{ "items": [ "\n\n
Abstract\n\nBackground\nUncertainty over the therapeutic benefit of parenteral remdesivir in coronavirus disease 2019 (COVID-19) has resulted in varying treatment guidelines.\n\n\nMethods\nIn a multicenter open-label, controlled, adaptive, pharmacometric platform trial, low-risk adult patients with early symptomatic COVID-19 were randomized to 1 of 8 treatment arms including intravenous remdesivir (200 mg followed by 100 mg daily for 5 days) or no study drug. The primary outcome was the rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance (estimated under a linear model fit to the daily log10 viral densities, days 0\u20137) in standardized duplicate oropharyngeal swab eluates, in a modified intention-to-treat population. This ongoing adaptive trial is registered at ClinicalTrials.gov (NCT05041907).\n\n\nResults\nThe 2 study arms enrolled 131 patients (remdesivir n = 67, no study drug n = 64) and estimated viral clearance rates from a median of 18 swab samples per patient (a total of 2356 quantitative polymerase chain reactions). Under the linear model, compared with the contemporaneous control arm (no study drug), remdesivir accelerated mean estimated viral clearance by 42% (95% credible interval, 18%\u201373%).\n\n\nConclusions\nParenteral remdesivir accelerates viral clearance in early symptomatic COVID-19. Pharmacometric assessment of therapeutics using the method described can determine in vivo clinical antiviral efficacy rapidly and efficiently.\n
\n \n\n \n \nBackground Glucose-6-phosphate dehydrogenase (G6PD) deficiency represents a barrier to the full deployment of anti-malarial drugs for vivax malaria elimination and of first-line antibiotics. Lack of established reference ranges for G6PD activity in breast-fed infants puts them at risk of drug-induced haemolysis and restricts access to safe treatment of their mothers. Methods The present work was undertaken to establish age-specific G6PD normal values using the gold standard spectrophotometric assay to support the future clinical use of tafenoquine in lactating women and safer antibiotic treatment in infants. Results Spectrophotometric results collected at the Thai-Myanmar border from 78 healthy infants between the ages of 2 and 6 months showed a trend of decreased enzymatic activity with increasing age (which did not reach statistical significance when comparing 2\u20133 months old against 4\u20136 months old infants) and provided a reference normal value of 100% activity for infants 2\u20136 months old of 10.18IU/gHb. Conclusions Normal reference G6PD activity in 2\u20136-month-old infants was approximately 140% of that observed in G6PD normal adults from the same population. Age specific G6PD activity thresholds should be used in paediatric populations to avoid drug-induced haemolysis.
\n \n\n \n \nThe pathophysiology of severe falciparum malaria involves a complex interaction between the host, parasite, and gut microbes. In this review, we focus on understanding parasite-induced intestinal injury and changes in the human intestinal microbiota composition in patients with Plasmodium falciparum malaria. During the blood stage of P. falciparum infection, infected red blood cells adhere to the vascular endothelium, leading to widespread microcirculatory obstruction in critical tissues, including the splanchnic vasculature. This process may cause intestinal injury and gut leakage. Epidemiological studies indicate higher rates of concurrent bacteraemia in severe malaria cases. Furthermore, severe malaria patients exhibit alterations in the composition and diversity of the intestinal microbiota, although the exact contribution to pathophysiology remains unclear. Mouse studies have demonstrated that the gut microbiota composition can impact susceptibility to Plasmodium infections. In patients with severe malaria, the microbiota shows an enrichment of pathobionts, including pathogens that are known to cause concomitant bloodstream infections. Microbial metabolites have also been detected in the plasma of severe malaria patients, potentially contributing to metabolic acidosis and other clinical complications. However, establishing causal relationships requires intervention studies targeting the gut microbiota.
\n \n\n \n \nEarly detection could increase the treatment efficiency and prevent the recurrence of malaria disease. To track and detect malarial sporozoites, novel drug delivery systems have been explored for their ability to target these parasites specifically. This study investigates the potential of micelles to track Plasmodium vivax by targeting the Plasmodium vivax hexose transporter using glucose-based interactions. In vitro experiments were conducted using glucose/SPIO/Nile red (targeted) micelles and methoxy/SPIO/Nile red (nontargeted) micelles, revealing that the targeted micelles exhibited stronger fluorescence with the sporozoites and higher relative R2* values compared to the nontargeted micelles. These findings suggest that targeted micelles could be used for the specific detection of Plasmodium sporozoites using fluorescence imaging and MRI techniques, offering a promising approach for efficient malaria parasite detection.
