Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) is a rare autosomal dominant genetic disorder. It may also involve many other organ systems, leading to complications such as exocrine pancreatic insufficiency, liver dysfunction, lymphedema, and developmental delay. The FAM111B has been determined as the pathogenic gene associated with POIKTMP syndrome, whose protein product plays a critical role in regulating essential cellular processes including DNA repair and replication, cell cycle progression, apoptosis, nuclear transport, and telomere length maintenance. This article has provided a comprehensive review for the genetic basis of POIKTMP syndrome and its correlation with various phenotypes, which may offer insights for basic research and clinical diagnosis of this disease.
Humans ; Pulmonary Fibrosis/genetics* ; Skin Diseases, Genetic/genetics*

Introduction: Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CFTR gene. Complications such as cystic fibrosis–related diabetes (CFRD) are well recognized. The association between CF and autoimmune thyroid disease, however, is rare and poorly understood. We report a case of CFRD complicated by Graves’ disease. Case: A 22-year-old male was diagnosed with CF at age 5, confirmed by a positive sweat chloride test. Following the diagnosis, lifelong pancreatic enzyme replacement therapy (Creon) was initiated to treat exocrine pancreatic insufficiency. In 2021, he developed type 3c diabetes, attributed to endocrine pancreatic insufficiency, and required regular basal insulin therapy. In early 2024, he developed hypokalemic periodic paralysis with proximal myopathy, despite potassium correction, and was admitted to the hospital. On admission, examination revealed a fine tremor and diffuse bilateral neck swelling. Biochemical evaluation showed thyrotoxicosis with Free T4 of 37 pmol/L and thyroid-stimulating hormone (TSH) <0.01 mIU/L. He started a tapering dose of carbimazole and propranolol. An urgent neck ultrasound showed a heterogeneous thyroid parenchyma with increased vascularity and no nodules. Elevated anti-thyroid peroxidase (anti-thyroid peroxidase, >600 IU/mL) and TSH receptor antibodies (thyrotropin receptor antibody, 2.57 IU/L) confirmed a diagnosis of Graves’ disease. During follow-ups, he had issues with compliance with the antithyroid therapy. However, the latest thyroid function test in February 2026 showed Free T4 of 20.5 pmol/L with suppressed TSH of <0.01 mIU/L. He remains clinically euthyroid throughout the follow-up. Conclusion This case highlights a rare but clinically relevant coexistence. Clinicians managing symptomatic CF patients should vigilantly screen for thyroid dysfunction to ensure early diagnosis and timely intervention. Early recognition and treatment may improve patient outcomes. Further research is needed to clarify the immunological link between CF and autoimmunity.
Cystic Fibrosis ; Graves Disease

Schistosomiasis, a snail-borne disease caused by infection with a trematode parasite of the genus Schistosoma, is one of the most neglected tropical diseases in the world. One of its rare complications is hepatosplenic schistosomiasis which ultimately leads to fibrosis and presinusoidal portal hypertension.

We report a case of a 13-year-old Filipino male from Quezon City with previous one year residence in the endemic island of Leyte, presenting with melena. Diagnostic work-up revealed hepatosplenomegaly and periportal fibrosis with multiple hepatic nodules on ultrasound, positive Schistosoma japonicum eggs on Kato-Katz stool examination technique, and findings of esophageal varices on upper endoscopy. The patient was managed with praziquantel, propranolol, and endoscopic rubber band ligation of the esophageal varices, with note of resolution of bleeding, and improvement on sonographic liver findings.

The degree of liver fibrosis from schistosomiasis is affected by poorly understood mechanisms which affect its severity, progression, and complications, regardless of biosocial factors including egg burden and duration of parasite exposure. This is the first case report on a Filipino adolescent to document significant interval improvement, within four weeks of treatment, of the characteristic fibrotic pattern in hepatosplenic schistosomiasis. Hepatosplenic schistosomiasis is still often missed out as the diagnosis in patients who consult with common symptoms, and high index of suspicion is recommended for those with history of residence in endemic areas. Likewise, treatment focusing on parasite eradication can aid in promptly addressing the resulting fibrosis and its complications.

