Mild Elevation Research Articles

Treatment of an accident of imidacloprid poisoning.

Objective: Accidental oral imidacloprid poisoning occurred in a family in Shandong, China, in May 2023. This study aimed to analyze the clinical characteristics of this imidacloprid poisoning event and investigated the detection of toxicants. Methods: Clinical data of four patients with oral imidacloprid poisoning were collected and retrospectively analyzed. The relevant literature was then reviewed. Results: Four patients from the same family received different oral doses of imidacloprid. The main clinical manifestations were digestive and neurological symptoms, including nausea, vomiting, and varying degrees of consciousness. Laboratory tests showed an increased white blood cell count, neutrophil proportion, and mild elevation of transaminase and urea nitrogen levels in some patients. Following comprehensive treatment, which included hemoperfusion, gastric lavage, total gastrointestinal decontamination, and drug symptomatic treatment, the patient's symptoms were quickly relieved, and the concentration of imidacloprid in the blood rapidly decreased. Conclusion: Toxicant detection is an important criterion for the differential diagnosis of poisoning and is helpful for disease assessment, treatment plan formulation, and in determining patient prognosis.

Effects of angiotensin receptor-neprilysin inhibitor on ketone body metabolism in pre-heart failure/heart failure patients

Recently, a mild elevation of the blood ketone levels was found to exert multifaceted cardioprotective effects. To investigate the effect of angiotensin receptor neprilysin inhibitors (ARNIs) on the blood ketone body levels, 46 stable pre-heart failure (HF)/HF patients were studied, including 23 who switched from angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) to ARNIs (ARNI group) and 23 who continued treatment with ACE inhibitors or ARBs (control group). At baseline, there were no significant differences in the total ketone body (TKB) levels between the two groups. Three months later, the TKB levels in the ARNI group were higher than the baseline values (baseline to 3 months: 71 [51, 122] to 92 [61, 270] μmol/L, P < 0.01). In the control group, no significant change was observed between the baseline and 3 months later. A multiple regression analysis demonstrated that the initiation of ARNI and an increase in the blood non-esterified fatty acid (NEFA) levels at 3 months increased the percentage changes in the TKB levels from baseline to 3 months (%ΔTKB level) (initiation of ARNI: P = 0.017, NEFA level at 3 months: P < 0.001). These results indicate that ARNI administration induces a mild elevation of the blood TKB levels in pre-HF/HF patients.

Prospective Evaluation of the Kaiser Permanente Prostate Cancer Risk Calculator in Biopsy-Naïve Men With Mild PSA Elevations.

Our goal was to assess the impact of providing prostate cancer risk estimates to patients and urologists among biopsy-naïve men with mild PSA elevations. This prospective intervention study was conducted in urology departments in Kaiser Permanente Northern California among biopsy-naïve men with mild PSA elevations (<10 ng/mL) between March 2021 and March 2023. The intervention was providing prostate cancer risk estimates for intermediate-/high-grade cancer (Grade Groups 2-5) and any cancer to patients and urologists using our previously validated risk calculator. Biopsy outcomes were compared to a historical comparison group biopsied between January 2016 and December 2019. Over 24 months, the risk calculator was used to estimate risk for 1962 men, of whom 1455 (74%) accepted the biopsy. The men who accepted the biopsy had higher predicted intermediate-/high-grade cancer risks (median 24%, interquartile range [IQR] 17%-31%, vs 20%, IQR 14%-29%; P < .0001) and higher predicted risks for any cancer (median 48%, IQR 40%-56%, vs 45%, IQR 37%-53%, respectively; P < .0001) than those who declined the biopsy. Compared to the historical group, use of the risk calculator resulted in a biopsy population enriched with intermediate-/high-grade cancer: 29% vs 25%; similar rates of low-grade cancer: 24% vs 24%; and fewer negative biopsies: 47% vs 51%, respectively; overall P = .013. In biopsy-naïve men with mild PSA elevations, use of this risk calculator resulted in a biopsy population that had more intermediate-/high-grade cancer and fewer negative biopsies compared to a historical group.

