Background & Aims:Current guidelines recommend intravenous (i.v.) albumin for different indications in decompensated cirrhosis, but iatrogenic hypervolemia following i.v. albumin is increasingly reported. We aimed to characterize intravascular volume status using point-of-care ultrasound (POCUS) of the inferior vena cava (IVC) during passive leg raise (PLR) and i.v. albumin, potentially facilitating clinical management and adjustment of albumin dosage. Methods:This prospective pilot cohort included patients with decompensated cirrhosis requiring i.v. albumin. We assessed changes in minimal and maximal IVC diameters (IVCmin and IVCmax, respectively) and collapsibility index (IVCCI) during PLR and after i.v. albumin. We defined severe intravascular volume overload as IVCmax >2.1 cm and IVCCI <20%. Clinical outcomes were recorded until 3 months after POCUS. Results:We included 81 measurements in 55 patients (70.9% men; median age 62 years; 58.2% alcohol-related cirrhosis; median Child-Pugh score 9 points; 89.1% paracentesis; median 40 g i.v. albumin; 5.5 L ascites). We found a significant increase in IVC diameters both during PLR (change in mean [Δ] IVCmin +20.7%, Δ IVCmax +14.1%, p <0.01) and after i.v. albumin (Δ IVCmin +58.8%, Δ IVCmax +48.2%, p <0.01). There was a significant decrease in IVCCI during PLR (relative Δ -11.1%, p <0.01) and after i.v. albumin (relative Δ -18.0%, p <0.01). Potential severe intravascular volume overload occurred on 17 occasions (21%) after i.v. albumin, more frequently in women than in men (40% vs. 15.7%, p <0.01), and showed higher cumulative incidence rates in variceal bleeding after 1 (16.7% vs. 0%, p = 0.01) and 3 months (18.2% vs. 0%, p = 0.01). Conclusions:Potential severe intravascular volume overload after i.v. albumin was detected in every fifth patient with decompensated cirrhosis. Thus, there is a need to develop strategies for individualizing volume management in patients with decompensated cirrhosis. Impact and implications:Iatrogenic volume overload after albumin infusions in patients with cirrhosis is a potentially harmful side effect, but no policy for monitoring intravascular volume overload using non-invasive tools has been suggested so far. New-onset potential volume overload was detected in almost one out of five men and four out of 10 women and was associated with increases in N-terminal prohormone of brain natriuretic peptide, lower mean arterial pressure during albumin infusion, and higher serum sodium levels. Our results from this proof-of-concept study emphasize the need for larger prospective cohort studies to validate our findings and introduce strategies for individualizing volume management in patients with decompensated cirrhosis.

BACKGROUND:Staging of liver fibrosis traditionally relied on liver histology; however, transient elastography (TE) and more recently two-dimensional shear wave elastography (2D-SWE) evolved to noninvasive alternatives. Hence, we evaluated the diagnostic accuracy of 2D-SWE assessed by the Canon Aplio i800 ultrasound system using liver biopsy as reference and compared the performance to TE.METHODS:In total, 108 adult patients with chronic liver disease undergoing liver biopsy, 2D-SWE and TE were enrolled prospectively at the University Hospital Zurich. Diagnostic accuracies were evaluated using the area under the receiver operating characteristic (AUROC) analysis, and optimal cut-off values by Youden's index.RESULTS:Diagnostic accuracy of 2D-SWE was good for significant (≥F2; AUROC 85.2%, 95% confidence interval (95%CI):76.2-91.2%) as well as severe fibrosis (≥F3; AUROC 86.8%, 95%CI: 78.1-92.4%) and excellent for cirrhosis (AUROC 95.6%, 95%CI: 89.9-98.1%), compared to histology. TE performed equally well (significant fibrosis: 87.5%, 95%CI: 77.7-93.3%; severe fibrosis: 89.7%, 95%CI: 82.0-94.3%; cirrhosis: 96%, 95%CI: 90.4-98.4%), and accuracy was not statistically different to 2D-SWE. 2D-SWE optimal cut-off values were 6.5, 9.8 and 13.1 kPa for significant fibrosis, severe fibrosis and cirrhosis, respectively.CONCLUSIONS:Performance of 2D-SWE was good to excellent and well comparable with TE, supporting the application of this 2D-SWE system in the diagnostic workup of chronic liver disease.

