Surrogate Serum Research Articles

Exercise improves surrogate measures of liver histological response in metabolic dysfunction-associated steatotic liver disease.

Exercise is recommended for the management of metabolic dysfunction-associated steatotic liver disease (MASLD), yet effects on liver histology remain unknown, especially without significant weight loss. We aimed to examine changes in surrogate measures of liver histological response with exercise training. We conducted a post hoc pooled analysis of three randomised controlled trials (duration: 12-20 weeks) comparing aerobic exercise interventions with controls. The primary outcome measure was a ≥30% relative reduction in (MRI-measured) liver fat, as a surrogate measure of liver histological response (the threshold necessary for fibrosis improvement). Secondary outcome measures were changes in other biomarkers of liver fibrosis, anthropometry, body composition and aerobic fitness. Eighty-eight adults (exercise: 54, control: 34; male: 67%) were included with mean (SD) age 51 (11) years and body mass index 33.3 (5.2) kg/m2. Following the intervention, exercise had ~5-fold (OR [95%CI]: 4.86 [1.72, 13.8], p = .002) greater odds of ≥30% relative reduction in MRI-measured liver fat compared with control. This paralleled the improvements in anthropometry (waist and hip circumference reduction), body composition (body fat, visceral and subcutaneous adipose tissue) and aerobic fitness (V̇O2peak, ventilatory threshold and exercise capacity). Importantly, these effects were independent of clinically significant body weight loss (<3% body weight). Exercise training led to clinically meaningful improvements in surrogate serum- and imaging-based measures of liver histological change, without clinically meaningful body weight reduction. These data reinforce the weight-neutral benefit of exercise training and suggest that aerobic training may improve liver fibrosis in patients with MASLD.

Association between food consumption and serum aryl hydrocarbon receptor ligand activity among middle-aged Korean adults.

The diet is an important route of exposure to endocrine-disrupting chemicals (EDCs). However, few studies have investigated the association between dietary intake and EDC exposure levels among Koreans. In an earlier study, we showed that the bioactivity of serum aryl hydrocarbon receptor ligands (AhRLs) could be a surrogate biomarker to indicate exposure to EDCs and that they inhibit mitochondrial function. We also found that the mitochondria-inhibiting substances (MIS) in serum ascertained by intracellular adenosine triphosphate (MIS-ATP) and reactive oxygen species (MIS-ROS) levels could be biomarkers of exposure to EDCs, as they showed a strong correlation with AhRL and the levels of EDCs in the blood. Here, we investigated the association between the consumption of specific foods and surrogate serum biomarkers for EDCs, namely AhRL, MIS-ATP, and MIS-ROS, among middle-aged Korean adults. A total of 1,466 participants aged 45-76 yrs from the Ansung cohort of the Korean Genome and Epidemiology Study were included. Food consumption, including that of meat, fish, vegetables, and fruits, was measured using a semiquantitative food frequency questionnaire. Fish intake was positively associated with AhRL (β = 0.0035, P = 0.0166), whereas cruciferous vegetable intake was negatively associated with AhRL (β = -0.0007, P = 0.0488). Cruciferous vegetable intake was positively associated with the MIS-ATP levels (β = 0.0051, P = 0.0420). A higher intake of fish was significantly associated with an increased risk of high AhRL (tertile: odds ratio [OR], 1.49; 95% confidence intervals (CIs), 1.08-2.06; P for trend = 0.0305). In addition, the second-highest tertile of cruciferous vegetable intake had lower odds of high AhRL than the lowest tertile (OR, 0.73; 95% CIs, 0.54-0.97), although no significant linear trend was observed. Consumption of different types of foods may be differentially associated with EDC exposure in middle-aged Korean adults.

Decreased serum creatinine to cystatin C ratio is associated with low tongue pressure.

