IMPORTANCE: Knowing the rate of liver fibrosis progression in hepatitis C virus (HCV)-infected persons can help inform patients and providers (clinicians, medical institutions or organizations, and ...third-party payers) in making treatment decisions. OBJECTIVE: To determine the rate and factors associated with liver fibrosis progression and hepatic decompensation in persons after acquiring HCV infection. DESIGN, SETTING, AND PARTICIPANTS: Secondary data analysis of persons in the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES), a national Veterans Affairs (VA) database, between 2002 and 2012. Among 610 514 persons in ERCHIVES (half were HCV positive), we identified those with an initial negative and subsequent positive test result for HCV antibody and positive HCV RNA test result (HCV+). Controls had 2 negative HCV antibody test results (HCV−) in a comparable time frame and were matched 1:1 on age (in 5-year blocks), race, and sex. We excluded persons with human immunodeficiency virus, hepatitis B, less than 24 months of follow-up, hepatocellular carcinoma, and cirrhosis at baseline. MAIN OUTCOMES AND MEASURES: Progression of liver fibrosis as estimated by the Fibrosis-4 (FIB-4) index; development of cirrhosis, defined by a FIB-4 score greater than 3.5; and development of hepatic decompensation. RESULTS: The evaluable data set consisted of 1840 persons who were HCV+ and 1840 HCV− controls. The HCV+ persons were younger and had a lower mean (SD) body mass index (27.39 5.51 vs 29.49 6.16; P < .001), a higher prevalence of alcohol and drug abuse and dependence diagnoses, and higher serum aminotransferase levels, but had a lower prevalence of diabetes and hypertension. Fibrosis progression started early after infection among HCV+ persons and tapered off after 5 years. A total of 452 cirrhosis and 85 hepatic decompensation events were recorded. After 10 years of follow-up, HCV+ persons were more likely to have a diagnosis of cirrhosis compared with HCV− controls (18.4% vs 6.1%). Nine years after diagnosis of cirrhosis, hepatic decompensation events were uncommon but had a higher rate in the HCV+ group (1.79% vs 0.33%). CONCLUSIONS AND RELEVANCE: Persons who seroconverted for HCV have a more rapid progression of liver fibrosis and accelerated time to development of cirrhosis after seroconversion compared with HCV− controls. Fibrosis progression occurs early after infection; however, hepatic decompensation is uncommon after diagnosis of cirrhosis.
Historically, liver allografts with >30% macrosteatosis (MaS) on donor biopsy have been associated with early allograft dysfunction and worse graft survival; however, successful outcomes have been ...reported in small cohorts. This study proposes an elevated MaS threshold for organ utilization without detriment to graft survival.
The UNOS Standard Transplant Analysis and Research database was evaluated for transplants between 2006-2015. Graft survival up to 1-year was evaluated by Kaplan-Meier (KM) survival analyses, and by univariate and multivariable logistic regression analyses, including donor and recipient characteristics. Odds ratios (OR) with 95% confidence intervals (CI) for risk of graft loss are reported.
Thirty-day risk of graft loss was increased with MaS as low as 10-19% (OR 95% CI 1.301 1.055-1.605, p<0.0001) and peaked with MaS 50-59% (2.921 1.672-5.103). At 1-year, risk of graft loss remained elevated with MaS 40-49% (1.465 1.002-2.142) and MaS 50-59% (1.978 1.281-3.056, p = 0.0224). Multivariable models were created for Lower and Higher MELD recipients and MaS cutoffs were established. In Lower MELD recipients, organs with ≥50% MaS had increased risk of graft loss at 30 days (2.451 1.541-3.897, p = 0.0008) and 1-year post-transplant (1.720 1.224-2.418, p = 0.0125). Higher MELD recipients had increased risk of graft loss at 30 days with allografts showing MaS ≥40% (4.204 1.440-5.076, p = 0.0016). At 1-year the risk remained increased, but MaS was not significant predictor of graft loss.048 1.131-3.710, p = 0.0616). In both MELD cohorts, organs with MaS levels below threshold had similar survival to those transplanted without a donor biopsy.