Non-invasive tests (NITs) and liver stiffness measurement (LSM) in particular, have entered clinical practice over 20 years ago as point-of-care tests to diagnose liver fibrosis in patients with compensated chronic liver disease. Since then, NITs use has evolved thanks to a large number of studies in all major etiologies of liver disease, and they have become important tools to stratify the risk of portal hypertension and liver-related events. The Baveno VII consensus workshop provided several novel recommendations regarding the use of well-established and novel NITs in the specific setting of portal hypertension screening, diagnosis and follow-up. The Baveno VII expert panels paid special attention to summarizing the existing data into simple clinical rules able to guide clinicians in their practice. The "rule of five" for LSM is a tool to stratify the risk of liver-related events, and LSM alone or in combination with platelet count, can be used now to rule-in and rule-out compensated advanced chronic liver disease (cACLD) and clinically significant portal hypertension, as well as to rule-out high-risk varices. Use of NITs in obese subjects with non-alcoholic fatty liver disease (NAFLD) and patients with viral hepatitis C that has been successfully treated, require specific knowledge. This review will update the reader on these aspects.

To compare the diagnostic performance of T1 mapping and MR elastography (MRE) for staging of hepatic fibrosis and grading inflammation with histopathology as standard of reference. 68 patients with various liver diseases undergoing liver biopsy for suspected fibrosis or with an established diagnosis of cirrhosis prospectively underwent look-locker inversion recovery T1 mapping and MRE. T1 relaxation time and liver stiffness (LS) were measured by two readers. Hepatic fibrosis and inflammation were histopathologically staged according to a standardized fibrosis (F0–F4) and inflammation (A0–A2) score. For statistical analysis, independent t test, and Mann–Whitney U test and ROC analysis were performed, the latter to determine the performance of T1 mapping and MRE for fibrosis staging and inflammation grading, as compared to histopathology. Histopathological analysis diagnosed 9 patients with F0 (13.2

Introduction: The use of proton-pump inhibitors (PPI) may be associated with an increased risk of gastric cancer (GC). Objective: To review and meta-analyse available literature investigating the association between PPI use and GC risk. Methods: Two independent reviewers systematically searched Ovid MEDLINE, EMBASE, and Cochrane Library (inception to July 2020) for case-control and cohort studies assessing the association between PPI use and GC according to a predefined protocol in PROSPERO (CRD42018102536). Reviewers independently assessed study quality, extracted data, and meta-analysed available and newly calculated odds ratios (ORs) using a random-effects model, and stratified for GC site (cardia versus non-cardia) and PPI duration (<1 year, 1–3 years, >3 years). Results: We screened 2,396 records and included five retrospective cohort and eight case-control studies comprising 1,662,881 individuals in our meta-analysis. In random-effect models, we found an increased GC risk in PPI users [OR: 1.94, 95% confidence interval (95% CI): 1.47–2.56] with high statistical heterogeneity (I2 = 82%) and overall moderate risk of bias. Stratified analyses indicated a significant risk increase in non-cardia (OR: 2.20, 95% CI: 1.44–3.36, I2 = 77%) with a similar non-significant trend in cardia regions (OR: 1.77, 95% CI: 0.72–4.36, I2 = 66%). There was no GC increase with longer durations of PPI exposure (<1 year: OR: 2.29, 95% CI: 2.13–2.47, I2 = 0%; 1–3 years: OR: 1.46, 95% CI: 0.53–4.01, I2 = 35%; >3 years: OR: 2.08, 95% CI: 0.56–7.77, I2 = 61%). Conclusion: We found a twofold increased GC risk among PPI users, but this association does not confirm causation and studies are highly heterogeneous. PPI should only be prescribed when strictly indicated.

