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The Lancet. Healthy Longevity Jul 2024Ageing hallmarks, characterising features of cellular ageing, have a role in the pathophysiology of many age-related diseases. We examined whether obesity is associated...
BACKGROUND
Ageing hallmarks, characterising features of cellular ageing, have a role in the pathophysiology of many age-related diseases. We examined whether obesity is associated with an increased risk of developing such hallmark-related diseases.
METHODS
In this multicohort study, we included people aged 38-72 years with data on weight, height, and waist circumference measured during a clinical examination at baseline between March 13, 2006, and Oct 1, 2010, from the UK Biobank with follow-up until Nov 12, 2021. To test reproducibility of the findings (replication analysis), we used data from people aged 40 years or older included in the Finnish Public Sector study and the Finnish Health and Social Support study who responded to the study surveys, had data on BMI, and were successfully linked to electronic health records from national registers up to Dec 31, 2016. Obesity and clinical characteristics were assessed at baseline. Via linkage to national health records, participants were followed up for 83 diseases related to nine ageing hallmarks (genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication). Outcomes were the first instance of hallmark-related disease, in addition to co-occurrence of three or more hallmark-related diseases and mortality.
FINDINGS
496 530 adults (mean age 57·0 years [SD 8·1]) from the UK Biobank were included in the primary analysis, and 83 249 (mean age 48·2 years [6·4]) adults from the Finnish cohorts were included in the replication analysis. Median follow-up was 12·7 years (IQR 12·0-13·4) in the UK Biobank and 14·0 years (8·0-15·0) in the Finnish cohorts. After adjusting for demographic characteristics, lifestyle factors, and depression, UK Biobank participants with obesity (BMI ≥30·0 kg/m) had a 1·40 (95% CI 1·38-1·41) times higher hazard ratio for the first hallmark-related disease than those with a healthy weight (BMI 18·5-24·9 kg/m). The corresponding hazard ratios for three co-occurring diseases were 2·92 (95% CI 2·64-3·22) for deregulated nutrient sensing, 2·73 (2·46-3·02) for telomere attrition, 2·33 (2·10-2·60) for epigenetic alterations, 2·30 (2·14-2·48) for mitochondrial dysfunction, 2·23 (2·04-2·45) for stem cell exhaustion, 2·02 (1·89-2·16) for altered intercellular communication, 2·01 (1·89-2·15) for cellular senescence, 1·83 (1·67-2·00) for loss of proteostasis, and 1·39 (1·27-1·52) for genomic instability. These findings were replicated in the Finnish cohorts. In both studies, the associations between other risk factors (low education, unhealthy dietary factors [available only in the UK Biobank], smoking, high alcohol consumption, physical inactivity, and depression) and hallmark-related diseases were weaker than those with obesity. 45-60% of the excess mortality in people with obesity was attributable to hallmark-related diseases.
INTERPRETATION
Obesity might have an important role in the development of diseases associated with cellular ageing. Tackling ageing mechanisms could potentially help to reduce the disease and mortality burden resulting from the obesity epidemic.
FUNDING
Wellcome Trust, UK Medical Research Council, US National Institute on Aging, Academy of Finland, and Finnish Foundation for Cardiovascular Research.
TRANSLATIONS
For the German and Finnish translations of the abstract see Supplementary Materials section.
Topics: Humans; Obesity; Middle Aged; Male; Female; Aged; Adult; Cellular Senescence; Finland; Cohort Studies; Risk Factors; Aging; United Kingdom; Body Mass Index
PubMed: 38945128
DOI: 10.1016/S2666-7568(24)00087-4 -
Thrombosis Research Jun 2024Primary liver cancer is the third leading cause of cancer related deaths worldwide, and the disease is associated with high incidence rate of thrombosis. Studies...
BACKGROUND
Primary liver cancer is the third leading cause of cancer related deaths worldwide, and the disease is associated with high incidence rate of thrombosis. Studies indicate that Tissue Factor Pathway Inhibitor (TFPI) plays a role in cancer development. We aimed to study its expression, clinical role and regulation by micro RNAs (miRNAs) in hepatocellular carcinoma (HCC).
METHODS
Publically available datasets were used for clinical analysis of TFPI and miRNAs expression by web analysis tools. miRNA mimics targeting TFPIα 3'untranslated region (UTR) were selected from target prediction programs and verified by luciferase reporter assay. In vitro effects of miRNAs overexpression in HCC cell lines on TFPI expression and cell proliferation and apoptosis were analysed.
