Search

Hospitals in low- and middle-income countries (LMICs) could benefit from decision support technologies to reduce time to triage, diagnosis, and surgery for patients with traumatic brain injury (TBI). Corticosteroid Randomization after Significant Head Injury (CRASH) and International Mission for Prognosis and Clinical Trials in Traumatic Brain Injury (IMPACT) are robust examples of TBI prognostic models, although they have yet to be validated in Sub-Saharan Africa (SSA). Moreover, machine learning and improved data quality in LMICs provide an opportunity to develop context-specific, and potentially more accurate, prognostic models. We aim to externally validate CRASH and IMPACT on our TBI registry and compare their performances to that of the locally derived model (from the Kilimanjaro Christian Medical Center [KCMC]). We developed a machine learning-based prognostic model from a TBI registry collected at a regional referral hospital in Moshi, Tanzania. We also used the core CRASH and IMPACT online risk calculators to generate risk scores for each patient. We compared the discrimination (area under the curve [AUC]) and calibration before and after Platt scaling (Brier, Hosmer-Lemeshow Test, and calibration plots) for CRASH, IMPACT, and the KCMC model. The outcome of interest was unfavorable in-hospital outcome defined as a Glasgow Outcome Scale score of 1-3. There were 2972 patients included in the TBI registry, of whom 11% had an unfavorable outcome. The AUCs for the KCMC model, CRASH, and IMPACT were 0.919, 0.876, and 0.821, respectively. Prior to Platt scaling, CRASH was the best calibrated model (χ

OBJECTIVES To describe knowledge, attitudes, and practices (KAP) regarding ischemic heart disease (IHD) among adults with HIV in Tanzania. METHODS Adults presenting for routine HIV care at a clinic in northern Tanzania were consecutively enrolled and were administered a standardised KAP survey. For each participant, an IHD knowledge score was calculated by tallying correct answers to the IHD knowledge questions, with maximum score 10. Individual 5-year risk of cardiovascular event was calculated using the Harvard NHANES model. Associations between participant characteristics and IHD knowledge scores were assessed via Welch's t-test. RESULTS Among the 500 participants, the mean (SD) age was 45.3 (11.4) years and 139 (27.8%) were males. Most participants recognised high blood pressure (n = 313, 62.6%) as a risk factor for IHD, but fewer identified diabetes as a risk factor (n = 241, 48.2%), or knew that aspirin reduces the risk of a secondary cardiovascular event (n = 73, 14.6%). Higher IHD knowledge score was associated with post-primary education (mean 6.27 vs. 5.35, p = 0.001) and with >10% 5-year risk of cardiovascular event (mean 5.97 vs. 5.41, p = 0.045). Most participants believed there were things they could do to reduce their chances of having a heart attack (n = 361, 72.2%). While participants indicated that they adhered to their prescribed medications (n = 488, 97.6%), only 106 (21.2%) attended regular health check-ups. CONCLUSION Efforts are needed to improve gaps in IHD knowledge, and increase uptake of cardiovascular preventative practices among Tanzanian adults with HIV.

CD4+ regulatory T (Treg) cells, dependent upon the transcription factor Foxp3, contribute to tumour immunosuppression but are also required for immune homeostasis. There is interest in developing therapies that selectively target the immunosuppressive function of Treg cells within tumours without disrupting their systemic anti‐inflammatory function. High levels of expression of chemokine (C‐C motif) receptor 8 (CCR8) discriminate Treg cells within tumours from those found in systemic lymphoid tissues. It has recently been proposed that disruption of CCR8 function using blocking anti‐CCR8 antibodies results in reduced accumulation of Treg cells within tumours and disruption of their immunosuppressive function. Here, using Ccr8 −/− mice, we show that CCR8 function is not required for Treg cell accumulation or immunosuppression in the context of syngeneic MC38 colorectal adenocarcinoma and B16 melanoma tumours. We observed high levels of CCR8 expression on tumour‐infiltrating Treg cells which were abolished in Ccr8 −/− mice. High levels of CCR8 marked cells with high levels of suppressive function. However, whereas systemic ablation of Treg cells resulted in strikingly diminished tumour burden, growth of subcutaneously implanted tumours was unaffected by systemic CCR8 loss. Consistently, we observed minimal impact of systemic CCR8 ablation on the frequency, phenotype and function of tumour‐infiltrating Treg cells and conventional T (Tconv) function. These findings suggest that CCR8 is not required for Treg cell accumulation and immunosuppressive function within tumours and that depletion of CCR8+ Treg cells rather than blockade of CCR8 function is a more promising avenue for selective immunotherapy., There is interest in developing therapies that selectively target the immunosuppressive function of Treg cells within tumours without disrupting their systemic anti‐inflammatory function. It has recently been proposed that disruption of CCR8 function using blocking anti‐CCR8 antibodies results in reduced accumulation of Treg cells within tumours and disruption of their immunosuppressive function.​We show that CCR8 marks highly suppressive Treg cells within tumours but is not required for Treg cell accumulation and immunosuppressive function within tumours, suggesting that depletion of CCR8+ Treg cells rather than blockade of CCR8 function is a more promising avenue for selective immunotherapy.

Members of the fungal genus Phyllosticta can colonize a variety of plant hosts, including several Citrus species such as Citrus sinensis (orange), Citrus limon (lemon), and Citrus maxima (pomelo). Some Phyllosticta species have the capacity to cause disease, such as Citrus Black Spot, while others have only been observed as endophytes. Thus far, genomic differences underlying lifestyle adaptations of Phyllosticta species have not yet been studied. Furthermore, the lifestyle of Phyllosticta citrichinaensis is ambiguous, as it has been described as a weak pathogen but Koch’s postulates may not have been established and the presence of this species was never reported to cause any crop or economic losses. Here, we examined the genomic differences between pathogenic and endophytic Phyllosticta spp. colonizing Citrus and specifically aimed to elucidate the lifestyle of Phyllosticta citrichinaensis. We found several genomic differences between species of different lifestyles, including groups of genes that were only present in pathogens or endophytes. We also observed that species, based on their carbohydrate active enzymes, group independent of their phylogenetic association, and this clustering correlated with trophy prediction. Phyllosticta citrichinaensis shows an intermediate lifestyle, sharing genomic and phenotypic attributes of both pathogens and endophytes. We thus present the first genomic comparison of multiple citrus-colonizing pathogens and endophytes of the genus Phyllosticta, and therefore provide the basis for further comparative studies into the lifestyle adaptations within this genus.

Background: Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction.Methods: Genome-wide analysis of remission (nremit = 1852, nnonremit = 3299) and percentage improvement (n = 5218) was performed. Single nucleotide polymorphism–based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA.Results: Neither genome-wide association study identified genome-wide significant associations. Single nucleotide polymorphism–based heritability was significantly different from zero for remission (h2 = 0.132, SE = 0.056) but not for percentage improvement (h2 = −0.018, SE = 0.032). Better antidepressant response was negatively associated with genetic risk for schizophrenia and positively associated with genetic propensity for educational attainment. Leave-one-out validation of antidepressant response polygenic scores demonstrated significant evidence of out-of-sample prediction, though results varied in external cohorts. Gene-based analyses identified ETV4 and DHX8 as significantly associated with antidepressant response.Conclusions: This study demonstrates that antidepressant response is influenced by common genetic variation, has a genetic overlap schizophrenia and educational attainment, and provides a useful resource for future research. Larger sample sizes are required to attain the potential of genetics for understanding and predicting antidepressant response.

