To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

CONTEXT:With age, the prevalence of subclinical hypothyroidism rises. However, incidence and determinants of spontaneous normalization remain largely unknown. OBJECTIVE:To investigate incidence and determinants of spontaneous normalization of TSH levels in older adults with subclinical hypothyroidism. DESIGN:Pooled data were used from the (1) pretrial population and (2) in-trial placebo group from 2 randomized, double-blind, placebo-controlled trials (Thyroid Hormone Replacement for Untreated Older Adults With Subclinical Hypothyroidism Trial and Institute for Evidence-Based Medicine in Old Age thyroid 80-plus thyroid trial). SETTING:Community-dwelling 65+ adults with subclinical hypothyroidism from the Netherlands, Switzerland, Ireland, and the United Kingdom. PARTICIPANTS:The pretrial population (N = 2335) consisted of older adults with biochemical subclinical hypothyroidism, defined as ≥1 elevated TSH measurement (≥4.60 mIU/L) and a free T4 within the laboratory-specific reference range. Individuals with persistent subclinical hypothyroidism, defined as ≥2 elevated TSH measurements ≥3 months apart, were randomized to levothyroxine/placebo, of which the in-trial placebo group (N = 361) was included. MAIN OUTCOME MEASURES:Incidence of spontaneous normalization of TSH levels and associations between participant characteristics and normalization. RESULTS:In the pretrial phase, TSH levels normalized in 60.8% of participants in a median follow-up of 1 year. In the in-trial phase, levels normalized in 39.9% of participants after 1 year of follow-up. Younger age, female sex, lower initial TSH level, higher initial free T4 level, absence of thyroid peroxidase antibodies, and a follow-up measurement in summer were independent determinants for normalization. CONCLUSION:Because TSH levels spontaneously normalized in a large proportion of older adults with subclinical hypothyroidism (also after confirmation by repeat measurement), a third measurement may be recommended before considering treatment. TRIAL REGISTRATION:ClinicalTrials.gov, NCT01660126 and Netherlands Trial Register, NTR3851.

ABSTRACT:Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program along with TOPMed-based imputation of genotypes in additional samples to identify genetic associations with circulating FVIII and VWF levels in a single-variant meta-analysis, including up to 45 289 participants. Gene-based aggregate tests were implemented in TOPMed. We identified 3 candidate causal genes and tested their functional effect on FVIII release from human liver endothelial cells (HLECs) and VWF release from human umbilical vein endothelial cells. Mendelian randomization was also performed to provide evidence for causal associations of FVIII and VWF with thrombotic outcomes. We identified associations (P < 5 × 10-9) at 7 new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and 1 for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multiphenotype analysis of FVIII and VWF identified another 3 new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, whereas silencing of B3GNT2, CD36, and PDIA3 decreased release of VWF by HVECs. Mendelian randomization supports causal association of higher FVIII and VWF with increased risk of thrombotic outcomes. Seven new loci were identified for FVIII and 1 for VWF, with evidence supporting causal associations of FVIII and VWF with thrombotic outcomes. B3GNT2, CD36, and PDIA3 modulate the release of FVIII and/or VWF in vitro.

Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole genome sequencing (WGS) data provides better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program (n=32,572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=131,340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, four are driven by common variants of small effect with reported MAF at least 10 percentage points higher in African populations. Three signals (SERPINA1, ZFP36L2, and TLR10) contain predicted deleterious missense variants. Two loci, SOCS3 and HPN, each harbor two conditionally distinct, non-coding variants. The gene region encoding the fibrinogen protein chain subunits (FGG;FGB;FGA), contains 7 distinct signals, including one novel signal driven by rs28577061, a variant common in African ancestry populations but extremely rare in Europeans (MAFAFR=0.180; MAFEUR=0.008). Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.

