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Mosquitoes serve as the major vector transmitting malaria, dengue, yellow fever and several other diseases of human concern. Rising in mosquito-borne diseases and consequent fatalities throughout the world has made the management of mosquitoes of paramount importance. With the use of various insecticidal agents and their indiscriminate application in the fields for vector control; other issues such as multiple insecticide resistance, lethality to non-specific targets and adverse effects on human and environmental health have emerged making the situation more critical. Hence, the focus of researchers has diverted to the use of Insect Growth Regulators (IGRs) that affect the growth and development of the insects without inducing any appreciable toxic effects. The paper comprehensively reviews various IGRs and their potential use against insect pests and mosquito vectors. A special emphasis has been laid on the utilization of diflubenzuron, its larvicidal potency and growth regulatory effects against mosquitoes. The paper also delivers a detailed discussion on various approaches governing with the application of diflubenzuron, a chitin synthesis inhibitor, for its potent effects over a wide range of other insect species, low toxicity to humans, safety to other non-target animals, negligible deleterious environmental impact along with the possible development of resistance in the mosquitoes, thereby providing insights and the direction for the future in terms of the innovative and technological perspective. Keeping in view the role of multifarious mechanisms in the development of resistance; use of various synergistic compounds, such as hydrolase inhibitors - profenofos and S,S,S-tributyl phosphorotrithioate; glutathione S-transferase inhibitor – diethylmaleate; and oxidase inhibitor - piperonyl butoxide (PBO); has been recommended in combination with IGRs to enhance their efficacy, and reduce or reverse the resistance in target mosquitoes. Another compound, verapamil, has been found extremely efficient in imparting synergistic effect to diflubenzuron by inhibiting P-glycoproteins, a transporter of the insecticides causing their efflux from the cell. Recommendations have been made for safe and effective mosquito control measures, adequate policies and increased awareness about the mosquito-borne diseases among the masses. In addition, regular surveillance of mosquitoes is endorsed for the formulation of an efficient mosquito management strategy.

Malaria, Zika virus, West Nile virus, Dengue fever, and Lyme disease are common causes of morbidity and mortality around the world. While arthropod bites may cause local inflammation and discomfort, a greater concern is the potential to develop deadly systemic infection. The use of insect repellents (IR) to prevent systemic infections constitutes a fundamental public health effort. Cost-effectiveness, availability, and high-efficacy against arthropod vectors are key characteristics of an ideal IR. Currently, numerous IRs are available on the market, with DEET (N,N-diethyl-3-methylbenzamide) being the most widely used. DEET has an excellent safety profile and remarkable protection against mosquitoes and various other arthropods. Other EPA-registered IR ingredients (permethrin, picaridin, IR3535, oil of lemon eucalyptus, oil of citronella, catnip oil, and 2-undecanone) are alternative IRs of great interest due to some having efficacies comparable to that of DEET. These alternative IRs possess low toxicity and favorable customer experiences in utilization (e.g., cosmetically pleasant, naturally occurring). This review summarizes currently available EPA-registered IRs: the origins, mechanisms of action, side effect profiles, and available formulations will be discussed. This review will enable the clinician to select the best IR option to meet patients' needs and provide the greatest protection from arthropod bites and sequelae.

Cues involved in mate seeking and recognition prevent hybridization and can be involved in speciation processes. In malaria mosquitoes, females of the two sibling species Anopheles gambiae s.s. and An. coluzzii mate in monospecific male swarms and hybrids are rare. Long-range sex pheromones driving this behavior have been debated in literature but to date, no study has proven their existence or their absence. Here, we attempted to bring to light their existence. To put all the odds in our favor, we used different chemical ecology methods such as behavioral and electrophysiological assays as well chemical analyses, and we worked with mosquitoes at their optimal physiological mating state i.e. with swarming males during their natural swarming windows. Despite all our efforts, our results support the absence of long-range sex pheromones involved in swarm detection and recognition by females. We briefly discuss the implications of this finding in ecology, evolution and for control strategies.

Background Protection against Plasmodium falciparum is observed in a population deficient in glucose-6-phosphate dehydrogenase (G6PD), particularly in African and Mediterranean regions. However, such protection remains unknown among G6PD-deficient individuals in Southeast Asia. Methods In this study, we assessed the invasion and maturation of P falciparum K1 in a culture of erythrocytes isolated from Thai subjects carrying Viangchan (871G > A) and Mahidol (487G > A). Results We found that the parasites lost their ability to invade hemizygous and homozygous G6PD-deficient erythrocytes of Viangchan and Mahidol variants in the second and third cycles of intraerythrocytic development. It is interesting to note that P falciparum parasites selectively grew in erythrocytes from hemi- and homozygous genotypes with normal G6PD activity. Moreover, externalization of phosphatidylserine upon P falciparum infection was significantly increased only in Viangchan hemizygous variant cells. Conclusions This study is the first to show that blockage of invasion in long-term culture and potentially enhanced removal of parasitized erythrocytes were observed for the first time in erythrocytes from Viangchan and Mahidol G6PD-deficient individuals.

Introduction By providing timely actionable results for prompt management, point-of-care testing (POCT) kits have revolutionised medical care for various diseases, ranging from infectious diseases like malaria to genetic disorders, such as sickle cell disease (SCD). They are, however, underutilised in the diagnosis of SCD in developing countries, where the need is greatest. Objective The study was aimed at assessing the sensitivity of HemoTypeSC POCT among a cohort of children with SCD, previously diagnosed by Alkaline cellulose acetate hemoglobin electrophoresis (ACAE), with or without high-performance liquid chromatography (HPLC). Methods In this descriptive cross-sectional study, HemoTypeSC test was conducted on all participants and its sensitivity was determined by comparing results with those obtained using ACAE. Discordance was verified with HPLC. Results One hundred and forty-five children aged one to 19 years were studied. There were 84 males and 61 females (male: female ratio = 1.4: 1). The HemoTypeSC was able to correctly diagnose sickle cell anemia (SCA) and hemoglobin SC in all (100%) of the children tested. Conclusion The HemoTypeSC shows high sensitivity in detecting SCA and hemoglobin SC. Hence, it is useful for targeted screening of individuals suspected of having SCD, leading to rapid diagnosis of these hemoglobinopathies, even in resource-constrained settings.

The genus Aloe is widely used for medicinal purposes throughout its predominantly African distribution, but detailed knowledge of the contemporary value of aloes is patchy. The main aim of this study was to determine the value of Aloe in the Highlands of Ethiopia, a region of rich Aloe diversity, by documenting local uses and perceptions of the sustainability of the species used. Amhara and Tigray community members participated in semi-structured interviews from 110 respondents aged 24-72. Eleven species of Aloe were recorded for medicine, social and environmental uses, animal food, and as bee plants managed for honey production. Of these, the majority of use records were for human medicine to treat malaria and wounds. We found no evidence of non-sustainable harvesting for medicine, but extensive habitat loss and interest in the commercial uses of Aloe present acute threats and indicate the vulnerability of Aloe species in the central and northern Highlands of Ethiopia.

Malaria is a mosquito-borne disease that results in millions of cases and deaths annually. The development of a fast computational method that identifies secretory proteins of the malaria parasite is important for research on antimalarial drugs and vaccines. Thus, a method was developed to identify the secretory proteins of malaria parasites. In this method, a reduced alphabet was selected to recode the original protein sequence. A feature synthesis method was used to synthesise three different types of feature information. Finally, the random forest method was used as a classifier to identify the secretory proteins. In addition, a web server was developed to share the proposed algorithm. Experiments using the benchmark dataset demonstrated that the overall accuracy achieved by the proposed method was greater than 97.8 percent using the 10-fold cross-validation method. Furthermore, the reduced schemes and characteristic performance analyses are discussed.