Objective Balancing bleeding risk and stroke risk in patients with atrial fibrillation (AF) is a common challenge. Though several bleeding risk scores exist, most have not included patients on direct oral anticoagulants (DOACs). We aimed at developing a novel bleeding risk score for patients with AF on oral anticoagulants (OAC) including both vitamin K antagonists (VKA) and DOACs. Methods We included patients with AF on OACs from a prospective multicenter cohort study in Switzerland (SWISS-AF). The outcome was time to first bleeding. Bleeding events were defined as major or clinically relevant non-major bleeding. We used backward elimination to identify bleeding risk variables. We derived the score using a point score system based on the beta-coefficients from the multivariable model. We used the Brier score for model calibration (<0.25 indicating good calibration), and Harrel's c-statistics for model discrimination. Results We included 2147 patients with AF on OAC (72.5% male, mean age 73.4 +/- 8.2 years), of whom 1209 (56.3%) took DOACs. After a follow-up of 4.4 years, a total of 255 (11.9%) bleeding events occurred. After backward elimination, age > 75 years, history of cancer, prior major hemorrhage, and arterial hypertension remained in the final prediction model. The Brier score was 0.23 (95% confidence interval [CI] 0.19-0.27), the c-statistic at 12 months was 0.71 (95% CI 0.63-0.80). Conclusion In this prospective cohort study of AF patients and predominantly DOAC users, we successfully derived a bleeding risk prediction model with good calibration and discrimination.

Introduction: The use of proton-pump inhibitors (PPI) may be associated with an increased risk of gastric cancer (GC). Objective: To review and meta-analyse available literature investigating the association between PPI use and GC risk. Methods: Two independent reviewers systematically searched Ovid MEDLINE, EMBASE, and Cochrane Library (inception to July 2020) for case-control and cohort studies assessing the association between PPI use and GC according to a predefined protocol in PROSPERO (CRD42018102536). Reviewers independently assessed study quality, extracted data, and meta-analysed available and newly calculated odds ratios (ORs) using a random-effects model, and stratified for GC site (cardia versus non-cardia) and PPI duration (<1 year, 1-3 years, >3 years). Results: We screened 2,396 records and included five retrospective cohort and eight case-control studies comprising 1,662,881 individuals in our meta-analysis. In random-effect models, we found an increased GC risk in PPI users [OR: 1.94, 95% confidence interval (95% CI): 1.47-2.56] with high statistical heterogeneity (I-2 = 82%) and overall moderate risk of bias. Stratified analyses indicated a significant risk increase in non-cardia (OR: 2.20, 95% CI: 1.44-3.36, I-2 = 77%) with a similar non-significant trend in cardia regions (OR: 1.77, 95% CI: 0.72-4.36, I-2 = 66%). There was no GC increase with longer durations of PPI exposure (<1 year: OR: 2.29, 95% CI: 2.13-2.47, I-2 = 0%; 1-3 years: OR: 1.46, 95% CI: 0.53-4.01, I-2 = 35%; >3 years: OR: 2.08, 95% CI: 0.56-7.77, I-2 = 61%). Conclusion: We found a twofold increased GC risk among PPI users, but this association does not confirm causation and studies are highly heterogeneous. PPI should only be prescribed when strictly indicated.