“Dark and bright sides” of Gilbert’s syndrome

Gilbert’s syndrome, also known as benign hyperbilirubinemia, was described more than 100 years ago. It has usually been considered a physiological abnormality characterized by a mild elevation of the systemic level of unconjugated bilirubin, in the absence of any underlying liver or overt RBC hemolysis. The molecular basis of Gilbert’s syndrome lies in the impairment of the conjugation of bilirubin with glucuronic acid in the hepatocytes, which is mediated by a specific hepatic enzyme named bilirubin-UDP-glucuronosyl transferase 1A1 that forms bilirubin diglucuronoside. Clearance of various xenobiotics, which are not substrates for glucuronosylation, is impaired in patients with Gilbert’s syndrome; their detailed list is provided in the article. Fatigue, asthenia, and various vaguely defined dyspeptic complaints attributed to Gilbert’s syndrome in the past are no longer considered a part of this condition, and proper evaluation of possible causes is required in these cases. Since the re-discovery of the potent antioxidant effects of bilirubin in the late 1980s, as well as the multiple intracellular signalling pathways affected by bilirubin, an ever-increasing body of evidence suggests that individuals with Gilbert’s syndrome may benefit from the mild hyperbilirubinemia and are actually protected from the development of a wide range of “diseases of civilization”, such as cardiovascular diseases, certain cancers, and autoimmune or neurodegenerative diseases. Gilbert’s syndrome is defined phenotypically, and therefore not according to predisposing genetic markers, as the elevation of serum unconjugated bilirubin concentration above the upper limit of normal, with no laboratory signs of hemolysis or liver damage. This review analyses the current state of medical knowledge given recent discoveries in this rapidly developing field, as well as their possible clinical significance, and provides a new perspective on this condition.

Clinical Features and Risk Factors for Drug-Induced Liver Injury: A Retrospective Study From China

PurposeWith the prolongation of human life expectancy and the outbreak of COVID-19, antineoplastic agents, anti-infective drugs, and cardiovascular system drugs have been widely applied, resulting in a growing incidence of drug-induced liver injury (DILI) year by year. This study aimed to investigate signals, clinical characteristics, and risk factors in patients with liver injury. MethodsA retrospective analysis was conducted on inpatients clinically diagnosed with DILI from 2019 to 2021 in one tertiary hospital in mainland China. The hepatic biochemical indices, clinical manifestations and suspected drugs of the patients were counted. We determined causality assessed by the Roussel Uclaf Causality Assessment Method in patients that the biochemistry met the diagnostic criteria recommended by the International Serious Adverse Events Consortium and compared them with contemporaneous patients diagnosed as DILI but with hepatic biochemical abnormalities only to identify the injure types and risk factors for DILI. FindingsA total of 1167 patients from 2639 initial participants with DILI were included. According to the injured target cells, it can be divided into hepatocellular injury type 351 cases (30.08%), cholestatic injury type 97 cases (8.31%), mixed injury type 27 cases (2.31%), and biochemical abnormal only type 692 cases (59.30%). It involved 1738 cases of suspected drugs, 349 drugs, and the top 3 drug categories were antineoplastic agents, anti-infectives, and traditional Chinese medicines, with Cyclophosphamide, Atorvastatin, and Liuzasulfapyridine as the top 3 in order of ranking. The main symptoms of patients were darker urine, decreased appetite, and yellow sclera. The overall prognosis of patients with DILI was favorable, with 280 recovered cases (23.99%), 691 improved cases (59.21%), 189 not improved cases (16.20%), and 7 deaths (0.60%). There were significant differences in gender, age, malignancy, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, gamma-glutamyltransferase, albumin, international normalized ratio, and prognosis among patients with different injury types (P < 0.05). Multiple logistic regression analysis showed that female (odds ratio [OR] = 1.897, P < 0.001), alcohol use (OR = 1.905, P = 0.001), malignancy (OR = 0.417, P < 0.001), and pregnancy (OR = 0.201, P = 0.011) were independent factors influencing DILI. ImplicationsFor most patients with liver injury, the manifestations are mild elevation of liver biochemistry without other symptoms (biochemical abnormal only type). The rest of the patients are predominantly of the hepatocellular injury type. Female and alcohol abuse patients are the risk factors of DILI, reminding clinicians to strengthen education on safe drug use, give individualized treatment, and regularly monitor liver function indexes in the patients.

Approach to the patient with abnormal liver biochemistry

Altered liver function tests are a common finding that requires careful interpretation and thorough correlation with the patient's clinical picture. This paper provides a systematic and practical approach to the management of patients with alterations in their liver biochemistry. The fundamental concepts of liver anatomy and physiology are reviewed, emphasizing the importance of understanding the microscopic organization of the organ and key metabolic processes. The most used liver tests, their interpretation and the patterns of alterations that may occur will be described, and the importance of a detailed anamnesis will be emphasized. Guidelines are provided for the diagnostic approach according to the pattern of alteration observed and the different patterns of transaminase elevation, from mild to moderate and severe, and their possible causes are discussed in detail. The importance of considering fatty liver disease as a frequent cause of mild and persistent transaminase elevations is highlighted, and noninvasive tools for the evaluation of liver fibrosis, such as specialized scores and markers, are mentioned. In summary, this document presents an updated and practical text for the proper interpretation of alterations in liver biochemistry, emphasizing the importance of a close correlation with the clinical context of the patient, which will allow an accurate diagnosis and appropriate management.

