Pre-existing cross-reactive immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins in infection-naive subjects have been described by several studies. In particular, regions of high homology between SARS-CoV-2 and common cold coronaviruses have been highlighted as a likely source of this cross-reactivity. However, the role of such cross-reactive responses in the outcome of SARS-CoV-2 infection and vaccination is currently unclear. Here, we review evidence regarding the impact of pre-existing humoral and T cell immune responses to outcomes of SARS-CoV-2 infection and vaccination. Furthermore, we discuss the importance of conserved coronavirus epitopes for the rational design of pan-coronavirus vaccines and consider cross-reactivity of immune responses to ancestral SARS-CoV-2 and SARS-CoV-2 variants, as well as their impact on COVID-19 vaccination.
\n \n\n \n \nWe developed surveillance guidance for COVID-19 in 9 temporary camps for displaced persons along the Thailand-Myanmar border. Arrangements were made for testing of persons presenting with acute respiratory infection, influenza-like illness, or who met the Thailand national COVID-19 Person Under Investigation case definition. In addition, testing was performed for persons who had traveled outside of the camps in outbreak-affected areas or who departed Thailand as resettling refugees. During the first 18 months of surveillance, May 2020-October 2021, a total of 6,190 specimens were tested, and 15 outbreaks (i.e., >1 confirmed COVID-19 cases) were detected in 7 camps. Of those, 5 outbreaks were limited to a single case. Outbreaks during the Delta variant surge were particularly challenging to control. Adapting and implementing COVID-19 surveillance measures in the camp setting were successful in detecting COVID-19 outbreaks and preventing widespread disease during the initial phase of the pandemic in Thailand.
\n \n\n \n \nBackgroundMalaria in the first trimester of pregnancy is associated with adverse pregnancy outcomes. Artemisinin-based combination therapies (ACTs) are a highly effective, first-line treatment for uncomplicated Plasmodium falciparum malaria, except in the first trimester of pregnancy, when quinine with clindamycin is recommended due to concerns about the potential embryotoxicity of artemisinins. We compared adverse pregnancy outcomes after artemisinin-based treatment (ABT) versus non-ABTs in the first trimester of pregnancy.MethodsFor this systematic review and individual patient data (IPD) meta-analysis, we searched MEDLINE, Embase, and the Malaria in Pregnancy Library for prospective cohort studies published between Nov 1, 2015, and Dec 21, 2021, containing data on outcomes of pregnancies exposed to ABT and non-ABT in the first trimester. The results of this search were added to those of a previous systematic review that included publications published up until November, 2015. We included pregnancies enrolled before the pregnancy outcome was known. We excluded pregnancies with missing estimated gestational age or exposure information, multiple gestation pregnancies, and if the fetus was confirmed to be unviable before antimalarial treatment. The primary endpoint was adverse pregnancy outcome, defined as a composite of either miscarriage, stillbirth, or major congenital anomalies. A one-stage IPD meta-analysis was done by use of shared-frailty Cox models. This study is registered with PROSPERO, number CRD42015032371.FindingsWe identified seven eligible studies that included 12 cohorts. All 12 cohorts contributed IPD, including 34\u2009178 pregnancies, 737 with confirmed first-trimester exposure to ABTs and 1076 with confirmed first-trimester exposure to non-ABTs. Adverse pregnancy outcomes occurred in 42 (5\u00b77%) of 736 ABT-exposed pregnancies compared with 96 (8\u00b79%) of 1074 non-ABT-exposed pregnancies in the first trimester (adjusted hazard ratio [aHR] 0\u00b771, 95% CI 0\u00b749-1\u00b703). Similar results were seen for the individual components of miscarriage (aHR=0\u00b774, 0\u00b747-1\u00b717), stillbirth (aHR=0\u00b771, 0\u00b732-1\u00b757), and major congenital anomalies (aHR=0\u00b760, 0\u00b713-2\u00b787). The risk of adverse pregnancy outcomes was lower with artemether-lumefantrine than with oral quinine in the first trimester of pregnancy (25 [4\u00b78%] of 524 vs 84 [9\u00b72%] of 915; aHR 0\u00b758, 0\u00b736-0\u00b792).InterpretationWe found no evidence of embryotoxicity or teratogenicity based on the risk of miscarriage, stillbirth, or major congenital anomalies associated with ABT during the first trimester of pregnancy. Given that treatment with artemether-lumefantrine was associated with fewer adverse pregnancy outcomes than quinine, and because of the known superior tolerability and antimalarial effectiveness of ACTs, artemether-lumefantrine should be considered the preferred treatment for uncomplicated P falciparum malaria in the first trimester. If artemether-lumefantrine is unavailable, other ACTs (except artesunate-sulfadoxine-pyrimethamine) should be preferred to quinine. Continued active pharmacovigilance is warranted.FundingMedicines for Malaria Venture, WHO, and the Worldwide Antimalarial Resistance Network funded by the Bill & Melinda Gates Foundation.