Diverticulosis and diverticulitis are leading indications for colorectal surgery in Western countries. Abdominal pain, functional disorders, and low health-related quality of life (HRQoL) can limit the outcome of abdominal surgery even in the absence of complications. Therefore, we aimed to review current evidence on postoperative long-term outcomes including HRQoL, functional disorders, abdominal pain, and patients' satisfaction after diverticular surgery for diverticulosis/diverticulitis. We performed a PubMed database search (inception: 17 December 2020). Identified publications were screened and outcome parameters extracted. In summary, HRQoL increased after diverticular surgery in 9 out of 10 longitudinal cohort studies. Similarly, patients' satisfaction with treatment and their choice to undergo surgery was commonly reported as high or very good, as reported in eight studies. In a randomized control trial and retrospective cohort, elective diverticular surgery was superior to conservative treatment regarding HRQoL. In cross-sectional analyses, chronic abdominal pain and functional disorders including defaecation disorders or diarrhoea/obstipation were found in a relevant fraction of patients. Incontinence ranged from 5% to 25% with insufficient data for comparison before and after surgery. However, functional disorders did not result in decreased HRQoL in most studies, and no increase in functional disorders was observed after elective diverticular surgery in longitudinal analyses. We conclude that HRQoL among operated patients with diverticular disease improved in most studies after surgery. Functional disorders and postoperative abdominal pain can be present after elective diverticular surgery; however, no increase in functional disorders was observed in longitudinal studies. Functional disorders after diverticular surgery need to be carefully discussed with the patient before surgery and a careful clinical assessment before surgery including incontinence scoring should be considered.

BackgroundSubclinical hyperthyroidism (SHyper) has been associated with increased risk of hip and other fractures, but the linking mechanisms remain unclear. ObjectiveTo investigate the association between subclinical thyroid dysfunction and bone loss. MethodsIndividual participant data analysis was performed after a systematic literature search in MEDLINE/EMBASE (1946-2016). Two reviewers independently screened and selected prospective cohorts providing baseline thyroid status and serial bone mineral density (BMD) measurements. We classified thyroid status as euthyroidism (thyroid-stimulating hormone [TSH] 0.45-4.49 mIU/L), SHyper (TSH < 0.45 mIU/L) and subclinical hypothyroidism (SHypo, TSH 4.50-19.99 mIU/L) both with normal free thyroxine levels. Our primary outcome was annualized percentage BMD change (%BMD) from serial dual X-ray absorptiometry scans of the femoral neck, total hip and lumbar spine, obtained from multivariable regression in a random-effects two-step approach. ResultsAmongst 5458 individuals (median age 72 years, 49.1% women) from six prospective cohorts, 451 (8.3%) had SHypo and 284 (5.2%) had SHyper. During 36 569 person-years of follow-up, those with SHyper had a greater annual bone loss at the femoral neck versus euthyroidism: %BMD = -0.18 (95% CI: -0.34, -0.02; I-2 = 0%), with a nonstatistically significant pattern at the total hip: %BMD = -0.14 (95% CI: -0.38, 0.10; I-2 = 53%), but not at the lumbar spine: %BMD = 0.03 (95% CI: -0.30, 0.36; I-2 = 25%); especially participants with TSH < 0.10 mIU/L showed an increased bone loss in the femoral neck (% BMD = -0.59; [95% CI: -0.99, -0.19]) and total hip region (%BMD = -0.46 [95% CI: -1.05, -0.13]). In contrast, SHypo was not associated with bone loss at any site. ConclusionAmongst adults, SHyper was associated with increased femoral neck bone loss, potentially contributing to the increased fracture risk.

