Effects of next-generation, dual-active-ingredient, long-lasting insecticidal net deployment on insecticide resistance in malaria vectors in Tanzania: an analysis of a 3-year, cluster-randomised controlled trial.

BACKGROUND: Insecticide resistance among malaria-vector species is a pervasive problem that might jeopardise global disease-control efforts. Novel vector-control tools with different modes of action, including long-lasting insecticidal nets (LLINs) incorporating new active ingredients, are urgently needed to delay the evolution and spread of insecticide resistance. We aimed to measure phenotypic and genotypic insecticide-resistance profiles among wild Anopheles collected over 3 years to assess the longitudinal effects of dual-active-ingredient LLINs on insecticide resistance. METHODS: For this analysis, data nested in a 3-year, four parallel-arm, superiority cluster-randomised controlled trial (cRCT) in Tanzania, collected from 84 clusters (39 307 households) formed of 72 villages in the Misungwi district, were used to measure insecticide-resistance profiles among female Anopheles mosquitoes via insecticide-resistance bioassays and quantitative RT-PCR of metabolic-resistance genes. Wild, blood-fed, indoor-resting mosquitoes were collected annually during the rainy seasons from house walls in clusters from all four trial groups. Mosquitoes were morphologically identified as An gambiae sensu lato (SL) or An funestus SL before separate bioassay testing. The primary outcomes were lethal-dose values for α-cypermethrin, permethrin, and piperonyl butoxide pre-exposure plus permethrin-resistance intensity bioassays, mortality 72 h after insecticidal exposure for chlorfenapyr bioassays, fertility reduction 72 h after insecticidal exposure for pyriproxyfen bioassays, and fold change in metabolic-enzyme expression relative to an insecticide-susceptible laboratory strain. All primary outcomes were measured in An funestus SL 1 year, 2 years, and 3 years after LLIN distribution. Primary outcomes were also assessed in An gambiae SL if enough mosquitoes were collected. The cRCT is registered with ClinicalTrials.gov (NCT03554616). FINDINGS: Between May 24, 2019, and Oct 25, 2021, 47 224 female Anopheles were collected for resistance monitoring. In the pyrethroid (PY)-LLIN group, there were significant increases in α-cypermethrin-resistance intensity (year 1 LD50=9·52 vs year 2 76·20, p<0·0001) and permethrin-resistance intensity (year 1 13·27 vs year 2 35·83, p=0·0019) in An funestus SL. In the pyriproxyfen PY-LLIN group, there was similar increase in α-cypermethrin-resistance intensity (year 1 0·71 vs year 2 81·56, p<0·0001) and permethrin-resistance intensity (year 1 5·68 vs year 2 50·14, p<0·0001). In the piperonyl butoxide PY-LLIN group, α-cypermethrin-resistance intensity (year 1 33·26 vs year 3 70·22, p=0·0071) and permethrin-resistance intensity (year 1 47·09 vs year 3 2635·29, p<0·0001) also increased over time. In the chlorfenapyr PY-LLIN group, there were no effects on α-cypermethrin-resistance intensity (year 1 0·42 vs year 3 0·99, p=0·54) or permethrin-resistance intensity (data were not estimable due to nearly 100% mortality). There were also minimal reductions in chlorfenapyr susceptibility. However, in the chlorfenapyr PY-LLIN group, a significant decline in piperonyl-butoxide synergy was seen by year 3 (year 1 0·02 vs year 3 0·26, p=0·020). Highly over-expressed detoxification enzymes showed dynamic patterns of selection throughout the trial. INTERPRETATION: Our phenotypic data supports trial epidemiological findings; chlorfenapyr PY-LLINs provided superior protection from malaria across multiple transmission seasons, with few effects on insecticide-resistance selection. Rapid pyrethroid-resistance intensification in the piperonyl butoxide PY-LLIN group and pre-existing tolerance of pyriproxyfen in vector populations might explain the poorer performance of these two interventions regarding malaria outcomes. Further work is required to elucidate the potential mechanisms driving cross-resistance between pyrethroids and novel active ingredients to better inform the design of pre-emptive resistance-management strategies. FUNDING: UK Department for International Development; UK Medical Research Council; Wellcome Trust; UK Department of Health and Social Care; UK Foreign, Commonwealth and Development Office; and The Bill and Melinda Gates Foundation via the Innovative Vector Control Consortium.

Minimizing Ionizing Radiation in Evaluating Suspected Appendicitis in Children Before and After the Release of the ACEP Clinical Policy.

