Characteristics of the Western Province, Zambia, trial site for evaluation of attractive targeted sugar baits for malaria vector control.

BACKGROUND: The attractive targeted sugar bait (ATSB) is a novel malaria vector control tool designed to attract and kill mosquitoes using a sugar-based bait, laced with oral toxicant. Western Province, Zambia, was one of three countries selected for a series of phase III cluster randomized controlled trials of the Westham ATSB Sarabi version 1.2. The trial sites in Kenya, Mali, and Zambia were selected to represent a range of different ecologies and malaria transmission settings across sub-Saharan Africa. This case study describes the key characteristics of the ATSB Zambia trial site to allow for interpretation of the results relative to the Kenya and Mali sites. METHODS: This study site characterization incorporates data from the trial baseline epidemiological and mosquito sugar feeding surveys conducted in 2021, as well as relevant literature on the study area. RESULTS: CHARACTERIZATION OF THE TRIAL SITE: The trial site in Zambia was comprised of 70 trial-designed clusters in Kaoma, Nkeyema, and Luampa districts. Population settlements in the trial site were dispersed across a large geographic area with sparsely populated villages. The overall population density in the 70 study clusters was 65.7 people per square kilometre with a total site population of 122,023 people living in a geographic area that covered 1858 square kilometres. However, the study clusters were distributed over a total area of approximately 11,728 square kilometres. The region was tropical with intense and seasonal malaria transmission. An abundance of trees and other plants in the trial site were potential sources of sugar meals for malaria vectors. Fourteen Anopheles species were endemic in the site and Anopheles funestus was the dominant vector, likely accounting for around 95% of all Plasmodium falciparum malaria infections. Despite high coverage of indoor residual spraying and insecticide-treated nets, the baseline malaria prevalence during the peak malaria transmission season was 50% among people ages six months and older. CONCLUSION: Malaria transmission remains high in Western Province, Zambia, despite coverage with vector control tools. New strategies are needed to address the drivers of malaria transmission in this region and other malaria-endemic areas in sub-Saharan Africa.

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.

The Application of a New, Modified Algorithm for the Differentiation of Regular Ventricular and Pre-Excited Tachycardias.

BACKGROUND: The three-step Brugada group algorithm is the only published electrocardiographical (ECG) algorithm for differentiating ventricular tachycardia (VT) from pre-excited tachycardia (PXT) as a cause of regular wide QRS complex tachycardia (WCT). This study aimed to improve the diagnostic accuracy of the Brugada group algorithm. METHODS: This study modified the Brugada group algorithm by adding a new aVR lead criterion (initial positive deflection in lead aVR and the QRS complex area above the baseline is greater than the area below the baseline). The Brugada group algorithm and the new, modified four-step algorithm in 300 WCT ECGs (241 VTs, 59 PXTs) was applied. If any of the criteria were fulfilled, VT was diagnosed; if none were fulfilled, a diagnosis of PXT was established. RESULTS: The test accuracy, VT diagnosis sensitivity, and negative predictive value (NPV) of the new, modified algorithm were significantly greater than that of the Brugada group algorithm: test accuracy 220 of 300 (73%) vs 182 of 300 (61%); sensitivity 73% vs 55% (p<0.001 for both); NPV 40% vs 31% (p=0.0205). The VT diagnosis specificity of the Brugada group algorithm was greater than that of the new, modified algorithm (83% vs 75%; p=0.019). There was no significant difference between the new, modified and Brugada group algorithms in the positive predictive values (92% vs 93%, respectively) for a VT diagnosis, and positive and negative likelihood ratio values (2.87 vs 3.26; 0.36 vs 0.54, respectively). CONCLUSIONS: The new, modified algorithm proved to be more sensitive for the differentiation of VT from PXT than the Brugada group algorithm.

Device-device interaction between cardiac implantable electronic devices and continuous-flow left ventricular assist devices.

The current design of an innovative left ventricular assist device (LVAD) makes use of magnetic levitation technology, which enables the rotors of the device to be completely suspended by magnetic force, reducing friction and blood or plasma damage. However, this electromagnetic field can result in electromagnetic interference (EMI), which can interfere with proper functioning of another cardiac implantable electronic device (CIED) in its direct proximity. Approximately 80% of patients with an LVAD have a CIED, most frequently an implantable cardioverter-defibrillator (ICD). Several device-device interactions have been reported, including EMI-induced inappropriate shocks, inability to establish telemetry connection, EMI-induced premature battery depletion, undersensing by the device, and other CIED malfunctions. Unfortunately, additional procedures, including generator exchange, lead adjustment, and system extraction, are frequently required because of these interactions. In some circumstances, the additional procedure might be preventable or avoidable with appropriate solutions. In this article, we describe how EMI from the LVAD impacts the functionality of the CIED and provide possible management options, including manufacturer-specific information, for the current CIEDs (eg, transvenous and leadless pacemakers, transvenous and subcutaneous ICDs, and transvenous cardiac resynchronization therapy pacemakers and ICDs).

