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1.
Metabolism ; 161: 156028, 2024 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-39270816

RESUMO

Metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD), has become the leading cause of chronic liver disease worldwide. Optimal dietary intervention strategies for MAFLD are not standardized. This study aimed to achieve consensus on prevention of MAFLD through dietary modification. A multidisciplinary panel of 55 international experts, including specialists in hepatology, gastroenterology, dietetics, endocrinology and other medical specialties from six continents collaborated in a Delphi-based consensus development process. The consensus statements covered aspects ranging from epidemiology to mechanisms, management, and dietary recommendations for MAFLD. The recommended dietary strategies emphasize adherence to a balanced diet with controlled energy intake and personalized nutritional interventions, such as calorie restriction, high-protein, or low-carbohydrate diets. Specific dietary advice encouraged increasing the consumption of whole grains, plant-based proteins, fish, seafood, low-fat or fat-free dairy products, liquid plant oils, and deeply colored fruits and vegetables. Concurrently, it advised reducing the intake of red and processed meats, saturated and trans fats, ultra-processed foods, added sugars, and alcohol. Additionally, maintaining the Mediterranean or DASH diet, minimizing sedentary behavior, and engaging in regular physical activity are recommended. These consensus statements lay the foundation for customized dietary guidelines and proposing avenues for further research on nutrition and MAFLD.

2.
Lancet Reg Health West Pac ; 51: 101185, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39282135

RESUMO

Background: Monitoring hepatitis B virus (HBV) and hepatitis C virus (HCV) liver-related morbidity and mortality is key to evaluate progress towards elimination targets. Methods: HBV and HCV notifications in NSW, Australia (1995-2022) were linked to hospital and mortality records. Temporal trends in decompensated cirrhosis (DC), hepatocellular carcinoma (HCC), and mortality were evaluated among people notified for HBV and HCV. Segmented Poisson regression models were used to assess the impact of the viral hepatitis elimination era (1 January 2015-31 December 2022) on advanced liver disease and mortality. Findings: During 1995-2022, there were 64,865 people with an HBV notification and 112,277 people with an HCV notification in NSW. Between 2002 and 2022, there were significant reductions in age-adjusted HBV- and HCV-related DC, HCC, and liver-related mortality. Among those with HBV, age-standardised incidence per 1000 person-years (py) in 2002, 2015, and 2022 was 3.08, 1.47, and 1.16 for DC (p < 0.001); 2.97, 1.45, and 0.75 for HCC (p < 0.001); and 2.84, 1.93, and 1.40 for liver-related mortality (p < 0.001). Among those with HCV, age-standardised incidence per 1000 py in 2002, 2015, and 2022, was 5.53, 4.57, and 2.31 for DC (p < 0.001); 2.22, 2.59, and 1.87 for HCC (p < 0.001); and 3.89, 4.73, and 3.16 for liver-related mortality (p < 0.001). In 2022, absolute liver-related mortality per 100,000 population was 0.95 for HBV and 3.56 for HCV. In adjusted analyses, older age, comorbidity, and a history of alcohol use disorder were associated with increased liver-related mortality among those with HBV and HCV. Interpretation: This population-level study demonstrated declining risks of DC, HCC, and mortality, with HBV-related declines commencing well before elimination era while HCV-related declines were mostly during elimination era. Population liver mortality indicates elimination target achieved for combined viral hepatitis and HBV, but not HCV. Funding: The Kirby Institute, UNSW Sydney, and New South Wales Ministry of Health, Australia.

