganda. All women received the standard 6-dose AL treatment regimen for Plasmodium falciparum malaria with intensive PK samples collected over 21 days and 42-days of clinical follow-up. PK exposure parameters were calculated for artemether, its active metabolite dihydroartemisinin (DHA), and lumefantrine to determine the impact of efavirenz. Results Nine HIV-infected and 30 HIV-uninfected pregnant women completed intensive PK evaluations. Relative to controls, concomitant efavirenz therapy lowered the 8-hour artemether concentration by 76% (P = 0.013), DHA peak concentration by 46% (P = 0.033), and day 7 and 14 lumefantrine concentration by 61% and 81% (P = 0.046 and 0.023), respectively. In addition, there were nonsignificant reductions in DHA area under the concentration-time curve0-8hr (35%, P = 0.057) and lumefantrine area under the concentration-time curve0-∞ (34%, P = 0.063) with efavirenz therapy. Conclusions Pregnant HIV-infected women receiving efavirenz-based antiretroviral therapy during malaria treatment with AL showed reduced exposure to both the artemisinin and lumefantrine. These data suggest that malaria and HIV coinfected pregnant women may require adjustments in AL dosage or treatment duration to achieve exposure comparable with HIV-uninfected pregnant women.

Background Blood smear microscopy remains the gold-standard method to diagnose and quantify malaria parasite density. In addition, parasite genotyping of select loci is the most utilized method for distinguishing recrudescent and new infections and to determine the number of strains per sample. In research settings, blood may be obtained from capillary or venous compartments, and results from these matrices have been used interchangeably. Our aim was to compare quantitative results for parasite density and strain complexity from both compartments. Methods In a prospective observational study, children and adults presenting with uncomplicated Plasmodium falciparum malaria, simultaneous capillary and venous blood smears and dried blood spots were collected over 42-days following treatment with artemether-lumefantrine. Blood smears were read by two microscopists, any discrepancies resolved by a third reader. Parasite DNA fingerprinting was conducted using six microsatellites. Bland Altman analysis and paired t-test/McNemar’s test were used to assess the difference in density readings and measurements. Results Two hundred twenty-three participants were included in the analysis (177 children (35 HIV-infected/142 HIV-uninfected), 21 HIV-uninfected pregnant women, and 25 HIV-uninfected non-pregnant adults). Parasite density measurements did not statistically differ between capillary and venous blood smears at the time of presentation, nor over the course of 42-day follow-up. Characterization of merozoite surface protein-2 (MSP-2) genetic polymorphism demonstrated a higher level of strain diversity at the time of presentation in venous samples, as compared with capillary specimens (p = 0.02). There was a high degree of variability in genotype-corrected outcomes when pairs of samples from each compartment were compared using MSP-2 alone, although the variability was reduced with the use of multiple markers. Conclusions Parasite density measurements do not statistically differ between capillary and venous compartments in all studied demographic groups at the time of presentation with malaria, or over the course of follow-up. More strains were detected by MSP-2 genotyping in venous samples than in capillary samples at the time of malaria diagnosis. The use of multiple polymorphic markers reduces the impact of variability in strain detection on genotype-corrected outcomes. This study confirms that both capillary and venous compartments can be used for sampling with confidence in the clinical research setting. Trial registration The trial was registered at ClinicalTrials.gov under registration no. NCT01717885. Electronic supplementary material The online version of this article (10.1186/s12879-019-4174-1) contains supplementary material, which is available to authorized users.

Background: Nursing homes are high-risk COVID-19 settings with residents who are typically older and have multiple comorbidities. SARS-CoV-2 testing occurs frequently in nursing homes, with current public health guidance suggesting that repeat testing is generally not warranted in the 90 days following initial positive test results. Interpretation of repeat positive tests beyond 90 days is challenging and the consequences of decisions following these tests are significant. Methods: We utilized a surveillance system for COVID-19 to identify Connecticut nursing home residents who tested positive for SARS-CoV-2 by RNA-based testing ≥ 90 days after initial positive results. We analyzed statewide nursing home testing data over a 9-month period, from the first Connecticut nursing home case identified on March 15 through December 15, 2020, when nursing home COVID-19 vaccinations began in Connecticut. Findings: We identified 156 residents (median age 75 years) with positive RNA-based PCR tests occurring ≥90 days after an initial positive test. Residents with repeat positives tests represented approximately 2·6% (156/6,079) of nursing home residents surviving beyond 90 days of their initial SARS-CoV-2 diagnosis statewide since the start of the pandemic, with a median time to repeat positivity of 135 days (range 90-245 days). Deaths were reported in 12·8% (20/156) of residents following the repeat positive test, with 80% (16/20) having one or more intervening negative RT-PCR tests prior to the repeat positive test. Interpretation: Our analysis suggests that repeat positive testing in nursing home populations may exceed those reported in younger age groups. Repeat positive tests beyond 90 days may accompany severe outcomes, and should be investigated. Data shed light on the duration of protective immunity following natural infection in this subset of largely elderly and medically frail individuals. Funding: This work was conducted in the context of the Connecticut DPH COVID-19 response and not supported by specific funding. Declaration of Interests: None to declare.

This study describes the point prevalence of polymerase chain reaction tests positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among residents of a sample of Connecticut nursing homes in the first half of May 2020.

Background: Since 2014, seasonal malaria chemoprevention (SMC) with amodiaquine-sulfadoxine-pyrimethamine (AQ-SP) has been implemented on a large scale during the high malaria transmission season in Burkina Faso. We report in this paper the prevalence of microscopic and submicroscopic malaria infection at the outset and after the first round of SMC in children under five years old in Bama, Burkina Faso, as well as host and parasite factors involved in mediating the efficacy and tolerability of SMC. Methods: Two sequential cross-sectional surveys were conducted in late July and August 2017 during the first month of SMC in a rural area in southwest Burkina Faso. Blood smears and dried blood spots were collected from 106 and 93 children under five, respectively, at the start of SMC and again three weeks later. Malaria infection was detected by microscopy and by PCR from dried blood spots. For all children, day 7 plasma concentrations of desethyl-amodiaquine (DEAQ) were measured and CYP2C8 genetic variants influencing AQ metabolism were genotyped. Samples were additionally genotyped for pfcrt K76T and pfmdr1 N86Y, molecular markers associated with reduced amodiaquine susceptibility. Results: 2.8% (3/106) of children were positive for Plasmodium falciparum infection by microscopy and 13.2% (14/106) by nested PCR within 2 days of SMC administration. Three weeks after SMC administration, in the same households, 4.3% (4/93) of samples were positive by microscopy and 14.0% (13/93) by PCR (p=0.0007). CYP2C8*2, associated with impaired amodiaquine metabolism, was common with an allelic frequency of 17.1% (95%CI=10.0-24.2). Day 7 concentration of DEAQ ranged from 0.48 to 362.80 ng/mL with a median concentration of 56.34 ng/mL. Pfmdr1 N86 predominated at both time points, whilst a non-significant trend towards a higher prevalence of pfcrt 76T was seen at week 3. Conclusion: This study showed a moderate prevalence of low-level malaria parasitemia in children 3 weeks following SMC during the first month of administration. Day 7 concentrations of the active DEAQ metabolite varied widely, likely reflecting variability in adherence and possibly metabolism. Our findings highlight factors that may contribute to the effectiveness of SMC in children in a high transmission setting.