Tongue strength plays an important role in the process of food intake, and low tongue pressure has been associated with aspiration pneumonia, cognitive decline, and mortality. However, special equipment for tongue pressure measurement is uncommon in general practice. Recently, the serum creatinine-to-cystatin C (Cr/CysC) ratio has been validated as a marker of muscle volume mass. Thus, we aimed to investigate the association of the serum Cr/CysC ratio with tongue pressure in a cross-sectional study. This single-center, cross-sectional study enrolled 73 participants (mean age, 71.7 years; men, 49.3%) who regularly attended the hospital for treatment of chronic disease. A tongue pressure of <30 kPa was defined as low tongue pressure. We evaluated the relationships between the serum Cr/CysC ratio and tongue pressure using multiple regression analysis. The serum Cr/CysC ratio was correlated with tongue pressure (R2 = 0.25, P < 0.0001). In multiple regression analyses adjusted for confounders including age, sex, body mass index, and serum albumin, the association remained significant (P = 0.0001). In logistic analyses, the multivariable-adjusted odds ratios of the Cr/CysC ratio for tertiles 1 and 2 compared with tertile 3 for low tongue pressure were 7.81 (95% confidence interval, 1.45-51.73) and 2.71 (95% confidence interval, 0.60-13.19), respectively. We demonstrated that a decreased serum Cr/CysC ratio was associated with a higher risk of low tongue pressure. Our findings suggest that this simple serum surrogate marker may be a first step toward an intervention for oral function by general practitioners. Geriatr Gerontol Int 2024; 24: 102-108.

OA16 Identification of surrogate serum proteomic biomarkers associated with ultrasound power Doppler in psoriatic arthritis

Abstract Background/Aims An area of key unmet need in psoriatic arthritis (PsA) is the identification of biomarker(s) which predict those likely to respond to a specific therapy; in order to achieve that, an objective measure of disease activity would be ideal. Ultrasound power Doppler (PD) is a semi-quantitative measure of inflammation. However, ultrasound is time-consuming and requires specific expertise, whereas a blood-based surrogate biomarker of PD would be easier to apply clinically, and could serve as an objective outcome measure of response. Our aim is to identify proteomic biomarkers associated with PD in PsA patients. Methods Twenty-six patients with PsA (fulfilling CASPAR criteria) were recruited prospectively. All underwent 66-joint ultrasound examination and presence of PD was recorded. There were 7 patients without PD(-) and 19 with PD(+) detectable in at least 1 joint. Proteomics data for 1,073 proteins were generated using sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH MS). Proteins with high levels of missing data were filtered (&amp;gt;30%) followed by random forest analysis. Differentially expressed proteins (DEPs) based on PD status were identified. Protein-protein interaction network analysis was performed using the search tool for retrieval of interacting genes (STRING), Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO). Results Following pre-processing, 553 proteins were available for analysis. Seventeen DEPs were identified (p-values &amp;lt;0.05) (Table 1). Among these, ERAP2, an enzyme involved in MHC-I ligand processing and a known risk factor for inflammatory diseases, had the largest fold change (-0.64 95%CI -1.20 to -0.07, p = 0.03). Network analysis revealed that the 17 DEPs were significantly enriched (p &amp;lt; 0.001) in the PD+ group. KEGG pathway analysis identified the association of the DEPs in leukocyte transendothelial migration (strength 1.5 FDR=0.04). GO analysis of the DEPs revealed involvement in immunoglobulin receptor binding (strength 2.28 FDR=0.03). Conclusion We identified several potential serum proteomic biomarkers correlated with disease activity, as assessed by the presence of PD, in PsA; these provide insights into the biological mechanisms underlying synovitis in PsA. Validation in a larger cohort and functional studies are required to determine the role of these proteins in mediating inflammation in PsA. Disclosure R.M. Hum: None. N. Nair: None. S.F. Ling: None. A. Barton: None. P. Ho: None. D. Plant: None.

Tailoring the clinical management of colorectal cancer by 18F-FDG PET/CT.

Colorectal cancer (CRC) is among the most commonly diagnosed gastrointestinal malignancies worldwide. It is inadequate to handle in terms of staging and restaging only based on morphological imaging modalities and serum surrogate markers. And the correct and timely staging of CRC is imperative to prognosis and management. When compared to established sequential, multimodal conventional diagnostic methods, the molecular and functional imaging 18F-FDG PET/CT shows superiorities for tailoring appropriate treatment maneuvers to each patient. This review aims to summarize the utilities of 18F-FDG PET/CT in CRC, focusing on primary staging, follow-up assessment of tumor responses and diagnostic of recurrence. In addition, we also summarize the technical considerations of PET/CT and the conventional imaging modalities in those patients who are either newly diagnosed with CRC or has already been treated from this cancer.