\n \n\n \n \nBackgroundTuberculosis (TB) is a leading cause of morbidity and mortality in children but epidemiological data are scarce, particularly for hard-to-reach populations. We aimed to identify the risk factors for unsuccessful outcome and TB mortality in migrant children at a supportive residential TB programme on the Thailand-Myanmar border.MethodsWe conducted retrospective analysis of routine programmatic data for children (aged\u2009\u2264\u200915\u00a0years old) with TB diagnosed either clinically or bacteriologically between 2013 and 2018. Treatment outcomes were described and risk factors for unsuccessful outcome and death were identified using multivariable logistic regression.ResultsChildhood TB accounted for a high proportion of all TB diagnoses at this TB programme (398/2304; 17.3%). Bacteriological testing was done on a quarter (24.9%) of the cohort and most children were diagnosed on clinical grounds (94.0%). Among those enrolled on treatment (n\u2009=\u2009367), 90.5% completed treatment successfully. Unsuccessful treatment outcomes occurred in 42/398 (10.6%) children, comprising 26 (6.5%) lost to follow-up, one (0.3%) treatment failure and 15 (3.8%) deaths. In multivariable analysis, extra-pulmonary TB [adjusted OR (aOR) 3.56 (95% CI 1.12-10.98)], bacteriologically confirmed TB [aOR 6.07 (1.68-21.92)] and unknown HIV status [aOR 42.29 (10.00-178.78)] were independent risk factors for unsuccessful outcome. HIV-positive status [aOR 5.95 (1.67-21.22)] and bacteriological confirmation [aOR 9.31 (1.97-44.03)] were risk factors for death in the secondary analysis.ConclusionsChildren bear a substantial burden of TB disease within this migrant population. Treatment success rate exceeded the WHO End TB target of 90%, suggesting that similar vulnerable populations could benefit from the enhanced social support offered by this TB programme, but better child-friendly diagnostics are needed to improve the quality of diagnoses.
\n \n\n \n \nDeep learning based models have had great success in object detection, but the state of the art models have not yet been widely applied to biological image data. We apply for the first time an object detection model previously used on natural images to identify cells and recognize their stages in brightfield microscopy images of malaria-infected blood. Many micro-organisms like malaria parasites are still studied by expert manual inspection and hand counting. This type of object detection task is challenging due to factors like variations in cell shape, density, and color, and uncertainty of some cell classes. In addition, annotated data useful for training is scarce, and the class distribution is inherently highly imbalanced due to the dominance of uninfected red blood cells. We use Faster Region-based Convolutional Neural Network (Faster R-CNN), one of the top performing object detection models in recent years, pre-trained on ImageNet but fine tuned with our data, and compare it to a baseline, which is based on a traditional approach consisting of cell segmentation, extraction of several single-cell features, and classification using random forests. To conduct our initial study, we collect and label a dataset of 1300 fields of view consisting of around 100,000 individual cells. We demonstrate that Faster R-CNN outperforms our baseline and put the results in context of human performance.
\n \n\n \n \nIn malaria, rosetting is a phenomenon involving the cytoadherence of uninfected erythrocytes to infected erythrocytes (IRBC) harboring the late erythrocytic stage of Plasmodium spp. Recently, artesunate-stimulated rosetting has been demonstrated to confer a survival advantage to P. falciparum late-stage IRBC. This study investigated the rosetting response of P. falciparum and P. vivax clinical isolates to ex vivo antimalarial treatments. Brief exposure of IRBC to chloroquine, mefloquine, amodiaquine, quinine, and lumefantrine increased the rosetting rates of P. falciparum and P. vivax. Furthermore, the ex vivo combination of artesunate with mefloquine and piperaquine also resulted in increased the rosetting rates. Drug-mediated rosette-stimulation has important implications for the therapeutic failure of rapidly cleared drugs such as artesunate. However, further work is needed to establish the ramifications of increased rosetting rates by drugs with longer half-lifves, such as chloroquine, mefloquine, and piperaquine.
\n \n\n \n \nWhat genes determine in vitro growth and nutrient utilization in asexual blood-stage malaria parasites? Competition experiments between NF54, clone 3D7, a lab-adapted African parasite, and a recently isolated Asian parasite (NHP4026) reveal contrasting outcomes in different media: 3D7 outcompetes NHP4026 in media containing human serum, while NHP4026 outcompetes 3D7 in media containing AlbuMAX, a commercial lipid-rich bovine serum formulation. To determine the basis for this polymorphism, we conducted parasite genetic crosses using humanized mice and compared genome-wide allele frequency changes in three independent progeny populations cultured in media containing human serum or AlbuMAX. This bulk segregant analysis detected three quantitative trait loci (QTL) regions [on chromosome (chr) 2 containing aspartate transaminase AST; chr 13 containing EBA-140; and chr 14 containing cysteine protease ATG4] linked with differential growth in serum or AlbuMAX in each of the three independent progeny pools. Selection driving differential growth was strong (s = 0.10 - 0.23 per 48-hour lifecycle). We conducted validation experiments for the strongest QTL on chr 13: competition experiments between \u0394EBA-140 and 3D7 wildtype parasites showed fitness reversals in the two medium types as seen in the parental parasites, validating this locus as the causative gene. These results (i) demonstrate the effectiveness of bulk segregant analysis for dissecting fitness traits in P. falciparum genetic crosses, and (ii) reveal intimate links between red blood cell invasion and nutrient composition of growth media. Use of parasite crosses combined with bulk segregant analysis will allow systematic dissection of key nutrient acquisition/metabolism and red blood cell invasion pathways in P. falciparum.