The Arctic is warming and significant changes to the landscape, including increased vegetative cover ("greening"), are expected in the near future. These landscape changes may alter nitrogen (N) availability in terrestrial, stream, and coastal ecosystems, where production is often N limited, but the exact changes in nutrient cycling are uncertain. Here, we analyzed the relationship between vegetation greenness (i.e., NDVI) and dissolved inorganic (DIN) and organic (DON) concentrations in streams draining 14 headwater catchments (mean 3.6 km2, range 0.4-11 km2) across three samplings in the Zackenberg area, Northeast Greenland. We found large variation in DIN and DON concentrations across the sampled streams. We further show that this variation is correlated to water temperature and catchment NDVI, such that increased vegetation greenness and temperature correlated with lower DIN, and increased greenness also correlated with higher DON concentrations in streams. The results suggest that increased terrestrial vegetation due to rising air temperature could substantially alter dissolved N concentrations and form in streams, with potentially cascading impacts on coastal areas. This study links terrestrial vegetation cover to stream water chemistry in High Arctic headwater catchments. We found significant spatial and seasonal variation in dissolved inorganic nitrogen (DIN) and dissolved organic nitrogen (DON) availability in streams. Nitrate (NO3- ${{\text{NO}}_{3}}<^>{-}$) concentration in stream water decreases and DON increases with increasing spectral median normalized difference vegetation index (NDVI) in the stream catchment (i.e., proxy for terrestrial vegetation). This shift in the form of available nitrogen (N) has significant implications as terrestrial vegetation is changing quickly in High Arctic areas, which may then alter the amount and the dominant form of N exported from catchments to coastal areas. High terrestrial vegetation greenness (NDVI) correlates negatively with dissolved inorganic nitrogen concentrations in High Arctic catchmentsDissolved inorganic nitrogen decreases and organic nitrogen increases with increased terrestrial vegetation greennessFuture climate changes in High Arctic areas may alter the amount and form of nitrogen exported from land to sea

Objective to investigate the association between variability and loss of body weight with subsequent cognitive performance and activities of daily living in older individuals. Design cross-sectional cohort study. Setting PROspective Study of Pravastatin in the Elderly at Risk, multicentre trial with participants from Scotland, Ireland and the Netherlands. Subjects 4,309 participants without severe cognitive dysfunction (mean age 75.1 years, standard deviation (SD) = 3.3), at higher risk for cardiovascular disease (CVD). Methods body weight was measured every 3 months for 2.5 years. Weight loss was defined as an average slope across all weight measurements and as >= 5% decrease in baseline body weight during follow-up. Visit-to-visit variability was defined as the SD of weight measurements (kg) between visits. Four tests of cognitive function were examined: Stroop test, letter-digit coding test (LDCT), immediate and delayed picture-word learning tests. Two measures of daily living activities: Barthel Index (BI) and instrumental activities of daily living (IADL). All tests were examined at month 30. Results both larger body weight variability and loss of >= 5% of baseline weight were independently associated with worse scores on all cognitive tests, but minimally with BI and IADL. Compared with participants with stable weight, participants with significant weight loss performed 5.83 seconds (95% CI 3.74; 7.92) slower on the Stroop test, coded 1.72 digits less (95% CI -2.21; -1.13) on the LDCT and remembered 0.71 pictures less (95% CI -0.93; -0.48) on the delayed picture-word learning test. Conclusion in older people at higher risk for CVD, weight loss and variability are independent risk-factors for worse cognitive function.

CONTEXT:Subclinical thyroid dysfunction and anemia are common disorders, and both have increasing prevalence with advancing age. OBJECTIVE:The aim of this study was to assess whether levothyroxine treatment leads to a rise in hemoglobin levels in older persons with subclinical hypothyroidism. METHODS:This preplanned combined analysis of 2 randomized controlled trials included community-dwelling persons aged 65 years and older with subclinical hypothyroidism who were randomly assigned to levothyroxine or placebo treatment. The levothyroxine dose was periodically titrated aiming at thyroid stimulating hormone (TSH) level within the reference range, with mock titrations in the placebo group. The main outcome measure was the change in hemoglobin level after 12 months. RESULTS:Analyses included 669 participants (placebo n = 337, levothyroxine n = 332) with a median age of 75 years (range, 65-97) and mean baseline hemoglobin of 13.8 ± 1.3 g/dL. Although levothyroxine treatment resulted in a reduction in TSH from baseline after 12 months of follow-up compared with placebo, the change in hemoglobin level was not different between the levothyroxine and the placebo groups (-0.03 g/dL [95% CI, -0.16 to 0.11]). Similar results were found in stratified analyses including sex, age, or TSH levels. No difference in change of hemoglobin levels after 12 months was identified in 69 participants with anemia at baseline (-0.33 g/dL [95% CI, -0.87 to 0.21]). CONCLUSION:In persons aged 65 years and older with subclinical hypothyroidism, treatment with levothyroxine does not lead to a rise in hemoglobin levels, regardless of the presence of anemia.

