Elevated Liver Enzyme Levels Research Articles

Drug-induced Steatohepatitis Caused by Long-term Use of Topical Steroids for Atopic Dermatitis: A Case Report.

Atopic dermatitis is common in children and often treated with topical corticosteroids (TCs). A boy in his late teens who had been using TCs for atopic dermatitis was diagnosed with liver damage during a health checkup. A medical examination revealed severe steatotic liver disease and elevated liver enzyme levels despite the absence of typical symptoms such as central obesity. After discontinuation of TCs, an improvement in liver enzyme levels was observed, leading to the diagnosis of drug-induced steatohepatitis. This case underscores the potential liver risks associated with prolonged TC use in children, highlighting the need for parental education.

Barriers to care linkage and educational impact on unnecessary MASLD referrals.

The importance of primary care physicians (PCPs) in managing metabolic dysfunction-associated steatotic liver disease (MASLD) has increased. This study aimed to assess the effectiveness of an online educational program on MASLD among physicians. In total, 869 physicians (72 physicians at referral centers and 797 PCPs) participated in this study. They completed an initial survey regarding their clinical practices for patients with MASLD, followed by a second online survey 8 weeks after receiving a series of seven weekly sets of educational materials on MASLD. In the baseline survey, most PCPs did not routinely evaluate the stage of hepatic fibrosis in MASLD; they typically initiated assessments based on elevated liver enzyme levels. Only a limited number of PCPs used vibration-controlled transient elastography. The main hurdles in managing MASLD were "the absence of a fee for patient education" for PCPs and "short consultation time" for referral-center physicians. In the follow-up survey, the percentage of liver fibrosis assessments using noninvasive tests increased from 7.0 to 11.2%. Additionally, evaluations for cardiovascular disease increased from 3.9 to 8.2%, and the risk of ischemic stroke increased from 13.7 to 16.9%. The percentage of immediate referrals of patients to specialists after an MASLD diagnosis decreased from 15.4 to 12.3%. The discrepancies in management strategies and viewpoints regarding MASLD between PCPs and referral-center physicians can hinder efforts to mitigate the disease burden. Increasing awareness among PCPs regarding MASLD through a 7-week education program led to a reduction in unnecessary referral rates and an increase in cardiovascular evaluations.

Investigation of the efficacy and safety of wild- type and triple-gene knockout pig RBC transfusions in nonhuman primates.

Decreasing rates of blood donation and close margins between blood supply and demand pose challenges in healthcare. Genetically engineered pig red blood cells (pRBCs) have been explored as alternatives to human RBCs for transfusion, and triple-gene knockout (TKO) modification improves the compatibility of pRBCs with human blood in vitro. In this study, we assessed the efficacy and risks of transfusing wild-type (WT)- and TKO-pRBCs into nonhuman primates (NHPs). Blood from O-type WT and TKO pigs was processed to produce pRBCs for transfusion, which were transfused or not into NHPs (n=4 per group: WT, TKO, and control) after 25% total blood volume withdrawal: their biological responses were compared. Hematological, biochemical, and immunological parameters were measured before, immediately after, and at intervals following transfusion. Two months later, a second transfusion was performed in three NHPs of the transfusion group. Transfusion of both WT- and TKO-pRBCs significantly improved RBC counts, hematocrit, and hemoglobin levels up to the first day post-transfusion, compared to the controls. The transfusion groups showed instant complement activation and rapid elicitation of anti-pig antibodies, as well as elevated liver enzyme and bilirubin levels post-transfusion. Despite the higher agglutination titers with WT-pRBCs in the pre-transfusion crossmatch, the differences between the WT and TKO groups were not remarkable except for less impairment of liver function in the TKO group. After the second transfusion, more pronounced adverse responses without any hematological gain were observed. WT- and TKO-pRBC transfusions effectively increased hematologic parameters on the first day, with rapid clearance from circulation thereafter. However, pRBC transfusion triggers strong antibody responses, limiting the benefits of the pRBC transfusion and increasing the risk of adverse reactions.

