Search Results (17)

Marfan syndrome (MFS) is a systemic connective tissue disorder stemming from mutations in the gene encoding Fibrillin-1 (Fbn1), a key extracellular matrix glycoprotein. This condition manifests with various clinical features, the most critical of which is the formation of aortic root aneurysms. Reduced nitric oxide (NO) production due to diminished endothelial nitric oxide synthase (eNOS) activity has been linked to MFS aortic aneurysm pathology. Caveolin-1 (Cav1), a structural protein of plasma membrane caveolae, is known to inhibit eNOS activity, suggesting its involvement in MFS aneurysm progression by modulating NO levels. In this study, we examined the role of Cav1 in aortic smooth muscle and endothelial function, aortic wall elasticity, and wall strength in male and female MFS mice (FBN1^+/Cys1041Gly) by generating developing Cav1-deficient MFS mice (MFS/Cav1KO). Our findings reveal that Cav1 ablation leads to a pronounced reduction in aortic smooth muscle contraction in response to phenylephrine, attributable to an increase in NO production in the aortic wall. Furthermore, we observed enhanced aortic relaxation responses to acetylcholine in MFS/Cav1KO mice, further underscoring Cav1’s inhibitory impact on NO synthesis within the aorta. Notably, van Gieson staining and chamber myography analyses showed improved elastin fiber structure and wall strength in male MFS/Cav1KO mice, whereas these effects were absent in female counterparts. Cav1’s regulatory influence on aortic root aneurysm development in MFS through NO-mediated modulation of smooth muscle and endothelial function, with notable sex-dependent variations. Full article

Hypoalbuminemia associates with poor acute ischemic stroke (AIS) outcomes. We hypothesised a non-linear relationship and aimed to systematically assess this association using prospective stroke data from the Norfolk and Norwich Stroke and TIA Register. Consecutive AIS patients aged ≥40 years admitted December 2003–December 2016 were included. Outcomes: In-hospital mortality, poor discharge, functional outcome (modified Rankin score 3–6), prolonged length of stay (PLoS) > 4 days, and long-term mortality. Restricted cubic spline regressions investigated the albumin–outcome relationship. We updated a systematic review (PubMed, Scopus, and Embase databases, January 2020–June 2023) and undertook a meta-analysis. A total of 9979 patients were included; mean age (standard deviation) = 78.3 (11.2) years; mean serum albumin 36.69 g/L (5.38). Compared to the cohort median, albumin < 37 g/L associated with up to two-fold higher long-term mortality (HR_max; 95% CI = 2.01; 1.61–2.49) and in-hospital mortality (RR_max; 95% CI = 1.48; 1.21–1.80). Albumin > 44 g/L associated with up to 12% higher long-term mortality (HR_max1.12; 1.06–1.19). Nine studies met our inclusion criteria totalling 23,597 patients. Low albumin associated with increased risk of long-term mortality (two studies; relative risk 1.57 (95% CI 1.11–2.22; I² = 81.28)), as did low-normal albumin (RR 1.10 (95% CI 1.01–1.20; I² = 0.00)). Strong evidence indicates increased long-term mortality in AIS patients with low or low-normal albumin on admission. Full article

While animal model studies have extensively defined the mechanisms controlling cell diversity in the developing mammalian lung, there exists a significant knowledge gap with regards to late-stage human lung development. The NHLBI Molecular Atlas of Lung Development Program (LungMAP) seeks to fill this gap by creating a structural, cellular and molecular atlas of the human and mouse lung. Transcriptomic profiling at the single-cell level created a cellular atlas of newborn human lungs. Frozen single-cell isolates obtained from two newborn human lungs from the LungMAP Human Tissue Core Biorepository, were captured, and library preparation was completed on the Chromium 10X system. Data was analyzed in Seurat, and cellular annotation was performed using the ToppGene functional analysis tool. Transcriptional interrogation of 5500 newborn human lung cells identified distinct clusters representing multiple populations of epithelial, endothelial, fibroblasts, pericytes, smooth muscle, immune cells and their gene signatures. Computational integration of data from newborn human cells and with 32,000 cells from postnatal days 1 through 10 mouse lungs generated by the LungMAP Cincinnati Research Center facilitated the identification of distinct cellular lineages among all the major cell types. Integration of the newborn human and mouse cellular transcriptomes also demonstrated cell type-specific differences in maturation states of newborn human lung cells. Specifically, newborn human lung matrix fibroblasts could be separated into those representative of younger cells (n = 393), or older cells (n = 158). Cells with each molecular profile were spatially resolved within newborn human lung tissue. This is the first comprehensive molecular map of the cellular landscape of neonatal human lung, including biomarkers for cells at distinct states of maturity. Full article

