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Pyrethroid-treated nets have reduced malaria in endemic areas, but insecticide resistance has hindered progress, prompting WHO to recommend piperonyl butoxide (PBO) based long-lasting insecticidal nets (LLINs). Kenya adopted PBO nets, but their usage is not well documented. This study aims to assess the uptake and effect of PBO nets versus pyrethroid-only LLINs (pyrethroid-LLINs) on malaria transmission in Western Kenya. A cross-sectional study was conducted in Muhoroni Sub-County, Kisumu County, one year after net distribution between November and December 2023. Twelve villages were randomly selected, comprising 380 households and divided into two intervention arms of six villages. Group 1, with 181 households, received pyrethroid-LLIN, while Group 2, with 199 households, received PBO-LLINs. Data on net ownership and usage was collected using a standardized semi-structured questionnaire. Finger prick blood smears were collected on slides for microscopic examination, while dry blood spots (DBS) on filter paper were collected for real-time PCR (RT-PCR) diagnosis of Plasmodium infection in both intervention groups. Logistic regression was used to identify factors influencing net ownership and malaria prevalence, while a generalized linear model assessed factors affecting net usage. The χ² test was used to evaluate differences in demographic characteristics between the intervention arms. Overall, higher net ownership and usage was recorded in PBO-LLINs group compared to the pyrethroid-LLIN group after one year of net distribution. Among households, 89% in the pyrethroid-LLIN group and 96% in the PBO-LLIN group owned at least one net. Net usage was 80.2% in the pyrethroid-LLIN group and 87.6% in the PBO-LLIN group. Net attrition rate was 17.9% in pyrethroid-LLIN and 7.6% for PBO-LLIN group. Households with nets were 1.3 times more likely to use them [aOR=1.338 (95% CI = 1.224-1.462), p < 0.001). Bed ownership was 50.8% in the pyrethroid-LLIN group and 55.3% in the PBO-LLIN group. Not owning a bed decreased the likelihood of net usage by 13.3% [aOR=0.867 (95% CI = 0.816-0.920), p < 0.001]. Between the two groups, 75.7% of households in the pyrethroid-LLIN group and 66.8% in the PBO-LLIN group reported bedbug infestations in their homes. Bedbug infestation significantly affected net ownership (p = 0.018). Malaria parasite prevalence was 34.7% by qPCR in the pyrethroid-LLIN group and 29.0% in the PBO-LLIN group, with a prevalence ratio of 0.84 (95% CI: 0.65-1.03). The study observed higher bednet ownership, usage, and lower malaria prevalence in the PBO-LLIN clusters compared to the pyrethroid-LLIN clusters. However, bedbug infestations and insufficient sleeping beds hindered net ownership and usage, limiting their overall effectiveness. These findings highlight the need for National Malaria Control Programs (NMCPs) to enhance community education on proper net use and maintenance through targeted initiatives, such as household visits and local workshops. Furthermore, incorporating bedbug control strategies and regular surveillance will improve compliance and net usage. Addressing these challenges will maximize the impact of PBO-LLINs and other next-generation nets, strengthening malaria control and elimination efforts in both urban and rural settings.

