Elevated Alkaline Phosphatase Research Articles

Functionalization of titanium using KR-12 peptide: antibacterial and osteogenic properties

Titanium implants are widely used in orthopedic and dental applications owing to their biocompatibility and mechanical stability. Nonetheless, they encounter significant challenges pertaining to infection and poor osteointegration. We investigated the feasibility of two different coating strategies for titanium with the antimicrobial peptide KR-12: direct binding by way of carbodiimide chemistry and indirect attachment through a polydopamine (PDA) layer, comparing these approaches in a comprehensive study. This study assessed the immobilization efficiency, antibacterial efficacy, and osteogenic capability of both coating techniques. The findings indicated that PDA-mediated immobilization achieved greater KR-12 binding efficiency (36.80%) compared with direct covalent binding (24.08%) and enhanced antibacterial effectiveness against Staphylococcus aureus, with colony counts decreasing by 98% for the Ti-PDA-KR12 group and by 95% for the Ti-KR12 group compared with the control group. In vitro investigations utilizing rat bone marrow–derived mesenchymal stem cells demonstrated that PDA-KR12-coated surfaces markedly enhanced cell adhesion, proliferation, and osteogenic differentiation, as indicated by elevated alkaline phosphatase activity, osteocalcin synthesis, and upregulation of osteogenesis-associated gene markers. Our findings indicate that PDA-mediated peptide immobilization is a superior approach for augmenting both the antibacterial characteristics and osteogenic potential of titanium implants, presenting a possible method to enhance implant performance.

The Role of [18F]FDG PET and Clinicopathologic Factors in Detecting and Predicting Bone Marrow Involvement in Non-Hodgkin Lymphoma

Background/Objectives: This study evaluates the diagnostic accuracy of [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) using bone marrow biopsy (BMB) and clinical follow-up as reference standards. It further identifies predictive factors for bone marrow involvement (BMI) in non-Hodgkin lymphoma (NHL) patients. Methods: NHL patients who underwent [18F]FDG PET and BMB at diagnosis in a tertiary cancer center were included in this study. Diagnostic accuracy was analyzed, and logistic regression was performed to identify BMI predictors using Stata software version 17. A retrospective analysis of 262 NHL patients was conducted. Results: Concordance rates between [18F]FDG PET and BMB and between [18F]FDG PET and clinical follow-up were 75.6% and 88.1%, respectively. The primary cause of discordance between [18F]FDG PET and BMB was the detection of extra-iliac focal hypermetabolic bone marrow lesions by [18F]FDG PET, which were negative on BMB. The sensitivity, specificity, and accuracy of [18F]FDG PET were 62.9%, 80%, and 75.6%, respectively, with BMB as a reference, and 74.1%, 97.5%, and 88.2%, respectively, with clinical follow-up as a reference. The focal bone marrow [18F]FDG pattern was the most reliable indicator of BMI. Univariate logistic regression showed that advanced NHL stage, elevated alkaline phosphatase, thrombocytopenia, leukopenia, and elevated lactate dehydrogenase were significant predictors of BMI. Multivariate analysis revealed advanced NHL stage and thrombocytopenia as clinical predictors. Conclusions: [18F]FDG PET is a reliable tool for assessing BMI, providing comprehensive total-body evaluation and identifying extra-iliac involvement beyond the scope of BMB. The collective interpretation of molecular imaging, clinical, and biochemical factors is crucial for predicting BMI.

Clinical Characteristics of Primary and Overlap Sjögren's Syndrome-Associated Pulmonary Arterial Hypertension: A Multicenter Retrospective Study.