Introduction A significant number of climbers on Mount Kilimanjaro are affected by altitude-related disorders. The aim of this study was to determine the main causes of morbidity and mortality in a representative cohort of climbers based on local hospital records. Methods We conducted a 2-y retrospective chart review of all patients presenting to the main referral hospital in the region after a climb on Mount Kilimanjaro, including all relevant records and referrals for postmortem studies. Results We identified 62 climbers who presented to the hospital: 47 inpatients and 15 outpatients. Fifty-six presented with high altitude illness, which included acute mountain sickness (n=8; 14%), high altitude pulmonary edema (HAPE) (n=30; 54%), high altitude cerebral edema (HACE) (n=7; 12%), and combined HAPE/HACE (n=11; 20%). The mean altitude of symptom onset ranged from 4600±750 m for HAPE to 5000±430 m for HAPE/HACE. The vast majority of inpatients (n=41; 87%) were improved on discharge. Twenty-one deceased climbers, most having died while climbing (n=17; 81%), underwent postmortem evaluation. Causes of death were HAPE (n=16; 76%), HAPE/HACE (n=3; 14%), trauma (1), and cardiopulmonary (1). Conclusions HAPE was the main cause of death during climbing as well as for hospital admissions. The vast majority of climbers who presented to hospital made a full recovery.

Background The Kilimanjaro region has one of the highest levels of reported alcohol intake per capita in Tanzania. Age at first drink has been found to be associated with alcohol problems in adulthood, but there is less information on the age of first drink in the Kilimanjaro region and its associations with alcohol-related consequences later in life. Furthermore, local alcohol cost and availability may influence the prevalence of alcohol use and alcohol use disorders. Method Data on the age of first drink, alcohol use disorder identification tool (AUDIT), number and type of alcohol consequences (DrInC), and perceived alcohol at low cost and high availability for children and adolescents were collected from an alcohol and health behavior survey of injury patients (N = 242) in Moshi, Tanzania. Generalized linear models were used to test age at first drink, perceived alcohol cost and availability, and their association with the AUDIT and DrInC scores, and current alcohol use, respectively. Results Consuming alcohol before age 18 was significantly associated with higher AUDIT and DrInC scores, with odds ratios of 1.22 (CI: 1.004, 1.47) and 1.72 (CI: 1.11, 2.63), respectively. Female gender is strongly associated with less alcohol use and alcohol consequences, represented by an odds ratio of 3.70 (CI: 1.72, 8.33) for an AUDIT score above 8 and an odds ratio of 3.84 (CI: 2.13, 6.67) with the DrInC score. Perceived high availability of alcohol for children is significantly related to higher alcohol use quantity, with the odds ratio of 1.6 (CI: 1.17, 2.20). Conclusions The first use of alcohol before the age of 18 is associated with higher alcohol use and alcohol-related adverse consequences. In Tanzania, age at first drink is an important target for interventions aiming to prevent negative alcohol-related consequences later in life.

Contains fulltext : 248656.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10(-6)) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10(-7); rs73033497, p = 8.8 × 10(-7); rs7914279, p = 6.4 × 10(-7)), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

After decades of research, our understanding of when and why individuals infected with Plasmodium falciparum develop clinical malaria is still limited. Correlates of immune protection are often sought through prospective cohort studies, where measured host factors are correlated against the incidence of clinical disease over a set period of time. However, robustly inferring individual-level protection from these population-level findings has proved difficult due to small effect sizes and high levels of variance underlying such data. In order to better understand the nature of these inter-individual variations, we analysed the long-term malaria epidemiology of children ≤12 years old growing up under seasonal exposure to the parasite in the sub-location of Junju, Kenya. Despite the cohort’s limited geographic expanse (ca. 3km x 10km), our data reveal a high degree of spatial and temporal variability in malaria prevalence and incidence rates, causing individuals to experience varying levels of exposure to the parasite at different times during their life. Analysing individual-level infection histories further reveal an unexpectedly high variability in the rate at which children experience clinical malaria episodes. Besides exposure to the parasite, measured as disease prevalence in the surrounding area, we find that the birth time of year has an independent effect on the individual’s risk of experiencing a clinical episode. Furthermore, our analyses reveal that those children with a history of an above average number of episodes are more likely to experience further episodes during the upcoming transmission season. These findings are indicative of phenotypic differences in the rates by which children acquire clinical protection to malaria and offer important insights into the natural variability underlying malaria epidemiology.

Background Appropriate referrals of injured patients could improve clinical outcomes and management of healthcare resources. To gain insights for system development, we interrogated the current situation by assessing burden, patient demography, causes of injury, trauma mortality and the care-process. Methods We used an observational, cross-sectional study design and convenience sampling to review patient charts from 3 major hospitals and the death registry in Tanzania. Results Injury constitutes 9–13% of the Emergency Centre census. Inpatient trauma-deaths were 8%; however, the trauma death registry figures exceeded the ‘inpatient deaths’ and recorded up to 16%. Most patients arrive through a hospital referral system (82%) and use a hospital transport network (76%). Only 8% of the trauma admissions possessed National Health Insurance. Road traffic collision (RTC) (69%), assault (20%) and falls (9%) were the leading causes of injury. The care process revealed a normal primary-survey rate of 73–90%. Deficiencies in recording were in the assessment of: Airway and breathing (67%), circulation (40%) and disability (80%). Most patients had non-operative management (42–57%) or surgery for wound care or skeletal injuries (43%). Laparotomies were performed in 26%, while craniotomy and chest drain-insertion were each performed in 10%. Conclusion The burden of trauma is high, and the leading causes are: RTC, assault, and falls. Deaths recorded in the death registries outweigh in-hospital deaths for up to twofold. There are challenges in the care process, funding and recording. We found a functional hospital referral-network, transport system, and death registry.

Background Prevention and treatment of malaria during pregnancy is crucial in dealing with maternal mortality and adverse fetal outcomes. The World Health Organization recommendation to treat all pregnant women with sulfadoxine-pyrimethamine (SP) through antenatal care structures was implemented in Kenya in the year 1998, but concerns about its effectiveness in preventing malaria in pregnancy has arisen due to the spread of SP resistant parasites. This study aimed to determine the prevalence of SP resistance markers in Plasmodium falciparum parasites isolated from pregnant women seeking antenatal care at Msambweni County Referral Hospital, located in coastal Kenya, between the year 2013 and 2015. Methods This hospital-based study included 106 malaria positive whole blood samples for analysis of SP resistance markers within the Pfdhfr gene (codons 51, 59 and 108) and Pfdhps gene (codons 437 and 540). The venous blood collected from all pregnant women was tested for malaria via light microscopy, then the malaria positive samples were separated into plasma and red cells and stored in a − 86° freezer for further studies. Archived red blood cells were processed for molecular characterization of SP resistance markers within the Pfdhfr and Pfdhps genes using real time PCR platform and Sanger sequencing. Results All samples had at least one mutation in the genes associated with drug resistance; polymorphism prevalence of Pfdhfr51I, 59R and 108N was at 88.7%, 78.3% and 93.4%, respectively, while Pfdhps polymorphism accounted for 94.3% and 91.5% at 437G and 540E, respectively. Quintuple mutations (at all the five codons) conferring total SP resistance had the highest prevalence of 85.8%. Quadruple mutations were observed at a frequency of 10.4%, and 24.5% had a mixed outcome of both wildtype and mutant genotypes in the genes of interest. Conclusion The data suggest a high prevalence of P. falciparum genetic variations conferring resistance to SP among pregnant women, which may explain reduced efficacy of IPTp treatment in Kenya. There is need for extensive SP resistance profiling in Kenya to inform IPTp drug choices for successful malaria prevention during pregnancy.