Using antenatal care as a platform for malaria surveillance data collection: study protocol.

BACKGROUND: While many malaria-endemic countries have health management information systems that can measure and report malaria trends in a timely manner, these routine systems have limitations. Periodic community cross-sectional household surveys are used to estimate malaria prevalence and intervention coverage but lack geographic granularity and are resource intensive. Incorporating malaria testing for all women at their first antenatal care (ANC) visit (i.e., ANC1) could provide a more timely and granular source of data for monitoring trends in malaria burden and intervention coverage. This article describes a protocol designed to assess if ANC-based surveillance could be a pragmatic tool to monitor malaria. METHODS: This is an observational, cross-sectional study conducted in Benin, Burkina Faso, Mozambique, Nigeria, Tanzania, and Zambia. Pregnant women attending ANC1 in selected health facilities will be tested for malaria infection by rapid diagnostic test and administered a brief questionnaire to capture key indicators of malaria control intervention coverage and care-seeking behaviour. In each location, contemporaneous cross-sectional household surveys will be leveraged to assess correlations between estimates obtained using each method, and the use of ANC data as a tool to track trends in malaria burden and intervention coverage will be validated. RESULTS: This study will assess malaria prevalence at ANC1 aggregated at health facility and district levels, and by gravidity relative to current pregnancy (i.e., gravida 1, gravida 2, and gravida 3 +). ANC1 malaria prevalence will be presented as monthly trends. Additionally, correlation between ANC1 and household survey-derived estimates of malaria prevalence, bed net ownership and use, and care-seeking will be assessed. CONCLUSION: ANC1-based surveillance has the potential to provide a cost-effective, localized measure of malaria prevalence that is representative of the general population and useful for tracking monthly changes in parasite prevalence, as well as providing population-representative estimates of intervention coverage and care-seeking behavior. This study will evaluate the representativeness of these measures and collect information on operational feasibility, usefulness for programmatic decision-making, and potential for scale-up of malaria ANC1 surveillance.

Effectiveness of community case management of malaria on severe malaria and inpatient malaria deaths in Zambia: a dose-response study using routine health information system data.

BACKGROUND: Community case management of malaria (CCM) has been expanded in many settings, but there are limited data describing the impact of these services in routine implementation settings or at large scale. Zambia has intensively expanded CCM since 2013, whereby trained volunteer community health workers (CHW) use rapid diagnostic tests and artemether-lumefantrine to diagnose and treat uncomplicated malaria. METHODS: This retrospective, observational study explored associations between changing malaria service point (health facility or CHW) density per 1000 people and severe malaria admissions or malaria inpatient deaths by district and month in a dose-response approach, using existing routine and programmatic data. Negative binomial generalized linear mixed-effect models were used to assess the impact of increasing one additional malaria service point per 1000 population, and of achieving Zambia's interim target of 1 service point per 750 population. Access to insecticide-treated nets, indoor-residual spraying, and rainfall anomaly were included in models to reduce potential confounding. RESULTS: The study captured 310,855 malaria admissions and 7158 inpatient malaria deaths over 83 districts (seven provinces) from January 2015 to May 2020. Total CHWs increased from 43 to 4503 during the study period, while health facilities increased from 1263 to 1765. After accounting for covariates, an increase of one malaria service point per 1000 was associated with a 19% reduction in severe malaria admissions among children under five (incidence rate ratio [IRR] 0.81, 95% confidence interval [CI] 0.75-0.87, p < 0.001) and 23% reduction in malaria deaths among under-fives (IRR 0.77, 95% CI 0.66-0.91). After categorizing the exposure of population per malaria service point, there was evidence for an effect on malaria admissions and inpatient malaria deaths among children under five only when reaching the target of one malaria service point per 750 population. CONCLUSIONS: CCM is an effective strategy for preventing severe malaria and deaths in areas such as Zambia where malaria diagnosis and treatment access remains challenging. These results support the continued investment in CCM scale-up in similar settings, to improve access to malaria diagnosis and treatment.

A Woman With Recurrent Torsade de Pointes.

A woman in her mid-40s presented to the emergency department after a fall with head trauma. During day 15 of admission, the patient had 3 episodes of torsade de pointes while taking 50 mg of oral metoprolol succinate daily. What would you do next?

Randomized evaluation of redo ablation procedures of atrial fibrillation with focal impulse and rotor modulation-guided procedures: the REDO-FIRM study.