\n \n\n \n \nMalaria is a tropical disease caused by parasites in the genus Plasmodium, which still presents 241 million cases and nearly 627,000 deaths recently. In this work, we used the dielectrophoresis (DEP) to characterize red blood cells in a microchannel. The purpose of this work is to determine the difference between the normal and the malaria-infected cells based on the DEP characteristics. The samples were infected cells and normal red blood cells, which were either prepared in culture or obtained from volunteers. Diamond-shaped and curved micropillars were used to create different degrees of DEP in the gap between them. The DEP crossover frequencies were observed with the diamond-shaped micropillars. The cell velocity under negative dielectrophoresis (nDEP) at a low frequency was examined with the curved micropillars. The measured lower crossover frequencies were remarkably different between the malaria-infected cells and the normal cells, whereas the higher crossover frequencies were similar among the samples. The velocity under nDEP was lower for the infected cells than the normal cells. The results imply that the malaria infection significantly decreases the capacitance but increases the conductance of the cell membrane, whereas a change in cytoplasmic conductivity may occur in a later stage of infection.
\n \n\n \n \nBackgroundEndothelial cells (ECs) play a major role in malaria pathogenesis, as a point of direct contact of parasitized red blood cells to the blood vessel wall. The study of cytoskeleton structures of ECs, whose main functions are to maintain shape and provide strength to the EC membrane is important in determining the severe sequelae of Plasmodium falciparum malaria. The work investigated the cytoskeletal changes (microfilaments-actin, microtubules-tubulin and intermediate filaments-vimentin) in ECs induced by malaria sera (Plasmodium vivax, uncomplicated P. falciparum and complicated P. falciparum), in relation to the levels of pro-inflammatory cytokines.MethodsMorphology and fluorescence intensity of EC cytoskeleton stimulated with malaria sera were evaluated using immunofluorescence technique. Levels of tumour necrosis factor (TNF) and interferon (IFN)-gamma (\u03b3) were determined using enzyme-linked immunosorbent assay (ELISA). Control experimental groups included ECs incubated with media alone and non-malaria patient sera. Experimental groups consisted of ECs incubated with malaria sera from P. vivax, uncomplicated P. falciparum and complicated P. falciparum. Morphological scores of cytoskeletal alterations and fluorescence intensity were compared across each experiment group, and correlated with TNF and IFN-\u03b3.ResultsThe four morphological changes of cytoskeleton included (1) shrinkage of cytoskeleton and ECs with cortical condensation, (2) appearance of eccentric nuclei, (3) presence of \"spiking pattern\" of cytoskeleton and EC membrane, and (4) fragmentation and discontinuity of cytoskeleton and ECs. Significant damages were noted in actin filaments compared to tubulin and vimentin filaments in ECs stimulated with sera from complicated P. falciparum malaria. Morphological damages to cytoskeleton was positively correlated with fluorescence intensity and the levels of TNF and IFN-\u03b3.ConclusionsECs stimulated with sera from complicated P. falciparum malaria showed cytoskeletal alterations and increased in fluorescence intensity, which was associated with high levels of TNF and IFN-\u03b3. Cytoskeletal changes of ECs incubated with complicated P. falciparum malaria sera can lead to EC junctional alteration and permeability changes, which is mediated through apoptotic pathway. The findings can serve as a basis to explore measures to strengthen EC cytoskeleton and alleviate severe malaria complications such as pulmonary oedema and cerebral malaria. In addition, immunofluorescence intensity of cytoskeleton could be investigated as potential prognostic indicator for malaria severity.
\n \n\n \n \nBackgroundMalaria continues to pose a significant health threat. Rapid identification of malaria infections and the deployment of active surveillance tools are crucial for achieving malaria elimination in regions where malaria is endemic, such as certain areas of Thailand. In this study, an anomaly detection system is introduced as an early warning mechanism for potential malaria outbreaks in countries like Thailand.MethodsUnsupervised clustering-based, and time series-based anomaly detection algorithms are developed and compared to identify abnormal malaria activity in Thailand. Additionally, a user interface tailored for anomaly detection is designed, enabling the Thai malaria surveillance team to utilize these algorithms and visualize regions exhibiting unusual malaria patterns.ResultsNine distinct anomaly detection algorithms we developed. Their efficacy in pinpointing verified outbreaks was assessed using malaria case data from Thailand spanning 2012 to 2022. The historical average threshold-based anomaly detection method triggered three times fewer alerts, while correctly identifying the same number of verified outbreaks when compared to the current method used in Thailand. A limitation of this analysis is the small number of verified outbreaks; further consultation with the Division of Vector Borne Disease could help identify more verified outbreaks. The developed dashboard, designed specifically for anomaly detection, allows disease surveillance professionals to easily identify and visualize unusual malaria activity at a provincial level across Thailand.ConclusionAn enhanced early warning system is proposed to bolster malaria elimination efforts for countries with a similar malaria profile to Thailand. The developed anomaly detection algorithms, after thorough comparison, have been optimized for integration with the current malaria surveillance infrastructure. An anomaly detection dashboard for Thailand is built and supports early detection of abnormal malaria activity. In summary, the proposed early warning system enhances the identification process for provinces at risk of outbreaks and offers easy integration with Thailand's established malaria surveillance framework.