Introduction The prevalence of cardiovascular disease in sub-Saharan Africa is substantial and growing. Much remains to be learned about the relative burden of acute coronary syndrome (ACS), heart failure, and stroke on emergency departments and hospital admissions. Methods A retrospective chart review of admissions from September 2017 through March 2018 was conducted at the emergency department of a tertiary care center in northern Tanzania. Stroke admission volume was compared to previously published data from the same hospital and adjusted for population growth. Results Of 2418 adult admissions, heart failure and stroke were the two most common admission diagnoses, accounting for 294 (12.2%) and 204 (8.4%) admissions, respectively. ACS was uncommon, accounting for 9 (0.3%) admissions. Of patients admitted for heart failure, uncontrolled hypertension was the most commonly identified etiology of heart failure, cited in 124 (42.2%) cases. Ischemic heart disease was cited as the etiology in only 1 (0.3%) case. Adjusting for population growth, the annual volume of stroke admissions increased 70-fold in 43 years, from 2.9 admissions per 100,000 population in 1974 to 202.2 admissions per 100,000 in 2017. Conclusions The burden of heart failure and stroke on hospital admissions in Tanzania is substantial, and the volume of stroke admissions is rising precipitously. ACS is a rare diagnosis, and the distribution of cardiovascular disease phenotypes in Tanzania differs from what has been observed outside of Africa. Further research is needed to ascertain the reasons for these differences., Highlights • In northern Tanzania, acute coronary syndrome is a rare admission diagnosis • Heart failure and stroke are the most common admission diagnoses • The burden of stroke admissions in this community is rising rapidly

Significance Recently, investigators have shown that only a few driver gene mutational events appear to be needed for cancer to occur. However, the reason that some mutational events precede others in the same cancer and the explanation for tissue-specific differences in this timing, remain mysterious. We here combine mathematical modeling with epidemiologic studies and sequencing data to address these questions. We suggest that the first driver event in cancers generally occurred at early ages and provide estimates for the fitness of different types of drivers during tumor evolution, showing how they vary with the tissue of origin., Cancer is driven by the sequential accumulation of genetic and epigenetic changes in oncogenes and tumor suppressor genes. The timing of these events is not well understood. Moreover, it is currently unknown why the same driver gene change appears as an early event in some cancer types and as a later event, or not at all, in others. These questions have become even more topical with the recent progress brought by genome-wide sequencing studies of cancer. Focusing on mutational events, we provide a mathematical model of the full process of tumor evolution that includes different types of fitness advantages for driver genes and carrying-capacity considerations. The model is able to recapitulate a substantial proportion of the observed cancer incidence in several cancer types (colorectal, pancreatic, and leukemia) and inherited conditions (Lynch and familial adenomatous polyposis), by changing only 2 tissue-specific parameters: the number of stem cells in a tissue and its cell division frequency. The model sheds light on the evolutionary dynamics of cancer by suggesting a generalized early onset of tumorigenesis followed by slow mutational waves, in contrast to previous conclusions. Formulas and estimates are provided for the fitness increases induced by driver mutations, often much larger than previously described, and highly tissue dependent. Our results suggest a mechanistic explanation for why the selective fitness advantage introduced by specific driver genes is tissue dependent.

OBJECTIVES: To increase understanding of knowledge, attitudes, and preventative practices regarding ischemic heart disease (IHD) in sub-Saharan Africa in order to develop patient-centered interventions to improve care and outcomes. STUDY DESIGN: Prospective observational study. METHODS: Adult patients presenting with chest pain or shortness of breath to an emergency department in northern Tanzania were enrolled. A questionnaire was adapted from existing knowledge attitude and practice surveys regarding cardiovascular disease and the WHO STEPS instrument. Individual five-year risk of cardiovascular event was determined by validated models based on age, sex, systolic blood pressure, body mass index, diabetes, and smoking status. An IHD knowledge score was calculated by giving one point for each correct response to the knowledge-related items, with a maximum score of 10. Associations between IHD knowledge and patient characteristics were assessed by Welch’s t-test. RESULTS: A total of 349 patients were enrolled, with median (IQR) age 60 (45, 72) years. Of participants, 259 (74.2%) had hypertension, and 228 (65.3%) had greater than 10% five-year risk of cardiovascular event. The mean (sd) knowledge score was 4.8 (3.3). The majority of respondents (224, 64.2%) recognized obesity as a risk factor for heart attack, while a minority (34, 9.7%) knew that a daily aspirin could reduce the risk of cardiovascular event. Greater IHD knowledge was associated with younger age (p = 0.045) and higher levels of education (p < 0.001) but not higher risk of cardiovascular disease (p = 0.123). Most respondents expressed a willingness to diet to improve their health (322, 92.3%) and a preference for treatment from a physician rather than a traditional healer for a heart attack (321, 92.0%). A minority of patients reported exercising regularly (88, 25.2%) or seeing a doctor routinely for check-ups (100, 28.7%). CONCLUSIONS: High-risk emergency department patients in northern Tanzania have moderate knowledge regarding IHD but do not consistently engage in healthy preventive practices. Patient-centered interventions are needed to improve IHD knowledge and practices in high-risk populations.

Humoral responses to COVID-19 vaccines in people living with HIV (PLWH) remain incompletely understood. We measured circulating antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, ACE2 displacement and live viral neutralization activities one month following the first and second COVID-19 vaccine doses in 100 adult PLWH and 152 controls. All PLWH were receiving suppressive antiretroviral therapy, with median CD4+ T-cell counts of 710 (IQR 525-935) cells/mm3. Nadir CD4+ T-cell counts ranged as low as 3. After adjustment for sociodemographic, health and vaccine-related variables, HIV infection was significantly associated with 0.2 log10 lower anti-RBD antibody concentrations (p=0.03) and ∼11% lower ACE2 displacement activity (p=0.02), but not lower viral neutralization (p=0.1) after one vaccine dose. Following two doses however, HIV was no longer significantly associated with the magnitude of any response measured. Rather, older age, a higher burden of chronic health conditions, and having received two ChAdOx1 doses (versus a heterologous or dual mRNA vaccine regimen) were independently associated with lower responses. After two vaccine doses, no significant correlation was observed between the most recent or nadir CD4+ T-cell counts and vaccine responses in PLWH. These results suggest that PLWH with well-controlled viral loads on antiretroviral therapy and CD4+ T-cell counts in a healthy range will generally not require a third COVID-19 vaccine dose as part of their initial immunization series, though other factors such as older age, co-morbidities, vaccine regimen type, and durability of vaccine responses will influence when this group may benefit from additional doses. Further studies of PLWH who are not receiving antiretroviral treatment and/or who have low CD4+ T-cell counts are needed.

Background Rigorous incidence data for acute myocardial infarction (AMI) in sub‐Saharan Africa are lacking. Consequently, modeling studies based on limited data have suggested that the burden of AMI and AMI‐associated mortality in sub‐Saharan Africa is lower than in other world regions. Methods and Results We estimated the incidence of AMI in northern Tanzania in 2019 by integrating data from a prospective surveillance study (681 participants) and a community survey of healthcare‐seeking behavior (718 participants). In the surveillance study, adults presenting to an emergency department with chest pain or shortness of breath were screened for AMI with ECG and troponin testing. AMI was defined by the Fourth Universal Definition of AMI criteria. Mortality was assessed 30 days following enrollment via in‐person or telephone interviews. In the cluster‐based community survey, adults in northern Tanzania were asked where they would present for chest pain or shortness of breath. Multipliers were applied to account for AMI cases that would have been missed by our surveillance methods. The estimated annual incidence of AMI was 172 (207 among men and 139 among women) cases per 100 000 people. The age‐standardized annual incidence was 211 (263 among men and 170 among women) per 100 000 people. The estimated annual incidence of AMI‐associated mortality was 87 deaths per 100 000 people, and the age‐standardized annual incidence was 102 deaths per 100 000 people. Conclusions The incidence of AMI and AMI‐associated mortality in northern Tanzania is much higher than previously estimated and similar to that observed in high‐income countries.

