Prevalence of steatotic liver disease, advanced fibrosis and cirrhosis among community-dwelling overweight and obese individuals in the USA.

BACKGROUND: There are limited prospective data among overweight and obese individuals on the prevalence of advanced fibrosis, and cirrhosis using advanced MRI-based methods in the USA. The aim of this study was to fill that gap in knowledge by prospectively determining the MRI-based prevalence of steatotic liver disease (SLD) and its subcategories, advanced fibrosis and cirrhosis among overweight and obese individuals residing in the USA. METHODS: This is a cross-sectional analysis of prospectively enrolled overweight or obese adults aged 40-75 years from primary care and community-based settings in Southern California. Participants were classified as having SLD if MRI proton density fat fraction ≥5%, and subclassified as metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction and alcohol-associated liver disease (MetALD) and alcohol-related liver disease (ALD) consistently with the new nomenclature guidance per AASLD-EASL-ALEH. Advanced fibrosis and cirrhosis were defined as magnetic resonance elastography (MRE) ≥3.63 kPa and MRE ≥4.67 kPa, respectively. RESULTS: The cohort included 539 participants with mean (±SD) age of 51.5 (±13.1) years and body mass index of 32.6 (±6.2) kg/m2, respectively. The prevalence of SLD, advanced fibrosis and cirrhosis was 75%, 10.8% and 4.5%, respectively. The prevalence of MASLD, MetALD and ALD was 67.3%, 4.8% and 2.6%, respectively. There was no difference in prevalence of advanced fibrosis and cirrhosis among subcategories. CONCLUSIONS: Using advanced MRI methods among community-dwelling overweight and obese adults, the prevalence of cirrhosis was 4.5%. Most common SLD subcategory was MASLD with 67% of individuals, whereas MetALD and ALD were less common. Systematic screening for advanced fibrosis among overweight/obese adults may be considered.

The impact of genetic risk on the prevalence of advanced fibrosis and cirrhosis in prospectively assessed patients with type 2 diabetes.

BACKGROUND: Genetic factors contribute to the risk and severity of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the utility of genetic testing in risk stratification remains poorly characterised. AIMS: To examine the influence of genetic risk on advanced fibrosis and cirrhosis in patients with type 2 diabetes mellitus (T2DM) and the utility of a polygenic risk score (PRS) in screening guidelines. METHODS: We prospectively enrolled adults aged ≥50 years with T2DM recruited from clinics. PRS was the sum of risk alleles in PNPLA3, TM6SF2 and SERPINA1 minus the protective variant in HSD17B13. We performed magnetic resonance elastography and vibration-controlled transient elastography to assess for advanced fibrosis and cirrhosis. RESULTS: Of 382 included patients, the mean age and BMI were 64.8 (±8.4) years and 31.7 (±6.2) kg/m2 respectively. The prevalence of advanced fibrosis and cirrhosis were 12.3% and 5.2% respectively; higher PRS was associated with increased risk of cirrhosis (2.7% vs. 7.5%, p = 0.037). High PRS was associated with increased risk of advanced fibrosis among those with fibrosis-4 index (FIB-4) index <1.3 (9.6% vs. 2.3%, p = 0.036) but was not significantly different in other FIB-4 categories. Incorporating PRS determination into the American Gastroenterological Association and American Association for the Study of Liver Diseases screening guidelines prevented approximately 20% of all participants with advanced fibrosis from being inappropriately classified as low risk. CONCLUSIONS: Utilising a well-phenotyped, prospective cohort of adults with T2DM, we found that adding an assessment of genetic risk to recommendations to screen at-risk populations may improve risk prediction.

A prospective study on the prevalence of at-risk MASH in patients with type 2 diabetes mellitus in the United States.

