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In patients with metabolic dysfunction-associated steatotic liver disease, sleep disturbance is highly prevalent and associated with a profound impairment of health-related quality of life
No full textBackground and aims: Metabolic dysfunctional-associated steatotic liver disease (MASLD) patients have impaired health-related quality of life and other patient-reported outcomes (PROs) which can be exacerbated by comorbidities, including sleep disorders. Our aim was to assess the prevalence of sleep disturbance and its association with PROs in MASLD. Method: Patients with MASLD were prospectively enrolled into the Global NAFLD MASLD Registry™ (GNR). Clinical and PROs (FACIT-F, CLDQ-MASH, and WPAI) data were analyzed by the presence of sleep disturbance (defined as CLDQ-MASH Sleep score of ≤4 on a 1–7 scale). Results: 5342 MASLD patients from 17 countries in the GNR were included: mean (SD) age 53 (13) years, 48% male and 60% obese, 41% had type 2 diabetes (T2D), 46% hypertension, 43% hyperlipidemia, 15% with advanced fibrosis (by biopsy or FIB-4 or transient elastography), 20% depression, 52% clinically overt fatigue, 32% abdominal pain, and 20% sleep apnea. Prevalence of sleep disturbance among MASLD was 34%. MASLD patients and sleep disturbance were more commonly female (63% vs. 46%), with more components of metabolic syndrome (obesity 65% vs. 57%, T2D 47% vs. 37%, hypertension 54% vs. 42%, hyperlipidemia 51% vs. 39%), non-hepatic comorbidities (anxiety 52% vs. 24%, depression 31% vs. 13%, clinically overt fatigue 60% vs. 48%) and sleep apnea (26% vs. 16%) than those without sleep disturbance (all p \u3c 0.01). In logistic regression model, presence of sleep disturbance in MASLD was associated with older age, female sex, history of anxiety, depression, clinically overt fatigue, abdominal pain, smoking, lack of regular exercise, and presence of significant pruritus (all p \u3c 0.01). In MASLD patients with sleep disturbance, PRO scores in all domains of CLDQ-MASH and FACIT-F were lower (up to −25% of a score range size), and work productivity impairment was higher (mean [SD] 0.30 [0.33] vs. 0.11 [0.23]) (all p \u3c 0.0001). In particular, the presence of sleep disturbance was strongly associated with lower fatigue scores of CLDQ-MASH and FACIT-F (more fatigue) and with lower pruritus scores (more pruritus) of CLDQ-MASH (effect size −17% to −23%, all p \u3c 0.0001). In multiple regression analysis, sleep disturbance was independently associated with lower PRO scores in all domains of CLDQ-MASH, FACIT-F, and WPAI (beta up to −15%). Other independent predictors of lower PRO scores in MASLD included age, female sex, comorbidities (metabolic syndrome components, psychiatric disorders, clinically overt fatigue, and sleep apnea), advanced fibrosis, smoking, and lack of regular exercise (p \u3c 0.05). Conclusion: Sleep disturbance is highly prevalent in patients with MASLD. It is associated with fatigue and pruritus, non-hepatic comorbidities, lifestyle factors, and substantial impairment in HRQL and work productivity. Patients with MASLD should be assessed for sleep disturbances and advised accordingly
Luminal flow in the connecting tubule induces afferent arteriole vasodilation
No full textBACKGROUND: Renal autoregulatory mechanisms modulate renal blood flow. Connecting tubule glomerular feedback (CNTGF) is a vasodilator mechanism in the connecting tubule (CNT), triggered paracrinally when high sodium levels are detected via the epithelial sodium channel (ENaC). The primary activation factor of CNTGF-whether NaCl concentration, independent luminal flow, or the combined total sodium delivery-is still unclear. We hypothesized that increasing luminal flow in the CNT induces CNTGF via O2(-) generation and ENaC activation.
METHODS: Rabbit afferent arterioles (Af-Arts) with adjacent CNTs were microperfused ex-vivo with variable flow rates and sodium concentrations ranging from \u3c 1 to 80 mM and from 5 to 40 nL/min flow rates.