To explore the clinical characteristics and risk factors for adverse outcomes in patients with Sjögren's Syndrome-associated pulmonary arterial hypertension (SS-PAH). A retrospective analysis was conducted on SS-PAH patients diagnosed by right heart catheterization (RHC) between March 2013 and March 2024 across four Chinese medical centers. Patients were categorized into primary SS-PAH (pSS-PAH) and overlap SS-PAH, based on the presence of additional autoimmune diseases. We compared clinical and demographic data, echocardiographic and hemodynamic parameters, treatment strategies, and event-free survival between the groups. Statistical analyses included t-tests, Wilcoxon rank-sum tests, χ2 tests, Fisher's exact tests, and Kaplan-Meier survival analysis. Overlap SS-PAH was most commonly associated with systemic lupus erythematosus (SLE). Compared with pSS-PAH, overlap SS-PAH patients had a lower proportion of WHO functional class III-IV, lower pulmonary vascular resistance (PVR), and higher cardiac index (CI). They also showed higher treatment success rates and better event-free survival. However, overlap SS-PAH patients with primary biliary cholangitis (PBC) or autoimmune hepatitis (AIH) had significantly lower 1-year event-free survival rates, older age, and elevated alkaline phosphatase (ALP) levels. Overlap SS-PAH generally has a better prognosis than pSS-PAH, with improved exercise capacity and milder hemodynamic abnormalities. However, overlap with PBC/AIH is associated with a poorer prognosis. These findings highlight the heterogeneity of SS-PAH and the need for tailored treatment based on underlying autoimmune conditions. NCT05980728, https://clinicaltrials.gov.

Associations between environmental glyphosate exposure and glucose homeostasis indices in US general adults: a national population-based cross-sectional study

As glyphosate’s application becomes increasingly widespread across the globe, its potential adverse effects on humans have garnered growing concerns. Little evidence has revealed the associations between glyphosate and glucose homeostasis. A total of 2094 individuals were recruited from the NHANES 2013–2018. Urinary glyphosate, alkaline phosphatase (ALP), fasting plasma glucose (FPG), fasting insulin, and glycated hemoglobin A1c (HbA1c) were measured. Homeostatic model assessment of beta-cell function (HOMA2-β), insulin resistance (HOMA2-IR), and insulin sensitivity (HOMA2-IS) were assessed. Generalized linear models and mediation analyses were fitted to estimate the potential associations between glyphosate, glucose homeostasis, and ALP. Urinary glyphosate demonstrated a statistically significant positive association with FPG and HbA1c in a linear positive dose–response manner, while showing a linear negative association with HOMA2-β. Each doubling increase in urinary glyphosate was associated with a 1.13%, 1.50%, and − 2.80% alteration in FPG, HbA1c, and HOMA2-β, respectively. Obesity modified the association between urinary glyphosate and glucose dyshomeostasis with stronger associations in obese individuals. In addition, elevated ALP significantly mediated the associations of urinary glyphosate with FPG and HbA1c, with mediated proportions of 9.91% and 20.23%, respectively. Environmental glyphosate exposure was associated with glucose dyshomeostasis, which was more pronounced in obese individuals and was partly mediated by ALP.

A Real-World Pharmacovigilance Study of FDA Adverse Event Reporting System Events for Obeticholic Acid.

Based on the Adverse Event Reporting System (FAERS) data from the US FDA, this study mined the adverse drug reactions of obeticholic acid (OCA) in the real world and provided reference for clinical safe drug use. Adverse event reports for OCA from the second quarter of 2016 to the third quarter of 2023 were extracted. The analysis for adverse reaction signal detection was conducted using reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker methods. A total of 5661 OCA-related adverse event reports were collected, and 105 OCA-related adverse reaction signals were obtained, involving 14 systems, among which 46 new signals were not previously mentioned in the product labeling. Severe adverse event of OCA accounted for a relatively high proportion (1445 cases, 25.53%), among which the number of hospitalization reports was the largest (1042 cases, 18.41%). The top five adverse events were pruritus, fatigue, constipation, elevated blood alkaline phosphatase, and abdominal distention. The top five adverse reaction signals intensity were abnormal blood alkaline phosphatase, abnormal ratio of albumin globulin, spider nevus, combined with abnormal bilirubin, and γ-abnormal glutamyl transferase. Based on the pharmacovigilance study of the FAERS database, it is necessary to strengthen the clinical medication monitoring of OCA, so as to provide reference for effective pharmaceutical monitoring and rational clinical medication.

Elevated liver enzymes and diabetes in the PERSIAN Guilan cohort study.

