Search

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer.

Abstract White matter hyperintensities index structural abnormalities in the cerebral white matter, including axonal damage. The latter may promote atrophy of the cerebral cortex, a key feature of dementia. Here, we report a study of 51,065 individuals from 10 cohorts demonstrating that higher white matter hyperintensity volume associates with lower cortical thickness. The meta-GWAS of white matter hyperintensities-associated cortical ‘atrophy’ identifies 20 genome-wide significant loci, and enrichment in genes specific to vascular cell types, astrocytes, and oligodendrocytes. White matter hyperintensities-associated cortical ‘atrophy’ showed positive genetic correlations with vascular-risk traits and plasma biomarkers of neurodegeneration, and negative genetic correlations with cognitive functioning. 15 of the 20 loci regulated the expression of 54 genes in the cerebral cortex that, together with their co-expressed genes, were enriched in biological processes of axonal cytoskeleton and intracellular transport. The white matter hyperintensities-cortical thickness associations were most pronounced in cortical regions with higher expression of genes specific to excitatory neurons with long-range axons traversing through the white matter. The meta-GWAS-based polygenic risk score predicts vascular and all-cause dementia in an independent sample of 500,348 individuals. Thus, the genetics of white matter hyperintensities-related cortical atrophy involves vascular and neuronal processes and increases dementia risk.

Abstract Telomere shortening is a prominent hallmark of aging and is emerging as a characteristic feature of Myelodysplastic Syndromes (MDS) and Idiopathic Pulmonary Fibrosis (IPF). Optimal telomerase activity prevents progressive shortening of telomeres that triggers DNA damage responses. However, the upstream regulation of telomerase holoenzyme components remains poorly defined. Here, we identify RIOK2, a master regulator of human blood cell development, as a critical transcription factor for telomere maintenance. Mechanistically, loss of RIOK2 or its DNA-binding/transactivation properties downregulates mRNA expression of both TRiC and dyskerin complex subunits that impairs telomerase activity, thereby causing telomere shortening. We further show that RIOK2 expression is diminished in aged individuals and IPF patients, and it strongly correlates with shortened telomeres in MDS patient-derived bone marrow cells. Importantly, ectopic expression of RIOK2 alleviates telomere shortening in IPF patient-derived primary lung fibroblasts. Hence, increasing RIOK2 levels prevents telomere shortening, thus offering therapeutic strategies for telomere biology disorders.

Abstract The heterogeneity and complexity of symptom presentation, comorbidities and genetic factors pose challenges to the identification of biological mechanisms underlying complex diseases. Current approaches used to identify biological subtypes of major depressive disorder (MDD) mainly focus on clinical characteristics that cannot be linked to specific biological models. Here, we examined multimorbidities to identify MDD subtypes with distinct genetic and non-genetic factors. We leveraged dynamic Bayesian network approaches to determine a minimal set of multimorbidities relevant to MDD and identified seven clusters of disease-burden trajectories throughout the lifespan among 1.2 million participants from cohorts in the UK, Finland, and Spain. The clusters had clear protective- and risk-factor profiles as well as age-specific clinical courses mainly driven by inflammatory processes, and a comprehensive map of heritability and genetic correlations among these clusters was revealed. Our results can guide the development of personalized treatments for MDD based on the unique genetic, clinical and non-genetic risk-factor profiles of patients.

This study examined adults' frequent, efficient and adaptive use of direct subtraction (DS) and subtraction by addition (SBA) in mental multi-digit subtraction with the choice/no-choice method. Participants were offered subtractions in one choice condition (choice between DS and SBA) and two no-choice conditions (mandatory use of either DS or SBA). SBA was used as frequently as DS in the choice condition. DS was most accurate on subtractions with a large difference (e.g., 502 - 18), while SBA was fastest on subtractions with a small difference (e.g., 903 - 886). In general, participants were adaptive for task characteristics and their personal speed characteristics. We further analyzed task-based adaptivity on an individual level via a Latent Class Analysis. Results showed that two-thirds of the participants were adaptive to task characteristics, and that these adaptive participants were the most proficient in accuracy and speed in the choice condition. We further examined whether executive functions (updating, inhibition, shifting) were related to individual differences in strategy efficiency and task-based adaptivity. In line with our hypothesis, updating was related to strategy efficiency, such that participants with higher updating skills were more accurate. In contrast to our expectations, inhibition and shifting were not related to task-based strategy adaptivity. This study highlights adults' efficient and adaptive use of arithmetic strategies, and its association with their proficiency and executive functions.