The Differential Systemic Biological Effects between Computer Navigation and Conventional Total Knee Arthroplasty (TKA) Surgeries: A Prospective Study

Distal femur reaming-free total knee arthroplasty (TKA) was reported to possess lower risk of acute myocardial infarction (AMI) or venous thromboembolism (VTE) than conventional TKA in a retrospective population-based study. We tried to offer prospective biological evidence by comparing the levels of AMI and VTE serum surrogate markers among the patients undertaking navigation and conventional TKAs to support these observations. Thirty-four participants undertaking navigation TKA and 34 patients receiving conventional TKA were recruited between February 2013 and December 2015. Blood samples were drawn from all participants before TKA, and 24 and 72 h after TKA, to assess the concentration of soluble P-selectin, matrix metalloproteinase-9 (MMP-9), C-reactive protein (CRP), and interleukin-8 (IL-8) between the participants undergoing navigation and conventional TKAs. We showed that significantly lower serum levels of soluble P-selectin 24 h after, as well as CRP 24 and 72 h after TKA could be observed in the navigation cohort. The more prominent surge of serum soluble P-selectin and CRP were perceived 24 and 72 h after TKA among the participants undergoing conventional TKA. Based upon our prospective biological evidence, the merits of navigation TKA are strengthened by lower levels of AMI and VTE serum surrogate markers.

Efficacy and safety of fenofibrate addition therapy in patients with cirrhotic primary biliary cholangitis with incomplete response to ursodeoxycholic acid.

Fenofibrate (FF) has shown potential benefits in patients with primary biliary cholangitis (PBC) who have an incomplete response to ursodeoxycholic acid (UDCA). However, the efficacy and safety of FF in patients with cirrhosis remain unclear. To evaluate the efficacy and safety of additional FF therapy in patients with PBC-related cirrhosis with an incomplete response to UDCA, we conducted a retrospective analysis comparing the clinical results of additional FF therapy and continued UDCA monotherapy. A total of 59 patients were included; 27 cases underwent UDCA monotherapy and 32 cases underwent UDCA combined with FF therapy. A significant difference in alkaline phosphatase (ALP) normalization was achieved in the FF group compared to the UDCA group (37% vs. 11%, respectively; p=0.020). Additional FF therapy was an independent risk factor for ALP normalization (hazard ratio, 7.679; 95% confidence interval, 2.059-28.633; p=0.003). Hepatic deterioration was experienced by 40% versus 48% (p=0.562) while 11% vs. 37% (p=0.111) experienced liver-related mortality or liver transplantation in the FF and UDCA groups, respectively. Compared to UDCA monotherapy, additional FF therapy was associated with lower United Kingdom (UK)-PBC risk score and surrogate serum indices of liver fibrosis. After 12 months of add-on FF therapy, median ALP level and UK-PBC risk score decreased 35% and 52% from baseline (p=0.001 and 0.210, respectively). Serum aminotransferase, triglyceride, and cholesterol decreased progressively, while total bilirubin, serum creatinine, blood urea, estimated glomerular filtration rate, aspartate aminotransferase-to-platelet ratio index, and fibrosis-4 index remained stable in FF-treated cirrhotic cases during follow-up. No significant adverse effects associated with additional FF therapy were observed in our cohort. Conclusion: Additional FF therapy was associated with higher ALP normalization rates and lower UK-PBC risk scores in patients with cirrhotic PBC with an incomplete response to UDCA. In addition, FF therapy seemed safe and well tolerated with a low frequency of adverse effects in patients with cirrhosis.

Serum Insulin-Like Growth Factor-1 (IGF-1) Age-Specific Reference Values for Healthy Adult Population of Serbia.

Insulin-like growth factor-1 (IGF-1) is main serum surrogate marker of growth hormone (GH) secretion, used in diagnostics and treatment of GH deficiency (GHD) and acromegaly. Regional, ethnic, racial or nutritional factors obscure cross-population applicability of IGF-1 reference values. Establishment of population- and assay-specific reference values requires sizable representative cohort of healthy subjects. In representative sample of healthy adult population of Serbia (N=1200, 21-80 years, 1:1 male:female) serum IGF-1 was analyzed by Siemens Immulite 2000 assay under uniform laboratory conditions. Upper and lower limit of reference range (5th - 95th percentile) were calculated for each of the 12 quinquennial age intervals. IGF-1 distribution was normalized and standard deviation score (SDS) calculated by Logarithmic and LMS methods. IGF-1 and age correlated significantly, with most prominent decline at 21-50 years, followed by a plateau up to age of 70. Gender differences were not significant overall. Plateau in age-related IGF-1 decline was less prominent in women. Correlations of IGF-1 with body mass index (BMI) or waist to hip ratio (WHR) were insignificant. Superior IGF-1 SDS transformation was achieved with LMS method, while logarithmic method was simpler to use. Normative age-specific serum IGF-1 reference values were established on a representative cohort of healthy adults in Serbia. Our results support recommendations against necessity for gender-specific or BMI- and WHR-specific reference ranges. Population-based data serve to generate IGF-1 SDS, which is valuable in rational application of consensus guidelines, proper longitudinal follow-up, advancement in efficacy and safety and personalization of treatment targets.

