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JHEP Reports : Innovation in Hepatology Jul 2024Treatment of alcohol use disorder (AUD) improves survival in patients with alcohol-related cirrhosis. However, medications for alcohol use disorder (MAUD) are...
BACKGROUND & AIMS
Treatment of alcohol use disorder (AUD) improves survival in patients with alcohol-related cirrhosis. However, medications for alcohol use disorder (MAUD) are underutilized in this population, partially due to concerns regarding drug-induced liver injury (DILI). Our aim was to evaluate the safety of naltrexone in patients with cirrhosis.
METHODS
This was a retrospective study of patients with cirrhosis who were prescribed naltrexone using the VOCAL (Veterans Outcomes and Costs Associated with Liver Disease) database. Patients with new initiation of naltrexone after diagnosis of cirrhosis who had liver enzymes checked within a 3-month time frame were included. A chart review was performed on patients who developed alanine aminotransferase or alkaline phosphatase elevations to more than 2× or 5× the upper limit of normal, respectively. The RUCAM (Roussel Uclaf causality assessment method) was used to determine if DILI occurred.
RESULTS
A total of 3,285 patients with cirrhosis were initiated on naltrexone, of whom 2,940 had laboratory testing during the high-risk DILI period. Only 2% of patients had liver enzyme elevations, and among those, 30 (48%) were classified as "DILI excluded" and 32 (52%) were classified as "DILI unlikely". No patients were classified as possible, probable, or highly probable DILI. No deaths or new decompensations were attributed to naltrexone.
CONCLUSIONS
Naltrexone in patients with cirrhosis was not associated with development of DILI using RUCAM scoring. Naltrexone appears to be safe in patients with compensated and decompensated cirrhosis.
IMPACT AND IMPLICATIONS
Naltrexone is an effective medication for treating alcohol use disorder but is underutilized in patients with underlying liver disease due to historical concerns regarding hepatotoxicity. This retrospective study shows no drug-induced liver injury in a large cohort of patients with cirrhosis with new initiation of naltrexone. This study may encourage providers to prescribe naltrexone to patients with existing liver disease with ongoing alcohol use disorder.
PubMed: 38961852
DOI: 10.1016/j.jhepr.2024.101095 -
JGH Open : An Open Access Journal of... Jul 2024Celiac disease (CD), a gluten-related disease, is a multi-system rare disorder mainly involving the gastrointestinal tract. The clinical signs of CD are exceedingly...
Celiac disease (CD), a gluten-related disease, is a multi-system rare disorder mainly involving the gastrointestinal tract. The clinical signs of CD are exceedingly heterogeneous, which increases the difficulty of clinical differential diagnosis. Neurological manifestations are one of the non-classical CD symptoms. As some patients present only neurological symptoms at early stages, the diagnosis of CD is always delayed. Correct diagnosis and management could decrease patient morbidity and deaths. A 32-year-old male was admitted to the hospital due to progressive muscle atrophy of both lower limbs and lumbar stiffness. Based on positive gluten-sensitive enteropathy autoantibody profiles and gastroscopy foundation, the diagnosis of CD was established. The patient was instructed to gluten-free diet. The antibody titer of gluten-sensitive enteropathy autoantibodies decreased, and the patient's symptoms alleviated. We emphasize the importance of CD screening in patients with neurological disorders of unknown aetiology.
PubMed: 38961851
DOI: 10.1002/jgh3.13117 -
Journal of Applied Physiology... Jul 2024Alzheimer's Disease (AD) is the 5 leading cause of death in older adults and treatment options are severely lacking. Recent findings demonstrate a strong relationship...