In conjunction with recipient selection, organs with MaS up to 50% may be safely used without detriment to outcomes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mitochondrial disease is a family of genetic disorders characterized by defects in the generation and regulation of energy. Epilepsy is a common symptom of mitochondrial disease, and in the vast ...majority of cases, refractory to commonly used antiepileptic drugs. Ferroptosis is a recently-described form of iron- and lipid-dependent regulated cell death associated with glutathione depletion and production of lipid peroxides by lipoxygenase enzymes. Activation of the ferroptosis pathway has been implicated in a growing number of disorders, including epilepsy. Given that ferroptosis is regulated by balancing the activities of glutathione peroxidase-4 (GPX4) and 15-lipoxygenase (15-LO), targeting these enzymes may provide a rational therapeutic strategy to modulate seizure. The clinical-stage therapeutic vatiquinone (EPI-743, α-tocotrienol quinone) was reported to reduce seizure frequency and associated morbidity in children with the mitochondrial disorder pontocerebellar hypoplasia type 6. We sought to elucidate the molecular mechanism of EPI-743 and explore the potential of targeting 15-LO to treat additional mitochondrial disease-associated epilepsies.
Primary fibroblasts and B-lymphocytes derived from patients with mitochondrial disease-associated epilepsy were cultured under standardized conditions. Ferroptosis was induced by treatment with the irreversible GPX4 inhibitor RSL3 or a combination of pharmacological glutathione depletion and excess iron. EPI-743 was co-administered and endpoints, including cell viability and 15-LO-dependent lipid oxidation, were measured.
EPI-743 potently prevented ferroptosis in patient cells representing five distinct pediatric disease syndromes with associated epilepsy. Cytoprotection was preceded by a dose-dependent decrease in general lipid oxidation and the specific 15-LO product 15-hydroxyeicosatetraenoic acid (15-HETE).
These findings support the continued clinical evaluation of EPI-743 as a therapeutic agent for PCH6 and other mitochondrial diseases with associated epilepsy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background Pediatric trauma involving the bones of the face is associated with severe injury and disability. Although much is known about the epidemiology of facial fractures in adults, little is ...known about national injury patterns and outcomes in children in the US. Study Design The epidemiology of facial injuries in children and adolescents (ages 0 to 18 years) was described using the National Trauma Data Bank (2001 to 2005) to examine facial fracture pattern, mechanism, and concomitant injury by age. Results A total of 12,739 (4.6%) facial fractures were identified among 277,008 pediatric trauma patient admissions. The proportion of patients with facial fractures increased substantially with age. The most common facial fractures were mandible (32.7%), nasal (30.2%), and maxillary/zygoma (28.6%). The most common mechanisms of injury were motor vehicle collision (55.1%), violence (11.8%), and falls (8.6%). These fracture patterns and mechanisms of injury varied with age. Compared with patients without facial fractures, patients with fractures exhibited substantial injury severity, hospital lengths of stay, ICU lengths of stay, ventilator days, and hospital charges. In addition, patients with facial fractures had more severe associated injury to the head and chest and considerably higher overall mortality. Conclusions Causes and patterns of facial fractures vary with age. Cranial and central facial injuries are more common among toddlers and infants, and mandible injuries are more common among adolescents. Although bony craniofacial trauma is relatively uncommon among the pediatric population, it remains a substantial source of mortality, morbidity, and hospital resource use. Continued efforts toward injury prevention are warranted.