The following study aimed to systematically review and meta-analyse the literature on the relations between markers of nutritional status and long-term mortality, recurrence and all-cause hospital readmission following myocardial infarction (MI). Medline, EMBASE and Web of Science were searched for prospective cohort studies reporting the relationship between anthropometric and biochemical markers of nutritional status and nutritional assessment tools on long-term mortality, recurrence and all-cause hospital readmission in adult patients with an MI. Two reviewers conducted screening, data extraction and critical appraisal independently. Random-effects meta-analysis was performed. Twenty-seven studies were included in the qualitative synthesis and twenty-four in the meta-analysis. All eligible studies analysed BMI as their exposure of interest. Relative to normal weight, mortality was highest in underweight patients (adjusted Hazard Ratio (95% confidence interval): 1.42 (1.24–1.62)) and lower in both overweight (0.85 (0.76–0.94)) and obese patients (0.86 (0.81–0.91)), over a mean follow-up ranging from 6 months to 17 years. No statistically significant associations were identified between different BMI categories for the outcomes of recurrence and hospital readmission. Patients with low BMI carried a significant mortality risk post-MI; however due to the known limitations associated with BMI measurement, further evidence regarding the prognostic utility of other nutritional markers is required. Full article

Is suicide the unforgivable sin? Most Western arguments against suicide stem from Christian arguments. Christianity has a long-standing position that suicide is morally wrong. However, on the issue of suicide and salvation, Christianity is divided. Debate, discussion, and interpretation through the centuries have led to two different positions. This result has divided the Christian community in multiple ways. These beliefs have likely impacted the level of stigma associated with suicide losses, suicide attempts, and suicide survivors within Christianity. The stigma of suicide can be lethal if it is not properly addressed. Stigma can easily push people away from caring communities of support and from God. This paper examines the two predominate Christian theological positions on suicide and highlights areas where stigma has hindered help, support, and care. Lowering the negative effects of suicidal stigma is a foundational piece of the solution for communities of faith to engage people at risk of suicide. Full article

Food production is a major contributor to environmental damage. More environmentally sustainable foods could incur higher costs for consumers. In this review, we explore whether consumers are willing to pay (WTP) more for foods with environmental sustainability labels (‘ecolabels’). Six electronic databases were searched for experiments on consumers’ willingness to pay for ecolabelled food. Monetary values were converted to Purchasing Power Parity dollars and adjusted for country-specific inflation. Studies were meta-analysed and effect sizes with confidence intervals were calculated for the whole sample and for pre-specified subgroups defined as meat-dairy, seafood, and fruits-vegetables-nuts. Meta-regressions tested the role of label attributes and demographic characteristics on participants’ WTP. Forty-three discrete choice experiments (DCEs) with 41,777 participants were eligible for inclusion. Thirty-five DCEs (n = 35,725) had usable data for the meta-analysis. Participants were willing to pay a premium of 3.79 PPP$/kg (95%CI 2.7, 4.89, p ≤ 0.001) for ecolabelled foods. WTP was higher for organic labels compared to other labels. Women and people with lower levels of education expressed higher WTP. Ecolabels may increase consumers’ willingness to pay more for environmentally sustainable products and could be part of a strategy to encourage a transition to more sustainable diets. Full article