Transdermal exposure to Chrome-III oxide resulting in intoxicaitons and morbidity in two tanning workers—a case report

Here, we report two cases of chrome-III oxide intoxications following transdermal exposure in tanning workers. A 58-year-old man (case 1) and his 41-year-old co-worker (case 2) were brought to our ED with unconsciousness six hours after accidental transdermal exposure to chrome-III oxide crystals (Tankrom® AB, Chrome-III oxide 25.5% and Schorlemmer Basicity 33%). Upon arrival, both patients presented with agitation and chemical burns affecting 11% (case 1) and 3% (case 2) of their total body surface area, respectively. Chemical burns were mainly distributed on injured skin. Initial arterial blood gas analysis revealed moderate (case 1, pH: 7.268) to mild acidosis (case 2, pH: 7.352). One of our patients (case 1) had significant respiratory depression. Laboratory results of case 1 and case 2 showed increased white blood cell counts, (16,630 mm3 and 19,950 mm3) and elevated blood glucose (178 mg/dL and 193 mg/dL), creatinine (1.33 mg/dL and 1.52 mg/dL), liver enzyme (aspartate aminotransferase/alanine aminotransferase of 416/322 U/L and 141/118 U/L) and creatine phosphokinase level (474 U/L and 566 U/L), respectively. Radiologic examinations revealed an orbital wall fracture and L2 compression fracture in case 1, while case 2 had a subdural hematoma, subarachnoid hemorrhage and scapular fracture and had to undergo an operation for external ventricular drainage. Both patients became alert on day three (case 1) and day six (case 2) and were discharged on day 27. We serially measured their serum and urinary chromium concentrations after hospital arrival. The calculated serum half-lives were 35.7 hours and 25.1 hours, and urinary half-lives were 2.3 hours and 2.5 hours in case 1 and case 2, respectively. We suggest that transdermal exposure to chrome-III oxide, especially to injured skin, may result in significant toxicity and morbidity. Therefore, it is essential to take necessary precautions and preventive measures to avoid transdermal exposure to chromium.

Regorafenib therapy as a third-line treatment for metastatic colorectal cancer: A single center long term experience.

This study examined the effects of regorafenib (Reg) on progression-free survival (PFS), overall survival (OS), and adverse events (AEs) in metastatic colorectal cancer (mCRC) patients who underwent targeted treatment and chemotherapy. Reg was administered as a third-line treatment to 84 patients who had undergone 2 rounds of chemotherapy and targeted therapy and subsequently experienced progression. Treatment was initiated with a daily dose of 80 or 120 mg, based on the patient's ability to tolerate the medication, which was increased to 160 mg/day. The median PFS with Reg was 4 ± 0.2 months, while the median OS was 9 ± 1.2 months. When compared to patients who started Reg treatment at 80 mg, patients starting at 160 mg had longer median PFS and OS (PFS:6 ± 2.1 months vs 4 ± 0.2 months; P = .05; OS:13 ± 0.7 months vs 6 ± 1.3 months; P = .069). Patients with right-sided colon cancer who received Reg as third-line therapy had a significantly longer mPFS than those with left-sided colon cancer (8 months ± 4 vs 4 months ± 0.3, P = .039). Patients with KRAS mutations had a prolonged mPFS than those with panRAS-wild type (6 ± 1.6 months vs 4 ± 0.3 months, P = .06). The mPFS contribution in the BRAF mutant subgroup with poor prognosis is promising, as it is similar to that of patients without BRAF mutations (4 months ± 0.8 × 4 months ± 0.5, P = .74). The most common AEs reported were elevated liver enzyme levels and dermatological toxicities.

Danazol for the Treatment of Myelodysplastic Syndromes: A Systematic Review

Purpose To study the potential utility of danazol for treating patients with myelodysplastic syndromes, with a focus on efficacy and adverse effects (AEs). Methods MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus were searched for relevant publications from inception June 1, 1950, until June 28, 2022. The studies were screened by title and abstract, followed by full-text screening. The quality of the included studies was assessed via a prespecified set of questionnaires. Data on the efficacy measures and adverse outcomes were extracted and included in a descriptive summary. Results Nine studies consisting of 246 participants were included in our review. The overall quality of the included studies was fair. The age of the participants ranged from 61 to 78 years. In all 9 studies, more male patients had been enrolled than female patients. Overall, a proportion of patients in all the studies reported a desired major response to a danazol dose of 400 to 800 mg/day. Few studies did not observe any improvement in the platelet count. Elevated liver enzyme levels, weight gain, headache, dermatitis, and weakness were the most common AEs observed. One study reported a fatal intracerebral hemorrhage in 1 participant. Conclusions Danazol has been effective in increasing platelet count and hemoglobin level. Despite a few AEs, danazol is a safe drug for the treatment of patients with myelodysplastic syndromes.

