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Genes play a strong role in Alzheimer’s disease (AD), with late-onset AD showing heritability of 58–79% and early-onset AD showing over 90%. Genetic association provides a robust platform to build our understanding of the etiology of this complex disease. Over 50 loci are now implicated for AD, suggesting that AD is a disease of multiple components, as supported by pathway analyses (immunity, endocytosis, cholesterol transport, ubiquitination, amyloid-β and tau processing). Over 50% of late-onset AD heritability has been captured, allowing researchers to calculate the accumulation of AD genetic risk through polygenic risk scores. A polygenic risk score predicts disease with up to 90% accuracy and is an exciting tool in our research armory that could allow selection of those with high polygenic risk scores for clinical trials and precision medicine. It could also allow cellular modelling of the combined risk. Here we propose the multiplex model as a new perspective from which to understand AD. The multiplex model reflects the combination of some, or all, of these model components (genetic and environmental), in a tissue-specific manner, to trigger or sustain a disease cascade, which ultimately results in the cell and synaptic loss observed in AD.

Background Gestational diabetes mellitus (GDM) - a transitory form of diabetes induced by pregnancy - has potentially important short and long-term health consequences for both the mother and her baby. There is no globally agreed definition of GDM, but definition changes have increased the incidence in some countries in recent years, with some research suggesting minimal clinical improvement in outcomes. The aim of this qualitative systematic review was to identify the psychosocial experiences a diagnosis of GDM has on women during pregnancy and the postpartum period. Methods We searched CINAHL, EMBASE, MEDLINE and PsycINFO databases for studies that provided qualitative data on the psychosocial experiences of a diagnosis of GDM on women across any stage of pregnancy and/or the postpartum period. We appraised the methodological quality of the included studies using the Critical Appraisal Skills Programme Checklist for Qualitative Studies and used thematic analysis to synthesis the data. Results Of 840 studies identified, 41 studies of diverse populations met the selection criteria. The synthesis revealed eight key themes: initial psychological impact; communicating the diagnosis; knowledge of GDM; risk perception; management of GDM; burden of GDM; social support; and gaining control. The identified benefits of a GDM diagnosis were largely behavioural and included an opportunity to make healthy eating changes. The identified harms were emotional, financial and cultural. Women commented about the added responsibility (eating regimens, appointments), financial constraints (expensive food, medical bills) and conflicts with their cultural practices (alternative eating, lack of information about traditional food). Some women reported living in fear of risking the health of their baby and conducted extreme behaviours such as purging and starving themselves. Conclusion A diagnosis of GDM has wide reaching consequences that are common to a diverse group of women. Threshold cut-offs for blood glucose levels have been determined using the risk of physiological harms to mother and baby. It may also be advantageous to consider the harms and benefits from a psychosocial and a physiological perspective. This may avoid unnecessary burden to an already vulnerable population.

Sporadic Alzheimer’s disease (AD) is a complex genetic disease, and the leading cause of dementia worldwide. Over the past 3 decades, extensive pioneering research has discovered more than 70 common and rare genetic risk variants. These discoveries have contributed massively to our understanding of the pathogenesis of AD but approximately half of the heritability for AD remains unaccounted for. There are regions of the genome that are not assayed by mainstream genotype and sequencing technology. These regions, known as the Dark Genome, often harbour large structural DNA variants that are likely relevant to disease risk. Here, we describe the dark genome and review current technological and bioinformatics advances that will enable researchers to shed light on these hidden regions of the genome. We highlight the potential importance of the hidden genome in complex disease and how these strategies will assist in identifying the missing heritability of AD. Identification of novel protein-coding structural variation that increases risk of AD will open new avenues for translational research and new drug targets that have the potential for clinical benefit to delay or even prevent clinical symptoms of disease.

Habitat fragmentation and isolation threaten the survival of several wide‐ranging species, such as tigers, through increased risk from diseases, disasters, climate change, and genetic depression. Identification of the habitat most likely to achieve connectivity among protected areas is vital for the long‐term persistence of tigers. We aimed to improve the mapping of potential transfrontier protected area corridors for tigers by connecting sites within the Terai Arc Landscape in Nepal and to those in India, highlighting targeted conservation actions needed along these corridors to maintain long‐term connectivity. We used least‐cost corridor modeling and circuit theory to identify potential corridors and bottlenecks in the study area. The landscape's resistance to tigers' movement was gathered from expert opinions to inform corridor modeling. We identified nine potential tiger corridors in the Terai Arc Landscape—Nepal that aligned strongly with the remaining intact habitats of the Siwalik landscape, which could facilitate tiger movement. Banke‐Bardia and Chitwan‐Parsa‐Valimiki complexes and Lagga‐Bhagga and Khata corridors were identified as high‐priority conservation cores and corridors. While our model exhibited congruence with most established corridors in the landscape, it has identified the need to enhance existing corridors to improve landscape connectivity. Several pinch points posing an increased risk to connectivity were identified. Most of these were located near the protected area boundaries and along the Nepal–India border. The Siwalik landscape holds the key to long‐term connectivity in the study area; however, immediate conservation attention is needed, particularly at pinch points, to secure this connectivity for tigers. Validation of identified corridors through empirical research and their conservation is a priority. Identification of the habitat most likely to achieve connectivity among protected areas is vital for the long‐term persistence of tigers. We used least‐cost corridor modeling and circuit theory to identify potential tiger corridors and bottlenecks in the Terai Arc Landscape in Nepal. The Siwalik hills in the study area holds the key to potential connectivity among protected areas; however, immediate conservation attention is needed, particularly at pinchpoints, to secure this connectivity for tigers.