OBJECTIVES:Various informant-based questionnaires are used in clinical practice to screen for pre-stroke cognitive problems. However, there is no guidance on which tool should be preferred. We compared the validity of the two most commonly used informant-based tools. METHODS:We recruited consecutively admitted stroke patients. Patients' informants completed the Informant Questionnaire for Cognitive Decline in the Elderly Short Form (IQCODE-SF, 16-item) and Ascertain Dementia 8 (AD8). We assessed construct validity (accuracy) against a semi-structured clinical interview for dementia or mild cognitive impairment (MCI), describing test accuracy metrics and comparing area under ROC curves (AUROC). We described criterion validity by evaluating associations between test scores and neuroimaging markers of dementia and overall 'brain frailty'. Finally, we described prognostic validity comparing ROC curves for 18-month clinical outcomes of dementia, death, stroke, and disability. RESULTS:One-hundred-thirty-seven patient-informant dyads were recruited. At usual clinical cut-points, the IQCODE-SF had comparable sensitivity to the AD8 (both = 92%) for pre-stroke dementia, but superior specificity (IQCODE-SF: 82% vs. AD8: 58%). Youden index suggested that the optimal AD8 threshold for diagnosis of dementia is ≥4. The IQCODE-SF demonstrated stronger associations with markers of generalised and medial-temporal lobe atrophy, neurovascular disease, and overall brain frailty. IQCODE-SF also demonstrated greater accuracy for predicting future dementia (IQCODE-SF AUROC = 0.903, 95% CI = 0.798-1.00; AD8 AUROC = 0.821, 95% CI = 0.664-0.977). CONCLUSIONS:Both IQCODE-SF and AD8 are valid measures of pre-stroke dementia. Higher cut points for AD8 may improve performance in the acute stroke setting. Based on consistent superiority across a range of validity analyses, IQCODE-SF may be preferable to AD8 for pre-stroke dementia screening.

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

Background: Evidence is required to guide the redesign of health care for older people who require hospital admission. Objectives: We assessed the clinical effectiveness and cost-effectiveness of geriatrician-led admission avoidance hospital at home with comprehensive geriatric assessment, the experiences of older people and their caregivers, and how the services differed. Design: A multisite, randomised, open trial of comprehensive geriatric assessment hospital at home, compared with admission to hospital, using a 2 : 1 (hospital at home to hospital) ratio, and a parallel economic and process evaluation. Participants were randomised using a secure online system. Setting: Participants were recruited from primary care or acute hospital assessment units from nine sites across the UK. Participants: Older people who required hospital admission because of an acute change in health. Intervention: Geriatrician-led admission avoidance hospital at home with comprehensive geriatric assessment. Main outcome measures: The main outcome, ‘living at home’ (the inverse of death or living in a residential care setting), was measured at 6-month follow-up. Secondary outcomes at 6 months were the incidence of delirium, mortality, new long-term residential care, cognitive impairment, ability to perform activities of daily living, quality-adjusted survival, length of stay and transfer to hospital. Secondary outcomes at 12 months were living at home, new long-term residential care and mortality. Results: Participants were allocated to hospital at home (n = 700) or to hospital (n = 355). All reported relative risks (RRs) were adjusted and are reported for hospital at home compared with hospital. There were no significant differences between the groups in the proportions of patients ‘living at home’ at 6 months [528/672 (78.6%) vs. 247/328 (75.3%), RR 1.05, 95% confidence interval (CI) 0.95 to 1.15; p = 0.36] or at 12 months [443/670 (66.1%) vs. 219/325 (67.4%), RR 0.99, 95% CI 0.89 to 1.10; p = 0.80]; mortality at 6 months [114/673 (16.9%) vs. 58/328 (17.7%), RR 0.98, 95% CI 0.65 to 1.47; p = 0.92] or at 12 months [188/670 (28.1%) vs. 82/325 (25.2%), RR 1.14, 95% CI 0.80 to 1.62]; the proportion of patients with cognitive impairment [273/407 (67.1%) vs. 115/183 (62.8%), RR 1.06, 95% CI 0.93 to 1.21; p = 0.36]; or in ability to perform the activities of daily living as measured by the Barthel Index (mean difference 0.24, 95% CI –0.33 to 0.80; p = 0.411; hospital at home, n = 521 patients contributed data; hospital, n = 256 patients contributed data) or Comorbidity Index (adjusted mean difference 0.0002, 95% CI –0.15 to 0.15; p = 0.10; hospital at home, n = 474 patients contributed data; hospital, n = 227 patients contributed data) at 6 months. The varying denominator reflects the number of participants who contributed data to the different outcomes. There was a significant reduction in the RR of living in residential care at 6 months [37/646 (5.7%) vs. 27/311 (8.7%), RR 0.58, 95% CI 0.45 to 0.76; p < 0.001] and 12 months [39/646 (6.0%) vs. 27/311 (8.7%), RR 0.61, 95% CI 0.46 to 0.82; p < 0.001], a significant reduction in risk of delirium at 1 month [10/602 (1.7%) vs. 13/295 (4.4%), RR 0.38, 95% CI 0.19 to 0.76; p = 0.006] and an increased risk of transfer to hospital at 1 month [173/672 (25.7%) vs. 64/330 (19.4%), RR 1.32, 95% CI 1.06 to 1.64; p = 0.012], but not at 6 months [343/631 (54.40%) vs. 171/302 (56.6%), RR 0.95, 95% CI 0.86 to 1.06; p = 0.40]. Patient satisfaction was in favour of hospital at home. An unexpected adverse event that might have been related to the research was reported to the Research Ethics Committee. At 6 months, there was a mean difference in NHS, personal social care and informal care costs (mean difference –£3017, 95% CI –£5765 to –£269), and no difference in quality-adjusted survival. Older people and caregivers played a crucial role in supporting the delivery of health care. In hospital at home this included monitoring a patient’s health and managing transitional care arrangements. Limitations: The findings are most applicable to patients referred from an acute hospital assessment unit. Conclusions: Comprehensive geriatric assessment hospital at home can provide a cost-effective alternative to hospitalisation for selected older people. Further research that includes a stronger element of carer support might generate evidence to improve health outcomes. Trial registration: This trial is registered as ISRCTN60477865. Funding: This project was funded by the National Institute for Health Research (NIHR) Health and Social Care Delivery Research programme and will be published in full in Health and Social Care Delivery Research; Vol. 10, No. 2. See the NIHR Journals Library website for further project information.