BACKGROUND: There are limited data on the prevalence and treatment of at-risk metabolic dysfunction-associated steatohepatitis (MASH) among patients with type 2 diabetes (T2DM) in the United States. AIM: To estimate the prevalence of at-risk MASH in a prospectively recruited cohort of adults with T2DM using new nomenclature endorsed by multiple societies. METHODS: This prospective study enrolled adults aged ≥50 with T2DM from primary care and endocrinology clinics in southern California from 2016 to 2023. Metabolic dysfunction-associated steatotic liver disease (MASLD) was defined by an magnetic resonance imaging proton density fat fraction ≥5% and at least one metabolic risk factor without any other chronic liver disease or secondary cause for hepatic steatosis. RESULTS: We included 530 adult patients with T2DM. The mean (±SD) age and body mass index (BMI) were 64.4 (±8.1) years and 31.5 (±6.1) kg/m2, respectively. Among patients with T2DM, the prevalence of MASLD, at-risk MASH and cirrhosis was 69.6%, 13.6% and 6.8%, respectively. Among patients with co-existing T2DM and obesity, the prevalence of MASLD, at-risk MASH and cirrhosis was 77.8%, 15.9% and 9.0%, respectively, and was higher than in participants without obesity (p < 0.0001, 0.0543 and 0.0128, respectively). CONCLUSION: Among adults aged ≥50 years with T2DM, the prevalence of MASLD, at-risk MASH and cirrhosis is high, posing a significant risk for liver-related morbidity and mortality. Approximately 14% of patients with T2DM may be candidates for pharmacologic therapies specific to MASH-related fibrosis.

MASH Resolution Index: development and validation of a non-invasive score to detect histological resolution of MASH.

BACKGROUND: Dynamic changes in non-invasive tests, such as changes in alanine aminotransferase (ALT) and MRI proton-density-fat-fraction (MRI-PDFF), may help to detect metabolic dysfunction-associated steatohepatitis (MASH) resolution, but a combination of non-invasive tests may be more accurate than either alone. We developed a novel non-invasive score, the MASH Resolution Index, to detect the histological resolution of MASH. METHODS: This study included a derivation cohort of 95 well-characterised adult participants (67% female) with biopsy-confirmed MASH who underwent contemporaneous laboratory testing, MRI-PDFF and liver biopsy at two time points. The primary objective was to develop a non-invasive score to detect MASH resolution with no worsening of fibrosis. The most predictive logistic regression model was selected based on the highest area under the receiver operating curve (AUC), and the lowest Akaike information criterion and Bayesian information criterion. The model was then externally validated in a distinct cohort of 163 participants with MASH from a clinical trial. RESULTS: The median (IQR) age and body mass index were 55 (45-62) years and 32.0 (30-37) kg/m2, respectively, in the derivation cohort. The most accurate model (MASH Resolution Index) included MRI-PDFF, ALT and aspartate aminotransferase. The index had an AUC of 0.81 (95% CI 0.69 to 0.93) for detecting MASH resolution in the derivation cohort. The score calibrated well and performed robustly in a distinct external validation cohort (AUC 0.83, 95% CI 0.76 to 0.91), and outperformed changes in ALT and MRI-PDFF. CONCLUSION: The MASH Resolution Index may be a useful score to non-invasively identify MASH resolution.

Validation of AGA clinical care pathway and AASLD practice guidance for nonalcoholic fatty liver disease in a prospective cohort of patients with type 2 diabetes.