Cardioprotective effect of cemtirestat treatment in male Zucker diabetic fatty rats: a pilot study

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Slovak Research and Development under the contract no. 21-0410 (APVV) and 20-0411 (APVV) and VEGA grant no. 2/0006/23 Introduction Type 2 Diabetes Mellitus (T2DM), the most common metabolic disorder in human population is caused by defective insulin secretion and reduced tissue responsiveness to insulin. T2DM is characterized by hyperglycaemia accompanied by oxidative stress and inflammation that results in organopathy. The Zucker diabetic fatty rats (ZDF) are established animal model for research of T2DM associated with obesity, and for efficacy of novel treatments. Myocardial electrical coupling protein, connexin43 (Cx43) is one of the key factors affecting heart function and arrhythmogenesis. We have previously shown upregulation of Cx43 in type 1 DM rats that was associated with reduced susceptibility to malignant arrhythmias. However, it is not known whether T2DM affects Cx43 expression and/or function in the heart as well as in brown adipose tissue (BAT). The purpose of our study was to examine expression of Cx43 in heart and BAT as well as the effect of treatment with highly selective and efficient aldose reductase inhibitor enriched with antioxidant activity, Cemtirestat. Methods: Forty 4-month-old male ZDF rats (fa/+ and fa/fa) were divided into 4 groups: 1) untreated control lean rats (fa/+), 2) control lean rats treated with Cemtirestat, 3) untreated diabetic fatty rats (fa/fa), 4) diabetic fatty rats treated with Cemtirestat (2,55 mg/kg/day). After 6 months of treatment, biometric parameters were registered and left ventricle (LV) + BAT were used for Western blot analysis of Cx43, PKCɛ (phosphorylates Cx43) and PKCδ (implicated in pro­apoptotic signaling). BAT and LV tissue sections were also used for immunolabeling of Cx43 to examine its topology. Results: Increase of body weight, heart weight, LV weight, adiposity, plasma triglycerides, cholesterol and blood glucose were registered in ZDF fa/fa rats. T2DM resulted in altered localisation of Cx43 that was not affected by treatment with Cemtirestat. Expression of Cx43 was significantly decreased in LV of fa/fa rats and restored with Cemtirestat. Moreover, BAT exhibited significantly lower expression of total Cx43 in fa/fa rats, that was moderately increased by Cemtirestat. The expression of PKCɛ was significantly decreased in both, LV and BAT of fa/fa rats with mild elevation of PKCɛ in LV of treated fa/fa rats. Cemtirestat slightly normalized increased expression of PKCδ in LV of fa/fa rats, but had no effect on lower PKCδ levels in BAT of fa/fa rats. Echocardiographic examination did not show significant difference between treated and untreated groups of rats and showed mild differences between diabetic and control rats. In conclusions, findings point out that T2DM downregulates Cx43 in the heart and BAT, however further studies are necessary for understanding the mechanisms implicated in every step in the development of T2DM cardiopathy and arrhythmogenesis as well as BAT alterations. Further research is required to determine factors involved in cardioprotective effects of Cemtirestat.

Elucidating the impact of Y chromosome microdeletions and altered gene expression on male fertility in assisted reproduction.

Genetic abnormalities like Y chromosome microdeletions are implicated in male infertility. This study investigated the association of azoospermia factor (AZF) region microdeletions with unsuccessful assisted reproductive techniques (ART), including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). This cross-sectional analysis study examined 80 Iranian oligospermic men (mean age 34years) with prior failed ICSI and IVF cycles (IR.IAU.TNB.REC.1401.041). Semen analysis evaluated quantity/quality parameters based on World Health Organization guidelines. Participants were stratified by sperm DNA fragmentation (SDF) levels into: control (SDF < 15%, n = 20), mild elevation (15% ≤ SDF ≤ 30%, n = 60), and high (SDF > 30%, n = 20). Multiplex PCR mapped AZF microdeletions in the high SDF group. The AZF-associated genes were selected by RNA Seq analysis, and the candidate genes were checked for expression level by real-time PCR. High SDF individuals exhibited poorer semen metrics, including 69% lower sperm concentration (P = 0.04) than those without SDF. Of this subset, 45% (9/20 men) harboured predominately AZF microdeletions. Men with AZF microdeletions showed higher SDF (32% vs 21%, P = 0.02) and altered AZF-associated genes expression. As USP9Y 3-fold, UTY 1.3-fold, and BPY2 1-fold revealed up-regulation, while IQCF1 8-fold, CDY 6.5-fold, DAZ 6-fold, and DDX3Y 1-fold underwent down-regulation. The PAWP gene was also down-regulated (5.7-fold, P = 0.029) in the IVF/ICSI failure group. AZF microdeletions significantly impact male infertility and ART outcomes. High SDF individuals exhibited poorer semen metrics, with 45% AZF microdeletions. These microdeletions altered AZF-associated genes expression, affecting fertility mediator PAWP independently. Dual AZF and SDF screening enables personalized management in severe male infertility, potentially explaining IVF/ICSI failures.