Long-lasting insecticidal nets (LLINs) are vital for malaria control in sub-Saharan Africa, but their durability is challenged by fabric decay and pyrethroid resistance. This study assessed the physical integrity and bioefficacy of piperonyl butoxide-LLINs (PBO-LLINs) and pyrethroid-only LLINs (pyrethroid-LLINs) after 1.5 years of use in western Kenya, where resistance is widespread. A survey on net integrity and insecticide efficacy was conducted in randomly selected households (101-107 per group per visit) from three villages per net type group in Muhoroni Sub-County, Kisumu County. Physical integrity surveys were done after every six months while residual bio-efficacy was after every three months for 18 months. Physical integrity and residual bio-efficacy studies were conducted following WHO guidelines. PBO-LLINs exhibited higher physical integrity than pyrethroid-LLINs over time. At 18 months, 45.2% (61/135) of pyrethroid-LLINs and 21.8% (31/142) of PBO-LLINs were torn, with pHI values of 2494.1 ± 1696.4 and 1618.6 ± 1056.7, respectively. Net type, net age and house wall structures significantly influenced net integrity (p < 0.05). Torn nets were significantly more common in pyrethroid-LLIN households with mud-unplastered [OR=5.323 (95% CI = 1.685-16.816), p = 0.004] and corrugated iron walls [OR=6.31 (95% CI = 2.10-18.93), p < 0.001] and in PBO-LLIN households with mud-unplastered walls [OR=9.823 (95% CI = 1.487-64.898), p = 0.018]. Against the Kisumu susceptible Anopheles gambiae s.s, both net types decreased in mortality at baseline (when new) from 97.6% to 18.4% and 98.6% to 18.5% for pyrethroid and PBO-LLINs respectively at 18 months. Against a Bungoma pyrethroid-resistant Anopheles gambiae s.s, mosquito mortality with pyrethroid-LLINs declined from 36.9% when new to 6.8% at 18 months, while PBO-LLINs dropped from 55.6% to 11.8%. Both physical integrity and bioefficacy of LLINs declined significantly within 18 months. The findings demonstrate that not all nets in the field offer maximum protection by this time point, calling for net care education and further evaluation of PBO-LLINs especially in pyrethroid-resistant regions.

Persons with submicroscopic malaria infection are a major reservoir of gametocytes that sustain malaria transmission in sub-Saharan Africa. Despite recent decreases in the national malaria burden in Kenya due to vector control interventions, malaria transmission continues to be high in western regions of the country bordering Lake Victoria. The objective of this study was to advance knowledge of the topographical, demographic and behavioral risk factors associated with submicroscopic malaria infection in the Lake Victoria basin in Kisumu County. Cross-sectional community surveys for malaria infection were undertaken in three eco-epidemiologically distinct zones in Nyakach sub-County, Kisumu. Adjacent regions were topologically characterized as lakeshore, hillside and highland plateau. Surveys were conducted during the 2019 and 2020 wet and dry seasons. Finger prick blood smears and dry blood spots (DBS) on filter paper were collected from 1,777 healthy volunteers for microscopic inspection and real time-PCR (RT-PCR) diagnosis of Plasmodium infection. Persons who were PCR positive but blood smear negative were considered to harbor submicroscopic infections. Topographical, demographic and behavioral risk factors were correlated with community prevalence of submicroscopic infections. Out of a total of 1,777 blood samples collected, 14.2% (253/1,777) were diagnosed as submicroscopic infections. Blood smear microscopy and RT-PCR, respectively, detected 3.7% (66/1,777) and 18% (319/1,777) infections. Blood smears results were exclusively positive for P. falciparum, whereas RT-PCR also detected P. malariae and P. ovale mono- and co-infections. Submicroscopic infection prevalence was associated with topographical variation (χ2 = 39.344, df = 2, p<0.0001). The highest prevalence was observed in the lakeshore zone (20.6%, n = 622) followed by the hillside (13.6%, n = 595) and highland plateau zones (7.9%, n = 560). Infection prevalence varied significantly according to season (χ2 = 17.374, df = 3, p<0.0001). The highest prevalence was observed in residents of the lakeshore zone in the 2019 dry season (29.9%, n = 167) and 2020 and 2019 rainy seasons (21.5%, n = 144 and 18.1%, n = 155, respectively). In both the rainy and dry seasons the likelihood of submicroscopic infection was higher in the lakeshore (AOR: 2.71, 95% CI = 1.85-3.95; p<0.0001) and hillside (AOR: 1.74, 95% CI = 1.17-2.61, p = 0.007) than in the highland plateau zones. Residence in the lakeshore zone (p<0.0001), male sex (p = 0.025), school age (p = 0.002), and living in mud houses (p = 0.044) increased the risk of submicroscopic malaria infection. Bed net use (p = 0.112) and occupation (p = 0.116) were not associated with submicroscopic infection prevalence. Topographic features of the local landscape and seasonality are major correlates of submicroscopic malaria infection in the Lake Victoria area of western Kenya. Diagnostic tests more sensitive than blood smear microscopy will allow for monitoring and targeting geographic sites where additional vector interventions are needed to reduce malaria transmission.