This paper presents the first systematic investigation of the effect of epidemic shocks on civil violence. The identification exploits exogenous within cell × year variation in conditions that are suitable for malaria transmission using a panel database with month-by-month variation at a resolution of 1∘×1∘ latitude/longitude for Africa. Suitable conditions increase civil violence in areas with populations susceptible to epidemic outbreaks. The effect is immediate, related to the acute phase of the epidemic and largest during short harvesting seasons of subsistence crops. Genetic immunities and antimalaria policies attenuate the effect. The results deliver new insights for prevention and attenuation policies and for potential consequences of climate change.

Among all the parasitic diseases in humans, malaria is the most significant and malicious one. The widespread species are Plasmodium falciparum and Plasmodium vivax, but the infection caused by the former is the deadliest. According to the November 2018 report of the World Health Organization (WHO), a total of 219 million cases of malaria were reported globally in 2017, which led to an estimated 435,000 deaths. Mortality due to malaria is estimated at 1.5 - 2.7 million deaths each year. Among all the complications associated with Plasmodium falciparum infection, cerebral malaria (CM) is the most fretful, accounting for almost 13% of all malaria-related deaths. CM is a medical emergency that requires immediate clinical testing and treatment. A compromised microcirculation, with sequestration of parasitized erythrocytes, is central in the disease pathology. No effective therapeutic agents are available yet for the treatment of CM, and therefore, potential interventions are needed to be developed urgently. The currently available anti-malarial drugs lack lipophilicity and are thus not able to reach the brain tissues. Therefore, safe, cost-effective agents with improved lipophilicity possessing the potential to target brain tissues are needed to be searched in order to fight CM worldwide. The aim of present review is to systematically revise the published research work available concerning the development and evaluation of some potential drug targets in the management of CM.

Malaria is a major cause of suffering, disease, and death worldwide and is considered the most important of all human parasitic diseases. Malaria is still endemic in most tropical and sub-tropical areas and globalization has contributed to an increase of imported cases around the world. We report a Plasmodium ovale infection in a traveler with recent return from a long land trip across West Africa. He declared adherence to mefloquine chemoprophylaxis only at the start of the trip. Initially, he was seen at two different hospitals and in both he was screened for malaria by microscopy and rapid diagnostic test, but his diagnosis was not confirmed. The traveler was then diagnosed at our hospital with a malaria infection by Plasmodium ovale. Complete blood count showed mild anemia, but leukocytes and platelets were already normal. Symptoms resolved in 24 hours after treatment started. Microscopy of stained blood films remains the gold standard for malaria diagnosis, which is critically dependent on trained eyes. In non-endemic regions with few cases during the year, training programs in malaria microscopy are crucial. The aim is to prevent the reintroduction of malaria in Europe, reduce individual morbidity and suffering, and thus contribute towards reduction in deaths caused by this disease.A malária é uma das principais causas de sofrimento, doença e morte no mundo e é considerada a mais importante doença parasitária em humanos. A malária ainda é endémica na maioria das áreas tropicais e sub-tropicais e a globalização tem contribuído para o aumento de casos em todo o mundo. Relatamos um caso de infeção por Plasmodium ovale num viajante com regresso recente de uma viagem por terra por vários países de África Ocidental. O viajante aderiu à profilaxia com mefloquina apenas no início da viagem. Já em Portugal, sentindo-se doente, febril, dirigiu-se a dois hospitais, onde realizou despiste para malária por microscopia e teste rápido, que foram descritos como negativos. Posteriormente, o viajante dirigiu-se ao nosso serviço onde foi diagnosticada uma infeção de malária por Plasmodium ovale. Os achados analíticos revelaram uma contagem de leucócitos normal, anemia moderada e, uma contagem de plaquetas já normal. Os sintomas terminaram com apenas 24 horas de tratamento. O método de referência do diagnóstico de malária continua a ser a microscopia, que é altamente dependente da experiência do pessoal do laboratório. Em regiões não endémicas com poucos casos durante o ano, é essencial promover e manter programas de capacitação em microscopia para prevenir a reintrodução da malária na Europa, diminuir a morbilidade e o sofrimento, e contribuir assim, para a redução do número de mortes pela doença.

Malaria is parasitic disease cause by Plasmodium infection. In Thailand, co-infections of Plasmodium vivax and P. falciparum are commonly found. P. vivax infection has been increasing in the past decade. The objective of this study was to investigate the genetic diversity patterns of Plasmodium vivax merozoite surface protein 3 (PvMSP-3) genes in total of 450 isolates collected from Thai-neighboring border during two different periods (2009-20 14 and 2015 -2016) using polymerase chain reaction (PCR) - restriction fragment length polymorphism (RFLP) method. Three major types of PvMSP-3α (A, B, and C) and PvMSP-3β (A, B, and C) were detected based on PCR products size. Forty five and 23 of PvMSP-3α and, 41 and 30 alleles of PvMSP-3β genes from the first period and second period, respectively, with difference frequencies of samples were distinguished. The results strongly indicate genetic diversity patterns of PvMSP-3 in the second period especially samples from Thai-Myanmar border. These two polymorphic genes could be used as a molecular epidemiologic marker for genotyping P. vivax isolate in Thailand.

In recent decades, RNA-based therapeutics have transitioned from a near impossibility to a compelling treatment alternative for genetic disorders and infectious diseases. The mRNA vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are truly groundbreaking, and new adaptations are already being proposed to fight other microbes. Unfortunately, the potential of RNA-based therapeutics to treat human fungal infections has remained mostly absent from the conversation, despite the fact that invasive fungal infections kill as many per year as tuberculosis and even more than malaria. Here, we argue that RNA-based therapeutics should be investigated for the treatment of human fungal infections and discuss several major roadblocks and potential circumventions that may allow for the realization of RNA-based therapies against human fungal pathogens.

Malaria is an important and worldwide fatal disease that has been widely reported by the World Health Organization (WHO), and it has about 219 million cases worldwide, with 435,000 of those mortal. The common malaria diagnosis approach is heavily reliant on highly trained experts, who use a microscope to examine the samples. Therefore, there is a need to create an automated solution for the diagnosis of malaria. One of the main objectives of this work is to create a design tool that could be used to diagnose malaria from the image of a blood sample. In this paper, we firstly developed a graphical user interface that could be used to help segment red blood cells and infected cells and allow the users to analyze the blood samples. Secondly, a Feed-forward Neural Network (FNN) is designed to classify the cells into two classes. The achieved results show that the proposed techniques can be used to detect malaria, as it has achieved 92% accuracy with a database that contains 27,560 benchmark images.

Malaria, a parasite based infectious disease spread by anopheles mosquitos, is widespread, affecting people of all ages. Malaria blood-borne pathogens cause approximately 110 million clinical cases of malaria and between one and two million deaths associated with Plasmodium falciparum each year worldwide, including Bangladesh. In this paper, we develop a human–mosquito transmission dynamics malaria model and analyse of the system properties and solutions. Both analytical and numerical results suggest that if the basic reproduction number R 0 1 , the disease-free equilibrium is asymptotically stable, meaning malaria naturally dies out. Further, if R 0 > 1 , the malaria disease persists in the population. We also provide the model calibration to estimate parameters with year-wise malaria incidence data from 2001 to 2014 in Bangladesh. Sensitivity analysis also performs to identify the most critical parameters through the partial rank correlation coefficient method. We found that the contact rate of both humans and mosquitoes had the most extensive influence on malaria prevalence. Finally, the impacts of progression rate, disease-related death rate, recovery rate and the rate of losing immunity are examined through numerical simulations and graphical analysis.