RESULTS
TFPI expression was significantly increased in HCC tumours compared to normal tissue. Low TFPI tumour expression was associated with better survival probability. Four candidate miRNAs were selected from the target prediction programs. miR-7-5p and miR-1236-3p were validated in HepG2 and Huh7 cells to reduce TFPI mRNA and protein levels following overexpression. Furthermore, miR-7-5p and miR-1236-3p reduced TFPIα-3'UTR-controlled luciferase activity. The two validated miRNAs inhibited proliferation of HepG2 cells, and had clinical significance in HCC.
CONCLUSIONS
TFPI was increased in HCC tumours compared to normal tissue and high TFPI expression was associated with an unfavorable outcome in HCC patients. miR-7-5p and miR-1236-3p were identified as novel regulators of TFPI in vitro.
PubMed: 38945092
DOI: 10.1016/j.thromres.2024.109073 -
International Journal of Surgery Case... Jun 2024Adrenal Cavernous Hemangioma is an extremely rare histological type of adrenal tumors, typically asymptomatic and occasionally revealed by a symptom or complication....
INTRODUCTION AND IMPORTANCE
Adrenal Cavernous Hemangioma is an extremely rare histological type of adrenal tumors, typically asymptomatic and occasionally revealed by a symptom or complication. Here, we report an atypical symptomatic case to enrich the limited international case series.
CASE PRESENTATION
We present the case of an 80-year-old woman who underwent laparoscopic left adrenalectomy for a painful and potentially malignant left adrenal neoplasm, leading to the discovery of a five-centimeter adrenal cavernous hemangioma. The post-operative course was uneventful. The postoperative course was uneventful, and the chronic lumbar pain described initially vanished at the six-month follow-up.
CLINICAL DISCUSSION
Adrenal cavernous hemangioma is typically silent and incidentally discovered on cross-sectional imaging. Symptomatic or complicated forms are extremely rare. Clinical, biological, radiological and histology assessment are crucial for management. Therapeutic decisions depend on the malignancy probability and the functional nature of the adrenal neoplasm, considering surgery versus conservative approaches. Patient's point-of-view and background are also determining factors in the decision-making process. Mini-invasive adrenalectomy is superior to open approach, when feasible and safe.
CONCLUSION
Adrenal cavernous hemangioma is a rare benign vascular tumor often discovered on adrenalectomy specimen. This case illustrates a rare cause of chronic lumbar pain. It also underscores the importance of a multidisciplinary medical decision for this kind of tumors.
PubMed: 38945012
DOI: 10.1016/j.ijscr.2024.109936 -
Lung Cancer (Amsterdam, Netherlands) Jun 2024Immunotherapy-based treatments have demonstrated high efficacy in patients with advanced and locally advanced non-small-cell lung cancer (NSCLC). BRAF mutations affect a...
BACKGROUND
Immunotherapy-based treatments have demonstrated high efficacy in patients with advanced and locally advanced non-small-cell lung cancer (NSCLC). BRAF mutations affect a small but significant fraction of NSCLC. The efficacy of these therapies in this subgroup of patients is unknown.
MATERIALS AND METHODS
Plasma and tissue samples from 116 resectable stage IIIA/B NSCLC patients, included in NADIM and NADIM II clinical trials (NADIM cohort), and from a prospective academic cohort with 84 stage IV NSCLC patients (BLI-O cohort), were analyzed by next-generation sequencing.
RESULTS
The p.G464E, p.G466R, p.G466V, p.G469V, p.L597Q, p.T599I, p.V600E (n = 2) BRAF mutations, were identified in four (3.45 %) samples from the NADIM cohort, all of which were cases treated with neoadjuvant chemoimmunotherapy (CH-IO), and four (4.76 %) samples from the BLI-O cohort, corresponding to cases treated with first-line immunotherapy (n = 2) or CH-IO (n = 2). All these patients were alive and had no evidence of disease at data cut-off. Conversely, patients with BRAF wild-type (wt) tumors in the BLI-O cohort had a median progression-free survival (PFS) of 5.49 months and a median overall survival (OS) of 12.00 months (P-LogRank = 0.013 and 0.046, respectively). Likewise, PFS and OS probabilities at 36 months were 60.5 % and 76.1 % for patients with BRAF-wt tumors in the NADIM cohort. The pathological complete response (pCR) rate after neoadjuvant CH-IO in patients with BRAF-positive tumors (n = 4) was 100 %, whereas the pCR rate in the BRAF-wt population was 44.3 % (RR: 2.26; 95 % CI: 1.78-2.85; P < 0.001).