Non-invasive methods are increasingly important for understanding archaeological sites and their contexts. Larger earth-built constructions are nevertheless still difficult to study without extensive excavations. At the recently discovered Viking-Age ring fortress Borgring in Denmark a suite of non-destructive methods was applied with the aim of understanding how this highly eroded earthen fortress was constructed, and investigating how the construction of such a large monument altered the landscape. The methods were 1) residual relief modelling of airborne laser scanning data, 2) electromagnetic induction (DualEM 421 s) survey combined with coring, and 3) soil magnetic susceptibility measurements all to produce a 3D model of the palaeo-landscape and the fortress. We found that the narrow natural promontory was enlarged to make space for the construction of the fortress' rampart. The magnetic susceptibility of turfs from the rampart showed that both wetland and upland areas were alternately used for different compartments and explained the segmented anomalies comprising its construction. The combined results revealed a better archaeological understanding of the construction of the rampart, that the modifications of the landscape was somewhat comparative to the contemporary Fyrkat ring fortress site, and that the understanding of the landscape modifications were improved significantly by a multi-method 3D approach.

Background and Aims : Unintentional weight loss and higher variability in body weight are associated with increased risk of cardiovascular outcomes. We examined whether this extends to cognitive function in a cohort of older people with or at increased risk of atherosclerotic cardiovascular disease.Methods: We studied 4,309 participants from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) with either existing atherosclerosis or at higher risk thereof. Body weight was measured every three months for 2.5 years. Weight loss was defined as an average slope across all weight measurements and as ≥5% decrease in baseline body weight during follow-up. Visit-to-visit variability was defined as the SD of weight measurements (kg) between visits. Four tests of cognitive function were examined: Stroop test, Letter-Digit Coding test (LDCT), immediate and delayed Picture-Word learning tests. All tests were performed at month 30.Results: Both larger visit-to-visit body weight variation and loss of ≥5% of baseline weight were independently associated with worse scores on all cognitive tests. Compared to participants who maintained stable weight, participants with significant weight loss scored 5.87 seconds (95%CI 3.78; 7.96) slower on the Stroop test and coded 1.74 digits less (95%CI -2.33; -1.14) on the LDCT. Furthermore, participants with high variability in body weight performed 4.60 seconds (95%CI 2.60; 6.59) slower on the Stroop test and coded 1.97 digits less (95%CI -2.53; -1.41) on the LDCT.Conclusions: In older people with or at increased risk of atherosclerotic cardiovascular disease, higher variability and loss of body weight are independent risk-factors for worse cognitive function. Background and Aims : Unintentional weight loss and higher variability in body weight are associated with increased risk of cardiovascular outcomes. We examined whether this extends to cognitive function in a cohort of older people with or at increased risk of atherosclerotic cardiovascular disease. Methods: We studied 4,309 participants from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) with either existing atherosclerosis or at higher risk thereof. Body weight was measured every three months for 2.5 years. Weight loss was defined as an average slope across all weight measurements and as ≥5% decrease in baseline body weight during follow-up. Visit-to-visit variability was defined as the SD of weight measurements (kg) between visits. Four tests of cognitive function were examined: Stroop test, Letter-Digit Coding test (LDCT), immediate and delayed Picture-Word learning tests. All tests were performed at month 30. Results: Both larger visit-to-visit body weight variation and loss of ≥5% of baseline weight were independently associated with worse scores on all cognitive tests. Compared to participants who maintained stable weight, participants with significant weight loss scored 5.87 seconds (95%CI 3.78; 7.96) slower on the Stroop test and coded 1.74 digits less (95%CI -2.33; -1.14) on the LDCT. Furthermore, participants with high variability in body weight performed 4.60 seconds (95%CI 2.60; 6.59) slower on the Stroop test and coded 1.97 digits less (95%CI -2.53; -1.41) on the LDCT. Conclusions: In older people with or at increased risk of atherosclerotic cardiovascular disease, higher variability and loss of body weight are independent risk-factors for worse cognitive function.

