Monthly sulfadoxine/pyrimethamine-amodiaquine or dihydroartemisinin-piperaquine as malaria chemoprevention in young Kenyan children with sickle cell anemia: A randomized controlled trial.

BACKGROUND: Children with sickle cell anemia (SCA) in areas of Africa with endemic malaria transmission are commonly prescribed malaria chemoprevention. Chemoprevention regimens vary between countries, and the comparative efficacy of prevention regimens is largely unknown. METHODS AND FINDINGS: We enrolled Kenyan children aged 1 to 10 years with homozygous hemoglobin S (HbSS) in a randomized, open-label trial conducted between January 23, 2018, and December 15, 2020, in Homa Bay, Kenya. Children were assigned 1:1:1 to daily Proguanil (the standard of care), monthly sulfadoxine/pyrimethamine-amodiaquine (SP-AQ), or monthly dihydroartemisinin-piperaquine (DP) and followed monthly for 12 months. The primary outcome was the cumulative incidence of clinical malaria at 12 months, and the main secondary outcome was the cumulative incidence of painful events by self-report. Secondary outcomes included other parasitologic, hematologic, and general events. Negative binomial models were used to estimate incidence rate ratios (IRRs) per patient-year (PPY) at risk relative to Proguanil. The primary analytic population was the As-Treated population. A total of 246 children were randomized to daily Proguanil (n = 81), monthly SP-AQ (n = 83), or monthly DP (n = 82). Overall, 53.3% (n = 131) were boys and the mean age was 4.6 ± 2.5 years. The clinical malaria incidence was 0.04 episodes/PPY; relative to the daily Proguanil group, incidence rates were not significantly different in the monthly SP-AQ (IRR: 3.05, 95% confidence interval [CI]: 0.36 to 26.14; p = 0.39) and DP (IRR: 1.36, 95% CI: 0.21 to 8.85; p = 0.90) groups. Among secondary outcomes, relative to the daily Proguanil group, the incidence of painful events was not significantly different in the monthly SP-AQ and DP groups, while monthly DP was associated with a reduced rate of dactylitis (IRR: 0.47; 95% CI: 0.23 to 0.96; p = 0.038). The incidence of Plasmodium falciparum infection relative to daily Proguanil was similar in the monthly SP-AQ group (IRR 0.46; 95% CI: 0.17 to 1.20; p = 0.13) but reduced with monthly DP (IRR 0.21; 95% CI: 0.08 to 0.56; p = 0.002). Serious adverse events were common and distributed between groups, although compared to daily Proguanil (n = 2), more children died receiving monthly SP-AQ (n = 7; hazard ratio [HR] 5.44; 95% CI: 0.92 to 32.11; p = 0.064) but not DP (n = 1; HR 0.61; 95% CI 0.04 to 9.22; p = 0.89), although differences did not reach statistical significance for either SP-AQ or DP. Study limitations include the unexpectedly limited transmission of P. falciparum in the study setting, the high use of hydroxyurea, and the enhanced supportive care for trial participants, which may limit generalizability to higher-transmission settings where routine sickle cell care is more limited. CONCLUSIONS: In this study with limited malaria transmission, malaria chemoprevention in Kenyan children with SCA with monthly SP-AQ or DP did not reduce clinical malaria, but DP was associated with reduced dactylitis and P. falciparum parasitization. Pragmatic studies of chemoprevention in higher malaria transmission settings are warranted. TRIAL REGISTRATION: clinicaltrials.gov (NCT03178643). Pan-African Clinical Trials Registry: PACTR201707002371165.

Supply-side and demand-side factors influencing uptake of malaria testing services in the community: lessons for scale-up from a post-hoc analysis of a cluster randomised, community-based trial in western Kenya.

