DNA methylation associated with postpartum depressive symptoms overlaps findings from a genome-wide association meta-analysis of depression

Background Perinatal depressive symptoms have been linked to adverse maternal and infant health outcomes. The etiology associated with perinatal depressive psychopathology is poorly understood, but accumulating evidence suggests that understanding inter-individual differences in DNA methylation (DNAm) patterning may provide insight regarding the genomic regions salient to the risk liability of perinatal depressive psychopathology. Results Genome-wide DNAm was measured in maternal peripheral blood using the Infinium MethylationEPIC microarray. Ninety-two participants (46% African-American) had DNAm samples that passed all quality control metrics, and all participants were within 7 months of delivery. Linear models were constructed to identify differentially methylated sites and regions, and permutation testing was utilized to assess significance. Differentially methylated regions (DMRs) were defined as genomic regions of consistent DNAm change with at least two probes within 1 kb of each other. Maternal age, current smoking status, estimated cell-type proportions, ancestry-relevant principal components, days since delivery, and chip position served as covariates to adjust for technical and biological factors. Current postpartum depressive symptoms were measured using the Edinburgh Postnatal Depression Scale. Ninety-eight DMRs were significant (false discovery rate \u3c 5%) and overlapped 92 genes. Three of the regions overlap loci from the latest Psychiatric Genomics Consortium meta-analysis of depression. Conclusions Many of the genes identified in this analysis corroborate previous allelic, transcriptomic, and DNAm association results related to depressive phenotypes. Future work should integrate data from multi-omic platforms to understand the functional relevance of these DMRs and refine DNAm association results by limiting phenotypic heterogeneity and clarifying if DNAm differences relate to the timing of onset, severity, duration of perinatal mental health outcomes of the current pregnancy or to previous history of depressive psychopathology

Prospective Longitudinal Study of the Pregnancy DNA Methylome: The US Pregnancy, Race, Environment, Genes (PREG) Study

Purpose The goal of the Pregnancy, Race, Environment, Genes study was to understand how social and environmental determinants of health (SEDH), pregnancy-specific environments (PSE) and biological processes influence the timing of birth and account for the racial disparity in preterm birth. The study followed a racially diverse longitudinal cohort throughout pregnancy and included repeated measures of PSE and DNA methylation (DNAm) over the course of gestation and up to 1 year into the postpartum period. Participants All women were between 18 and 40 years of age with singleton pregnancies and no diagnosis of diabetes or indication of assisted reproductive technology. Both mother and father had to self-identify as either African-American (AA) or European-American (EA). Maternal peripheral blood samples along with self-report questionnaires measuring SEDH and PSE factors were collected at four pregnancy visits, and umbilical cord blood was obtained at birth. A subset of participants returned for two additional postpartum visits, during which additional questionnaires and maternal blood samples were collected. The pregnancy and postpartum extension included n=240 (AA=126; EA=114) and n=104 (AA=50; EA=54), respectively. Findings to date One hundred seventy-seven women (AA=89, EA=88) met full inclusion criteria out of a total of 240 who were initially enrolled. Of the 63 participants who met exclusion criteria after enrolment, 44 (69.8%) were associated with a medical reason. Mean gestational age at birth was significantly shorter for the AA participants by 5.1 days (M=272.5 (SD=10.5) days vs M=277.6 (SD=8.3)). Future plans Future studies will focus on identifying key environmental factors that influence DNAm change across pregnancy and account for racial differences in preterm birth

An argument for pandemic risk management using a multidisciplinary One Health approach to governance: an Australian case study