Since Ladusaw (1979) the term ‘free choice indefinite’ is the generally accepted term for the meaning of any in primarily modal and generic sentences, such as Any owl hunts mice, but not for what is generally called the ‘polarity-sensitive’ or ‘negative polarity’ meaning, as in Did you take any? At least part of the inspiration for Ladusaw was Vendler (1967), but Vendler took a notion of ‘freedom of choice’ to characterize all uses of any. This paper has three goals: (i) to offer a critical survey, updating earlier ones by Horn (2000a, 2000b, 2005) of the question whether English any has one meaning – a univocal account – or two – an ambiguist account, with the two alleged meanings involving negative polarity, on the one hand, and free choice, on the other hand; (ii) to confirm, in agreement with much current work, that Vendler (1967) was right, and to suggest, in disagreement with most if not all current work, to make terminology reflect the insight and no longer restrict the term ‘free choice’ to just a few of the meanings of any; and (iii) to offer a new univocal approach of any, hypothesizing its meaning to contain the components ‘existence’ and ‘free choice’, and using the notion of ‘at-issueness’.

Abstract Background Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia. Methods We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes. Results The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues. Conclusions VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.

In healthcare, improvement leaders have been inspired by the frameworks from industry which have been adapted into control systems and certifications to improve quality of care for people. To address the challenge to regain trust in healthcare design and delivery, we propose a conceptual framework, i.e. the “House of Trust”. This House brings together the Juran Trilogy, the emerging concept of co-production in quality management and the multidimensional definition of quality, which describes core values as an integral part of the system to deliver person- and kin-centered care. In the “House of Trust” patients, their kin, healthcare providers, executives and managers feel at home, with a sense of belonging. If we want to build a care organization that inspires and radiates confidence to all stakeholders, highlighting the basic interactions between front- and back-office is required. An organization with both well-organized back- and front-offices can enable all to benefit from the trust each of them needs and deserves. A quality system does not depend on government inspection and regulations nor on external accreditation to develop itself into a House of Trust. Success will only be achieved if all involved continuously question themselves about the technical dimensions of quality and their core values during the “moment of truth”.

Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (n = 41 326), whole-exome sequencing (n = 15 965), or exome chip (n = 5249) data contributed 13 776 and 7079 extreme small vessel disease samples for the genome-wide association study and whole-exome association study, respectively. The genome-wide association study identified significant association of common variants in 11 loci with extreme small vessel disease, of which the chr12q24.11 locus was not previously reported to be associated with any MRI marker of cerebral small vessel disease. The whole-exome association study identified significant associations of extreme small vessel disease with common variants in the 5' UTR region of EFEMP1 (chr2p16.1) and one probably damaging common missense variant in TRIM47 (chr17q25.1). Mendelian randomization supports the causal association of extensive small vessel disease severity with increased risk of stroke and Alzheimer's disease. Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. We observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology. Overall, our comprehensive gene-mapping study and preliminary functional evaluation suggests a putative role of TRIM47 in the pathophysiology of cerebral small vessel disease, making it an important candidate for extensive in vivo explorations and future translational work.

Due to the high wastepaper recyclability and water-loop system closure, packaging paper mills struggle with increased fines, causing runnability issues. Cellulase enzymes are a preferred treatment choice for the improvement of the pulp refining in stock preparation area but are not widely used or easy to introduce in the production process. Different cellulase enzymes were tested, and those with the highest activity were introduced to the white-water (WW) samples with the aim to reduce fines content as potentially new enzyme applications on the paper machine. The first portion of the study involved the development of an experiment model to find and confirm the optimal enzyme process parameters (40 °C, pH 5.7, reaction time 3 h, and 0.18% v/v enzyme addition) for laboratory made white-water. The second portion of the study included turbidity, colloidal charge, flow cytometry (FCM), and chemical oxygen demand (COD) analysis on industrial and laboratory made white-water samples at optimized process parameters. Obtained results corresponded to reduced fines content in white-water samples, which justified commercial usage of cellulase enzymes on recycled paper machine short loop and potentially increased machine runnability without negative influence on wastewater treatment plant.