In social hierarchies, dominant individuals experience reproductive and health benefits, but the costs of social dominance remain a topic of debate. Prevailing hypotheses predict that higher-ranking males experience higher testosterone and glucocorticoid (stress hormone) levels than lower-ranking males when hierarchies are unstable but not otherwise. In this long-term study of rank-related stress in a natural population of savannah baboons (Papio cynocephalus), high-ranking males had higher testosterone and lower glucocorticoid levels than other males, regardless of hierarchy stability. The singular exception was for the highest-ranking (alpha) males, who exhibited both high testosterone and high glucocorticoid levels. In particular, alpha males exhibited much higher stress hormone levels than second-ranking (beta) males, suggesting that being at the very top may be more costly than previously thought.

A good understanding of mosquito ecology is imperative for integrated vector control of malaria. In breeding sites, Anopheles larvae are concurrently exposed to predators and parasites. However, to our knowledge, there is no study on combined effects of predators and parasites on development and survival of larvae and their carry-over effects on adult survivorship and susceptibility to further parasite infection. This study focused on effects of the nymphs of the dragonfly Pantala flavescens and the parasitic fungus Beauveria bassiana on Anopheles gambiae, to determine: predation efficacy of nymphs against An. gambiae larvae; development rate of An. gambiae larvae in the presence of one, two or four constrained nymphs; efficacy of B. bassiana against An. gambiae larvae at doses of 3, 6 and 12 mg; and survival of adult mosquitoes exposed to B. bassiana, following pre-exposure to a constrained predator and/or parasite at the larval stage. The experiments consisted of survival bioassays quantified as pupation day, or dead larvae and/or adults. Nymphs had an average predation efficacy of 88.3% (95% CI: 87.5–89.1) at 24 hours, against An. gambiae larvae. The presence of one or two nymphs reduced development time of larvae by 0.65 and 0.35 days, respectively. However, development time of larvae exposed to four nymphs was similar to the control larvae. Larvae exposed to 3, 6 and 12 mg of B. bassiana were 2.0, 2.5 and 3.5 times more likely to die, respectively, compared to control larvae. Adults not pre-exposed, those pre-exposed to predator, parasite, or both were 45.8, 67.4, 50.9 and 112.0 times more likely to die, respectively …

Background Plasmodium falciparum malaria is a leading cause of pediatric morbidity and mortality in holoendemic transmission areas. Severe malarial anemia [SMA, hemoglobin (Hb) < 5.0 g/dL in children] is the most common clinical manifestation of severe malaria in such regions. Although innate immune response genes are known to influence the development of SMA, the role of natural killer (NK) cells in malaria pathogenesis remains largely undefined. As such, we examined the impact of genetic variation in the gene encoding a primary NK cell receptor, natural cytotoxicity-triggering receptor 3 (NCR3), on the occurrence of malaria and SMA episodes over time. Methods Susceptibility to malaria, SMA, and all-cause mortality was determined in carriers of NCR3 genetic variants (i.e., rs2736191:C > G and rs11575837:C > T) and their haplotypes. The prospective observational study was conducted over a 36 mos. follow-up period in a cohort of children ( n  = 1,515, aged 1.9–40 mos.) residing in a holoendemic P. falciparum transmission region, Siaya, Kenya. Results Poisson regression modeling, controlling for anemia-promoting covariates, revealed a significantly increased risk of malaria in carriers of the homozygous mutant allele genotype (TT) for rs11575837 after multiple test correction [Incidence rate ratio (IRR) = 1.540, 95% CI = 1.114–2.129, P  = 0.009]. Increased risk of SMA was observed for rs2736191 in children who inherited the CG genotype (IRR = 1.269, 95% CI = 1.009–1.597, P  = 0.041) and in the additive model (presence of 1 or 2 copies) (IRR = 1.198, 95% CI = 1.030–1.393, P  = 0.019), but was not significant after multiple test correction. Modeling of the haplotypes revealed that the CC haplotype had a significant additive effect for protection against SMA (i.e., reduced risk for development of SMA) after multiple test correction (IRR = 0.823, 95% CI = 0.711–0.952, P  = 0.009). Although increased susceptibility to SMA was present in carriers of the GC haplotype (IRR = 1.276, 95% CI = 1.030–1.581, P  = 0.026) with an additive effect (IRR = 1.182, 95% CI = 1.018–1.372, P  = 0.029), the results did not remain significant after multiple test correction. None of the NCR3 genotypes or haplotypes were associated with all-cause mortality. Conclusions Variation in NCR3 alters susceptibility to malaria and SMA during the acquisition of naturally-acquired malarial immunity. These results highlight the importance of NK cells in the innate immune response to malaria.