AIMS: REDO-FIRM evaluated safety and effectiveness of conventional vs. focal impulse and rotor modulation (FIRM)-guided ablation of recurrent persistent or paroxysmal atrial fibrillation (AF) after an initial AF ablation procedure. METHODS AND RESULTS: This prospective, multicentre, randomized study included patients with a single prior AF ablation, but with recurrent AF and reconnected pulmonary veins (PVs). Conventional ablation generally included PV re-isolation; however, additional ablation was permitted per physician discretion. In the FIRM arm, beyond PV re-isolation, basket catheter-based FIRM mapping created dynamic animations of putative rotors, which were targeted for ablation. Between May 2016 and July 2019, 269 subjects were randomized, with 243 subjects completing 12-month follow-up. Ablation beyond re-pulmonary vein isolation, the FIRM vs. Conventional arms did not differ significantly: cavo-tricuspid isthmus -9.0% vs. 15.3%, caval vein isolation -1.5% vs. 0.8%, non-PV trigger -2.2% vs. 3.8%, other -11.9% vs. 13.0%. Single procedure 12-month freedom from AF/atrial tachycardia/atrial flutter-recurrence was 63.3% (76/120) vs. 59.0% (72/122) in the FIRM and Conventional arms (P = 0.3503). Efficacy was similar in the paroxysmal and persistent AF subgroups (P = 0.22 and P = 0.48). The 10-day and 12-month safety endpoints were achieved in 93.3% vs. 93.8% (P = 0.89) and 88.4% vs. 93.4% (P = 0.22) in the FIRM and Conventional arms, respectively. CONCLUSIONS: In REDO-FIRM, as compared to standard ablation, FIRM-guided ablation did not provide additional efficacy in redo ablation procedures, but FIRM-guided ablation was equally safe. Additional studies are necessary to identify any potential population able to benefit from FIRM-guided ablation.

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.

Stochastic termination of spiral wave dynamics in cardiac tissue.

Rotating spiral waves are self-organized features in spatially extended excitable media and may play an important role in cardiac arrhythmias including atrial fibrillation (AF). In homogeneous media, spiral wave dynamics are perpetuated through spiral wave breakup, leading to the continuous birth and death of spiral waves, but have a finite probability of termination. In non-homogeneous media, however, heterogeneities can act as anchoring sources that result in sustained spiral wave activity. It is thus unclear how and if AF may terminate following the removal of putative spiral wave sources in patients. Here, we address this question using computer simulations in which a stable spiral wave is trapped by an heterogeneity and is surrounded by spiral wave breakup. We show that, following ablation of spatial heterogeneity to render that region of the medium unexcitable, termination of spiral wave dynamics is stochastic and Poisson-distributed. Furthermore, we show that the dynamics can be accurately described by a master equation using birth and death rates. To validate these predictions in vivo, we mapped spiral wave activity in patients with AF and targeted the locations of spiral wave sources using radiofrequency ablation. Targeted ablation was indeed able to terminate AF, but only after a variable delay of up to several minutes. Furthermore, and consistent with numerical simulations, termination was not accompanied by gradual temporal or spatial organization. Our results suggest that spiral wave sources and tissue heterogeneities play a critical role in the maintenance of AF and that the removal of sources results in spiral wave dynamics with a finite termination time, which could have important clinical implications.

Termination of macroreentrant atrial arrhythmias by pacing stimuli without global propagation.

BACKGROUND: Electrical stimulation during ventricular tachycardia resulting in tachycardia termination without global propagation (TWGP) is a well-recognized phenomenon. However, there is a paucity of literature showing a similar phenomenon in atrial arrhythmias. OBJECTIVE: The purpose of the study was to evaluate the significance of TWGP in atrial arrhythmias. METHODS: Electrophysiological studies performed from 2000 to 2019 at Methodist Hospital, Indiana University were reviewed retrospectively. Thirty-four patients were identified in whom stimulation during atrial tachycardia/flutter resulted in TWGP. RESULTS: Of the 34 patients, 12 (29%) had cavotricuspid isthmus (CTI)-dependent atrial flutter and 22 (71%) had other atrial arrhythmias during which TWGP was seen. Mean age of the population was 53 ± 13 years; and 68% were male. Previous catheter ablation for atrial fibrillation, atrial flutter, or other atrial tachyarrhythmias had been performed in 70.5%, and 44% previously had undergone cardiac surgery involving the atria. Congenital heart disease was present in 20.5%; 3 patients were status post lung transplant. Mean cycle length of atrial arrhythmia in which TWGP was seen was 317 ± 76 ms. The sites at which TWGP was seen reproducibly were highly specific for successful termination of the arrhythmias with radiofrequency energy. The arrhythmia circuits were 12 CTI-dependent atrial flutter, 11 left atrial macroreentrant atrial tachycardia (MRAT), 1 involving both left and right atria, and 8 were other right atrial MRAT. CONCLUSION: Termination of macroreentrant atrial arrhythmias by pacing stimuli without global propagation identifies a narrow diastolic isthmus at which catheter ablation is highly effective.