Abstract Background Leishmaniasis is a common neglected tropical disease in Ethiopia. Visceral leishmaniasis (VL) caused by Leishmania donovani presents in the lowlands, while cutaneous leishmaniasis (CL) affects people living in the highlands. Although CL is described as being caused by Leishmania aethiopica, there is also evidence of L. tropica and L. major isolated from a patient, sand flies and potential reservoirs. Information on species causing CL in Ethiopia is patchy, and no nation-wide study has ever been done. Understanding which species are causing CL in Ethiopia can have important implications for patient management and disease prevention. Methods We analyzed stored routine samples and biobanked DNA isolates from previously conducted studies of CL patients from different centers in the north, center and south of Ethiopia. Species typing was performed using ITS-1 PCR with high-resolution melt (HRM) analysis, followed by HSP70 amplicon sequencing on a selection of the samples. Additionally, sociodemographic, clinical and laboratory data of patients were analyzed. Results Of the 226 CL samples collected, the Leishmania species could be determined for 105 (45.5%). Leishmania aethiopica was identified in 101 (96.2%) samples from across the country. In four samples originating from Amhara region, northwestern Ethiopia, L. donovani was identified by ITS-1 HRM PCR, of which two were confirmed with HSP70 sequences. While none of these four patients had symptoms of VL, two originated from known VL endemic areas. Conclusions The majority of CL was caused by L. aethiopica, but CL due to L. tropica and L. major cannot be ruled out. Our study is the first to our knowledge to demonstrate CL patients caused by L. donovani in Ethiopia. This should spark future research to investigate where, how and to which extent such transmission takes place, how it differs genetically from L. donovani causing VL and whether such patients can be diagnosed and treated successfully with the currently available tools and drugs. Graphical Abstract

Abstract Background Measuring quality is essential to drive improvement initiatives in hospitals. An instrument that measures healthcare quality multidimensionally and integrates patients’, kin’s and professionals’ perspectives is lacking. We aimed to develop and validate an instrument to measure healthcare quality multidimensionally from a multistakeholder perspective. Methods A multi-method approach started by establishing content and face validity, followed by a multi-centre study in 17 Flemish (Belgian) hospitals to assess construct validity through confirmatory factor analysis, criterion validity through determining Pearson’s correlations and reliability through Cronbach’s alpha measurement. The instrument FlaQuM-Quickscan measures ‘Healthcare quality for patients and kin’ (part 1) and ‘Healthcare quality for professionals’ (part 2). This bipartite instrument mirrors 15 quality items and 3 general items (the overall quality score, recommendation score and intention-to-stay score). A process evaluation was organised to identify effective strategies in instrument distribution by conducting semi-structured interviews with quality managers. Results By involving experts in the development of quality items and through pilot testing by a multi-stakeholder group, the content and face validity of instrument items was ensured. In total, 13,615 respondents (5,891 Patients/kin and 7,724 Professionals) completed the FlaQuM-Quickscan. Confirmatory factor analyses showed good to very good fit and correlations supported the associations between the quality items and general items for both instrument parts. Cronbach’s alphas supported the internal consistency. The process evaluation revealed that supportive technical structures and approaching respondents individually were effective strategies to distribute the instrument. Conclusions The FlaQuM-Quickscan is a valid instrument to measure healthcare quality experiences multidimensionally from an integrated multistakeholder perspective. This new instrument offers unique and detailed data to design sustainable quality management systems in hospitals. Based on these data, hospital management and policymakers can set quality priorities for patients’, kin’s and professionals’ care. Future research should investigate the transferability to other healthcare systems and examine between-stakeholders and between-hospitals variation.

BackgroundSuicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.MethodsWe conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.ResultsTwo loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.ConclusionsOur results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.

Abstract Background Encounter decision aids (EDAs) are tools that can support shared decision making (SDM), up to the clinical encounter. However, adoption of these tools has been limited, as they are hard to produce, to keep up-to-date, and are not available for many decisions. The MAGIC Evidence Ecosystem Foundation has created a new generation of decision aids that are generically produced along digitally structured guidelines and evidence summaries, in an electronic authoring and publication platform (MAGICapp). We explored general practitioners’ (GPs) and patients' experiences with five selected decision aids linked to BMJ Rapid Recommendations in primary care. Methods We applied a qualitative user testing design to evaluate user experiences for both GPs and patients. We translated five EDAs relevant to primary care, and observed the clinical encounters of 11 GPs when they used the EDA with their patients. We conducted a semi-structured interview with each patient after the consultation and a think-aloud interview with each GPs after multiple consultations. We used the Qualitative Analysis Guide (QUAGOL) for data analysis. Results Direct observations and user testing analysis of 31 clinical encounters showed an overall positive experience. The EDAs created better involvement in decision making and resulted in meaningful insights for patients and clinicians. The design and its interactive, multilayered structure made the tool enjoyable and well-organized. Difficult terminology, scales and numbers hindered understanding of certain information, which was sometimes perceived as too specialized or even intimidating. GPs thought the EDA was not suitable for every patient. They perceived a learning curve was required and the need for time investment was a concern. The EDAs were considered trustworthy as they were provided by a credible source. Conclusions This study showed that EDAs can be useful tools in primary care by supporting actual shared decision making and enhancing patient involvement. The graphical approach and clear representation help patients better understand their options. To overcome barriers such as health literacy and GPs attitudes, effort is still needed to make the EDAs as accessible, intuitive and inclusive as possible through use of plain language, uniform design, rapid access and training. Trial registration The study protocol was approved by the The Research Ethics Committee UZ/KU Leuven (Belgium) on 31–10-2019 with reference number MP011977.