BACKGROUND AND AIMS: Recently, the American Gastroenterological Association and the American Association for the Study of Liver Diseases developed clinical pathways to evaluate populations at high risk for NAFLD. We assessed the diagnostic performance of the new guidance in a well-phenotyped cohort of patients with Type 2 diabetes mellitus (T2DM). APPROACH AND RESULTS: This prospective study enrolled patients age ≥50 years with T2DM. Participants underwent a standardized clinical research visit with MRI and ultrasound-based assessment of liver fat and stiffness and Enhanced Liver Fibrosis (ELF) testing. Of 417 participants (36% men) with T2DM with FIB-4 and MRE data, the prevalence of NAFLD was 64% and 12% had advanced fibrosis (MRE≥3.63 kPa). Applying the American Gastroenterological Association pathway of FIB-4 and vibration-controlled transient elastography, the false negative rate was 3.3% and 18% would qualify for specialty referral. Applying the FIB-4 + ELF American Association for the Study of Liver Diseases pathway, the false negative rate was 4.5%, but 50% would qualify for specialty referral. Applying higher ELF cut points improved the pathway, yielding a similar false negative rate of 4.9% but decreased specialty referral to 27%. CONCLUSION: Validation of the American Gastroenterological Association clinical pathway in a prospectively recruited cohort with T2DM revealed a low false negative rate and avoided specialty referral in a large percentage of patients. The American Association for the Study of Liver Diseases pathway with FIB-4 + ELF resulted in a high rate of specialty referral, which improved with the utilization of higher ELF cut points and may serve as an alternative for primary care and endocrinology clinics without access to vibration-controlled transient elastography.

Development and Validation of the Nonalcoholic Fatty Liver Disease Familial Risk Score to Detect Advanced Fibrosis: A Prospective, Multicenter Study.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD)-related fibrosis is heritable, but it is unclear how family history may be used to identify first-degree relatives with advanced fibrosis. We aimed to develop and validate a simple risk score to identify first-degree relatives of probands who have undergone assessment of liver fibrosis who are at higher risk of NAFLD with advanced fibrosis. METHODS: This prospective, cross-sectional, familial study consisted of a derivation cohort from San Diego, California, and a validation cohort from Helsinki, Finland. This study included consecutive adult probands (n = 242) with NAFLD and advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD, with at least 1 of their first-degree relatives. All included probands and first-degree relatives underwent evaluation of liver fibrosis, the majority by magnetic resonance elastography. RESULTS: A total of 396 first-degree relatives (64% male) were included. The median age and body mass index were 47 years (interquartile range, 32-62 y) and 27.6 kg/m2 (interquartile range, 24.1-32.5 kg/m2), respectively. Age (1 point), type 2 diabetes (1 point), obesity (2 points), and proband with NAFLD and advanced fibrosis (2 points) were predictors of advanced fibrosis among first-degree relatives in the derivation cohort (n = 220) and formed the NAFLD Familial Risk Score. The area under the receiver operator characteristic curve of the NAFLD Familial Risk Score for detecting advanced fibrosis was 0.94 in the validation cohort (n = 176). The NAFLD Familial Risk Score outperformed the Fibrosis-4 index in the validation cohort (area under the receiver operator characteristic curve, 0.94 vs 0.70; P = .02). CONCLUSIONS: The NAFLD Familial Risk Score is a simple and accurate clinical tool to identify advanced fibrosis in first-degree relatives. These data may have implications for surveillance in NAFLD.

Ramipril for the Treatment of COVID-19: RAMIC, a Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

INTRODUCTION: Retrospective studies report that angiotensin-converting enzyme inhibitors (ACEIs) may reduce the severity of COVID-19, but prospective data on de novo treatment with ACEIs are limited. The RAMIC trial was a randomized, multicenter, placebo-controlled, double-blind, allocation-concealed clinical trial to examine the efficacy of de novo ramipril versus placebo for the treatment of COVID-19. METHODS: Eligible participants were aged 18 years and older with a confirmed diagnosis of SARS-CoV-2 infection, recruited from urgent care clinics, emergency departments, and hospital inpatient wards at eight sites in the USA. Participants were randomly assigned to daily ramipril 2.5 mg or placebo orally in a 2:1 ratio, using permuted block randomization. Analyses were conducted on an intention-to-treat basis. The primary outcome was a composite of mortality, intensive care unit (ICU) admission, or invasive mechanical ventilation by day 14. RESULTS: Between 27 May 2020 and 19 April 2021, a total of 114 participants (51% female) were randomized to ramipril (n = 79) or placebo (n = 35). The overall mean (± SD) age and BMI were 45 (± 15) years and 33 (± 8) kg/m2. Two participants in the ramipril group required ICU admission and one died, compared with none in the placebo group. There were no significant differences between ramipril and placebo in the primary endpoint (ICU admission, mechanical ventilation, or death) (3% versus 0%, p = 1.00) or adverse events (27% versus 29%, p = 0.82). The study was terminated early because of a low event rate and subsequent Emergency Use Authorization of therapies for COVID-19. CONCLUSION: De novo ramipril was not different compared with placebo in improving or worsening clinical outcomes from COVID-19 but appeared safe in non-critically ill patients with COVID-19. TRIAL REGISTRATION: Clinicaltrials.gov NCT04366050.

