The influence of human genetic variation on early transcriptional responses and protective immunity following immunization with Rotarix vaccine in infants in Ho Chi Minh City in Vietnam : a study protocol for an open single-arm interventional trial [awaiting peer review]

Background: Rotavirus (RoV) remains the leading cause of acute gastroenteritis in infants and children aged under five years in both high- and low-middle-income countries (LMICs). In LMICs, RoV infections are associated with substantial mortality. Two RoV vaccines (Rotarix and Rotateq) are widely available for use in infants, both of which have been shown to be highly efficacious in Europe and North America. However, for unknown reasons, these RoV vaccines have markedly lower efficacy in LMICs. We hypothesize that poor RoV vaccine efficacy across in certain regions may be associated with genetic heritability or gene expression in the human host. Methods/design: We designed an open-label single-arm interventional trial with the Rotarix RoV vaccine to identify genetic and transcriptomic markers associated with generating a protective immune response against RoV. Overall, 1,000 infants will be recruited prior to Expanded Program on Immunization (EPI) vaccinations at two months of age and vaccinated with oral Rotarix vaccine at two and three months, after which the infants will be followed-up for diarrheal disease until 18 months of age. Blood sampling for genetics, transcriptomics, and immunological analysis will be conducted before each Rotarix vaccination, 2-3 days post-vaccination, and at each follow-up visit (i.e. 6, 12 and 18 months of age). Stool samples will be collected during each diarrheal episode to identify RoV infection. The primary outcome will be Rotarix vaccine failure events (i.e. symptomatic RoV infection despite vaccination), secondary outcomes will be antibody responses and genotypic characterization of the infection virus in Rotarix failure events. Discussion: This study will be the largest and best powered study of its kind to be conducted to date in infants, and will be critical for our understanding of RoV immunity, human genetics in the Vietnam population, and mechanisms determining RoV vaccine-mediated protection. Registration: ClinicalTrials.gov, ID: NCT03587389. Registered on 16 July 2018

Novel genetic loci underlying human intracranial volume identified through genome-wide association

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five novel loci for intracranial volume and confirmed two known signals. Four of the loci are also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic=0.748), which indicated a similar genetic background and allowed for the identification of four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, Parkinson’s disease, and enriched near genes involved in growth pathways including PI3K–AKT signaling. These findings identify biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

Genetic architecture of subcortical brain structures in 38,851 individuals

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease

Genetic architecture of subcortical brain structures in 38,851 individuals

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease

Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial

Background Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population. Methods AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2–15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921. Findings Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76–1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [<1%]; p=0·038) at 6 months. Interpretation Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke

Assisting Vietnamese Mango Farmers to Capture Greater Benefits through Improved Supply Chain Management

In the developing countries, traditional supply chains for fresh produce are giving way to new supermarket-led supply chains. The rapid transformation in the fruit and vegetable sector is due to the meteoric rise of supermarkets, hypermarkets, superstores, neighborhood stores, convenience stores, and discount stores, which are impacting on smallholder farmers. Th is change is also impacting on both upstream and downstream market intermediaries through the demand for safe, high-quality produce that has been produced in a sustainable manner. Problems with procurement in traditional supply chains include few product standards, inconsistent supply, highly variable transaction costs, and limited market information. Supermarkets are now setting new procurement practices and supply systems which focus on reducing costs and improving quality to enable them to sell at lower prices. Th is will allow them to win over consumers and to obtain a larger market share. However, the ability of smallholder farmers, collector agents, and wholesalers in the Mekong Delta to meet safe food levels and the quality demands of domestic and overseas supermarkets can only be obtained through improving their production and supply chain practices. The implementation of new production and postharvest practices and the modernization of these supply chains may preclude many smallholder farmers from participating. Smallholder farmers must develop risk minimization strategies, such as forming collaborative marketing groups, implementing new crop management and production systems, improving the packaging, and creating more efficient transport methods and handling practices to provide a safe, competitively priced, high-quality product. Understanding the supply chain and where to intervene are essential if farmers and all supply chain participants are to benefi t. In this paper, we describe mango supply chains in the Mekong Delta, provide empirical data collected from surveys, and highlight improvements smallholder farmers have been making to achieve greater benefits