Chronic kidney disease (CKD) causes loss of lean body mass by multiple mechanisms. This study examines whether autophagy-mediated proteolysis contributes to CKD-induced muscle wasting. We tested ...autophagy in the muscle of CKD mice with plantaris muscle overloading to mimic resistance exercise or with acupuncture plus low-frequency electrical stimulation (Acu/LFES) treatment. In CKD muscle, Bnip3, Beclin-1, and LC3II mRNAs and proteins were increased compared with those in control muscle, indicating autophagosome-lysosome formation induction. Acu/LFES suppressed the CKD-induced upregulation of autophagy. However, overloading increased autophagy-related proteins in normal and CKD muscle. Serum from uremic mice induces autophagy formation but did not increase the myosin degradation or actin break down in cultured muscle satellite cells. We examined mitochondrial biogenesis, copy number, and ATP production in cultured myotubes, and found all three aspects to be decreased by uremic serum. Inhibition of autophagy partially reversed this decline in cultured myotubes. In CKD mice, the mitochondrial copy number, biogenesis marker peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), mitochondrial transcription factor A (TFAM), and mitochondrial fusion marker Mitofusin-2 (Mfn2) are decreased. Both muscle overloading and Acu/LFES increased mitochondrial copy number, and reversed the CKD-induced decreases in PGC-1α, TFAM, and Mfn2. We conclude that the autophagy is activated in the muscle of CKD mice. However, myofibrillar protein is not directly broken down through autophagy. Instead, CKD-induced upregulation of autophagy leads to dysfunction of mitochondria and decrease of ATP production.
The purpose of this study was to perform a systematic review of the existing literature on the incidence of hypertrophic scarring and the psychosocial impact of burn scars. In a comprehensive ...literature review, the authors identified 48 articles published since 1965 and written in English which reported the incidence and risk factors for hypertrophic scarring or assessed outcomes related to scarring. Most studies had important methodological limitations limiting the generalizability of the findings. In particular, the absence of standardized valid measures of scarring and other outcome variables was a major barrier to drawing strong conclusions. Among studies on hypertrophic scarring, the prevalence rate varied between 32 and 72%. Identified risk factors included dark skin, female gender, young age, burn site on neck and upper limb, multiple surgical procedures, meshed skin graph, time to healing, and burn severity. With regard to psychosocial outcomes, two studies compared pediatric burn survivors with a nonburn comparison group on a body image measure; neither study found differences between groups. Across studies, burn severity and location had a modest relationship with psychosocial outcome variables. Psychosocial variables such as social comfort and perceived stigmatization were more highly associated with body image than burn characteristics. To advance our knowledge of the epidemiology of scars and the burden of scars, future studies need to implement more rigorous methodologies. In particular, standardized valid measures of scarring and other outcomes should be developed. This process could be facilitated by an international collaboration among burn centers.
The bacterial domain produces numerous types of sphingolipids with various physiological functions. In the human microbiome, commensal and pathogenic bacteria use these lipids to modulate the host ...inflammatory system. Despite their growing importance, their biosynthetic pathway remains undefined since several key eukaryotic ceramide synthesis enzymes have no bacterial homolog. Here we used genomic and biochemical approaches to identify six proteins comprising the complete pathway for bacterial ceramide synthesis. Bioinformatic analyses revealed the widespread potential for bacterial ceramide synthesis leading to our discovery of a Gram-positive species that produces ceramides. Biochemical evidence demonstrated that the bacterial pathway operates in a different order from that in eukaryotes. Furthermore, phylogenetic analyses support the hypothesis that the bacterial and eukaryotic ceramide pathways evolved independently.
Radionuclide shuntography (RS) performed using 99mTc-DTPA injected into the reservoir of CSF shunts enables evaluation of CSF flow for suspected shunt malfunctions. The goal of this study was to ...report the authors' institutional experience with RS and evaluate its utility and associated complications.
The authors retrospectively reviewed all RS studies performed between November 2003 and June 2022. Patients with shunted hydrocephalus who were ≥ 18 years of age were included. Patients undergoing RS for evaluation of Ommaya reservoirs were excluded. Demographics, hydrocephalus etiology, presenting symptoms, study results, subsequent management, complications, and intraoperative diagnoses were recorded. Chi-square tests were reported for categorical variables and standard 2 × 2 contingency methods were used for sensitivity/specificity analysis.