Alzheimer's Disease (AD) is the 5 leading cause of death in older adults and treatment options are severely lacking. Recent findings demonstrate a strong relationship between skeletal muscle and cognitive function, with evidence supporting that muscle quality and cognitive function are positively correlated in older adults. Conversely, decreased muscle function is associated with a 3-fold increased risk of cognitive decline. Based on these observations, the purpose of this study was to investigate the negative effects of muscle disuse (via a model of hindlimb immobilization (HLI)) on hippocampal insulin sensitivity and mitochondrial function and identify the potential mechanisms involved. HLI for 10 days in 4-month-old female Wistar rats resulted in the following novel findings: 1) hippocampal insulin resistance and deficits in whole body glucose homeostasis, 2) dramatically increased mitochondrial reactive oxygen species (ROS) production in the hippocampus, 3) elevated markers for amyloidogenic cleavage of APP and tau protein in the hippocampus, 4) and reduced BDNF expression. These findings were associated with global changes in iron homeostasis, with muscle disuse producing muscle iron accumulation in association with decreased serum and whole brain iron levels. We report the novel finding that muscle disuse alters brain iron homeostasis and reveal a strong negative correlation between muscle and brain iron content. Overall, HLI-induced muscle disuse has robust negative effects on hippocampal insulin sensitivity and ROS production in association with altered brain iron homeostasis. This work provides potential novel mechanisms that may help explain how loss of muscle function contributes to cognitive decline and AD risk.
PubMed: 38961821
DOI: 10.1152/japplphysiol.00234.2024 -
Tropical Medicine & International... Jul 2024The objective of this study is to assess the outcomes of children, adolescents and young adults with HIV reported as lost to follow-up, correct mortality estimates for...
Correcting mortality estimates among children and youth on antiretroviral therapy in southern Africa: A comparative analysis between a multi-country tracing study and linkage to a health information exchange.
OBJECTIVES
The objective of this study is to assess the outcomes of children, adolescents and young adults with HIV reported as lost to follow-up, correct mortality estimates for children, adolescents and young adults with HIV for unascertained outcomes in those loss to follow-up (LTFU) based on tracing and linkage data separately using data from the International epidemiology Databases to Evaluate AIDS in Southern Africa.
METHODS
We included data from two different populations of children, adolescents and young adults with HIV; (1) clinical data from children, adolescents and young adults with HIV aged ≤24 years from Lesotho, Malawi, Mozambique, Zambia and Zimbabwe; (2) clinical data from children, adolescents and young adults with HIV aged ≤14 years from the Western Cape (WC) in South Africa. Outcomes of patients lost to follow-up were available from (1) a tracing study and (2) linkage to a health information exchange. For both populations, we compared six methods for correcting mortality estimates for all children, adolescents and young adults with HIV.
RESULTS
We found substantial variations of mortality estimates among children, adolescents and young adults with HIV reported as lost to follow-up versus those retained in care. Ascertained mortality was higher among lost and traceable children, adolescents and young adults with HIV and lower among lost and linkable than those retained in care (mortality: 13.4% [traced] vs. 12.6% [retained-other Southern Africa countries]; 3.4% [linked] vs. 9.4% [retained-WC]). A high proportion of lost to follow-up children, adolescents and young adults with HIV had self-transferred (21.0% and 47.0%) in the traced and linked samples, respectively. The uncorrected method of non-informative censoring yielded the lowest mortality estimates among all methods for both tracing (6.0%) and linkage (4.0%) approaches at 2 years from ART start. Among corrected methods using ascertained data, multiple imputation, incorporating ascertained data (MI(asc.)) and inverse probability weighting with logistic weights were most robust for the tracing approach. In contrast, for the linkage approach, MI(asc.) was the most robust.
CONCLUSIONS
Our findings emphasise that lost to follow-up is non-ignorable and both tracing and linkage improved outcome ascertainment: tracing identified substantial mortality in those reported as lost to follow-up, whereas linkage did not identify out-of-facility deaths, but showed that a large proportion of those reported as lost to follow-up were self-transfers.