(1) Background: Genomic precision medicine (PM) utilises people’s genomic data to inform the delivery of preventive and therapeutic health care. PM has not been well-established for use with people of Aboriginal and Torres Strait Islander ancestry due to the paucity of genomic data from these communities. We report the development of a new protocol using co-design methods to enhance the potential use of PM for Aboriginal Australians. (2) Methods: This iterative qualitative study consists of five main phases. Phase-I will ensure appropriate governance of the project and establishment of a Project Advisory Committee. Following an initial consultation with the Aboriginal community, Phase-II will invite community members to participate in co-design workshops. In Phase-III, the Chief Investigators will participate in co-design workshops and document generated ideas. The notes shall be analysed thematically in Phase-IV with Aboriginal community representatives, and the summary will be disseminated to the communities. In Phase-V, we will evaluate the co-design process and adapt our protocol for the use in partnership with other communities. (3) Discussion: This study protocol represents a crucial first step to ensure that PM research is relevant and acceptable to Aboriginal Australians. Without fair access to PM, the gap in health outcome between Aboriginal and non-Aboriginal Australians will continue to widen. Full article

Dehydration is prevalent in hospitalised patients and is associated with increased morbidity and mortality, particularly among the elderly (≥65 years). We aimed at comparing the performance of intracellular water to extracellular water ratio (ICW/ECW), calculated through a bioelectrical impedance analysis (BIA) of blood urea nitrogen, with the creatinine ratio (BUN/Cr) to predict poor outcomes in a cohort of prospectively identified patients. Data were combined from a cohort of elderly patients (≥65 years) admitted to hospital with fragility fracture (n = 125) and older adults aged ≥50 years admitted to hospital with stroke (n = 40). The association between hydration status and study outcomes (unfavourable discharge destination (rehabilitation, another ward, or death) and prolonged hospitalisation (>10 days)) was examined using logistic regression. The overall diagnostic accuracy of each hydration status measurement was assessed using the area under the receiver operating characteristic (ROC) curve. In 165 participants (mean age (SD) of 76.7 (9.2) years), an ICW/ECW ratio below the 25th percentile was associated with increased odds of poor discharge destination (OR (95% CI) = 4.25 (1.59–11.34)). Neither the relationship between the BUN/Cr ratio and prolonged stay nor discharge destination was significant. A BIA could be used utilised in conjunction with biochemical measurements to inform patient prognosis. Full article

Previously, we found that risk of colorectal cancer (CRC) is increased in individuals with serum antibody response to both Helicobacter pylori (HP) Vacuolating Cytotoxin (VacA) toxin or Streptococcus gallolyticus (SGG) pilus protein Gallo2178. In the present analysis, we tested the hypothesis that combined seropositivity to both antigens is a better indicator of CRC risk than seropositivity to single antigens. We used multiplex serologic assays to analyze pre-diagnostic serum for antibody responses from 4063 incident CRC cases and 4063 matched controls from 10 US cohorts. To examine whether combined SGG Gallo2178 and HP VacA sero-status was associated with CRC risk, we used conditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Compared to dual sero-negative individuals, there was no increased risk for individuals sero-positive to SGG Gallo2178 only (OR: 0.93; 95% CI: 0.66–1.31) or to HP VacA only (OR: 1.08; 95% CI: 0.98–1.19). However, dual sero-positive individuals had a >50% increased odds of developing CRC (OR: 1.54; 95% CI: 1.16–2.04), suggesting an interaction between antibody responses to these two pathogens and CRC risk (p_interaction = 0.06). In conclusion, this study suggests that dual sero-positivity to HP VacA and SGG Gallo2178 is an indicator of increased risk of CRC. Full article