Clinical and histologic factors associated with discordance between steatosis grade derived from histology vs. MRI-PDFF in NAFLD.

BACKGROUND: Magnetic resonance imaging-proton density fat fraction (MRI-PDFF) is an excellent biomarker for the non-invasive quantification of hepatic steatosis. AIM: To examine clinical and histologic factors associated with discordance between steatosis grade determined by histology and MRI-PDFF in patients with non-alcoholic fatty liver disease (NAFLD) METHODS: We included 728 patients with biopsy-proven NAFLD from UC San Diego (n = 414) and Yokohama City University (n = 314) who underwent MRI-PDFF and liver biopsy. Patients were stratified by steatosis, and matched with MRI-PDFF cut-points for each steatosis grade: 0 (MRI-PDFF < 6.4%), 1 (MRI-PDFF: 6.4%-17.4%), 2 (MRI-PDFF: 17.4%-22.1%), 3 (MRI-PDFF ≥ 22.1%). Primary outcome was major discordance defined as ≥2 steatosis grade difference determined by histology and MRI-PDFF. RESULTS: Mean (±SD) age and BMI were 55.3 (±13.8) years and 29.9 (±4.9) kg/m2 , respectively. The distributions of histology and MRI-PDFF-determined steatosis were 5.5% grade 0 (n = 40), 44.8% 1 (n = 326, 44.8%), 33.9% 2 (n = 247), and 15.8% 3 (n = 115) vs. 23.5% grade 0 (n = 171), 49.7% 1 (n = 362), 12.9% 2 (n = 94), and 13.9% 3 (n = 101). Major discordance rate was 6.6% (n = 48). Most cases with major discordance had greater histology-determined steatosis grade (n = 40, 88.3%), higher serum AST and liver stiffness, and greater likelihood of fibrosis ≥2, ballooning ≥1 and lobular inflammation ≥2 (all p < 0.05). CONCLUSION: Histology overestimates steatosis grade compared to MRI-PDFF. Patients with advanced NASH are likely to be upgraded on steatosis grade by histology. These data have important implications for steatosis estimation and reporting on histology in clinical practice and trials, especially in patients with stage 2 fibrosis.

Using pressure-driven flow systems to evaluate laser speckle contrast imaging.

Significance: Microfluidic flow phantom studies are commonly used for characterizing the performance of laser speckle contrast imaging (LSCI) instruments. The selection of the flow control system is critical for the reliable generation of flow during testing. The majority of recent LSCI studies using microfluidics used syringe pumps for flow control. Aim: We quantified the uncertainty in flow generation for a syringe pump and a pressure-regulated flow system. We then assessed the performance of both LSCI and multi-exposure speckle imaging (MESI) using the pressure-regulated flow system across a range of flow speeds. Approach: The syringe pump and pressure-regulated flow systems were evaluated during stepped flow profile experiments in a microfluidic device using an inline flow sensor. The uncertainty associated with each flow system was calculated and used to determine the reliability for instrument testing. The pressure-regulated flow system was then used to characterize the relative performance of LSCI and MESI during stepped flow profile experiments while using the inline flow sensor as reference. Results: The pressure-regulated flow system produced much more stable and reproducible flow outputs compared to the syringe pump. The expanded uncertainty for the syringe pump was 8 to 20 × higher than that of the pressure-regulated flow system across the tested flow speeds. Using the pressure-regulated flow system, MESI outperformed single-exposure LSCI at all flow speeds and closely mirrored the flow sensor measurements, with average errors of 4.6 % ± 2.6 % and 15.7 % ± 4.6 % , respectively. Conclusions: Pressure-regulated flow systems should be used instead of syringe pumps when assessing the performance of flow measurement techniques with microfluidic studies. MESI offers more accurate relative flow measurements than traditional LSCI across a wide range of flow speeds.