Evaluating the Impact of Programmatic Mass Drug Administration for Malaria in Zambia Using Routine Incidence Data.

BACKGROUND: In 2016, the Zambian National Malaria Elimination Centre started programmatic mass drug administration (pMDA) campaigns with dihydroartemisinin-piperaquine as a malaria elimination tool in Southern Province. Two rounds were administered, 2 months apart (coverage 70% and 57%, respectively). We evaluated the impact of 1 year of pMDA on malaria incidence using routine data. METHODS: We conducted an interrupted time series with comparison group analysis on monthly incidence data collected at the health facility catchment area (HFCA) level, with a negative binomial model using generalized estimating equations. Programmatic mass drug administration was conducted in HFCAs with greater than 50 cases/1000 people per year. Ten HFCAs with incidence rates marginally above this threshold (pMDA group) were compared with 20 HFCAs marginally below (comparison group). RESULTS: The pMDA HFCAs saw a 46% greater decrease in incidence at the time of intervention than the comparison areas (incidence rate ratio = 0.536; confidence interval = 0.337-0.852); however, incidence increased toward the end of the season. No HFCAs saw a transmission interruption. CONCLUSIONS: Programmatic mass drug administration, implemented during 1 year with imperfect coverage in low transmission areas with suboptimal vector control coverage, significantly reduced incidence. However, elimination will require additional tools. Routine data are important resources for programmatic impact evaluations and should be considered for future analyses.

Reactive focal drug administration associated with decreased malaria transmission in an elimination setting: Serological evidence from the cluster-randomized CoRE study.

Efforts to eliminate malaria transmission need evidence-based strategies. However, accurately assessing end-game malaria elimination strategies is challenging due to the low level of transmission and the rarity of infections. We hypothesised that presumptively treating individuals during reactive case detection (RCD) would reduce transmission and that serology would more sensitively detect this change over standard approaches. We conducted a cluster randomised control trial (NCT02654912) of presumptive reactive focal drug administration (RFDA-intervention) compared to the standard of care, reactive focal test and treat (RFTAT-control) in Southern Province, Zambia-an area of low seasonal transmission (overall incidence of ~3 per 1,000). We measured routine malaria incidence from health facilities as well as PCR parasite prevalence / antimalarial seroprevalence in an endline cross-sectional population survey. No significant difference was identified from routine incidence data and endline prevalence by polymerase chain reaction (PCR) had insufficient numbers of malaria infections (i.e., 16 infections among 6,276 children) to assess the intervention. Comparing long-term serological markers, we found a 19% (95% CI = 4-32%) reduction in seropositivity for the RFDA intervention using a difference in differences approach incorporating serological positivity and age. We also found a 37% (95% CI = 2-59%) reduction in seropositivity to short-term serological markers in a post-only comparison. These serological analyses provide compelling evidence that RFDA both has an impact on malaria transmission and is an appropriate end-game malaria elimination strategy. Furthermore, serology provides a more sensitive approach to measure changes in transmission that other approaches miss, particularly in very low transmission settings. Trial Registration: Registered at www.clinicaltrials.gov (NCT02654912, 13/1/2016).

Removing the complexity from wide complex tachycardia.

Correctly diagnosing the cause of wide QRS tachycardias remain an area of difficulty for many clinicians. The authors provide a concise update to the different ECG algorithms that have been developed as well as caveats in their application.

Mutations in conserved residues of the myosin chaperone UNC-45 result in both reduced stability and chaperoning activity.

Proper muscle development and function depend on myosin being properly folded and integrated into the thick filament structure. For this to occur the myosin chaperone UNC-45, or UNC-45B, must be present and able to chaperone myosin. Here we use a combination of in vivo C. elegans experiments and in vitro biophysical experiments to analyze the effects of six missense mutations in conserved regions of UNC-45/UNC-45B. We found that the phenotype of paralysis and disorganized thick filaments in 5/6 of the mutant nematode strains can likely be attributed to both reduced steady state UNC-45 protein levels and reduced chaperone activity. Interestingly, the biophysical assays performed on purified proteins show that all of the mutations result in reduced myosin chaperone activity but not overall protein stability. This suggests that these mutations only cause protein instability in the in vivo setting and that these conserved regions may be involved in UNC-45 protein stability/regulation via posttranslational modifications, protein-protein interactions, or some other unknown mechanism.