Diabetes mellitus (DM) is highly consequential to global health among chronic diseases. Due to a limited researches that have examined relationships between liver enzymes and DM, this study aimed to investigate the link between elevated liver enzymes and diabetes among Prospective Epidemiological Research Studies in Iran (PERSIAN) Guilan cohort study (PGCS) population. This cross-sectional study was conducted on 10519 individuals. The demographic and clinical information of the participants was recorded. The changes in alanine aminotransferases (ALT) and aspartate aminotransferases (AST), alkaline phosphatase (ALP), and γ-glutamyltransferase (GGT) were evaluated. IBM SPSS Version 21 was used to analyze the data, with a significance level < 0.05. The frequency of diabetes was 24.1% and was more prevalent in women than men (27.4% vs. 20.2%, p< 0.001). After removing all confederates, patients with elevated ALT, AST, GGT, and ALP levels were 1.27, 1.27, 1.52, and 1.46 times more likely to have diabetes, respectively. The likelihood of developing diabetes rose in correlation with the number of elevated liver enzymes, up to almost 1.77-fold among subjects with three or four increased liver enzymes. Patients diagnosed with diabetes exhibited significantly increased levels of liver enzymes compared to those without diabetes. Also, impairment of three or four liver enzymes demonstrated a positive correlation with an elevated likelihood of DM. This indicates the importance of considering the liver status in the management of the DM population.

NEDD4's effect on osteoblastogenesis potential of bone mesenchymal stem cells in rats concerned with PI3K/Akt pathway.

Neural precursor cell expressed developmentally down-regulated 4 (NEDD4) is an E3 ubiquitin ligase implicated in craniofacial development. Emerging evidence suggests that NEDD4 may down-regulates Akt signaling, a key element of the PI3K/Akt pathway involved in cell differentiation. This study aimed to investigate NEDD4's role in bone mesenchymal stem cells (BMSCs) differentiation and its interaction with the PI3K/Akt pathway. BMSCs were isolated from SD rats, and NEDD4 expression increased during osteogenic differentiation. Silencing NEDD4 with siRNA elevated alkaline phosphatase (ALP), osteocalcin (OCN), Akt, and mTORC1 expression during induction, while subsequent treatment with LY294002 (a broad spectrum PI3K inhibitor) reduced Akt, mTORC1, ALP, and OCN levels. These findings suggest that NEDD4 may inhibit BMSCs differentiation by suppressing the PI3K/Akt pathway during osteogenesis.

Prevalence of Vitamin D Deficiency With Biochemical Abnormalities in Children Undergoing Vitamin D Testing.

Vitamin D deficiency (VDD) in children can cause hypocalcaemia and rickets, but the prevalence of these complications and the 25-hydroxyvitamin D (25OHD) concentrations below which they arise is uncertain. We investigated this in children (< 18 years) with 25OHD measurements. We obtained 25OHD results from the regional laboratory database, alongside albumin-adjusted serum calcium (aCa), parathyroid hormone (PTH) and alkaline phosphatase (ALP) within 6 months of the index 25OHD. We defined confirmed VDD with biochemical abnormalities (VDDba) as all of low aCa, elevated PTH and elevated ALP. Possible/potential VDDba were defined as 2/3 VDDba criteria with the third test missing (possible), or in the normal range (potential). Clinical records of identified cases were reviewed, and a consensus diagnosis was reached. A total of 30,663 25OHD measurements were identified over 11.5 years (1 January 2009 to 15 June 2020); mean age 8 y, 47% female. After excluding ineligible results, 12,858 25OHD measurements from 9516 individuals with ≥ 2 aCa, PTH and ALP were analysed. Median 25OHD was 61 nmol/L; 36% < 50 nmol/L, 10% < 25 nmol/L. In total, 152 index 25OHD measurements were categorised as VDDba (30 confirmed, 23 possible and 99 potential). Following record review, 118 individuals (111 < 3 years) had 120 clinically confirmed VDDba episodes (62 clinical rickets, 15 biochemical rickets, 16 hypocalcaemia, 23 secondary hyperparathyroidism and 4 partially treated rickets). Fifty-six had undetectable 25OHD, and 104 < 25 nmol/L. The proportion of clinically confirmed VDDba was 0.9% for all eligible 25OHD measurements, and 8% for 25OHD < 25 nmol/L. VDDba is uncommon in children undergoing 25OHD testing, and occurs almost entirely in children < 3 years.

Outcomes and molecular profiles in sarcomatoid carcinoma of unknown primary: the Mayo Clinic experience.