1803-P: Antifibrotic Effect of a Novel Long-Acting GLP-1/GIP/Glucagon Triple Agonist (HM15211) in BDL-Induced Liver Fibrosis Mice

Fibrosis due to nonalcoholic steatohepatitis (NASH) remains a major cause of liver-related mortality. However, no medication has been approved despite accelerated drug development. Since multiple biological pathways are involved, strategy simultaneously targeting multiple pathways might be required to effectively treat fibrosis. To address this, we developed a novel long-acting GLP-1/GIP/Glucagon triple agonist, HM15211. Previously, HM15211 significantly improved fibrosis as well as steatosis and inflammation in MCD-diet mice. In addition to the diet-induced models, bile duct ligation (BDL) has also been extensively used as an animal model of fibrosis. Here, we further investigated the anti-fibrotic effects of HM15211 in BDL-induced fibrosis mice. Two days post BDL (single ligation), the mice were administered either with HM152111 or obeticholic acid (OCA) for 2 weeks, followed by histological analysis. HM15211 treatment showed greater reduction in hepatic hydroxyproline (HP) (450.5, 351.7 and 253.6 nmol/g liver for vehicle, OCA and HM15211) and fibrosis score (1.7, 1.8 and 1.0 for vehicle, OCA and HM15211) compared to OCA. Consistently, HM15211, but not OCA, treatment was associated with the reduction of serum surrogate markers of fibrosis including TGF-β (-61.4, 9.1% vs. vehicle for HM15211, OCA), TIMP-1 (-71.6, -13.9% vs. vehicle), and hyaluronic acid (-68.9, 25.0% vs. vehicle). To further clarify its benefits in fibrosis, BDL (double ligation) mice with an extended induction period (up to 2 weeks) was used. Notably, despite the progression to advanced liver fibrosis, HM15211 treatment still attenuated HP (571.5 and 334.3 nmol/g liver for vehicle and HM15211) and fibrosis score markedly. Considering the pathologic features of BDL mice (liver fibrosis without liver fat accumulation), these results demonstrate the direct anti-fibrotic effect of HM15211. Further studies are needed to assess the clinical relevance of these findings. Disclosure J. Kim: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. H. Kwon: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. D. Kim: Board Member; Self; Hanmi Pharmaceutical. S. Bae: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. I. Choi: Board Member; Self; Hanmi Pharmaceutical.

NMR-derived targeted serum metabolic biomarkers appraisal of bladder cancer: A pre- and post-operative evaluation

With high morbidity and mortality, urinary bladder cancer (BC) ranks fifth among common cancers globally. The inherent limitations of urine cytology and cystoscopy, and marginal enhancements in the rate of survival promt us to develop surrogate serum based metabolic biomarkers of screening, identification, and follow-up protocols of management for BC patients. Earlier, we exhibited that abnormal expression levels of dimethylamine (DMA), malonate, lactate, glutamine, histidine, and valine in serum may be used as signature metabolites to differentiate BC from healthy controls (HC) (J. Proteome Res. 2013; 12(12):5839-50). Here we further gauge and validate these observations by comparing pre-operative to post-operative follow-up BC patients. This study was conducted on 160 sera samples involving HC (n = 52), pre-operative (n = 55) and post-operative (n = 53) BC cases. 1H nuclear magnetic resonance (NMR) spectroscopy was used to generate serum metabolic profiles and to gauge aberrantly expressed metabolites. The targeted metabolomic approach revealed that the expression levels of these signature metabolites were progressively and significantly decreased in post-operative follow-up at the interval of 30, 60, and 90 days compared to pre-operative BC sera samples and were maintained at HC levels. Serum metabolic biomarkers appear to be an inspiring and least-invasive tactic for detection and prognosticating BC patient follow-up.