STUDY OBJECTIVE: The aim of this study was to examine the impact of the ACEP (American College of Emergency Physicians) clinical policy regarding diagnosis of suspected appendicitis on changing practice in the pediatric emergency department (ED) in the absence of a formal departmental protocol. METHODS: This was a retrospective chart review in a pediatric ED in which patients aged 2 to 18 years were evaluated for appendicitis via ultrasound, computed tomography (CT), or both, over a 7-year study period. We compared rates of CT utilization in the period before the release of the ACEP clinical policy regarding diagnosis and treatment of appendicitis (2008-2009) and the period after (2010-2014). Other metrics of interest were ultrasound results and physician response to results, as well as surrogate markers for quality of care. RESULTS: Seven hundred pediatric ED visits were included, with 200 prepolicy release and 500 postrelease. Computed tomography utilization decreased significantly postpolicy release from 43.5% (95% confidence interval [CI], 36.6%-50.3%) to 22.2% (95% CI, 18.5%-25.8%). The proportion of ultrasounds with indeterminate results also decreased, with 71.5% (95% CI, 65.1%-77.9%) and 55.1% (95% CI, 50.7%-59.5%) in the pre and post groups, respectively. Physicians ordered fewer CTs after indeterminate ultrasounds, decreasing from 63.7% (95% CI, 56.9%-70.5%) to 48.3%% (95% CI, 43.9%-52.7%). CONCLUSIONS: After the release of the clinical policy, CT utilization decreased significantly suggesting possible effectiveness of the policy in bringing about change in practice. Subsequently, there was an increase in the definitiveness in the ultrasound results. Physicians also evolved in their response to indeterminate ultrasound results, with fewer CTs ordered reflexively after indeterminate results.

Helium, inorganic and organic carbon isotopes of fluids and gases across the Costa Rica convergent margin.

In 2017, fluid and gas samples were collected across the Costa Rican Arc. He and Ne isotopes, C isotopes as well as total organic and inorganic carbon concentrations were measured. The samples (n = 24) from 2017 are accompanied by (n = 17) samples collected in 2008, 2010 and 2012. He-isotopes ranged from arc-like (6.8 RA) to crustal (0.5 RA). Measured dissolved inorganic carbon (DIC) δ13CVPDB values varied from 3.55 to -21.57‰, with dissolved organic carbon (DOC) following the trends of DIC. Gas phase CO2 only occurs within ~20 km of the arc; δ13CVPDB values varied from -0.84 to -5.23‰. Onsite, pH, conductivity, temperature and dissolved oxygen (DO) were measured; pH ranged from 0.9-10.0, conductivity from 200-91,900 µS/cm, temperatures from 23-89 °C and DO from 2-84%. Data were used to develop a model which suggests that ~91 ± 4.0% of carbon released from the slab/mantle beneath the Costa Rican forearc is sequestered within the crust by calcite deposition with an additional 3.3 ± 1.3% incorporated into autotrophic biomass.

Association of Hospital Resources and Imaging Choice for Appendicitis in Pediatric Emergency Departments.

OBJECTIVE: Abdominal pain and concern for appendicitis are common chief complaints in patients presenting to the pediatric emergency department (PED). Although many professional organizations recommend decreasing use of computed tomography (CT) and choosing ultrasound as first-line imaging for pediatric appendicitis, significant variability persists in imaging utilization. This study investigated practice variation across children's hospitals in the diagnostic imaging evaluation of appendicitis and determined hospital-level characteristics associated with the likelihood of ultrasound as the first imaging modality. METHODS: This was a multicenter (seven children's hospitals) retrospective investigation. Data from chart review of 160 consecutive patients aged 3-18 years diagnosed with appendicitis from each site were compared with a survey of site medical directors regarding hospital resource availability, usual practices, and departmental-level demographics. RESULTS: In the diagnostic evaluation of 1,090 children with appendicitis, CT scan was performed first for 22.4% of patients, with a range across PEDs of 3.1% to 83.8%. Ultrasound was performed for 54.0% of patients with a range of 2.5% to 96.9%. The only hospital-level factor significantly associated with ultrasound as the first imaging modality was 24-hour availability of in-house ultrasound (odds ratio = 29.2, 95% confidence interval = 1.2-691.8). CONCLUSION: Across children's hospitals, significant practice variation exists regarding diagnostic imaging in the evaluation of patients with appendicitis. Variation in hospital-level resources may impact the diagnostic evaluation of patients with appendicitis. Availability of 24-hour in-house ultrasound significantly increases the likelihood of ultrasound as first imaging and decreases CT scans. Hospitals aiming to increase the use of ultrasound should consider adding 24-hour in-house coverage.

A case of infantile star anise toxicity.

Chinese star anise (Illicium verum) is a popular herbal remedy for infantile colic. Contamination with a related species of Japanese star anise (Illicium anisatum) has been related to cases of toxicity in infants. We report the case of a 3-month-old infant girl who presented to the emergency department with signs and symptoms of toxicity after recent star anise ingestion. Her presentation is consistent with other reports of toxicity that include particular gastrointestinal and neurological findings. A discussion of the clinical aspects of star anise toxicity, differential diagnosis, and management follows.