MANAGEMENT OF HELLP SYNDROME BEFORE DELIVERY: A SYSTEMATIC REVIEW

Background: HELLP syndrome, named for 3 features of the disease (hemolysis, elevated liver enzyme levels, and low platelet levels), is a life-threatening condition that can potentially complicate pregnancy. HELLP was once known as edema-proteinuria-hypertension gestosis type B in the early 20th century and was later renamed in 1982 by Louis Weinstein. The aim: This study aims to show management of HELLP syndrome before delivery. Methods: By comparing itself to the standards set by the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020, this study was able to show that it met all of the requirements. So, the experts were able to make sure that the study was as up-to-date as it was possible to be. For this search approach, publications that came out between 2013 and 2023 were taken into account. Several different online reference sources, like Pubmed and SagePub, were used to do this. It was decided not to take into account review pieces, works that had already been published, or works that were only half done. Result: In the PubMed database, the results of our search on SagePub brought up 110 articles. The results of the search conducted for the last year of 2013 yielded a total 23 articles for PubMed and 75 articles for SagePub. The result from title screening, a total 8 articles for PubMed and 28 articles for SagePub. In the end, we compiled a total of 10 papers. We included five research that met the criteria. Conclusion: HELLP syndrome is an important complications in pregnancy which increases maternal and fetal mortality. This disease usually remits with supportive treatment which includes prescription of corticosteroid, magnesium sulfate, stabilization of mother and pregnancy termination. Plasmapheresis is a treatment of choice which improves clinical outcomes in complicated cases.

Association between polycyclic aromatic hydrocarbon exposure and liver function: The mediating roles of inflammation and oxidative stress

Polycyclic aromatic hydrocarbon (PAH) exposure has been associated with adverse health effects, and accumulating evidence suggests that PAH exposure may impair liver function. However, the underlying mechanisms linking PAH exposure and liver function impairment remain unclear. This study aimed to explore the association between PAH exposure and liver function biomarkers, and the mediating effects of inflammation and oxidative stress. The cross-sectional study included 155 adults and their urinary PAH metabolites (OH-PAHs) were determined, and eight liver function biomarkers were measured in paired serum samples. A comprehensive statistical analysis investigated the linear, non-linear, individual, and joint effects of the association between urinary OH-PAHs and liver function biomarkers. The results indicated significant positive associations between urinary OH-PAH concentrations and liver function biomarker levels, suggesting that PAH exposure may adversely affect liver function. 2-hydroxyfluorene was identified as the individual metabolite contributing significantly to elevated gamma-glutamyl transferase levels. Further stratification by gender revealed that this association is more pronounced in males. Moreover, we observed significant mediation effects of the oxidative stress biomarker 8-hydroxy-2′-deoxyguanosine and the inflammatory biomarkers C-reactive protein and white blood cell count on this association. The physiological responses triggered by PAH exposure are mediated by inflammation, which serves as a link between oxidative stress, cellular injury, and elevated liver enzyme levels. The results demonstrated that increased inflammation and oxidative stress mediated the association between increased urinary OH-PAHs and elevated liver function biomarkers. The results contribute to a better understanding of the potential mechanisms underlying PAH exposure's hepatotoxic effects.

Effects of Gardenia Ternifolia Leaf Extract on antioxidant and hepatic enzymes in sniper-induced toxicity in Albino rats

Aim: This study evaluates the effects of Gardenia ternifolia leaf extract on antioxidant and hepatic enzymes in sniper-induced toxicity in albino rats. Methodology: A total of 42 male albino rats weighing 120g to 150g, grouped into 6 groups of 7rats each. Group 1 (Negative control), Group 2 (Positive control), Group 3 (Therapeutic Low Dose), Group 4 (Therapeutic High Dose), Group 5 (Prophylactic Low Dose) and Group 6 (Prophylactic High Dose). After 4 weeks of treatment, the rats were anaesthetized, sacrificed and blood samples collected. The Liver was also harvested for histological analysis. Superoxide dismutase (SOD) and glutathione peroxidase (GPx) were estimated using a rat-specific sandwich-enzyme linked immunosorbent assay (ELISA) method. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were carried out using Reitman Frankel method. Alkaline phosphatase (ALP) was carried out using colorimetric phenolphthalein method. The liver tissue was prepared and stained using standard Haematoxylin and Eosin (H & E) staining technique and captured using scope TekTM device. Results: The mean SOD and GPx values for the therapeutic and prophylactic groups were significantly higher (P <.05) when compared with the positive control. The mean SOD and GPx values in the therapeutic groups were not significantly different (P >.05) from the negative control. The mean ALT, AST and ALP values for the therapeutic and prophylactic groups were significantly lower (P <.05) than the positive control but significantly higher (P <.05) than the negative control. Histology analysis of liver indicated normal histoarchitecture in the negative control while in the positive control, there were severe cell degeneration, distortion, necrosis and death of the hepatocytes. The Therapeutic Low Dose and Prophylactic Low Dose groups indicated severe degeneration and hypertrophy of hepatocytes. The Therapeutic High Dose and Prophylactic High Dose groups showed less deposit, well delineated radiating hepatocytes and near normal cytoarchitecture. Conclusion: Administration of Sniper® (dichlorvos) led to an increase in oxidative stress; depletion of antioxidant enzyme levels. It elevated liver enzymes levels, caused histopathological changes and death of cells in the liver. The treatment with leaf extract of Gardenia ternifolia ameliorated the effect of dichlorvos toxicity, restored the anti-oxidant and liver enzyme levels especially the high dose extract.