BACKGROUND

Non-Alcoholic Fatty Liver Disease (NAFLD) is common in Type 2 Diabetes Mellitus (T2DM). The FIB-4 index is one of the most-studied non-invasive biomarkers that combines age and laboratory parameters (platelet count, alanine-and aspartate- aminotransferase) to evaluate underlying hepatic fibrosis. This study aims to determine the diagnostic value of Fibrosis-4 (FIB-4) index scoring in screening for non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus, which is a high-risk population in development of advance fibrosis.

A single center, analytical cross-sectional study was conducted among adult T2DM patients with and without NAFLD seen at the Out-Patient Department (OPD) and those with NAFLD enrolled under the Liver Disease Databank of the Liver Disease and Transplant Center in collaboration with Research and Biotechnology Division at St. Luke’s Medical Center, Quezon City. Medical history was obtained by reviewing charts of eligible patients using data collection form. Liver ultrasound was used as the reference standard in the diagnosis of NAFLD. The FIB-4 index was calculated with this formula: age (years) x AST (U/L)/(platelets (10^9/L) x ALT (U/L)^1/2.

A total of 305 adult patients with type 2 diabetes mellitus were included in the study. The prevalence of non-alcoholic fatty liver disease based on ultrasound among diabetic patients is 76.07%. The median age (p = 0.0204), AST (p < 0.00001), ALT (p < 0.00001) were significantly higher in patients with NAFLD than those without. Platelet count (p = 0.0002) was significantly lower in patients with NAFLD than those without. The proportion of patients with low platelet count, high AST and high ALT were significantly higher in patients with NALFD than those without. In this study, the FIB-4 index cutoff score for screening of NAFLD is ≥0.76, which has an accuracy of 66.23%, sensitivity of 75%, specificity of 38.3%, PPV of 79.46% and NPV of 32.56% in detecting fatty liver.

A FIB-4 index value of ≥0.76 has an acceptable sensitivity for screening NAFLD even in the absence of fibrosis among patients with T2DM. However, due to its low specificity, additional tests to establish NAFLD diagnosis may be required.

BACKGROUND AND OBJECTIVE

Evidence regarding the impact of performing endoscopy within 12 hours of variceal bleeding (VB) on outcomes is inconclusive, and there is a lack of local data on this topic. This study aimed to determine if the timing of endoscopy is associated with clinical outcomes.

This was a single-center retrospective cohort study which included adult cirrhotic patients admitted for VB from January 2016 to September 2022. The primary outcomes were in-hospital and 6-week mortality. Secondary outcomes included 5-day rebleeding, length of hospital stay (LOS), and blood transfusion requirements (BTR). The relationships between timing of endoscopy and outcomes were evaluated using regression analysis.

In 140 patients, 5.7% underwent urgent endoscopy (?12 hours). The overall median door-to-endoscopy time (DET) was 39.4 hours (IQR 20.0-73.4). The overall in-hospital mortality, 6-week mortality, and 5-day rebleeding rates were 12.9%, 11.4%, and 8.6%, respectively, without significant variability at different DET (p >0.05). Prolonged LOS was evident when endoscopy was delayed to >12 hours from admission (3.5 [IQR 2.25-5.75] vs 6 days [IQR 4-9.75], p = 0.021), while BTR was greater starting at endoscopies performed at >24 hours from admission (1 [0-2] vs 2 units [1-3], p = 0.000). Delayed endoscopy was significantly correlated with LOS (Beta 0.316, SE 0.011, p = 0.000) and BTR (Beta 0.214, SE 0.469, p = 0.003), but not with mortality and early rebleeding.

Timing of endoscopy may be independent of mortality and early rebleeding. Timely endoscopy may shorten hospitalization and decrease need for blood transfusion. Other factors affecting clinical outcomes may be at play.