CONCLUSION
BRAF mutations may be a good prognostic factor for advanced and locally advanced NSCLC patients undergoing immunotherapy-based treatments.
PubMed: 38945004
DOI: 10.1016/j.lungcan.2024.107865 -
Journal of Gastrointestinal and Liver... Jun 2024During the coronavirus disease 2019 (COVID-19) pandemic a significant proportion of patients with severe acute respiratory distress syndrome (ARDS) due to COVID-19...
BACKGROUND AND AIMS
During the coronavirus disease 2019 (COVID-19) pandemic a significant proportion of patients with severe acute respiratory distress syndrome (ARDS) due to COVID-19 infection developed secondary sclerosing cholangitis (SSC) as a hepatobiliary complication.
METHODS
17 patients were endoscopically diagnosed and treated with COVID-19 SSC from February 2020 until October 2022 at our center. We retrospectively reviewed and analyzed the data to define risk factors, establish endoscopic treatment options, and to estimate incidence and outcomes.
RESULTS
258 patients with COVID-19 infection were admitted to our tertiary center and mechanically ventilated. 10 patients developed COVID-19 SSC in-house, and 7 patients were transferred for further endoscopic treatment. All 17 patients were mechanically ventilated, received vasoactive substances and 12 of them were treated with extracorporeal membrane oxygenation therapy. Endoscopic retrograde cholangiography (ERC) was performed in all patients to establish the diagnosis of COVID-19 SSC and evaluate endoscopic treatment options. All ERCs revealed biliary casts. 9 patients had developed severe rarefication of the intrahepatic bile ducts and 4 showed biliary strictures. As endoscopic treatment approaches, casts were removed repeatedly, and strictures were dilated. During the study period, 14 patients died (82%). 3 patients are in follow-up to reassess the need for liver transplantation.
CONCLUSIONS
COVID-19 SSC was observed in 2.6 % of the patients with severe COVID-19 in our center. We show that endoscopic approaches offer the opportunity to extract casts and to treat biliary strictures. As the mortality rate of COVID-19 SSC is high, endoscopic treatment can be of great clinical relevance as a bridge to liver transplantation.
Topics: Humans; COVID-19; Male; Female; Cholangitis, Sclerosing; Middle Aged; Retrospective Studies; Cholangiopancreatography, Endoscopic Retrograde; Tertiary Care Centers; Aged; SARS-CoV-2; Adult; Treatment Outcome; Risk Factors; Liver Transplantation
PubMed: 38944874
DOI: 10.15403/jgld-5476 -
Journal of Gastrointestinal and Liver... Jun 2024Progression to hepatocellular carcinoma (HCC) is restricted by viral suppression in chronic hepatitis B (CHB); however, some patients still progress despite antiviral...
BACKGROUND AND AIMS
Progression to hepatocellular carcinoma (HCC) is restricted by viral suppression in chronic hepatitis B (CHB); however, some patients still progress despite antiviral therapy. Presence of single nucleotide polymorphisms (SNPs) such as PNPLA3 rs738409 and TM6SF2 rs58542926 are associated with the development and progression of steatotic liver disease to HCC, whereas a splice variant in HSD17B13 rs72613567:TA has been shown to be protective. We investigated the role of these SNPs in the development or prognosis of HCC in pure CHB etiology, in the absence of hepatic steatosis, remains unknown.
MATERIALS
We analysed PNPLA3 rs738409, TM6SF2 rs58542926, and HSD17B13 rs72613567 SNPs in a prospectively recruited cohort (n=323) consisting of healthy controls, CHB and CHB-HCC patients without hepatic steatosis. SNPs were determined by PCR analysis and associations for the alleles and genotypes were investigated using adjusted-logistic regression analyses. The overall survival (OS) data were collected from CHB-HCC patients for survival analysis.
RESULTS
The genotype and allelic distribution of PNPLA3 rs738409, TM6SF2 rs58542926, and HSD17B13 rs72613567 were similar between healthy controls, CHB, and CHB-HCC groups. No genotype, allele or haplotype analysis was found to be associated with increased risk for CHB-HCC. Survival analysis revealed no genotype or allele to be associated with OS in patients with CHB-HCC.