A prospective study on the prevalence of NAFLD, advanced fibrosis, cirrhosis and hepatocellular carcinoma in people with type 2 diabetes.

BACKGROUND & AIMS: There are limited prospective data on patients with type 2 diabetes mellitus (T2DM) specifically enrolled and systematically assessed for advanced fibrosis or cirrhosis due to non-alcoholic fatty liver disease (NAFLD). Therefore, we aimed to evaluate the prevalence of advanced fibrosis and cirrhosis in a prospectively recruited cohort of adults with T2DM. METHODS: This prospective study enrolled adults aged ≥50 years with T2DM, recruited from primary care or endocrinology clinics. Participants underwent a standardized clinical research visit with MRI-proton density fat fraction (MRI-PDFF), magnetic resonance elastography (MRE), vibration-controlled transient elastography (VCTE) and controlled-attenuation parameter. NAFLD was defined as MRI-PDFF ≥5% after exclusion of other liver diseases. Advanced fibrosis and cirrhosis were defined by established liver stiffness cut-off points on MRE or VCTE if MRE was not available. RESULTS: Of 524 patients screened, 501 adults (63% female) with T2DM met eligibility. The mean age and BMI were 64.6 (±8.1) years and 31.4 (±5.9) kg/m2, respectively. The prevalence of NAFLD, advanced fibrosis and cirrhosis was 65%, 14% and 6%, respectively. In multivariable adjusted models, adjusted for age and sex, obesity and insulin use were associated with increased odds of advanced fibrosis (odds ratio 2.50; 95% CI 1.38-4.54; p = 0.003 and odds ratio 2.71; 95% CI 1.33-5.50; p = 0.006, respectively). Among 29 patients with cirrhosis, two were found to have hepatocellular carcinoma and one patient had gallbladder adenocarcinoma. CONCLUSION: Utilizing a uniquely well-phenotyped prospective cohort of patients aged ≥50 years with T2DM, we found that the prevalence of advanced fibrosis was 14% and that of cirrhosis was 6%. These data underscore the high risk of advanced fibrosis/cirrhosis in adults aged ≥50 years with T2DM. IMPACT AND IMPLICATIONS: Non-alcoholic fatty liver disease (NAFLD) is common in patients with type 2 diabetes (T2DM), however, there are limited prospective data characterizing the prevalence of advanced fibrosis and cirrhosis using the most accurate non-invasive biomarkers of liver fat and fibrosis. We show that 14% of older adults with T2DM have advanced fibrosis and 6% have cirrhosis, which places them at risk for liver failure and liver cancer. Accurate prevalence rates and comparative analysis regarding the diagnostic accuracy of non-invasive tests in this population will guide the optimal screening strategy and future cost-effectiveness analyses. These results will inform future Hepatology and Endocrinology practice guidelines regarding NAFLD screening programs in older adults with T2DM.

Risk of advanced fibrosis in first-degree relatives of patients with nonalcoholic fatty liver disease.