3.
Artigo em Inglês | MEDLINE | ID: mdl-39243795

RESUMO

BACKGROUND: Infections have a poor prognosis in inpatients with cirrhosis. We aimed to determine regional variations in infections and their association with clinical outcomes in a global cohort of inpatients with cirrhosis. METHODS: In this prospective cohort study initiated by the CLEARED Consortium, we enrolled adults (aged >18 years) with cirrhosis who were non-electively admitted to 98 hospitals from 26 countries or regions across six continents between Nov 5, 2021, and Dec 10, 2022. Data at admission, during hospitalisation, and for 30 days after discharge were collected through patient reports and chart reviews. Collected data included demographics; country and country income level per World Bank classifications (high-income countries [HICs], upper-middle-income countries [UMICs], and low-income or lower-middle-income countries [L-LMICs]); comorbidities; characteristics related to cirrhosis and the infections, including types, culture results, and drug resistance profile; antibiotic use; and disease course while hospitalised and for 30 days post-discharge. The primary outcome was in-hospital death or hospice referral in those with versus those without an admission infection (defined by the presence of infection on or within 48 h of admission). Multivariable log-binomial regression for in-hospital death or hospice referral was performed to identify risk factors. FINDINGS: Of 4550 patients screened, 4238 patients (mean age 56·1 years [SD 13·3]; 2711 [64·0%] male and 1527 [36·0%] female) with complete data were enrolled. 1351 (31·9%) had admission infections. A higher proportion of patients in L-LMICs had infections (318 [41·7%] of 762 vs 444 [58·3%] without infection) than in UMICs (588 [30·6%] of 1922 vs 1334 [69·4%]) or HICs (445 [28·6%] of 1554 vs 1109 [71·4%]). Patients with admission infections had worse severity of cirrhosis and were more likely to have had an infection or been hospitalised in the preceding 6 months. The most common specific infection types were spontaneous bacterial peritonitis (391 [28·9%] of 1351), pneumonia (233 [17·2%]), and urinary tract infections (193 [14·3%]). 549 (40·6%) patients were culture-positive for bacterial or fungal infections, with the lowest culture-positive rates in Africa and mainland China. Most of the isolated organisms were Gram-negative (345 [63%] of 549), then Gram-positive (157 [29%]), and then fungi or mixed (47 [9%]), with Escherichia coli, Klebsiella pneumoniae, and Enterococcus spp being the top three isolated pathogens. The overall rate of drug resistance was 40% (220 of 549 with positive cultures), being highest in UMICs. The most used empirical antimicrobials were third-generation cephalosporins (453 [37%] of 1241), followed by the broad-spectrum ß-lactams and ß-lactamase inhibitors (289 [23%]). De-escalation was observed in 62 (20%) of 304 patients who had their antibiotics changed. Patients with versus without admission infections had a higher rate of in-hospital death or hospice transfer (299 [22·1%] of 1351 vs 232 [8·0%] of 2887; p<0·0001), a result replicated in multivariable analysis (adjusted risk ratio 1·75 [95% CI 1·42-2·06]; p<0·0001). Older age, self-reported female gender, not being in a HIC, lactulose use, and higher MELD-Na score were also associated with in-hospital death or hospice transfer on multivariable analysis. INTERPRETATION: In the CLEARED Consortium cohort of inpatients with cirrhosis, the rates and types of infections, causative organisms, and culture-positivity varied substantially across regions, and infections were associated with a higher mortality risk. Culture positivity, which guides appropriate antibiotic use, was low. Taking a global perspective, considering regional variations in infections, drug resistance, and resources, could help to alleviate disparities in burden and outcomes. FUNDING: US Department of Veterans Affairs, the Richmond Institute for Veterans Research, the National Natural Science Foundation of China, Shanghai Rising-Star Program, the National Council for Scientific and Technological Development of Brazil, and Shanghai Municipal Key Clinical Specialty.

4.
J Assoc Physicians India ; 72(9S): 27-31, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39291570

RESUMO

Torsemide is a loop diuretic used to manage edema associated with chronic kidney disease (CKD) and acute kidney injury (AKI). It acts by inhibiting sodium and chloride ions reabsorption in the ascending limb of the loop of Henle, thereby increasing urine output and reducing fluid accumulation. Compared to other diuretics, torsemide has an extended duration of action, higher bioavailability, and its elimination route is primarily through the hepatic route, making it effective in patients with CKD and AKI. Clinical studies indicate that torsemide can improve symptoms of fluid overload and potentially enhance renal function.