Summary Background WHO recently approved a partially effective vaccine that reduces clinical malaria in children, but increased vaccine activity is required to pursue malaria elimination. A phase 1 clinical trial was done in Mali, west Africa, to assess the safety, immunogenicity, and protective efficacy of a three-dose regimen of Plasmodium falciparum sporozoite (PfSPZ) Vaccine (a metabolically active, non-replicating, whole malaria sporozoite vaccine) against homologous controlled human malaria infection (CHMI) and natural P falciparum infection. Methods We recruited healthy non-pregnant adults aged 18–50 years in Doneguebougou, Mali, and surrounding villages (Banambani, Toubana, Torodo, Sirababougou, Zorokoro) for an open-label, dose-escalation pilot study and, thereafter, a randomised, double-blind, placebo-controlled main trial. Pilot study participants were enrolled on an as-available basis to one group of CHMI infectivity controls and three staggered vaccine groups receiving: one dose of 4·5 × 105, one dose of 9 × 105, or three doses of 1·8 × 106 PfSPZ via direct venous inoculation at approximately 8 week intervals, followed by homologous CHMI 5 weeks later with infectious PfSPZ by direct venous inoculation (PfSPZ Challenge). Main cohort participants were stratified by village and randomly assigned (1:1) to receive three doses of 1·8 × 106 PfSPZ or normal saline at 1, 13, and 19 week intervals using permuted block design by the study statistician. The primary outcome was safety and tolerability of at least one vaccine dose; the secondary outcome was vaccine efficacy against homologous PfSPZ CHMI (pilot study) or against naturally transmitted P falciparum infection (main study) measured by thick blood smear. Combined artesunate and amodiaquine was administered to eliminate pre-existing parasitaemia. Outcomes were analysed by modified intention to treat (mITT; including all participants who received at least one dose of investigational product; safety and vaccine efficacy) and per protocol (vaccine efficacy). This trial is registered with ClinicalTrials.gov , number NCT02627456 . Findings Between Dec 20, 2015, and April 30, 2016, we enrolled 56 participants into the pilot study (five received the 4·5 × 105 dose, five received 9 × 105, 30 received 1·8 × 106, 15 were CHMI controls, and one withdrew before vaccination) and 120 participants into the main study cohort with 60 participants assigned PfSPZ Vaccine and 60 placebo in the main study. Adverse events and laboratory abnormalities post-vaccination in all dosing groups were few, mainly mild, and did not differ significantly between vaccine groups (all p>0·05). Unexpected severe transaminitis occured in four participants: one participant in pilot phase that received 1·8 × 106 PfSPZ Vaccine, one participant in main phase that received 1·8 × 106 PfSPZ Vaccine, and two participants in the main phase placebo group. During PfSPZ CHMI, approximately 5 weeks after the third dose of 1·8 × 106 PfSPZ, none of 29 vaccinees and one of 15 controls became positive on thick blood smear; subsequent post-hoc PCR analysis for submicroscopic blood stage infections detected P falciparum parasites in none of the 29 vaccine recipients and eight of 15 controls during CHMI. In the main trial, 32 (58%) of 55 vaccine recipients and 42 (78%) of 54 controls became positive on thick blood smear during 24-week surveillance after vaccination. Vaccine efficacy (1–hazard ratio) was 0·51 per protocol (95% CI 0·20–0·70; log-rank p=0·0042) and 0·39 by mITT (0·04–0·62; p=0·033); vaccine efficacy (1–risk ratio) was 0·24 per-protocol (0·02–0·41; p=0·031) and 0·22 mITT (0·01–0·39; p=0·041). Interpretation A three-dose regimen of PfSPZ Vaccine was safe, well tolerated, and conferred 51% vaccine efficacy against intense natural P falciparum transmission, similar to 52% vaccine efficacy reported for a five-dose regimen in a previous trial. Funding US National Institute of Allergy and Infectious Diseases, National Institutes of Health, Sanaria. Translation For the French translation of the abstract see Supplementary Materials section.

Seasonal malaria chemoprevention (SMC) was adopted in Mali in 2012 for preventing malaria in children younger than 5 years. Although this strategy has been highly effective in reducing childhood malaria, an uptick in malaria occurrence has occurred in children 5 to 15 years of age. This study aimed to investigate the feasibility of providing SMC to older children. A cohort of 350 children age 5 to 14 years were monitored during the 2019 transmission season in Dangassa, Mali. The intervention group received five monthly rounds of sulfadoxine–pyrimethamine plus amodiaquine, whereas the control group consisted of untreated children. Community acceptance for extending SMC was assessed during the final round. Logistic regression models were applied to compare the risk of Plasmodium falciparum malaria infection, anemia, and fever between the intervention and control groups. Kaplan-Meier survival analyses were used to compare the time to P. falciparum parasitemia infection between the groups. The community acceptance rate was 96.5% (139 of 144). Significant declines were observed in the prevalence of P. falciparum parasitemia (adjusted odds ratio, 0.22; 95% CI, 0.11–0.42) and anemia (adjusted odds ratio, 0.15; 95% CI, 0.07–0.28) in the intervention group compared with the control group. The cumulative incidence of P. falciparum infections was significantly greater (75.4%, 104 of 138) in the control group compared with the intervention group (40.7%, 61 of 143, P = 0.001). This study reveals that expanding SMC to older children is likely feasible, has high community acceptance, and is in reducing uncomplicated malaria and anemia in older children.

Functional characterization of the multitude of poorly-described proteins in the human malarial pathogen, Plasmodium falciparum, requires tools to enable genome-scale perturbation studies. Here we present GeneTargeter (genetargeter.mit.edu), a software tool for automating the design of homology-directed repair donor vectors to achieve gene knockouts, conditional knockdowns, and epitope tagging of P. falciparum genes. We demonstrate GeneTargeter facilitated genome-scale design of six different types of knockout and conditional knockdown constructs for the P. falciparum genome, and validate the computational design process experimentally with successful donor vector assembly. The software's modular, customizable nature makes it extendable to additional plasmids and genomes.

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/, Purpose: Fluid management is challenging in malaria patients given the risks associated with intravascular fluid depletion and iatrogenic fluid overload leading to pulmonary oedema. Given the limitations of the physical examination in guiding fluid therapy, we evaluated point-of-care ultrasound (POCUS) of the inferior vena cava (IVC) and lungs as a novel tool to assess volume status and detect early oedema in malaria patients. Methods: To assess the correlation between IVC and lung ultrasound (LUS) indices and clinical signs of hypovolaemia and pulmonary oedema, respectively, concurrent clinical and sonographic examinations were performed in an observational study of 48 malaria patients and 62 healthy participants across age groups in Gabon. Results: IVC collapsibility index (CI) ≥ 50% on enrolment reflecting intravascular fluid depletion was associated with an increased number of clinical signs of hypovolaemia in severe and uncomplicated malaria. With exception of dry mucous membranes, IVC-CI correlated with most clinical signs of hypovolaemia, most notably sunken eyes (r = 0.35, p = 0.0001) and prolonged capillary refill (r = 0.35, p = 0.001). IVC-to-aorta ratio ≤ 0.8 was not associated with any clinical signs of hypovolaemia on enrolment. Among malaria patients, a B-pattern on enrolment reflecting interstitial fluid was associated with dyspnoea (p = 0.0003), crepitations and SpO2 ≤ 94% (both p < 0.0001), but not tachypnoea (p = 0.069). Severe malaria patients had increased IVC-CI (p < 0.0001) and more B-patterns (p = 0.004) on enrolment relative to uncomplicated malaria and controls. Conclusion: In malaria patients, POCUS of the IVC and lungs may improve the assessment of volume status and detect early oedema, which could help to manage fluids in these patients.

Malaria is a leading cause of death in children less than 5 years of age globally, and a common cause of fever in the returning North American traveler. New tools in the fight against malaria have been developed over the past decades: potent artemisinin derivatives; rapid diagnostic tests; long-lasting insecticidal bed nets; and a new vaccine, RTS,S/AS01. Thwarting these advances, parasite and Anopheles vector resistance are emerging. In the meantime, clinicians will continue to see malaria among febrile travelers from the tropics. Early recognition, diagnosis, and treatment can be lifesaving, but rely on the vigilance of frontline clinicians.