\n \n\n \n \nImportanceBreast cancer (BC) is the leading cancer among women in Namibia. Examining the BC journey in this multiracial country where inequalities remain large is needed to inform effective interventions to reduce BC mortality.ObjectiveTo describe the entire BC journey of Namibian women by race, utilizing the World Health Organization Global Breast Cancer Initiative (GBCI) framework.Design, setting, and participantsThis cohort study used the Namibian subset of the African Breast Cancer-Disparities in Outcomes prospective cohort. Participants were all Namibian residents with confirmed incident BC who presented at the main national public oncology center of the Windhoek Central Hospital (WCH). Follow-up started from recruitment (September 8, 2014, to October 5, 2016) and ended up to 3 years after diagnosis (December 13, 2014, to September 27, 2019). Data analysis was conducted from June 2022 to August 2023.ExposuresParticipants' self-reported ethnicities were aggregated into 3 population groups: Black, mixed ancestry, and White.Main outcomes and measuresThree-year overall survival (OS) was examined using Cox models, and summary statistics were used to describe women's BC journey, including GBCI pillar key performance indicators: (1) early stage (TNM I or II) diagnosis (population benchmark \u226560%), (2) prompt diagnosis, ie, 60 days or less to first health care practitioner visit (population benchmark 100%), and (3) completion of recommended multimodal treatment (MT, ie, surgery plus chemotherapy) (population benchmark \u226580%).ResultsOf 405 women, there were 300 (74%) Black (mean [SD] age, 53 [15] years), 49 (12%) mixed ancestry (mean [SD] age, 53 [7] years), and 56 (14%) White (mean [SD] age, 59 [12] years) patients. Three-year OS was lowest in Black women (60% [95% CI, 54%-66%]; mixed ancestry: 80% [95% CI, 65%-89%]; White: 89% [95% CI, 77%-95%]), who had lower prevalence of early stage diagnosis (Black: 37% [95% CI, 31%-42%]; mixed ancestry and White: 75% [95% CI, 66%-83%]) and timely diagnosis (Black: 60% [95% CI, 54%-66%]; mixed ancestry and White: 77% [95% CI, 69%-85%]), while MT completion (Black: 53% [95% CI, 46%-59%]; mixed ancestry and White: 63% [95% CI, 50%-73%]) was low in all women.Conclusions and relevanceIn this cohort study of 405 Namibian residents with BC, marked racial disparities in survival were paralleled by inequities all along the BC journey. To improve BC survival, interventions are needed to promote earlier diagnosis in Black Namibian women and to increase MT initiation and completion in all women.
\n \n\n \n \nBackgroundThe geographical, demographic, and socioeconomic distributions of malaria and malnutrition largely overlap. It remains unknown whether malnutrition affects the efficacy of WHO-recommended artemisinin-based combination therapies (ACTs). A previous systematic review was inconclusive as data were sparse and heterogeneous, indicating that other methodological approaches, such as individual patient data meta-analysis, should be considered. The objective of this study was to conduct such a meta-analysis to assess the effect of malnutrition (wasting and stunting) on treatment outcomes in children younger than 5 years treated with an ACT for uncomplicated falciparum malaria.MethodsWe conducted a meta-analysis of individual patient data from studies identified through a systematic review of literature published between 1980 and 2018 in PubMed, Global Health, and Cochrane Libraries (PROSPERO CRD42017056934) and inspection of the WorldWide Antimalarial Resistance Network (WWARN) repository for ACT efficacy studies, including children younger than 5 years with uncomplicated falciparum malaria. The association of either acute (wasting) or chronic (stunting) malnutrition with day 42 PCR-adjusted risk of recrudescence (ie, return of the same infection) or reinfection after therapy was investigated using Cox regression, and with day 2 parasite positivity using logistic regression.FindingsData were included from all 36 studies targeted, 31 from Africa. Of 11\u2008301 eligible children in 75 study sites, 11\u00b75% were wasted (weight-for-height Z score [WHZ] InterpretationChildren younger than 5 years with acute malnutrition and presenting with uncomplicated falciparum malaria were at higher risk of delayed parasite clearance, ACT treatment failure, and reinfections. Stunting was more prevalent, but not associated with changes in ACT efficacy. Acute malnutrition is known to impact medicine absorption and metabolism. Further study to inform dose optimisation of ACTs in wasted children is urgently needed.FundingBill & Melinda Gates Foundation.TranslationFor the French translation of the abstract see Supplementary Materials section.