Background Nutritional deficiencies, including vitamin D and iron deficiency, are prevalent among children living in sub-Saharan Africa. Vitamin D inhibits the transcription of the iron hormone hepcidin thus permitting efficient iron absorption, and iron deficiency alters vitamin D metabolism. Studies have reported associations between vitamin D and iron status, but little is known about their association in African populations. Objective We aimed to evaluate the association between vitamin D and iron status in African children. Methods In this cross-sectional study, we measured biomarkers of iron status, inflammation and 25-hydroxyvitamin D (25(OH)D) levels in 4509 children aged 0.3 months to 8 years from Kenya, Uganda, Burkina Faso, The Gambia and South Africa. We used regression analyses to evaluate the association between vitamin D and iron status. Results Stunting, underweight, inflammation and malaria were highly prevalent. Overall prevalence of iron deficiency was 35.1%, while the prevalence of vitamin D deficiency was 0.6% and 7.8% as defined by 25(OH)D levels of 75 nmol/L. 25(OH)D levels were positively associated with ferritin, hepcidin and soluble transferrin receptor levels and negatively associated with serum iron and transferrin saturation in multivariable regression analyses. Vitamin D status was not associated with hemoglobin levels or anemia. Conclusions These findings suggest that vitamin D deficiency may variably influence different iron compartments and measures of iron status in young African children. Additional research is required to confirm these findings and determine direction of causality. The interplay between vitamin D and iron status should be considered in strategies to manage these nutrient deficiencies in African populations.

Crocodile blood has long been used as a traditional medicine in many Asian countries to treat diseases such as asthma, allergies, and many others. Yet, only recently has the safety and effectiveness of using crocodile blood as a medicine been examined using modern scientific methods; with both conserved and novel active components identified from crocodile blood. Further in vitro and in vivo investigations found that crocodile blood can have a wide range of beneficial effects, including antimicrobial, antiviral, anti-oxidative, anti-inflammatory, antitumour effects, anti-anaemia, and enhancement of wound healing. A systematic research of literature published in English-language journals up to April 2020 was conducted in PubMed, Google Scholar, and Web of Science. Based on the biological and chemical knowledge of crocodile immunity and crocodile blood, this article aims to: provide a critical review on the proposed properties of crocodile blood, identify the knowledge gap and offer some insights for future investigations regarding the use of crocodile blood as a medication or dietary supplement.

Gram-negative bacteria belonging to the Enterobacter cloacae complex are increasingly implicated in difficult-to-treat nosocomial infections, as exemplified by a recently characterized highly carbapenem-resistant clinical Enterobacter roggenkampii isolate with sequence type (ST) 232. While mechanisms of carbapenem resistance are well-understood, little is known about the responses of highly drug-resistant bacteria to these antibiotics. Our present study was therefore aimed at charting the responses of the E. roggenkampii ST232 isolate to the carbapenem imipenem, using a ‘stable isotope labeling of amino acids in cell culture’ approach for quantitative mass spectrometry. This unveiled diverse responses of E. roggenkampii ST232 to imipenem, especially altered levels of proteins for cell wall biogenesis, central carbon metabolism, respiration, iron–sulfur cluster synthesis, and metal homeostasis. These observations suggest a scenario where imipenem-challenged bacteria reduce metabolic activity to save resources otherwise used for cell wall biogenesis, and to limit formation of detrimental reactive oxygen species at the cytoplasmic membrane due to respiration and Fenton chemistry. We consider these observations important, because knowing the adaptive responses of a highly resistant bacterium of the E. cloacae complex to last-resort antibiotics, such as imipenem, provides a ‘sneak preview’ into the future development of antibiotic resistance in this emerging group of pathogens.

Immunoglobulin A is the dominant antibody isotype found in mucosal secretions and enforces host-microbiota symbiosis in mice, yet selective IgA-deficiency (sIgAd) in humans is often described as asymptomatic. Here, we determined the effects of IgA deficiency on human gut microbiota composition and evaluated the possibility that mucosal secretion of IgM can compensate for a lack of secretory IgA. We used 16S rRNA gene sequencing and bacterial cell sorting to evaluate gut microbiota composition and taxa-specific antibody coating of the gut microbiota in 15 sIgAd subjects and matched controls. Despite the secretion of compensatory IgM into the gut lumen, sIgAd subjects displayed an altered gut microbiota composition as compared to healthy controls. These alterations were characterized by a trend towards decreased overall microbial diversity as well as significant shifts in the relative abundances of specific microbial taxa. While secretory IgA in healthy controls targeted a defined subset of the microbiota via high-level coating, compensatory IgM in sIgAd subjects showed less specificity than IgA and bound a broader subset of the microbiota. We conclude that IgA plays a critical and non-redundant role in controlling gut microbiota composition in humans and that secretory IgA has evolved to maintain a diverse and stable gut microbial community.

Background The incidence of acute coronary syndrome (ACS) is growing across sub-Saharan Africa and many healthcare systems are ill-equipped for this growing burden. Evidence suggests that healthcare providers may be underdiagnosing and undertreating ACS, leading to poor health outcomes. The goal of this study was to examine provider perspectives on barriers to ACS care in Tanzania in order to identify opportunities for interventions to improve care. Methods Semistructured in-depth interviews were conducted with physicians and clinical officers from emergency departments and outpatient departments in northern Tanzania. Thematic analysis was conducted using an iterative cycle of coding and consensus building. Results The 11 participants included six physicians and five clinical officers from health centers, community hospitals and one referral hospital. Providers identified barriers related to providers, systems and patients. Provider-related barriers included inadequate training regarding ACS and poor application of textbook-based knowledge. System-related barriers included lack of diagnostic equipment, unavailability of treatments, referral system delays, lack of data regarding disease burden, absence of locally relevant guidelines and cost of care. Patient-related barriers included inadequate ACS knowledge, inappropriate healthcare-seeking behavior and non-adherence. Conclusions This study identified actionable barriers to ACS care in northern Tanzania. Multifaceted interventions are urgently needed to improve care.

Rift Valley fever virus (RVFV), an emerging arboviral and zoonotic bunyavirus, causes severe disease in livestock and humans. Here, we report the isolation of a panel of monoclonal antibodies (mAbs) from the B cells of immune individuals following natural infection in Kenya or immunization with MP-12 vaccine. The B cell responses of individuals who were vaccinated or naturally infected recognized similar epitopes on both Gc and Gn proteins. The Gn-specific mAbs and two mAbs that do not recognize either monomeric Gc or Gn alone but recognized the hetero-oligomer glycoprotein complex (Gc+Gn) when Gc and Gn were coexpressed exhibited potent neutralizing activities in vitro, while Gc-specific mAbs exhibited relatively lower neutralizing capacity. The two Gc+Gn-specific mAbs and the Gn domain A-specific mAbs inhibited RVFV fusion to cells, suggesting that mAbs can inhibit the exposure of the fusion loop in Gc, a class II fusion protein, and thus prevent fusion by an indirect mechanism without direct fusion loop contact. Competition-binding analysis with coexpressed Gc/Gn and mutagenesis library screening indicated that these mAbs recognize four major antigenic sites, with two sites of vulnerability for neutralization on Gn. In experimental models of infection in mice, representative mAbs recognizing three of the antigenic sites reduced morbidity and mortality when used at a low dose in both prophylactic and therapeutic settings. This study identifies multiple candidate mAbs that may be suitable for use in humans against RVFV infection and highlights fusion inhibition against bunyaviruses as a potential contributor to potent antibody-mediated neutralization.