Background Malaria in pregnancy, including asymptomatic infection, has a detrimental impact on foetal development. Individual patient data (IPD) meta-analysis was conducted to compare the association between antimalarial treatments and adverse pregnancy outcomes, including placental malaria, accompanied with the gestational age at diagnosis of uncomplicated falciparum malaria infection. Methods A systematic review and one-stage IPD meta-analysis of studies assessing the efficacy of artemisinin-based and quinine-based treatments for patent microscopic uncomplicated falciparum malaria infection (hereinafter uncomplicated falciparum malaria) in pregnancy was conducted. The risks of stillbirth (pregnancy loss at ≥ 28.0 weeks of gestation), moderate to late preterm birth (PTB, live birth between 32.0 and Results Of the 22 eligible studies (n = 5015), IPD from16 studies were shared, representing 95.0% (n = 4765) of the women enrolled in literature. Malaria treatment in this pooled analysis mostly occurred in the second (68.4%, 3064/4501) or third trimester (31.6%, 1421/4501), with gestational age confirmed by ultrasound in 91.5% (4120/4503). Quinine (n = 184) and five commonly used artemisinin-based combination therapies (ACTs) were included: artemether-lumefantrine (n = 1087), artesunate-amodiaquine (n = 775), artesunate-mefloquine (n = 965), and dihydroartemisinin-piperaquine (n = 837). The overall pooled proportion of stillbirth was 1.1% (84/4361), PTB 10.0% (619/4131), SGA 32.3% (1007/3707), and placental malaria 80.1% (2543/3035), and there were no significant differences of considered outcomes by ACT. Higher parasitaemia before treatment was associated with a higher risk of SGA (adjusted odds ratio [aOR] 1.14 per 10-fold increase, 95% confidence interval [CI] 1.03 to 1.26, p = 0.009) and deposition of malaria pigment in the placenta (aOR 1.67 per 10-fold increase, 95% CI 1.42 to 1.96, p Conclusions The risks of stillbirth, PTB, SGA, and placental malaria were not different between the commonly used ACTs. The risk of SGA was high among pregnant women infected with falciparum malaria despite treatment with highly effective drugs. Reduction of malaria-associated adverse birth outcomes requires effective prevention in pregnant women.

Background The radical cure of Plasmodium vivax and P. ovale requires treatment with primaquine or tafenoquine to clear dormant liver stages. Either drug can induce haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, necessitating screening. The reference diagnostic method for G6PD activity is ultraviolet (UV) spectrophotometry; however, a universal G6PD activity threshold above which these drugs can be safely administered is not yet defined. Our study aimed to quantify assay-based variation in G6PD spectrophotometry and to explore the diagnostic implications of applying a universal threshold. Methods and findings Individual-level data were pooled from studies that used G6PD spectrophotometry. Studies were identified via PubMed search (25 April 2018) and unpublished contributions from contacted authors (PROSPERO: CRD42019121414). Studies were excluded if they assessed only individuals with known haematological conditions, were family studies, or had insufficient details. Studies of malaria patients were included but analysed separately. Included studies were assessed for risk of bias using an adapted form of the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. Repeatability and intra- and interlaboratory variability in G6PD activity measurements were compared between studies and pooled across the dataset. A universal threshold for G6PD deficiency was derived, and its diagnostic performance was compared to site-specific thresholds. Study participants (n = 15,811) were aged between 0 and 86 years, and 44.4% (7,083) were women. Median (range) activity of G6PD normal (G6PDn) control samples was 10.0 U/g Hb (6.3–14.0) for the Trinity assay and 8.3 U/g Hb (6.8–15.6) for the Randox assay. G6PD activity distributions varied significantly between studies. For the 13 studies that used the Trinity assay, the adjusted male median (AMM; a standardised metric of 100% G6PD activity) varied from 5.7 to 12.6 U/g Hb (p < 0.001). Assay precision varied between laboratories, as assessed by variance in control measurements (from 0.1 to 1.5 U/g Hb; p < 0.001) and study-wise mean coefficient of variation (CV) of replicate measures (from 1.6% to 14.9%; p < 0.001). A universal threshold of 100% G6PD activity was defined as 9.4 U/g Hb, yielding diagnostic thresholds of 6.6 U/g Hb (70% activity) and 2.8 U/g Hb (30% activity). These thresholds diagnosed individuals with less than 30% G6PD activity with study-wise sensitivity from 89% (95% CI: 81%–94%) to 100% (95% CI: 96%–100%) and specificity from 96% (95% CI: 89%–99%) to 100% (100%–100%). However, when considering intermediate deficiency (, Daniel Pfeffer and coauthors report on the assessment of glucose-6-phosphate dehydrogenase activity, which is required for safe use of some malaria treatments., Author summary Why was this study done? Complete cure of vivax malaria, the most geographically widespread malaria species, requires the use of 8-aminoquinoline drugs to clear dormant liver stages of the parasite (‘radical cure’); however, these drugs can cause severe haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Ultraviolet (UV) spectrophotometry is used as the reference test to measure G6PD activity, for validating new point-of-care diagnostics, and to determine population-specific definitions of G6PD deficiency. Currently, there is no universal threshold to define G6PD deficiency, and each laboratory must invest time and resources to derive site- and laboratory-specific definitions of G6PD deficiency. What did the researchers do and find? We pooled measurements of G6PD activity from studies conducted across different countries and laboratories worldwide. We assessed the comparability of spectrophotometry results between these laboratories to see whether a universal definition and diagnostic cutoff for G6PD deficiency could be determined. There was substantial variation in the performance and absolute measurements of spectrophotometry conducted in different laboratories, hindering the definition of a universal cutoff for G6PD deficiency. What do these findings mean? These findings highlight the importance of quality-control measures to minimise the influence of laboratory procedures on observed measurements. The data suggest that while a robust universal, assay-specific G6PD activity cutoff value can be established for diagnosis of severe G6PD deficiency (

Treating malaria in HIV-coinfected individuals should consider potential drug-drug interactions. Artemether-lumefantrine is the most widely recommended treatment for uncomplicated malaria globally. Lumefantrine is metabolized by CYP3A4, an enzyme that commonly used antiretrovirals often induce or inhibit. A population pharmacokinetic meta-analysis was conducted using individual participant data from 10 studies with 6,100 lumefantrine concentrations from 793 nonpregnant adult participants (41% HIV-malaria-coinfected, 36% malaria-infected, 20% HIV-infected, and 3% healthy volunteers)., Treating malaria in HIV-coinfected individuals should consider potential drug-drug interactions. Artemether-lumefantrine is the most widely recommended treatment for uncomplicated malaria globally. Lumefantrine is metabolized by CYP3A4, an enzyme that commonly used antiretrovirals often induce or inhibit. A population pharmacokinetic meta-analysis was conducted using individual participant data from 10 studies with 6,100 lumefantrine concentrations from 793 nonpregnant adult participants (41% HIV-malaria-coinfected, 36% malaria-infected, 20% HIV-infected, and 3% healthy volunteers). Lumefantrine exposure increased 3.4-fold with coadministration of lopinavir-ritonavir-based antiretroviral therapy (ART), while it decreased by 47% with efavirenz-based ART and by 59% in the patients with rifampin-based antituberculosis treatment. Nevirapine- or dolutegravir-based ART and malaria or HIV infection were not associated with significant effects. Monte Carlo simulations showed that those on concomitant efavirenz or rifampin have 49% and 80% probability of day 7 concentrations