Background Malaria remains a public health problem in Kenya despite sustained interventions deployed by the government. One of the major impediments to effective malaria control is a lack of accurate diagnosis and effective treatment. This study was conducted to assess clinical malaria incidence and treatment seeking profiles of febrile cases in western Kenya. Methods Active case detection of malaria was carried out in three eco-epidemiologically distinct zones topologically characterized as lakeshore, hillside, and highland plateau in Kisumu County, western Kenya, from March 2020 to March 2021. Community Health Volunteers (CHVs) conducted biweekly visits to residents in their households to interview and examine for febrile illness. A febrile case was defined as an individual having fever (axillary temperature ≥ 37.5 °C) during examination or complaints of fever and other nonspecific malaria related symptoms 1–2 days before examination. Prior to the biweekly malaria testing by the CHVs, the participants' treatment seeking methods were based on their behaviors in response to febrile illness. In suspected malaria cases, finger-prick blood samples were taken and tested for malaria parasites with ultra-sensitive Alere ® malaria rapid diagnostic tests (RDT) and subjected to real-time polymerase chain reaction (RT-PCR) for quality control examination. Results Of the total 5838 residents interviewed, 2205 residents had high temperature or reported febrile illness in the previous two days before the visit. Clinical malaria incidence (cases/1000people/month) was highest in the lakeshore zone (24.3), followed by the hillside (18.7) and the highland plateau zone (10.3). Clinical malaria incidence showed significant difference across gender (χ 2  = 7.57; df = 2, p  = 0.0227) and age group (χ 2  = 58.34; df = 4, p  < 0.0001). Treatment seeking patterns of malaria febrile cases showed significant difference with doing nothing (48.7%) and purchasing antimalarials from drug shops (38.1%) being the most common health-seeking pattern among the 2205 febrile residents (χ 2  = 21.875; df = 4, p  < 0.0001). Caregivers of 802 school-aged children aged 5–14 years with fever primarily sought treatment from drug shops (28.9%) and public hospitals (14.0%), with significant lower proportions of children receiving treatment from traditional medication (2.9%) and private hospital (4.4%) ( p  < 0.0001). There was no significant difference in care givers' treatment seeking patterns for feverish children under the age of five ( p  = 0.086). Residents with clinical malaria cases in the lakeshore and hillside zones sought treatment primarily from public hospitals (61.9%, 60/97) traditional medication (51.1%, 23/45) respectively ( p  < 0.0001). However, there was no significant difference in the treatment seeking patterns of highland plateau residents with clinical malaria ( p  = 0.431).The main factors associated with the decision to seek treatment were the travel distance to the health facility, the severity of the disease, confidence in the treatment, and affordability. Conclusion Clinical malaria incidence remains highest in the Lakeshore (24.3cases/1000 people/month) despite high LLINs coverage (90%). The travel distance to the health facility, severity of disease and affordability were mainly associated with 80% of residents either self-medicating or doing nothing to alleviate their illness. The findings of this study suggest that the Ministry of Health should strengthen community case management of malaria by providing supportive supervision of community health volunteers to advocate for community awareness, early diagnosis, and treatment of malaria.