ASCITIC INTERLEUKIN 6 AND SERUM PROCALCITONIN FOR EARLY DETECTION OF SPONTANEOUS BACTERIAL PERITONITIS IN ADVANCED LIVER CIRRHOSIS

Background: Liver cirrhosis is associated with frequent bacterial infections that increase mortality. Spontaneous bacterial peritonitis (SBP) is an important cause of mortality and morbidity in such patients with ascites. A polymorphonuclear (PMN) cell count >250/μl in the ascitic fluid is the current gold standard for diagnosing SBP which is considered a subjective test. Early diagnosis of SBP although vital is difficult in these patients. Interleukin 6 is pro-inflammatory marker that increases earlier in bacterial infection than other inflammatory markers. This is crucial in cirrhotic patients to initiate treatment accordingly.Objective: Evaluate the role of IL 6 together with other inflammatory markers in early diagnosis of SBP and as prognostic markers as well.Patients and methods: The study was conducted on 60 cirrhotic patients with ascites divided into 2 groups. Group I included 30 cirrhotic patients with sterile ascites and group II, 30 patients with SBP. Liver profile, serum creatinine, serum sodium, ascitic IL6 , C-reactive protein, serum pro-calcitonin , and ascitic fluid analysis were done for all patients in both groups. Exclusion criteria included; acute infection, diabetes mellitus, coronary vascular disease, collagen vascular disease and any form of sepsis.Results: Ascitic IL6 mean value was 2171.5(62.2 – 5000) and 342.5(146 – 2567) pg/ml in groups I and II respectively which was significantly higher in group I than among group II patients (P 780 pg/ml and >0.4ng/ml respectively.Conclusion: Ascitic IL6 and serum procalcitonin can be used as a valuable surrogate serum marker for early diagnosis of SBP in cirrhotic patients.

CXCL13 as biomarker for histological involvement in Sjögren's syndrome.

SS is an autoimmune condition characterized by systemic B-cell activation, autoantibody production and ectopic germinal centres' formation within the salivary gland (SG). The extent of SG infiltrate has been proposed as a biomarker of disease severity. Plasma levels of CXCL13 correlate with germinal centres' activity in animal models and disease severity in SS, suggesting its potential use as a surrogate serum marker to monitor local B-cell activation. The aim of this study was to evaluate the potential role of CXCL13 as a biomarker of SG pathology in two independent SS cohorts. 109 patients with SS were recruited at Sapienza University of Rome (Italy) (n = 60), or at Queen Elizabeth Hospital in Birmingham and Barts Health NHS Trust in London (n = 49). Both sera and matched minor SG biopsy were available. Sicca (n = 57) and healthy subjects' (n = 19) sera were used as control. CXCL13 serum level was higher in SS patients compared with controls. Correlations between its serum levels and a series of histomorphological parameters, including size of the aggregates and the presence germinal centres', were observed. Our data foster the use of CXCL13 to monitor the extent of local pathology in SS and its validation in longitudinal clinical studies.

Diagnosis of Bronchial Asthma in Children 3–6 Years Old by Using Serum Periostin and Surrogate Markers of Eosinophilic Inflammation (Blood Eosinophils and Total IgE): a Cross-Sectional Study

Background. It is difficult to diagnose bronchial asthma (BA) in children under the age of 6 due to the limited ability to study respiratory function. Therefore, it is relevant to search for such diagnostic markers of BA that do not require the active participation of a child.Objective. Our aim was to assess the diagnostic value of serum periostin levels in comparison with surrogate markers of eosinophilic inflammation (total IgE and blood eosinophils) for the diagnosis of BA in preschool children.Methods. A cross-sectional study included children 3–6 years of age with BA and healthy peers. The levels of serum periostin (ELISA), total IgE (chemiluminescent method), blood eosinophils (counted on a hematological analyzer) were determined. To study the diagnostic value of peripheral blood parameters ROC-analysis was used.Results. Children with BA (n = 56) compared with the healthy group (n = 29) showed higher levels of serum periostin (median and quartile) — 5.7 (3.4, 8.0) and 2.7 (1, 7; 3.6) ng/ml (p &lt; 0.001), total IgE — 180 (122; 622) and 55 (45; 87) IU/ml (p &lt; 0.001), blood eosinophils — 6.1% (3.8; 8.0) and 3.6% (2.7; 4.1) (p &lt; 0.001). The area under the ROC curve (AUC) for serum periostin was 0.81 (95% CI 0.73–0.89), for total IgE — 0.86 (95% CI 0.77–0.92), for blood eosinophils — 0.77 (95% CI 0.67–0.86). Independent predictors of serum periostin were total IgE and the number of exacerbations of BA over the past 12 months &gt; 2 (R2 = 0.527).Conclusion. The level of serum periostin in preschool children with BA is higher than in their healthy peers. The diagnostic value of serum periostin in BA is in the range from moderate to good and is comparable to that for the levels of blood eosinophils and total IgE.

ACOG Committee Opinion No. 774 Summary: Opportunistic Salpingectomy as a Strategy for Epithelial Ovarian Cancer Prevention.