Nursing home placement after stroke indicates a poor outcome but numbers placed vary between hospitals. The aim of this study is to determine whether between-hospital variations in new nursing home placements post-stroke are reliant solely on case-mix differences or whether service heterogeneity plays a role. A prospective, multi-center cohort study of acute stroke patients admitted to eight National Health Service acute hospitals within the Anglia Stroke and Heart Clinical Network between 2009 and 2011 was conducted. We modeled the association between hospitals (as a fixed-effect) and rates of new discharges to nursing homes using multiple logistic regression, adjusting for important patient risk factors. Descriptive and graphical data analyses were undertaken to explore the role of hospital characteristics. Of 1335 stroke admissions, 135 (10%) were discharged to a nursing home but rates varied considerably from 6% to 19% between hospitals. The hospital with the highest adjusted odds ratio of nursing home discharges (OR 4.26; 95% CI 1.69 to 10.73), was the only hospital that did not provide rehabilitation beds in the stroke unit. Increasing hospital size appeared to be related to an increased odds of nursing home placement, although attenuated by the number of hospital stroke admissions. Our results highlight the potential influence of hospital characteristics on this important outcome, independently of patient-level factors. Full article

This paper seeks to address the need for a more nuanced understanding of public perceptions of risk-related events by investigating the nature of and drivers for a ‘concerned public’ to an environmental issue, using the case study of the ash dieback outbreak in the UK. Q Methodology, an approach that combines both quantitative and qualitative data through factor analysis to identify different ways of thinking about a particular issue, was used to investigate the subjective response of local publics to ash dieback in East Kent, England, one of the early outbreak locations. Five narratives are identified, distinguishing perceptions of risk and management preferences: (1) call for better biosecurity; (2) resilient nature and techno-scientific solutions; (3) fatalistic; (4) disinterested; and (5) pro-active citizens. Four narratives demonstrated concern about the impacts of ash dieback on woodland ecosystems, but beliefs about whether the disease arrived in the UK on infected imported nursery stock or on windblown spores varied. The results of this study contribute to improving understanding of the drivers of differing public perceptions of tree health risks, an important consideration for designing socially acceptable strategies for managing tree pests and diseases, and other environmental risks, in the future. Full article

Previously thought to be mainly a disorder of childhood and early adult life, coeliac disease (CeD) is increasingly diagnosed in older adults. This may be important given the association between CeD and osteoporosis. The primary aim of this study was to determine the seroprevalence of undiagnosed CeD (‘at-risk serology’) in an older Australian community and relate this to a diagnosis of osteoporosis and fractures during a follow-up period of 12 years. We included participants from the Hunter Community Study (2004–2007) aged 55–85, who had anti-tissue transglutaminase (tTG) titres, human leukocyte antigen (HLA) genotypes, and bone mineral density measurements at baseline. Follow-up data included subsequent diagnosis of CeD and fractures using hospital information. ‘At-risk’ serology was defined as both tTG and HLA positivity. Complete results were obtained from 2122 patients. The prevalence of ‘at-risk’ serology was 5%. At baseline, 3.4% fulfilled criteria for a diagnosis of osteoporosis. During a mean of 9.7 years of follow-up, 7.4% of the cohort suffered at least one fracture and 0.7% were subsequently diagnosed with CeD. At-risk serology was significantly associated with osteoporosis in a multivariate model (odds ratio 2.83, 95% confidence interval 1.29–6.22); there was insufficient power to look at the outcome of fractures. The results of this study demonstrate that at-risk CeD serology was significantly associated with concurrent osteoporosis but not future fractures. Most individuals with a serological diagnosis of CeD were not diagnosed with CeD during the follow-up period according to medical records. Coeliac disease likely remains under-diagnosed. Full article