Association of admission serum triglyceride levels with intensive care unit hospitalization rates in acute pancreatitis patients: A retrospective study.

Acute pancreatitis (AP) is a complex and unpredictable condition, of which hypertriglyceridemia (HTG) is the third most prevalent cause. This study aimed to conduct a retrospective analysis of clinical data from hospitalized AP patients to uncover a potential correlation between triglyceride (TG) levels and the necessity for intensive care unit (ICU) admission. This retrospective cohort study utilized the Medical Information Mart for Intensive Care IV 2.2 (MIMIC-IV) critical care dataset, incorporating data from 698 patients with hypertriglyceridemic acute pancreatitis (HTG-AP). The analysis employed the RCS model along with univariate and multivariate logistic regression methods to affirm the association between triglyceride levels and ICU admission. Subgroup analysis was performed to investigate specific populations. The study included 698 patients with AP, 42.41% of whom experienced HTG during hospitalization. RCS analysis revealed a linear association between TG levels and risk of ICU admission (p for nonlinear = .219, p for overall = .009). Multivariate logistic regression analysis indicated an increased risk of ICU admission in the TG range of 1.7-5.65 mmol/L (aOR = 1.83, 95% CI 1.12-2.99, P = .015) and TG >11.3 mmol/L (aOR = 5.69, 95% CI 2.36-13.74, P < .001) compared to the normal group. Similar results were observed across the various subgroups. As triglyceride levels increased, there was a corresponding increase in ICU admissions. Patients within the 1.7 to 5.65 mmol/L and > 11.3 mmol/L triglyceride groups exhibited higher rates of ICU admissions. Moreover, we observed a higher risk of ICU hospitalization even with mild TG elevation.

Calcineurin inhibitor-related hyperkalemia is caused by hyporeninemic hypoaldosteronism and fludrocortisone is an effective treatment: Report of a case series and review of the literature.

Calcineurin inhibitors (CNIs) are widely used in transplantation. Although CNI-related hyperkalemia is common (10%-60.6%), the underlying pathogenetic mechanism is not well-elucidated and may lead to dose adjustment or treatment withdrawal. The aim of this study is to describe CNI-related hyperkalemia due to hyporeninemic hypoaldosteronism in pediatric transplant recipients who were successfully treated with fludrocortisone. In a total of 55 hematopoietic stem cell (HSCT) and 35 kidney transplant recipients followed according to institutional immunosuppression protocols, recipients diagnosed with CNI-related hyperkalemia were reviewed. Recipients who were receiving intravenous fluid, potassium, or were diagnosed with hemolysis, acute graft rejection, or had an eGFR < 30 mL/min/1.73m2, were excluded. A detailed analysis of clinical history as well as biochemical studies was carried out to reveal possible pathophysiology. Three pediatric transplant recipients (one HSCT, two kidney transplantation) with findings of hyperkalemia, hyponatremia, and a mild elevation in blood urea nitrogen while on CNIs were recruited. Urinary potassium excretion was diminished while sodium excretion was increased. Plasma aldosterone levels were low, and renin was not increased in response. Primary adrenal insufficiency was ruled out, and hyporeninemic hypoaldosteronism was diagnosed. CNI-related hyperkalemia was detected earlier in case 1, who had HSCT (22 days), than in the second and third cases, who had kidney transplantation (24 and 30 months post-transplantation, respectively). The discrepancy was hypothesized to be explained by higher overall CNI dose due to higher serum target CNI used in HSCT than kidney transplantation. Electrolyte imbalance was reversed upon administration of physiologic dose fludrocortisone (0.05 mg, daily), while fludrocortisone was ceased after CNI withdrawal in case 1, which is additional evidence for the etiological association of CNIs and hyporeninemic hypoaldosteronism. Our three cases strengthen the premise that CNI-related hyperkalemia may be due to hyporeninemic hypoaldosteronism, and the timing and severity may be related to CNI dose. Fludrocortisone is a safe and effective treatment in CNI-related hyperkalemia, providing maintenance of CNIs, which are one of the essential therapeutic agents for pediatric transplantation.