BACKGROUND:Delivering hospital-level care with comprehensive geriatric assessment (CGA) in the home is one approach to deal with the increased demand for bed-based hospital care, but clinical effectiveness is uncertain.OBJECTIVE:To assess the clinical effectiveness of admission avoidance hospital at home (HAH) with CGA for older persons.DESIGN:Multisite randomized trial. (ISRCTN registry number: ISRCTN60477865).SETTING:9 hospital and community sites in the United Kingdom.PATIENTS:1055 older persons who were medically unwell, were physiologically stable, and were referred for a hospital admission.INTERVENTION:Admission avoidance HAH with CGA versus hospital admission with CGA when available using 2:1 randomization.MEASUREMENTS:The primary outcome of living at home was measured at 6 months. Secondary outcomes were new admission to long-term residential care, death, health status, delirium, and patient satisfaction.RESULTS:Participants had a mean age of 83.3 years (SD, 7.0). At 6-month follow-up, 528 of 672 (78.6%) participants in the CGA HAH group versus 247 of 328 (75.3%) participants in the hospital group were living at home (relative risk [RR], 1.05 [95% CI, 0.95 to 1.15]; P = 0.36); 114 of 673 (16.9%) versus 58 of 328 (17.7%) had died (RR, 0.98 [CI, 0.65 to 1.47]; P = 0.92); and 37 of 646 (5.7%) versus 27 of 311 (8.7%) were in long-term residential care (RR, 0.58 [CI, 0.45 to 0.76]; P < 0.001).LIMITATION:The findings are most applicable to older persons referred from a hospital short-stay acute medical assessment unit; episodes of delirium may have been undetected.CONCLUSION:Admission avoidance HAH with CGA led to similar outcomes as hospital admission in the proportion of older persons living at home as well as a decrease in admissions to long-term residential care at 6 months. This type of service can provide an alternative to hospitalization for selected older persons.PRIMARY FUNDING SOURCE:The National Institute for Health Research Health Services and Delivery Research Programme (12/209/66).

Understanding past water management is crucial to address contemporary human-environmental challenges in sub-Saharan Africa, where urban growth is impacting upon water availability and supply. This study integrates soil profiles, high-resolution topographic data, historical sources, and socioecological memory to reconstruct how the ancient urban society at Great Zimbabwe negotiated water security. New evidence shows for the first time that closed depressions known as dhaka pits were used by the inhabitants of Great Zimbabwe for water storage and harvesting for a long time, possibly since the emergence of settlement in the mid-second millennium CE. These pits were part of a landscape-scale water management system that exploited catchment hydrology and groundwater by means of artificial dhaka reservoirs, wells, and springs to secure water for subsistence, farming, ritual and ceremony services. This study highlights the need for precise dating of the construction and functioning period of this water management system at Great Zimbabwe. Understanding past water management in such a water-scarce region is important for reconstructing how the ancient Great Zimbabwe urban society negotiated water security, but also for understanding contemporary human-environmental challenges.

Aims Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown. Methods and results We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality. Conclusion The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.