\n \n\n \n \nBackground: Targeted malaria elimination strategies require highly sensitive tests to detect low density malaria infections (LDMI). Commonly used methods for malaria diagnosis such as light microscopy and antigen-based rapid diagnostic tests (RDTs) are not sensitive enough for reliable identification of infections with parasitaemia below 200 parasites per milliliter of blood. While targeted malaria elimination efforts on the Thailand-Myanmar border have successfully used high sample volume ultrasensitive quantitative PCR (uPCR) to determine malaria prevalence, the necessity for venous collection and processing of large quantities of patient blood limits the widespread tractability of this method. Methods: Here we evaluated a real-time reverse transcription PCR (RT-qPCR) method that reduces the required sample volume compared to uPCR. To do this, 304 samples collected from an active case detection program in Kayin state, Myanmar were compared using uPCR and RT-qPCR. Results: Plasmodium spp. RT-qPCR\u00a0confirmed 18 of 21 uPCR Plasmodium falciparum positives, while P. falciparum specific\u00a0RT-qPCR confirmed 17 of the 21 uPCR P. falciparum positives. Combining both RT-qPCR results increased the sensitivity to 100% and specificity was 95.1%. Conclusion: Malaria detection in areas of low transmission and LDMI can benefit from the increased sensitivity of ribosomal RNA detection by RT-PCR, especially where sample volume is limited. Isolation of high quality RNA also allows for downstream analysis of malaria transcripts.
\n \n\n \n \nBackgroundObesity predominantly affects populations in high-income countries and those countries facing epidemiological transition. The risk of childhood obesity is increased among infants who had overweight or obesity at birth, but in low-resource settings one in five infants are born small for gestational age. We aimed to study the relationships between: (1) maternal metabolite signatures; (2) fetal abdominal growth; and (3) postnatal growth, adiposity, and neurodevelopment.MethodsIn the prospective, multinational, observational INTERBIO-21st fetal study, conducted in maternity units in Pelotas (Brazil), Nairobi (Kenya), Karachi (Pakistan), Soweto (South Africa), Mae Sot (Thailand), and Oxford (UK), we enrolled women (\u226518 years, with a BMI of less than 35 kg/m2, natural conception, and a singleton pregnancy) who initiated antenatal care before 14 weeks' gestation. Ultrasound scans were performed every 5\u00b11 weeks until delivery to measure fetal growth and feto-placental blood flow, and we used finite mixture models to derive growth trajectories of abdominal circumference. The infants' health, growth, and development were monitored from birth to age 2 years. Early pregnancy maternal blood and umbilical cord venous blood samples were collected for untargeted metabolomic analysis.FindingsFrom Feb 8, 2012, to Nov 30, 2019, we enrolled 3598 pregnant women and followed up their infants to 2 years of age. We identified four ultrasound-derived trajectories of fetal abdominal circumference growth that accelerated or decelerated within a crucial 20-25 week gestational age window: faltering growth, early accelerating growth, late accelerating growth, and median growth tracking. These distinct phenotypes had matching feto-placental blood flow patterns throughout pregnancy, and different growth, adiposity, vision, and neurodevelopment outcomes in early childhood. There were 709 maternal metabolites with positive effect for the faltering growth phenotype and 54 for the early accelerating growth phenotype; 31 maternal metabolites had a negative effect for the faltering growth phenotype and 76 for the early accelerating growth phenotype. Metabolites associated with the faltering growth phenotype had statistically significant odds ratios close to 1\u00b75 (ie, suggesting upregulation of metabolic pathways of impaired fetal growth). The metabolites had a reciprocal relationship with the early accelerating growth phenotype, with statistically significant odds ratios close to 0.6 (ie, suggesting downregulation of fetal growth acceleration). The maternal metabolite signatures included 5-hydroxy-eicosatetraenoic acid, and 11 phosphatidylcholines linked to oxylipin or saturated fatty acid sidechains. The fungicide, chlorothalonil, was highly abundant in the early accelerating growth phenotype group.InterpretationEarly pregnancy lipid biology associated with fetal abdominal growth trajectories is an indicator of patterns of growth, adiposity, vision, and neurodevelopment up to the age of 2 years. Our findings could contribute to the earlier identification of infants at risk of obesity.FundingBill & Melinda Gates Foundation.
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