Sarcomatoid carcinomas (SC) are rare tumors with both epithelial and mesenchymal characteristics, linked to aggressive behavior and poor prognosis. Sarcomatoid carcinoma of unknown primary (SCUP) is an exceedingly rare subset with limited literature and no standardized management guidelines. This study aims to characterize the clinical presentations, treatment patterns, and genomic landscape of SCUP. Data were retrospectively collected from the Mayo Clinic Rochester Cancer of Unknown Primary Registry. Patients included had biopsy-proven SC with no identifiable primary tumor despite comprehensive diagnostic evaluations. Baseline characteristics, immunohistochemistry (IHC) results, next-generation sequencing (NGS) data, and treatment outcomes were analyzed. Statistical analyses included descriptive statistics, Kaplan-Meier survival estimates, and Cox proportional hazards regression. Fifty-two SCUP patients were identified, with a median age of 60 years. Most patients presented with widely metastatic disease, particularly lytic bone lesions. Elevated alkaline phosphatase (ALP) was noted in nearly half of the patients. IHC showed high positivity for AE1/AE3 and OSCAR antibodies. Tumor NGS revealed 247 alterations, with TP53 being the most common mutation. Patients receiving definitive therapy had a median overall survival (OS) of 72 months, significantly longer than those receiving systemic therapy (14 months). Immunotherapy was a significant prognostic factor, reducing the risk of death by 90%. This study provides essential insights into the clinical and genomic characteristics of SCUP, advocating for the integration of definitive therapy and immunotherapy in treatment protocols. Further prospective studies are needed to validate these findings and improve patient outcomes.

Assessment of Trace elements (Zinc, Copper) in Iraqi Patients with Chronic Kidney Disease on Dialysis

Background: In the context of insufficient healthcare accessibility for a substantial segment of the global populace, chronic kidney disease (CKD) has emerged as a significant contributor to mortality, ranked subsequent to cardiovascular disease and neoplasia, demonstrating a notable increase over the preceding two decades. This rising burden of CKD is further exacerbated by a deficient understanding of its underlying pathogenesis. Therefore, it was important to study all the variables in the human body that contribute to monitoring the patient's condition or preventing the patient's condition from deteriorating. In this study, we highlighted some trace elements (zinc and copper), and monitored the change in these elements between patients and healthy people. We indicated the possibility of monitoring the results of tests for these elements to predict the condition of patients from the first stage to the final stages of chronic renal failure patients on dialysis. purpose: To assess the trace elements (zinc, copper) in Chronic kidney disease patients compared with healthy control. Methods: A total forty (40) patient with chronic kidney disease were studied among them twenty (20) female and twenty (20) male patients and forty (40) healthy as control of them were eighteen (18) females and twenty-two (22) males. Their ages (patients and controls) were ranged from (18 – 70). Blood samples were collected from patients and control to evaluate serum levels of serum trace elements (zinc, copper) and evaluate the routine markers (urea, creatinine, Alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase) and this was done by spectrophotometry. Results The Zinc levels in the patients (80.69±51.30 μg/dl) were lower than in the control group (97.42±38.61 μg/dl) (p=0.10773) and The Copper levels in the patients are significantly higher (116.33±71.20 μg/dl) than in the control group (74.77±46.16 μg/dl) (p=0.00304). while The Alanine Aminotransferase and Aspartate Aminotransferase levels in the patients are lower than in the control group, but the difference is not statistically significant for ALT (p=0.13235) and is significant for AST (p=0.02982). the Alkaline Phosphatase, Urea, and Serum Creatinine levels in the patients were all significantly higher than in the control group (p&lt;0.00001 for all). Conclusion: A notable elevation in alkaline phosphatase and copper levels is observed in chronic kidney disease patients, alongside a modest decrease in serum zinc in those with end-stage chronic kidney disease compared to healthy individuals, indicating these biomarkers' potential diagnostic utility in advanced stages of the disease. The correlation between AST/ALT and CKD progression highlights the impact of liver enzyme alterations during chronic kidney disease.