The emergence of SARS-CoV-2 and the subsequent COVID-19 pandemic has resulted in significant global impact. However, COVID-19 is just one of several high-impact infectious diseases that emerged from wildlife and are linked to the human relationship with nature. The rate of emergence of new zoonoses (diseases of animal origin) is increasing, driven by human-induced environmental changes that threaten biodiversity on a global scale. This increase is directly linked to environmental drivers including biodiversity loss, climate change and unsustainable resource extraction. Australia is a biodiversity hotspot and is subject to sustained and significant environmental change, increasing the risk of it being a location for pandemic origin. Moreover, the global integration of markets means that consumption trends in Australia contributes to the risk of disease spill-over in our regional neighbours in Asia-Pacific, and beyond. Despite the clear causal link between anthropogenic pressures on the environment and increasing pandemic risks, Australia’s response to the COVID-19 pandemic, like most of the world, has centred largely on public health strategies, with a clear focus on reactive management. Yet, the span of expertise and evidence relevant to the governance of pandemic risk management is much wider than public health and epidemiology. It involves animal/wildlife health, biosecurity, conservation sciences, social sciences, behavioural psychology, law, policy and economic analyses to name just a few. The authors are a team of multidisciplinary practitioners and researchers who have worked together to analyse, synthesise, and harmonise the links between pandemic risk management approaches and issues in different disciplines to provide a holistic overview of current practice, and conclude the need for reform in Australia. We discuss the adoption of a comprehensive and interdisciplinary ‘One Health’ approach to pandemic risk management in Australia. A key goal of the One Health approach is to be proactive in countering threats of emerging infectious diseases and zoonoses through a recognition of the interdependence between human, animal, and environmental health. Developing ways to implement a One Health approach to pandemic prevention would not only reduce the risk of future pandemics emerging in or entering Australia, but also provide a model for prevention strategies around the world

Prevalence, Cardiac Phenotype, and Outcomes of Transthyretin Variants in the UK Biobank Population

Importance: The population prevalence of cardiac transthyretin amyloidosis (ATTR) caused by pathogenic variation in the TTR gene (vATTR) is unknown. // Objective: To estimate the population prevalence of disease-causing TTR variants and evaluate associated phenotypes and outcomes. // Design, Setting, and Participants: This population-based cohort study analyzed UK Biobank (UKB) participants with whole-exome sequencing, electrocardiogram, and cardiovascular magnetic resonance data. Participants were enrolled from 2006 to 2010, with a median follow-up of 12 (IQR, 11-13) years (cutoff date for the analysis, March 12, 2024). Sixty-two candidate TTR variants were extracted based on rarity (minor allele frequency ≤0.0001) and/or previously described associations with amyloidosis if more frequent. // Exposure: Carrier status for TTR variants. // Main Outcomes and Measures: Associations of TTR carrier status with vATTR prevalence and cardiovascular imaging and electrocardiogram traits were explored using descriptive statistics. Associations between TTR carrier status and atrial fibrillation, conduction disease, heart failure, and all-cause mortality were evaluated using adjusted Cox proportional hazards models. Genotypic and diagnostic concordance was examined using International Statistical Classification of Diseases, Tenth Revision codes from the hospital record. // Results: The overall cohort included 469 789 UKB participants (mean [SD] age, 56.5 [8.1] years; 54.2% female and 45.8% male). A likely pathogenic/pathogenic (LP/P) TTR variant was detected in 473 (0.1%) participants, with Val142Ile being the most prevalent (367 [77.6%]); 91 individuals (0.02%) were carriers of a variant of unknown significance . The overall prevalence of LP/P variants was 0.02% (105 of 444 243) in participants with European ancestry and 4.3% (321 of 7533) in participants with African ancestry. The LP/P variants were associated with higher left ventricular mass indexed to body surface area (β = 4.66; 95% CI, 1.87-7.44), and Val142Ile was associated with a longer PR interval (β = 18.34; 95% CI, 5.41-31.27). The LP/P carrier status was associated with a higher risk of heart failure (hazard ratio [HR], 2.68; 95% CI, 1.75-4.12) and conduction disease (HR, 1.88; 95% CI, 1.25-2.83). Higher all-cause mortality risk was observed for non-Val142Ile LP/P variants (HR, 1.98; 95% CI, 1.06-3.67). Thirteen participants (2.8%) with LP/P variants had diagnostic codes compatible with cardiac or neurologic amyloidosis. Variants of unknown significance were not associated with outcomes. // Conclusions and Relevance: This study found that approximately 1 in 1000 UKB participants were LP/P TTR variant carriers, exceeding previously reported prevalence. The findings emphasize the need for clinical vigilance in identifying individuals at risk of developing vATTR and associated poor outcomes