OBJECTIVES: Maximising the impact of community-based programmes requires understanding how supply of, and demand for, the intervention interact at the point of delivery. DESIGN: Post-hoc analysis from a large-scale community health worker (CHW) study designed to increase the uptake of malaria diagnostic testing. SETTING: Respondents were identified during a household survey in western Kenya between July 2016 and April 2017. PARTICIPANTS: Household members with fever in the last 4 weeks were interviewed at 12 and 18 months post-implementation. We collected monthly testing data from 244 participating CHWs and conducted semistructured interviews with a random sample of 70 CHWs. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was diagnostic testing before treatment for a recent fever. The secondary outcomes were receiving a test from a CHW and tests done per month by each CHW. RESULTS: 55% (n=948 of 1738) reported having a malaria diagnostic test for their recent illness, of which 38.4% were tested by a CHW. Being aware of a local CHW (adjusted OR=1.50, 95% CI: 1.10 to 2.04) and belonging to the wealthiest households (vs least wealthy) were associated with higher testing (adjusted OR=1.53, 95% CI: 1.14 to 2.06). Wealthier households were less likely to receive their test from a CHW compared with poorer households (adjusted OR=0.32, 95% CI: 0.17 to 0.62). Confidence in artemether-lumefantrine to cure malaria (adjusted OR=2.75, 95% CI: 1.54 to 4.92) and perceived accuracy of a malaria rapid diagnostic test (adjusted OR=2.43, 95% CI: 1.12 to 5.27) were positively associated with testing by a CHW. Specific CHW attributes were associated with performing a higher monthly number of tests including formal employment, serving more than 50 households (vs <50) and serving areas with a higher test positivity. On demand side, confidence of the respondent in a test performed by a CHW was strongly associated with seeking a test from a CHW. CONCLUSION: Scale-up of community-based malaria testing is feasible and effective in increasing uptake among the poorest households. To maximise impact, it is important to recognise factors that may restrict delivery and demand for such services. TRIAL REGISTRATION NUMBER: NCT02461628; Post-results.

Electronic, Structural, and Optical Properties of Mono-Doped and Co-Doped (210) TiO2 Brookite Surfaces for Application in Dye-Sensitized Solar Cells-A First Principles Study.

Titanium dioxide (TiO2) polymorphs have recently gained a lot of attention in dye-sensitized solar cells (DSSCs). The brookite polymorph, among other TiO2 polymorphs, is now becoming the focus of research in DSSC applications, despite the difficulties in obtaining it as a pure phase experimentally. The current theoretical study used different nonmetals (C, S and N) and (C-S, C-N and S-N) as dopants and co-dopants, respectively, to investigate the effects of mono-doping and co-doping on the electronic, structural, and optical structure properties of (210) TiO2 brookite surfaces, which is the most exposed surface of brookite. The results show that due to the narrowing of the band gap and the presence of impurity levels in the band gap, all mono-doped and co-doped TiO2 brookite (210) surfaces exhibit some redshift. In particular, the C-doped, and C-N co-doped TiO2 brookite (210) surfaces exhibit better absorption in the visible region of the electromagnetic spectrum in comparison to the pure, S-doped, N-doped, C-S co-doped and N-S co-doped TiO2 brookite (210) surfaces.

Elucidating the Trajectory of the Charge Transfer Mechanism and Recombination Process of Hybrid Perovskite Solar Cells.

Perovskite-based solar cells (PSCs) have attracted attraction in the photovoltaic community since their inception in 2009. To optimize the performance of hybrid perovskite cells, a primary and crucial strategy is to unravel the dominant charge transport mechanisms and interfacial properties of the contact materials. This study focused on the charge transfer process and interfacial recombination within the n-i-p architecture of solar cell devices. The motivation for this paper was to investigate the impacts of recombination mechanisms that exist within the interface in order to quantify their effects on the cell performance and stability. To achieve our objectives, we firstly provided a rationale for the photoluminescence and UV-Vis measurements on perovskite thin film to allow for disentangling of different recombination pathways. Secondly, we used the ideality factor and impedance spectroscopy measurements to investigate the recombination mechanisms in the device. Our findings suggest that charge loss in PSCs is dependent mainly on the configuration of the cells and layer morphology, and hardly on the material preparation of the perovskite itself. This was deduced from individual analyses of the perovskite film and device, which suggest that major recombination most likely occur at the interface.

Gbetagamma signaling promotes breast cancer cell migration and invasion.