Retrospective Cross-Sectional Study Reviewing the Effectiveness of Mycophenolate Mofetil on Saudi Children With Nephrotic Syndrome.

Background Idiopathic nephrotic syndrome (INS) is the most common form of nephrotic syndrome (NS) in children. It is often associated with minimal change disease (MCD). Corticosteroid therapy is the initial treatment, but many patients experience relapses, leading to steroid-dependent nephrotic syndrome (SDNS) or frequently relapsing steroid-sensitive nephrotic syndrome (FR-SSNS). To avoid prolonged steroid use, mycophenolate mofetil (MMF) is used as an immunosuppressive alternative. MMF is safe and effective for treating SDNS and FR-SSNS in children, with studies showing reduced relapse rates. The current study aims to evaluate MMF's effectiveness and safety in Saudi children with NS and identify factors that affect its efficacy. Methods A retrospective cross-sectional study was conducted at King Abdullah Specialized Children's Hospital (KASCH) in Riyadh, Saudi Arabia. The study included children aged one to 14 years diagnosed with NS who received MMF therapy. Data were collected from medical records from 2000 to 2020. Ethical considerations were followed, and statistical analysis was performed using IBM SPSS Statistics for Windows, version 25 (released 2017; IBM Corp., Armonk, New York, United States). Baseline characteristics and responsiveness to MMF were examined. Results In our study, 45 participants (25 males, 20 females) with NS were treated with MMF. Most participants were steroid-dependent (84.44%) and had frequent relapses. MMF was effective in 84.4% of cases, with a significant reduction in relapse; the mean number of relapses decreased from 3.5 before MMF to 1.6 after MMF (p-value = 0.00002). Moreover, 40% of the participants were completely free of relapse after the introduction of MMF. The average duration of the MMF therapy was 45 months. Post-MMF side effects were rare but documented. Gastrointestinal symptoms were extremely rare. Elevated liver enzyme levels were reported in 8.88% (four cases) of the participants. Leukopenia, a more common adverse effect, was reported in 26.66% of cases during the MMF therapy. The average daily dose of steroid was reduced from 12.5 mg/day pre MMF to 2 mg/day post MMF with a p-value of 0.00229. Conclusion Our study evaluated the use of MMF in 45 participants with NS. We found that MMF was effective in 84.4% of cases, leading to a significant reduction in the number of relapses. Post-MMF side effects were relatively rare, except for leukopenia that was reported in 26.66%. In addition, the average rate of reduction of steroid exposure before and after MMF was significant. These findings suggest that MMF is a promising treatment option for children with NS and an alternative therapy to long-term steroid use, due to its safety and effectiveness, although close monitoring for potential side effects is essential.

Experimental infection of non-immunosuppressed and immunosuppressed goats reveals differential pathogenesis of Babesia aktasi n. sp.

Babesiosis is an acute and persistent tick-borne disease caused by protozoan parasites of the genus Babesia. These hemoparasites affect vertebrates globally, resulting in symptoms such as high fever, anemia, jaundice, and even death. Advancements in molecular parasitology revealed new Babesia species/genotypes affecting sheep and goats, including Babesia aktasi n. sp., which is highly prevalent in goats from Turkiye's Mediterranean region. The objective of this study was to investigate the pathogenesis of B. aktasi infection in immunosuppressed (n=7) and non-immunosuppressed (n=6) goats. These animals were experimentally infected with fresh B. aktasi infected blood, and their clinical signs, hematological and serum biochemical parameters were monitored throughout the infection. The presence of parasites in the blood of immunosuppressed goats was detected by microscopic examination between 4 and 6 days after infection, accompanied by fever and increasing parasitemia. Goats that succumbed acute disease exhibited severe clinical signs, such as anemia, hemoglobinuria, and loss of appetite. However, the goats that survived showed milder clinical signs. In the non-immunosuppressed group, piroplasm forms of B. aktasi were observed in the blood within 2-5 days after inoculation, but with low (0.01-0.2%) parasitemia. Although these goats showed loss of appetite, typical signs of babesiosis were absent except for increased body temperature. Hematological analysis revealed significant decreases in the levels of red blood cells, leukocytes and platelet values post-infection in immunosuppressed goats, while no significant hematological changes were observed in non-immunosuppressed goats. In addition, serum biochemical analysis showed elevated transaminase liver enzymes levels, decreased glucose, and lower total protein values in the immunosuppressed group post-infection. Babesia aktasi, caused mild disease with minor clinical symptoms in non-immunosuppressed goats. However, in immunosuppressed goats, it exhibited remarkable pathogenicity, leading to severe clinical infections and death. In conclusion, this study provides valuable insights into the pathogenicity of the parasite and will serve as a foundation for future research aimed at developing effective prevention and control strategies against babesiosis in small ruminants. Further research is required to investigate the pathogenicity of B. aktasi in various goat breeds, other potential hosts, the vector ticks involved, and its presence in natural reservoirs.