Background: Studies of long-term malaria cohorts have provided essential insights into how Plasmodium falciparum interacts with humans, and influences the development of antimalarial immunity. Immunity to malaria is acquired gradually after multiple infections, some of which present with clinical symptoms. However, there is considerable variation in the number of clinical episodes experienced by children of the same age within the same cohort. Understanding this variation in clinical symptoms and how it relates to the development of naturally acquired immunity is crucial in identifying how and when some children stop experiencing further malaria episodes. Where variability in clinical episodes may result from different rates of acquisition of immunity, or from variable exposure to the parasite. Methods: Using data from a longitudinal cohort of children residing in an area of moderate P. falciparum transmission in Kilifi district, Kenya, we fitted cumulative episode curves as monotonic-increasing splines, to 56 children under surveillance for malaria from the age of 5 to 15. Results: There was large variability in the accumulation of numbers of clinical malaria episodes experienced by the children, despite being of similar age and living in the same general location. One group of children from a particular sub-region of the cohort stopped accumulating clinical malaria episodes earlier than other children in the study. Despite lack of further clinical episodes of malaria, these children had higher asymptomatic parasite densities and higher antibody titres to a panel of P. falciparum blood-stage antigens. Conclusions: This suggests development of clinical immunity rather than lack of exposure to the parasite, and supports the view that this immunity to malaria disease is maintained by a greater exposure to P. falciparum, and thus higher parasite burdens. Our study illustrates the complexity of anti-malaria immunity and underscores the need for analyses which can sufficiently reflect the heterogeneity within endemic populations.

Climate change and variability influence temperature and rainfall, which impact vector abundance and the dynamics of vector-borne disease transmission. Climate change is projected to increase the frequency and intensity of extreme climate events. Mosquito-borne diseases, such as dengue fever, are primarily transmitted by Aedes aegypti mosquitoes. Freshwater availability and temperature affect dengue vector populations via a variety of biological processes and thus influence the ability of mosquitoes to effectively transmit disease. However, the effect of droughts, floods, heat waves, and cold waves is not well understood. Using vector, climate, and dengue disease data collected between 2013 and 2019 in Kenya, this retrospective cohort study aims to elucidate the impact of extreme rainfall and temperature on mosquito abundance and the risk of arboviral infections. To define extreme periods of rainfall and land surface temperature (LST), we calculated monthly anomalies as deviations from long-term means (1983–2019 for rainfall, 2000–2019 for LST) across four study locations in Kenya. We classified extreme climate events as the upper and lower 10% of these calculated LST or rainfall deviations. Monthly Ae. aegypti abundance was recorded in Kenya using four trapping methods. Blood samples were also collected from children with febrile illness presenting to four field sites and tested for dengue virus using an IgG enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR). We found that mosquito eggs and adults were significantly more abundant one month following an abnormally wet month. The relationship between mosquito abundance and dengue risk follows a non-linear association. Our findings suggest that early warnings and targeted interventions during periods of abnormal rainfall and temperature, especially flooding, can potentially contribute to reductions in risk of viral transmission., Author summary Dengue is a rapidly spreading mosquito-borne disease transmitted primarily by Aedes aegypti mosquitoes. As climate change leads to extremes in rainfall and temperature, the abundance and populations of these vectors will be affected, thus influencing transmission of dengue. Using satellite-derived climate data for Kenya, we classified months that experienced highly abnormal rainfall and temperature as extreme climate events (floods, droughts, heat waves, or cold waves). We compared the average monthly Ae. aegypti abundance and confirmed dengue counts following extreme climate months using lag periods of one month and two months, respectively. This study utilized several statistical models to account for differences among study sites and time. Floods resulted in significantly increased egg and adult abundance. Our results contributed to a better understanding of the effect of climate variability and change on dengue. As suggested by our observed increase in vector counts yet a relatively unchanged dengue infection risk, human behavior can help reduce viral transmission. Targeted interventions should be focused on both reducing vector populations and limiting human-vector contact, especially during these climate anomalies.

Hay fever patients can be helped in managing their symptoms by predicting the severity of the upcoming grass pollen seasons., Allergic rhinitis is an inflammation in the nose caused by overreaction of the immune system to allergens in the air. Managing allergic rhinitis symptoms is challenging and requires timely intervention. The following are major questions often posed by those with allergic rhinitis: How should I prepare for the forthcoming season? How will the season’s severity develop over the years? No country yet provides clear guidance addressing these questions. We propose two previously unexplored approaches for forecasting the severity of the grass pollen season on the basis of statistical and mechanistic models. The results suggest annual severity is largely governed by preseasonal meteorological conditions. The mechanistic model suggests climate change will increase the season severity by up to 60%, in line with experimental chamber studies. These models can be used as forecasting tools for advising individuals with hay fever and health care professionals how to prepare for the grass pollen season.

The use of cannabis for the treatment of migraine has become an area of interest with the legalization of medical cannabis in the USA. Understanding the mechanisms of cannabinoids, available studies, and best clinical recommendations is crucial for headache providers to best serve patients. Patients utilizing medical cannabis for migraine have reported improvement in migraine profile and common comorbidities. Reduction in prescription medication is also common, especially opioids. Side effects exist, with the majority being mild. Not enough data is available for specific dose recommendations, but THC and CBD appear to mediate these observed effects. The purpose of this article is twofold: review the limited research surrounding cannabis for migraine disease and reflect on clinical management experiences to provide recommendations that best capture the potential use of cannabis for migraine.

Climate drives population dynamics through multiple mechanisms, which can lead to seemingly context-dependent effects of climate on natural populations. For climate-sensitive diseases, such as dengue, chikungunya, and Zika, climate appears to have opposing effects in different contexts. Here we show that a model, parameterized with laboratory measured climate-driven mosquito physiology, captures three key epidemic characteristics across ecologically and culturally distinct settings in Ecuador and Kenya: the number, timing, and duration of outbreaks. The model generates a range of disease dynamics consistent with observed Aedes aegypti abundances and laboratory-confirmed arboviral incidence with variable accuracy (28–85% for vectors, 44–88% for incidence). The model predicted vector dynamics better in sites with a smaller proportion of young children in the population, lower mean temperature, and homes with piped water and made of cement. Models with limited calibration that robustly capture climate-virus relationships can help guide intervention efforts and climate change disease projections., The effects of climate on vector-borne disease systems are highly context-dependent. Here, the authors incorporate laboratory-measured physiological traits of the mosquito Aedes aegypti into climate-driven mechanistic models to predict number, timing, and duration of outbreaks in Ecuador and Kenya.

Transmission of SARS-CoV-2 is uncontrolled in many parts of the world; control is compounded in some areas by the higher transmission potential of the B.1.1.7 variant1, which has now been reported in 94 countries. It is unclear whether the response of the virus to vaccines against SARS-CoV-2 on the basis of the prototypic strain will be affected by the mutations found in B.1.1.7. Here we assess the immune responses of individuals after vaccination with the mRNA-based vaccine BNT162b22. We measured neutralizing antibody responses after the first and second immunizations using pseudoviruses that expressed the wild-type spike protein or a mutated spike protein that contained the eight amino acid changes found in the B.1.1.7 variant. The sera from individuals who received the vaccine exhibited a broad range of neutralizing titres against the wild-type pseudoviruses that were modestly reduced against the B.1.1.7 variant. This reduction was also evident in sera from some patients who had recovered from COVID-19. Decreased neutralization of the B.1.1.7 variant was also observed for monoclonal antibodies that target the N-terminal domain (9 out of 10) and the receptor-binding motif (5 out of 31), but not for monoclonal antibodies that recognize the receptor-binding domain that bind outside the receptor-binding motif. Introduction of the mutation that encodes the E484K substitution in the B.1.1.7 background to reflect a newly emerged variant of concern (VOC 202102/02) led to a more-substantial loss of neutralizing activity by vaccine-elicited antibodies and monoclonal antibodies (19 out of 31) compared with the loss of neutralizing activity conferred by the mutations in B.1.1.7 alone. The emergence of the E484K substitution in a B.1.1.7 background represents a threat to the efficacy of the BNT162b2 vaccine.