BACKGROUNDA pilot, single-center study showed that first-degree relatives of probands with nonalcoholic fatty liver disease (NAFLD) cirrhosis have a high risk of advanced fibrosis. We aimed to validate these findings using 2 independent cohorts from the US and Europe.METHODSThis prospective study included probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD, with at least 1 first-degree relative. A total of 396 first-degree relatives - 220 in a derivation cohort and 176 in a validation cohort - were enrolled in the study, and liver fibrosis was evaluated using magnetic resonance elastography and other noninvasive imaging modalities. The primary outcome was prevalence of advanced fibrosis in first-degree relatives.RESULTSPrevalence of advanced fibrosis in first-degree relatives of probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD was 15.6%, 5.9%, and 1.3%, respectively (P = 0.002), in the derivation cohort, and 14.0%, 2.6%, and 1.3%, respectively (P = 0.004), in the validation cohort. In multivariable-adjusted logistic regression models, age of ≥50 years (adjusted OR [aOR]: 2.63, 95% CI 1.0-6.7), male sex (aOR: 3.79, 95% CI 1.6-9.2), diabetes mellitus (aOR: 3.37, 95% CI 1.3-9), and a first-degree relative with NAFLD with advanced fibrosis (aOR: 11.8, 95% CI 2.5-57) were significant predictors of presence of advanced fibrosis (all P < 0.05).CONCLUSIONFirst-degree relatives of probands with NAFLD with advanced fibrosis have significantly increased risk of advanced fibrosis. Routine screening should be done in the first-degree relatives of patients with advanced fibrosis.FUNDINGSupported by NCATS (5UL1TR001442), NIDDK (U01DK061734, U01DK130190, R01DK106419, R01DK121378, R01DK124318, P30DK120515, K23DK119460), NHLBI (P01HL147835), and NIAAA (U01AA029019); Academy of Finland grant 309263; the Novo Nordisk, EVO, and Sigrid Jusélius Foundations; and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement 777377. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and the EFPIA.

Head-to-head comparison between MEFIB, MAST, and FAST for detecting stage 2 fibrosis or higher among patients with NAFLD.

BACKGROUND & AIMS: Patients with non-alcoholic fatty liver disease (NAFLD) and significant fibrosis (fibrosis stage ≥2) are candidates for pharmacological trials. The aim of this study was to perform a head-to-head comparison of the diagnostic test characteristics of three non-invasive stiffness-based models including MEFIB (magnetic resonance elastography [MRE] plus FIB-4), MAST (magnetic resonance imaging [MRI]-aspartate aminotransferase [AST]), and FAST (FibroScan-AST) for detecting significant fibrosis. METHODS: This prospective study included 563 patients with biopsy-proven NAFLD undergoing contemporaneous MRE, MRI proton density fat fraction (MRI-PDFF) and FibroScan from two prospective cohorts derived from Southern California and Japan. Diagnostic performances of models were evaluated by area under the receiver-operating characteristic curve (AUC). RESULTS: The mean age of the cohort was 56.5 years (51% were women). Significant fibrosis was observed in 51.2%. To detect significant fibrosis, MEFIB outperformed both MAST and FAST (both p <0.001); AUCs for MEFIB, MAST, and FAST were 0.901 (95% CI 0.875-0.928), 0.770 (95% CI 0.730-0.810), and 0.725 (95% CI 0.683-0.767), respectively. Using rule-in criteria, the positive predictive value of MEFIB (95.3%) was significantly higher than that of FAST (83.5%, p = 0.001) and numerically but not statistically greater than that of MAST (90.0%, p = 0.056). Notably, MEFIB's rule-in criteria covered more of the study population than MAST (34.1% vs. 26.6%; p = 0.006). Using rule-out criteria, the negative predictive value of MEFIB (90.1%) was significantly higher than that of either MAST (69.6%) or FAST (71.8%) (both p <0.001). Furthermore, to diagnose "at risk" non-alcoholic steatohepatitis defined as NAFLD activity score ≥4 and fibrosis stage ≥2, MEFIB outperformed both MAST and FAST (both p <0.05); AUCs for MEFIB, MAST, and FAST were 0.768 (95% CI 0.728-0.808), 0.719 (95% CI 0.671-0.766), and 0.687 (95% CI 0.640-0.733), respectively. CONCLUSIONS: MEFIB was better than MAST and FAST for detection of significant fibrosis as well as "at risk" NASH. All three models provide utility for the risk stratification of NAFLD. LAY SUMMARY: Non-alcoholic fatty liver disease (NAFLD) affects over 25% of the general population worldwide and is one of the main causes of chronic liver disease. Because so many individuals have NAFLD, it is not practical to perform liver biopsies to identify those with more severe disease who may require pharmacological interventions. Therefore, accurate non-invasive tests are crucial. Herein, we compared three such tests and found that a test called MEFIB was the best at detecting patients who might require treatment.

