BACKGROUND:The effect of meal fat sequence and excess body fat on postprandial changes in vitamin E absorption is unclear. OBJECTIVES:We investigated postprandial changes in plasma vitamin E enrichment in response to varied dietary fat sequences in healthy women and excess body and liver fat in women with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS:Vitamin E [α-tocopherol (α-T)] pharmacokinetics were assessed using deuterium (d)-labeled α-T administered orally [d3-RRR-α-tocopherol (d3-α-T)] and intravenously [d6-RRR-α-tocopherol (d6-α-T)]. A total of 13 healthy women received oral and intravenous (IV) α-T (30 mg) with a liquid breakfast containing 40% or 0% fat, followed by 30% fat lunch and dinner at 4 h and 8 h, or a 12-h fast (0% fat-fast). A total of 6 women with MASLD and 10 normal weight controls received oral and IV α-T (2 mg) with similar meal sequence. Major outcomes were postprandial plasma α-T %enrichment, maximal concentration (Cmax), and area under the curves (AUCs) at 4, 12, and 24 h. Exploratory outcomes included the second meal effect (SME), defined as mean change in pre-2nd meal compared with post-2nd meal d3-α-T %enrichment at 4 h and 12 h, respectively. RESULTS:At 4-h oral d3-α-T %enrichment, Cmax and AUC0-4 h were not statistically different between 40% and 0% fat groups. Following the 2nd meal at 4 h, SME was 55% higher in the 0% group than in the 40% group (15.8% ± 1.1% compared with 10.2% ± 1.1%, P < 0.009), resulting in greater Cmax and AUC in the 0% group at 12 and 24 h (P < 0.04). Compared with the 0% group, the 0% fat-fast group showed reduced oral d3-α-T %enrichment, whereas no differences were seen with IV d6-α-T %enrichments. Compared with controls, the obese/MASLD cohort had 31% lower SME (0.87% ± 0.1% compared with 1.26% ± 0.1%, P = 0.047), resulting in reduced Cmax and AUC (P < 0.04) at 24 h. CONCLUSIONS:The variation in the meal fat sequence (0%-30% compared with 40%-30% fat) significantly enhanced SME and postprandial d3-α-T %enrichment, whereas obesity/MASLD attenuated SME and postprandial vitamin E %enrichment.

CONTEXT:Tumor volume doubling time (TVDT) is emerging as a useful tool in predicting oncologic outcomes. There are limited data on the prognostic role of TVDT in metastatic medullary thyroid cancer (MTC). OBJECTIVE:The goal of this study was to assess the value of TVDT in predicting disease-specific survival (DSS) in patients with hereditary and sporadic MTC. METHODS:This was an Institutional Review Board-approved cohort study including patients with metastatic MTC having at least 3 consecutive imaging studies. TVDT of up to the 5 largest lesions per organ was calculated using a standardized formula. The association between TVDT and DSS was analyzed using Kaplan-Meier survival curves. Cox proportional regression model was used to account for confounding factors. RESULTS:The study sample consisted of 51 patients presenting with 286 metastatic lesions measured with 457 scans during the follow-up of 51 (IQR, 25-102) months. Median age was 19 years (IQR, 15-41), 53% female patients. Cumulative volumes of all metastatic lesions and proportion of patients with TVDT of < 1 year were higher in patients with sporadic as compared with hereditary MTC (P < .01). Factors independently associated with shorter DSS were TVDT of < 1 year based on 3 initial and 3 last scans as well as lung, brain, and prostate as the organs with the fastest growing tumor. TVDT based on 2-dimensional and 3-dimensional measurements showed strong correlation (r = 0.94, P < .05). CONCLUSION:Measurements from 3 baseline and 3 most recent scans preceding follow-up visit enable calculation of TVDT and can be used as predictors of mortality from MTC.