Chemical Profiling, In-Silico Investigation and In Vivo Toxicity Assessment of Lacatomtom (A Psychoactive Mixture) on Selected Indices in Albino Wistar Rats

Introduction/Objective: The use of lacatomtom (LTT), a psychoactive mixture of tomtom (TT) candies with lacasera (LC) beverage, has recently increased among young Nigerians and Africans. There isn't much scientific study on the constituent and effects of this psychoactive substance. Methods: Herein, LTT was chemically-profiled using GCMS analysis, and the toxicological effects were examined in albino rats. In vivo experiment consists of five groups of six rats each (group 2 - LTT ad libitum; groups 1, 3, &amp; 4 - TTT, TT, LC (1 mL) mg/mL kg/body weight once/day respectively, group 5 - distilled water ad libitum). Identified constituents were examined against human monoamine oxidase (hMOA) and human catechol O-methyltransferase (hCOMT) using in silico methods. Results: Forty-seven chemical compounds were identified. Ad libitum intake of LTT elevated plasma alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, creatinine, total cholesterol, and LDL-cholesterol levels. The docked poses, binding scores, and interactions with amino acids informed the selection of (4-Methoxymethoxy-hex-5-ynylidene)-cyclohexane (MM) (-9.4 kcal/mol) and 3-(hydroxyphenylmethyl)-3,4-dimethyl-1-phenylpentan-2-one (HP) for hCOMT (- 9.4 kcal/mol), while propionylcodeine (-10.1 kcal/mol) and HP (-8.9 kcal/mol) for hMOA. Topdocked compounds (TDC) demonstrated the potential to permeate the blood-brain barrier. TDC was predicted to be a positive substrate of the P-glycoprotein and presents inhibitory potential for cytochrome P450 descriptors. HP was mutagenic and could induce human hepatotoxicity and druginduced liver injury, while propionylcodeine had a human hepatotoxic prediction. Conclusion: The present study, for the first time, confirmed the potential toxicity of lacatomtom to the liver, kidney, heart, and central nervous system supported by the identified top-docked compounds regarded as potential psychoactive constituents of hMOA and hCOMT.

Clinico-Pathological Evaluation of Critically Ailing Dogs with Special Reference to Thrombocytopenia

Background: Thrombocytopenia is the decrease in the number of platelets in blood. In dogs, thrombocytopenia occurs due to a multitude of aetiologies such as haemoprotozoal infections, bacterial infections, viral infections, non-infectious etiologies such as immune dysregulation, neoplasia and even due to miscellaneous conditions. Diagnosis of thrombocytopenia is done mostly by estimation of platelet count in automated haematology analysers and by evaluation of platelet count in blood smears. As clinical research focusing exclusively on canine thrombocytopenia is very limited in India, the present study was carried out to study the aetiology of canine thrombocytopenia and to obtain extensive information regarding qualitative and quantitative changes in platelets in various emergency conditions of dogs. Methods: 450 dogs were diagnosed with thrombocytopenia based on platelet count and a detailed investigation was carried out on the thrombocytopenic dogs to identify the aetiologic agents and to record the quantitative and qualitative changes in platelets. Result: Population incidence of thrombocytopenia in critically ill dog population was recorded as 34.09 per cent. Haemoparasitic infection, renal disorders, hyperthermia and sepsis were recorded as the major causes of thrombocytopenia. Haematobiochemical investigation revealed a significant reduction (p less than 0.01) of hemoglobin, RBC and PCV values and elevation in blood urea nitrogen (BUN), creatinine, alkaline phosphatase (ALP), total bilirubin, direct bilirubin and phosphorus. A mortality of 10.67% (48/450) was recorded in the thrombocytopenic dogs.

Alkaline phosphatase is associated with vascular depression in patients with severe white matter hyperintensities.