PubMed: 38961819
DOI: 10.1111/tmi.14030 -
Phytotherapy Research : PTR Jul 2024Autophagy and endoplasmic reticulum (ER) stress are conserved processes that generally promote survival, but can induce cell death when physiological thresholds are... (Review)
Review
Autophagy and endoplasmic reticulum (ER) stress are conserved processes that generally promote survival, but can induce cell death when physiological thresholds are crossed. The pro-survival aspects of these processes are exploited by cancer cells for tumor development and progression. Therefore, anticancer drugs targeting autophagy or ER stress to induce cell death and/or block the pro-survival aspects are being investigated extensively. Consistently, several phytochemicals have been reported to exert their anticancer effects by modulating autophagy and/or ER stress. Various phytochemicals (e.g., celastrol, curcumin, emodin, resveratrol, among others) activate the unfolded protein response to induce ER stress-mediated apoptosis through different pathways. Similarly, various phytochemicals induce autophagy through different mechanisms (namely mechanistic target of Rapamycin [mTOR] inhibition). However, phytochemical-induced autophagy can function either as a cytoprotective mechanism or as programmed cell death type II. Interestingly, at times, the same phytochemical (e.g., 6-gingerol, emodin, shikonin, among others) can induce cytoprotective autophagy or programmed cell death type II depending on cellular contexts, such as cancer type. Although there is well-documented mechanistic interplay between autophagy and ER stress, only a one-way modulation was noted with some phytochemicals (carnosol, capsaicin, cryptotanshinone, guangsangon E, kaempferol, and δ-tocotrienol): ER stress-dependent autophagy. Plant extracts are sources of potent phytochemicals and while numerous phytochemicals have been investigated in preclinical and clinical studies, the search for novel phytochemicals with anticancer effects is ongoing from plant extracts used in traditional medicine (e.g., Origanum majorana). Nonetheless, the clinical translation of phytochemicals, a promising avenue for cancer therapeutics, is hindered by several limitations that need to be addressed in future studies.
PubMed: 38961675
DOI: 10.1002/ptr.8283 -
International Journal of Epidemiology Jun 2024Numerous studies have linked fine particulate matter (PM2.5) to increased cardiovascular mortality. Less is known how the PM2.5-cardiovascular mortality association...
BACKGROUND
Numerous studies have linked fine particulate matter (PM2.5) to increased cardiovascular mortality. Less is known how the PM2.5-cardiovascular mortality association varies by use of cardiovascular medications. This study sought to quantify effect modification by statin use status on the associations between long-term exposure to PM2.5 and mortality from any cardiovascular cause, coronary heart disease (CHD), and stroke.
METHODS
In this nested case-control study, we followed 1.2 million community-dwelling adults aged ≥66 years who lived in Ontario, Canada from 2000 through 2018. Cases were patients who died from the three causes. Each case was individually matched to up to 30 randomly selected controls using incidence density sampling. Conditional logistic regression models were used to estimate odds ratios (ORs) for the associations between PM2.5 and mortality. We evaluated the presence of effect modification considering both multiplicative (ratio of ORs) and additive scales (the relative excess risk due to interaction, RERI).
RESULTS
Exposure to PM2.5 increased the risks for cardiovascular, CHD, and stroke mortality. For all three causes of death, compared with statin users, stronger PM2.5-mortality associations were observed among non-users [e.g. for cardiovascular mortality corresponding to each interquartile range increase in PM2.5, OR = 1.042 (95% CI, 1.032-1.053) vs OR = 1.009 (95% CI, 0.996-1.022) in users, ratio of ORs = 1.033 (95% CI, 1.019-1.047), RERI = 0.039 (95% CI, 0.025-0.050)]. Among users, partially adherent users exhibited a higher risk of PM2.5-associated mortality than fully adherent users.
CONCLUSIONS
The associations of chronic exposure to PM2.5 with cardiovascular and CHD mortality were stronger among statin non-users compared to users.
Topics: Humans; Particulate Matter; Male; Aged; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Case-Control Studies; Ontario; Cardiovascular Diseases; Aged, 80 and over; Coronary Disease; Stroke; Environmental Exposure; Logistic Models; Risk Factors; Independent Living; Odds Ratio
PubMed: 38961644
DOI: 10.1093/ije/dyae084 -
ESC Heart Failure Jul 2024Right ventricular (RV) failure is one of the leading causes of death in patients with pulmonary hypertension (PH). Conventional echocardiographic parameters are not...