BACKGROUND:Osteogenesis imperfecta (OI) is a rare hereditary disorder of connective tissue. A Danish national registry study surprisingly identified digestive causes as one of the leading causes of OI mortality. However, there is a dearth of prospective data describing gastrointestinal symptoms in OI. Our aim was to assess common gastrointestinal symptoms in an OI patient population and compare it to the general U.S. POPULATION: METHODS:OI patients enrolled in a natural history protocol (NCT03575221) were prospectively evaluated for gastrointestinal symptoms and provided with PROMIS questionnaires for six gastrointestinal symptoms. The HMSS application was used to obtain T scores, score of 50 (and standard deviation of 10) representing the average of the general U.S. POPULATION: RESULTS:41 OI patients were included. Median age 28 years (IQR 18-26), median BMI 28 kg/m2 (IQR 21-34), and 54 % female. OI type IV 61 %, OI type III 20 %, and remaining patients had OI type VI, VII, XIV. The mean T score for the six gastrointestinal symptoms ranged from 46 to 49, within 1 SD from the general U.S. POPULATION:Subgroup analyses showed no differences based on age, mobility, BMI, type of OI and genetic mutations (COL1A1 vs COL1A2), except increased abdominal pain with age. Patients with severe scoliosis (>50°) reported increased nausea and vomiting, and diarrhea compared to patients with mild to moderate scoliosis. DISCUSSION:We report the largest cohort of OI patients evaluated prospectively and directly for gastrointestinal complaints. Study patients, which excluded type I OI, did not report gastrointestinal symptoms higher than the general population except for abdominal pain in older patients. OI patients should be carefully evaluated in the same way as any other patient presenting with gastrointestinal complaints.

INTRODUCTION: Splenic stiffness (SS) measurement (SSM) is an evolving noninvasive assessment to evaluate portal hypertension. Studies with respect to SSM in patients with alcohol use disorder are limited. METHODS: We studied patients seeking treatment for alcohol use disorder in an inpatient treatment protocol at the National Institutes of Health and parsed SSM into 3 groups based on degree of change. RESULTS: The improved SS group had statistically higher initial SSM and a nonstatistically increased liver stiffness measurement compared with others. DISCUSSION: SS is dynamic in a subset of patients immediately after alcohol cessation, and improved SS is associated with a normalization of platelet count.

SummaryBackground and AimsThe Fontan palliation is the final stage of surgery for many children born with univentricular physiology. Almost all Fontan patients develop liver fibrosis which may eventually lead to cirrhosis and hepatocellular carcinoma (HCC). These are important causes of morbidity and mortality in these patients. We performed a systematic review and meta‐analysis to assess the incidence of cirrhosis and HCC in Fontan patients and stratify it based on time since surgery.MethodsA literature search of seven databases identified 1158 records. Studies reporting the number of cirrhosis and HCC cases in Fontan patients and time since Fontan surgery were included. In the cirrhosis cohort, we included only those studies where all patients underwent liver biopsy.ResultsA total of 23 studies were included: 12 and 13 studies in the cirrhosis and HCC cohorts, respectively, with two studies included in both cohorts. The incidence of cirrhosis was 0.97 per 100 patient‐years (95% CI 0.57–1.63), with the incidence and cumulative incidence ≥20 years post Fontan surgery being 1.61 per 100 patient‐years (95% CI 1.24–2.08) and 32.2% (95% CI 25.8%–39.4%), respectively. The incidence of HCC was 0.12 per 100 patient‐years (95% CI 0.07–0.21), with the incidence and cumulative incidence ≥20 years post Fontan surgery being 0.20 per 100 patient‐years (95% CI 0.12–0.35) and 3.9% (95% CI 2.2%–6.8%), respectively. Only about 70% of patients with HCC (20/28) had underlying cirrhosis.ConclusionThe incidence of cirrhosis and HCC increases over time, especially at ≥20 years post Fontan surgery. Studies are needed to further identify at‐risk patients in order to streamline surveillance for these highly morbid conditions.