RESULTS: Perfusion of the CNT with 5 mM NaCl and increasing flow rates from 5 to 10, 20, and 40 nL/min caused a flow-rate-dependent dilation of the Af-Art (P \u3c 0.001). Adding the ENaC blocker benzamil inhibited flow-induced Af-Art dilation, indicating a CNTGF response. In contrast, perfusion of the CNT with \u3c 1 mM NaCl did not result in flow-induced CNTGF vasodilation (P \u3e 0.05). Multiple linear regression modeling (R(2) = 0.51; P \u3c 0.001) demonstrated that tubular flow (β = 0.163 ± 0.04; P \u3c 0.001) and sodium concentration (β = 0.14 ± 0.03; P \u3c 0.001) are independent variables that induce afferent arteriole vasodilation. Tempol reduced flow-induced CNTGF, and L-NAME did not influence this effect.
CONCLUSION: Increased luminal flow in the CNT induces CNTGF activation via ENaC, partially due to flow-stimulated O2- production and independent of nitric oxide synthase (NOS) activity
Lipid droplet targeting of the lipase coactivator ABHD5 and the fatty liver disease-causing variant PNPLA3 I148M is required to promote liver steatosis
No full textThe storage and release of triacylglycerol (TAG) in lipid droplets (LDs) is regulated by dynamic protein interactions. α/β Hydrolase domain-containing protein 5 (ABHD5; also known as CGI-58) is a membrane/LD-bound protein that functions as a co-activator of patatin-like phospholipase domain-containing 2 (PNPLA2; also known as adipose triglyceride lipase) the rate-limiting enzyme for TAG hydrolysis. The dysregulation of TAG hydrolysis is involved in various metabolic diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD). We previously demonstrated that ABHD5 interacted with PNPLA3, a closely related family member to PNPLA2. Importantly, a common missense variant in PNPLA3 (I148M) is the greatest genetic risk factor for MASLD. PNPLA3 148M functions to sequester ABHD5 and prevent coactivation of PNPLA2, which has implications for initiating MASLD; however, the exact mechanisms involved are not understood. Here, we demonstrate that LD targeting of both ABHD5 and PNPLA3 I148M is required for the interaction. Molecular modeling demonstrates important residues in the C terminus of PNPLA3 for LD binding and fluorescence cross-correlation spectroscopy demonstrates that PNPLA3 I148M has greater association with ABHD5 than WT PNPLA3. Moreover, the C terminus of PNPLA3 is sufficient for functional targeting of PNPLAs to LD and the interaction with ABHD5. In addition, ABHD5 is a general binding partner of LD-bound PNPLAs. Finally, PNPLA3 I148M targeting to LD is required to promote steatosis in vitro and in the liver. Overall results suggest that the interaction of PNPLA3 I148M with ABHD5 on LD is required to promote liver steatosis
Levetiracetam and valproic acid in glioma: antiseizure and potential antineoplastic effects
No full textSeizures are a frequent complication in glioma. Incidence of brain tumor-related epilepsy (BTRE) in high-grade glioma (HGG) is an estimated \u3e 25% and in low-grade glioma (LGG) is approximately 72%. Two first-line antiseizure medications (ASMs) for BTRE include levetiracetam (LEV) and valproic acid (VPA). Use of VPA has decreased because of a broader side effect profile, potential interaction with chemotherapeutic drugs, and availability of newer generation agents. In refractory BTRE, LEV and VPA may be prescribed together to enhance seizure control. VPA and LEV have gained attention for their purported antineoplastic effects and synergistic role with temozolomide. VPA is suggested to modulate anticancer activity in vitro through multiple mechanisms. In addition, retrospective studies indicate increased overall survival in patients with epileptogenic HGGs who are managed with LEV or VPA rather than other ASMs. However, these studies have numerous limitations. It is also reported that patients with glioma and a seizure history have a longer survival. This extended survival, if one exists, may be only observed in certain gliomas with corresponding patient characteristics. We provide a brief overview of the management of BTRE, VPA and LEV as anticonvulsants and antineoplastics, and the factors that may be associated with survival in epileptogenic glioma
MicroRNA signature for early prediction of knee osteoarthritis structural progression using integrated machine and deep learning approaches
No full textOBJECTIVE: Conventional methodologies are ineffective in predicting the rapid progression of knee osteoarthritis (OA). MicroRNAs (miRNAs) show promise as biomarkers for patient stratification. We aimed to develop a miRNA prognosis model for identifying knee OA structural progressors/non-progressors using integrated machine/deep learning tools.