CaMKK2 as an emerging treatment target for bipolar disorder

Current pharmacological treatments for bipolar disorder are inadequate and based on serendipitously discovered drugs often with limited efficacy, burdensome side-effects, and unclear mechanisms of action. Advances in drug development for the treatment of bipolar disorder remain incremental and have come largely from repurposing drugs used for other psychiatric conditions, a strategy that has failed to find truly revolutionary therapies, as it does not target the mood instability that characterises the condition. The lack of therapeutic innovation in the bipolar disorder field is largely due to a poor understanding of the underlying disease mechanisms and the consequent absence of validated drug targets. A compelling new treatment target is the Ca2+-calmodulin dependent protein kinase kinase-2 (CaMKK2) enzyme. CaMKK2 is highly enriched in brain neurons and regulates energy metabolism and neuronal processes that underpin higher order functions such as long-term memory, mood, and other affective functions. Loss-of-function polymorphisms and a rare missense mutation in human CAMKK2 are associated with bipolar disorder, and genetic deletion of Camkk2 in mice causes bipolar-like behaviours similar to those in patients. Furthermore, these behaviours are ameliorated by lithium, which increases CaMKK2 activity. In this review, we discuss multiple convergent lines of evidence that support targeting of CaMKK2 as a new treatment strategy for bipolar disorder

Policy ideas through the prism of knowledge regimes and framing

Policymakers are often confronted with problems that involve ambiguity and uncertainty (Zahariadis, 2003). In order to make sense of such problems and to identify possible solutions, they are on the lookout for policy ideas

A qualitative study of carers' experiences of dementia cafes : a place to feel supported and be yourself

Abstract Background Unpaid, informal carers or caregivers play an important role in supporting people living with dementia but the role can be challenging and carers themselves may benefit from support. Alzheimer’s, dementia or memory cafés are one such form of support . These cafés are usually provided in the voluntary sector and are a place where people with dementia and those supporting them, usually family carers, can meet with others in similar situations. Methods Using semi-structured interviews, this qualitative study explored the experiences of 11 carers from five dementia cafés in and around London, England. Results Thematic analysis resulted in the identification of four key themes. Cafés provide a relaxed, welcoming atmosphere where carers can go where they feel supported and accepted. Café attendance often brought a sense of normality to these carers’ lives. Carers and those they care for look forward to going and often enjoy both the activities provided and socialising with others. Other highlighted benefits included peer support from other carers, information provision and support from the volunteer café coordinators. Despite diversity in how the cafés were run and in the activities offered, there were many reported similarities amongst carers in the value ascribed to attending the cafés. Conclusions Dementia cafés appear to be a valuable, perhaps unique form of support for carers giving them brief respite from their caring role. Future research incorporating mixed methods is needed to understand the perspectives of those living with dementia

Automated cardiovascular magnetic resonance image analysis with fully convolutional networks

Background: Cardiovascular magnetic resonance (CMR) imaging is a standard imaging modality for assessing cardiovascular diseases (CVDs), the leading cause of death globally. CMR enables accurate quantification of the cardiac chamber volume, ejection fraction and myocardial mass, providing information for diagnosis and monitoring of CVDs. However, for years, clinicians have been relying on manual approaches for CMR image analysis, which is time consuming and prone to subjective errors. It is a major clinical challenge to automatically derive quantitative and clinically relevant information from CMR images. Methods: Deep neural networks have shown a great potential in image pattern recognition and segmentation for a variety of tasks. Here we demonstrate an automated analysis method for CMR images, which is based on a fully convolutional network (FCN). The network is trained and evaluated on a large-scale dataset from the UK Biobank, consisting of 4,875 subjects with 93,500 pixelwise annotated images. The performance of the method has been evaluated using a number of technical metrics, including the Dice metric, mean contour distance and Hausdorff distance, as well as clinically relevant measures, including left ventricle (LV) end-diastolic volume (LVEDV) and end-systolic volume (LVESV), LV mass (LVM); right ventricle (RV) end-diastolic volume (RVEDV) and end-systolic volume (RVESV). Results: By combining FCN with a large-scale annotated dataset, the proposed automated method achieves a high performance in segmenting the LV and RV on short-axis CMR images and the left atrium (LA) and right atrium (RA) on long-axis CMR images. On a short-axis image test set of 600 subjects, it achieves an average Dice metric of 0.94 for the LV cavity, 0.88 for the LV myocardium and 0.90 for the RV cavity. The mean absolute difference between automated measurement and manual measurement was 6.1 mL for LVEDV, 5.3 mL for LVESV, 6.9 gram for LVM, 8.5 mL for RVEDV and 7.2 mL for RVESV. On long-axis image test sets, the average Dice metric was 0.93 for the LA cavity (2-chamber view), 0.95 for the LA cavity (4-chamber view) and 0.96 for the RA cavity (4-chamber view). The performance is comparable to human inter-observer variability. Conclusions: We show that an automated method achieves a performance on par with human experts in analysing CMR images and deriving clinically relevant measures