BACKGROUND:Alcohol cessation is the only intervention that both prevents and halts the progressions of alcohol-associated liver disease. The aim of this study was to assess the relationship between a return to alcohol use and consultation with hepatology in treatment-seeking patients with alcohol use disorder (AUD). METHODS:Two hundred forty-two patients with AUD were enrolled in an inpatient treatment program, with hepatology consultation provided for 143 (59%) patients at the request of the primary team. Patients not seen by hepatology served as controls. The primary outcome was any alcohol use after discharge assessed using AUDIT-C at 26 weeks after discharge. RESULTS:For the primary endpoint, AUDIT at week 26, 61% of the hepatology group and 28% of the controls completed the questionnaire (p=0.07). For the secondary endpoint at week 52, these numbers were 22% and 11% (p = 0.6). At week 26, 39 (45%) patients in the hepatology group versus 31 (70%) controls (p = 0.006) returned to alcohol use. Patients evaluated by hepatology had decreased rates of hazardous alcohol use compared to controls, with 36 (41%) versus 29 (66%) (p = 0.008) of the patients, respectively, reporting hazardous use. There were no significant differences in baseline characteristics between groups and no difference in rates of prescribing AUD therapy. There was no difference in outcomes at 52 weeks. CONCLUSIONS:Patients evaluated by hepatology had significantly lower rates of return to alcohol use and lower rates of hazardous drinking at 26 weeks but not at 52 weeks. These findings suggest that hepatology evaluation during inpatient treatment of AUD may lead to decreased rates of early return to alcohol use.

Background: Long-term management of intermediate- and high-risk differentiated thyroid cancer (DTC) involves thyrotropin (TSH) suppression with thyroid hormone to prevent potential stimulation of TSH receptors on DTC cells, leading to tumor growth. However, the current guidelines recommending TSH suppression are based on low- to moderate-quality evidence. Methods: We performed a systematic review and meta-analysis of studies evaluating the role of TSH suppression in intermediate- and high-risk DTC patients (>= 18 years) treated as per regional guideline-based therapy with a follow-up duration of 5 years (PROSPERO #252396). TSH suppression was defined as "below normal reference range" or, when known, <0.5 mIU/L. Primary outcome measures included (i) composite of progression-free survival (PFS), disease-free survival (DFS), and relapse-free survival (RLFS), and (ii) composite of disease-specific survival (DSS), and overall survival (OS). Secondary outcome included a composite of cardiac or skeletal adverse events. All outcomes and comparisons were represented as TSH suppression versus TSH nonsuppression. Randomized controlled trials, cohort studies, and case-control studies were included for analysis. Pooled hazard ratio (HR) and 95% confidence interval (CI) were calculated using random-effects model. Results: Abstract screening was performed on 6,369 studies. After the exclusion of irrelevant studies and full-text screening, nine studies were selected for the final meta-analysis. Based on seven studies (3,591 patients), the composite outcome of PFS, DFS, and RLFS was not significantly different between TSH suppression and nonsuppression groups (HR: 0.75; 95% CI: 0.48-1.17; I-2 = 76%). Similarly, a DSS and OS composite outcome assessment based on four studies (3,616 patients) did not favor TSH suppression (HR: 0.69; 95% CI: 0.31-1.52; I-2 = 88%). Even after excluding studies of lower quality, the primary outcomes were not significantly different between the TSH suppression and nonsuppression cohorts. The secondary outcome, obtained from two studies (1,294 patients), was significantly higher in the TSH-suppressed groups (HR: 1.82; 95% CI: 1.30-2.55; I-2 = 0%). Significant study heterogeneity was noted for primary outcomes. Conclusion: TSH suppression in intermediate- and high-risk DTC may not improve survival outcomes but may increase the risk of secondary complications. However, the limited evidence and study heterogeneity warrant cautious interpretation of our findings.