Postoperative liver injury after sevoflurane or propofol anesthesia in patients undergoing non-cardiac surgery: a retrospective cohort study

Although sevoflurane is generally considered safe, reports suggest that sevoflurane may cause postoperative liver injury more frequently than previously believed. Therefore, we aimed to compare the incidence of clinically significant postoperative liver injury following non-cardiac surgery between patients who underwent sevoflurane anesthesia and propofol-based total intravenous anesthesia. We retrospectively reviewed adult surgical patients from January 2010 to September 2022 who underwent general anesthesia in our center using sevoflurane or propofol over 3 h. After 1:1 propensity score matching, the incidence of postoperative liver injury was compared between the two groups. Out of 58,300 patients reviewed, 44,345 patients were included in the analysis. After propensity score matching, 7767 patients were included in each group. The incidence of postoperative liver injury was 1.4% in the sevoflurane group, which was similar to that in the propofol group (1.6%; p = 0.432). Comparison of the severity of postoperative alanine aminotransferase elevation showed that the incidence of borderline and mild elevation was higher in the sevoflurane group, but there was no difference in the incidence of moderate and severe elevation. In conclusion, sevoflurane anesthesia over 3 h was not associated with a higher incidence of clinically significant postoperative liver injury compared to propofol anesthesia.

Reduction of spermine synthase enhances autophagy to suppress Tau accumulation

Precise polyamine metabolism regulation is vital for cells and organisms. Mutations in spermine synthase (SMS) cause Snyder–Robinson intellectual disability syndrome (SRS), characterized by significant spermidine accumulation and autophagy blockage in the nervous system. Emerging evidence connects polyamine metabolism with other autophagy-related diseases, such as Tauopathy, however, the functional intersection between polyamine metabolism and autophagy in the context of these diseases remains unclear. Here, we altered SMS expression level to investigate the regulation of autophagy by modulated polyamine metabolism in Tauopathy in Drosophila and human cellular models. Interestingly, while complete loss of Drosophila spermine synthase (dSms) impairs lysosomal function and blocks autophagic flux recapitulating SRS disease phenotype, partial loss of dSms enhanced autophagic flux, reduced Tau protein accumulation, and led to extended lifespan and improved climbing performance in Tauopathy flies. Measurement of polyamine levels detected a mild elevation of spermidine in flies with partial loss of dSms. Similarly, in human neuronal or glial cells, partial loss of SMS by siRNA-mediated knockdown upregulated autophagic flux and reduced Tau protein accumulation. Importantly, proteomics analysis of postmortem brain tissue from Alzheimer’s disease (AD) patients showed a significant albeit modest elevation of SMS level. Taken together, our study uncovers a functional correlation between polyamine metabolism and autophagy in AD: SMS reduction upregulates autophagy, suppresses Tau accumulation, and ameliorates neurodegeneration and cell death. These findings provide a new potential therapeutic target for AD.

Sluggish rise of the western Gangdese mountains after India-Eurasia collision

With the most prominent topography on Earth, the Tibetan Plateau has profound influences on the hydrologic cycle and climate dynamics in Asia. However, the regional uplift history of the Tibetan Plateau remains highly debated. Here, we use europium anomalies and LREE/HREE ratio in detrital zircon, combined with whole-rock La/YbN ratio, to constrain the crustal thickness and topographic evolution of the Gangdese mountains in southern Tibet. Europium anomaly, controlled by pressure-sensitive minerals plagioclase and garnet, has been shown to correlate with crustal thickness. Our results reveal contrasting crustal thickening histories of the eastern (east of ∼88°E) and western (west of ∼88°E) parts of the Gangdese. Prior to the India-Eurasia collision (∼60–55 Ma), the crust of the eastern Gangdese thickened continuously from ∼40 km to nearly 60 km, while the western Gangdese maintained a mildly thickened crust of ∼50 km. Both parts underwent substantial thinning (to 40–45 km) immediately before the India-Eurasia collision, but the eastern Gangdese re-thickened rapidly afterwards. In the western Gangdese, post-collisional thickening was delayed until ∼40–20 Ma, which resulted in a mild elevation of ∼2000 m for most areas of southern Tibet until the late Oligocene. This diachronous uplift of the Gangdese after collision may have resulted from more mantle-derived magma additions in the eastern Gangdese before collision, which could rheologically weaken its lithosphere. We suggest that the diachronous uplift of the Gangdese after the India-Eurasia collision may have dominated the moisture transfer pattern across southern Tibet through the late Eocene and intensified the South Asian monsoon through the Oligocene-Miocene boundary (∼25–20 Ma).