AIMS
Right ventricular (RV) failure is one of the leading causes of death in patients with pulmonary hypertension (PH). Conventional echocardiographic parameters are not included in risk stratification and follow-up for prognostic assessment due to PH's diverse nature and the RV's complex geometry. RV outflow tract velocity time integral (RVOT VTI) is a simple, non-invasive estimate of pulmonary flow and an echocardiographic surrogate of RV stroke volume. In this study, we aimed to define the prognostic value of RVOT VTI in PH patients.
METHODS
Sixty-three subjects with idiopathic PAH (IPAH) (n = 23), connective tissue disease-associated PAH (CTD-associated PAH) (n = 19) and chronic thromboembolic pulmonary hypertension (CTEPH) (n = 21) were retrospectively included. A comprehensive two-dimensional echocardiographic evaluation, including RVOT-VTI measurement, was performed during the follow-up and the New York Heart Association functional class (NYHA FC), 6 min walk distance (6MWD) and brain natriuretic peptide (BNP) levels were recorded.
RESULTS
The median age of the whole cohort was 63 years (52-68), and 47 (74.6%) of the patients were women. The median follow-up period was 20 months (11-33), and 20 (31.7%) patients died in this period. BNP values were higher [317 (210-641) vs 161 (47-466), P = 0.02], and 6MWD values were lower [197.5 ± 89.5 vs 339 ± 146.3, P < 0.0001] in the non-survivor group, and the non-survivor group had a worse NYHA-FC (P = 0.02). Among echocardiographic data, tricuspid annular plane systolic excursion (TAPSE) (15.4 ± 4.8 vs 18.6 ± 4.2, P = 0.01) and RVOT VTI (11.9 ± 4.1 vs 17.2 ± 4.3, P < 0.0001) values were lower whereas right atrial area (RAA) (26.9 ± 10.1 vs 22.2 ± 7.1, P = 0.04) values were higher in the non-survivor group. The area under curve of the RVOT VTI for predicting mortality was 0.82 [95% confidence interval (CI) 0.715-0.940, P < 0.0001], and the best cut-off value was 14.7 cm with a sensitivity of 80% and specificity of 77%. Survival was significantly lower in subjects with RVOT VTI ≤ 14.7 cm (log-rank P < 0.0001). Survival rates for patients with RVOT VTI ≤ 14.7 cm were 70% at 1 year, 50% at 2 years, %29 at 3 years and 21% at 5 years. The univariate determinants of all-cause mortality were BNP [hazard ratio (HR) 1.001 (1.001-1.002), P = 0.001], 6MWD [HR 0.994 (0.990-0.999), P = 0.012] and NYHA-FC III-IV [HR 3.335 (1.103-10.083), P = 0.03], TAPSE [HR 0.838 (0.775-0.929), P = 0.001], RAA [HR 1.072 (1.013-1.135), P = 0.016] and RVOT VTI [HR 0.819 (0.740-0.906), P < 0.0001]. RVOT VTI was found to be the only independent determinant of mortality [HR 0.857 (0.766-0.960), P = 0.008].
CONCLUSIONS
The decreased RVOT VTI predicts mortality in patients with PH and each 1 mm decrease in RVOT VTI increases the risk of mortality by 14.3%. This parameter might serve as an additional parameter in the follow-up of these patients especially when 6MWD and NYHA-FC could not be determined.
PubMed: 38961603
DOI: 10.1002/ehf2.14934 -
Salud Colectiva Jun 2024The purpose of this paper is to delve into the ethical aspects experienced by the healthcare team when they receive the directive to limit therapeutic effort or a...