Cerebrovascular disease (CVD) poses a substantial risk for depression. Elevated levels of alkaline phosphatase (ALP) serve not only as an independent predictive factor for acute cerebrovascular events and unfavorable prognoses but also as a significant predictor of depression in premenopausal women. Nevertheless, the association between elevated ALP levels and vascular depression (VDe) in patients presenting with white matter hyperintensities (WMHs) remains unclear. In a cross-sectional survey, 265 individuals diagnosed with CVD were incorporated. Baseline demographic information, fasting blood parameters, and MRI data were systematically gathered for analysis. All patients were divided into a severe WMHs (sWMHs) group and a mild WMHs (mWMHs) group based on their Fazekas score. Univariate analysis of potential variables among different subgroups of patients with scores of Hamilton Rating Scale for Depression (HAMD) was performed. Subsequently, the diagnostic effectiveness of multivariables for positive VDe within two WMHs groups was assessed using binary logistic regression. The diagnostic capability of the multivariate approach for VDe was further scrutinized through ordinal logistic regression. (1) Hypersensitivity C-reactive protein (hs-CRP, p = 0.031), high-density lipoprotein cholesterol (HDL-C, p = 0.038), apolipoprotein A1 (APOA1, p = 0.009), and ALP (p = 0.011) exhibited distinct expression in patients with mWMHs across varying HAMD scores. In contrast, erythrocyte counts (p = 0.024), hemoglobin (Hb, p = 0.011), hs-CRP (p = 0.002), and ALP (p = 0.021) displayed differential expression in patients with sWMHs across different HAMD scores. (2) ALP and hs-CRP combined with APOA1 or Hb can improve the diagnostic efficiency of positive VDe in sWMHs [AUC = 0.849, 95% CI (0.753, 0.946), p < 0.001] or mWMHs [AUC = 0.718, 95% CI (0.603, 0.834), p = 0.002] patients, respectively. (3) Alkaline phosphatase (ALP) [OR = 1.016, 95% CI (1.003, 1.028), p = 0.016] is correlated with VDe in patients with sWMHs, a relationship that persisted even following adjustments for age and sex. The amalgamation of multiple markers enhances the diagnostic efficacy of VDe through WMHs classification. Serum ALP is associated with VDe in sWMHs patients.

Genetic, Clinical, and Biochemical Characterization ofa Large Cohort of Palestinian Patients With Fanconi-Bickel Syndrome.

This study aims to investigate the clinical, biochemical, and genetic characteristics of Fanconi-Bickel syndrome (FBS) in a cohort of 20 individuals from Palestine and to identify novel pathogenic variants. A retrospective analysis was conducted on medical records from Al-Makassed Hospital's pediatric department spanning 2015 to 2023. Individuals diagnosed with FBS via molecular genetic testing were included in the study. Among the 20 genetically confirmed FBS patients, hepatomegaly was prevalent in 95%, whereas 70% exhibited both developmental delay and hypophosphatemic rickets, and 68.4% experienced growth retardation. Hypertriglyceridemia (HTG) was universal. Elevated liver enzymes and alkaline phosphatase were common, along with hypophosphatemia (95%) and urinary abnormalities. Genetic analysis revealed five distinct SLC2A2 pathogenic variants, including three previously unreported variants: p.Gln23Arg (c.68A > G), p.Thr353Arg (c.1058_1059delinsGG), and an exon 7 deletion. This study presents the largest single-center cohort of FBS patients, expanding our understanding of the disorder's phenotypic and genotypic spectrum. Despite FBS generally carrying a favorable prognosis, timely diagnosis remains crucial to prevent severe complications.

REVISÃO DE LITERATURA: MANEJO DO PACIENTE COM COLANGITE ESCLEROSANTE PRIMÁRIA

The primary sclerosing cholangitis (PSC) is a progressive, idiopathic, immune mediated disease, characterized by intra or extrahepatic cholestasis, Inflammation and fibrosis of the bile ducts, which may progress to liver cirrhosis or cholangiocarcinoma (CCA) in the vast majority of patients. Objective: Analyze what the current literature discusses about the management of PSC. Method: A systematic review was carried out using the PubMed and SciELO database, applying the descriptors "Primary Sclerosing Cholangitis" AND "Cholangite" AND "Clinical management" AND Cholangiocarcmoma. Discussion: It is more common in men, with an average diagnosis at 35 years old. The PSC has a wide range of symptoms and stages of the disease. In the beginning, symptoms are rare and patients may be asymptomatic. The most commonly found symptoms are pruritus, fatigue, right upper quadrant abdominal pain, jaundice, fever, and weight loss. In about 75% of patients with PSC, liver function tests are chronically abnormal and fluctuating with a most commonly found pattern of cholestatic condition with elevation of alkaline phosphatase (AF) and yglutamyl transferase (GGT). Although endoscopic retrograde cholangiopancreatography (ERCP) is conventionally considered the gold standard test for the diagnosis of PSC, the main modality of choice currently for Imaging diagnosis in patients with suspected PSC is magnetic resonance cholangiopancreatography (CPRM). Due to the absence of effective medical therapy for PSC, liver transplantation (LT) remains the only curative option. There is little evidence for the use of medications as a way to inhibit the progression of the disease. Still several new drugs are under investigation, representing the potential to improve survival and clinical outcomes in PSC. Final considerations: We conclude that it is extremely important to approach the management of PSC. The diagnosis is a great challenge since its clinical, laboratory and imaging aspects overlap, as it was portrayed during this exposure. Nevertheless, due to the various differential diagnoses ofjaundice with cholestatic pattern, the etiological search is crucial and the absence of effective medical therapy, with several new drugs under analysis, should guide further studies to improve the survival and clinical outcomes of these patients. Another point to be considered is that there is a scarcity of data in the literature that address the PSC in the Brazilian population.