Assuntos
Edema , Insuficiência Renal Crônica , Torasemida , Humanos , Insuficiência Renal Crônica/complicações , Edema/etiologia , Edema/tratamento farmacológico , Diuréticos/uso terapêutico , Inibidores de Simportadores de Cloreto de Sódio e Potássio/uso terapêutico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/tratamento farmacológico , Sulfonamidas/uso terapêutico
5.
Diabetes Obes Metab ; 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39285685

RESUMO

AIMS: To explore the associations between cuprotosis-related genes (CRGs) across different stages of liver disease in metabolic dysfunction-associated fatty liver disease (MAFLD), including hepatocellular carcinoma (HCC). MATERIALS AND METHODS: We analysed several bulk RNA sequencing datasets from patients with MAFLD (n = 331) and MAFLD-related HCC (n = 271) and two MAFLD single-cell RNA sequencing datasets. To investigate the associations between CRGs and MAFLD, we performed differential correlation, logistic regression and functional enrichment analyses. We also validated the findings in an independent Wenzhou PERSONS cohort of MAFLD patients (n = 656) used for a genome-wide association study (GWAS). RESULTS: GLS, GCSH and ATP7B genes showed significant differences across the MAFLD spectrum and were significantly associated with liver fibrosis stages. GLS was closely associated with fibrosis stages in patients with MAFLD and those with MAFLD-related HCC. GLS is predominantly expressed in monocytes and T cells in MAFLD. During the progression of metabolic dysfunction-associated fatty liver to metabolic-associated steatohepatitis, GLS expression in T cells decreased. GWAS revealed that multiple single nucleotide polymorphisms in GLS were associated with clinical indicators of MAFLD. CONCLUSIONS: GLS may contribute to liver inflammation and fibrosis in MAFLD mainly through cuprotosis and T-cell activation, promoting the progression of MAFLD to HCC. These findings suggest that cuprotosis may play a role in MAFLD progression, potentially providing new insights into MAFLD pathogenesis.

6.
Liver Int ; 2024 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-39248164

RESUMO

INTRODUCTION: The recently developed Freiburg Index of Post-TIPS Survival (FIPS) allows improved risk classification of patients with decompensated cirrhosis allocated to transjugular intrahepatic portosystemic shunt (TIPS) implantation. This study investigated the prognostic value of the FIPS in patients hospitalized with acute decompensation of cirrhosis (AD), outside the setting of TIPS implantation. METHODS: A total of 1133 patients with AD were included in a retrospective, multi-centre study. Ninety-day, 180-day and 1-year mortality were recorded and the FIPS' performance in predicting mortality at these time points was analysed using ROC analyses. RESULTS: Ninety-day, 180-day and 1-year mortality were 17.7%, 24.4% and 30.8%. Uni- and multivariable Cox regression models showed that the FIPS independently predicted 1-year mortality in the study cohort (HR 1.806, 95% CI 1.632-1.998, p < .0001). In ROC analyses, the FIPS offered consistently high performance in the prediction of mortality within 1 year after AD (area under the receiver operator characteristic [AUROC]: 1-year mortality .712 [.679-.746], 180-day mortality .740 [.705-.775] and 90-day mortality .761 [.721-.801]). In fact, in the subgroup of patients presenting with variceal bleeding, the FIPS even showed significantly improved discriminatory performance in the prediction of long-term mortality (AUROC 1-year mortality: .782 [.724-.839]) in comparison with established prognostic scores, such as the CLIF-C AD score (.724 [.660-.788], p = .0071) or MELD 3.0 (.726 [.662-.790], p = .0042). CONCLUSIONS: The FIPS accurately predicts mortality in patients with AD and seems to offer superior prognostication of long-term mortality in patients with variceal bleeding.