New vector-control tools are urgently needed to reduce malaria in areas where there is significant transmission after deployment of indoor residual spraying (IRS) and insecticide treated nets. Insecticide-treated livestock (ITL) is a potential novel strategy by which zoophagic mosquitos are killed after feeding upon animals treated with an insecticide. Although there are several insecticide candidates in the pipeline with a wide efficacy range against mosquitos, additional field studies with epidemiological outcomes are required to test the impact of this intervention on malaria transmission. Insecticides under consideration have long been used in livestock to improve animal health and productivity, but each has food and environmental safety considerations. Therefore, moving ITL from a concept to implementation will require a One Health framework.

Abstract: Malaria caused by Plasmodium falciparum is one of the major infectious diseases in the world. It is essential to exploit an effective method to predict secretory proteins of malaria parasites to develop effective cures and treatment. Biochemical assays can provide details for accurate identification of the secretory proteins, but these methods are expensive and time-consuming. In this paper, we summarized the machine learningbased identification algorithms and compared the construction strategies between different computational methods. Also, we discussed the use of machine learning to improve the ability of algorithms to identify proteins secreted by malaria parasites.

Early transcribed membrane proteins form a unique protein family in malaria parasites. These molecules are expressed during Plasmodium intracellular phases and inserted at the parasite parasitophorus vacuole membrane, which constitutes the host–parasite interface. Upregulated in infectious sporozoites 4 (UIS4) is an essential early transcribed membrane protein of liver stages of the murine malaria model parasite Plasmodium berghei. Despite its relevance for liver stage maturation, the molecular functions of UIS4 remain elusive, and UIS4 orthologs in human malaria parasites have not yet been identified. In order to characterise functional domains of UIS4, we generated P. berghei parasites carrying a carboxy-terminally truncated version of UIS4. We observed that uis4Δc parasites are severely impaired in liver stage development, similar to uis4(−) parasites, indicating an important role of the C-terminal domain for UIS4 function. To test whether members of the P. falciparum early transcribed membrane protein family are potential UIS4 orthologs, we selected candidates based on structural homology and parasitophorous vacuole membrane localization. We generated transgenic P. berghei parasites where UIS4 was replaced by Plasmodium falciparum ETRAMP8 or ETRAMP10.3. Both early transcribed membrane proteins were expressed in transgenic parasite lines, but liver stage maturation was impaired, indicating that the selected early transcribed membrane proteins failed to substitute the function of UIS4. As a control, we included the UIS4 ortholog from the murine parasite Plasmodium chaubaudi. We observed that PcUIS4 successfully restores UIS4 function in P. berghei. Together, these results suggest that Plasmodium parasites express tailor-made parasitophorous vacuole membrane proteins that might at least partially explain the narrow host range of malaria parasites.

Background: Malaria is endemic in many states of India. Though there are reports of maternal and congenital malaria from endemic areas, however, there remains a paucity of data from hilly terrains. The present study evaluated the prevalence, clinical and microbiological spectrum of maternal and congenital malaria at a tertiary health care facility in Northern India over a period of 18 months. Methods: In this observational study, mothers along with their newborns were evaluated for malaria by maternal, placental, and cord blood smear examination and rapid point-of-care diagnostic serological tests. Positive cases were confirmed by polymerase chain reaction. Mother-newborn duos were followed up till discharge from the hospital. Results: A total of 843 mothers delivered during the study period and were screened along with their newborns and placentae. A total of Ten (1.18%) mothers had evidence of malarial parasitemia (Plasmodium vivax, n=7 and Pl. falciparum, n=3), however, none of the placental and cord blood samples were positive for malaria. Overall, 127 (15.1%) neonates required admission in neonatal intensive care unit for various morbidities. Incidence of small for gestational age (SGA) was high (n=210; 24.9%). Multivariate logistic regression analysis demonstrated maternal malaria to be an independent contributor for SGA [Odds Ratio (95% Confidence Interval), 10.7 (2.06 - 49.72)]. However, only 2% variance of SGA could be explained by maternal malaria alone. Conclusions: We report an encouragingly lower incidence of maternal malaria in mothers attending for delivery and a ‘Zero’ incidence for placental and congenital malaria during the study period as compared to national data (upto 7.4% in non-immune mothers), although maternal malaria could be a causative factor for SGA.

Background: In recent years, many aspects of the physiological role of PCSK9 have been elucidated, in particular regarding its role in lipid metabolism, cardiovascular risk but also its role in innate immunity. Increasing evidence is available on the involvement of PCSK9 in the pathogenesis of viral infections, mainly HCV, as well as in the regulation of host response to bacterial infections, mainly sepsis and septic shock. Moreover, the action of PCSK9 has been investigated as a crucial step in the pathogenesis of malaria infection and disease severity. Objective: Aim of this paper is to review available published literature on the role of PCSK9 in a wide array of infectious diseases. Conclusion: Besides the ongoing investigation on PCSK9 inhibition among HIV-infected patients for the treatment of HIV- and ART-related hyperlipidemia, preclinical studies indicate how PCSK9 is involved in reducing the replication of HCV. Moreover, a protective role of PCSK9 inhibition has also been proposed against dengue and SARS-CoV-2 viral infections. Interestingly, high plasmatic PCSK9 levels have been described in patients with sepsis. Finally, a loss of function in the PCSK9-encoding gene has been reported to possibly reduce mortality in malaria infection.

Mushrooms represent a large family of fleshy fungi that have been of high interest since ancient ages due to their medicinal and nutritional importance. Therefore, it can represent a significant source of bioactive compounds in malaria control. The few numbers of studies on in vitro antiplasmodial and insecticidal properties of their extracts and chemical constituents led to interesting results reported in numerous scientific publications. This review aims to provide a comprehensive compilation of literature up to 2021 on the antiplasmodial, insecticidal as well as cytotoxic chemical constituents of medicinal mushrooms that can help in the management of malaria both against the parasite Plasmodium falciparum and the mosquitoe Anopheles stephensis acting as a vector of malaria through its bites. For this purpose, some searches have been done in some online libraries using keywords like Basidiomycete, mushroom, malaria, Plasmodium, Anopheles and antiplasmodial without language restriction. Among the reported compounds, 51 selected ones displayed significant antiplasmodial potency with IC50 values lower than 10 μM against P. falciparum strains sensitive or resistant to chloroquine. For instance, ganoderic acid AW1 demonstrated a strong antiplasmodial activity with IC50 of 257.8 nM against P. falciparum D6, while strong activities were displayed by ganoweberianones A (IC50 = 0.050 μM) and B (IC50 = 0.46 μM) against P. falciparum K1. Moreover, some mushroom methanol extracts demonstrated good larvicidal and ovicidal activities against Anopheles stephensis. This paper provides further insights into the development of new antiplasmodial drugs or new potent eco-friendly pesticides to control mosquito vectors.

In 2010, the World Health Organization changed its guidance on malaria case management, recommending parasitological confirmation of all suspected cases before treatment with an antimalarial. This recommendation was in large part as a result of the availability of quality assured malaria rapid diagnostic tests (RDTs) that made it possible for malaria diagnosis to be performed by laboratory staff in all health facilities irrespective of the facility’s place in the tiered health system. Community health workers and other non-laboratory health workers who traditionally did not perform malaria testing due to the technical and logistic demands of smear microscopy were now able to test for malaria. The use of RDTs has led to substantial increases in testing rates, improved quality of case management, as well as more accurate reporting of malaria cases. Although current RDTs have limitations, they remain one of the most important tools in contemporary malaria control. Further improvements to existing products, such as increased sensitivity for non-falciparum tests, diversification of Plasmodium falciparum antigen targets, along with strengthened health system support for current RDTs will further enhance their utility in malaria control and prevention.