The authors identified 211 RS procedures performed in 142 patients. The mean age at procedure was 55.6 ± 20.9 years (mean ± SD). Normal pressure hydrocephalus was the most common hydrocephalus etiology (37.0%), followed by congenital malformations (26.1%) and idiopathic intracranial hypertension (15.6%). Successful radionuclide injection was achieved in 207 studies (98.1%). Shunt patency was confirmed in 63.8% of successful injections, whereas malfunction was demonstrated in 27.1% and abnormally slow flow was seen in 9.2%. RS studies demonstrating shunt malfunction were more likely to result in subsequent revisions than were studies showing patency (86.6% vs 2.9%; p < 0.0001). The overall sensitivity and specificity of RS for detecting shunt malfunction was 92.3% and 96.2%, respectively. The median follow-up time was 29 months, with 151 cases having ≥ 6 months of follow-up. There were no complications or infections attributable to RS in this cohort.
RS is a useful and safe tool in the workup of shunt malfunction.
Genetically defined Leigh syndrome is a rare, fatal inherited neurodegenerative disorder that predominantly affects children. No treatment is available. EPI-743 is a novel small molecule developed ...for the treatment of Leigh syndrome and other inherited mitochondrial diseases. In compassionate use cases and in an FDA Expanded Access protocol, children with Leigh syndrome treated with EPI-743 demonstrated objective signs of neurologic and neuromuscular improvement. To confirm these initial findings, a phase 2A open label trial of EPI-743 for children with genetically-confirmed Leigh syndrome was conducted and herein we report the results.
A single arm clinical trial was performed in children with genetically defined Leigh syndrome. Subjects were treated for 6months with EPI-743 three times daily and all were eligible for a treatment extension phase. The primary objective of the trial was to arrest disease progression as assessed by neuromuscular and quality of life metrics. Results were compared to the reported natural history of the disease.
Ten consecutive children, ages 1–13years, were enrolled; they possessed seven different genetic defects. All children exhibited reversal of disease progression regardless of genetic determinant or disease severity. The primary endpoints—Newcastle Pediatric Mitochondrial Disease Scale, the Gross Motor Function Measure, and PedsQL Neuromuscular Module—demonstrated statistically significant improvement (p<0.05). In addition, all children had an improvement of one class on the Movement Disorder-Childhood Rating Scale. No significant drug-related adverse events were recorded.
In comparison to the natural history of Leigh syndrome, EPI-743 improves clinical outcomes in children with genetically confirmed Leigh syndrome.
► We performed a prospective open label trial of the novel therapeutic EPI-743 for children with Leigh syndrome ► There was a statistically significant improvement in all trial outcome measurements signifying arrest and reversal of disease progression ► There were no drug related adverse events or clinical laboratory abnormalities
COVID-19 pathogen SARS-CoV-2 has infected hundreds of millions and caused over 5 million deaths to date. Although multiple vaccines are available, breakthrough infections occur especially by emerging ...variants. Effective therapeutic options such as monoclonal antibodies (mAbs) are still critical. Here, we report the development, cryo-EM structures, and functional analyses of mAbs that potently neutralize SARS-CoV-2 variants of concern. By high-throughput single cell sequencing of B cells from spike receptor binding domain (RBD) immunized animals, we identify two highly potent SARS-CoV-2 neutralizing mAb clones that have single-digit nanomolar affinity and low-picomolar avidity, and generate a bispecific antibody. Lead antibodies show strong inhibitory activity against historical SARS-CoV-2 and several emerging variants of concern. We solve several cryo-EM structures at ~3 Å resolution of these neutralizing antibodies in complex with prefusion spike trimer ectodomain, and reveal distinct epitopes, binding patterns, and conformations. The lead clones also show potent efficacy in vivo against authentic SARS-CoV-2 in both prophylactic and therapeutic settings. We also generate and characterize a humanized antibody to facilitate translation and drug development. The humanized clone also has strong potency against both the original virus and the B.1.617.2 Delta variant. These mAbs expand the repertoire of therapeutics against SARS-CoV-2 and emerging variants.
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