7.
Nat Cardiovasc Res ; 3(2): 145-165, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-39196193

RESUMO

Preclinical data have confirmed that human pluripotent stem cell-derived cardiomyocytes (PSC-CMs) can remuscularize the injured or diseased heart, with several clinical trials now in planning or recruitment stages. However, because ventricular arrhythmias represent a complication following engraftment of intramyocardially injected PSC-CMs, it is necessary to provide treatment strategies to control or prevent engraftment arrhythmias (EAs). Here, we show in a porcine model of myocardial infarction and PSC-CM transplantation that EAs are mechanistically linked to cellular heterogeneity in the input PSC-CM and resultant graft. Specifically, we identify atrial and pacemaker-like cardiomyocytes as culprit arrhythmogenic subpopulations. Two unique surface marker signatures, signal regulatory protein α (SIRPA)+CD90-CD200+ and SIRPA+CD90-CD200-, identify arrhythmogenic and non-arrhythmogenic cardiomyocytes, respectively. Our data suggest that modifications to current PSC-CM-production and/or PSC-CM-selection protocols could potentially prevent EAs. We further show that pharmacologic and interventional anti-arrhythmic strategies can control and potentially abolish these arrhythmias.


Assuntos
Arritmias Cardíacas , Miócitos Cardíacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/transplante , Animais , Arritmias Cardíacas/terapia , Humanos , Modelos Animais de Doenças , Infarto do Miocárdio/terapia , Suínos , Células Cultivadas , Diferenciação Celular , Células-Tronco Pluripotentes Induzidas/transplante , Potenciais de Ação/fisiologia , Potenciais de Ação/efeitos dos fármacos , Fenótipo , Biomarcadores/metabolismo , Células-Tronco Pluripotentes/transplante , Transplante de Células-Tronco/métodos , Antiarrítmicos/uso terapêutico , Antiarrítmicos/farmacologia , Frequência Cardíaca/fisiologia
8.
Drug Alcohol Rev ; 43(6): 1559-1572, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39091194

RESUMO

INTRODUCTION: Alcohol use is common in patients with chronic hepatitis C virus (HCV) infection. We examined the impact of alcohol use on direct-acting antiviral (DAA) therapy outcome and the clinical course of liver disease and 2-year survival for patients receiving HCV DAA therapy. METHODS: Adults (n = 2624) recruited from 26 Australian hospital liver clinics during 2016-2021 were followed up for 2 years. Risky alcohol use was defined by a combination of self-report (≥40 g/day of ethanol), physician-reported history of problematic alcohol use, and anti-craving medication prescription via population-based database linkage. We examined factors associated with advanced liver fibrosis and survival using multivariable logistic and Cox regression. RESULTS: Among 1634 patients (62.3%) with risky alcohol use, 24.6% reported consuming ≥40 g/day of alcohol, 98.3% physician-reported problematic alcohol use; only 4.1% were dispensed naltrexone/acamprosate. One hundred and forty-three patients with cirrhosis reported ≥40 g/day of alcohol, 6 (4.3%) were prescribed naltrexone/acamprosate. Risky alcohol use was associated with advanced fibrosis (adjusted-odds ratio 1.69, 95% confidence interval 1.32-2.17) and patients were over-represented for cirrhosis (45.1% vs. 25.6% in no-risky alcohol use [p < 0.001]) and hepatocellular carcinoma (5.7% vs. 2.5% [p < 0.001]). Sustained viral response (p = 0.319) and 2-year survival (adjusted-hazard ratio 1.98, 95% confidence interval 0.84-4.63) after DAA therapy were not associated with risky alcohol use. DISCUSSION AND CONCLUSIONS: Risky alcohol use in HCV patients was prevalent, but did not reduce HCV cure. Treatment for alcohol dependence was low. Risky alcohol use may be under-recognised in liver clinics. Better integration of addiction medicine into liver services and increased resourcing and addiction medicine training opportunities for hepatologists may help address this.