Equity and justice in climate change adaptation : Policy and practical implication in Nigeria

Over the past decade, justice and equity have become a quasi-universal answer to problems of environmental governance. The principles of justice and equity emerged as a useful entry point in global governance to explore the responsibilities, distribution, and procedures required for just climate change adaptation. These principles are designed primarily through the establishment of funding mechanisms, top-down guides, and frameworks for adaptation, and other adaptation instruments from the UNFCCC process, to ensure effective adaptation for vulnerable countries like Nigeria that have contributed least to the issue of climate change but lack adaptive capacity. Global adaptation instruments have been acknowledged for adaptation in Nigeria. Climate change has a detrimental impact on Nigeria as a nation, with the burden falling disproportionately on the local government areas. As Nigeria develop national plans and policies to adapt to the consequences of climate change, these plans will have significant consequences for local government areas where adaptation practices occur. Although the local government’s adaptation burden raises the prospects for justice and equity, its policy and practical implication remains less explored. This chapter explores the principles of justice and equity in national adaptation policy and adaptation practices in eight local government areas in southeast Nigeria. The chapter argues that some factors make it challenging to achieve equity and justice in local adaptation practices. With the use of a qualitative approach (interview (n = 52), observation, and document analysis), this chapter identified some of the factors that constraints equity and justice in local government adaptation in southeast Nigeria.publishedVersio

Participatory monitoring and evaluation approaches that influence decision-making: lessons from a maternal and newborn study in Eastern Uganda

BACKGROUND: The use of participatory monitoring and evaluation (M&E) approaches is important for guiding local decision-making, promoting the implementation of effective interventions and addressing emerging issues in the course of implementation. In this article, we explore how participatory M&E approaches helped to identify key design and implementation issues and how they influenced stakeholders’ decision-making in eastern Uganda. METHOD: The data for this paper is drawn from a retrospective reflection of various M&E approaches used in a maternal and newborn health project that was implemented in three districts in eastern Uganda. The methods included qualitative and quantitative M&E techniques such as key informant interviews, formal surveys and supportive supervision, as well as participatory approaches, notably participatory impact pathway analysis. RESULTS: At the design stage, the M&E approaches were useful for identifying key local problems and feasible local solutions and informing the activities that were subsequently implemented. During the implementation phase, the M&E approaches provided evidence that informed decision-making and helped identify emerging issues, such as weak implementation by some village health teams, health facility constraints such as poor use of standard guidelines, lack of placenta disposal pits, inadequate fuel for the ambulance at some facilities, and poor care for low birth weight infants. Sharing this information with key stakeholders prompted them to take appropriate actions. For example, the sub-county leadership constructed placenta disposal pits, the district health officer provided fuel for ambulances, and health workers received refresher training and mentorship on how to care for newborns. CONCLUSION: Diverse sources of information and perspectives can help researchers and decision-makers understand and adapt evidence to contexts for more effective interventions. Supporting districts to have crosscutting, routine information generating and sharing platforms that bring together stakeholders from different sectors is therefore crucial for the successful implementation of complex development interventions