Oral submucous fibrosis (OSF), characterized by excessive deposition of extracellular matrix (ECM) that causes oral mucosal tissue sclerosis, and even cancer transformation, is a chronic, progressive fibrosis disease. However, despite some advancements in recent years, no targeted antifibrotic strategies for OSF have been approved; likely because the complicated mechanisms that initiate and drive fibrosis remain to be determined. In this review, we briefly introduce the epidemiology and etiology of OSF. Then, we highlight how cell-intrinsic changes in significant structural cells can drive fibrotic response by regulating biological behaviors, secretion function, and activation of ECM-producing myofibroblasts. In addition, we also discuss the role of innate and adaptive immune cells and how they contribute to the pathogenesis of OSF. Finally, we summarize strategies to interrupt key mechanisms that cause OSF, including modulation of the ECM, inhibition of inflammation, improvement of vascular disturbance. This review will provide potential routes for developing novel anti-OSF therapeutics.
Humans ; Oral Submucous Fibrosis/immunology* ; Extracellular Matrix/metabolism* ; Myofibroblasts

Abnormal accumulation of collagen fibrils is a hallmark feature of oral submucous fibrosis (OSF). However, the precise characteristics and underlying mechanisms remain unclear, impeding the advancement of potential therapeutic approaches. Here, we observed that collagen I, the main component of the extracellular matrix, first accumulated in the lamina propria and subsequently in the submucosa of OSF specimens as the disease progressed. Using RNA-seq and Immunofluorescence in OSF specimens, we screened the cartilage oligomeric matrix protein (COMP) responsible for the abnormal collagen accumulation. Genetic COMP deficiency reduced arecoline-stimulated collagen I deposition significantly in vivo. In comparison, both COMP and collagen I were upregulated under arecoline stimulation in wild-type mice. Human oral buccal mucosal fibroblasts (hBMFs) also exhibited increased secretion of COMP and collagen I after stimulation in vitro. COMP knockdown in hBMFs downregulates arecoline-stimulated collagen I secretion. We further demonstrated that hBMFs present heterogeneous responses to arecoline stimulation, of which COMP-positive fibroblasts secrete more collagen I. Since COMP is a molecular bridge with Fibril-associated collagens with Interrupted Triple helices (FACIT) in the collagen network, we further screened and identified collagen XIV, a FACIT member, co-localizing with both COMP and collagen I. Collagen XIV expression increased under arecoline stimulation in wild-type mice, whereas it was hardly expressed in the Comp^-/- mice, even with under stimulation. In summary, we found that COMP may mediates abnormal collagen I deposition by functions with collagen XIV during the progression of OSF, suggesting its potential to be targeted in treating OSF.
Oral Submucous Fibrosis/pathology* ; Cartilage Oligomeric Matrix Protein/genetics* ; Animals ; Mice ; Humans ; Fibroblasts/metabolism* ; Collagen Type I/metabolism* ; Arecoline/pharmacology* ; Mouth Mucosa/metabolism* ; Cells, Cultured ; Fluorescent Antibody Technique

Cytoskeletal network dysregulation is a pivotal determinant in various immunodeficiencies and autoinflammatory conditions. This report reviews the significance of actin remodeling in disease pathogenesis, focusing on the Arp2/3 complex and its regulatory subunit actin related protein 2/3 complex subunit 1B (ARPC1B). A spectrum of cellular dysfunctions associated with ARPC1B deficiency, impacting diverse immune cell types, is elucidated. The study presents a patient featuring recurrent and persistent eosinophilia attributed to homozygous ARPC1B mutation alongside concomitant compound heterozygous cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. We used ARPC1B antibody to stain the patient's peripheral blood lymphocytes and those of the control. The defect in the ARPC1B gene in the present patient caused absent/low expression by immunofluorescence microscopy. The intricate interplay between cytoskeletal defects and immunological manifestations underscores the complexity of disease phenotypes, warranting further exploration for targeted therapeutic strategies.
Humans ; Actin-Related Protein 2-3 Complex/genetics* ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics* ; Eosinophilia/genetics* ; Homozygote ; Mutation ; Recurrence