The purpose of this paper is to delve into the ethical aspects experienced by the healthcare team when they receive the directive to limit therapeutic effort or a do-not-resuscitate order. From an interpretative, qualitative paradigm with a content analysis approach, a process based on three phases was conducted: pre-analysis in which categories were identified, the projection of the analysis, and inductive analysis. During 2023, interviews were conducted in the clinical setting of a high-complexity hospital in Chile with 56 members of the healthcare teams from critical and emergency units, from which four categories emerged: a) the risk of violating patients' rights by using do-not-resuscitate orders and limiting therapeutic effort; b) the gap in the interpretation of the legal framework addressing the care and attention of patients at the end of life or with terminal illnesses by the healthcare team; c) ethical conflicts in end-of-life care; and d) efficient care versus holistic care in patients with terminal illness. There are significant gaps in bioethics training and aspects of a good death in healthcare teams facing the directive to limit therapeutic effort and not resuscitate. It is suggested to train personnel and work on a consensus guide to address the ethical aspects of a good death.
Topics: Humans; Chile; Resuscitation Orders; Patient Care Team; Terminal Care; Qualitative Research; Patient Rights; Female; Male; Attitude of Health Personnel; Interviews as Topic
PubMed: 38961602
DOI: 10.18294/sc.2024.4821 -
Journal of Veterinary Internal Medicine Jul 2024Benefit of adding a second-line immunosuppressive drug to glucocorticoids for the treatment of non-associative immune-mediated hemolytic anemia (naIMHA) in dogs has not...
BACKGROUND
Benefit of adding a second-line immunosuppressive drug to glucocorticoids for the treatment of non-associative immune-mediated hemolytic anemia (naIMHA) in dogs has not been defined prospectively.
HYPOTHESIS/OBJECTIVES
Evaluate the effectiveness of different immunosuppressive protocols in naIMHA dogs.
ANIMALS
Forty-three client-owned dogs.
METHODS
Open label, randomized, clinical trial. Dogs were treated with methylprednisolone (M-group), methylprednisolone plus cyclosporine (MC-group) or methylprednisolone plus mycophenolate mofetil (MM-group). Dogs were defined as responders by disappearance of signs of immune-mediated destruction and hematocrit stabilization. Frequency of responders was compared between M-group and combined protocols (MC and MM-group evaluated together), and among the 3 different therapeutic groups at 14 (T14), 30 (T30), 60 (T60) days after admission. Frequency of complications, length of hospitalization and relapse were also compared. Death rate was evaluated at discharge, T60 and 365 (T365) days.
RESULTS
Proportion of responders was not significantly different between M-group and combined protocols (MC and MM-groups), nor among the 3 therapeutic groups at T14, T30, and T60 (P > .17). Frequency of relapse, complications, and length of hospitalization were not significantly different between M-group and dogs treated with combined protocols, nor among the 3 treatment groups (P > .22). Death was significantly more common only for MM-group compared with MC-group at T60 (+42.8%; 95% CI: 11.5-67.4; P = .009), and at T365 (+50%; 95% CI: 17.5-73.2; P = .003).
CONCLUSIONS AND CLINICAL IMPORTANCE
Combined immunosuppressive therapy did not improve hematological response in naIMHA.
PubMed: 38961558
DOI: 10.1111/jvim.17122 -
The International Journal of... Jul 2024Despite its historical decline, TB remains a significant cause of infectious disease-related global deaths. The lack of reliable diagnostic tests for vulnerable groups,... (Review)
Review
Despite its historical decline, TB remains a significant cause of infectious disease-related global deaths. The lack of reliable diagnostic tests for vulnerable groups, such as children and immunocompromised patients, remains a challenge for TB control. For decades, it has been recognised that exhaled breath has great potential as a non-invasive and universally accessible clinical alternative to sputum and invasive sampling methods. Although translation into clinical practice has not yet occurred, there has been significant progress with promising results in various applications, including diagnosis, estimation of infectiousness, and monitoring of treatment response. More recently, the COVID-19 pandemic reignited global interest in this field and technological advances have further accelerated its development. In the coming decade, breath sampling will enhance our understanding of respiratory infectious diseases and host-immune responses, which may lead to clinical applications. Here we discuss the diagnostic landscape of TB and the current state of the art of breath sampling.
Topics: Humans; Breath Tests; Tuberculosis, Pulmonary; COVID-19; Exhalation; SARS-CoV-2
PubMed: 38961554
DOI: 10.5588/ijtld.23.0411