Context Hyperthyroidism is associated with increased fracture risk, but it is not clear if lower thyroid-stimulating hormone (TSH) and higher free thyroxine (FT4) in euthyroid individuals are associated with fracture risk. Objective To evaluate the association of TSH and FT4 with incident fractures in euthyroid individuals. Design Individual participant data analysis. Setting Thirteen prospective cohort studies with baseline examinations between 1981 and 2002. Participants Adults with baseline TSH 0.45 to 4.49 mIU/L. Main Outcome Measures Primary outcome was incident hip fracture. Secondary outcomes were any, nonvertebral, and vertebral fractures. Results were presented as hazard ratios (HRs) with 95% confidence interval (CI) adjusted for age and sex. For clinical relevance, we studied TSH according to five categories: 0.45 to 0.99 mIU/L; 1.00 to 1.49 mIU/L; 1.50 to 2.49 mIU/L; 2.50 to 3.49 mIU/L; and 3.50 to 4.49 mIU/L (reference). FT4 was assessed as study-specific standard deviation increase, because assays varied between cohorts. Results During 659,059 person-years, 2,565 out of 56,835 participants had hip fracture (4.5%; 12 studies with data on hip fracture). The pooled adjusted HR (95% CI) for hip fracture was 1.25 (1.05 to 1.49) for TSH 0.45 to 0.99 mIU/L, 1.19 (1.01 to 1.41) for TSH 1.00 to 1.49 mIU/L, 1.09 (0.93 to 1.28) for TSH 1.50 to 2.49 mIU/L, and 1.12 (0.94 to 1.33) for TSH 2.50 to 3.49 mIU/L (P for trend = 0.004). Hip fracture was also associated with FT4 [HR (95% CI) 1.22 (1.11 to 1.35) per one standard deviation increase in FT4]. FT4 only was associated with any and nonvertebral fractures. Results remained similar in sensitivity analyses. Conclusions Among euthyroid adults, lower TSH and higher FT4 are associated with an increased risk of hip fracture. These findings may help refine the definition of optimal ranges of thyroid function tests.

Extrahepatic manifestations of hepatitis C virus (HCV) infection are a rare but serious condition. This article summarizes the current literature on the association between HCV and endocrine and pulmonary manifestations, as well as idiopathic thrombocytopenic purpura (ITP). HCV may directly infect extrahepatic tissues and interact with the immune system predisposing for obstructive and interstitial lung disease, ITP, autoimmune thyroiditis , infertility , growth hormone and adrenal deficiencies, osteoporosis, and potentially lung and thyroid cancers . However, in many cases, the current evidence is divergent and cannot sufficiently confirm a true association, which emphasizes the need for future targeted projects in this field.

Background Venous thromboembolism (VTE) and subclinical thyroid dysfunction (SCTD) are both common in elderly patients. SCTD has been related to a hypercoagulable state and an increased thromboembolic risk. However, prospective data on the relationship between SCTD and VTE are lacking.Objectives To investigate the relationship between SCTD and recurrent VTE (rVTE), all-cause mortality, and thrombophilic biomarkers.Patients Elderly patients with VTE were studied.Methods In a prospective multicenter cohort, thyroid hormones and thrombophilic biomarkers were measured 1 year after acute VTE, as both may be influenced by acute thrombosis. We defined subclinical hypothyroidism (SHypo) as elevated thyroid-stimulating hormone (TSH) levels (4.50-19.99 mIU L-1), and subclinical hyperthyroidism (SHyper) as TSH levels of < 0.45 mIU L-1, both with normal free thyroxine levels. Outcomes were incidence of rVTE and overall mortality during follow-up starting after the 1-year blood sampling.Results Of 561 participants (58% with anticoagulation), 6% had SHypo and 5% had SHyper. After 20.8 months of mean follow-up, 9% developed rVTE and 10% died. The rVTE incidence rate was 7.2 (95% confidence interval [CI] 2.7-19.2) per 100 patient-years in SHypo participants, 0.0 (95% CI 0.0-7.6) in SHyper participants, and 5.9 (95% CI 4.4-7.8) in euthyroid participants. In multivariate analyses, the sub-hazard ratio for rVTE was 0.00 (95% CI 0.00-0.58) in SHyper participants and 1.50 (95% CI 0.52-4.34) in SHypo participants as compared with euthyroid participants, without increased levels of thrombophilic biomarkers. SHyper (hazard ratio [HR] 0.80, 95% CI 0.23-2.81) and SHypo (HR 0.99, 95% CI 0.30-3.29) were not associated with mortality.Conclusion In elderly patients, SHyper may be associated with lower rVTE risks. SHypo showed a non-statistically significant pattern of an association with rVTE, without increased mortality or differences in thrombophilic biomarkers.