CTNI-26. A PHASE II STUDY OF SACITUZUMAB GOVITECAN IN RECURRENT GLIOBLASTOMA

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive and common form of primary brain cancer. GBM expresses trophoblast cell-surface antigen 2 (Trop2) which correlates with proliferation rate, microvessel density, histological grade and clinical survival. Sacituzumab Govitecan (SG) is an antibody-drug conjugate targeting Trop2 with a chemotherapy payload, SN-38. This drug has been approved for triple-negative and hormone-receptor positive metastatic breast cancer. METHODS We conducted multi-center (UT Health San Antonio, Cleveland Clinic, Texas Oncology in Austin), open-label, single-arm phase 2 study using a 2-stage adaptive Bayesian design. Patients with recurrent GBM (rGBM), IDH wild-type, following standard-of-care chemoradiation, received SG (10mg/kg IV, days 1 and 8 every 21 days). Patients were assessed by RANO and CTCAE v5. The primary endpoint was PFS of patients on SG as compared to a historical control of lomustine. RESULTS As of interim analysis cutoff, 24 patients have been screened with 20 patients enrolled. The average age was 58.8 years. 65% of patients identified as male. 95% were Caucasian with 20% identifying as Spanish, Hispanic or Latino. Adverse events (AE) include lymphopenia (40%), neutropenia (40%), hypokalemia (35%), elevated alkaline phosphatase (30%), anemia (30%) with most AE being grade ≤ and no grade 5 observed. 4 patients had grade ≥3 neutropenia attributable to SG. 20% had stable disease as best response with the rest being progressive disease. The mean PFS and OS were 7.0 and 2.0 months, respectively. Of 19 evaluable samples, 63% had positive Trop2 expression (H-Score ≥100, mean 123.6±74 [0.6, 269.2]). A post-hoc analysis of OS log survival time vs H-Score (n=19) using an accelerated failure time model showed that survival correlated with H-Score (p=0.0361). CONCLUSIONS In the interim analysis of this study of patients with rGBM, Sacituzumab was found to be well-tolerated. Further study of those patients bearing tumors with elevated H-scores may be warranted.

Prognostic Impact of a Histologic Grading Scheme in Dogs Diagnosed With Rib Chondrosarcoma.

Data regarding the outcome of canine rib chondrosarcoma is sparse and varied. While grade of tumour is associated with outcome for canine appendicular chondrosarcoma, the association of grade with outcome for canine rib chondrosarcoma is unclear. This study aimed to correlate the grade of canine rib chondrosarcoma with median survival time. Retrospectively, cases of primary rib chondrosarcoma were identified, and tumours were graded based on a 3-tier adapted human grading scheme. Twenty-two patients were included in the survival analysis. The median survival time was 1427 days (range: 27-3354 days). This was not significantly different for patients with grade I versus II versus III (p = 0.82), grade I-II versus III (p = 0.34), or grade I versus II-III (p = 0.49). No variables assessed including age, weight, tumour location (cranial vs. caudal thorax; left vs. right hemithorax), tumour location on rib (proximal, middle, and distal), radiographic appearance (lytic, proliferative, or mixed), elevated serum alkaline phosphatase activity, grade, grade specific histologic features (matrix production, architecture, pleomorphism, cellularity, necrosis, and total score), adjunct therapy post-surgical excision, development of metastatic disease post-surgery, or local recurrence post-surgery were found to impact the risk of death due to chondrosarcoma. In this limited group of patients, the grading scheme reported here, and the other variables assessed did not appear to offer additional prognostic information. However, this data must be interpreted considering the small sample size and thus low statistical power. Additional studies are needed to determine the true impact of grade on outcome for canine rib chondrosarcomas.