Abstract 12 — Prevalence and Risk Factors of Non-Alcoholic Fatty Liver Disease in Patients with Rheumatoid Arthritis: A Nationwide Population-Based Study

Background Rheumatoid arthritis (RA) is a debilitating and financially burdensome disease because of frequent presence of comorbidities including metabolic and cardiovascular abnormalities. Growing evidence suggests a link between RA and nonalcoholic fatty liver disease (NAFLD). We aimed to determine the prevalence and explore the risk factors of developing NAFLD in RA population. Methods This population-based, cross-sectional study utilized data on US adults aged [Formula: see text]20 years old from the National Health and Nutrition Examination Survey (NHANES) 2017-2018, a representative sample of the general US population. Diagnosis of RA was derived from questionnaire data. NAFLD was defined by controlled attenuation parameter (CAP) scores of [Formula: see text]278 dB/m using vibration controlled transient elastography (VCTE) in the absence of other liver disease. Weighted multiple regression analysis was further performed to assess the independent risk factors. Results Of 2,848 people included in this study, 224 of them had self-reported RA. The prevalence of NAFLD in the overall sample was 41%, with a numerically higher prevalence in RA patients than those without arthritis (47% vs. 40%, p=0.30). Compared to those without NAFLD, RA patients with concomitant NAFLD had more prevalent metabolic comorbidities including obese (75% vs. 32%, p=0.006), central obesity (100% vs. 71%, p=0.008), diabetes (39% vs. 14%, p=0.003) and hyperlipidemia (88% vs. 76%, p=0.042). Regarding laboratory findings, RA patients with NAFLD exhibited higher levels of triglyceride (188 mg/dL vs. 131 mg/dL, p=0.010), fasting plasma glucose (131 mg/dL vs. 109 mg/dL, p=0.010) and HbA1c (5.77% vs. 6.41%, p=0.002). Meanwhile, elevated levels of liver enzymes (ALT: 29 U/L vs. 19 U/L, p=0.015; AST: 25 U/L vs. 19 U/L, p=0.007) and inflammatory indicator CRP (5.1 mg/dL vs. 3.4 mg/dL, p<0.001]) were more frequently reported in RA patients with NAFLD as compared with those without. Further, weighted multivariate logistic regression analysis showed that the presence of central obesity (adjusted OR=1.56 [95% CI 1.16-2.11], p=0.008) and diabetes (adjusted OR=1.28 [95% CI 1.07-1.54], p=0.014) were significantly associated with prevalent NAFLD in patients with RA. Conclusion In this population-based study, about one in two patients with RA had NAFLD, which is higher than its overall prevalence among general population. Central obesity and diabetes are predisposing factors for NAFLD in RA. Our results highlight the importance of active NAFLD screening in RA population, especially for high-risk subsets.

Unveiling the interplay between NSAID-induced dysbiosis and autoimmune liver disease in children: insights into the hidden gateway to autism spectrum disorders. Evidence from ex vivo, in vivo, and clinical studies.