Opportunistic salpingectomy may offer obstetrician-gynecologists and other health care providers the opportunity to decrease the risk of ovarian cancer in their patients who are already undergoing pelvic surgery for benign disease. By performing salpingectomy when patients undergo an operation during which the fallopian tubes could be removed in addition to the primary surgical procedure (eg, hysterectomy), the risk of ovarian cancer is reduced. Although opportunistic salpingectomy offers the opportunity to significantly decrease the risk of ovarian cancer, it does not eliminate the risk of ovarian cancer entirely. Counseling women who are undergoing routine pelvic surgery about the risks and benefits of salpingectomy should include an informed consent discussion about the role of oophorectomy and bilateral salpingo-oophorectomy. Bilateral salpingo-oophorectomy that causes surgical menopause reduces the risk of ovarian cancer but may increase the risk of cardiovascular disease, cancer other than ovarian cancer, osteoporosis, cognitive impairment, and all-cause mortality. Salpingectomy at the time of hysterectomy or as a means of tubal sterilization appears to be safe and does not increase the risk of complications such as blood transfusions, readmissions, postoperative complications, infections, or fever compared with hysterectomy alone or tubal ligation. The risks and benefits of salpingectomy should be discussed with patients who desire permanent sterilization. Additionally, ovarian function does not appear to be affected by salpingectomy at the time of hysterectomy based on surrogate serum markers or response to in vitro fertilization. Plans to perform an opportunistic salpingectomy should not alter the intended route of hysterectomy. Obstetrician-gynecologists should continue to observe and practice minimally invasive techniques. This Committee Opinion has been updated to include new information on the benefit of salpingectomy for cancer reduction, the feasibility of salpingectomy during vaginal hysterectomy, and long-term follow-up of women after salpingectomy.

ACOG Committee Opinion No. 774: Opportunistic Salpingectomy as a Strategy for Epithelial Ovarian Cancer Prevention.

Opportunistic salpingectomy may offer obstetrician-gynecologists and other health care providers the opportunity to decrease the risk of ovarian cancer in their patients who are already undergoing pelvic surgery for benign disease. By performing salpingectomy when patients undergo an operation during which the fallopian tubes could be removed in addition to the primary surgical procedure (eg, hysterectomy), the risk of ovarian cancer is reduced. Although opportunistic salpingectomy offers the opportunity to significantly decrease the risk of ovarian cancer, it does not eliminate the risk of ovarian cancer entirely. Counseling women who are undergoing routine pelvic surgery about the risks and benefits of salpingectomy should include an informed consent discussion about the role of oophorectomy and bilateral salpingo-oophorectomy. Bilateral salpingo-oophorectomy that causes surgical menopause reduces the risk of ovarian cancer but may increase the risk of cardiovascular disease, cancer other than ovarian cancer, osteoporosis, cognitive impairment, and all-cause mortality. Salpingectomy at the time of hysterectomy or as a means of tubal sterilization appears to be safe and does not increase the risk of complications such as blood transfusions, readmissions, postoperative complications, infections, or fever compared with hysterectomy alone or tubal ligation. The risks and benefits of salpingectomy should be discussed with patients who desire permanent sterilization. Additionally, ovarian function does not appear to be affected by salpingectomy at the time of hysterectomy based on surrogate serum markers or response to in vitro fertilization. Plans to perform an opportunistic salpingectomy should not alter the intended route of hysterectomy. Obstetrician-gynecologists should continue to observe and practice minimally invasive techniques. This Committee Opinion has been updated to include new information on the benefit of salpingectomy for cancer reduction, the feasibility of salpingectomy during vaginal hysterectomy, and long-term follow-up of women after salpingectomy.

Serum GP73 combined AST and GGT reflects moderate to severe liver inflammation in chronic hepatitis B

BackgroundNon-invasive method to identify chronic hepatitis B (CHB) patients with at least moderate inflammatory lesion but no increased ALT is an unmet need.We evaluated Golgi protein 73 (GP73) based hepatic inflammation model (HIM) as a serum surrogate for liver necroinflammatory activity, especially in those with ALT less than traditional upper concentration. MethodsThe diagnostic performances of HIM were evaluated in 2 independent cohorts of liver biopsy proved CHB patients by receiver operating characteristic (ROC) curve analysis. ResultsHIM, a suggested index combined GP73, gamma-glutamyltransferase and AST, could significantly improve the diagnostic accuracy for liver necroinflammation (Area under ROC, AUROC: 0.890). More importantly, HIM still exhibit excellent diagnostic value (AUROC: 0.873) to identify patients with at least moderate liver necroinflammatory activity but with ALT <40 U/l. Serum GP73 was the major source of improvement for diagnostic model's accuracy. ConclusionHIM is probably a promising non-invasive index to identify CHB patients with moderate to severe liver necroinflammation, especially in those with ALT <40 U/l.