Signaling through G protein-coupled receptors (GPCRs) promotes breast cancer metastasis. G proteins convey GPCR signals by dissociating into Galpha and Gbetagamma subunits. The aim of the present study was to determine whether blockade of Gbetagamma signaling suppresses breast cancer cell migration and invasion, which are critical components of metastasis. Conditioned media (CM) of NIH-3T3 fibroblasts are widely used as chemoattractants in in vitro cancer metastasis studies. Expression of a Gbetagamma scavenger peptide attenuated NIH-3T3 CM-induced migration and invasion of both metastatic breast cancer MDA-MB-231 and MDA-MB-436 cells by 40 to 50% without effects on cell viability. Migration and invasion of cells in response to NIH-3T3 CM were also blocked by 8-(4,5,6-trihydroxy-3-oxo-3H-xanthen-9-yl)-1-naph-thalene-carboxylic acid) (M119K), a Gbetagamma inhibitor, with maximum inhibition exceeding 80% and half-maximal inhibitory concentration (IC50) values of 1 to 2 microM. M119K also attenuated Rac-dependent formation of lamellipodia, a key structure required for metastasis. Constitutively active Rac1 rescued Gbetagamma blockade-mediated inhibition of breast cancer cell migration, whereas dominant negative Rac1 inhibited cell migration similar to Gbetagamma blockade. Furthermore, M119K suppressed Gi protein-coupled CXC chemokine receptor 4 (CXCR4)-dependent MDA-MB-231 cell migration by 80% with an IC50 value of 1 microM, whereas tyrosine kinase receptor-dependent cell migration was significantly less inhibited. However, CXCR4-dependent inhibition of adenylyl cyclase, a Gialpha-mediated response in MDA-MB-231 cells, was not blocked by M119K but was blocked by pertussis toxin, which selectively inactivates Gialpha. This report is the first to directly demonstrate the role of Gbetagamma in cancer cell migration and invasion and suggests that targeting Gbetagamma signaling pathways may provide a novel strategy for suppressing breast cancer metastasis.

The relative importance of material and non-material incentives for community health workers: Evidence from a discrete choice experiment in Western Kenya.

Motivating community health workers (CHWs), many of whom are volunteers, is important for the sustainability of integrated community case management programs. Given the limited budgets of many of these programs, and the increasingly important role played by CHWs, it is crucial to not only identify important motivators driving their engagement, but also which incentives could have the greatest impact on CHW motivation in their role. In this study, we aimed to assess CHWs' relative preferences for material and non-material incentives. We conducted a discrete choice experiment (DCE) with 199 randomly selected CHWs, working in 32 communities in western Kenya, to measure the relative importance that CHWs place on different incentives. Each CHW completed a series of 10 choice tasks (8 random, 2 fixed), where they had to choose between two hypothetical positions that had varying levels of monthly mobile phone airtime, training, monthly transport bonus, community appreciation and health facility staff appreciation of their work. Data was analyzed using mixed logit models. CHWs' most preferred job characteristic was high levels of community appreciation for their work which was valued approximately equivalently to receiving a 2000 Kenya Shillings (~US $20) monthly transport allowance. These incentives were valued more than appreciation from health facility staff or trainings six times per year. This study demonstrates that investing in efforts to improve community members' knowledge and recognition of CHWs' contribution to community health may have a significant impact on CHWs' motivation and retention in their role.

Motivation and satisfaction among community health workers administering rapid diagnostic tests for malaria in Western Kenya.

BACKGROUND: The continued success of community case management (CCM) programs in low-resource settings depends on the ability of these programs to retain the community health workers (CHWs), many of whom are volunteers, and maintain their high-quality performance. This study aims to identify factors related to the motivation and satisfaction of CHWs working in a malaria CCM program in two sub-counties in Western Kenya. METHODS: We interviewed 70 CHWs who were trained to administer malaria rapid diagnostic tests as part of a broader study evaluating a malaria CCM program. We identified factors related to CHWs' motivation and their satisfaction with participation in the program, as well as the feasibility of program scale-up. We used principal components analysis to develop an overall CHW satisfaction score and assessed associations between this score and individual CHW characteristics as well as their experiences in the program. RESULTS: The majority of CHWs reported that they were motivated to perform their role in this malaria CCM program by a personal desire to help their community (69%). The most common challenge CHWs reported was a lack of community understanding about malaria diagnostic testing and CHWs' role in the program (39%). Most CHWs (89%) reported that their involvement in the diagnostic testing intervention had either a neutral or a net positive effect on their other CHW activities, including improving skills applicable to other tasks. CHWs who said they strongly agreed with the statement that their work with the malaria program was appreciated by the community had a 0.76 standard deviation (SD) increase in their overall satisfaction score (95% confidence interval CI = 0.10-1.24, P = 0.03). Almost all CHWs (99%) strongly agreed that they wanted to continue their role in the malaria program. CONCLUSIONS: Overall, CHWs reported high satisfaction with their role in community-based malaria diagnosis, though they faced challenges primarily related to community understanding and appreciation of the services they provided. CHWs' perceptions that the malaria program generally did not interfere with their other activities is encouraging for the sustainability and scale-up of similar CHW programs.