To investigate performance of the Months of the Year Backwards (MOTYB) test in older hospitalised patients with delirium, dementia, and no cognitive impairment. Half of the patients with delirium (46%) could not engage with MOTYB compared to only 11% of patients with dementia without delirium. In patients able to give responses, those with delirium or dementia performed significantly worse than those without cognitive impairment. Our findings show the potential value of analysing response patterns, especially initial engagement, self-correction, and ability to continue to do the task in addition to considering exclusively the capacity to correctly recite the months until July, June or January. To investigate performance of the Months of the Year Backwards (MOTYB) test in older hospitalised patients with delirium, dementia, and no cognitive impairment. Secondary analysis of data from a case–control study of 149 hospitalised patients aged ≥ 65 years with delirium [with or without dementia (N = 50)], dementia [without delirium (N = 46)], and no cognitive impairment (N = 53). Verbatim transcripts of MOTYB audio recordings were analysed to determine group differences in response patterns. In the total sample [median age 85y (IQR 80–88), 82% female], patients with delirium were more often unable to recite months backward to November (36/50 = 72%) than patients with dementia (21/46 = 46%; p < 0.01) and both differed significantly from patients without cognitive impairment (2/53 = 4%; p’s < 0.001). 121/149 (81%) of patients were able to engage with the test. Patients with delirium were more often unable to engage with MOTYB (23/50 = 46%; e.g., due to reduced arousal) than patients with dementia (5/46 = 11%; p < 0.001); both groups differed significantly (p’s < 0.001) from patients without cognitive impairment (0/53 = 0%). There was no statistically significant difference between patients with delirium (2/27 = 7%) and patients with dementia (8/41 = 20%) in completing MOTYB to January, but performance in both groups differed (p < 0.001 and p < 0.02, respectively) from patients without cognitive impairment (35/53 = 66%). Delirium was associated with inability to engage with MOTYB and low rates of completion. In patients able to engage with the test, error-free completion rates were low in delirium and dementia. Recording of engagement and patterns of errors may add useful information to MOTYB scoring.

Rivers have always been a magnet for human settlement, providing resources, such as water, food, and energy, and communication and travel routes. Climate- and human-made changes to the environment can easily affect the fragile balance between the 'natural' and the 'urban', causing droughts, floods, and other changes in riverine systems that challenge economic, environmental, and social sustainability. This is especially true in semi-arid regions and in times of rapid climate change and human-driven deterioration of the environment. Therefore a deeper understanding is needed of the evolution of urban-riverine relationships within long-term historical frameworks. This article presents an integrative and interdisciplinary programme for research, which although exemplified by one case study - the city of Gerasa/Jerash and its hinterland in modern Jordan - can be applied to other locations and regions with benefits.

Abstract Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome‐wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow‐up following heart failure diagnosis ranged from 2 to 116 months. Forty‐nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34–90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low‐frequency variants (allele frequency 0.01–0.05) at P < 5 × 10−8 under an additive genetic model. Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

Objective To conduct a comprehensive analysis of circulating metabolites and incident stroke in large prospective population-based settings. Methods We investigated the association of metabolites with risk of stroke in 7 prospective cohort studies including 1,791 incident stroke events among 38,797 participants in whom circulating metabolites were measured by nuclear magnetic resonance technology. The relationship between metabolites and stroke was assessed with Cox proportional hazards regression models. The analyses were performed considering all incident stroke events and ischemic and hemorrhagic events separately. Results The analyses revealed 10 significant metabolite associations. Amino acid histidine (hazard ratio [HR] per SD 0.90, 95% confidence interval [CI] 0.85, 0.94; p = 4.45 × 10−5), glycolysis-related metabolite pyruvate (HR per SD 1.09, 95% CI 1.04, 1.14; p = 7.45 × 10−4), acute-phase reaction marker glycoprotein acetyls (HR per SD 1.09, 95% CI 1.03, 1.15; p = 1.27 × 10−3), cholesterol in high-density lipoprotein (HDL) 2, and several other lipoprotein particles were associated with risk of stroke. When focused on incident ischemic stroke, a significant association was observed with phenylalanine (HR per SD 1.12, 95% CI 1.05, 1.19; p = 4.13 × 10−4) and total and free cholesterol in large HDL particles. Conclusions We found association of amino acids, glycolysis-related metabolites, acute-phase reaction markers, and several lipoprotein subfractions with the risk of stroke. These findings support the potential of metabolomics to provide new insights into the metabolic changes preceding stroke.