Serum hepatitis B core-related antigen (HBcrAg) correlates with covalently closed circular DNA transcriptional activity in chronic hepatitis B patients

It has been proposed that serum hepatitis B core-related antigen (HBcrAg) reflects intrahepatic covalently closed circular (ccc)DNA levels. However, the correlation of HBcrAg with serum and intrahepatic viral markers and liver histology has not been comprehensively investigated in a large sample. We aimed to determine if HBcrAg could be a useful therapeutic marker in patients with chronic hepatitis B. HBcrAg was measured by chemiluminescent enzyme immunoassay in 130 (36 hepatitis B e antigen [HBeAg]+ and 94 HBeAg-) biopsy proven, untreated, patients with chronic hepatitis B. HBcrAg levels were correlated with: a) serum hepatitis B virus (HBV)-DNA, quantitative hepatitis B surface antigen and alanine aminotransferase levels; b) intrahepatic total (t)HBV-DNA, cccDNA, pregenomic (pg)RNA and cccDNA transcriptional activity (defined as pgRNA/cccDNA ratio); c) fibrosis and necroinflammatory activity scores. HBcrAg levels were significantly higher in HBeAg+ vs. HBeAg- patients and correlated with serum HBV-DNA, intrahepatic tHBV-DNA, pgRNA and cccDNA levels, and transcriptional activity. Patients who were negative for HBcrAg (<3 LogU/ml) had less liver cccDNA and lower cccDNA activity than the HBcrAg+ group. Principal component analysis coupled with unsupervised clustering identified that in a subgroup of HBeAg- patients, higher HBcrAg levels were associated with higher serum HBV-DNA, intrahepatic tHBV-DNA, pgRNA, cccDNA transcriptional activity and with higher fibrosis and necroinflammatory activity scores. Our results indicate that HBcrAg is a surrogate marker of both intrahepatic cccDNA and its transcriptional activity. HBcrAg could be useful in the evaluation of new antiviral therapies aiming at a functional cure of HBV infection either by directly or indirectly targeting the intrahepatic cccDNA pool. Hepatitis B virus causes a chronic infection which develops into severe liver disease and liver cancer. The viral covalently closed circular DNA (cccDNA) is responsible for the persistence of the infection in hepatocytes. To better manage patient treatment and follow-up, and to develop new antiviral treatments directly targeting the intrahepatic pool of cccDNA, serum surrogate markers reflecting the viral activity in the liver are urgently needed. In this work, we demonstrate that quantification of hepatitis B core-related antigen in serum correlates with cccDNA amount and activity and could be used to monitor disease progression.

Serum Interleukin-8, Osteopontin, and Monocyte Chemoattractant Protein 1 Are Associated With Hepatic Fibrosis in Patients With Nonalcoholic Fatty Liver Disease.

The severity of hepatic fibrosis is the primary predictor of liver‐related morbidity and mortality in patients with nonalcoholic fatty liver disease (NAFLD). Unfortunately, noninvasive serum biomarkers for NAFLD‐associated fibrosis are limited. We analyzed baseline serum samples for 24 cytokines of 97 patients with biopsy‐proven NAFLD. These patients were prospectively enrolled in a clinical study (ClinicalTrials.gov NCT00794716) to identify cytokines associated with liver fibrosis in patients with nonalcoholic steatohepatitis. Patients were stratified according to severity of hepatic fibrosis (mild, stage 0‐1, n = 37; moderate, stage 2, n = 40; and advanced, stage 3‐4, n = 20) while controlling for age, race, sex, body mass index, and diabetes mellitus. Interleukin‐8 (IL‐8), osteopontin (OPN), and monocyte chemoattractant protein 1 (MCP1) were associated with liver fibrosis (P < 0.001, P = 0.005, P = 0.016, respectively). After controlling for steatosis, lobular inflammation, hepatocyte ballooning, age, sex, body mass index, diabetes mellitus, hypertension, and metabolic syndrome status, IL‐8 remained strongly associated with fibrosis (P = 0.001). Furthermore, IL‐8 was also a strong predictor of increased fibrotic liver injury compared to established markers of hepatic fibrosis. Hepatic gene expression from 72 patients with NAFLD (n = 40 mild fibrosis; n = 32 advanced fibrosis) from the Duke University Health System NAFLD Clinical Database and Biorepository revealed IL‐8, MCP1, and OPN gene expression to be increased and differentially expressed in patients with advanced hepatic fibrosis. Thus, serum IL‐8, MCP1, and OPN may reflect up‐regulated gene expression during liver fibrosis in NAFLD. Conclusion: Serum IL‐8, MCP1, and OPN may serve as a test for advanced hepatic fibrosis in NAFLD and thus reveal novel targets for antifibrotic therapies. The increased serum IL‐8, MCP1, and OPN that correspond with associated hepatic gene expression lend strength to such analytes as ideal surrogate serum biomarkers for severity of hepatic fibrosis.