Background & Aims:Results of randomized clinical trials are often first presented as conference abstracts, but these abstracts may be difficult to find, and trial results included in the abstract may not be followed by subsequent journal publications. In a review of abstracts submitted to eight major medical and surgical conferences in 2017, we identified 237 abstracts reporting primary results of randomized clinical trials accepted for presentation at three major gastroenterology and hepatology conferences. The aims of this new analysis were to determine the publication rate for these abstracts and the proportion of publications that included trial registration numbers in the publication abstract. Methods:Clinical trial registries, PubMed, Europe PMC, and Google Scholar were searched through November 1, 2021, for publications reporting trial results for the selected abstracts. Publications were reviewed to determine if they included a trial registration number and if the registration number was in the abstract. Results:Publications were found for 157 abstracts (66%) within four years of the conference. Publications were found more frequently for the 194 abstracts reporting results of registered trials (144, 74%) than for the 43 abstracts reporting unregistered trials (13, 30%), but only 67% of these 144 publications included the registration number in the publication abstract. Ten unpublished trials had summary results posted on ClinicalTrials.gov. Conclusions:Clinical trial results could be more accessible if all trials were registered, authors included registration numbers in both conference and journal abstracts, and journal editors required the inclusion of registration numbers in publication abstracts for registered clinical trials.

Abstract Disclosure: N. Behairy: None. S. Gubbi: None. M.G. Pascoal: None. A. Bharadwaj: None. E.C. Wright: None. T. Abijo: None. N. Uttarkar Vikram: None. P. Veeraraghavan: None. C. Cochran: None. J. Glod: None. J. Klubo-Gwiezdzinska: None. Predictive Value of Tumor Volumetrics in Patients with Medullary Thyroid Cancer Background Medullary thyroid cancer (MTC) is a rare endocrine malignancy that can present either as a sporadic disease or as a part of inherited autosomal dominant multiple endocrine neoplasia type 2A (MEN2A) and 2B (MEN2B) syndromes. There is limited data on the prognostic value of the tumor volume (TV) doubling time (TVDT) in patients with sporadic and familial MTC. Therefore, the goal of this study was to examine the association between TVDT and disease-specific survival (DSS) in patients with metastatic MTC. Material and Methods This cohort study included patients with metastatic MTC for whom at least 3 follow-up CT/MRI scans revealed ≥2 measurable lesions and up to the 5 largest lesions in each affected organ were analyzed. The tumor volumes were measured in 2 dimensions (2D) per standard practice reporting and 3 dimensions (3D) using an ellipsoid formula. The average TVDT of all measured lesions in each organ with metastatic deposits was calculated using a previously reported formula. Calcitonin (Ct-DT) and CEA doubling times (CEA-DT) were assessed using the American Thyroid Association Guidelines calculator. The association between DSS and TVDT, Ct-DT, and CEA-DT was tested using Cox regression. Correlations were assessed using a Spearman correlation coefficient. The study was approved by the Institution Review Board. Results The study cohort consisted of 51 patients (27 women, 53%) with age at the initial scan 24 ± 17 years and an average primary tumor size of 3.3±2.0 cm. Seven patients presented with sporadic MTC, 12 with MEN2A and 32 with MEN2B. During a follow-up of 8.0±4.3 years, 28/51 (55%) patients had disease progression and required systemic or local therapies and 9/51 (18%) patients died. A total of 456 scans were analyzed documenting that the organs with the most rapid TVDT were neck masses in 25/51 (49%), liver metastases in 16/51 (31%), lung nodules in 7/51 (14%) and prostate lesions in 3/51 (6%) patients. There was a strong correlation between 2D and 3D TVDT (r = 0.96) as well as between Ct-DT and CEA-DT (r = 0.82). However, the correlation between 2D TVDT and Ct-DT and CEA-DT were low (r = 0.45 for both). The DSS hazard ratios (HR) for DT <1 year compared to ≥3 years were 8.2 (1.5-45.4) for 2D TVDT, 8.7 (1.6-48.2) for 3D TVDT, 15.9 (1.72-146.7) for Ct-DT, and 11.72 (2.0-68.7) for CEA-DT. DSS was not associated with either familial or sporadic etiology of MTC (p = 0.38), gender (p = 0.12), or age at initial scan (p = 0.85). Conclusions Apart from Ct-DT and CEA-DT, TVDT is a valuable prognostic factor in metastatic MTC. Given a strong correlation between 2D and 3D TVDT, standard 2D-based TVDT measurements might be used as an easily obtained and clinically feasible prognostic marker of DSS in MTC patients. Presentation Date: Saturday, June 17, 2023