Convolutional Neural Networks Improve Radiologists’ Performance in Breast Cancer Screening for Vietnamese patients

Nowadays, breast cancer is one of the leading cancers in Vietnam, and it causes approximately 6000 deaths every year. The rate of breast cancer patients was calculated as 26.4/100000 persons in 2018. There are 21,555 new cases reported in 2020. However, these figures can be reduced with early detection and diagnosis of breast cancer disease in women through mammographic imaging. In many hospitals in Vietnam, there is a lack of experienced breast cancer radiologists. Therefore, it is helpful to develop an intelligent system to improve radiologists’ performance in breast cancer screening for Vietnamese patients. Our research aims to develop a convolutional neural network-based system for classifying breast cancer X-Ray images into three classes of BI-RADS categories as BI-RADS 1 (“normal”), BI-RADS 23 (“benign”) and BI-RADS 045 (“incomplete and malignance”). This classification system is developed based on the convolutional neural network with ResNet 50. The system is trained and tested on a breast cancer image dataset of Vietnamese patients containing 7912 images provided by Hanoi Medical University Hospital radiologists. The system accuracy uses the testing set achieved a macAUC (a macro average of the three AUCs) of 0.754. To validate our model, we performed a reader study with the breast cancer radiologists of the Hanoi Medical University Hospital, reading about 500 random images of the test set. We confirmed the efficacy of our model, which achieved performance comparable to a committee of two radiologists when presented with the same data. Additionally, the system takes only 6 seconds to interpret a breast cancer X-Ray image instead of 450 seconds interpreted by a Vietnamese radiologist. Therefore, our system can be considered as a “second radiologist,” which can improve radiologists’ performance in breast cancer screening for Vietnamese patients

Pathways to malaria persistence in remote central Vietnam: a mixed-method study of health care and the community

<p>Abstract</p> <p>Background</p> <p>There is increasing interest in underlying socio-cultural, economic, environmental and health-system influences on the persistence of malaria. Vietnam is a Mekong regional 'success story' after dramatic declines in malaria incidence following introduction of a national control program providing free bed-nets, diagnosis and treatment. Malaria has largely retreated to pockets near international borders in central Vietnam, where it remains a burden particularly among impoverished ethnic minorities. In these areas commune and village health workers are lynchpins of the program. This study in the central province of Quang Tri aimed to contribute to more effective malaria control in Vietnam by documenting the <it>non-biological </it>pathways to malaria persistence in two districts.</p> <p>Methods</p> <p>Multiple and mixed (qualitative and quantitative) methods were used. The formative stage comprised community meetings, observation of bed-net use, and focus group discussions and semi-structured interviews with health managers, providers and community. Formative results were used to guide development of tools for the assessment stage, which included a provider quiz, structured surveys with 160 community members and 16 village health workers, and quality check of microscopy facilities and health records at district and commune levels. Descriptive statistics and chi-square analysis were used for quantitative data.</p> <p>Results</p> <p>The study's key findings were the inadequacy of bed-nets (only 45% of households were fully covered) and sub-optimal diagnosis and treatment at local levels. Bed-net insufficiencies were exacerbated by customary sleeping patterns and population mobility. While care at district level seemed good, about a third of patients reportedly self-discharged early and many were lost to follow-up. Commune and village data suggested that approximately half of febrile patients were treated presumptively, and 10 village health workers did not carry artesunate to treat the potentially deadly and common <it>P. falciparum </it>malaria. Some staff lacked diagnostic skills, time for duties, and quality microscopy equipment. A few gaps were found in community knowledge and reported behaviours.</p> <p>Conclusion</p> <p>Malaria control cannot be achieved through community education alone in this region. Whilst appropriate awareness-raising is needed, it is most urgent to address weaknesses at systems level, including bed-net distribution, health provider staffing and skills, as well as equipment and supplies.</p