Assessing national vector control micro-planning in Zambia using the 2021 malaria indicator survey.

BACKGROUND: In 2020, the Zambia National Malaria Elimination Centre targeted the distribution of long-lasting insecticidal nets (LLINs) and indoor-residual spraying (IRS) campaigns based on sub-district micro-planning, where specified geographical areas at the health facility catchment level were assigned to receive either LLINs or IRS. Using data from the 2021 Malaria Indicator Survey (MIS), the objectives of this analysis were to (1) assess how well the micro-planning was followed in distributing LLINs and IRS, (2) investigate factors that contributed to whether households received what was planned, and (3) investigate how overall coverage observed in the 2021 MIS compared to the 2018 MIS conducted prior to micro-planning. METHODS: Households' receipt of ≥ 1 LLIN, and/or IRS within the past 12 months in the 2021 MIS, was compared against the micro-planning area under which the households fell. GPS points for 3,550 households were overlayed onto digitized micro-planning maps in order to determine what micro-plan the households fell under, and thus whether they received their planned intervention. Mixed-effects regression models were conducted to investigate what factors affected whether these households: (1) received their planned intervention, and (2) received any intervention. Finally, coverage indicators between the 2021 and 2018 MIS were compared. RESULTS: Overall, 60.0% (95%CI 55.4, 64.4) of households under a micro-plan received their assigned intervention, with significantly higher coverage of the planned intervention in LLIN-assigned areas (75.7% [95%CI 69.5, 80.9]) compared to IRS-assigned areas (49.4% [95%CI: 44.4, 54.4]). Regression analysis indicated that households falling under the IRS micro-plan had significantly reduced odds of receiving their planned intervention (OR: 0.34 [95%CI 0.24, 0.48]), and significantly reduced odds of receiving any intervention (OR: 0.51 [95%CI 0.37, 0.72] ), compared to households under the LLIN micro-plan. Comparison between the 2021 and 2018 MIS indicated a 27% reduction in LLIN coverage nationally in 2021, while IRS coverage was similar. Additionally, between 2018 and 2021, there was a 13% increase in households that received neither intervention. CONCLUSIONS: This analysis shows that although the micro-planning strategy adopted in 2020 worked much better for LLIN-assigned areas compared to IRS-assigned areas, there was reduced overall vector control coverage in 2021 compared to 2018 before micro-planning.

Developing High-Resolution Population and Settlement Data for Impactful Malaria Interventions in Zambia.

Foundational high-resolution geospatial data products for population, settlements, infrastructure, and boundaries may greatly enhance the efficient planning of resource allocation during health sector interventions. To ensure the relevance and sustainability of such products, government partners must be involved from the beginning in their creation, improvement, and/or management, so they can be successfully applied to public health campaigns, such as malaria control and prevention. As an example, Zambia had an ambitious strategy of reaching the entire population with malaria vector control campaigns by late 2020 or early 2021, but they lacked the requisite accurate and up-to-date data on infrastructure and population distribution. To address this gap, the Geo-Referenced Infrastructure and Demographic Data for Development (GRID3) program, Akros, and other partners developed maps and planning templates to aid Zambia's National Malaria Elimination Program (NMEP) in operationalizing its strategy.

Leveraging risk maps of malaria vector abundance to guide control efforts reduces malaria incidence in Eastern Province, Zambia.

Although transmission of malaria and other mosquito-borne diseases is geographically heterogeneous, in sub-Saharan Africa risk maps are rarely used to determine which communities receive vector control interventions. We compared outcomes in areas receiving different indoor residual spray (IRS) strategies in Eastern Province, Zambia: (1) concentrating IRS interventions within a geographical area, (2) prioritizing communities to receive IRS based on predicted probabilities of Anopheles funestus, and (3) prioritizing communities to receive IRS based on observed malaria incidence at nearby health centers. Here we show that the use of predicted probabilities of An. funestus to guide IRS implementation saw the largest decrease in malaria incidence at health centers, a 13% reduction (95% confidence interval = 5-21%) compared to concentrating IRS geographically and a 37% reduction (95% confidence interval = 30-44%) compared to targeting IRS based on health facility incidence. These results suggest that vector control programs could produce better outcomes by prioritizing IRS according to malaria-vector risk maps.

Accuracy and impact of spatial aids based upon satellite enumeration to improve indoor residual spraying spatial coverage.