Background Nursing homes are high-risk COVID-19 settings with residents who are typically older and have multiple comorbidities. SARS-CoV-2 testing occurs frequently in nursing homes, with public health guidance suggesting that repeat testing is generally not warranted in the 90 days following initial positive test results. Interpretation of repeat positive tests beyond 90 days is challenging and the consequences of decisions following these tests are significant. Methods We utilized a surveillance system for COVID-19 to identify Connecticut nursing home residents who tested positive for SARS-CoV-2 by RNA-based testing ≥ 90 days after initial positive results. We analyzed statewide nursing home testing data over a 9-month period, from the first Connecticut nursing home case identified on March 15 through December 15, 2020, when nursing home COVID-19 vaccinations began in Connecticut. Findings We identified 156 residents (median age 75 years) with positive RNA-based PCR tests occurring ≥90 days after an initial positive test. Residents with repeat positives tests represented approximately 2.6% (156/6,079) of nursing home residents surviving beyond 90 days of their initial SARS-CoV-2 diagnosis statewide since the start of the pandemic, with a median time to repeat positivity of 135 days (range 90–245 days). Deaths were reported in 12.8% (20/156) of residents following the repeat positive test, with 80% (16/20) having one or more intervening negative RT-PCR tests prior to the repeat positive test. Interpretation Our analysis suggests that repeat positive testing in nursing home populations may exceed those reported in younger age groups. Repeat positive tests beyond 90 days may accompany severe outcomes, and should be prospectively investigated with genomic, virologic and additional data, when feasible. Data shed light on the duration of protective immunity following natural infection in this subset of largely elderly and medically frail individuals. Funding This work was conducted in the context of the Connecticut DPH COVID-19 response and not supported by specific funding.

Laboratory data and prior pediatric reports indicate that HIV protease inhibitor (PI)–based antiretroviral therapy (ARV) kills gametocytes and reduces rates of gametocytemia, but not asymptomatic parasitemia, in a high malaria-transmission area. To determine whether ARV regimen impacts these rates in areas with less-intense malaria transmission, we compared asymptomatic parasitemia and gametocytemia rates in HIV-infected children by ARV regimen in Lilongwe, Malawi, an area of low-to-moderate transmission intensity. HIV PI lopinavir–ritonavir (LPV–rtv) ARV– or non-nucleoside reverse transcriptase inhibitor nevirapine ARV–treated children did not differ in the rates of polymerase chain reaction-detected asymptomatic parasitemia (relative risk [RR] 0.43 95% confidence interval [CI] [0.16, 1.18], P value 0.10) or microscopically detected gametocytemia with LPV–rtv ARV during symptomatic malaria (RR 0.48 95% CI [0.22,1.04] P value 0.06). LPV–rtv ARV was not associated with reduced rates of asymptomatic parasitemia, or gametocytemia on days of symptomatic malaria episodes, in HIV-infected children. Larger studies should evaluate whether ARV impacts transmission.

Summary Background Ivermectin is widely used in mass drug administrations for controlling neglected parasitic diseases, and can be lethal to malaria vectors that bite treated humans. Therefore, it could be a new tool to reduce plasmodium transmission. We tested the hypothesis that frequently repeated mass administrations of ivermectin to village residents would reduce clinical malaria episodes in children and would be well tolerated with minimal harms. Methods We invited villages (clusters) in Burkina Faso to participate in a single-blind (outcomes assessor), parallel-assignment, two-arm, cluster-randomised trial over the 2015 rainy season. Villages were assigned (1:1) by random draw to either the intervention group or the control group. In both groups, all eligible participants who consented to the treatment and were at least 90 cm in height received single oral doses of ivermectin (150–200 μg/kg) and albendazole (400 mg), and those in the intervention group received five further doses of ivermectin alone at 3-week intervals thereafter over the 18-week treatment phase. The primary outcome was cumulative incidence of uncomplicated malaria episodes over 18 weeks (analysed on a cluster intention-to-treat basis) in an active case detection cohort of children aged 5 years or younger living in the study villages. This trial is registered with ClinicalTrials.gov, number NCT02509481. Findings Eight villages agreed to participate, and four were randomly assigned to each group. 2712 participants (1333 [49%] males and 1379 [51%] females; median age 15 years [IQR 6–34]), including 590 children aged 5 years or younger, provided consent and were enrolled between May 22 and July 20, 2015 (except for 77 participants enrolled after these dates because of unavailability before the first mass drug administration, travel into the village during the trial, or birth), with 1447 enrolled into the intervention group and 1265 into the control group. 330 (23%) participants in the intervention group and 233 (18%) in the control group met the exclusion criteria for mass drug administration. Most children in the active case detection cohort were not treated because of height restrictions. 14 (4%) children in the intervention group and 10 (4%) in the control group were lost to follow-up. Cumulative malaria incidence was reduced in the intervention group (648 episodes among 327 children; estimated mean 2·00 episodes per child) compared with the control group (647 episodes among 263 children; 2·49 episodes per child; risk difference −0·49 [95% CI −0·79 to −0·21], p=0·0009, adjusted for sex and clustering). The risk of adverse events among all participants did not differ between groups (45 events [3%] among 1447 participants in the intervention group vs 24 events [2%] among 1265 in the control group; risk ratio 1·63 [1·01 to 2·67]; risk difference 1·21 [0·04 to 2·38], p=0·060), and no adverse reactions were reported. Interpretation Frequently repeated mass administrations of ivermectin during the malaria transmission season can reduce malaria episodes among children without significantly increasing harms in the populace. Funding Bill & Melinda Gates Foundation.