Assuntos
Consumo de Bebidas Alcoólicas , Antivirais , Hepatite C Crônica , Cirrose Hepática , Humanos , Hepatite C Crônica/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Austrália/epidemiologia , Estudos Prospectivos , Antivirais/uso terapêutico , Consumo de Bebidas Alcoólicas/epidemiologia , Adulto , Cirrose Hepática/epidemiologia , Resultado do Tratamento , Idoso , Progressão da Doença , Fatores de Risco
9.
Hepatol Int ; 2024 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-39196505

RESUMO

BACKGROUND AND AIMS: The applicability of the proposed metabolic dysfunction-associated steatotic liver disease (MASLD) definition has not been validated. We aimed to characterize the profiles and long-term survival of people meeting the criteria for MASLD, but not that of metabolic dysfunction-associated fatty liver disease (MAFLD), i.e. MASLD only. METHODS: Using data from the Third National Health and Nutrition Examination Survey (NHANES III) 1988-1994, 7791 adult participants were included and categorized into four distinct groups: no SLD, non-MAFLD MASLD, MASLD-MAFLD, and cryptogenic SLD (steatosis without metabolic dysfunction). RESULTS: Participants in the MASLD-only group were younger and had better metabolic profiles and fibrosis degree compared to those with MASLD-MAFLD and those with no SLD. Their profiles were comparable to those with cryptogenic SLD. Similarly, the MASLD-only group tend to have lower cumulative incidence of all-cause and cardiovascular mortality. Clustering analysis showed that MASLD only clusters differently from individuals with MASLD-MAFLD. CONCLUSIONS: MASLD only is a distinct clinical group with substantial heterogeneity compared to those captured using the MAFLD criteria.

10.
PLoS One ; 19(8): e0307268, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39093910

RESUMO

INTRODUCTION: Understanding genetic contributors to sarcopenia (age-related loss of muscle strength and mass) is key to finding effective therapies. Variants of the bradykinin receptor 2 (BDKRB2) have been linked to athletic and muscle performance. The rs1799722-9 and rs5810761 T alleles have been shown to be overrepresented in endurance athletes, possibly due to increased transcriptional rates of the receptor. These variants have been rarely studied in older people or people with sarcopenia. METHODS: We performed a post hoc sub-study of the Leucine and ACE (LACE) inhibitor trial, which enrolled 145 participants aged ≥70 years with low grip strength and low gait speed. Participants' blood samples were genotyped for rs179972 using TaqMan and rs5810761 by amplification through Hotstar Taq. Genotypes were compared with outcomes of physical performance and body composition measures. RESULTS: Data from 136 individuals were included in the analysis. For rs1799722 the genotype frequency (TT: 17, CC: 48, CT: 71) remained in Hardy-Weinberg Equilibrium (HWE p = 0.248). There was no difference between the genotypes for six-Minute Walk Distance (6MWD) or Short Physical Performance Battery (SPPB). Men with the TT genotype had a significantly greater 6MWD than other genotypes (TT 400m vs CT 310m vs CC 314m, p = 0.027), and greater leg muscle mass (TT 17.59kg vs CT 15.04kg vs CC 15.65kg, p = 0.007). For rs5810761, the genotype frequency (-9-9: 31, +9+9: 43, -9+9: 60) remained in HWE (p = 0.269). The +9+9 genotype was associated with a significant change in SPPB score at 12 months (-9-9 0 vs -9+9 0 vs +9+9-1, p<0.001), suggesting an improvement. In men, the -9-9 genotype was associated with lower arm fat (-9-9 2.39kg vs -9+9 2.72kg vs +9+9 2.76kg, p = 0.019). CONCLUSION: In men, the rs1799722 TT genotype was associated with longer 6MWD and greater leg muscle mass, while the rs5810761 -9-9 genotype was associated with lower arm fat mass.


Assuntos
Desempenho Físico Funcional , Receptor B2 da Bradicinina , Sarcopenia , Humanos , Masculino , Idoso , Feminino , Receptor B2 da Bradicinina/genética , Sarcopenia/genética , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Genótipo , Alelos , Polimorfismo de Nucleotídeo Único , Composição Corporal , Leucina/genética , Idoso de 80 Anos ou mais , Força da Mão , Força Muscular/genética
13.
BMC Cancer ; 24(1): 813, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38973009