BACKGROUND: Indoor residual spraying (IRS) is a key tool in the fight to control, eliminate and ultimately eradicate malaria. IRS protection is based on a communal effect such that an individual's protection primarily relies on the community-level coverage of IRS with limited protection being provided by household-level coverage. To ensure a communal effect is achieved through IRS, achieving high and uniform community-level coverage should be the ultimate priority of an IRS campaign. Ensuring high community-level coverage of IRS in malaria-endemic areas is challenging given the lack of information available about both the location and number of households needing IRS in any given area. A process termed 'mSpray' has been developed and implemented and involves use of satellite imagery for enumeration for planning IRS and a mobile application to guide IRS implementation. This study assessed (1) the accuracy of the satellite enumeration and (2) how various degrees of spatial aid provided through the mSpray process affected community-level IRS coverage during the 2015 spray campaign in Zambia. METHODS: A 2-stage sampling process was applied to assess accuracy of satellite enumeration to determine number and location of sprayable structures. Results indicated an overall sensitivity of 94% for satellite enumeration compared to finding structures on the ground. RESULTS: After adjusting for structure size, roof, and wall type, households in Nchelenge District where all types of satellite-based spatial aids (paper-based maps plus use of the mobile mSpray application) were used were more likely to have received IRS than Kasama district where maps used were not based on satellite enumeration. The probability of a household being sprayed in Nchelenge district where tablet-based maps were used, did not differ statistically from that of a household in Samfya District, where detailed paper-based spatial aids based on satellite enumeration were provided. CONCLUSION: IRS coverage from the 2015 spray season benefited from the use of spatial aids based upon satellite enumeration. These spatial aids can guide costly IRS planning and implementation leading to attainment of higher spatial coverage, and likely improve disease impact.

Modulation of drug-linker design to enhance in vivo potency of homogeneous antibody-drug conjugates.

Antibody-drug conjugates (ADCs) are a promising class of anticancer agents which have undergone substantial development over the past decade and are now achieving clinical success. The development of novel site-specific conjugation technologies enables the systematic study of architectural features within the antibody conjugated drug linker that may affect overall therapeutic indices. Here we describe the results of a systematic study investigating the impact of drug-linker design on the in vivo properties of a series of homogeneous ADCs with a conserved site of conjugation, a monodisperse drug loading, a lysosomal release functionality and monomethyl auristatin E as a cytotoxic payload. The ADCs, which differed only in the relative position of certain drug-linker elements within the reagent, were first evaluated in vitro using anti-proliferation assays and in vivo using mouse pharmacokinetics (PK). Regardless of the position of a discrete polymer unit, the ADCs showed comparable in vitro potencies, but the in vivo PK properties varied widely. The best performing drug-linker design was further used to prepare ADCs with different drug loadings of 4, 6 and 8 drugs per antibody and compared to Adcetris® in a Karpas-299 mouse xenograft model. The most efficacious ADC showed complete tumor regression and 10/10 tumor free survivors at a single 0.5mg/kg dose. This study revealed drug-linker design as a critical parameter in ADC development, with the potential to enhance ADC in vivo potency for producing more efficacious ADCs.

Targeting indoor residual spraying for malaria using epidemiological data: a case study of the Zambia experience.

BACKGROUND: In Zambia and other sub-Saharan African countries affected by ongoing malaria transmission, indoor residual spraying (IRS) for malaria prevention has typically been implemented over large areas, e.g., district-wide, and targeted to peri-urban areas. However, there is a recent shift in some countries, including Zambia, towards the adoption of a more strategic and targeted IRS approach, in coordination with increased emphasis on universal coverage of long-lasting insecticidal nets (LLINs) and effective insecticide resistance management. A true targeted approach would deliver IRS to sub-district areas identified as high-risk, with the goal of maximizing the prevention of malaria cases and deaths. RESULTS: Together with the Government of the Republic of Zambia, a new methodology was developed applying geographic information systems and satellite imagery to support a targeted IRS campaign during the 2014 spray season using health management information system data. DISCUSSION/CONCLUSION: This case study focuses on the developed methodology while also highlighting the significant research gaps which must be filled to guide countries on the most effective strategy for IRS targeting in the context of universal LLIN coverage and evolving insecticide resistance.

Open-source satellite enumeration to map households: planning and targeting indoor residual spraying for malaria.

BACKGROUND: Defining the number and location of sprayable structures (houses) is foundational to plan and monitor indoor residual spray (IRS) implementation, a primary intervention used to control the transmission of malaria. Only by mapping the location and type of all sprayable structures can IRS operations be planned, estimates of spray coverage determined, and targeted delivery of IRS to specific locations be achieved. Previously, field-based enumeration has been used to guide IRS campaigns, however, this approach is costly, time-consuming and difficult to scale. As a result, field-based enumeration typically fails to map all structures in a given area, making estimations less reliable and reducing the enumerated coverage. METHODS: Using open source satellite imagery and Geographic Information System software, satellite enumeration was conducted to guide IRS operations in 15 districts (91,302 km(2)) in northern Zambia during the 2014 spray season. Cost of satellite enumeration was compared to standard enumeration. Enumerated households were sampled to estimate sprayable surface area and wall type from the satellite enumeration using linear and logistic regression, respectively. RESULTS: In comparison to the traditional field-based enumeration procedure, satellite-based enumeration was 22 times faster, and 10 times less costly. An estimated 98 % of the satellite enumerated buildings correctly classified roof type. Predicted surface area of each household correlated at a value of 0.91 with measured surface area of each household. CONCLUSION: For IRS campaigns, high quality and high coverage enumeration data aid in planning, through informed insecticide procurement. Through the identification of geographical areas and populations to target, enumeration data guide operations and assist monitoring and evaluation of IRS through the unbiased estimation of coverage achieved. Satellite enumeration represents a quick, cheap and accurate system to provide these data, and has potential applications beyond IRS for delivery of other targeted or non-targeted interventions (e.g. net distributions, mass drug administration, immunization campaigns, or even sampling frames for field studies).