Respiratory Health Associated With Systemic Metal Exposure in Post-9/11 Veterans in the Department of Veterans Affairs Toxic Embedded Fragment Registry.

Adverse respiratory outcomes in post-9/11 veterans with elevated urinary metal measures and enrolled in the VA's Toxic Embedded Fragment registry were compared to those without elevated urinary metals. Veterans completed questionnaires, underwent pulmonary physiology tests (pulmonary function and oscillometry), and provided urine samples for analysis of 13 metals. Respiratory symptoms, diagnoses, and physiology measures were compared in veterans with ≥1 urine metal elevation to those without metal elevations, adjusted for covariates, including smoking. Among 402 study participants, 24% had elevated urine metals, often just exceeding upper limits of reference values. Compared to veterans without elevated metals, those with elevated metals had had higher FEV 1 values but similar frequencies of respiratory symptoms and diagnoses and abnormalities on pulmonary physiology tests. Mild systemic metal elevations in post-9/11 veterans are not associated with adverse respiratory health outcomes.

Magnetic resonance cholangiopancreatography in acute cholecystitis: Is it necessary for patients with normal common bile duct diameter?

AbstractAimInvestigating concurrent choledocholithiasis in patients with acute cholecystitis (AC) and normal common bile duct (CBD) diameter on ultrasound by performing magnetic resonance cholangiopancreatography (MRCP) can be challenging. This study aims to determine the conditions that necessitate MRCP before surgery and its potential impact on the course of treatment for these patients.Patients and methodsWe included 100 patients with AC and normal CBD diameter who were admitted to Shahid Modarres Hospital from September 2019 to September 2022. Patients with elevated levels of any liver serum markers above the upper limit of normal underwent MRCP.ResultsThe MRCP results were positive in 45.16% of cases and altered the type of treatment in 35.48% of them. The findings indicated that direct [area under the curve (AUC) = 0.782; 95% confidence interval (CI) 0.597–0.909] and total bilirubin (AUC = 0.697; 95% CI 0.507–0.849) were significantly effective in predicting the positive findings for concurrent CBD stone or Mirizzi's syndrome on MRCP. The optimal cutoff values for direct and total bilirubin were found to be above 1.02 and 2.19 mg/dL. Concerning the alteration of treatment approaches, direct bilirubin demonstrated predictive value (P = .014) at levels above 1.02 mg/dL.ConclusionsIn cases of AC with a normal CBD diameter on ultrasound and mild elevations in liver function parameters, including total and direct bilirubin, it is not routinely necessary to perform MRCP. However, if these laboratory values exceed a certain threshold, MRCP is recommended as it may reveal alternative diagnoses that could alter the clinical management.

Clinical analysis and literature review of two paediatric cases of anti-IgLON5 antibody-related encephalitis.

Anti-IgLON5 antibody-related encephalitis is a rare autoimmune disorder of the central nervous system, predominantly occurring in middle-aged elderly individuals, with paediatric cases being exceptionally rare. This study aims to enhance the understanding of paediatric anti-IgLON5 antibody-related encephalitis by summarising its clinical and therapeutic characteristics. A retrospective analysis was conducted on two paediatric patients diagnosed with anti-IgLON5 antibody-related encephalitis at Hunan Children's Hospital from August 2022 to November 2023. This involved reviewing their medical records and follow-up data, in addition to a literature review. The study involved two patients, one male and one female, aged between 2.5 and 9.6 years, both presenting with an acute/subacute course of illness. Clinically, both exhibited movement disorders (including dystonia, involuntary movements, and ataxia), cognitive impairments, sleep disturbances, and psychiatric symptoms. Patient 1 experienced epileptic seizures, while Patient 2 exhibited brainstem symptoms and abnormal eye movements. Neither patient showed autonomic dysfunction. Patient 1 had normal cerebrospinal fluid (CSF) and Brain MRI findings, whereas Patient 2 showed moderate leukocytosis and mild protein elevation in the CSF, and Brain MRI revealed symmetrical lesions in the basal ganglia and cerebellum. Oligoclonal bands in the CSF were positive in both cases. Both patients tested negative for HLA-DQB*05:01 and HLA-DRB*10:01. They received both first-line and second-line immunotherapies, with Patient 2 showing a poor response to treatment. Paediatric cases of anti-IgLON5 antibody-related encephalitis similarly present sleep disturbances as a core symptom, alongside various forms of movement disorders. Immunotherapy is partially effective. Compared to adult patients, these paediatric cases tend to exhibit more pronounced psychiatric symptoms, a more rapid onset, and more evident inflammatory changes in the CSF. The condition appears to have a limited association with HLA-DQB*05:01 and HLA-DRB*10:01 polymorphisms.