The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5-90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology.

Objectives Infographics have the potential to enhance knowledge translation and implementation of clinical practice guidelines at the point of care. They can provide a synoptic view of recommendations, their rationale and supporting evidence. They should be understandable and easy to use. Little evaluation of these infographics regarding user experience has taken place. We explored general practitioners’ experiences with five selected BMJ Rapid Recommendation infographics suited for primary care.Methods An iterative, qualitative user testing design was applied on two consecutive groups of 10 general practitioners for five selected infographics. The physicians used the infographics before clinical encounters and we performed hybrid think-aloud interviews afterwards. 20 interviews were analysed using the Qualitative Analysis Guide of Leuven.Results Many clinicians reported that the infographics were simple and rewarding to use, time-efficient and easy to understand. They were perceived as innovative and their knowledge basis as trustworthy and supportive for decision-making. The interactive, expandable format was preferred over a static version as general practitioners focused mainly on the core message. Rapid access through the electronic health record was highly desirable. The main issues were about the use of complex scales and terminology. Understanding terminology related to evidence appraisal as well as the interpretation of statistics and unfamiliar scales remained difficult, despite the infographics.Conclusions General practitioners perceive infographics as useful tools for guideline translation and implementation in primary care. They offer information in an enjoyable and user friendly format and are used mainly for rapid, tailored and just in time information retrieval. We recommend future infographic producers to provide information as concise as possible, carefully define the core message and explore ways to enhance the understandability of statistics and difficult concepts related to evidence appraisal.Trial registration number MP011977.

Minimal phenotyping refers to the reliance on the use of a small number of self-reported items for disease case identification, increasingly used in genome-wide association studies (GWAS). Here we report differences in genetic architecture between depression defined by minimal phenotyping and strictly defined major depressive disorder (MDD): the former has a lower genotype-derived heritability that cannot be explained by inclusion of milder cases and a higher proportion of the genome contributing to this shared genetic liability with other conditions than for strictly defined MDD. GWAS based on minimal phenotyping definitions preferentially identifies loci that are not specific to MDD, and, although it generates highly predictive polygenic risk scores, the predictive power can be explained entirely by large sample sizes rather than by specificity for MDD. Our results show that reliance on results from minimal phenotyping may bias views of the genetic architecture of MDD and impede the ability to identify pathways specific to MDD.

We discovered a hybrid Leishmania parasite in Costa Rica that is genetically similar to hybrids from Panama. Genome analyses demonstrated the hybrid is triploid and identified L. braziliensis and L. guyanensis–related strains as parents. Our findings highlight the existence of poorly sampled Leishmania (Viannia) variants infectious to humans.

This study examined adults’ frequent, efficient and adaptive use of direct subtraction (DS) and subtraction by addition (SBA) in mental multi-digit subtraction with the choice/no-choice method. Participants were offered subtractions in one choice condition (choice between DS and SBA) and two no-choice conditions (mandatory use of either DS or SBA). SBA was used as frequently as DS in the choice condition. DS was most accurate on subtractions with a large difference (e.g., 502 – 18), while SBA was fastest on subtractions with a small difference (e.g., 903 – 886). In general, participants were adaptive for task characteristics and their personal speed characteristics. We further analyzed task-based adaptivity on an individual level via a Latent Class Analysis. Results showed that two-thirds of the participants were adaptive to task characteristics, and that these adaptive participants were the most proficient in accuracy and speed in the choice condition. We further examined whether executive functions (updating, inhibition, shifting) were related to individual differences in strategy efficiency and task-based adaptivity. In line with our hypothesis, updating was related to strategy efficiency, such that participants with higher updating skills were more accurate. In contrast to our expectations, inhibition and shifting were not related to task-based strategy adaptivity. This study highlights adults’ efficient and adaptive use of arithmetic strategies, and its association with their proficiency and executive functions.

Abstract Background Immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 and its ligand (PD-1/PD-L1) have become the current standard-of-care for advanced cancers. This novel therapeutic approach comes with its costs in the form of immune-related adverse events (irAE), including endocrinopathy. Case presentation A 63-year-old woman was diagnosed with a non-small cell lung carcinoma of the right superior lobe, cT3N2M0. She developed thyrotoxicosis followed by hypothyroidism induced by consolidation immunotherapy with durvalumab (anti-PD-L1). Analysis of the human leukocyte antigen (HLA) region showed HLA-DR4 (susceptible) and DR13 (protective). The possible mechanisms are subsequently discussed in detail. Conclusions The case of a patient with thyroiditis associated with the PD-L1 inhibitor durvalumab is described, highlighting the need for proactive monitoring of thyroid hormone levels. Identifying biomarkers associated with an increased risk of ICI-induced side effects (such as HLA) is of interest for better patient selection, optimal management and improved understanding of the mechanisms involved.