Relapse of orthodontically corrected deepbites in accordance with growth pattern.

INTRODUCTION: A common orthodontic problem is a deep overbite malocclusion. Because of its high relapse tendency, it is also one of the most challenging problems to treat. To minimize relapse, the morphologic characteristics of patients need to be considered. The aim of this study was to compare deepbite relapse in 3 groups of patients categorized by vertical growth type. METHODS: The total sample included 60 patients treated at the University of Washington in Seattle, all with initial overbites greater than 50%. Data were collected from casts and cephalometric radiographs at 3 time points: pretreatment, posttreatment, and 10 years postretention. A mixed-effects model (analysis of variance) and post-hoc t tests were used for the statistical evaluations. RESULTS: The high-angle subjects showed the least deepbite relapse (0.1 ± 1.1 mm), whereas the low-angle (1.2 ± 0.9 mm) and the normal-angle (1.4 ± 1.3 mm) subjects had statistically significant relapses P <0.001. This overbite relapse might be partially due to changes in the mandibular and interincisal angles, which were also observed in these 2 groups. CONCLUSIONS: High-angle subjects tend to relapse less in overbite than do low-angle and normal-angle subjects in the long term.

Pyridyl-2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists: synthesis, pharmacokinetics, and in vivo potency.

A six-stage stereoselective synthesis of indanyl-7-(3'-pyridyl)-(3R,6R,7R)-2,5-diketopiperazines oxytocin antagonists from indene is described. SAR studies involving mono- and disubstitution in the 3'-pyridyl ring and variation of the 3-isobutyl group gave potent compounds (pK(i) > 9.0) with good aqueous solubility. Evaluation of the pharmacokinetic profile in the rat, dog, and cynomolgus monkey of those derivatives with low cynomolgus monkey and human intrinsic clearance gave 2',6'-dimethyl-3'-pyridyl R-sec-butyl morpholine amide Epelsiban (69), a highly potent oxytocin antagonist (pK(i) = 9.9) with >31000-fold selectivity over all three human vasopressin receptors hV1aR, hV2R, and hV1bR, with no significant P450 inhibition. Epelsiban has low levels of intrinsic clearance against the microsomes of four species, good bioavailability (55%) and comparable potency to atosiban in the rat, but is 100-fold more potent than the latter in vitro and was negative in the genotoxicity screens with a satisfactory oral safety profile in female rats.

Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with monoaryl P4 motifs.

Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa inhibitors, incorporating neutral and basic monoaryl P4 groups, ultimately producing potent inhibitors with effective levels of anticoagulant activity and extended oral pharmacokinetic profiles. However, time dependant inhibition of Cytochrome P450 3A4 was a particular issue with this series.

Structure and property based design of factor Xa inhibitors: biaryl pyrrolidin-2-ones incorporating basic heterocyclic motifs.

Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating basic biaryl P4 groups, producing highly potent inhibitors with significant anticoagulant activities and encouraging oral pharmacokinetic profiles.

Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with biaryl P4 motifs.

Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating biaryl P4 groups, producing highly potent inhibitors with encouraging oral pharmacokinetic profiles and significant but sub-optimal anticoagulant activities.

The discovery of GSK221149A: a potent and selective oxytocin antagonist.

Optimisation of a series of oxazole diketopiperazines has led to the discovery of a very potent and selective oxytocin antagonist GSK221149A. GSK221149A has been shown to inhibit oxytocin-induced uterine contractions in the anaesthetised rat.

Preoperative imaging of thyroid goiter: how imaging technique can influence anatomic appearance and create a potential for inaccurate interpretation.

The radiologist needs to be aware of a potential pitfall that can influence the imaging appearance of thyroid goiter. Whether the patient is imaged with the arms overhead or by the side may affect the apparent mediastinal excursion of a goiter. CT scans obtained with the patient's arms by the side are more accurate for determining substernal extent of goiter than when the arms are overhead, a position usually used in chest CT. Ultimately, this difference in imaging technique may have a profound effect on the adjacent structures impacted by the goiter and may influence the planned surgical approach.