Atypical memory B cells (aMBCs) are found in elevated numbers in individuals exposed to malaria. A key question is whether malaria induces aMBCs as a result of exposure to Ag, or non-Ag-specific mechanisms. We identified Plasmodium and bystander tetanus toxoid (TT) specific B cells in individuals from areas of previous and persistent exposure to malaria using tetramers. Malaria-specific B cells were more likely to be aMBCs than TT-specific B cells. However, TT-specific B cells from individuals with continuous exposure to malaria were more likely to be aMBCs than TT-specific B cells in individuals from areas where transmission has ceased. Finally, sequences of BCRs specific for a blood stage malaria-Ag were more highly mutated than sequences from TT-specific BCRs and under strong negative selection, indicative of ongoing antigenic pressure. Our data suggest both persistent Ag exposure and the inflammatory environment shape the B-cell response to malaria and bystander Ags.

Familial Adenomatous Polyposis (FAP) is an autosomal dominant disorder caused by mutation of the APC gene presenting with numerous colorectal adenomatous polyps and a near 100% risk of colon cancer. Preliminary research findings from our group indicate that FAP patients experience significant deficits across many cognitive domains. In the current study, fMRI brain metrics in a FAP population and matched controls were used to further the mechanistic understanding of reported cognitive deficits. This research identified and characterized any possible differences in resting brain networks and associations between neural network changes and cognition from 34 participants (18 FAP patients, 16 healthy controls). Functional connectivity analysis was performed using FSL with independent component analysis (ICA) to identify functional networks. Significant differences between cases and controls were observed in 8 well-established resting state networks. With the addition of an aggregate cognitive measure as a covariate, these differences were virtually non-existent, indicating a strong correlation between cognition and brain activity at the network level. The data indicate robust and pervasive effects on functional neural network activity among FAP patients and these effects are likely involved in cognitive deficits associated with this disease.

Introduction Recent studies have identified subtypes of small cell lung carcinoma (SCLC) defined by the RNA expression of ASCL1, NEUROD1, POU2F3, and YAP1 transcriptional regulators. There are only limited data on the distribution of these markers at the protein level and associated pathologic characteristics in clinical SCLC samples. Methods The expression of ASCL1, NEUROD1, POU2F3, and YAP1 was analyzed by immunohistochemistry in 174 patient samples with SCLC. Subtypes defined by these markers were correlated with histologic characteristics, expression of classic neuroendocrine markers (synaptophysin, chromogranin A, CD56, INSM1), and other SCLC markers, including the neuroendocrine phenotype-associated markers TTF-1 and DLL3. Results ASCL1 and NEUROD1 expression had the following distribution: (1) 41% ASCL1+/NEUROD1−; (2) 37% ASCL1+/NEUROD1+; (3) 8% ASCL1−/NEUROD1+; and (4) 14% ASCL1−/NEUROD1−. On the basis of their relative expression, 69% of cases were ASCL1-dominant and 17% were NEUROD1-dominant. POU2F3 was expressed in 7% of SCLC and was mutually exclusive of ASCL1 and NEUROD1. YAP1 was expressed at low levels, primarily in combined SCLC, and was not exclusive of other subtypes. Both ASCL1-dominant and NEUROD1-dominant subtypes were associated with neuroendocrine markerhigh/TTF-1high/DLL3high profile, whereas POU2F3 and other ASCL1/NEUROD1 double-negative tumors were neuroendocrine markerlow/TTF-1low/DLL3low. Conclusions This is the first comprehensive immunohistochemical and histopathologic analysis of novel SCLC subtypes in patient samples. We confirm that ASCL1/NEUROD1 double-negative tumors represent a distinct neuroendocrine-low subtype of SCLC, which is either uniquely associated with POU2F3 or lacks a known dominant regulator. The expression profiles of these markers appear more heterogeneous in native samples than in experimental models, particularly with regard to the high prevalence of ASCL1/NEUROD1 coexpression. These findings may have prognostic and therapeutic implications and warrant further clinical investigation.

The FPN Q248H mutation protects children from anemia, hemolysis, and iron deficiency, but not malaria or bacterial infection., Iron acquisition is critical for life. Ferroportin (FPN) exports iron from mature erythrocytes, and deletion of the Fpn gene results in hemolytic anemia and increased fatality in malaria-infected mice. The FPN Q248H mutation (glutamine to histidine at position 248) renders FPN partially resistant to hepcidin-induced degradation and was associated with protection from malaria in human studies of limited size. Using data from cohorts including over 18,000 African children, we show that the Q248H mutation is associated with modest protection against anemia, hemolysis, and iron deficiency, but we found little evidence of protection against severe malaria or bacteremia. We additionally observed no excess Plasmodium growth in Q248H erythrocytes ex vivo, nor evidence of selection driven by malaria exposure, suggesting that the Q248H mutation does not protect from malaria and is unlikely to deprive malaria parasites of iron essential for their growth.

Locating myxomatosis resistanceMyxomatosis is a viral infection that was deliberately introduced from American cottontail rabbits into European rabbit populations to control their population. Over the past 60 years or so, similar resistance variants have emerged in parallel in the United Kingdom, France, and Australia. Alveset al.discovered that the basis for this resistance is polygenic, with selection converging on several host immunity and proviral alleles (see the Perspective by Miller and Metcalf). Interestingly, it now seems that the virus is counterevolving immune suppressive traits.Science, this issue p.1319; see also p.1277

HIV Nef counteracts cellular host restriction factors SERINC3 and SERINC5, but our understanding of how naturally occurring global Nef sequence diversity impacts these activities is limited. Here, we quantify SERINC3 and SERINC5 internalization function for 339 Nef clones, representing the major pandemic HIV-1 group M subtypes A, B, C and D. We describe distinct subtype-associated hierarchies for Nef-mediated internalization of SERINC5, for which subtype B clones display the highest activities on average, and of SERINC3, for which subtype B clones display the lowest activities on average. We further identify Nef polymorphisms that modulate its ability to counteract SERINC proteins, including substitutions in the N-terminal domain that selectively impair SERINC3 internalization. Our findings demonstrate that the SERINC antagonism activities of HIV Nef differ markedly among major viral subtypes and between individual isolates within a subtype, suggesting that variation in these functions may contribute to global differences in viral pathogenesis., Author summary Cellular restriction factors dampen viral replication and reduce pathogenesis. In response, HIV has evolved a variety of mechanisms to counteract restriction factors, including the ability of its Nef protein to internalize Serine incorporator (SERINC) proteins 3 and 5 from the infected cell surface, thereby enhancing infectivity of viral particles. Nef displays substantial sequence diversity, but how this impacts SERINC antagonism remains unclear. To examine this, we used cell culture models to measure SERINC internalization function for 339 participant-derived Nef clones, representing four globally relevant HIV-1 group M subtypes. We observed significant variability in Nef function among circulating viral strains and subtypes. We also identified naturally occurring Nef mutations that modulate its ability to counteract SERINC proteins, including some that selectively impair SERINC3 internalization. These findings uncover viral features that may contribute to global differences in HIV pathogenesis and provide new insight into the interactions between Nef and SERINC restriction factors that can inform future mechanistic studies.

Malaria is caused by apicomplexan parasites of the genus Plasmodium. While infection continues to pose a risk for the majority of the global population, the burden of disease mainly resides in Sub-Saharan Africa. Although immunity develops against disease, this requires years of persistent exposure and is not associated with protection against infection. Repeat infections occur due to the parasite's ability to disrupt or evade the host immune responses. However, despite many years of study, the mechanisms of this disruption remain unclear. Previous studies have demonstrated a parasite-induced failure in dendritic cell (DCs) function affecting the generation of helper T cell responses. These T cells fail to help B cell responses, reducing the production of antibodies that are necessary to control malaria infection. This review focuses on our current understanding of the effect of Plasmodium parasite on DC function, DC-T cell interaction, and T cell activation. A better understanding of how parasites disrupt DC-T cell interactions will lead to new targets and approaches to reinstate adaptive immune responses and enhance parasite immunity.