Identification of upregulated phosphoinositide 3-kinase γ as a target to suppress breast cancer cell migration and invasion.

Metastasis is the major cause of breast cancer mortality. We recently reported that aberrant G-protein coupled receptor (GPCR) signaling promotes breast cancer metastasis by enhancing cancer cell migration and invasion. Phosphatidylinositol 3-kinase γ (PI3Kγ) is specifically activated by GPCRs. The goal of the present study was to determine the role of PI3Kγ in breast cancer cell migration and invasion. Immunohistochemical staining showed that the expression of PI3Kγ protein was significantly increased in invasive human breast carcinoma when compared to adjacent benign breast tissue or ductal carcinoma in situ. PI3Kγ was also detected in metastatic breast cancer cells, but not in normal breast epithelial cell line or in non-metastatic breast cancer cells. In contrast, PI3K isoforms α, ß and δ were ubiquitously expressed in these cell lines. Overexpression of recombinant PI3Kγ enhanced the metastatic ability of non-metastatic breast cancer cells. Conversely, migration and invasion of metastatic breast cancer cells were inhibited by a PI3Kγ inhibitor or by siRNA knockdown of PI3Kγ but not by inhibitors or siRNAs of PI3Kα or PI3Kß. Lamellipodia formation is a key step in cancer metastasis, and PI3Kγ blockade disrupted lamellipodia formation induced by the activation of GPCRs such as CXC chemokine receptor 4 and protease-activated receptor 1, but not by the epidermal growth factor tyrosine kinase receptor. Taken together, these results indicate that upregulated PI3Kγ conveys the metastatic signal initiated by GPCRs in breast cancer cells, and suggest that PI3Kγ may be a novel therapeutic target for development of chemotherapeutic agents to prevent breast cancer metastasis.

Breast cancer migration and invasion depend on proteasome degradation of regulator of G-protein signaling 4.

Aberrant signaling through G-protein coupled receptors promotes metastasis, the major cause of breast cancer death. We identified regulator of G-protein signaling 4 (RGS4) as a novel suppressor of breast cancer migration and invasion, important steps of metastatic cascades. By blocking signals initiated through G(i)-coupled receptors, such as protease-activated receptor 1 and CXC chemokine receptor 4, RGS4 disrupted Rac1-dependent lamellipodia formation, a key step involved in cancer migration and invasion. RGS4 has GTPase-activating protein (GAP) activity, which inhibits G-protein coupled receptor signaling by deactivating G-proteins. An RGS4 GAP-deficient mutant failed to inhibit migration and invasion of breast cancer cells in both in vitro assays and a mouse xenograft model. Interestingly, both established breast cancer cell lines and human breast cancer specimens showed that the highest levels of RGS4 protein were expressed in normal breast epithelia and that RGS4 down-regulation by proteasome degradation is an index of breast cancer invasiveness. Proteasome blockade increased endogenous RGS4 protein to levels that markedly inhibit breast cancer cell migration and invasion, which was reversed by an RGS4-targeted short hairpin RNA. Our findings point to the existence of a mechanism for posttranslational regulation of RGS4 function, which may have important implications for the acquisition of a metastatic phenotype by breast cancer cells. Preventing degradation of RGS4 protein should attenuate aberrant signal inputs from multiple G(i)-coupled receptors, thereby retarding the spread of breast cancer cells and making them targets for surgery, radiation, and immune treatment.