NEC is likely a NETs dependent process and markers of NETosis are predictive of NEC in mice and humans

Necrotizing enterocolitis (NEC) is one of the most devastating diseases affecting premature and mature infants. It is hypothesized that NEC is the result of neutrophils’ active role in hyperinflammation after bacterial gut colonization, through their nuclear DNA release and formation of neutrophil extracellular traps (NETs) to combat pathogens. The aim of this study was to evaluate the importance of NETs in NEC pathogenesis, as well as to identify and validate markers of NETosis to predict NEC. NEC was induced in mice by gavage feeding of Neocate and lipopolysaccharide, followed by ten minutes of hypoxia (5% O2) q12h for five days, starting on day four postpartum (p.p.). The interrelation of NEC and neutrophils, including NETs, was assessed macroscopically (i.e. NEC score, SYTOX Orange), microscopically (i.e. Chiu score, citrullinated histone H3, neutrophil elastase), and in blood samples (i.e. cell-free DNA (cfDNA), DNase). In order to determine the exact role of NETs in NEC pathogenesis, a protein arginine deiminase (PAD) inhibition model was established (preventing NETs formation in mice) by injecting BB-Cl-amidine once daily, starting on day one p.p. Additionally, human intestinal samples of diagnostically verified NEC were analyzed. In total, 76 mice were analyzed in the experiment. Serum cfDNA correlated positively with NEC manifestation, as measured by macroscopic NEC score (r = 0.53, p = 0.001), and microscopic evaluation with Chiu score (r = 0.56, p < 0.001). Markers of neutrophil activation and NETosis were significantly increased in animals with NEC and in human samples as compared to controls. Further, prevention of NETosis by protein arginine deiminase (PAD) inhibition in mice significantly reduced mortality, tissue damage, and inflammation in mice induced with NEC. Our results suggest that the hyperinflammation observed in NEC is a NETs-dependent process, as NEC severity was significantly reduced in mice incapable of forming NETs (PAD inhibition) and markers for NEC and NETs correlated positively during the time course of NEC induction. Further, serum surrogate markers of NETosis (such as cfDNA and DNase) appear to predict NEC in neonatal mice. As findings of the mouse NEC model correlate positively with human NEC samples immunohistochemically, the hyperinflammation reaction observed in mice could potentially be applied to human NEC pathogenesis.

Influence of Chitosan Treatment on Surrogate Serum Markers of Cholesterol Metabolism in Obese Subjects.

Chitosan treatment results in significantly lower serum low density lipoprotein (LDL) cholesterol concentrations. To assess the working mechanisms of chitosan, we measured serum surrogate markers of cholesterol absorption (campesterol, sitosterol, cholestanol), synthesis (lathosterol, lanosterol, desmosterol), and degradation to bile acids (7α-hydroxy-cholesterol, 27-hydroxy-cholesterol), corrected for cholesterol concentration (R_sterols). Over 12 weeks, 116 obese subjects (Body Mass Index, BMI 31.7, range 28.1–38.9 kg/m2) were studied under chitosan (n = 61) and placebo treatments (n = 55). The participants were briefly educated regarding improvement of nutrition quality and energy expenditure. Daily chitosan intake was 3200 mg. Serum LDL cholesterol concentration decreased significantly more (p = 0.0252) under chitosan (−8.67 ± 18.18 mg/dL, 5.6%) than under placebo treatment (−1.00 ± 24.22 mg/dL, 0.9%). This reduction was not associated with the expected greater decreases in markers of cholesterol absorption under chitosan treatment. Also, increases in markers of cholesterol synthesis and bile acid synthesis under chitosan treatment were not any greater than under placebo treatment. In conclusion, a significant selective reduction of serum LDL cholesterol under chitosan treatment is neither associated with a reduction of serum surrogate markers of cholesterol absorption, nor with increases of markers for cholesterol and bile acid synthesis.