\n \n\n \n \nThe Central African Republic (CAR) has experienced repeated mpox outbreaks since 2001. Although several mpox epidemiological risk factors for zoonotic and interhuman transmission have been documented, the reasons for more frequent epidemic outbreaks are less well understood, relying on vague explanatory categories, including deforestation, hunting, and civil unrest. To gain insight into increasingly frequent outbreaks, we undertook an ethnohistorical, eco-anthropological analysis in two CAR regions: the Lobaye prefecture, experiencing one or more annual outbreaks in the past decade, and the Sangha-Mbaere prefecture, with a longer history of mpox but less frequent outbreaks. We comparatively examined changing political economies, forest use practices, and understandings of mpox. In 2022, we conducted 40 qualitative ethnohistorical, anthropological interviews and participant-observation of forest activities in two languages (Sango and French). We compared contemporary practices with hunting, trapping, and meet consumption practices, documented through quantitative and qualitative observation in one research site, over 6 months in 1993. We find increased rodent capture and consumption in both sites in the past 30 years and expanded practices of other potentially risky activities. Simultaneously, we also identify important differences in risky practices between our Lobaye and Sangha-Mbaere participants. In addition, Lobaye and Sangha participants underscored historical processes of decline producing mpox among other emergences, but they framed these declension processes diversely as economic, political, nutritional, and moral. Our findings are important because they mobilize new types of evidence to shed light on the processual dynamics of mpox outbreaks in the CAR. This study also reveals variability across two sites within the same country, highlighting the importance of comparative, fine-grained anthropological and historical research to identify underlying dynamics of mpox outbreaks. Finally, our study points to the need for mpox interventions and risk communication accounting for these regional differences, even within a single country.
\n \n\n \n \nImportanceObligate intracellular bacteria, or those only capable of growth inside other living cells, have limited opportunities for horizontal gene transfer with other microbes due to their isolated replicative niche. The human pathogen Ot, an obligate intracellular bacterium causing scrub typhus, encodes an unusually high copy number of a ~40 gene mobile genetic element that typically facilitates genetic transfer across microbes. This proliferated element is heavily degraded in Ot and previously assumed to be inactive. Here, we conducted a detailed analysis of this element in eight Ot strains and discovered two strains with at least one intact copy. This implies that the element is still capable of moving across Ot populations and suggests that the genome of this bacterium may be even more dynamic than previously appreciated. Our work raises questions about intracellular microbial evolution and sounds an alarm for gene-based efforts focused on diagnosing and combatting scrub typhus.
\n \n\n \n \nAbstract\nBackground\nDiagnosis of tuberculous meningitis (TBM) is hampered by the lack of a gold standard. Current microbiological tests lack sensitivity and clinical diagnostic approaches are subjective. We therefore built a diagnostic model that can be used before microbiological test results are known.\n\nMethods\nWe included 659 individuals aged $$\\ge 16$$\n\n\u2265\n16\n\n years with suspected brain infections from a prospective observational study conducted in Vietnam. We fitted a logistic regression diagnostic model for TBM status, with unknown values estimated via a latent class model on three mycobacterial tests: Ziehl\u2013Neelsen smear, Mycobacterial culture, and GeneXpert. We additionally re-evaluated mycobacterial test performance, estimated individual mycobacillary burden, and quantified the reduction in TBM risk after confirmatory tests were negative. We also fitted a simplified model and developed a scoring table for early screening. All models were compared and validated internally.\n\nResults\nParticipants with HIV, miliary TB, long symptom duration, and high cerebrospinal fluid (CSF) lymphocyte count were more likely to have TBM. HIV and higher CSF protein were associated with higher mycobacillary burden. In the simplified model, HIV infection, clinical symptoms with long duration, and clinical or radiological evidence of extra-neural TB were associated with TBM At the cutpoints based on Youden\u2019s Index, the sensitivity and specificity in diagnosing TBM for our full and simplified models were 86.0% and 79.0%, and 88.0% and 75.0% respectively.\n\nConclusion\nOur diagnostic model shows reliable performance and can be developed as a decision assistant for clinicians to detect patients at high risk of TBM.\n\nSummary\nDiagnosis of tuberculous meningitis is hampered by the lack of gold standard. We developed a diagnostic model using latent class analysis, combining confirmatory test results and risk factors. Models were accurate, well-calibrated, and can support both clinical practice and research.\n