Autism spectrum disorders (ASD) represent a diverse group of neuropsychiatric conditions, and recent evidence has suggested a connection between ASD and microbial dysbiosis. Immune and gastrointestinal dysfunction are associated with dysbiosis, and there are indications that modulating the microbiota could improve ASD-related behaviors. Additionally, recent findings highlighted the significant impact of microbiota on the development of autoimmune liver diseases, and the occurrence of autoimmune liver disease in children with ASD is noteworthy. In the present study, we conducted both an in vivo study and a clinical study to explore the relationship between indomethacin-induced dysbiosis, autoimmune hepatitis (AIH), and the development of ASD. Our results revealed that indomethacin administration induced intestinal dysbiosis and bacterial translocation, confirmed by microbiological analysis showing positive bacterial translocation in blood cultures. Furthermore, indomethacin administration led to disturbed intestinal permeability, evidenced by the activation of the NLRP3 inflammasomes pathway and elevation of downstream biomarkers (TLR4, IL18, caspase 1). The histological analysis supported these findings, showing widened intestinal tight junctions, decreased mucosal thickness, inflammatory cell infiltrates, and collagen deposition. Additionally, the disturbance of intestinal permeability was associated with immune activation in liver tissue and the development of AIH, as indicated by altered liver function, elevated ASMA and ANA in serum, and histological markers of autoimmune hepatitis. These results indicate that NSAID-induced intestinal dysbiosis and AIH are robust triggers for ASD existence. These findings were further confirmed by conducting a clinical study that involved children with ASD, autoimmune hepatitis (AIH), and a history of NSAID intake. Children exposed to NSAIDs in early life and complicated by dysbiosis and AIH exhibited elevated serum levels of NLRP3, IL18, liver enzymes, ASMA, ANA, JAK1, and IL6. Further, the correlation analysis demonstrated a positive relationship between the measured parameters and the severity of ASD. Our findings suggest a potential link between NSAIDs, dysbiosis-induced AIH, and the development of ASD. The identified markers hold promise as indicators for early diagnosis and prognosis of ASD. This research highlights the importance of maintaining healthy gut microbiota and supports the necessity for further investigation into the role of dysbiosis and AIH in the etiology of ASD.

Simvastatin in Critically Ill Patients with Covid-19

BackgroundThe efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear.MethodsIn an ongoing international, multifactorial, adaptive platform, randomized, controlled trial, we evaluated simvastatin (80 mg daily) as compared with no statin (control) in critically ill patients with Covid-19 who were not receiving statins at baseline. The primary outcome was respiratory and cardiovascular organ support–free days, assessed on an ordinal scale combining in-hospital death (assigned a value of −1) and days free of organ support through day 21 in survivors; the analyis used a Bayesian hierarchical ordinal model. The adaptive design included prespecified statistical stopping criteria for superiority (>99% posterior probability that the odds ratio was >1) and futility (>95% posterior probability that the odds ratio was <1.2).ResultsEnrollment began on October 28, 2020. On January 8, 2023, enrollment was closed on the basis of a low anticipated likelihood that prespecified stopping criteria would be met as Covid-19 cases decreased. The final analysis included 2684 critically ill patients. The median number of organ support–free days was 11 (interquartile range, −1 to 17) in the simvastatin group and 7 (interquartile range, −1 to 16) in the control group; the posterior median adjusted odds ratio was 1.15 (95% credible interval, 0.98 to 1.34) for simvastatin as compared with control, yielding a 95.9% posterior probability of superiority. At 90 days, the hazard ratio for survival was 1.12 (95% credible interval, 0.95 to 1.32), yielding a 91.9% posterior probability of superiority of simvastatin. The results of secondary analyses were consistent with those of the primary analysis. Serious adverse events, such as elevated levels of liver enzymes and creatine kinase, were reported more frequently with simvastatin than with control.ConclusionsAlthough recruitment was stopped because cases had decreased, among critically ill patients with Covid-19, simvastatin did not meet the prespecified criteria for superiority to control. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.)

Rare Variant in Metallothionein 1E Increases the Risk of Type 2 Diabetes in a Chinese Population.

To uncover novel targets for the treatment of type 2 diabetes (T2D) by investigating rare variants with large effects in monogenic forms of the disease. We performed whole-exome sequencing in a family with diabetes. We validated the identified gene using Sanger sequencing in additional families and diabetes- and community-based cohorts. Wild-type and variant gene transgenic mouse models were used to study the gene function. Our analysis revealed a rare variant of the metallothionein 1E (MT1E) gene, p.C36Y, in a three-generation family with diabetes. This risk allele was associated with T2D or prediabetes in a community-based cohort. MT1E p.C36 carriers had higher HbA1c levels and greater BMI than those carrying the wild-type allele. Mice with forced expression of MT1E p.C36Y demonstrated increased weight gain, elevated postchallenge serum glucose and liver enzyme levels, and hepatic steatosis, similar to the phenotypes observed in human carriers of MT1E p.C36Y. In contrast, mice with forced expression of MT1E p.C36C displayed reduced weight and lower serum glucose and serum triglyceride levels. Forced expression of wild-type and variant MT1E demonstrated differential expression of genes related to lipid metabolism. Our results suggest that MT1E could be a promising target for drug development, because forced expression of MT1E p.C36C stabilized glucose metabolism and reduced body weight, whereas MT1E p.C36Y expression had the opposite effect. These findings highlight the importance of considering the impact of rare variants in the development of new T2D treatments.