Kidney fibrosis is the final common pathway of virtually all chronic kidney disease (CKD). However, despite great progress in recent years, no targeted antifibrotic therapies have been approved. Epidemiologic, clinical, and molecular evidence suggest that aging is a major contributor to the increasing incidence of CKD. Senescent renal tubular cells, fibroblasts, endothelial cells, and podocytes have been detected in the kidneys of patients with CKD and animal models. Nonetheless, although accumulated evidence supports the essential role of cellular senescence in CKD, the mechanisms that promote cell senescence and how senescent cells contribute to CKD remain largely unknown. In this review, we summarize the features of the cellular senescence of the kidney and discuss the possible functions of senescent cells in the pathogenesis of kidney fibrosis. We also address whether pharmacological approaches targeting senescent cells can be used to retard the the progression of kidney fibrosis.
Humans ; Cellular Senescence/physiology* ; Fibrosis ; Renal Insufficiency, Chronic/pathology* ; Kidney/pathology* ; Animals

BACKGROUND

Hepatitis B virus causes life-threatening chronic liver infection and increases the risk of death from cirrhosis and liver cancer. A three-dose series of universal HBV vaccination initiated from birth is effective against the disease. It is unclear if catch-up vaccination is also effective in those with incomplete or no HBV vaccination.

To review the evidence on the effect of HBV catch-up vaccination on children and adults to decrease HBV-related morbidity.

We searched MEDLINE, Cochrane CENTRAL, ChinaXiv, MedRXIV, BioRXIV, Google Scholar, and ongoing and completed trials on USA: https://clinicaltrials.gov/; China: http://www.chictr.org.cn/searchprojen.aspx, and WHO: https://www.who.int/clinical-trials-registry-platform. The last search date was 30 June 2023. We considered experimental or observational studies, meta-analysis/systematic reviews, completed trials and preprints that investigated the efficacy of catch-up HBV immunization in decreasing morbidity from hepatitis B infection including acute and chronic hepatitis B infection, liver cirrhosis, and hepatocellular carcinoma. There was no age and language restriction. Two reviewers independently rated the quality of included studies using Newcastle – Ottawa Quality Assessment Scale for cohort and crosssectional studies. GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach was used to determine the certainty of evidence. Data was presented as number (%) for categorical values. Differences between the unvaccinated and vaccinated group was described as relative risk or odds ratio for categorical variables. Data was pooled using Review Manager 5.4.

A total of four observational studies were included, one of which had data in children and adults [two (one with data in adults) studies in children; 3 in adults]. The cross-sectional study was assessed as good quality; and the three cohorts as fair to good. In children, a high certainty evidence study showed that catch up vaccination in 9 to 18 years old decreased risk of HBsAg positivity [RR: 0.09 (0.004, 0.21)], reduced HBV DNA detection [RR: 0.084 (0.026, 0.273)], and increased antiHBs seroconversion [RR: 2.08 (1.84, 2.33)]. The quality of evidence was deemed high based on a large treatment effect. Another low certainty evidence study in Italy showed that HBV mass immunization in 0-10 years old decreased the prevalence of HBsAg anti-HBc and increased anti-HBs seroconversion after vaccination.

In adults, three low certainty evidence studies were included. Two studies showed decreased incidence of acute hepatitis B [OR: 0.08 (0.05, 0.12), I2 = 33%]. Another study demonstrated a decreased prevalence of hepatocellular carcinoma with HBV vaccination with the incidence ratio of vaccinated with chronically infected at 0.04 (0.02, 0.07) showing a large magnitude of benefit for vaccination against HCC when chronic HBV infection is prevented. The studies were deemed to have low quality due to issue of directness and study design.

HBV catch-up vaccination in adults is effective in decreasing the prevalence of acute hepatitis B and hepatocellular carcinoma. It likewise decreased the prevalence of HBsAg and anti-HBc, and provided anti-HBs protection in 0 to 18 years.