Isolated Alkaline Phosphatase Elevation in Severe Osteoporosis Treatment: Implications of Teriparatide

Isolated Alkaline Phosphatase Elevation in Severe Osteoporosis Treatment: Implications of Teriparatide

Mass spectrometry-based metabolomics reveals metabolism of molnupiravir may lead to metabolic disorders and hepatotoxicity.

Molnupiravir (MO) is a pyrimidine nucleoside anti-SARS-CoV-2 drug. MO treatment could cause mild liver injury. However, the underlying mechanism of MO-induced liver injury and the metabolic pathway of MO in vivo are unclear. In this study, metabolomics analysis and molecular biology methods were used to explore these issues. Through metabolomics analysis, it was found that the homeostasis of pyrimidine, purine, lysophosphatidylcholine (LPC), and amino acids in mice was destroyed after MO treatment. A total of 80 changed metabolites were detected. Among these changed metabolites, 4-ethylphenyl sulfate, dihydrouracil, and LPC 20:0 was related to the elevation of alkaline phosphatase (ALP), interleukin-6 (IL6), and nuclear factor kappa-B (NF-κB). The levels of 4-ethylphenyl sulfate, dihydrouracil, and LPC 20:0 in plasma were positively correlated with their levels in the liver, suggesting that these metabolites were associated with MO-induced liver injury. MO treatment could increase NHC and cytidine levels, activate cytidine deaminase (CDA), and increase LPC levels. CDA and LPC could increase the mRNA expression level of toll-like receptor (TLR). The current study indicated that the elevation of hepatic TLR may be an important reason for MO leading to the liver injury.

Predicting mortality of type-2 diabetes mellitus by applying machine learning to electronic medical records in the west of scotland and hong kong

Abstract Introduction Type 2 diabetes mellitus (T2DM) is associated with accelerated development of atherosclerosis and a reduced life expectancy. Using machine learning (ML) to identify novel characteristics from electronic medical records (EMRs) associated with prognosis may increase prognostic precision and find new targets for investigation and treatment. Aim We used a novel ML approach to investigate the use of EMRs to predict all-cause mortality in two ethnically and geographically different populations; one from the West of Scotland (WoS) and the other from Hong Kong. Methods We obtained EMRs including demographics, prior comorbidities, laboratory measurements, medications, and mortality. Multivariable Cox regression and time-dependent random forest model were used to identify predictors of all-cause mortality in patients with T2DM. Subsequently, we applied a state-of-the-art ML interpretability method, to gain further insight into the key predictors. Results In WoS, 46,031 individuals received a new diagnosis of T2DM between 2009 and 2019. Their median age was 66 (IQR: 56 to 75) years. Within 10 years, 11,727 (25%) deaths were recorded. In Hong Kong, 273,876 patients with a first-attendance with T2DM at public hospitals or clinics were included, with follow-up until December 2019. The median age of the patients was 64 (IQR: 57 to 72) years. Within 10 years, 91,155 (33%) deaths were recorded. For both cohorts, the strongest predictor for all-cause mortality was prescription of loop diuretics (Figure 1). For the WoS, other important predictors were greater age, lower serum albumin, elevated alanine transaminase (ALT), increased alkaline phosphatase (ALP), and lower estimated glomerular function rate (eGFR) (c-index: 0.83; Brier score: 0.07). For Hong Kong, predictive variables were remarkably similar and included greater age, lower eGFR, lower haemoglobin and lymphocytes, lower serum albumin, and elevated ALP (c-index: 0.85; Brier score: 0.06). Multivariable Cox regression adjusting for age and sex showed a higher mortality amongst those prescribed loop diuretics compared to those who were not (WoS: hazard ratio: 1.549, 95% CI: 1.521 to 1.575; Hong Kong: hazard ratio: 1.745 (95% CI: 1.721 to 1.769). Only a minority of patients prescribed loop diuretics had a diagnosis of heart failure, end-stage renal disease or resistant hypertension. Conclusion Amongst patients with recent-onset T2DM, prescription of loop diuretics was the most important predictor of all-cause mortality in both WoS and Hong Kong. Prescription of loop diuretics might be a pharmacological marker of congestion and undiagnosed heart failure or loop diuretics might have deleterious effects on the outcome of patients with T2DM.Fig 1:Predictors of all-cause Mortality