Background Alzheimer’s disease (AD) has been associated with immune dysregulation in biomarker and genome-wide association studies (GWAS). GWAS hits include the genes encoding complement regulators clusterin ( CLU ) and complement receptor 1 ( CR1 ), recognised as key players in AD pathology, and complement proteins have been proposed as biomarkers. Main body To address whether changes in plasma complement protein levels in AD relate to AD-associated complement gene variants we first measured relevant plasma complement proteins (clusterin, C1q, C1s, CR1, factor H) in a large cohort comprising early onset AD (EOAD; n = 912), late onset AD (LOAD; n = 492) and control (n = 504) donors. Clusterin and C1q were significantly increased (p < 0.001) and sCR1 and factor H reduced (p < 0.01) in AD plasma versus controls. ROC analyses were performed to assess utility of the measured complement biomarkers, alone or in combination with amyloid beta, in predicting AD. C1q was the most predictive single complement biomarker (AUC 0.655 LOAD, 0.601 EOAD); combining C1q with other complement or neurodegeneration makers through stepAIC-informed models improved predictive values slightly. Effects of GWS SNPs (rs6656401, rs6691117 in CR1 ; rs11136000, rs9331888 in CLU ; rs3919533 in C1S ) on protein concentrations were assessed by comparing protein levels in carriers of the minor vs major allele. To identify new associations between SNPs and changes in plasma protein levels, we performed a GWAS combining genotyping data in the cohort with complement protein levels as endophenotype. SNPs in CR1 (rs6656401), C1S (rs3919533) and CFH (rs6664877) reached significance and influenced plasma levels of the corresponding protein, whereas SNPs in CLU did not influence clusterin levels. Conclusion Complement dysregulation is evident in AD and may contribute to pathology. AD-associated SNPs in CR1 , C1S and CFH impact plasma levels of the encoded proteins, suggesting a mechanism for impact on disease risk.

Rare coding variants across many genes contribute to schizophrenia liability, but they have only been implicated in 12 genes at exome-wide levels of significance. To increase power for gene discovery, we analyse exome-sequencing data for rare coding variants in a new sample of 4650 schizophrenia cases and 5719 controls, and combine these with published sequencing data for a total of 28,898 cases, 103,041 controls and 3444 proband-parent trios. We identify associations for STAG1 and ZNF136 at exome-wide significance, genes that were previously implicated in schizophrenia by the SCHEMA study at a false discovery rate of 5%. We also find associations at a false discovery rate of 5% for six genes that did not pass this statistical threshold in the SCHEMA study ( SLC6A1 , PCLO , ZMYND11 , BSCL2 , KLC1 and CGREF1 ). Among these genes, SLC6A1 and KLC1 are associated with damaging missense variants alone. STAG1 , SLC6A1 , ZMYND11 and CGREF1 are also enriched for rare coding variants in other developmental and psychiatric disorders. Moreover, STAG1 and KLC1 have fine-mapped common variant signals in schizophrenia. These findings provide insights into the neurobiology of schizophrenia, including further evidence suggesting an aetiological role for disrupted chromatin organisation. Here the authors analyse rare coding variants to identify schizophrenia risk genes. Associations are reported at exome-wide significance for STAG1 and ZNF136 , and at a false discovery rate of 5% for SLC6A1 , PCLO , ZMYND11 , BSCL2 , KLC1 and CGREF1 .

Emotional Freedom Technique (EFT) is an evidence-based self-help therapeutic method and over 100 studies demonstrate its efficacy. However, information about the physiological effects of EFT is limited. The current study sought to elucidate EFTs mechanisms of action across the central nervous system (CNS) by measuring heart rate variability (HRV) and heart coherence (HC); the circulatory system using resting heart rate (RHR) and blood pressure (BP); the endocrine system using cortisol, and the immune system using salivary immunoglobulin A (SigA). The second aim was to measure psychological symptoms. Participants (N = 203) were enrolled in a 4-day training workshop held in different locations. At one workshop (n = 31), participants also received comprehensive physiological testing. Posttest, significant declines were found in anxiety (−40%), depression (−35%), posttraumatic stress disorder (−32%), pain (−57%), and cravings (−74%), all P < .000. Happiness increased (+31%, P = .000) as did SigA (+113%, P = .017). Significant improvements were found in RHR (−8%, P = .001), cortisol (−37%, P < .000), systolic BP (−6%, P = .001), and diastolic BP (−8%, P < .000). Positive trends were observed for HRV and HC and gains were maintained on follow-up, indicating EFT results in positive health effects as well as increased mental well-being.