In a hepatitis C virus (HCV)-controlled human infection model (CHIM), healthy volunteers are inoculated with HCV and then treated. Residual hepatocellular carcinoma (HCC) risk after viral clearance is an important consideration when evaluating the CHIM. We estimate HCC risk in spontaneously cleared HCV and in noncirrhosis after sustained virological response (SVR) to HCV treatment in a systematic review and using data from 3 cohorts: German anti-D, Taiwan, and US Veterans Affairs (VA). For noncirrhosis SVR, the overall HCC rate is 0.33 per 100 patient-years in meta-analysis. HCC rates for the German, Taiwan, and US Veterans Affairs cohorts are 0, 0.14, and 0.02 per 100 patient-years, respectively. Past hepatitis B virus exposure was not accounted for in the Taiwan cohort, while VA patients were likely tested based on liver disease/risk factors, which may confound HCC outcomes. The German cohort with no HCC after 44 years is most comparable to the CHIM participants. Although it is difficult to precisely estimate HCC risk from an HCV CHIM, the data suggest the risk to be very low or negligible.

This chapter presents an overview of osteological evidence for the aurochs in the European Pleistocene and early Holo- cene. Some of the most important aurochs assemblages from Pleistocene and early Holocene Europe are described, from the time of the earliest evidence of this species on the continent, at around 650,000 years ago, through to the end of the Mesolithic period, setting them within their climatic and cultural context. Information on body size is also presented with a reassessment of previous data using new dates for some sites. Limitations are discussed and possible directions for future research proposed.

Hepatic chronic graft-versus-host disease (cGVHD) causes morbidity and current diagnostic criteria are nonspecific. An accurate diagnosis is imperative because overdiagnosis can lead to unnecessary treatment with immunosuppressive agents and raising the risk of opportunistic infections. We aim to characterize different patterns of liver injury and cytokine profiles associated with hepatic dysfunction in cGVHD, to evaluate the accuracy of the NIH Consensus Criteria (NCC) for hepatic cGVHD and to explore predictors for hepatic cGHVD. Patients were evaluated in this prospective cross-sectional study of patients with cGVHD recruited under a natural history protocol. Laboratory tests and cytokines were measured. The cGVHD were diagnosed and scored based on NCC. Clinically indicated liver biopsy specimens or autopsies were reviewed by an expert hepatopathologist (D.E.K.). Comparisons were made between groups, and univariable and multivariable logistic regression were calculated. Of the 302 patients enrolled, 151 fulfilled hepatic cGVHD based on NCC; however, 69% had at least 1 abnormal liver test result. Abnormal alanine aminotransferase (ALT) and aspartate aminotransferase were associated with lower platelets, higher total bilirubin (TB), total cholesterol, serum amyloid A, and IL 15. Abnormal ALP and gamma-glutamyl transpeptidase were associated with higher cholesterol, and IL7. Lower platelet count was associated with higher ALT, TB, and triglycerides and lower albumin. Of the 27 with liver tissue, 16 had histologic features of GVHD, only eight met clinical criteria for hepatic GVHD. Sensitivity and specificity of NCC in identifying hepatic GVHD were 50% and 27% (Kappa = -0.23). Only 6 had only hepatic GVHD, whereas 10 had hepatic GVHD with either iron overload, nodular regenerative hyperplasia, or steatosis. Multivariable logistic regression showed that ALP and total cholesterol were associated with hepatic GVHD and total cholesterol >220 mg/dL increased the sensitivity for histologic hepatic GVHD. In conclusion, abnormal liver enzymes in cGVHD are nonspecific and have poor correlation with histologic evidence for hepatic GVHD, highlighting the importance of histology. Cytokines provide insight into the pathogenesis of hepatic cGVHD. Decreased platelet count was associated with factors associated with liver disease including portal vein diameter, which may suggest progression of liver disease. This highlights the need of incorporating these factors in natural history study and using liver biopsy to understand the development of liver dysfunction in hematopoietic stem cell transplantation and to develop better instruments to decreased hepatic cGVHD related morbidity and mortality. The study was registered with a ClinicalTrials.gov identifier NCT00092235 Published by Elsevier Inc. on behalf of The American Society for Transplantation and Cellular Therapy.