Background To reduce the risk of drug-induced haemolysis, all patients should be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDd) prior to prescribing primaquine (PQ)-based radical cure for the treatment of vivax malaria. This systematic review and individual patient meta-analysis assessed the utility of a qualitative lateral flow assay from Access Bio/CareStart (Somerset, NJ) (CareStart Screening test for G6PD deficiency) for the diagnosis of G6PDd compared to the gold standard spectrophotometry (International Prospective Register of Systematic Reviews [PROSPERO]: CRD42019110994). Methods and findings Articles published on PubMed between 1 January 2011 and 27 September 2019 were screened. Articles reporting performance of the standard CSG from venous or capillary blood samples collected prospectively and considering spectrophotometry as gold standard (using kits from Trinity Biotech PLC, Wicklow, Ireland) were included. Authors of articles fulfilling the inclusion criteria were contacted to contribute anonymized individual data. Minimal data requested were sex of the participant, CSG result, spectrophotometry result in U/gHb, and haemoglobin (Hb) reading. The adjusted male median (AMM) was calculated per site and defined as 100% G6PD activity. G6PDd was defined as an enzyme activity of less than 30%. Pooled estimates for sensitivity and specificity, unconditional negative predictive value (NPV), positive likelihood ratio (LR+), and negative likelihood ratio (LR−) were calculated comparing CSG results to spectrophotometry using a random-effects bivariate model. Of 11 eligible published articles, individual data were available from 8 studies, 6 from Southeast Asia, 1 from Africa, and 1 from the Americas. A total of 5,815 individual participant data (IPD) were available, of which 5,777 results (99.3%) were considered for analysis, including data from 3,095 (53.6%) females. Overall, the CSG had a pooled sensitivity of 0.96 (95% CI 0.90–0.99) and a specificity of 0.95 (95% CI 0.92–0.96). When the prevalence of G6PDd was varied from 5% to 30%, the unconditional NPV was 0.99 (95% CI 0.94–1.00), with an LR+ and an LR− of 18.23 (95% CI 13.04–25.48) and 0.05 (95% CI 0.02–0.12), respectively. Performance was significantly better in males compared to females (p = 0.027) but did not differ significantly between samples collected from capillary or venous blood (p = 0.547). Limitations of the study include the lack of wide geographical representation of the included data and that the CSG results were generated under research conditions, and therefore may not reflect performance in routine settings. Conclusions The CSG performed well at the 30% threshold. Its high NPV suggests that the test is suitable to guide PQ treatment, and the high LR+ and low LR− render the test suitable to confirm and exclude G6PDd. Further operational studies are needed to confirm the utility of the test in remote endemic settings., In this systematic review and meta-analysis, Benedikt Ley and colleagues assess the performance of a point of care screening test for identifyint vivax malaria patients who are at risk of drug-induced haemolysis., Author summary Why was this study done? Glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDd) is the key determinant of severe haemolysis following primaquine (PQ)-based radical cure of vivax malaria. A widely available reliable point-of-care diagnostic for G6PDd will improve patient safety of PQ treatment. A rapid diagnostic G6PD test from Access Bio (Somerset, NJ) has operational characteristics that render the test suitable for use at the bedside. What did the researchers do and find? We reviewed the literature systematically and identified studies that had evaluated the G6PD test and compared results with those generated by the gold standard spectrophotometry. Individual participant data (IPD), available from 5,777 participants, demonstrated that the test had a 96% sensitivity for detecting G6PD-deficient individuals with a specificity of 95%. What do these findings mean? Under research conditions, the G6PD test reliably confirms and excludes G6PDd in patients with G6PD activity of less than 30% (the most widely applied cut-off activity to guide PQ-based radical cure). These findings will have to be confirmed in routine clinical settings.

Pharmacokinetic/pharmacodynamic studies of artemether-lumefantrine and 3 antiretroviral regimens were conducted in malaria-infected Ugandan children. Efavirenz-based treatment was associated with significant reductions in antimalarial exposure and higher risks of recurrent malaria. Caution in their concurrent use is warranted., Background. The optimal treatment of malaria in human immunodeficiency virus (HIV)–infected children requires consideration of critical drug–drug interactions in coinfected children, as these may significantly impact drug exposure and clinical outcomes. Methods. We conducted an intensive and sparse pharmacokinetic/pharmacodynamic study in Uganda of the most widely adopted artemisinin-based combination therapy, artemether-lumefantrine. HIV-infected children on 3 different first-line antiretroviral therapy (ART) regimens were compared to HIV-uninfected children not on ART, all of whom required treatment for Plasmodium falciparum malaria. Pharmacokinetic sampling for artemether, dihydroartemisinin, and lumefantrine exposure was conducted through day 21, and associations between drug exposure and outcomes through day 42 were investigated. Results. One hundred forty-five and 225 children were included in the intensive and sparse pharmacokinetic analyses, respectively. Compared with no ART, efavirenz (EFV) reduced exposure to all antimalarial components by 2.1- to 3.4-fold; lopinavir/ritonavir (LPV/r) increased lumefantrine exposure by 2.1-fold; and nevirapine reduced artemether exposure only. Day 7 concentrations of lumefantrine were 10-fold lower in children on EFV vs LPV/r-based ART, changes that were associated with an approximate 4-fold higher odds of recurrent malaria by day 28 in those on EFV vs LPV/r-based ART. Conclusions. The choice of ART in children living in a malaria-endemic region has highly significant impacts on the pharmacokinetics and pharmacodynamics of artemether-lumefantrine treatment. EFV-based ART reduces all antimalarial components and is associated with the highest risk of recurrent malaria following treatment. For those on EFV, close clinical follow-up for recurrent malaria following artemether-lumefantrine treatment, along with the study of modified dosing regimens that provide higher exposure, is warranted.

This prospective trial investigated the population pharmacokinetics of piperaquine, given with dihydroartemisinin to treat uncomplicated malaria in 107 Ugandan children 6 months to 2 years old, an age group previously unstudied. Current weight-based dosing does not adequately address physiological changes in early childhood. Patients were administered standard three-day oral doses and provided 1,282 capillary plasma concentrations from 218 malaria episodes. Less than 30% of treatments achieved 57 ng/mL on day 7. A three-compartment model with first-order absorption described the data well. Age had a statistically significant effect (p

Objective: The objective of this study is to determine the epidemiological effectiveness of a first-line antiretroviral regimen with HIV protease inhibitor for preventing recurrent malaria in children under the range of HIV prevalence levels and malaria transmission intensities encountered in sub-Saharan Africa. Design: Adynamicmodelofmalariatransmissionwasdevelopedusingclinicaldataon the protease inhibitor extended posttreatment prophylactic effect of the antimalarial treatment, artemether-lumefantrine, in addition to parameter estimates from the literature. Methods: To evaluate the benefits of HIV protease inhibitors on the health burden of recurrent malaria among children, we constructed a dynamic model of malaria transmission to both HIV-positive and HIV-negative children, parameterized by data from a recent clinical trial. The model was then evaluated under varying malaria transmission and HIV prevalence settings to determine the health benefits of HIV protease inhibitors in the context of artemether-lumefantrine treatment of malaria in children. Results: Comparing scenarios of low, intermediate and high newborn HIV prevalence, in a range of malaria transmission settings, our dynamic model predicts that artemetherlumefantrinewithHIVproteaseinhibitorbasedregimensprevents0.03‐0.10,5.2‐13.0 and 25.5‐65.8 annual incidences of malaria per 1000 children, respectively. In addition, HIV protease inhibitors save 0.002‐0.006, 0.22‐0.8, 1.04‐4.3 disabilityadjusted life-years per 1000 children annually. Considering only HIV-infected children, HIV protease inhibitors avert between 278 and 1043 annual incidences of malaria per 1000 children. Conclusion: The use of HIV protease inhibitor based regimens as first-line antiretroviral therapy for HIV is an effective measure for reducing recurrent malaria among HIVinfected children in areas where HIV and malaria are coendemic, and artemetherlumefantrine is a first-line antimalarial.