ObjectiveMore than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium.MethodsThe samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders.ResultsThree genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%).ConclusionsThis study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.

ABSTRACT: Objectives: Cutaneous leishmaniasis (CL) in Asia, Northern, and Sub-Saharan Africa is mainly caused by Leishmania major and Leishmania tropica. We describe and evaluate the treatment outcome of CL among travelers and migrants in Europe. Methods: We conducted a retrospective study of parasitological confirmed CL cases caused by L. major and L. tropica during 2013-2019 in Europe. Data were collected from medical records and databases within the LeishMan network. Results: Of 206 included cases of CL, 75 were identified as L. major and 131 as L. tropica. Of patients with L. tropica infection, 80% were migrants, whereas 53% of patients with L. major infection had been visiting friends and relatives. Among patients with L. tropica, 48% were younger than 15 years. Pentavalent antimony cured 73% (L. major) and 78% (L. tropica) of patients. The cure rate for intralesional administration was 86% and 67% for systemic, on L. tropica. Liposomal amphotericin B had a cure rate of 44-63%. Conclusion: L. major infections were mostly found in individuals visiting friends and relatives, whereas L. tropica were mainly identified in migrants. No patients with L. major relapsed. Pentavalent antimony, liposomal amphotericin B, and cryotherapy had cure rates in accordance with previous studies.

This paper aims to advance the general understanding of negative concord (as in English We don’t need no education) and connective negation (as in English neither … nor’) through an analysis of Persian. For negative concord with indefinites the analysis highlights differences between human vs. non-human and pronominal vs. nominal negative concord. It also deals with the problem that hič, the word that arguably marks negation in negative indefinites, also has a non-negative emphatic meaning in questions. For the relation between negative concord and connective negation the paper suggests the importance of two new parameters: (i) are the connective negator and the normal clausal negator similar? and (ii) can one of two negatively connected phrases precede the verb and the other follow it?

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.

Tegumentary leishmaniasis (TL) is endemic but neglected in southern Europe. Therefore, this study aimed to analyze the Leishmania strains causing TL cases in northeastern Italy, where an upsurge of TL cases has been observed in the last decade. Sections from 109 formalin-fixed and paraffin-embedded (FFPE) biopsies of skin and mucosal tissues were collected from TL cases in the selected area. Two DNA targets were amplified and sequenced: the ribosomal internal transcribed spacer 1 (ITS1) and the heat-shock protein 70 gene (hsp70). An in silico analysis was also performed on 149 genomes belonging to the Leishmania donovani complex. A total of 88 out of 109 (80.7%) samples from 83 TL cases were successfully typed by ITS1 and/or hsp70. ITS1 analysis identified L. infantum in 67 cases (91.8%), while L. major (n = 4, 5.5%) and L. tropica (n = 2, 2.7%) were detected in the remaining cases that were categorized as imported. Further, the hsp70 typing of 75 autochthonous cases showed the presence of eight distinct sequence variants belonging to the Leishmania donovani complex, with high genetic variability when compared to known L. infantum populations. In conclusion, our findings show that peculiar L. infantum variants are emerging in the novel focus on TL in northeastern Italy.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease representing the most common type of dementia in older adults. The major risk factors include increased age, genetic predisposition and socioeconomic factors. Among the genetic factors, the apolipoprotein E (ApoE) ε4 allele poses the greatest risk. Growing evidence suggests that cerebrovascular dysfunctions, including blood–brain barrier (BBB) leakage, are also linked to AD pathology. Within the scope of this paper, we, therefore, look upon the relationship between ApoE, BBB integrity and AD. In doing so, both brain-derived and peripheral ApoE will be considered. Despite the considerable evidence for the involvement of brain-derived ApoE ε4 in AD, information about the effect of peripheral ApoE ε4 on the central nervous system is scarce. However, a recent study demonstrated that peripheral ApoE ε4 might be sufficient to impair brain functions and aggravate amyloid-beta pathogenesis independent from brain-based ApoE ε4 expression. Building upon recent literature, we provide an insight into the latest research that has enhanced the understanding of how ApoE ε4, secreted either in the brain or the periphery, influences BBB integrity and consequently affects AD pathogenesis. Subsequently, we propose a pathway model based on current literature and discuss future research perspectives.

The article aims to advance the general understanding of negative concord through a comparative analysis of nominal and pronominal negative concord in Jamaican and Belizean Creole, based on the translations of the New Testament. It supplies a general characterization of Jamaican and Belizean negative concord and then focuses on negative concord with a negator like what corresponds to English not and either a pronoun or a nominal like what corresponds to English nobody or no man, respectively. The paper makes a strong plea for studying nominal negative concord in its own right. It shows how it differs from pronominal negative concord and for both it lays bare a variety of non-concordant patterns. It explains the variation in terms of a number of principles, one of which is what is standardly called the ‘Negative First’ principle, but it is defined in a new way. The article shows that there can be concord with definite negative nominals.