RESUMO

BACKGROUND: Therapeutic options for early-stage hepatocellular carcinoma (HCC) in individual patients can be limited by tumor and location, liver dysfunction and comorbidities. Many patients with early-stage HCC do not receive curative-intent therapies. Stereotactic ablative body radiotherapy (SABR) has emerged as an effective, non-invasive HCC treatment option, however, randomized evidence for SABR in the first line setting is lacking. METHODS: Trans-Tasman Radiation Oncology Group (TROG) 21.07 SOCRATES-HCC is a phase II, prospective, randomised trial comparing SABR to other current standard of care therapies for patients with a solitary HCC ≤ 8 cm, ineligible for surgical resection or transplantation. The study is divided into 2 cohorts. Cohort 1 will compromise 118 patients with tumors ≤ 3 cm eligible for thermal ablation randomly assigned (1:1 ratio) to thermal ablation or SABR. Cohort 2 will comprise 100 patients with tumors > 3 cm up to 8 cm in size, or tumors ≤ 3 cm ineligible for thermal ablation, randomly assigned (1:1 ratio) to SABR or best other standard of care therapy including transarterial therapies. The primary objective is to determine whether SABR results in superior freedom from local progression (FFLP) at 2 years compared to thermal ablation in cohort 1 and compared to best standard of care therapy in cohort 2. Secondary endpoints include progression free survival, overall survival, adverse events, patient reported outcomes and health economic analyses. DISCUSSION: The SOCRATES-HCC study will provide the first randomized, multicentre evaluation of the efficacy, safety and cost effectiveness of SABR versus other standard of care therapies in the first line treatment of unresectable, early-stage HCC. It is a broad, multicentre collaboration between hepatology, interventional radiology and radiation oncology groups around Australia, coordinated by TROG Cancer Research. TRIAL REGISTRATION: anzctr.org.au, ACTRN12621001444875, registered 21 October 2021.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Radiocirurgia , Padrão de Cuidado , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/cirurgia , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/radioterapia , Carcinoma Hepatocelular/cirurgia , Radiocirurgia/métodos , Estudos Prospectivos , Masculino , Feminino , Estadiamento de Neoplasias , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Idoso , Adulto
14.
Hepatol Int ; 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38886280
15.
Hepatol Int ; 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38900410

RESUMO

BACKGROUND AND AIMS: Healthy weight (lean) patients with metabolic dysfunction-associated fatty liver disease (MAFLD) have a more favorable metabolic and histological profile in cross-sectional studies compared with their non-lean counterparts. Paradoxically, they also have higher overall mortality. The underpinning pathophysiology of this paradox is not understood. Telomere attrition is associated with increased mortality in various diseases. METHODS: We investigated the role of telomere length in the pathogenesis of lean MAFLD in cohorts with biopsy-proven MAFLD (n = 303). We measured serum malondialdehyde (MDA) levels and hepatic 8-hydroxydeoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal (4-HNE) expression (reactive oxygen species (ROS) markers), growth/differentiation factor-15 (GDF-15) and tested the effect of H2O2 on telomere length and activity in hepatocyte cell lines. The association between leukocyte telomere length and mortality was examined. RESULTS: Telomere length was significantly lower in patients with lean MAFLD (p < 0.001). They also demonstrated an increase in ROS levels and decreases in GDF-15. H2O2 induced telomere shortening and reducing telomere activity in hepatocyte cell lines. We subsequently confirmed that telomere length shortening at baseline is associated with increased hazards of all-cause mortality; the deleterious effect was more profound in lean people. CONCLUSION: Differences in telomere length in part explain the increased mortality of lean compared to non-lean patients with MAFLD. The effect is in part mediated through ROS activation and provide opportunities for therapy.