Background Early diagnosis of suspected malaria cases with a rapid diagnostic test (RDT) has been shown to be an effective malaria control tool used in many resource-constrained settings. However, poor quality control and quality assurance hinder the accurate reporting of malaria diagnoses. Recent use of a portable, battery operated RDT reader (Deki Reader™, Fio Corporation) has shown to have high agreement with visual inspection across diverse health centre settings, however evidence of its feasibility and usability during cross sectional surveys are limited. This study aimed to evaluate the performance of the Deki Reader™ in a cross-sectional survey of children from southwestern Uganda. Methods A two-stage, stratified cluster sampling survey was conducted between July and October 2014 in three districts of southwestern Uganda, with varying malaria transmission intensities. A total of 566 children aged 6–59 months were included in the analysis. Blood samples were collected and tested for malaria using: the SD Bioline Malaria Ag Pf/Pan RDT and microscopy. Results were compared between visual inspection of the RDT and by the Deki Reader™. Diagnostic performance of both methods were compared to gold-standard microscopy. Results The sensitivity and specificity of the Deki Reader™ was 94.1% (95% CI 69.2–99.6%) and 95.6% (95% CI 93.4–97.1%), respectively. The overall percent agreement between the Deki Reader™ and visual RDT inspection was 98.9% (95% CI 93.2–99.8), with kappa statistic of 0.92 (95% CI 0.85–0.98). Conclusions The findings from this study suggest that the Deki Reader™ is comparable to visual inspection and performs well in detecting microscopy-positive Plasmodium falciparum cases in a household survey setting. However, the reader’s performance was highly dependent on ensuring adequate battery life and a work environment free of dirt particles.

Background Lumefantrine is a long-acting antimalarial drug with an elimination half-life of over 3 days and protein binding of 99 percent. Correlation of lumefantrine concentrations from capillary plasma via fingerprick (Cc) versus venous plasma (Cv) remains to be defined. Methods Venous and capillary plasma samples were collected simultaneously from children, pregnant women, and non-pregnant adults at 2, 24, 120hr post last dose of a standard 3-day artemether-lumefantrine regimen they received for uncomplicated malaria. Some of the enrolled children and pregnant women were also HIV-infected. Samples were analyzed via liquid chromatography tandem mass spectrometry. Linear regression analysis was performed using the program Stata® SE12.1. Results In children, the linear regression equations for Cc vs Cv at 2, 24, and 120hr (day 7) post dose are [Cc] = 1.05*[Cv]+95.0 (n = 142, R2 = 0.977), [Cc] = 0.995*[Cv]+56.7 (n = 147, R2 = 0.990) and [Cc] = 0.958*[Cv]+18.6 (n = 139, R2 = 0.994), respectively. For pregnant women, the equations are [Cc] = 1.04*[Cv]+68.1 (n = 43, R2 = 0.990), [Cc] = 0.997*[Cv]+37.3 (n = 43, R2 = 0.993) and [Cc] = 0.941*[Cv]+11.1 (n = 41, R2 = 0.941), respectively. For non-pregnant adults, the equations are [Cc] = 1.05*[Cv]-117 (n = 32, R2 = 0.958), [Cc] = 0.962*[Cv]+9.21 (n = 32, R2 = 0.964) and [Cc] = 1.04*[Cv]-40.1 (n = 32, R2 = 0.988), respectively. In summary, a linear relationship with a slope of ~1 was found for capillary and venous lumefantrine levels in children, pregnant women and non-pregnant adults at 2hr, 24hr and 120hr post last dose, representing absorption, distribution, and elimination phases. Conclusions Capillary and venous plasma concentration of lumefantrine can be used interchangeably at 1:1 ratio. Capillary sampling method via finger prick is a suitable alternative for sample collection in clinical studies.

BACKGROUNDThe antiretroviral drug nevirapine and the antimalarial artemisinin-based combination therapy artemether-lumefantrine are commonly co-administered to treat malaria in the context of HIV. Nevirapine is a known inhibitor of cytochrome P450 3A4, which metabolizes artemether and lumefantrine. To address the concern that the antiretroviral nevirapine impacts the antimalarial artemether-lumefantrine pharmacokinetics, a prospective non-randomized controlled study in children presenting with uncomplicated malaria and HIV in sub-Saharan Africa was carried out.METHODSParticipants received artemether-lumefantrine (20/120 mg weight-based BID) for 3 days during nevirapine-based antiretroviral therapy (ART) co-administration (158-266 mg/m2 QD). HIV positive participants who were not yet on ART drugs were also enrolled as the control group. The target enrollment was children aged 3-12 years (n = 24 in each group). Intensive pharmacokinetics after the last artemether-lumefantrine dose was assessed for artemether, its active metabolite dihydroartemisinin, and lumefantrine. Pharmacokinetic parameters (area under the plasma concentration vs. time curve (AUC), maximum concentration and day 7 lumefantrine concentrations) were estimated using non-compartmental methods and compared to controls.RESULTSNineteen children (16 on nevirapine and three not on ART) enrolled. Fifteen of the 16 (aged 4 to 11 years) on nevirapine-based ART were included in the pharmacokinetic analysis. Due to evolving WHO HIV treatment guidelines, insufficient children were enrolled in the control group (n = 3), so the pharmacokinetic data were compared to a historical control group of 20 HIV-uninfected children 5-12 years of age who also presented with malaria and underwent identical study procedures. Decreases of pharmacokinetic exposure [as estimated by AUC (AUC0-8hr)] were marginally significant for artemether (by -46%, p = 0.08) and dihydroartemisinin (-22%, p = 0.06) in the children on nevirapine-based ART, compared to when artemether-lumefantrine was administered alone. Similarly, peak concentration was decreased by 50% (p = 0.07) for artemether and 36% (p = 0.01) for dihydroartemisinin. In contrast, exposure to lumefantrine increased significantly in the context of nevirapine [AUC0-120hr:123% (pCONCLUSIONSNevirapine-based ART increases the exposure to lumefantrine in pre-pubescent children with a trend toward diminished artemether and dihydroartemisinin exposure. These findings contrast with other studies indicating NVP reduces or results in no change in exposure of antimalarial drugs, and may be specific to this age group (4-12 years). Considering the excellent safety profile of artemether-lumefantrine, the increase in lumefantrine is not of concern. However, the reduction in artemisinin exposure may warrant further study, and suggests that dosage adjustment of artemether-lumefantrine with nevirapine-based ART in children is likely warranted.