Arboviruses are among the most important emerging pathogens due to their increasing public health impact. In Kenya, continued population growth and associated urbanization are conducive to vector spread in both urban and rural environments, yet mechanisms of viral amplification in vector populations is often overlooked when assessing risks for outbreaks. Thus, the characterization of local arbovirus circulation in mosquito populations is imperative to better inform risk assessments and vector control practices. Aedes species mosquitoes were captured at varying stages of their life cycle during different seasons between January 2014 and May 2016 at four distinct sites in Kenya, and tested for chikungunya (CHIKV), dengue (DENV) and Zika (ZIKV) viruses by RT-PCR. CHIKV was detected in 45 (5.9%) and DENV in 3 (0.4%) mosquito pools. No ZIKV was detected. Significant regional variation in prevalence was observed, with greater frequency of CHIKV on the coast. DENV was detected exclusively on the coast. Both viruses were detected in immature mosquitoes of both sexes, providing evidence of transovarial transmission of these arboviruses in local mosquitoes. This phenomenon may be driving underlying viral maintenance that may largely contribute to periodic re-emergence among humans in Kenya., Author summary Transovarial transmission, or vertical transmission, is the spread of a pathogen from parent to offspring. It has been observed that some mosquito-borne viruses can be transmitted from female mosquitoes to their offspring during follicle development or during oviposition. The occurrence of transovarial transmission is evident in the presence of virally infected male mosquitoes, which typically do not take bloodmeals, and the presence of virus in immature mosquitoes of any sex. Transovarial transmission aids in the amplification of mosquito-borne viruses in the environment by increasing the number of infected mosquitoes in a given region, thus expanding the possibility of viral transmission to humans. The combination of transovarial transmission and the preservation of viable eggs during dry seasons may trigger sudden amplification of the virus after rainy periods, resulting in an outbreak. This study provides some of the first evidence of transovarial transmission of chikungunya and dengue viruses in Aedes aegypti mosquitoes in Africa during interepidemic periods, which has important implications for local virus persistence and epidemic patterns.

The full diversity of the circulating human B cell compartment is unknown. Flow cytometry analysis suggests that in addition to naïve and memory B cells, there exists a population of CD11c+, CD27− CD21− “atypical” B cells, that are associated with chronic or recurrent infection and autoimmunity. We used single cell RNA-seq approaches to examine the diversity of both antigen-specific B cells and total B cells in healthy subjects and individuals naturally-exposed to recurrent malaria infections. This analysis revealed two B cell lineages: a classical lineage of activated and resting memory B cells, and an atypical-like lineage. Surprisingly, the atypical lineage was common in both malaria exposed individuals and non-exposed healthy controls. Using barcoded antibodies in conjunction with our transcriptomic data, we found that atypical lineage cells in healthy individuals lack many atypical B markers and thus represent an undercounted cryptic population. We further determined using antigen specific probes that atypical cells can be induced by primary vaccination in humans and can be recalled upon boosting. Collectively these data suggest that atypical cells are not necessarily pathogenic but can be a normal component of B responses to antigen.

Background Iron deficiency (ID) is a major public health burden in African children and accurate prevalence estimates are important for effective nutritional interventions. However, ID may be incorrectly estimated in Africa because most measures of iron status are altered by inflammation and infections such as malaria. Through the current study, we have assessed different approaches to the prediction of iron status and estimated the burden of ID in African children. Methods We assayed iron and inflammatory biomarkers in 4853 children aged 0–8 years from Kenya, Uganda, Burkina Faso, South Africa, and The Gambia. We described iron status and its relationship with age, sex, inflammation, and malaria parasitemia. We defined ID using the WHO guideline (ferritin Results The prevalence of ID was highest at 1 year of age and in male infants. Inflammation and malaria parasitemia were associated with all iron biomarkers, although transferrin saturation was least affected. Overall prevalence of WHO-defined ID was 34% compared to 52% using the inflammation and malaria regression-corrected estimate. This unidentified burden of ID increased with age and was highest in countries with high prevalence of inflammation and malaria, where up to a quarter of iron-deficient children were misclassified as iron replete. Transferrin saturation Conclusions The prevalence of ID is underestimated in African children when defined using the WHO guidelines, especially in malaria-endemic populations, and the use of transferrin saturation may provide a more accurate approach. Further research is needed to identify the most accurate measures for determining the prevalence of ID in sub-Saharan Africa.

Background Iron deficiency (ID) and malaria are common causes of ill-health and disability among children living in sub-Saharan Africa. Although iron is critical for the acquisition of humoral immunity, little is known about the effects of ID on antibody responses to Plasmodium falciparum malaria. Methods The study included 1794 Kenyan and Ugandan children aged 0–7 years. We measured biomarkers of iron and inflammation, and antibodies to P. falciparum antigens including apical merozoite antigen 1 (anti-AMA-1) and merozoite surface antigen 1 (anti-MSP-1) in cross-sectional and longitudinal studies. Results The overall prevalence of ID was 31%. ID was associated with lower anti-AMA-1 and anti-MSP-1 antibody levels in pooled analyses adjusted for age, sex, study site, inflammation, and P. falciparum parasitemia (adjusted mean difference on a log-transformed scale (β) −0.46; 95 confidence interval [CI], −.66, −.25 P, Iron deficiency is associated with reduced P falciparum-specific antibody levels. Ferritin, transferrin saturation, hepcidin, and soluble transferrin receptor levels were associated with malaria-specific antibody levels. Iron deficiency in early life may influence subsequent malaria antibody levels.

Cooperative DNA binding is a key feature of transcriptional regulation. Here we examined the role of cooperativity in Notch signaling by CRISPR-mediated engineering of mice in which neither Notch1 nor Notch2 can homo- or heterodimerize, essential for cooperative binding to sequence-paired sites (SPS) located near many Notch-regulated genes. Although most known Notch-dependent phenotypes were unaffected in Notch1/2 dimer–deficient mice, a subset of tissues proved highly sensitive to loss of cooperativity. These phenotypes include heart development, compromised viability in combination with low gene dose, and the gut, developing ulcerative colitis in response to 1% dextran sulfate sodium (DSS). The most striking phenotypes—gender imbalance and splenic marginal zone B-cell lymphoma—emerged in combination with gene dose reduction or when challenged by chronic fur mite infestation. This study highlights the role of the environment in malignancy and colitis and is consistent with Notch-dependent anti-parasite immune responses being compromised in Notch dimer–deficient animals., This study reveals that dimerization of the signaling protein Notch contributes in vivo to intestinal homeostasis. Loss of cooperative DNA binding can manifest as Notch gain- or loss-of-function phenotypes. Importantly, mite infestation exacerbates all phenotypes, and triggers marginal zone B cell hyperproliferation in mutant animals, with implications for the role of dust mite allergies in human IBD and cancer.

Cooperative DNA binding is a key feature of transcriptional regulation. Here we examined the role of cooperativity in Notch signaling by CRISPR-mediated engineering of mice in which neither Notch1 nor Notch2 can homo- or heterodimerize, essential for cooperative binding to sequence paired sites (SPS) located near many Notch-regulated genes. While most known Notch-dependent phenotypes were unaffected in Notch1/2 dimer-deficient mice, a subset of tissues proved highly sensitive to loss of cooperativity. These phenotypes include heart development, compromising viability in combination with low gene dose, and the gut, developing ulcerative colitis in response to 1% DSS. The most striking phenotypes – gender imbalance and splenic marginal zone B cell lymphoma – emerged in combination with dose reduction or when challenged by chronic fur mite infestation. This study highlights the role of the environment in malignancy and colitis, and is consistent with Notch-dependent anti-parasite immune responses being compromised in the dimer deficient animals.HighlightsNotch dimerization has an in vivo role in contributing to intestinal homeostasisLoss of cooperativity can manifest as Notch gain or loss of function phenotypesMite infestation exacerbates all phenotypes, triggers MZB hyperproliferation in mutant animalsMite-infested mutant mice develop SMZL with age

Wolbachia , a common vertically transmitted symbiont, can protect insects against viral infection and prevent mosquitoes from transmitting viral pathogens. For this reason, Wolbachia- infected mosquitoes are being released to prevent the transmission of dengue and other arboviruses. An important question for the long-term success of these programmes is whether viruses can evolve to escape the antiviral effects of Wolbachia. We have found that Wolbachia altered the outcome of competition between strains of the DCV virus in Drosophila. However, Wolbachia still effectively blocked the virus genotypes that were favoured in the presence of the symbiont. We conclude that Wolbachia did cause an evolutionary response in viruses, but this has little or no impact on the effectiveness of virus blocking.