Sildenafil Versus Placebo for Early Pulmonary Vascular Disease in Scleroderma (SEPVADIS): protocol for a randomized controlled trial

BackgroundPulmonary hypertension (PH) is a leading cause of death in patients with systemic sclerosis (SSc). An important component of SSc patient management is early detection and treatment of PH. Recently the threshold for the diagnosis of PH has been lowered to a mean pulmonary artery pressure (mPAP) threshold of > 20 mmHg on right heart catheterization (RHC). However, it is unknown if PH-specific therapy is beneficial in SSc patients with mildly elevated pressure (SSc-MEP, mPAP 21–24 mmHg).MethodsThe SEPVADIS trial is a randomized, double-blind, placebo-controlled phase 2 trial of sildenafil in SSc-MEP patients with a target enrollment of 30 patients from two academic sites in the United States. The primary outcome is change in six-minute walk distance after 16 weeks of treatment. Secondary endpoints include change in pulmonary arterial compliance by RHC and right ventricular function by cardiac magnetic resonance imaging at 16 weeks. Echocardiography, serum N-terminal probrain natriuretic peptide, and health-related quality of life is being measured at 16 and 52 weeks.DiscussionThe SEPVADIS trial will be the first randomized study of sildenafil in SSc-MEP patients. The results of this trial will be used to inform a phase 3 study to investigate the efficacy of treating patients with mild elevations in mPAP.Trial registrationClinicalTrials.gov Identifier NCT04797286.

P024 Dermatomyositis, a blurred clinical picture

Abstract Background/Aims We present a case of MDA5 dermatomyositis(DM) in a 25-year-old male, initially presenting with seronegative inflammatory polyarthritis affecting the hands. No classic features of DM were noted and CK was normal. Sulfasalazine was started and subsequently stopped after an ALT rise. Lung-function performed prior to planned methotrexate was abnormal. A CT neck, thorax and abdomen showed unusual pulmonary appearances with focal basal ground glass opacities with reverse halo, without widespread interstitial lung disease(ILD). A bronchoscopy excluded atypical infection. He then developed scaly lesions over the extensor PIPJs, periungual lesions, periorbital swelling and sicca symptoms. CK remained normal, extended myositis screening was negative. LDH and troponins were elevated. A skin biopsy of the hand rash was consistent with dermatomyositis. Methods Muscle pain persisted and an MRI proximal muscles showed muscle oedema and inflammation. A muscle biopsy was requested but not performed as he developed an olecranon bursa with staphylococcal aureus infection. The bursa broke down, required wash-outs, antibiotics and was left to heal by secondary intention. A repeat myositis screen was positive for MDA5 antibody. Immunosuppression was delayed because of concerns that prednisolone, Mycophenolate mofetil(MMF) or Rituximab would cause further wound breakdown and increased risk of infection. The patient was monitored with serial lung-function but didn’t develop ILD. Dermatology confirmed there was active dermatomyositis in the wound edges. The wound only finally healed with additional IVIG therapy. The patient is now established on Rituximab, having been unable to tolerate MMF. Results This case highlights that continued reassessment of the evolving clinical picture is vital to reach the correct diagnosis, and that one should not be reassured by a normal CK. Instead the ALT rise (along with mild elevations of LDH and troponin) was likely reflecting muscle inflammation, not liver inflammation secondary to Sulfasalazine. The repeatedly infected olecranon bursa and large open wound raised concerns about immunosuppressive agents. However, the lack of healing was due to active DM and escalation of treatment was required rather than treatment delay. IVIG was given with excellent and rapid effect. This is licensed for refractory skin involvement in DM, to be considered when infection concern is high. Conclusion The pulmonary involvement with reverse halo sign was felt by the MDT to be nonspecific initially, with a wide differential. In the clinical context, this was reflecting an atypical presentation of MDA5 positive ILD. This antibody can be associated with rapidly progressive ILD and death in approximately one third of cases. Had our patient shown evidence of significant pulmonary progression, high dose immunosuppression would have been commenced despite potential infection risk. Not all patients testing positive for MDA5 develop rapidly progressive ILD but clinical suspicion should be high with frequent serial monitoring of lung function and radiology. Disclosure L. Maltas: None. J. Vila: None. A. Ray: None.