Asymptomatic malarial parasitemia is highly prevalent in Plasmodium falciparum endemic areas and often associated with increased prevalence of mild to moderate anemia. The aim of this study was to assess the prevalence of anemia during asymptomatic malaria parasitemia and its interplay with persistent infection in highly exposed individuals. A household-based longitudinal survey was undertaken in a malaria hyperendemic area in Cameroon using multiplex nested polymerase chain reaction to detect plasmodial infections. Residents with P. falciparum asymptomatic parasitemia were monitored over a 3-week period with the aid of structured questionnaires and weekly measurements of axillary temperatures. Of the 353 individuals included (median age: 26 years, range 2–86 years, male/female sex ratio 0.9), 328 (92.9%) were positive for malaria parasitemia of whom 266 (81.1%) were asymptomatic carriers. The prevalence of anemia in the study population was 38.6%, of which 69.2% were asymptomatic. Multivariate analyses identified high parasitemia (> 327 parasites/µL) and female gender as associated risk factors of asymptomatic malarial anemia in the population. Furthermore, risk analyses revealed female gender and anemia at the time of enrolment as key predictors of early development of febrile illness (< 3 weeks post enrolment) among the asymptomatic individuals. Together, the data reveal an extremely high prevalence of asymptomatic malaria parasitemia and anemia in the study area, unveiling for the first time the association of asymptomatic malarial anemia with early clinical conversion from asymptomatic to symptomatic infection. Furthermore, these findings underscore the negative impact of asymptomatic malaria parasitemia on individual health, necessitating the development of appropriate control and preventive measures.

Background\ud Causes of mortality are a crucial input for health systems for identifying appropriate interventions for child survival. We present an updated series of cause-specific mortality for neonates and children younger than 5 years from 2000 to 2019.\ud Methods\ud We updated cause-specific mortality estimates for neonates and children aged 1-59 months, stratified by level (low, moderate, or high) of mortality. We made a substantial change in the statistical methods used for previous estimates, transitioning to a Bayesian framework that includes a structure to account for unreported causes in verbal autopsy studies. We also used systematic covariate selection in the multinomial framework, gave more weight to nationally representative verbal autopsy studies using a random effects model, and included mortality due to tuberculosis.\ud Findings\ud In 2019, there were 5·30 million deaths (95% uncertainty range 4·92-5·68) among children younger than 5 years, primarily due to preterm birth complications (17·7%, 16·1-19·5), lower respiratory infections (13·9%, 12·0-15·1), intrapartum-related events (11·6%, 10·6-12·5), and diarrhoea (9·1%, 7·9-9·9), with 49·2% (47·3-51·9) due to infectious causes. Vaccine-preventable deaths, such as for lower respiratory infections, meningitis, and measles, constituted 21·7% (20·4-25·6) of under-5 deaths, and many other causes, such as diarrhoea, were preventable with low-cost interventions. Under-5 mortality has declined substantially since 2000, primarily because of a decrease in mortality due to lower respiratory infections, diarrhoea, preterm birth complications, intrapartum-related events, malaria, and measles. There is considerable variation in the extent and trends in cause-specific mortality across regions and for different strata of all-cause under-5 mortality.\ud Interpretation\ud Progress is needed to improve child health and end preventable deaths among children younger than 5 years. Countries should strategize how to reduce mortality among this age group using interventions that are relevant to their specific causes of death.\ud Funding\ud Bill & Melinda Gates Foundation; WHO.

Background: Purulia is a malaria-prone district in West Bengal, India, with approximately half of the jurisdictional blocks defined as malaria endemic. Methods: We examined the malaria incidence in each block of the district of Purulia for the period between January 1, 2016 and December 31, 2020. Per the Annual Parasite Incidence (API), 20 blocks of Purulia district were assigned to four different categories (0-3) and mapped using ArcGIS software version 10.8. An exponential decay model was fitted to forecast the trend of malaria cases for each block of the district for the 2021-2025 timeline. Findings: There was a sharp decrease in total malaria cases and API from 2016 to 2020. Plasmodium vivax (Pv) cases were decreased by 96.43%, Plasmodium falciparum (Pf) by 90.34%, and mixed infection cases by 92.78%. The majority of cases (72.63%) were found in the 15 year and older age group. Males were more prone to malaria (60.09%) than females. Malaria was highly prevalent among Scheduled Tribes (ST) (48.44%). Six blocks were reported in Category 3 (high risk) and none in Category 0 (no risk) in 2016 while no blocks were determined to be in Category 3 and three blocks were in Category 0 in 2020. The exponential decay model prediction is oriented towards gaining malaria-free status in thirteen blocks of the Purulia district by 2025. Interpretation: By efficiently diagnosing malaria, implementing a GIS system to track malaria incidences, fair usage of Long-lasting insecticidal nets (LLINs), and conducting effective awareness campaigns, malaria control could be possible. Nevertheless, consistent funding is needed to avoid reappearance and sustain eradication goals. Funding Information: None. Declaration of Interests: We declare no competing interests. Ethics Approval Statement: This study was permitted by Zilla Swasthya Bhawan, Purulia, Govt. of West Bengal (Memo No. 2041; Dated: 03.11.2020).

Driven by the malaria-protective effect of sickle-cell trait, balancing selection results in hemoglobin S equilibrium allele frequencies of between 15% and 20% in areas of high Plasmodium falciparum transmission in sub-Saharan Africa. From this we estimate that the malaria-attributable childhood mortality in the pretreatment era was between 15% and 24%.

Background Rapid diagnostic tests (RDTs) for malaria are a vital part of global malaria control. Over the past decade, RDT prices have declined, and quality has improved. However, the relationship between price and product quality and their larger implications on the market have yet to be characterized. This analysis used purchase data from the Global Fund together with product quality data from the World Health Organization (WHO) and Foundation for Innovative New Diagnostics (FIND) Malaria RDT Product Testing Programme to understand three unanswered questions: (1) Has the market share by quality of RDTs in the Global Fund’s procurement orders changed over time? (2) What is the relationship between unit price and RDT quality? (3) Has the market for RDTs financed by the Global Fund become more concentrated over time? Methods Data from 10,075 procurement transactions in the Global Fund’s database, which includes year, product, volume, and price, was merged with product quality data from all eight rounds of the WHO-FIND programme, which evaluated 227 unique RDT products. To describe trends in market share by quality level of RDT, descriptive statistics were used to analyse trends in market share from 2009 to 2018. A generalized linear regression model was then applied to characterize the relationship between price and panel detection score (PDS), adjusting for order volume, year purchased, product type, and manufacturer. Third, a Herfindahl–Hirschman Index (HHI) score was calculated to characterize the degree of market concentration. Results Lower-quality RDTs have lost market share between 2009 and 2018, as have the highest-quality RDTs. No statistically significant relationship between price per test and PDS was found when adjusting for order volume, product type, and year of purchase. The HHI was 3,570, indicating a highly concentrated market. Conclusions Advancements in RDT affordability, quality, and access over the past decade risk stagnation if health of the RDT market as a whole is neglected. These results suggest that from 2009 to 2018, this market was highly concentrated and that quality was not a distinguishing feature between RDTs. This information adds to previous reports noting concerns about the long-term sustainability of this market. Further research is needed to understand the causes and implications of these trends.

The skin microbiota plays an essential role in the protection against pathogens. It is our skin microbiota that makes us smell different from each other, rendering us more or less attractive to mosquitoes. Mosquitoes exploit skin bacterial odours to locate their hosts and are vectors of pathogens that can cause severe diseases such as malaria and dengue fever. A novel solution for long-lasting protection against insect vectors of disease could be attained by manipulating the bacterial commensals on human skin. The current options for protection against biting insects usually require topical application of repellents that evaporate within hours. We discuss possible routes for the use of commensal bacteria to create a microbial-based repellent.