Introduction: Little is known about the burden of hypertension and diabetes on emergency department (ED) utilization and hospitalizations in sub-Saharan Africa.Methods: A retrospective review of adult ED patients in northern Tanzania was performed from September 2017 through March 2018. Hypertension was defined as documented diagnosis of hypertension or blood pressure ≥ 140/90 mm Hg. Diabetes was defined as documented diagnosis of diabetes mellitus or random glucose ≥ 200 mg/dL.Results: Of 3961 adult ED patients, 1359 (34.3%) had hypertension, 518 (13.1%) had diabetes, and 273 (6.9%) had both. Both hypertension (OR 1.42, 95% CI 1.23-1.63, P

Legalization of medical cannabis has occurred in 33 states and the District of Columbia, and recreational use has increased exponentially since 2013. As a result, it is important to understand how cannabis interacts with other drugs and has potential risks for patients on concomitant medications. Components of medical cannabis can inhibit or compete for several cytochrome P450 (CYP) hepatic isoenzymes, UDP-glucuronosyltransferases, and P-glycoprotein. These enzymes and transporters are involved in the metabolism and absorption of numerous medications, including anticoagulants (ACs) and antiplatelet agents (APs), potentially causing harmful drug-drug interactions. ACs and/or APs are often prescribed to high-risk patients with cardiac conditions, a history of myocardial infarction, or stroke. Cannabis may cause these medications to be less efficacious and put patients at risk for recurrent cardiovascular and cerebrovascular events. Several case reports show cannabis may inhibit the metabolism of warfarin because of CYP2C9 interactions, resulting in increased plasma concentrations, increased international normalized ratio, and risk of bleeding. Cannabidiol inhibits CYP2C19, an isoenzyme responsible for the transformation of clopidogrel to its active thiol metabolite. This interaction could lead to subtherapeutic levels of active metabolite and possibly increased stroke risk. Within this review, a total of 665 articles were screened from PubMed and EMBASE. Four case reports, 1 in vitro study, and 1 pharmacokinetic article were found to be of relevance. This review serves to examine reported and potential cannabis interactions with APs/ACs to help inform patients and health care providers of possible risks and knowledge gaps.

Summary B‐cell and antibody responses to Plasmodium spp., the parasite that causes malaria, are critical for control of parasitemia and associated immunopathology. Antibodies also provide protection to reinfection. Long‐lasting B‐cell memory has been shown to occur in response to Plasmodium spp. in experimental model infections, and in human malaria. However, there are reports that antibody responses to several malaria antigens in young children living with malaria are not similarly long‐lived, suggesting a dysfunction in the maintenance of circulating antibodies. Some studies attribute this to the expansion of atypical memory B cells (AMB), which express multiple inhibitory receptors and activation markers, and are hyporesponsive to B‐cell receptor (BCR) restimulation in vitro. AMB are also expanded in other chronic infections such as tuberculosis, hepatitis B and C, and HIV, as well as in autoimmunity and old age, highlighting the importance of understanding their role in immunity. Whether AMB are dysfunctional remains controversial, as there are also studies in other infections showing that AMB can produce isotype‐switched antibodies and in mouse can contribute to protection against infection. In light of these controversies, we review the most recent literature on either side of the debate and challenge some of the currently held views regarding B‐cell responses to Plasmodium infections.

Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened\ud risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified\ud 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and\ud implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved\ud in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression\ud with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were\ud putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry\ud lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression\ud and imply that a continuous measure of risk underlies the clinical phenotype.

Biofilms provide refuge for cancerous bacteria Familial adenomatous polyposis (FAP) causes benign polyps along the colon. If left untreated, FAP leads to a high incidence of colon cancer. To understand how polyps influence tumor formation, Dejea et al. examined the colonic mucosa of FAP patients. They discovered biofilms containing the carcinogenic versions of the bacterial species Escherichia coli and Bacteroides fragilis . Colon tissue from FAP patients exhibited greater expression of two bacterial genes that produce secreted oncotoxins. Studies in mice showed that specific bacteria could work together to induce colon inflammation and tumor formation. Science , this issue p. 592

Aminopeptidase N (APN/CD13) is a multifunctional glycoprotein that acts as a peptidase, receptor, and signalling molecule in a tissue-dependent manner. The activities of APN have been implicated in the progression of many cancers, pointing toward significant therapeutic potential for cancer treatment. However, despite the tumour-specific functions of this protein that have been uncovered, the ubiquitous nature of its expression in normal tissues as generally reported remains a limitation to the potential utility of APN as a target for cancer therapeutics and drug discovery. With this in mind, we have extensively explored the literature, and present a comprehensive review that for the first-time provides evidence to support the suggestion that tumour-expressed APN may in fact be unique in structure, function, substrate specificity and activity, contrary to its nature in normal tissues. The review also focuses on the biology of APN, and its “moonlighting” functional roles in both normal physiology and cancer development. Several APN-targeting approaches that have been explored over recent decades as therapeutic strategies in cancer treatment, including APN-targeting agents reported both in preclinical and clinical studies, are also extensively discussed. This review concludes by posing critical questions about APN that remain unanswered and unexplored, hence providing opportunities for further research.

Reports of the beneficial roles of butyrate in cardiovascular diseases, such as atherosclerosis and ischemic stroke, are becoming increasingly abundant. However, the mechanisms of its bioactivities remain largely unknown. In this study, we explored the effects of butyrate on endothelial dysfunction and its potential underlying mechanism. In our study, ApoE-/- mice were fed with high-fat diet (HFD) for ten weeks to produce atherosclerosis models and concurrently treated with or without sodium butyrate daily. Thoracic aortas were subsequently isolated from C57BL/6 wild-type (WT), PPARδ-/-, endothelial-specific PPARδ wild-type (EC-specific PPARδ WT) and endothelial-specific PPARδ knockout (EC-specific PPARδ KO) mice were stimulated with interleukin (IL)-1β with or without butyrate ex vivo. Our results demonstrated that butyrate treatment rescued the impaired endothelium-dependent relaxations (EDRs) in thoracic aortas of HFD-fed ApoE-/- mice. Butyrate also rescued impaired EDRs in IL-1β-treated thoracic aorta ring ex vivo. Global and endothelial-specific knockout of PPARδ eliminated the protective effects of butyrate against IL-1β-induced impairment to EDRs. Butyrate abolished IL-1β-induced reactive oxygen species (ROS) production in endothelial cells while the inhibitory effect was incapacitated by genetic deletion of PPARδ or pharmacological inhibition of PPARδ. IL-1β increased NADPH oxidase 2 (NOX2) mRNA and protein expressions in endothelial cells, which were prevented by butyrate treatment, and the effects of butyrate were blunted following pharmacological inhibition of PPARδ. Importantly, butyrate treatment upregulated the miR-181b expression in atherosclerotic aortas and IL-1β-treated endothelial cells. Moreover, transfection of endothelial cells with miR-181b inhibitor abolished the suppressive effects of butyrate on NOX2 expressions and ROS generation in endothelial cells. To conclude, butyrate prevents endothelial dysfunction in atherosclerosis by reducing endothelial NOX2 expression and ROS production via the PPARδ/miR-181b pathway.