Background Malaria remains endemic in Afghanistan. National control and prevention strategies would be greatly enhanced through a better ability to forecast future trends in disease incidence. It is, therefore, of interest to develop a predictive tool for malaria patterns based on the current passive and affordable surveillance system in this resource-limited region. Methods This study employs data from Ministry of Public Health monthly reports from January 2005 to September 2015. Malaria incidence in Afghanistan was forecasted using autoregressive integrated moving average (ARIMA) models in order to build a predictive tool for malaria surveillance. Environmental and climate data were incorporated to assess whether they improve predictive power of models. Results Two models were identified, each appropriate for different time horizons. For near-term forecasts, malaria incidence can be predicted based on the number of cases in the four previous months and 12 months prior (Model 1); for longer-term prediction, malaria incidence can be predicted using the rates 1 and 12 months prior (Model 2). Next, climate and environmental variables were incorporated to assess whether the predictive power of proposed models could be improved. Enhanced vegetation index was found to have increased the predictive accuracy of longer-term forecasts. Conclusion Results indicate ARIMA models can be applied to forecast malaria patterns in Afghanistan, complementing current surveillance systems. The models provide a means to better understand malaria dynamics in a resource-limited context with minimal data input, yielding forecasts that can be used for public health planning at the national level. Electronic supplementary material The online version of this article (doi:10.1186/s12936-016-1602-1) contains supplementary material, which is available to authorized users.

Introduction Bhutan is progressing toward malaria elimination. The purpose of this evaluation was to assess the ability of the surveillance system from 2006 to 2012 to meet the objectives of the Bhutan Vector-borne Disease Control Program (VDCP) and to highlight priorities requiring attention as the nation transitions to elimination. Methods The evaluation was conducted using the Center for Disease Control guidelines for evaluating public health surveillance systems. Data sources included a search of publically available literature, VDCP program data, and interviews with malaria surveillance personnel. Blood slide quality assurance and control through formal assessment of slide preparation and measures of between-reader correlation were performed. Results Total malaria cases declined from 2006 to 2012. The average slide positivity rate decreased from 3.4% in 2006 to 0.2% in 2012. The proportion of non-residents in all cases increased to its highest value of 22.6% in 2012, and significant clustering in the border regions of India was noted, with Sarpang accounting for more cases than any other district from 2009 onward. Case detection was almost exclusively passive, but flexibility and sensitivity was demonstrated by the later addition of active case detection and specification of imported and locally acquired cases. Spatial data were limited to the village level, not allowing identification of transmission hotspots. For blood smears, statistical measures of between-reader agreement and predictive value were not computed. Blood smear quality was suboptimal by at least one criterion in over half of evaluated smears. Timeliness in reporting of cases was on a weekly to monthly basis, and did not meet the WHO goal of immediate notification. Conclusion As of 2012, the national malaria surveillance system demonstrated flexibility, representativeness, simplicity, and stability. The full potential for data analysis was not yet realized. Attaining the goal of malaria elimination will require system function enhancement through increased and more accurate case detection and rapid investigation, improved health worker training and accountability, focally targeted response measures, and, in particular, the challenge of finding re-introductions of infections from India. Many such measure have been undertaken or planned as part of the next phase of the Bhutan’s National Strategic Plan.

Background. The pharmacokinetics and pharmacodynamics of lumefantrine, a component of the most widely used treatment for malaria, artemether-lumefantrine, has not been adequately characterized in young children. Methods. Capillary whole-blood lumefantrine concentration and treatment outcomes were determined in 105 Ugandan children, ages 6 months to 2 years, who were treated for 249 episodes of Plasmodium falciparum malaria with artemether-lumefantrine. Results. Population pharmacokinetics for lumefantrine used a 2-compartment open model with first-order absorption. Age had a significant positive correlation with bioavailability in a model that included allometric scaling. Children not receiving trimethoprim-sulfamethoxazole with capillary whole blood concentrations 200 ng/mL (P =. 0007). However, for children receiving trimethoprim-sulfamethoxazole, the risk of recurrent parasitemia did not differ significantly on the basis of this threshold. Day 3 concentrations were a stronger predictor of 28-day recurrence than day 7 concentrations. Conclusions. We demonstrate that age, in addition to weight, is a determinant of lumefantrine exposure, and in the absence of trimethoprim-sulfamethoxazole, lumefantrine exposure is a determinant of recurrent parasitemia. Exposure levels in children aged 6 months to 2 years was generally lower than levels published for older children and adults. Further refinement of artemether-lumefantrine dosing to improve exposure in infants and very young children may be warranted. © 2016 The Author.

BackgroundHIV and malaria geographically overlap. HIV protease inhibitors kill malaria parasites in vitro and in vivo, but further evaluation in clinical studies is needed.MethodsThirty-one children from Malawi aged 4-62 months were followed every 3 months and at intercurrent illness visits for ≤47 months (September 2009-December 2011). We compared malaria parasite carriage by blood smear microscopy (BS) and confirmed clinical malaria incidence (CCM, or positive BS with malaria symptoms) in children initiated on HIV antiretroviral therapy (ART) with zidovudine, lamivudine, and either nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor, or lopinavir-ritonavir (LPV-rtv), a protease inhibitor.ResultsWe found an association between increased time to recurrent positive BS, but not CCM, when anti-malarial treatment and LPV-rtv based ART were used concurrently and when accounting for a LPV-rtv and antimalarial treatment interaction (adjusted HR 0.39; 95% CI (0.17,0.89); p = 0.03).ConclusionsLPV-rtv in combination with malaria treatment was associated with lower risk of recurrent positive BS, but not CCM, in HIV-infected children. Larger, randomized studies are needed to confirm these findings which may permit ART optimization for malaria-endemic settings.Trial registrationClinicalTrials.gov NCT00719602.

Dihydroartemisinin-piperaquine is being increasingly used as a first-line artemisinin combination treatment for malaria. The aim of this study was to describe the pharmacokinetic and pharmacodynamic properties of piperaquine in 236 children with uncomplicated falciparum malaria in Burkina Faso. They received a standard body weight-based oral 3-day fixed-dose dihydroartemisinin- piperaquine regimen. Capillary plasma concentration-time profiles were characterized using nonlinear mixed-effects modeling. The population pharmacokinetics of piperaquine were described accurately by a two-transit-compartment absorption model and a three-compartment distribution model. Body weight was a significant covariate affecting clearance and volume parameters. The individually predicted day 7 capillary plasma concentration of piperaquine was an important predictor (P

Artemisinin-based combination therapies (ACTs) are currently considered the first-line treatments for uncomplicated Plasmodium falciparum malaria. Among these, artemether-lumefantrine (AL) has been the most widely prescribed ACT in sub-Saharan Africa. Recent clinical trials conducted in sub-Saharan Africa have shown that dihydroartemisinin-piperaquine (DP), a most recent ACT, may have a longer post-treatment prophylactic period and post-treatment infection period (duration of gametocyte carriage) than AL. Using epidemiological and clinical data on the efficacy of AL and DP, we developed and parameterized a mathematical transmission model that we used to compare the population-level impact of AL and DP for reducing P. falciparum malaria transmission in sub-Saharan Africa. Our results showed that DP is likely to more effectively reduce malaria incidence of clinical episodes than AL. However in low P. falciparum transmission areas, DP and AL are likely to be equally effective in reducing malaria prevalence. The predictions of our model were shown to be robust to the empirical uncertainty summarizing the epidemiological parameters. DP should be considered as a replacement for AL as first-line treatment of uncomplicated malaria in highly endemic P. falciparum communities. To optimize the effectiveness of ACTs, it is necessary to tailor treatment policies to the transmission intensity in different settings.