Malaria is an infectious disease caused by Plasmodium parasites that are mainly transmitted through the bites of infected female Anopheles mosquitoes. The average annual number of malaria cases was less than ten in Taiwan in the last five years. Most of the cases were caused by Plasmodium vivax and Plasmodium falciparum, and were primarily diagnosed in travelers who returned from Southeast Asia and Africa. Here, we report the first case of Plasmodium ovale infection within five years that was confirmed by peripheral blood smear examination and molecular identification in a 25-year-old Asian female patient who returned from Uganda.

Asymptomatic malaria parasite carriers do not seek anti-malarial treatment and may constitute a silent infectious reservoir. In order to assess the level of asymptomatic and symptomatic carriage amongst adolescents in a highly endemic area, and to identify the risk factors associated with such carriage, we conducted a cross-sectional survey of 1032 adolescents (ages 10–19 years) from eight schools located in Ibadan, southwestern Nigeria in 2016. Blood films and blood spot filter paper samples were prepared for microscopy and DNA analysis. The prevalence of asymptomatic malaria was determined using microscopy, rapid diagnostic tests and PCR for 658 randomly selected samples. Of these, we found that 80% of asymptomatic schoolchildren were positive for malaria parasites by PCR, compared with 47% and 9%, determined by rapid diagnostic tests and microscopy, respectively. Malaria parasite species typing was performed using PCR targeting the mitochondrial CoxIII gene, and revealed high rates of carriage of Plasmodium malariae (53%) and Plasmodium ovale (24%). Most asymptomatic infections were co-infections of two or more species (62%), with Plasmodium falciparum + P. malariae the most common (35%), followed by P. falciparum + P. malariae + P. ovale (21%) and P. falciparum + P. ovale (6%). Single infections of P. falciparum, P. malariae and P. ovale accounted for 24%, 10% and 4% of all asymptomatic infections, respectively. To compare the species composition of asymptomatic and symptomatic infections, further sample collection was carried out in 2017 at one of the previously sampled schools, and at a nearby hospital. Whilst the species composition of the asymptomatic infections was similar to that observed in 2016, the symptomatic infections were markedly different, with single infections of P. falciparum observed in 91% of patients, P. falciparum + P. malariae in 5% and P. falciparum + P. ovale in 4%.

Radiation attenuated sporozoite (RAS), a whole parasite vaccine approach provides sterile protection against malaria. However, RAS immunization does not confer protection for long, and that has been correlated with the waning parasite-induced memory CD8+ T cell responses. Interestingly, an intermittent infectious (wild-type) sporozoite challenge to the RAS vaccinated mice lengthened the protection period from 6 to 18 months. Herein, we have studied the changes that infectious sporozoite brought in RAS-induced memory CD8+ T cells for conferring lengthened protection. We observed that the infectious sporozoite challenge has boosted the frequency of foreign antigen-experienced memory CD8+ T cells. In those CD8+ T cells, it has reduced the Annexin-V reactivity, raised Bcl-2 expression, and also more cells undergone homeostatic proliferation (Ki-67+ ). It has also scaled down the frequency of Nur77 and CX3CR1 high expressing cells in those memory CD8+ T cell populations which we further correlated with better survival signals. This article is protected by copyright. All rights reserved.

Amitav Ghosh novel The Calcutta Chromosome: a Novel of Fevers, Delirium and Discovery is considered, - an outstanding literary work in which the writer reveals a discourse of science versus counter-science from the earlier world of social, cultural and ethnical history of Indian subcontinent. India is home to the oldest continuous civilization, nevertheless, the long invasive rule of the Mughals and the Britishers has framed minds to undervalue the indigenous knowledge, practices, customs and discourses. Amitav Ghosh novel denies the Western supremacy in every field and puts a question mark in the invention of Anopheles maculipennis as the cause of malaria. Dr. Ronald Ross received the prestigious Nobel Prize in 1902 for his discovery of malaria parasite but Ami- tav Ghosh supports the contribution of Indian assistants Mangala and Laakhan who were not acknowledged by the British researchers. The novel reflects a postcolonial approach to interpret Western scientific mechanism, posits the question to unethical exploitation of native workers by the English and gives voice to the traditional knowledge of the subalterns. An integral part of Ghoshs approach in this novel is to illuminate the richness of ideas and complexity of Indigenous life, and to create a place where aboriginals are acknowledged for their remarkable contributions.

Background Pyrethroids are the most widely used insecticides for the control of malaria transmitting Anopheles gambiae mosquitoes and rapid increase in resistance to this insecticide class is of major concern. Pyrethroids target the Voltage Gated Sodium Channels (VGSCs), that have a key role in the normal function of the mosquitoes' nervous system. VGSC mutations L995F and L995S have long been associated with pyrethroid resistance and screening for their presence is routine in insecticide resistance management programs. Recently, a VGSC haplotype containing two amino acid substitutions associated with resistance in other species, V402L and I1527T, was identified. These two VGSC mutations are found in tight linkage and are mutually exclusive to the classical L995F/S mutations. Results We identify the presence of the V402L-I1527 T haplotype in resistant An. coluzzii colonized strains and in field populations from Burkina Faso at frequencies higher than previously reported; in some cases almost reaching fixation. Functional validation of V402L in insecticide resistance using a CRISPR/Cas9 genome modified line showed that it confers reduced mortality after exposure to all tested pyrethroids and DDT, but at lower levels compared to L995F. In contrast however to L995F, no fitness costs were identified for mosquitoes carrying V402L under laboratory conditions. Conclusion The V402L substitution confers pyrethroid resistance in An. gambiae in the absence of any other VGSC substitution and/or alternative resistance mechanisms. The lower fitness cost associated with this kdr mutation may provide a selective advantage over the classical kdr in some settings and genotyping at this locus should be added in the list of resistant alleles for routine screening. This article is protected by copyright. All rights reserved.

Mist Nibima is an essential herbal medicine used to treat malaria, bacterial, yeast, and COVID-19 infections. However, the drug has not been standardized and its active chemical ingredients are also not known. This study employed physicochemical, organoleptic, qualitative, and quantitate phytochemical analysis to established standards for Mist Nibima. Additionally, UHPLC was used to quantify the alkaloid cryptolepine in the drug using calibration curve. The chemical ingredients in Mist Nibima were thereafter characterized using UHPLC-MS. Organoleptic evaluation shows that Mist Nibima is a very bitter, cloudy, broom yellow decoction with the following physicochemical parameters: pH = 6.10 ± 0.08 (at 28.3°C), total solid residue = 5.34 ± 0.27%w/v, and specific gravity = 1.0099 ± 0.0000. The total alkaloid (23.71 ± 1.311%) content of the drug is 3 times its total saponins (7.993 ± 0.067%) content. Methyl cryptolepinoate (37.10%), cryptolepine (33.56%), quindoline (20.78%), 11-isopropylcryptolepine (5.16%), and hydroxycryptolepine (3.14%) were the active chemical ingredients in the drug with the concentrations of 18.64 ± 0.255, 16.85 ± 0.231, 10.42 ± 0.143, 2.56 ± 0.034, and 1.70 ± 0.023 µg/mL, respectively. Administration of a single oral therapeutic dose (30 mL) of Mist Nibima corresponds to ingestion of 559.2 ± 7.662, 505.5 ± 6.930, 312.6 ± 4.285, 76.8 ± 1.028, and 51.0 ± 0.699 µg of methyl cryptolepinoate, cryptolepine, quindoline, 11-isopropylcryptolepine, and hydroxycryptolepine, respectively. This translates into a corresponding daily dose of 1677.6 ± 22.986, 1516.5 ± 20.790, 937.8 ± 12.855, 230.4 ± 3.084, and 153.0 ± 2.097 µg of methyl cryptolepinoate, cryptolepine, quindoline, 11-isopropylcryptolepine, and hydroxycryptolepine. These results could now serve as tools for authentication, standardization, and quality control of Mist Nibima to ensure its chemical and pharmacological consistency and safety.