Abstract The Apolipoprotein E (APOE) gene polymorphism (rs429358 and rs7412) shows a well-established association with lipid profiles, but its effect on cardiovascular disease is still conflicting. Therefore, we examined the association of different APOE alleles with common carotid artery intima-media thickness (CCA-IMT), carotid plaques, incident myocardial infarction (MI) and stroke. We analyzed data from 3327 participants aged 20–79 years of the population-based Study of Health in Pomerania (SHIP) from Northeast Germany with a median follow-up time of 14.5 years. Linear, logistic, and Cox-regression models were used to assess the associations of the APOE polymorphism with CCA-IMT, carotid plaques, incident MI and stroke, respectively. In our study, the APOE E2 allele was associated with lower CCA-IMT at baseline compared to E3 homozygotes (β: − 0.02 [95% CI − 0.04, − 0.004]). Over the follow-up, 244 MI events and 218 stroke events were observed. APOE E2 and E4 allele were not associated with incident MI (E2 HR: 1.06 [95% CI 0.68, 1.66]; E4 HR: 1.03 [95% CI 0.73, 1.45]) and incident stroke (E2 HR: 0.79 [95% CI 0.48, 1.30]; E4 HR: 0.96 [95% CI 0.66, 1.38]) in any of the models adjusting for potential confounders. However, the positive association between CCA-IMT and incident MI was more pronounced in E2 carriers than E3 homozygotes. Thus, our study suggests that while APOE E2 allele may predispose individuals to lower CCA-IMT, E2 carriers may be more prone to MI than E3 homozygotes as the CCA-IMT increases. APOE E4 allele had no effect on CCA-IMT, plaques, MI or stroke.

Human factors research is still in its infancy in healthcare and other fields. Yet it has the potential to allow organisations and living labs to assess and improve innovation quality, while closely involving potential end users. "Human factors" involve a scientific focus on the interaction between individuals and systems with the goal of improving safety, performance, and user acceptability. Studies simulating challenging real-life circumstances in selected samples and using a multi-method approach can provide important insights for organisations and governments and allow for better and safer services for the end user. By combining existing theory and case examples, the current paper aims to situate human factors research and to help researchers determine when and how this methodology could be applied.

Abstract Purpose To discuss recent literature on posterior cruciate ligament (PCL) repair and report on the clinical and radiological outcomes. Methods A systematic review was conducted according to the PRISMA guidelines. In August 2022, three databases (PubMed, Scopus, and Cochrane Library) were searched for studies on PCL repair by two independent reviewers. Articles published between January 2000 and August 2022 focussing on the clinical and/or radiological outcomes, following PCL repair, were included. Patient demographic data, clinical evaluations, patient‑reported outcome measures, post‐operative complications and radiological outcomes were extracted. Results Nine studies met the inclusion criteria, covering 226 patients with a mean age ranging from 22.4 to 38.8 years and mean follow‐up periods ranging from 14 to 78.6 months. Seven studies (77.8%) were level IV and two studies (22.2%) were level III. Arthroscopic PCL repair was performed in four studies (44.4%) while the remaining five studies (55.6%) described open PCL repair. In four studies (44.4%) additional suture augmentation was applied. Arthrofibrosis affected a combined total of 24 patients (11.7%; range 0–21.0%) making it the most common complication and the overall failure rate was 5.6%, ranging from 0 to 15.8%. Two studies (22.2%) performed post‐operative MRI and confirmed PCL healing. Conclusion This systematic review indicates that PCL repair can be a safe procedure with an overall failure rate of 5.6%, ranging from 0% to 15.8%. However, more high quality research is necessary before widespread clinical implementation is warranted. Level of Evidence IV.

Abstract Evidence from previous studies suggests that elevated body mass index (BMI) and genetic risk for obesity is associated with reduced brain volume, particularly in areas of reward-related cognition, e.g. the medial prefrontal cortex (AC-MPFC), the orbitofrontal cortex (OFC), the striatum and the thalamus. However, only few studies examined the interplay between these factors in a joint approach. Moreover, previous findings are based on cross-sectional data. We investigated the longitudinal relationship between increased BMI, brain structural magnetic resonance imaging (MRI) parameters and genetic risk scores in a cohort of n = 502 community-dwelling participants from the Study of Health in Pomerania (SHIP) with a mean follow-up-time of 4.9 years. We found that (1) increased BMI values at baseline were associated with decreased brain parameters at follow-up. These effects were particularly pronounced for the OFC and AC-MPFC. (2) The genetic predisposition for BMI had no effect on brain parameters at baseline or follow-up. (3) The interaction between the genetic score for BMI and brain parameters had no effect on BMI at baseline. Finding a significant impact of overweight, but not genetic predisposition for obesity on altered brain structure suggests that metabolic mechanisms may underlie the relationship between obesity and altered brain structure.