METHODS: Baseline serum miRNAs from Osteoarthritis Initiative (OAI) participants were isolated and sequenced. Participants were categorized based on their likelihood of knee structural progression/non-progression using magnetic resonance imaging and X-ray data. For prediction model development, 152 OAI participants (91 progressors, 61 non-progressors) were used. MiRNA features were reduced through VarClusHi clustering. Key miRNAs and OA determinants (age, sex, body mass index, race) were identified using seven machine learning tools. The final prediction model was developed using advanced machine/deep learning techniques. Model performance was assessed with area under the curve (AUC) (95% confidence intervals) and accuracy. Monte Carlo cross-validation ensured robustness. Model validation used 30 OAI baseline plasma samples from an independent set of participants (14 progressors, 16 non-progressors).
RESULTS: Feature clustering selected 107 miRNAs. Elastic Net was chosen for feature selection. An optimized prediction model based on an Artificial Neural Network comprising age and four miRNAs (hsa-miR-556-3p, hsa-miR-3157-5p, hsa-miR-200a-5p, hsa-miR-141-3p) exhibited excellent performance (AUC, 0.94 [0.89, 0.97]; accuracy, 0.84 [0.77, 0.89]). Model validation performance (AUC, 0.81 [0.63, 0.92]; accuracy, 0.83 [0.66, 0.93]) demonstrated the potential for generalization.
CONCLUSION: This study introduces a novel miRNA prognosis model for knee OA patients at risk of structural progression. It requires five baseline features, demonstrates excellent performance, is validated with an independent set, and holds promise for future personalized therapeutic monitoring
Intracellular tenofovir-diphosphate concentrations in HIV pre-exposure prophylaxis users who underwent bariatric surgery
No full textOBJECTIVE: To measure concentrations of tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) among individuals taking tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC) or tenofovir alafenamide plus emtricitabine (TAF/FTC) who were scheduled to undergo or had already undergone bariatric surgery.
METHODS: We enrolled pre-exposure prophylaxis (PrEP) users attending clinics in Toronto or Ottawa who were undergoing or had undergone bariatric surgery. After participants completed a minimum of 7 days of consecutive PrEP dosing, we collected DBS samples immediately before they administered their next daily dose of PrEP. Participants who had already undergone bariatric surgery before enrolment provided a single sample at baseline only. One participant undergoing planned bariatric surgery provided samples preoperatively and on postoperative days 7, 28 and 84. TFV-DP was measured by liquid chromatography tandem mass spectrometry. We compared results against the population range TFV-DP at varying degrees of adherence and stratified by chronology of bariatric surgery, type of bariatric surgery and PrEP regimen.
RESULTS: Of seven eligible participants, all were gay, cis-gender men. Median age was 48 years (Q1-Q3: 44-51). Six participants underwent bariatric surgery before enrolment: four Roux-en-Y gastric bypass (RYGB) and two sleeve gastrectomy (SG). Four were taking TDF/FTC and two were taking TAF/FTC. All had therapeutic TFV-DP concentrations, except for one TDF/FTC participant who underwent SG. One participant taking TAF/FTC enrolled before receiving RYGB and displayed a slight decrease in TFV-DP over time, although all concentrations remained in the therapeutic range.
CONCLUSIONS: Tenofovir diphosphate concentrations were at or near therapeutic values in this small sample of men using oral PrEP who underwent RYGB or SG
The individual impact of machine perfusion on liver and kidney in simultaneous liver and kidney transplantation
No full textBackground: Liver machine perfusion (MP) has expanded the donor pool. Liver MP may expand donor selection criteria in simultaneous liver and kidney transplantation (SLK) as well. It was reported that kidney MP could reduce a risk of delayed graft function and improve kidney graft survival. MP use for both organs in SLK can potentially increase organ usage from donation after circulatory death donors (DCD) without compromising outcomes. Method: Recent practice trends and outcomes of SLK performed between 2015 and 2024 were investigated using the United Network for Organ Sharing database. Donor types and MP use for liver and/or kidney were captured and associations with outcomes were evaluated. Cox proportional hazard model was used for analyzing the factors related to 1-year liver or kidney graft failure. Result: In total, 6,956 adult SLK were performed between 2015 and 2024. SLK from DCD increased from 4.5% in 2015 to 16% in 2023. (Figure 1) The