The biochemical pattern defines MASLD phenotypes linked to distinct histology and prognosis

BackgroundMASLD can manifest as hepatocellular damage, which can result in mild elevation of aminotransferases. However, in some patients, MASLD presents with cholestatic pattern.ObjectiveTo assess the impact of the biochemical pattern on the natural course of MASLD, including liver damage in histology, the accuracy of non-invasive tests(NITs), and prognosis.MethodsMulticenter study enrolling 2156 patients with biopsy-proven MASLD, who were classified based on their[ALT/ULN)]/[(ALP/ULN)] levels at the time of biopsy: (a) hepatocellular pattern(H), > 5; (b) mixed pattern(M),2–5; (c) cholestatic pattern(C), < 2. Outcomes: (a) histological evaluation of the single components of NAS, MASH, and fibrosis; (b) NITs and transient elastography assessing advanced fibrosis; (c) prognosis determined by the appearance of decompensated cirrhosis and death.ResultsOut of the 2156 patients, 22.9% exhibited the H-pattern, whilst 31.7% exhibited the C-pattern. Severe steatosis, ballooning, lobular inflammation, and MASH (56.4% H vs. 41.9% M vs. 31.9% C) were more common in H-pattern (p = 0.0001),whilst C-pattern was linked to cirrhosis (5.8% H vs. 5.6% M vs. 10.9% C; p = 0.0001). FIB-4(0.74(95% CI 0.69–0.79) vs. 0.83 (95% CI 0.80–0.85); p = 0.005) and Hepamet Fibrosis Score(0.77 (95% CI 0.69–0.85) vs. 0.84 (95% CI 0.80–0.87); p = 0.044)exhibited lower AUROCs in the H-pattern. The C-pattern[HR 2.37 (95% CI 1.12–5.02); p = 0.024], along with age, diabetes, and cirrhosis were independently associated with mortality. Most patients maintained their initial biochemical pattern during the second evaluation.ConclusionsThe H-pattern exhibited greater necro-inflammation in the histology than the C-pattern, whereas the latter showed more cirrhosis. The accuracy of NITs in detecting fibrosis was decreased in H-pattern. The occurrence of decompensated events and mortality was predominant in C-pattern. Therefore, identifying MASLD phenotypes based on the biochemical presentation could be relevant for clinical practice.

Three-year outcomes of valoctocogene roxaparvovec gene therapy for hemophilia A

BackgroundValoctocogene roxaparvovec transfers a human factor (F)VIII coding sequence into hepatocytes of people with severe hemophilia A to provide bleeding protection. ObjectivesTo present 3-year efficacy and safety in the multicenter, open-label, single-arm, phase 3 GENEr8-1 trial. MethodsGENEr8-1 enrolled 134 adult males with severe hemophilia A who were receiving FVIII prophylaxis. Efficacy endpoints included annualized bleeding rate, annualized FVIII utilization, FVIII activity (chromogenic substrate assay; imputed as 1 IU/dL at baseline and 0 IU/dL after discontinuation), and the Haemophilia-Specific Quality of Life Questionnaire for Adults. Safety was assessed by adverse events (AEs). ResultsAt week 156, 131 of 134 participants remained in the study; overall, 17 of 134 resumed prophylaxis. Mean annualized bleeding rate for treated bleeds decreased from 4.8 (SD, 6.5) bleeds/y at baseline to 0.8 (SD, 2.3; P < .0001) bleeds/y after prophylaxis (prophylaxis cessation to last follow-up) and 0.97 (SD, 3.48) bleeds/y during year 3. Annualized FVIII utilization decreased 96.8% from baseline after prophylaxis and 94.2% during year 3. At week 156, mean and median FVIII activity were 18.4 (SD, 30.8) and 8.3 IU/dL, respectively. FVIII activity decrease was lower between years 2 and 3 than between years 1 and 2. At the end of year 3, clinically meaningful improvements in the Haemophilia-Specific Quality of Life Questionnaire for Adults Total Score were observed (mean change from baseline, 6.6; 95% CI, 4.24-8.87; P < .0001). Mild alanine aminotransferase elevations remained the most common AE during year 3 (23.7% of participants). A serious AE of B-cell acute lymphoblastic leukemia was considered unrelated to treatment. ConclusionHemostatic efficacy was maintained, and safety remained unchanged from previous years.