16.
Matrix Biol ; 132: 1-9, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38871093

RESUMO

Fibrosis, driven by fibroblast activities, is an important contributor to morbidity and mortality in most chronic diseases. Endotrophin, a signaling molecule derived from processing of type VI collagen by highly activated fibroblasts, is involved in fibrotic tissue remodeling. Circulating levels of endotrophin have been associated with an increased risk of mortality in multiple chronic diseases. We conducted a systematic literature review collecting evidence from original papers published between 2012 and January 2023 that reported associations between circulating endotrophin (PROC6) and mortality. Cohorts with data available to the study authors were included in an Individual Patient Data (IPD) meta-analysis that evaluated the association of PROC6 with mortality (PROSPERO registration number: CRD42023340215) after adjustment for age, sex and BMI, where available. In the IPD meta-analysis including sixteen cohorts of patients with different non-communicable chronic diseases (NCCDs) (N = 15,205) the estimated summary hazard ratio for 3-years all-cause mortality was 2.10 (95 % CI 1.75-2.52) for a 2-fold increase in PROC6, with some heterogeneity observed between the studies (I2=70 %). This meta-analysis is the first study documenting that fibroblast activities, as quantified by circulating endotrophin, are independently associated with mortality across a broad range of NCCDs. This indicates that, irrespective of disease, interstitial tissue remodeling, and consequently fibroblast activities, has a central role in adverse clinical outcomes, and should be considered with urgency from drug developers as a target to treat.


Assuntos
Biomarcadores , Humanos , Doença Crônica , Biomarcadores/sangue , Colágeno Tipo VI/sangue , Colágeno Tipo VI/metabolismo , Colágeno Tipo VI/genética , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Fragmentos de Peptídeos
17.
PLoS One ; 19(5): e0302786, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38722973

RESUMO

A role for exportin 4 (XPO4) in the pathogenesis of liver fibrosis was recently identified. We sought to determine changes in hepatic XPO4 promoter methylation levels during liver fibrosis. The quantitative real-time RT-PCR technique was used to quantify the mRNA level of XPO4. Additionally, pyrosequencing was utilized to assess the promoter methylation status of XPO4. The methylation rate of the XPO4 promoter was significantly increased with fibrosis in human and mouse models, while XPO4 mRNA expression negatively correlated with methylation of its promoter. DNA methyltransferases (DNMTs) levels (enzymes that drive DNA methylation) were upregulated in patients with liver fibrosis compared to healthy controls and in hepatic stellate cells upon transforming growth factor beta (TGFß) stimulation. The DNA methylation inhibitor 5-Aza or specific siRNAs for these DNMTs led to restoration of XPO4 expression. The process of DNA methylation plays a crucial role in the repression of XPO4 transcription in the context of liver fibrosis development.


Assuntos
Metilação de DNA , Carioferinas , Cirrose Hepática , Regiões Promotoras Genéticas , Animais , Humanos , Masculino , Camundongos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Carioferinas/genética , Carioferinas/metabolismo , Cirrose Hepática/genética , Cirrose Hepática/patologia , Cirrose Hepática/metabolismo , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/genética
18.
Artigo em Inglês | MEDLINE | ID: mdl-38739519

RESUMO

Intuitive regression control of prostheses relies on training algorithms to correlate biological recordings to motor intent. The quality of the training dataset is critical to run-time regression performance, but accurately labeling intended hand kinematics after hand amputation is challenging. In this study, we quantified the accuracy and precision of labeling hand kinematics using two common training paradigms: 1) mimic training, where participants mimic predetermined motions of a prosthesis, and 2) mirror training, where participants mirror their contralateral intact hand during synchronized bilateral movements. We first explored this question in healthy non-amputee individuals where the ground-truth kinematics could be readily determined using motion capture. Kinematic data showed that mimic training fails to account for biomechanical coupling and temporal changes in hand posture. Additionally, mirror training exhibited significantly higher accuracy and precision in labeling hand kinematics. These findings suggest that the mirror training approach generates a more faithful, albeit more complex, dataset. Accordingly, mirror training resulted in significantly better offline regression performance when using a large amount of training data and a non-linear neural network. Next, we explored these different training paradigms online, with a cohort of unilateral transradial amputees actively controlling a prosthesis in real-time to complete a functional task. Overall, we found that mirror training resulted in significantly faster task completion speeds and similar subjective workload. These results demonstrate that mirror training can potentially provide more dexterous control through the utilization of task-specific, user-selected training data. Consequently, these findings serve as a valuable guide for the next generation of myoelectric and neuroprostheses leveraging machine learning to provide more dexterous and intuitive control.


