Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci.

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.

The Bangladesh Risk of Acute Vascular Events (BRAVE) Study: objectives and design.

During recent decades, Bangladesh has experienced a rapid epidemiological transition from communicable to non-communicable diseases. Coronary heart disease (CHD), with myocardial infarction (MI) as its main manifestation, is a major cause of death in the country. However, there is limited reliable evidence about its determinants in this population. The Bangladesh Risk of Acute Vascular Events (BRAVE) study is an epidemiological bioresource established to examine environmental, genetic, lifestyle and biochemical determinants of CHD among the Bangladeshi population. By early 2015, the ongoing BRAVE study had recruited over 5000 confirmed first-ever MI cases, and over 5000 controls "frequency-matched" by age and sex. For each participant, information has been recorded on demographic factors, lifestyle, socioeconomic, clinical, and anthropometric characteristics. A 12-lead electrocardiogram has been recorded. Biological samples have been collected and stored, including extracted DNA, plasma, serum and whole blood. Additionally, for the 3000 cases and 3000 controls initially recruited, genotyping has been done using the CardioMetabochip+ and the Exome+ arrays. The mean age (standard deviation) of MI cases is 53 (10) years, with 88 % of cases being male and 46 % aged 50 years or younger. The median interval between reported onset of symptoms and hospital admission is 5 h. Initial analyses indicate that Bangladeshis are genetically distinct from major non-South Asian ethnicities, as well as distinct from other South Asian ethnicities. The BRAVE study is well-placed to serve as a powerful resource to investigate current and future hypotheses relating to environmental, biochemical and genetic causes of CHD in an important but under-studied South Asian population.

Stakeholder engagement to introduce a standardised register for improved inpatient care of newborns and sick children in Bangladesh.

Background: Despite a global decrease of 59% in under-five mortality rates from 1990 to 2021, child survival remains a pressing issue. This holds true for Bangladesh, as well. In response, the Government of Bangladesh introduced a standardised register for strengthening the inpatient management of newborns and sick children in 2021. Methods: We employed a comprehensive four-phase stakeholder engagement process to implement an inpatient register for newborns and sick children. The first stage included identifying and prioritising potential stakeholders at the national and district levels. We identified eight organisations involved in newborn and child health and selected 24 participants from various other sectors for workshops aimed at raising awareness about the register's introduction. These stakeholders also participated in the register's design, development strategies planning, and implementation phases. These phases were led by the 'National Newborn Health and IMCI programme' with support from various partners. A technical working group reviewed existing registers and helped prepare training materials. Feedback from each workshop was crucial in finalising the register. Results: The Government of Bangladesh has recognised the need for an indoor register for newborns and sick children, which was to be established in collaboration with development partners. This initiative can enhance the quality of care for sick children and increase service provider accountability. Due to its successful implementation, it will continue to be used in the Kushtia and Dinajpur districts, with plans for a nationwide scale-up. The Government has allocated funds in the next health sector programme for orientation and register printing. A strengths, weaknesses, opportunities, and threats (SWOT) analysis of the stakeholder engagement process highlighted strengths such as a context-specific approach and collaborative engagement, as well as challenges such as time resource requirements. Conclusions: Implementing an inpatient register for newborns and sick children through stakeholder engagement can effectively improve child health care services. Aside from challenges such as resource intensiveness and stakeholder commitments, success depended on the organising authority's expertise in relationship building, budget allocation, time management, and workforce dedication. Therefore, strategic planning, staff recruitment, networking, and budgeting are crucial for successful stakeholder engagement and health care initiatives.

Introducing a standardised register for strengthening the inpatient management of newborns and sick children: Implementation research in selected health facilities of Bangladesh.

Background: It is imperative to maintain accurate documentation of clinical interventions aimed at enhancing the quality of care for newborns and sick children. The National Newborn Health and IMCI programme of Bangladesh led the development of a standardised register for managing newborns and sick children under five years of age during inpatient care through stakeholder engagement. We aimed to assess the implementation outcomes of the standardised register in the inpatient department. Methods: We conducted implementation research in two district hospitals and two sub-district hospitals of Kushtia and Dinajpur districts from November 2022 to January 2023 to assess the implementation outcomes of the standardised register. We assessed the following World Health Organization implementation outcome variables: usability, acceptability, adoption (actual use), fidelity (completeness and accuracy), and utility (quality of care) of the register against preset benchmarks. We collected data through structured interviews with health care providers; participant enrolment; and data extraction from inpatient registers and case record forms. Results: The average usability and acceptability scores among health care providers were 73 (standard deviation (SD) = 14) and 82 (SD = 14) out of 100, respectively. The inpatient register recorded 96% (95% confidence interval (CI) = 95-97) of under-five children who were admitted to the inpatient department (adoption - actual use). The proportions of completed data elements in the inpatient register were above the preset benchmark of 70% for all the assessed data elements except 'investigation done' (24%; 95% CI = 23-26) (fidelity - completeness). The percentage agreements between government-appointed nurses posted and study-appointed nurses were above the preset benchmark of 70% for all the reported variables (fidelity - accuracy). The kappa coefficient for the overall level of agreement between these two groups regarding reported variables indicated moderate to substantial agreement. The proportion of newborns with sepsis receiving injectable antibiotics was 62% (95% CI = 47-75) (utility - quality of care). We observed some variability in the completeness and accuracy of the inpatient register by district and facility type. Conclusions: The inpatient register was positively received by health care providers, with evaluations of implementation outcome variables showing encouraging results. Our findings could inform evidence-based decision-making on the implementation and scale-up of the inpatient register in Bangladesh, as well as other low- and middle-income countries.