Characterization of gene-environment interactions (GEIs) in cancer is limited. We aimed at identifying GEIs in rectal cancer focusing on a relevant biologic process involving the angiogenesis pathway and relevant environmental exposures: cigarette smoking, alcohol consumption, and animal protein intake. We analyzed data from 747 rectal cancer cases and 956 controls from the Diet, Activity and Lifestyle as a Risk Factor for Rectal Cancer study. We applied a 3-step analysis approach: first, we searched for interactions among single nucleotide polymorphisms on the pathway genes; second, we searched for interactions among the genes, both steps using Logic regression; third, we examined the GEIs significant at the 5% level using logistic regression for cancer risk and Cox proportional hazards models for survival. Permutation-based test was used for multiple testing adjustment. We identified 8 significant GEIs associated with risk among 6 genes adjusting for multiple testing: TNF (OR = 1.85, 95% CI: 1.10, 3.11), TLR4 (OR = 2.34, 95% CI: 1.38, 3.98), and EGR2 (OR = 2.23, 95% CI: 1.04, 4.78) with smoking; IGF1R (OR = 1.69, 95% CI: 1.04, 2.72), TLR4 (OR = 2.10, 95% CI: 1.22, 3.60) and EGR2 (OR = 2.12, 95% CI: 1.01, 4.46) with alcohol; and PDGFB (OR = 1.75, 95% CI: 1.04, 2.92) and MMP1 (OR = 2.44, 95% CI: 1.24, 4.81) with protein. Five GEIs were associated with survival at the 5% significance level but not after multiple testing adjustment: CXCR1 (HR = 2.06, 95% CI: 1.13, 3.75) with smoking; and KDR (HR = 4.36, 95% CI: 1.62, 11.73), TLR2 (HR = 9.06, 95% CI: 1.14, 72.11), EGR2 (HR = 2.45, 95% CI: 1.42, 4.22), and EGFR (HR = 6.33, 95% CI: 1.95, 20.54) with protein. GEIs between angiogenesis genes and smoking, alcohol, and animal protein impact rectal cancer risk. Our results support the importance of considering the biologic hypothesis to characterize GEIs associated with cancer outcomes. Full article

Identification of factors that determine length of stay (LOS) in total anterior circulatory stroke (TACS) has potential for targeted intervention to reduce the associated health care burden. This study aimed to determine which factors predict LOS following either ischaemic or haemorrhagic TACS. The study sample population was drawn from the Norfolk and Norwich Stroke and Transient Ischemic Attack (TIA) Register (1996–2012), a prospective registry. 2965 patients admitted with TACS verified by a stroke specialist team were included. Primary analysis identified predictors of length of stay (LOS) in either haemorrhagic or ischaemic TACS. Secondary analyses identified predictors of LOS in patients who were discharged alive or who died during admission separately. Moderate (p = 0.014) to severe disability (p = 0.015) and history of congestive heart failure (p = 0.027) in the primary analysis and pre-stroke residence in a care facility among patients who survived to discharge (p = 0.013) were associated with a shorter length of stay. Factors associated with increased length of stay included presence of neurological lateralisation in the primary analysis (p = 0.004) and amongst patients who died (p = 0.003 and p = 0.014 for ischaemic and haemorrhagic stroke, respectively). Patients with advanced age (≥85 years) with haemorrhagic stroke had longer LOS regardless of mortality outcome. Patients with low pre-morbid disability (modified Rankin score ≤2 who died following haemorrhagic TACS also had longer LOS. Our study found predictors of LOS following TACS include neurological lateralisation, pre-stroke disability status, congestive heart failure, pre-morbid residence and age. The identification of such factors would assist in resource allocation and discharge planning. Full article

This study examines people’s response actions in the first 30 min after shaking stopped following earthquakes in Christchurch and Wellington, New Zealand, and Hitachi, Japan. Data collected from 257 respondents in Christchurch, 332 respondents in Hitachi, and 204 respondents in Wellington revealed notable similarities in some response actions immediately after the shaking stopped. In all four events, people were most likely to contact family members and seek additional information about the situation. However, there were notable differences among events in the frequency of resuming previous activities. Actions taken in the first 30 min were weakly related to: demographic variables, earthquake experience, contextual variables, and actions taken during the shaking, but were significantly related to perceived shaking intensity, risk perception and affective responses to the shaking, and damage/infrastructure disruption. These results have important implications for future research and practice because they identify promising avenues for emergency managers to communicate seismic risks and appropriate responses to risk area populations. Full article