Abstract The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5–90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology.

Abstract Background While docetaxel/cisplatin/5‐fluorouracil (DCF) outperforms CF in first‐line gastric adenocarcinoma, toxicity remains an issue. Methods This multicenter phase II trial randomized chemonaïve metastatic gastric adenocarcinoma patients to fractionated weekly DCF (D 40 mg/m2, C 35 mg/m², F 1800 mg/m² over 24 h, on days 1 and 8 every 3 weeks, arm (1) or fortnightly DCF (D 50 mg/m2, C 50 mg/m², F 2000 mg/m² over 48 h every 2 weeks, arm (2). Prophylactic granulocyte colony‐stimulating factor (G‐CSF) was not allowed. The primary endpoint was the rate of febrile neutropenia within the first six treatment weeks (early FN). Results A total of 106 eligible patients were recruited. The early and overall FN rates were 9.5% and 17% in arm 1, respectively, and 5.9% and 8% in arm 2, respectively. Grade ≥3 toxicities occurred in 81% of patients in arm 1 and 90% of patients in arm 2, the most common being neutropenia (33% vs. 61%), fatigue (27% vs. 25%), vomiting (21% vs. 12%), anorexia (19% vs. 18%), and diarrhea (17% vs. 10%). Median progression‐free survival and overall survival were 5.1 (95% CI, 3.2–6.5) and 8.2 months (95% CI, 6.0–14.5), respectively, in arm 1 and 5.2 (95% CI, 3.0–6.9) and 11.9 months (95% CI, 7.4–15.9), respectively, in arm 2. Conclusions Fractionated weekly and fortnightly DCF regimens are associated with a low risk of early FN, and a better hematological toxicity profile as compared to historical DCF without compromising efficacy. Both regimens offer greater convenience removing the need for systematic use of prophylactic G‐CSF.

Abstract In the Jê languages standard negators tend to take a post-verbal position. This paper asks why this should be the case and therefore discusses earlier accounts relating Jê standard negators to either negative verbs or privative postpositions. We argue that these accounts do not have to exclude each other. In particular, we propose that an existential negator can be reanalyzed as a privative one. We also argue that if the origin of the standard negator is a verb with the meaning ‘finish’, we may be dealing with a scenario that is similar to the ‘Negative Existential Cycle’. In both, the existential negator denies the existence of a state of affairs and then turns into a standard negator. But whereas in the Negative Existential Cycle the non-existence of a state of affairs is modelled on the non-existence of an object, in the ‘new’ scenario the non-existence of a state of affairs derives from the fact that a process or event has come to an end.

(1) Background: Filipendula ulmaria (L.) Maxim. (Rosaceae) (meadowsweet) is widely used in phytotherapy against inflammatory diseases. However, its active constituents are not exactly known. Moreover, it contains many constituents, such as flavonoid glycosides, which are not absorbed, but metabolized in the colon by gut microbiota, producing potentially active metabolites that can be absorbed. The aim of this study was to characterize the active constituents or metabolites. (2) Methods: A F. ulmaria extract was processed in an in vitro gastrointestinal biotransformation model, and the metabolites were characterized using UHPLC-ESI-QTOF-MS analysis. In vitro anti-inflammatory activity was evaluated by testing the inhibition of NF-κB activation, COX-1 and COX-2 enzyme inhibition. (3) Results: The simulation of gastrointestinal biotransformation showed a decrease in the relative abundance of glycosylated flavonoids such as rutin, spiraeoside and isoquercitrin in the colon compartment, and an increase in aglycons such as quercetin, apigenin, naringenin and kaempferol. The genuine as well as the metabolized extract showed a better inhibition of the COX-1 enzyme as compared to COX-2. A mix of aglycons present after biotransformation showed a significant inhibition of COX-1. (4) Conclusions: The anti-inflammatory activity of F. ulmaria may be explained by an additive or synergistic effect of genuine constituents and metabolites.