Abstract Hepatic graft‐versus‐host disease (HGVHD) contributes significantly to morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Clinical findings and liver biomarkers are neither sensitive nor specific. The relationship between clinical and histologic diagnoses of HGVHD was assessed premortem and at autopsy. Medical records from patients who underwent HSCT at the National Institutes of Health (NIH) Clinical Center between 2000 and 2012 and expired with autopsy were reviewed, and laboratory tests within 45 days of death were divided into 15‐day periods. Clinical diagnosis of HGVHD was based on Keystone Criteria or NIH Consensus Criteria, histologic diagnosis based on bile duct injury without significant inflammation, and exclusion of other potential etiologies. We included 37 patients, 17 of whom had a cholestatic pattern of liver injury and two had a mixed pattern. Fifteen were clinically diagnosed with HGVHD, two showed HGVHD on autopsy, and 13 had histologic evidence of other processes but no HGVHD. Biopsy or clinical diagnosis of GVHD of other organs during life did not correlate with HGVHD on autopsy. The diagnostic accuracy of the current criteria was poor (κ = −0.20). A logistic regression model accounting for dynamic changes included peak bilirubin 15 days before death, and an increase from period −30 (days 30 to 16 before death) to period −15 (15 days before death) showed an area under the receiver operating characteristic curve of 0.77. Infection was the immediate cause of death in 68% of patients. In conclusion, liver biomarkers at baseline and GVHD elsewhere are poor predictors of HGVHD on autopsy, and current clinical diagnostic criteria have unsatisfactory performance. Peak bilirubin and cholestatic injury predicted HGVHD on autopsy. A predictive model was developed accounting for changes over time. Further validation is needed.

Cattle were the most common domestic livestock animal throughout much of the Neolithic period in the area now occupied by modern day Switzerland, home to a significant number of sites dating to between approximately 4400 and 2500 cal BC. Many of these sites were located in wetland locations, resulting in very well-preserved large faunal assemblages which can be dated using dendrochronology with rare precision. This region is also particularly important for our knowledge of the spread of culture and innovation through Central Europe during the Neolithic period—its topography results in a natural corridor through which influences travelled from both the east and west. This study is the first to combine cattle data from across the whole of Switzerland, focusing on %NISP and biometrical data, in order to investigate how cattle husbandry changed over time, comparing the east and west of the region. A number of different temporal scales are used in order to look for broad patterns and then focus in for more detail. Results indicate that there is a clear correlation between %NISP and body size of cattle throughout much of the Swiss Neolithic and that cattle husbandry changed broadly in line with perceived cultural changes in both the east and west. Of particular interest is a clear increase in both %NISP and body size around the time of the introduction of the Corded Ware culture, contrary to the general pattern of cattle body size decrease seen across Europe at this time. This change is seen, however, in the west of Switzerland prior to the east and raises questions around alternative origins and areas of influence. Either way, the most likely explanation for the increase in cattle size is the introduction of a new population (or populations) of larger cattle into the region, which are incorporated into herds over a few hundred years, providing perhaps some of the earliest evidence for cattle “improvement” in Europe.