According to WHO, 2019 witnessed 229 million cases of malaria globally, of which Africa accounted for 94% of cases. Early diagnosis and treatment are the basis of malaria management, and the need for good chemoprophylaxis especially for people travelling to endemic areas is vital. There are a number of drug options available for the prophylaxis of malaria, mefloquine being one of the drugs used. Mefloquine has been around from the 1970s, and was developed in the United States keeping in mind the soldiers that were being deployed to areas where chloroquine resistant strains of Plasmodium were discovered. Mefloquine was preferred for its once a week dosage. Within a decade of its introduction, reports of the side effects associated with its long-term use surfaced. Mefloquine is now reported to cause a myriad of neuropsychiatric side effects including anxiety, sleep disturbance, depression, dizziness and frank psychosis, especially in patients with pre-existing psychiatric disorders. Many countries like the United States and the United Kingdom have updated their drug boxes to include the warning of these potential neuropsychiatric effects. This paper reviews the side effects of mefloquine and why there is a need to revisit its use in Indian drug policy., Graphical abstract Image 1

Malaria is caused by infection with Plasmodium parasites and results in significant health and economic impacts. Malaria eradication is hampered by parasite resistance to current drugs and the lack of a widely effective vaccine. Compounds that target epigenetic regulatory proteins, such as histone deacetylases (HDACs), may lead to new therapeutic agents with a different mechanism of action, thereby avoiding resistance mechanisms to current antimalarial drugs. The anticancer HDAC inhibitor AR-42, as its racemate (rac-AR-42), and 36 analogues were investigated for in vitro activity against P. falciparum. Rac-AR-42 and selected compounds were assessed for cytotoxicity against human cells, histone hyperacetylation, human HDAC1 inhibition and oral activity in a murine malaria model. Rac-AR-42 was tested for ex vivo asexual and in vitro exoerythrocytic stage activity against P. berghei murine malaria parasites. Rac-AR-42 and 13 achiral analogues were potent inhibitors of asexual intraerythrocytic stage P. falciparum 3D7 growth in vitro (IC50 5–50 nM), with four of these compounds having >50-fold selectivity for P. falciparum versus human cells (selectivity index 56–118). Rac-AR-42 induced in situ hyperacetylation of P. falciparum histone H4, consistent with PfHDAC(s) inhibition. Furthermore, rac-AR-42 potently inhibited P. berghei infected erythrocyte growth ex vivo (IC50 40 nM) and P. berghei exoerythrocytic forms in hepatocytes (IC50 1 nM). Oral administration of rac-AR-42 and two achiral analogues inhibited P. berghei growth in mice, with rac-AR-42 (50 mg/kg/day single dose for four days) curing all infections. These findings demonstrate curative properties for HDAC inhibitors in the oral treatment of experimental mouse malaria., Graphical abstract Image 1, Highlights • HDAC inhibitors rac-AR-42 and 13 analogues inhibit P. falciparum growth in vitro. • Rac-AR-42 inhibits P. berghei exoerythrocytic forms in hepatocytes (IC50 1 nM). • Rac-AR-42 causes in situ hyperacetylation of P. falciparum histone H4. • Rac-AR-42 cures P. berghei infected mice with oral dosing.

Background Antenatal care and skilled childbirth services are important interventions to improve maternal health and lower the risk of poor pregnancy outcomes and mortality. A growing body of literature has shown that geographic distance to clinics can be a disincentive towards seeking care during pregnancy. On the Thailand-Myanmar border antenatal clinics serving migrant populations have found high rates of loss to follow-up of 17.4%, but decades of civil conflict have made the underlying factors difficult to investigate. Here we perform a comprehensive study examining the geographic, demographic, and health-related factors contributing to loss to follow-up. Methods Using patient records we conducted a spatial and epidemiological analysis looking for predictors of loss to follow-up and pregnancy outcomes between 2007 and 2015. We used multivariable negative binomial regressions to assess for associations between distance travelled to the clinic and birth outcomes (loss to follow-up, pregnancy complications, and time of first presentation for antenatal care.) Results We found distance travelled to clinic strongly predicts loss to follow-up, miscarriage, malaria infections in pregnancy, and presentation for antenatal care after the first trimester. People lost to follow-up travelled 50% farther than people who had a normal singleton childbirth (a ratio of distances (DR) 1.5; 95% confidence interval (CI): 1.4 – 1.5). People with pregnancies complicated by miscarriage travelled 20% farther than those who did not have miscarriages (DR: 1.2; CI 1.1–1.3), and those with Plasmodium falciparum malaria in pregnancy travelled 60% farther than those without P. falciparum (DR: 1.6; CI: 1.6 – 1.8). People who delayed antenatal care until the third trimester travelled 50% farther compared to people who attended in the first trimester (DR: 1.5; CI: 1.4 – 1.5). Conclusions This analysis provides the first evidence of the complex impact of geography on access to antenatal services and pregnancy outcomes in the rural, remote, and politically complex Thailand-Myanmar border region. These findings can be used to help guide evidence-based interventions to increase uptake of maternal healthcare both in the Thailand-Myanmar region and in other rural, remote, and politically complicated environments.

This study investigated the effect of malaria parasitaemia on Plasmodium falciparum infected human erythrocytes oxidative stress biomarkers and haemoglobin levels. Seventy (70) human subjects of fifty (50) P. falciparum positive and twenty (20) control subjects between the ages of 10-60 years were selected for this study. Rapid Diagnostic Test (RDT) and microscopy were used to identify P. falciparum. The samples were matched based on age, sex and level of parasitaemia. Samples of blood were collected for the determination of P. falciparum, level of parasitaemia, anti-oxidant assay and haemoglobin levels; to assess the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), malondialdehyde (MDA), total protein (PRO), reduced glutathione (GSH), haemoglobin and Parasite density. Haemoglobin level was determined using a Coulter A-T Pierce haematology analyzer (Beckman Coulter, Inc. Fullerton, CA, USA). This study showed that the mean level of PRO, CAT, MDA and SOD was significantly higher among the P. falciparum positive patients to those in the control while GPx level was lower, also, the mean level of HGB was significantly lower in the P. falciparum positive patients to those in the control. MDA, SOD, GSH and PRO level were higher among age group (10-20) in the P. falciparum infected patients and lower in the control subjects when compared to other age groups. MDA, SOD and PRO level were higher in the males than the females in both the malaria positive and controls. This study indicates that high parasitaemic patients are at greater risk of anaemia and oxidative stress compared to low parasitaemic ones.