The H19 gene, which localizes within a chromosomal region on human chromosome 11p15 that is commonly lost in Wilms tumor (WT), encodes an imprinted untranslated RNA. However, the biological significance of the H19 noncoding transcript remains unresolved because replacement of the RNA transcript with a neocassette has no obvious phenotypic effect. Here we show that the human H19 locus also encodes a maternally expressed, translated gene, antisense to the known H19 transcript, which is conserved in primates. This gene, termed HOTS for H19 opposite tumor suppressor, encodes a protein that localizes to the nucleus and nucleolus and that interacts with the human enhancer of rudimentary homolog (ERH) protein. WTs that show loss of heterozygosity of 11p15 or loss of imprinting of IGF2 also silence HOTS (7/7 and 10/10, respectively). Overexpression of HOTS inhibits Wilms, rhabdoid, rhabdomyosarcoma, and choriocarcinoma tumor cell growth, and silencing HOTS by RNAi increases in vitro colony formation and in vivo tumor growth. These results demonstrate that the human H19 locus harbors an imprinted gene encoding a tumor suppressor protein within the long-sought WT2 locus.

Andy Feinberg and colleagues show in a colon cancer model that most DNA methylation alterations occur in sequence regions distinct from promoters or canonical CpG islands, termed 'CpG island shores', and that this methylation is strongly related to gene expression and can discriminate tissue types regardless of species of origin. For the past 25 years, it has been known that alterations in DNA methylation (DNAm) occur in cancer, including hypomethylation of oncogenes and hypermethylation of tumor suppressor genes. However, most studies of cancer methylation have assumed that functionally important DNAm will occur in promoters, and that most DNAm changes in cancer occur in CpG islands. Here we show that most methylation alterations in colon cancer occur not in promoters, and also not in CpG islands, but in sequences up to 2 kb distant, which we term 'CpG island shores'. CpG island shore methylation was strongly related to gene expression, and it was highly conserved in mouse, discriminating tissue types regardless of species of origin. There was a notable overlap (45–65%) of the locations of colon cancer–related methylation changes with those that distinguished normal tissues, with hypermethylation enriched closer to the associated CpG islands, and hypomethylation enriched further from the associated CpG island and resembling that of noncolon normal tissues. Thus, methylation changes in cancer are at sites that vary normally in tissue differentiation, consistent with the epigenetic progenitor model of cancer, which proposes that epigenetic alterations affecting tissue-specific differentiation are the predominant mechanism by which epigenetic changes cause cancer.

Background Identification and characterization of larval habitats, documentation of Anopheles spp. composition and abundance, and Plasmodium spp. infection burden are critical components of integrated vector management. The present study aimed to investigate the effect of landscape heterogeneity on entomological and parasitological indices of malaria in western Kenya. Methods A cross-sectional entomological and parasitological survey was conducted along an altitudinal transect in three eco-epidemiological zones: lakeshore along the lakeside, hillside, and highland plateau during the wet and dry seasons in 2020 in Kisumu County, Kenya. Larval habitats for Anopheles mosquitoes were identified and characterized. Adult mosquitoes were sampled using pyrethrum spray catches (PSC). Finger prick blood samples were taken from residents and examined for malaria parasites by real-time PCR (RT-PCR). Results Increased risk of Plasmodium falciparum infection was associated with residency in the lakeshore zone, school-age children, rainy season, and no ITNs ( χ 2  = 41.201, df  = 9, P  < 0.0001). Similarly, lakeshore zone and the rainy season significantly increased Anopheles spp. abundance. However, house structures such as wall type and whether the eave spaces were closed or open, as well as the use of ITNs, did not affect Anopheles spp. densities in the homes ( χ 2  = 38.695, df  = 7, P  < 0.0001). Anopheles funestus (41.8%) and An. arabiensis (29.1%) were the most abundant vectors in all zones. Sporozoite prevalence was 5.6% and 3.2% in the two species respectively. The lakeshore zone had the highest sporozoite prevalence (4.4%, 7/160) and inoculation rates (135.2 infective bites/person/year). High larval densities were significantly associated with lakeshore zone and hillside zones, animal hoof prints and tire truck larval habitats, wetland and pasture land, and the wet season. The larval habitat types differed significantly across the landscape zones and seasonality ( χ 2  = 1453.044, df  = 298, P  < 0.0001). Conclusion The empirical evidence on the impact of landscape heterogeneity and seasonality on vector densities, parasite transmission, and Plasmodium infections in humans emphasizes the importance of tailoring specific adaptive environmental management interventions to specific landscape attributes to have a significant impact on transmission reduction. Graphical abstract