Therapeutic Management of Cytauxon Felis in Cat

A Persian cat that was 4 months old and weighed 2 kg was brought to the Parel campus of the Mumbai Veterinary College in Mumbai, Maharashtra. Anorexia, pyrexia, and bodily weakness in the past. Clinical evaluation revealed the patient had a high temperature (104.3°F), was anemic, looked dull, and was dehydrated. Low hemoglobin, a low platelet count, and elevated liver enzyme levels are shown by a complete blood count, liver function tests, and kidney function tests. The cat was initially treated with injections of Oxytetracycline at 10 mg/kg body weight for three days before being switched to susp. Azithromycin at 10 mg/kg B.W. plus Tab. Atovaquone at 15 mg/kg B.W. along with fluid therapy, injections of Acetyl-cysteine at 140 mg/kg and then reduced to 50 mg/kg B.W., as well as oral multivitamins and pre-probiotics. Cat displayed full healing following 20 days of therapy.

Effect of polyene phosphatidylcholine/ursodeoxycholic acid/ademetionine on pregnancy outcomes in intrahepatic cholestasis.

Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder that occurs in pregnant women and can lead to a range of adverse pregnancy outcomes. The condition is typically marked by pruritus (itching) and elevated levels of liver enzymes and bile acids. The standard treatment for ICP has generally been ursodeoxycholic acid and ademetionine 1,4-butanedisulfonate, but the efficacy of this approach remains less than optimal. Recently, polyene phosphatidylcholine has emerged as a promising new therapeutic agent for ICP due to its potential hepatoprotective effects. To evaluate the effect of polyene phosphatidylcholine/ursodeoxycholic acid/ ademetionine 1,4-butanedisulfonate on bile acid levels, liver enzyme indices, and pregnancy outcomes in patients with ICP. From June 2020 to June 2021, 600 patients with ICP who were diagnosed and treated at our hospital were recruited and assigned at a ratio of 1:1 via random-number table method to receive either ursodeoxycholic acid/ademetionine 1,4-butanedisulfonate (control group, n = 300) or polyene phosphatidylcholine/ursodeoxycholic acid/ademetionine 1,4-butanedisulfonate (combined group, n = 300). Outcome measures included bile acids levels, liver enzyme indices, and pregnancy outcomes. Prior to treatment, no significant differences were observed between the two groups (P > 0.05). Post-treatment, patients in both groups had significantly lower pruritus scores, but the triple-drug combination group had lower scores than the dual-drug combination group (P < 0.05). The bile acid levels decreased significantly in both groups, but the decrease was more significant in the triple-drug group (P < 0.05). The triple-drug group also exhibited a greater reduction in the levels of certain liver enzymes and a lower incidence of adverse pregnancy outcomes compared to the dual-drug group (P < 0.05). Polyene phosphatidylcholine/ursodeoxycholic acid/ademetionine 1,4-butanedisulfonate effectively relieves pruritus and reduces bile acid levels and liver enzyme indices in patients with ICP, providing a positive impact on pregnancy outcome and a high safety profile. Further clinical trials are required prior to clinical application.

Prenatal transmission of severe acute respiratory syndrome coronavirus 2, resulting in neonatal severe acute pneumonia, from an asymptomatic mother: a case report

BackgroundWe report a case of prenatal coronavirus disease 2019, which evolved 6 days after birth into severe pneumonia with signs of multiple organ failure, in a mother with asymptomatic coronavirus disease 2019.Case presentationAt minute 11 of life, our patient from Afro-Caribbean had polypnea with mild signs of struggle; Silverman’s index was scored at three. Chest radiography showed bilateral opacities consistent with respiratory distress syndrome. On the 6th day of life, a thoracic computed tomography scan showed bilateral parenchymatous lesions (10–20%) in ground glass, compatible with coronavirus disease 2019-type infection. At the same time, the neonate showed signs of multiple organ failure (elevated liver and cardiac enzyme levels). She was treated with azithromycin (20 mg/kg/day) for 5 days. All the signs recovered fully by day 12. Real-time polymerase chain reaction results were positive in the first 30 min of life, suggesting prenatal transmission. Our patient has been followed until 2 years old and is developing well with no sequelae.ConclusionThis case report demonstrates the incompatibility between maternal asymptomatic coronavirus disease 2019 and severe neonatal lung involvement. We emphasize the need for vigilance to avoid missing the most severe forms of neonatal coronavirus disease 2019.