rate of donors with KDPI\u3e85% increased from 29% in 2015 to 35% in 2024. MP use for kidney and liver increased from 21% to 51% and 0% to 17%, respectively. (Figure 1) Overall, 37.8% of kidney allografts were placed on MP (N=2632) and 3.2% of liver allografts were placed on MP (N=222). DCD was found to be an independent risk factor of 1-year liver graft failure in the no liver MP group [hazard ration (HR) 1.51, 95%CI 1.16--1.97, p\u3c 0.01], but not in the liver MP group. KDPI\u3e85% was an independent risk factor of 1-year kidney graft failure in the no kidney MP group [HR 1.95, 95%CI1.20--3.17, p\u3c 0.01], but not in the kidney MP group. Conclusion: While DCD was a risk factor for liver graft failure in the absence of liver MP, it was not a risk factor when liver MP was used. Similarly, while KDPI\u3e85% was associated with an increased risk of kidney graft failure without kidney MP, kidney MP might mitigate this risk. MP for both organs might contribute to expanding the donor pool for SLK without compromising post- transplant outcomes. [Formula presented] DISCLOSURES: R. Oki: None. I. Rocha: None. S. Al-Juburi: None. L. Rajendran: None. E. Kerby: None. D. Kim: None. L. Malinzak: None. J. Denny: None. A. Yoshida: None. M. Abouljoud: None. S. Nagai: None
Mepolizumab alters gene regulatory networks of nasal airway type-2 and epithelial inflammation in urban children with asthma
No full textMepolizumab (anti-IL5 therapy) reduces asthma exacerbations in urban children with exacerbation-prone eosinophilic asthma. We previously utilized nasal transcriptomics to identify inflammatory pathways (gene co-expression modules) associated with asthma exacerbations despite this therapy. In this study, we applied differential gene correlation analysis on these targeted gene co-expression modules to gain better insight into the treatment effects on correlation structure within gene networks. Mepolizumab treatment resulted in loss of correlation amongst eosinophil-specific genes but conservation and even strengthening of correlation amongst mast cell-specific genes, T2 cytokines, and airway epithelial inflammatory genes. Notably, mepolizumab induced significant gain in correlation of genes associated with multiple aspects of airway epithelial inflammation including those related to extracellular matrix production and nitric oxide synthesis, and this change was associated with a poor clinical response to mepolizumab. These findings highlight that using differential gene correlation analysis offers insight into the molecular regulatory effects of treatment on gene interactions and may lead to better understanding of disease mechanisms and therapeutic responses. ClinicalTrials.gov ID: NCT03292588
Early Reduction of Pulmonary Artery Pressures Is Associated With Improved Mortality Among Medicare Beneficiaries With Heart Failure
No full textBACKGROUND: The early hemodynamic trajectories of heart failure patients receiving implantable pulmonary artery pressure monitor and the clinical implications of those trajectories are unknown in a contemporary real-world population.
OBJECTIVES: This study aims to determine whether baseline pulmonary artery diastolic pressure (PAD) and its early trajectories predict risk of mortality.
METHODS: Patients in Merlin.net implanted with the CardioMEMS sensor between 2017 and 2022 were linked to Medicare claims. Patients were categorized by PAD being acceptable (≤ 20 mm Hg) or elevated (\u3e20 mm Hg). Multivariable regression was used to evaluate the impact of baseline PAD (cohort A) and its early changes at 90 days (cohort B) on long-term mortality.
RESULTS: In cohort A (N = 9,579), baseline PAD was elevated in 64.1%. The 2-year risk of mortality was lower for those with acceptable vs elevated PAD at baseline (HR: 0.68 [95% CI: 0.62-0.73]; P \u3c 0.001). In cohort B (N = 8,452), 63.3% had elevated PAD at baseline; of those, 24.0% improved to having acceptable PAD (Δ: -6.5 ± 4.3 mm Hg), and 76.0% remained persistently elevated at 90 days despite experiencing a reduction (ΔPAD: -1.6 ± 4.3 mm Hg). Those with improved PAD (acceptable at 90 days from elevated at baseline) had lower mortality compared with those with persistently elevated PAD (HR: 0.72 [95% CI: 0.64-0.81]; P \u3c 0.001). Lower baseline PAD and no history of chronic obstructive pulmonary disease or atrial arrhythmia were associated with higher odds of improved PAD.
CONCLUSIONS: Among Medicare beneficiaries, CardioMEMS-guided management was associated with a reduction in PAD. Achieving acceptable PAD within 90 days of implant was associated with better survival. Our study highlights the need to develop novel strategies, including standardization of management algorithms that target elevated PAD