Background In Uganda, artemether-lumefantrine (AL) is first-line therapy and dihydroartemisinin-piperaquine (DP) second-line therapy for the treatment of uncomplicated malaria. This study evaluated the efficacy and safety of AL and DP in the management of uncomplicated falciparum malaria and measured the prevalence of molecular markers of resistance in three sentinel sites in Uganda from 2018 to 2019. Methods This was a randomized, open-label, phase IV clinical trial. Children aged 6 months to 10 years with uncomplicated falciparum malaria were randomly assigned to treatment with AL or DP and followed for 28 and 42 days, respectively. Genotyping was used to distinguish recrudescence from new infection, and a Bayesian algorithm was used to assign each treatment failure a posterior probability of recrudescence. For monitoring resistance, Pfk13 and Pfmdr1 genes were Sanger sequenced and plasmepsin-2 copy number was assessed by qPCR. Results There were no early treatment failures. The uncorrected 28-day cumulative efficacy of AL ranged from 41.2 to 71.2% and the PCR-corrected cumulative 28-day efficacy of AL ranged from 87.2 to 94.4%. The uncorrected 28-day cumulative efficacy of DP ranged from 95.8 to 97.9% and the PCR-corrected cumulative 28-day efficacy of DP ranged from 98.9 to 100%. The uncorrected 42-day efficacy of DP ranged from 73.5 to 87.4% and the PCR-corrected 42-day efficacy of DP ranged from 92.1 to 97.5%. There were no reported serious adverse events associated with any of the regimens. No resistance-associated mutations in the Pfk13 gene were found in the successfully sequenced samples. In the AL arm, the NFD haplotype (N86Y, Y184F, D1246Y) was the predominant Pfmdr1 haplotype, present in 78 of 127 (61%) and 76 of 110 (69%) of the day 0 and day of failure samples, respectively. All the day 0 samples in the DP arm had one copy of the plasmepsin-2 gene. Conclusions DP remains highly effective and safe for the treatment of uncomplicated malaria in Uganda. Recurrent infections with AL were common. In Busia and Arua, the 95% confidence interval for PCR-corrected AL efficacy fell below 90%. Further efficacy monitoring for AL, including pharmacokinetic studies, is recommended. Trial registration The trail was also registered with the ISRCTN registry with study Trial No. PACTR201811640750761

Human malaria continues to be a public health problem and an important cause of morbidity and mortality in the world. Malaria control is achieved through both individual protection against mosquito bites and drug treatment, which is hampered by the spread of Plasmodium falciparum resistance to most antimalarials, including artemisinin derivatives. One of the key pharmacological strategies for controlling malaria is to block transmission of the parasites to their mosquito vectors. Following this rational, MEFAS, a synthetic hybrid salt derived from artesunate (AS) and mefloquine has been previously reported for its activity against asexual P. falciparum parasites in vitro, in addition to a pronounced reduction in the viability of mature gametocytes. Herein, MEFAS was tested against asexual forms of Plasmodium vivax and for its ability to block malaria transmission in Anopheles darlingi mosquitoes in a membrane feeding assay using P. vivax field isolates. MEFAS demonstrated high potency, with a IC50 of 6.5 nM against asexual forms of P. vivax. At 50 μM, MEFAS completely blocked oocyst formation in mosquitoes, regardless of the oocyst number in the control group. At lower doses, MEFAS reduced oocyst prevalence by greater than 20%. At equivalent doses, AS irregularly reduced oocyst formation and caused only slight inhibition of mosquito infections. These results highlight the potential of MEFAS as a novel transmission-blocking molecule, as well as its high blood schizonticidal activity against P. vivax and P. falciparum field isolates, representing a starting point for further development of a new drug with dual antimalarial activity., Graphical abstract Image 1

Background Plasmodium falciparum gametocytaemia has been associated with anaemia. The aim of this review was to synthesize available evidence on the comparative effect of dihydroartemisinin-piperaquine (DHA-PQ) and artemether-lumefantrine (AL) on gametocyte clearance and haemoglobin recovery in children with uncomplicated P. falciparum malaria in Africa. Methods A systematic literature search was undertaken to identify relevant articles from online databases. The search was performed from August 2020 to 30 April 2021. Extracted data from eligible studies were pooled as risk ratios with 95% confidence intervals (CI). Results Gametocyte carriage was reduced in both treatment groups, with no significant difference found between the groups. However, on days 28 and 42, a significant increase in serum haemoglobin level from baseline was observed in the DHA-PQ group (standardized mean difference 0.15, 95% CI 0.05–0.26; participants=2715; studies=4; I2=32%, high quality of evidence) compared with the AL group (mean difference 0.35, 95% CI 0.12–0.59; participants=1434; studies=3; I2=35%, high quality of evidence). Conclusion DHA-PQ had a greater impact on haemoglobin recovery than AL on days 28 and 42; this difference was significant.

Malaria control and elimination require prompt diagnosis and accurate treatment. Conventional methods such as rapid diagnostic tests (RDTs) and microscopy lack the characteristics to detect low parasitemias, commonly found in asymptomatic parasitemias and/or submicroscopic malaria carriers. On the contrary, molecular methods have higher sensitivity and specificity. This study evaluated the performance of two commercial real-time polymerase chain reaction (PCR) assays, RealStar® Malaria PCR (RealStar-genus) and RealStar Malaria Screen&Type PCR (RealStar-species), compared with the reference Nested Multiplex Malaria PCR, for the detection of the main five Plasmodium species affecting humans. A total of 121 samples were evaluated. Values of sensitivity (98.9% and 97.8%) and specificity (100% and 96.7%) of the RealStar-genus and the RealStar-species assays, respectively, were very good. The limit of detection (LoD) for the RealStar-genus assay showed a mean value of 0.28 parasites/µL with Plasmodium falciparum samples; while, the LoD of the RealStar-species assay ranged from 0.09 parasites/µL for P. vivax to two parasites/µL for P. ovale. The time to complete a diagnosis was established in 4 hours. Our findings showed a very good concordance of both assays compared with the reference method, with a very good analytical sensitivity. RealStar-species assay was able to correctly characterize double and triple infections. Therefore, these RealStar assays have shown to be useful tools in malaria diagnosis in non-endemic countries and even endemic countries, and for malaria control in general, detecting low parasitemias with sensitivity similar to the most sensitive methods as nested PCR, but with lower time to get the results. This work was funded by projects PI14CIII/00014 and PI17CIII/00035 from the Instituto de Salud Carlos III (Ministry of Science and Innovation) and cofounded by the European Regional Development Fund. Altona Diagnostics also partially funded this study by donating the kits and funding the necessary consumables. Alexandra Martin Ramirez is supported by an ISCIII Rio Hortega contract. Sí

Summary It is the beginning of a new decade, where COVID-19 and the ‘big three’ (HIV/AID, malaria and tuberculosis) have raised public awareness of the type of challenges researchers face every day. Beyond these diseases, there are also still many more for which scientists are working to develop new therapies and their impact in healthcare is enormous too. This industry update covers the period 1–31 August 2021, and some examples of research and approvals for many other diseases excluding COVID-19 and the ‘big three’ are presented. There is a progressive trend of approvals of novel drug candidates and the proposal of new indications for the existing ones. Some patents related to rare diseases were also published during this month. Information and analyses were sourced from scientific literature, regulatory and patent agencies, websites and press releases of the companies (and not based upon personal opinion). The main reason of leaving COVID-19 research outside the scope of this update is mainly due to the rapid growth and change in this field; some preliminary results require further research and scientists must be aware of the final impact that this research could have on public opinion. Moreover, as a result of disruptions to health care in the face of COVID-19, several research groups simply stopped their research in other diseases and, for that reason, it is imperative to sum up some important advances in other critical diseases and health areas.

Emerging artemisinin resistance in Plasmodium falciparum malaria has the potential to become a global public health crisis. In Southeast Asia, this phenomenon clinically manifests in the form of delayed parasite clearance following artemisinin treatment. Reduced artemisinin susceptibility is limited to the early ring stage window, which is sufficient to allow parasites to survive the short half-life of artemisinin exposure. A screen of known clinically-implemented antimalarial drugs was performed to identify a drug capable of enhancing the killing activity of artemisinins during this critical resistance window. As a result, lumefantrine was found to increase the killing activity of artemisinin against an artemisinin-resistant clinical isolate harboring the C580Y kelch13 mutation. Isobologram analysis revealed synergism during the early ring stage resistance window, when lumefantrine was combined with artemether, an artemisinin derivative clinically partnered with lumefantrine. These findings suggest that lumefantrine should be clinically explored as a partner drug in artemisinin-based combination therapies to control emerging artemisinin resistance., Graphical abstract Image 1, Highlights • Artemisinin booster compound screening targeting the early ring resistance window in Plasmodium falciparum was performed. • Lumefantrine improves the activity of artesunate against the parasite during the resistance window. • Artemether and lumefantrine are synergistic during the early ring stage resistance window.