Pregnant women are at particularly high risk for morbidity and mortality from malaria, and pregnancy can markedly affect drug pharmacokinetics, yet the pharmacokinetics of antimalarial drugs in pregnancy has been little studied. An important malaria-control measure in Africa is intermittent preventive therapy (IPT) with sulfadoxine-pyrimethamine (SP) during pregnancy. We discuss IPT with SP in light of several concerns and highlight recent findings from a pharmacokinetic study of SP in this population.

Objective This study aimed to develop a rationale for the management of retinal detachments related to choroidal coloboma and to study the outcome of their management. Design The study design was a retrospective study. Participants A total of 85 eyes of 81 patients with retinal detachments related to coloboma of the choroid participated. Intervention All eyes underwent pars plana vitrectomy with internal tamponade using silicone oil (80 eyes) or perfluropropane gas (5 eyes). Behavior of the retina on fluid-air exchange was used to guide the further steps of surgery. Endolaser was performed along the coloboma border. Silicone oil was removed in 80% of eyes. The main outcome measures were retinal reattachment and visual recovery. Results Recurrent retinal detachment occurred in 16.3% of silicone oil-filled eyes and 60% of gas-filled eyes. After silicone oil removal, 15.6% of eyes had recurrent retinal detachment. After a mean follow-up of 13.4 months, 81.2% of eyes had attached retina and 69.4% recovered equal to or better than 10/200 visual acuity. Conclusion Retinal detachment secondary to coloboma of choroid is treated best by pars plana vitrectomy along with silicone oil tamponade. Gas tamponade has limited indications. Clinical evaluation of the extent of retinal detachment within the colobomatous area and the behavior of the retina on fluid-air exchange help the authors understand the pathogenesis of the retinal detachment and plan a rational therapy.

Although blunt ocular trauma frequently damages the crystalline lens, isolated rupture of the posterior capsule is an infrequently reported occurrence. The authors describe three patients with this unusual presentation. All patients underwent cataract extraction and intraocular lens (IOL) implantation using a limbal approach. There were no intraoperative complications. All patients achieved good postoperative visual acuity with well-positioned posterior chamber IOLs (in-the-bag in two eyes, sulcus fixated in one eye). Isolated rupture of the posterior capsule in young patients can be safely managed using the limbal approach and implantation of posterior chamber IOLs, is possible. [Ophthalmic Surg Lasers 1998;29:338-342.]

To describe the results of management of glass intraocular foreign bodies (IOFBs).A total of 51 eyes of 43 patients that sustained penetrating injury with glass IOFB were studied retrospectively. A total of 23.5% had IOFB only in the anterior segment; the rest had IOFB in the posterior segment alone or in both the anterior and posterior segments. Six eyes were followed conservatively despite IOFB in a functional eye. Removal of IOFB was combined with repair of retinal detachment (where present) using internal tamponade with gas or silicone oil or buckle.After a mean follow-up of 16.8 months, 66.7% of eyes recovered better than 6/60 (20/200) vision and 75.6% had attached retina. On univariate analysis, scleral entry wound, posterior segment IOFB, larger size of IOFB, and retinal damage were found to be associated with poor anatomic outcome. Lower presenting visual acuity, hyphema, retinal damage, subretinal hemorrhage, detached retina, and larger IOFB were associated with a poor functional result. Multivariate analysis identified retinal damage caused by the foreign body as the only factor significantly associated with poor anatomic as well as functional outcome.Glass IOFBs are caused in a majority of cases by blast injury. Bilaterality is not uncommon. Presence of retinal damage is predictive of poor functional and anatomic results. Overall results are modest with modern vitreoretinal surgical techniques.

* BACKGROUND AND OBJECTIVE: To investigate the risk factors associated with suprachoroidal hemorrhage (SCH) during vitrectomy. * PATIENTS AND METHODS: Of 6971 pars plana vitrectomies performed between May 1988 and December 1994, SCH occurred intraoperatively in 12 (0.17%) cases. Forty-two age- and sex-matched control subjects were selected by computer-generated random numbers. Preoperative and intraoperative variables were subjected to univariate and conditional logistic regression analysis. * RESULTS: Statistically significant risk factors for SCH after univariate analysis included myopia (P = .048), aphakia or pseudophakia (P = .024), rhegmatogenous retinal detachment (P = .044), scleral buckling and/or encirclage at vitrectomy (P = .029), and longer duration of surgery (P = .044). Multivariate analysis revealed independent risks associated with the absence of a lens and longer duration of the surgery. * CONCLUSION: A knowledge of the risk factors involved with SCH helps the physician to identify patients who are at a greater risk for this complication. [Ophthalmic Surg Lasers 1997;28:640-644.]

BACKGROUND: Although dihydroartemisinin-piperaquine (DP) is used primarily in children, pharmacokinetic/pharmacodynamic (PK/PD) data on DP use in young children are lacking. METHODS: We conducted a prospective PK/PD study of piperaquine in 107 young children in Uganda. Samples were collected up to 28 days after 218 episodes of malaria treatment, which occurred during follow-up periods of up to 5 months. Malaria follow-up was conducted actively to day 28 and passively to day 63. RESULTS: The median capillary piperaquine concentration on day 7 after treatment was 41.9 ng/mL. Low piperaquine concentrations were associated with an increased risk of recurrent malaria for up to 42 days, primarily in those receiving trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis. In children not receiving TMP-SMX, low piperaquine concentrations were only modestly associated with an increased risk of recurrent malaria. However, for children receiving TMP-SMX, associations were strong and evident for all sampling days, with PQ concentrations of ≤ 27.3 ng/mL on day 7 associated with a greatly increased risk of recurrent malaria. Notably, of 132 cases of recurrent malaria, 119 had detectable piperaquine concentrations at the time of presentation with recurrent malaria. CONCLUSIONS: These piperaquine PK/PD data represent the first in children

* BACKGROUND AND OBJECTIVES: Epimacular proliferation (EMP) represents a localized form of reproliferation at the macula. The significance of EMP in eyes that have undergone vitrectomy is still not clear. This study investigated the redetachment rate following silicone oil removal when combined with removal of EMP. * PATIENTS AND METHODS: Twenty-two consecutive eyes underwent removal of silicone oil and EME These eyes had attached retinas following silicone oil injection used as an adjunct to complex vitreoretinal surgery. * RESULTS: The retina remained attached in 19 (86.4%) of the eyes, with functional improvement in vision in 81.8% of the eyes. Visual acuity of 6/60 (20/200) or better was obtained in 12 (54.5%) of the eyes. The mean follow-up time was 6.3 months. * CONCLUSION: These results suggest that removal of EMP and silicone oil does not increase the risk of redetachment. [Ophthalmic Surg Lasers 1996;27:192-196.]