CONCLUSIONS
We could not demonstrate any association of PNPLA3 rs738409, TM6SF2 rs58542926, and HSD17B13 rs72613567 with the development or prognosis of CHB-HCC, supporting the initial hypothesis that they should be considered specific hotspots for liver diseases characterized with hepatic steatosis.
Topics: Humans; Membrane Proteins; Polymorphism, Single Nucleotide; Lipase; Female; Carcinoma, Hepatocellular; Liver Neoplasms; Male; Middle Aged; 17-Hydroxysteroid Dehydrogenases; Genetic Predisposition to Disease; Case-Control Studies; Hepatitis B, Chronic; Prognosis; Adult; Turkey; Risk Factors; Prospective Studies; Phenotype; Genetic Association Studies; Acyltransferases; Phospholipases A2, Calcium-Independent
PubMed: 38944871
DOI: 10.15403/jgld-5474 -
Journal of Gastrointestinal and Liver... Jun 2024The environmental factors, apart from gluten ingestion predisposing to coeliac disease are poorly known. Smoking is associated with many immune-mediated diseases, but...
BACKGROUND AND AIMS
The environmental factors, apart from gluten ingestion predisposing to coeliac disease are poorly known. Smoking is associated with many immune-mediated diseases, but research on coeliac disease is scarce. This study aims to investigate how smoking affects the clinical presentation, presence of comorbidities and response to gluten-free diet in coeliac disease.
METHODS
Altogether 815 adults with coeliac disease participated in a nationwide cross-sectional study. Participants were interviewed and smoking habits (never, former, or current smoker), clinical presentation of coeliac disease and presence of comorbidities were elicited. Serology and severity of small bowel mucosal lesions at diagnosis were gathered from the participants' medical records and follow-up serology was measured. Gastrointestinal symptoms and psychological well-being were assessed using validated questionnaires.
RESULTS
Current smokers were more often male and were diagnosed at younger ages than never or former smokers. There were no differences between the groups in clinical presentation, severity of symptoms or mucosal lesions at diagnosis or in dietary compliance and clinical, serological, and histological recovery. Musculoskeletal disorders, particularly osteoporosis and osteopenia, were more common in never smokers than in other groups (14.5% vs. 5.1% and 4.1%, p<0.001), and cardiovascular disorders were diagnosed more often in former smokers (36.2% vs. 23.5% and 21.9%, p=0.003).
CONCLUSIONS
Smoking does not seem to have an impact on the clinical presentation, severity of symptoms or mucosal damage in coeliac disease. Histological and clinical recovery as well as seroconversion on gluten-free diet are not affected by smoking status.
Topics: Humans; Celiac Disease; Male; Female; Cross-Sectional Studies; Middle Aged; Diet, Gluten-Free; Adult; Cigarette Smoking; Aged; Treatment Outcome; Comorbidity; Risk Factors; Smokers; Ex-Smokers; Intestinal Mucosa
PubMed: 38944862
DOI: 10.15403/jgld-5364 -
BMC Public Health Jun 2024This study aimed to examine prospective associations of different intensity levels and types of physical activity (PA) in early pregnancy with premature rupture of...
OBJECTIVE
This study aimed to examine prospective associations of different intensity levels and types of physical activity (PA) in early pregnancy with premature rupture of membranes (PROM) among Chinese pregnant women.
METHODS
A total of 6284 pregnant women were included from the Tongji-Shuangliu Birth Cohort. Household/caregiving, occupational, sports/exercise and transportation activities during early pregnancy were investigated by the pregnancy physical activity questionnaire (PPAQ), and the diagnosis of PROM was ascertained during the whole pregnancy. Multivariate logistic regression models were used to estimate the odds ratios (ORs) and 95% confidence interval (CI) for the associations between PA and PROM.
RESULTS
Among the 6284 pregnant women, 1246 were identified to have PROM (19.8%). Women undertaking the highest level (3 third tertile) of PA during pregnancy appeared to have a lower risk of PROM [OR = 0.68, 95%CI 0.58-0.80) when compared to those at the lowest tertile of PA. Similarly, women with increased levels of light intensity activity, moderate-vigorous intensive, household/caregiving activity and meeting exercise guidelines during pregnancy were associated with reduced risks of PROM (OR = 0.69, 95% CI 0.59-0.81, OR = 0.70, 95% CI 0.60-0.82, OR = 0.62, 95% CI 0.53-0.73 and OR = 0.82, 95% CI 0.70-0.97, respectively).