\n \n\n \n \nIntroductionCauses of deaths often go unrecorded in lower income countries, yet this information is critical. Verbal autopsy is a questionnaire interview with a family member or caregiver to elicit the symptoms and circumstances preceding a death and assign a probable cause. The social and cultural aspects of verbal autopsy have gotten less attention than the technical aspects and have not been widely explored in South and Southeast Asia settings.MethodsBetween October 2021 and March 2023, prior to implementing a verbal autopsy study at rural sites in Bangladesh, Cambodia, Laos, Myanmar and Thailand, focus group discussions were conducted with village heads, religious leaders and community members from varied demographic backgrounds. Thematic analysis elucidated customs and traditional views surrounding death to understand local ethnocultural sensitivities.ResultsWe found that death rituals varied greatly among religions, ethnicities and by socioeconomic status. Mourning periods were reported to last 3-100\u2009days and related to the cause of death, age and how close the deceased person was to the family. Participants advised that interviews should happen after mourning periods to avoid emotional distress, but not long after so as to avoid recall bias. Interviewers should be introduced to respondents by a trusted local person. To provide reassurance and confidentiality, a family's residence is the preferred interview location. Interview questions require careful local language translation, and community sensitisation is important before data collection.ConclusionVerbal autopsy is acceptable across a wide range of cultural settings in Southeast Asia, provided that local norms are preidentified and followed.
\n \n\n \n \nBackgroundThe long co-evolution of Homo sapiens and Plasmodium falciparum has resulted in the selection of numerous human genetic variants that confer an advantage against severe malaria and death. One such variant is the Dantu blood group antigen, which is associated with 74% protection against severe and complicated P. falciparum malaria infections in homozygous individuals, similar to that provided by the sickle haemoglobin allele (HbS). Recent in vitro studies suggest that Dantu exerts this protection by increasing the surface tension of red blood cells, thereby impeding the ability of P. falciparum merozoites to invade them and reducing parasite multiplication. However, no studies have yet explored this hypothesis in vivo.MethodsWe investigated the effect of Dantu on early phase P. falciparum (Pf) infections in a controlled human malaria infection (CHMI) study. 141 sickle-negative Kenyan adults were inoculated with 3.2 \u00d7 103 aseptic, purified, cryopreserved Pf sporozoites (PfSPZ Challenge) then monitored for blood-stage parasitaemia for 21 days by quantitative polymerase chain reaction (qPCR)analysis of the 18S ribosomal RNA P. falciparum gene. The primary endpoint was blood-stage P. falciparum parasitaemia of \u2265500/\u03bcl while the secondary endpoint was the receipt of antimalarial treatment in the presence of parasitaemia of any density. On study completion, all participants were genotyped both for Dantu and for four other polymorphisms that are associated with protection against severe falciparum malaria: \u03b1+-thalassaemia, blood group O, G6PD deficiency, and the rs4951074 allele in the red cell calcium transporter ATP2B4.ResultsThe primary endpoint was reached in 25/111 (22.5%) non-Dantu subjects in comparison to 0/27 (0%) Dantu heterozygotes and 0/3 (0.0%) Dantu homozygotes (p=0.01). Similarly, 49/111 (44.1%) non-Dantu subjects reached the secondary endpoint in comparison to only 7/27 (25.9%) and 0/3 (0.0%) Dantu heterozygotes and homozygotes, respectively (p=0.021). No significant impacts on either outcome were seen for any of the other genetic variants under study.ConclusionsThis study reveals, for the first time, that the Dantu blood group is associated with high-level protection against early, non-clinical, P. falciparum malaria infections in vivo. Learning more about the mechanisms involved could potentially lead to new approaches to the prevention or treatment of the disease. Our study illustrates the power of CHMI with PfSPZ Challenge for directly testing the protective impact of genotypes previously identified using other methods.FundingThe Kenya CHMI study was supported by an award from Wellcome (grant number 107499). SK was supported by a Training Fellowship (216444/Z/19/Z), TNW by a Senior Research Fellowship (202800/Z/16/Z), JCR by an Investigator Award (220266/Z/20/Z), and core support to the KEMRI-Wellcome Trust Research Programme in Kilifi, Kenya (203077), all from Wellcome. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. For the purpose of Open Access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.Clinical trial numberNCT02739763.
\n \n\n \n \n