Abstract A complex interplay between genetic and environmental factors determines the individual risk of depressive disorders. Vitamin D has been shown to stimulate the expression of the tryptophan hydroxylase 2 (TPH2) gene, which is the rate-limiting enzyme for serotonin production in the brain. Therefore, we investigate the hypothesis that serum vitamin D levels moderate the interaction between the serotonin transporter promotor gene polymorphism (5-HTTLPR) and childhood abuse in depressive disorders. Two independent samples from the Study of Health in Pomerania (SHIP-LEGEND: n = 1 997; SHIP-TREND-0: n = 2 939) were used. Depressive disorders were assessed using questionnaires (BDI-II, PHQ-9) and interview procedures (DSM-IV). Besides serum vitamin D levels (25(OH)D), a functional polymorphism (rs4588) of the vitamin D-binding protein is used as a proxy for 25(OH)D. S-allele carriers with childhood abuse and low 25(OH)D levels have a higher mean BDI-II score (13.25) than those with a higher 25(OH)D level (9.56), which was not observed in abused LL-carriers. This significant three-way interaction was replicated in individuals with lifetime major depressive disorders when using the rs4588 instead of 25(OH)D (p = 0.0076 in the combined sample). We conclude that vitamin D relevantly moderates the interaction between childhood abuse and the serotonergic system, thereby impacting vulnerability to depressive disorders.

Abstract Sleep and wakefulness are fundamental behavioral states of which the underlying molecular principles are becoming slowly elucidated. Transitions between these states require the coordination of multiple neurochemical and modulatory systems. In Caenorhabditis elegans sleep occurs during a larval transition stage called lethargus and is induced by somnogenic neuropeptides. Here, we identify two opposing neuropeptide/receptor signaling pathways: NLP-22 promotes behavioral quiescence, whereas NLP-2 promotes movement during lethargus, by signaling through gonadotropin-releasing hormone (GnRH) related receptors. Both NLP-2 and NLP-22 belong to the RPamide neuropeptide family and share sequence similarities with neuropeptides of the bilaterian GnRH, adipokinetic hormone (AKH) and corazonin family. RPamide neuropeptides dose-dependently activate the GnRH/AKH-like receptors GNRR-3 and GNRR-6 in a cellular receptor activation assay. In addition, nlp-22-induced locomotion quiescence requires the receptor gnrr-6. By contrast, wakefulness induced by nlp-2 overexpression is diminished by deletion of either gnrr-3 or gnrr-6. nlp-2 is expressed in a pair of olfactory AWA neurons and cycles with larval periodicity, as reported for nlp-22, which is expressed in RIA. Our data suggest that the somnogenic NLP-22 neuropeptide signals through GNRR-6, and that both GNRR-3 and GNRR-6 are required for the wake-promoting action of NLP-2 neuropeptides.

Learning and memory are regulated by neuropeptides. Here, the authors show that the neuropeptide CAPA-1 and its receptor NMUR-1 are required to retrieve learned salt avoidance in C. elegans. CAPA-1/NMUR-1 activation in AFD sensory neurons modulates locomotor programs to express learned avoidance.

BackgroundLiving labs in the health and well-being domain have become increasingly common over the past decade but vary in available infrastructure, implemented study designs, and outcome measures. The Horizon 2020 Project Virtual Health and Wellbeing Living Lab Infrastructure aims to harmonize living lab procedures and open living lab infrastructures to facilitate and promote research activities in the health and well-being domain in Europe and beyond. This protocol will describe the design of a joint research activity, focusing on the use of innovative technology for both rehabilitation interventions and data collection in a rehabilitation context. ObjectiveWith this joint research activity, this study primarily aims to gain insight into each living lab’s infrastructure and procedures to harmonize health and well-being living lab procedures and infrastructures in Europe and beyond, particularly in the context of rehabilitation. Secondarily, this study aims to investigate the potential of innovative technologies for rehabilitation through living lab methodologies. MethodsThis study has a mixed methods design comprising multiple phases. There are two main phases of data collection: cocreation (phase 1) and small-scale pilot studies (phase 2), which are preceded by a preliminary harmonization of procedures among the different international living labs. An intermediate phase further allows the implementation of minor adjustments to the intervention or protocol depending on the input that was obtained in the cocreation phase. A total of 6 small-scale pilot studies using innovative technologies for intervention or data collection will be performed across 4 countries. The target study sample comprises patients with stroke and older adults with mild cognitive impairment. The third and final phases involve Delphi procedures to reach a consensus on harmonized procedures and protocols. ResultsPhase 1 data collection will begin in March 2022, and phase 2 data collection will begin in June 2022. Results will include the output of the cocreation sessions, small-scale pilot studies, and advice on harmonizing procedures and protocols for health and well-being living labs focusing on rehabilitation. ConclusionsThe knowledge gained by the execution of this research will lead to harmonized procedures and protocols in a rehabilitation context for health and well-being living labs in Europe and beyond. In addition to the harmonized procedures and protocols in rehabilitation, we will also be able to provide new insights for improving the implementation of innovative technologies in rehabilitation. International Registered Report Identifier (IRRID)PRR1-10.2196/34537