CONCLUSIONS
High levels of PA of different intensities and PA of household/caregiving activities and meeting exercise guidelines during the first trimester were associated with a lower incidence of PROM.
TRIAL REGISTRATION
The data of human participants in this study were conducted in accordance with the Helsinki Declaration. This study has been approved by the Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China ([2017] No. S225). All participants provided written informed consent prior to enrollment. A statement to confirm that all methods were carried out in accordance with relevant guidelines and regulations.
Topics: Humans; Female; Pregnancy; Exercise; Adult; Fetal Membranes, Premature Rupture; China; Pregnancy Trimester, First; Prospective Studies; Birth Cohort; Young Adult; Surveys and Questionnaires; Risk Factors; Cohort Studies; East Asian People
PubMed: 38944666
DOI: 10.1186/s12889-024-18791-5 -
Nature Communications Jun 2024One-third of people with HIV in sub-Saharan Africa start antiretroviral therapy (ART) with advanced disease. We investigated associations between immune biomarkers and... (Randomized Controlled Trial)
Randomized Controlled Trial
One-third of people with HIV in sub-Saharan Africa start antiretroviral therapy (ART) with advanced disease. We investigated associations between immune biomarkers and mortality in participants with advanced HIV randomised to cotrimoxazole or enhanced antimicrobial prophylaxis in the Reduction of Early Mortality in HIV-Infected Adults and Children Starting Antiretroviral Therapy (REALITY) trial (ISRCTN43622374). Biomarkers were assayed using ELISA and Luminex. Associations between baseline values and all-cause 24-week mortality were analysed using Cox models, and for cause-specific mortality used Fine & Gray models, including prophylaxis randomisation, viral load, CD4, WHO stage, age, BMI, and site as covariates; and weighted according to inverse probability of selection into the substudy. Higher baseline CRP, IFN-γ, IL-6 and IP-10 were associated with higher all-cause mortality; and higher IL-23, IL-2 and RANTES with lower all-cause mortality. Associations varied by cause of death: tuberculosis-associated mortality was most strongly associated with higher CRP and sST2, and cryptococcosis-associated mortality with higher IL-4 and lower IL-8. Changes in I-FABP (p = 0.002), faecal alpha-1 antitrypsin (p = 0.01) and faecal myeloperoxidase (p = 0.005) between baseline and 4 weeks post-ART were greater in those receiving enhanced versus cotrimoxazole prophylaxis. Our findings highlight how the immune milieu shapes outcomes following ART initiation, and how adjunctive antimicrobials can modulate the gut environment in advanced HIV.
Topics: Humans; HIV Infections; Biomarkers; Africa South of the Sahara; Male; Female; Adult; Adolescent; Trimethoprim, Sulfamethoxazole Drug Combination; Viral Load; Young Adult; Anti-HIV Agents; Child
PubMed: 38944653
DOI: 10.1038/s41467-024-49317-7 -
The Science of the Total Environment Jun 2024This study contributes a first comparison of current and potential threats to Natural World Heritage Sites from climate change, as assessed by experts, when site and...
This study contributes a first comparison of current and potential threats to Natural World Heritage Sites from climate change, as assessed by experts, when site and location characteristics (size, year of inscription to the World Heritage list, continent, climate zone and kind of site) are controlled for. The probability of a threat as well as its intensity is analysed. Another novelty lies in the use of data from the IUCN Conservation Outlook assessment, covering all 245 Natural and Mixed World Heritage Sites across the world for three points in time: 2014, 2017 and 2020. The threat of climate change is broadly defined and includes temperature extremes, rising temperatures, disappearing glaciers, coral bleaching, droughts, desertification, and rising sea levels. Results based on a simultaneous Probit model with random effects show that the probability of actual and potential climate change threats increases over time, but with differences for size, kind of site and location. The probability that a threat is identified is highest for marine and coastal sites, and for those in Latin America, while it is significantly lower for sites on the African continent. Larger sites have a higher probability of being assessed as at risk and the severity of threats is found to be lower for recently inscribed sites. The rate at which the likelihood of a threat assessment increases is consistent for both current and future situations, while the probability of the most severe threat is larger for the current than the future period. A serious threat from climate change is assessed as highest for locations in the tropical monsoon (current period) or the tropical savannah climate (future period). Estimations also show that pure descriptive statistics or bivariate correlations may not correctly identify the risk or the dignity of a threat.
PubMed: 38944308
DOI: 10.1016/j.scitotenv.2024.174291