Assuntos
Algoritmos , Membros Artificiais , Eletromiografia , Mãos , Humanos , Eletromiografia/métodos , Fenômenos Biomecânicos , Masculino , Feminino , Adulto , Mãos/fisiologia , Reprodutibilidade dos Testes , Amputados/reabilitação , Redes Neurais de Computação , Desenho de Prótese , Movimento/fisiologia , Adulto Jovem , Voluntários Saudáveis , Dinâmica não Linear
19.
J Spinal Cord Med ; : 1-7, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38819985

RESUMO

CONTEXT: Spinal cord injury often results in neurogenic bladder affecting storage or emptying functions of the bladder. Clean intermittent catheterization (CIC) is considered the gold standard for patients with neurogenic bladder dysfunction. Our study aims to assess the adherence of patients to CIC following discharge from rehabilitation. OBJECTIVE: PRIMARY: To assess the adherence of patients with spinal cord injury in the community to self-CIC within 12 months of discharge. SECONDARY: To study the reasons and analyze the factors associated with discontinuation of CIC and to assess the perception of patients regarding CIC. METHODS: Prospective follow-up of a retrospective cohort in 121 individuals with paraplegia who were trained to do CIC for bladder management. After obtaining telephonic consent, a questionnaire-based interview was conducted. RESULTS: Out of 121 patients, 97 (80.2%) were males and 24 (19.8%) were females. The mean age was 35.8 ± 11.6 years. About 89 (73.6%) patients were continuing CIC as the primary mode of bladder management after discharge. However, only 18 (15%) patients were fully compliant with the CIC technique, 71 (59%) were partially compliant and 32 (26%) patients discontinued CIC. Reasons for the discontinuation of CIC included medical complications (78%), including leaks, recurrent UTI, hematuria, ulcers, back pain, and spasticity, and other factors like difficulty in following the timing of CIC (12.5%), issues with positioning (3.1%), and difficulty in restricting fluid intake (6.3%). CONCLUSION: This study highlights the need for regular follow-up as well as education of patients regarding CIC technique, complications, care, and hygiene while doing CIC which can result in improved adherence to CIC.

20.
Drug Alcohol Rev ; 43(5): 1247-1255, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38773898

RESUMO

INTRODUCTION: Hepatitis C virus (HCV) prevalence is high in the mental health population. We sought to evaluate testing and treatment uptake for HCV following the implementation of a universal nurse led study in inpatient and outpatient mental health populations. METHODS: From January 2018 to December 2020, we screened mental health inpatients (n = 322) and community mental health patients (n = 615) for HCV with either specialist hepatology nurses or mental health nurses (mental health nurse). RESULTS: 75.5% (464/615) of community patients and 100% (322/322) of inpatients consented to screening, with an HCV antibody-positive prevalence of 12.7% (59/464) in community patients and 19.6% (63/322) in inpatients. RNA detectable prevalence was 4.0% (22/464) and 7.5% (24/322), respectively. Community patients who were screened by specialist hepatology nurses were more likely to consent to screening (94.4% vs. 45.7%, p < 0.001) but had lower proportion of HCV antibody (10.5% vs. 20.3%, p < 0.001) and RNA detectable (4.0% vs. 7.5%, p = 0.018) when compared to mental health nurse screening. Engagement with treatment was 27.0% of community mental health patients and 45.8% of mental health inpatients undergoing treatment. All patients undergoing treatment and underwent sustained viral response (SVR) testing achieved SVR. DISCUSSION AND CONCLUSIONS: Universal screening of HCV using a nurse-led model has high rates of success in mental health patients with high proportions undergoing screening, with no reduction in the rates of SVR achieved with DAA therapy compared to the general population. Further work is needed to bridge the gap between identification of HCV and treatment among mental health patients.


Assuntos
Hepatite C Crônica , Humanos , Masculino , Hepatite C Crônica/epidemiologia , Hepatite C Crônica/tratamento farmacológico , Feminino , Estudos Prospectivos , Pessoa de Meia-Idade , Adulto , Hepacivirus , Antivirais/uso terapêutico , Transtornos Mentais/epidemiologia , Prevalência , Programas de Rastreamento/métodos , RNA Viral
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