Oral Orexin Receptor 2 Agonist in Narcolepsy Type 1

BackgroundNarcolepsy type 1 is caused by severe loss or lack of brain orexin neuropeptides.MethodsWe conducted a phase 2, randomized, placebo-controlled trial of TAK-994, an oral orexin receptor 2–selective agonist, in patients with narcolepsy type 1. Patients with confirmed narcolepsy type 1 according to clinical criteria were randomly assigned to receive twice-daily oral TAK-994 (30 mg, 90 mg, or 180 mg) or placebo. The primary end point was the mean change from baseline to week 8 in average sleep latency (the time it takes to fall asleep) on the Maintenance of Wakefulness Test (range, 0 to 40 minutes; normal ability to stay awake, ≥20 minutes). Secondary end points included the change in the Epworth Sleepiness Scale (ESS) score (range, 0 to 24, with higher scores indicating greater daytime sleepiness; normal, <10) and the weekly cataplexy rate.ResultsOf the 73 patients, 17 received TAK-994 at a dose of 30 mg twice daily, 20 received 90 mg twice daily, 19 received 180 mg twice daily, and 17 received placebo. The phase 2 trial and an extension trial were terminated early owing to hepatic adverse events. Primary end-point data were available for 41 patients (56%); the main reason for missing data was early trial termination. Least-squares mean changes to week 8 in average sleep latency on the MWT were 23.9 minutes in the 30-mg group, 27.4 minutes in the 90-mg group, 32.6 minutes in the 180-mg group, and −2.5 minutes in the placebo group (difference vs. placebo, 26.4 minutes in the 30-mg group, 29.9 minutes in the 90-mg group, and 35.0 minutes the 180-mg group; P<0.001 for all comparisons). Least-squares mean changes to week 8 in the ESS score were −12.2 in the 30-mg group, −13.5 in the 90-mg group, −15.1 in the 180-mg group, and −2.1 in the placebo group (difference vs. placebo, −10.1 in the 30-mg group, −11.4 in the 90-mg group, and −13.0 in the 180-mg group). Weekly incidences of cataplexy at week 8 were 0.27 in the 30-mg group, 1.14 in the 90-mg group, 0.88 in the 180-mg group, and 5.83 in the placebo group (rate ratio vs. placebo, 0.05 in the 30-mg group, 0.20 in the 90-mg group, and 0.15 in the 180-mg group). A total of 44 of 56 patients (79%) receiving TAK-994 had adverse events, most commonly urinary urgency or frequency. Clinically important elevations in liver-enzyme levels occurred in 5 patients, and drug-induced liver injury meeting Hy’s law criteria occurred in 3 patients.ConclusionsIn a phase 2 trial involving patients with narcolepsy type 1, an orexin receptor 2 agonist resulted in greater improvements on measures of sleepiness and cataplexy than placebo over a period of 8 weeks but was associated with hepatotoxic effects. (Funded by Takeda Development Center Americas; TAK-994-1501 and TAK-994-1504 ClinicalTrials.gov numbers, NCT04096560 and NCT04820842.)

Identifying risk factors for adverse events of pyridoxal phosphate in infantile epileptic spasms syndrome

IntroductionInfantile epileptic spasms syndrome (IESS) is characterized by epileptic spasms, regardless of hypsarrhythmia on electroencephalogram or neurodevelopmental delay. In Japan, pyridoxal 5′-phosphate (PLP) is often used as the first-line treatment for IESS because it is effective in a certain number of patients. Although several studies have reported serious adverse events following PLP treatment, no study has investigated the risk factors for such occurrences. ObjectiveTo investigate adverse events associated with PLP therapy for the treatment of IESS and to identify the associated risk factors. Materials and methodsWe retrospectively evaluated adverse events in 59 patients with IESS at Tottori University Hospital between January 1995 and September 2022. We subsequently collected and analyzed their clinical data and analyzed the risk factors associated with each adverse event. The cutoff values and relative risk (RR) were analyzed for items with significant associations with adverse events. ResultsTwenty-seven (51.9%) participants experienced adverse events, including vomiting in 16 participants (59.3%), elevated liver enzyme levels in 15 participants (55.6%), and rhabdomyolysis in two participants (3.4%). No significant differences were observed between the non-adverse events group and the overall adverse events group, as well as between the non-adverse events group and the vomiting group, in terms of the factors examined. However, when comparing the non-adverse events group with the group with elevated liver enzyme levels, age at PLP treatment showed a negative correlation, whereas PLP dose showed a positive correlation with elevated liver enzyme levels. The cutoff dose was 40 mg/kg/day (73.3% sensitivity and 60.7% specificity), and the cutoff age was 9 months (100% sensitivity and 40.0% specificity). RRs of doses ≥40 mg/kg/day and age <9 months were 2.6 and 3.6, respectively. ConclusionsAdverse events of PLP therapy, including vomiting, elevated liver enzymes, and rhabdomyolysis, were observed in approximately half of the participants. Age under 9 months and a dose ≥40 mg/kg/day were identified as risk factors for elevation of liver enzymes on PLP treatment in infants with IESS, with rhabdomyolysis can occur in the younger or higher dose cases.