Midlife obesity is a risk factor of late onset Alzheimer's disease (LOAD) but why this is the case remains unknown. As systemic inflammation is involved in both conditions, obesity-related neuroinflammation may contribute to damage in limbic structures important in LOAD. Here, we investigated the hypothesis that systemic inflammation would mediate central obesity related effects on limbic tissue microstructure in 166 asymptomatic individuals (38–71 years old). We employed MRI indices sensitive to myelin and neuroinflammation [macromolecular proton fraction (MPF) and kf] from quantitative magnetization transfer (qMT) together with indices from neurite orientation dispersion and density imaging (NODDI) to investigate the effects of central adiposity on the fornix, parahippocampal cingulum, uncinate fasciculus (compared with whole brain white matter and corticospinal tract) and the hippocampus. Central obesity was assessed with the Waist Hip Ratio (WHR) and abdominal visceral and subcutaneous fat area fractions (VFF, SFF), and systemic inflammation with blood plasma concentrations of leptin, adiponectin, C-reactive protein and interleukin 8. Men were significantly more centrally obese and had higher VFF than women. Individual differences in WHR and in VFF were negatively correlated with differences in fornix MPF and kf, but not with any differences in neurite microstructure. In women, age mediated the effects of VFF on fornix MPF and kf, whilst in men differences in the leptin and adiponectin ratio fully mediated the effect of WHR on fornix MPF. These results suggest that visceral fat related systemic inflammation may damage myelin-related properties of the fornix, a key limbic structure known to be involved in LOAD. •Central adiposity is linked to apparent myelin/inflammatory damage in the fornix.•Central adiposity is not linked to differences in apparent neurite microstructure.•Men were more centrally obese and had higher visceral fat fractions than women.•In women, age mediated the correlation between visceral fat and fornix myelin.•In men, adipokines mediated the correlation between WHR and fornix myelin.

A diagnostic label can have harms and benefits, particularly when provided following routine health screening tests. Whether these are discussed in clinical encounters is unknown. To investigate whether potential impacts of diagnostic labelling are discussed before routine screening for non-cancer health conditions and explore the perceived value of such discussions by general practitioners (GPs) and healthcare consumers. Eleven semi-structured interviews with GPs and two focus groups with eight consumers were conducted. Interviews and focus groups were audio-recorded, transcribed and analysed using thematic analysis methods based on framework analysis. Prior to routine screening, most GPs did not discuss the potential consequences of diagnostic labelling, and no consumer recalled discussions of this nature. In contrast, many GPs provided information regarding the screening procedure and possible test limitations. Both GPs and consumers identified that it would be valuable to discuss the potential impacts of a diagnostic label; however, preferences varied as to the content and timing (i.e. before or after screening) of this discussion. Six themes that examine the utility of discussing the consequences of diagnostic labelling were identified: patient empowerment, patient variability, condition-specific information, GP and patient interactions and relationship, GP role and responsibilities, and characteristics of screening. The practice and perceived value of discussing diagnostic labelling consequences were recognised as important by both GPs and consumers. However, preferences regarding the content of discussions and whether these occurred in clinical encounters before or after screening varied.

Overdiagnosis is considered a risk associated with the diagnosis of osteoporosis-as many people diagnosed won't experience harm from the condition. As yet there's little evidence on community understanding of overdiagnosis outside cancer- where it is an established risk of some screening programs-or effective ways to communicate about it. We examined community understanding around overdiagnosis of osteoporosis, to optimise communication strategies about this problem. Using a qualitative design we recruited a community sample of women, 50-80 years, from the Gold Coast community around Bond University, Australia, using random digit dialing, and conducted 5 focus groups with 41 women. A discussion guide and 4-part presentation were developed and piloted, with independent review from a consumer and clinical experts. Initial discussion had 4 segments: osteoporosis; bone density vs. other risk factors; medication; and overdiagnosis. The second half included the 4 short presentations and discussions on each. Analysis used Framework Analysis method. Initially participants described osteoporosis as bone degeneration causing some fear, demonstrated imprecise understanding of overdiagnosis, had a view osteoporosis couldn't be overdiagnosed as bone scans provided \"clear cut\" results, expressed belief in early diagnosis, and interest in prevention strategies enabling control. Following presentations, participants expressed some understanding of overdiagnosis, preference for describing osteoporosis as a \"risk factor\" not \"disease\", concern about a poor risk-benefit ratio for medications, and surprise and unease the definition of osteoporosis decided bone density of young women was \"normal\", without age adjustment. Limitations include English-speaking backgrounds of the sample and complex materials. Our findings suggest a gap between community expectations and how experts sometimes arbitrarily set low diagnostic thresholds which label those at risk as \"diseased\". Optimal communication about overdiagnosis could build on community scepticism about treatments, encouraging weighing up benefits and harms of tests and diagnoses, and framing this information as positively adding to knowledge.