BACKGROUND:The combination of short-acting dihydroartemisinin and long-acting piperaquine (DP) is among the first-line therapies for the treatment of uncomplicated Plasmodium falciparum malaria. Population pharmacokinetic models of piperaquine (PQ) based on data from acute treatment of young children can be used to predict exposure profiles of piperaquine under different DP chemoprevention regimens. The purpose of our study was to make such predictions in young children. METHODS:Based on a prior population pharmacokinetic model of PQ in young Ugandan children, we simulated capillary plasma concentration-time profiles (including their variability) of candidate chemoprevention regimens for a reference population of 1-2 year olds weighing at least 11 kg. Candidate regimens that were tested included monthly administration of standard therapeutic doses, bimonthly dosing, and weekly dosing (with and without a loading dose). RESULTS:Once daily doses of 320 mg for three days (960 mg total) at the beginning of each month are predicted to achieve an average steady-state trough capillary piperaquine concentration of 35 ng/mL, with 60% achieving a level of 30 ng/mL or higher. In contrast, weekly dosing of 320 mg (i.e., 33% higher amount per month) is predicted to approximately double the average steady-state trough concentration, increase the percent of children predicted to achieve 30 ng/mL or higher (94%), while at the same time lowering peak concentrations. Exposure at steady-state, reached at approximately 3 months of multiple dosing, is expected to be approximately 2-fold higher than exposure following initial dosing, due to accumulation. A loading dose improves early exposure, thereby reducing the risk of breakthrough infections at the initiation of chemoprevention. CONCLUSIONS:Once weekly chemoprevention of DP predicts favourable exposures with respect to both trough and peak concentrations. These predictions need to be verified, as well as safety evaluated, in field-based clinical studies of young children. Simulations based on prior knowledge provide a systematic information-driven approach to evaluate candidate DP chemopreventive regimens for future trial designs.

Mutations in beta-globin, glucose-6-phosphate dehydrogenase, and promoters for tumor necrosis factor-alpha and inducible nitric oxide synthase (iNOS) were examined for associations with the incidence of symptomatic malaria in a cohort of 307 Ugandan children. After adjustment of incidence rates for age, water source, use of preventative measures, and proximity to mosquito breeding sites, glucose-6-phosphate dehydrogenase A- heterozygous females had a significantly higher incidence of malaria (incidence rate ratio [IRR] = 1.63, P = 0.03) and a trend towards higher parasite densities (37,100 versus 26,200 parasites/microL; P = 0.18) compared with wild-type children. Male hemizygotes had trends in the same direction. Heterozygotes for sickle hemoglobin had trends toward a lower incidence of malaria and lower parasite density at presentation. Heterozygotes for the iNOS promoter G954C polymorphism, but not other promoter polymorphisms, had a significantly lower incidence of malaria compared with wild-type children (IRR = 0.69, P = 0.05). Host polymorphisms appear to impact upon the incidence of uncomplicated malaria in Ugandan children.

We assessed the prevalence and natural history of malarial parasitemia by use of microscopy and polymerase chain reaction (PCR) in 314 asymptomatic children in Kampala, Uganda. The prevalence of asymptomatic parasitemia was 17% by microscopy and 47% by PCR. Children with parasitemia identified by microscopy had a 5-fold higher rate of subsequent symptomatic malaria, compared with children without detectable parasitemia. Children with parasitemia identified by PCR alone had a similar rate of subsequent symptomatic malaria, compared with children without detectable parasitemia. Among microscopy-positive children who later developed symptomatic malaria, 47% had strains identical to those identified at enrollment, and the proportion of symptomatic episodes due to persistent strains remained high for 3 months. Among the PCR-positive/microscopy-negative children, only 17% had identical genotyping patterns at the onset of symptomatic malaria, with most of these episodes occurring during the first month. Asymptomatic parasitemia detected by microscopy, but not by PCR, strongly predicted subsequent clinical malaria, often due to persistent infection.

The stress on small self-sealing incisions in cataract surgery has resulted in the increased use of foldable intraocular lenses (IOL). Plate haptic silicone IOLs implanted with the help of an injector require extremely small incision lengths and are extensively used. The authors discuss difficulties in explanting such lenses, especially in inflamed eyes. Two patients who underwent plate-haptic silicone IOL explantation for postoperative bacterial endophthalmitis are described. Plate haptic IOLs have a tendency to dislocate posteriorly because of poor capsular fixation and increased posterior bowing. Enlarging a small rhexis prior to attempting explantation of these lenses reduces this complication. Difficulties inherent in explanting plate haptic silicone IOLs in inflamed eyes are discussed, along with suggestions to overcome them. [Ophthalmic Surg Lasers 1999;30:575-578.]

Purpose: The efficacy and safety of parabulbar anesthesia was investigated prospectively in 100 patients undergoing primary vitreoretinal surgery. Methods: The technique involved three steps: (1) orbicularis oculi injection, (2) subconjunctival injection, and (3) sub-Tenon irrigation. The effect of anesthesia was graded 0 to 5 depending on inadequate anesthesia-akinesia with or without local supplementation. Ninety-three patients underwent vitrectomy without buckling and 4 with an encircling band; 3 had scleral buckling. Mean duration of surgery was 89.38 minutes. Results: In 69% of patients (grades 4 and 5), no supplementation was required and in 31 % (grades 1–3), local supplementation was needed for inadequate anesthesia or akinesia or both. No ocular or systemic complication occurred. Early onset of anesthesia correlated with adequate anesthesia throughout the procedure ( P Conclusions: Parabulbar anesthesia is a safe and effective technique of local anesthesia in patients undergoing primary vitreoretinal surgery.

BACKGROUND: Achieving adequate antimalarial drug exposure is essential for curing malaria. Day 7 blood or plasma lumefantrine concentrations provide a simple measure of drug exposure that correlates well with artemether-lumefantrine efficacy. However, the 'therapeutic' day 7 lumefantrine concentration threshold needs to be defined better, particularly for important patient and parasite sub-populations. METHODS: The WorldWide Antimalarial Resistance Network (WWARN) conducted a large pooled analysis of individual pharmacokinetic-pharmacodynamic data from patients treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria, to define therapeutic day 7 lumefantrine concentrations and identify patient factors that substantially alter these concentrations. A systematic review of PubMed, Embase, Google Scholar, ClinicalTrials.gov and conference proceedings identified all relevant studies. Risk of bias in individual studies was evaluated based on study design, methodology and missing data. RESULTS: Of 31 studies identified through a systematic review, 26 studies were shared with WWARN and 21 studies with 2,787 patients were included. Recrudescence was associated with low day 7 lumefantrine concentrations (HR 1.59 (95% CI 1.36 to 1.85) per halving of day 7 concentrations) and high baseline parasitemia (HR 1.87 (95% CI 1.22 to 2.87) per 10-fold increase). Adjusted for mg/kg dose, day 7 concentrations were lowest in very young children (/=200 ng/ml were associated with >98% cure rates (if parasitemia /=200 ng/ml and high cure rates in most uncomplicated malaria patients. Three groups are at increased risk of treatment failure: very young children (particularly those underweight-for-age); patients with high parasitemias; and patients in very low transmission intensity areas with emerging parasite resistance. In these groups, adherence and treatment response should be monitored closely. Higher, more frequent, or prolonged dosage regimens should now be evaluated in very young children, particularly if malnourished, and in patients with hyperparasitemia.