Context: Although both overt hyper- and hypothyroidism are known to lead to cognitive impairment, data on the association between subclinical thyroid dysfunction and cognitive function are conflicting.Objective: This study sought to determine the risk of dementia and cognitive decline associated with subclinical thyroid dysfunction among prospective cohorts.Data Sources: We searched in MEDLINE and EMBASE from inception until November 2014.Study Selection: Two physicians identified prospective cohorts that assessed thyroid function and cognitive outcomes (dementia; Mini-Mental State Examination [MMSE]).Data Extraction: Data were extracted by one reviewer following standardized protocols and verified by a second reviewer. The primary outcome was dementia and decline in cognitive function was the secondary outcome.Data Synthesis: Eleven prospective cohorts followed 16,805 participants during a median followup of 44.4 months. Five studies analyzed the risk of dementia in subclinical hyperthyroidism (SHyper) (n = 6410), six in subclinical hypothyroidism (SHypo) (n = 7401). Five studies analyzed MMSE decline in SHyper (n = 7895), seven in SHypo (n = 8960). In random-effects models, the pooled adjusted risk ratio for dementia in SHyper was 1.67 (95% confidence interval, 1.04; 2.69) and 1.14 (95% confidence interval, 0.84; 1.55) in SHypo vs euthyroidism, both without evidence of significant heterogeneity (I-2 = 0.0%). The pooled mean MMSE decline from baseline to followup (mean 32 mo) did not significantly differ between SHyper or SHypo vs euthyroidism.Conclusions: SHyper might be associated with an elevated risk for dementia, whereas SHypo is not, and both conditions are not associated with faster decline in MMSE over time. Available data are limited, and additional large, high-quality studies are needed.

37 Context: While both overt hyperand hypothyroidism are known to lead to cognitive impairment, data on 38 the association between subclinical thyroid dysfunction and cognitive function are conflicting. 39 Objective: To determine the risk of dementia and cognitive decline associated with subclinical thyroid 40 dysfunction among prospective cohort studies. 41 Data Sources: Search in MEDLINE and EMBASE (inception until November 2014) and reference lists of 42 key articles without language restrictions. 43 Study Selection: Two physicians identified prospective cohorts that assessed thyroid function at baseline 44 and cognitive outcomes (dementia; Mini-Mental State Examination, MMSE). 45 Data Extraction: Data were extracted by one reviewer following standardized protocols and verified by a 46 second reviewer. Both reviewers independently assessed study quality. The primary outcomes were de47 mentia and decline in cognitive function measured by MMSE. We calculated risk ratios and 95% confi48 dence intervals using random-effects models. 49 Data Synthesis: Eleven prospective cohorts followed 16,805 participants during a median follow-up of 50 44.4 months. Five studies analyzed the risk of dementia in subclinical hyperthyroidism (n=6410), six in 51 subclinical hypothyroidism (n=7401). Five studies analyzed MMSE decline in subclinical hyperthyroid52 ism (n=7895), seven in subclinical hypothyroidism (n=8960). In random-effects models, the pooled ad53 justed RR for dementia in subclinical hyperthyroidism was 1.67 (95% confidence interval [CI] 1.04-2.69) 54 and 1.14 (95%CI 0.84-1.55) in subclinical hypothyroidism versus euthyroidism, both without evidence of 55 significant heterogeneity (I2=0.0%). Sensitivity analyses pooling only studies with formal outcome adjudi56 cation or population-based studies yielded similar results. The pooled mean MMSE decline from baseline 57 to follow-up (mean 32 months) did not significantly differ between subclinical hyperor hypothyroidism 58 versus euthyroidism. 59 Conclusions: Subclinical hyperthyroidism might be associated with an elevated risk for dementia, while 60 subclinical hypothyroidism is not, and both conditions are not associated with faster decline in MMSE 61 over time. Available data are limited, and additional large, high-quality studies are needed. 62 63 Formatted: Highlight

The present survey aims at determining the prevalence of extreme obesity (defined as a body mass index (BMI) ≥ 99.5th percentile) for the first time in Austria and at investigating the relationship between weight status and mother tongue in a representative Viennese sample of 24,989 children and adolescents (2–16 years) with a percentage of approximately 46 % of migration background.