Dynamics of isoflurane-induced vasodilation and blood flow of cerebral vasculature revealed by multi-exposure speckle imaging.

BACKGROUND: Anesthetized animal models are used extensively during neurophysiological and behavioral studies despite systemic effects from anesthesia that undermine both accurate interpretation and translation to awake human physiology. The majority of work examining the impact of anesthesia on cerebral blood flow (CBF) has been restricted to before and after measurements with limited spatial resolution. NEW METHOD: We used multi-exposure speckle imaging (MESI), an advanced form of laser speckle contrast imaging (LSCI), to characterize the dynamics of isoflurane anesthesia induction on cerebral vasculature and blood flow in the mouse brain. RESULTS: The large anatomical changes caused by isoflurane are depicted with wide-field imagery and video highlighting the induction of general anesthesia. Within minutes of exposure, both vessel diameter and blood flow increased drastically compared to the awake state and remained elevated for the duration of imaging. An examination of the dynamics of anesthesia induction reveals that blood flow increased faster in arteries than in veins or parenchyma regions. COMPARISON WITH EXISTING METHODS: MESI offers robust hemodynamic measurements across large fields-of-view and high temporal resolutions sufficient for continuous visualization of cerebrovascular events featuring major changes in blood flow. CONCLUSION: The large alterations caused by isoflurane anesthesia to the cortical vasculature and CBF are readily characterized using MESI. These changes are unrepresentative of normal physiology and provide further evidence that neuroscience experiments would benefit from transitioning to un-anesthetized awake animal models.

Promoting gender equity in very young adolescents: targeting a window of opportunity for social emotional learning and identity development.

BACKGROUND: The transition from childhood to adolescence is a uniquely sensitive period for social and emotional learning in the trajectory of human development. This transition is characterized by rapid physical growth, sexual maturation, cognitive and behavioral changes and dynamic changes in social relationships. This pivotal transition provides a window of opportunity for social emotional learning that can shape early adolescent identity formation and gender norms, beliefs and behaviors. The objective of this study is to evaluate the potential of a social emotional learning intervention for very young adolescents (VYAs) to improve social emotional mindsets and skills. METHODS: Discover Learning is a social emotional learning intervention designed for VYAs (10-11 years of age) to support development of social emotional mindsets and skills from four primary schools in Dar es Salaam, Tanzania. The intervention delivered three different packages of learning experiences to three arms of the study. 528 VYAs were randomized to each of the three study arms (A-Content learning, B-Content learning and reflection, and C-Content learning, reflection and experiential practice). A quantitative survey was administered to all participants before and after the intervention to capture changes in social emotional mindsets and skills. A discrete choice experiment measured changes in gender norms, beliefs and behaviors. RESULTS: 528 VYAs were included in the analysis. Participants in all three arms of the study demonstrated significant improvements in social emotional mindsets and skills outcomes (generosity, curiosity, growth mindset, persistence, purpose and teamwork). However, Group C (who received experiential social learning opportunities in small, mixed-gender groups and a parent and community learning components demonstrated larger treatment effects on key outcomes in comparison to Groups A and B. Results indicate Group C participants had greater change in gender equity outcomes (OR = 1.69, p = <0.001) compared to Group A (OR = 1.30, p = <0.001) and Group B (OR = 1.23, p = 0.004). CONCLUSION: These findings provide evidence that social emotional learning interventions targeting VYAs can improve social emotional mindsets and skills and gender equity outcomes. The findings indicate the importance of experiential learning activities in mixed-gender groups during the unique developmental window of early adolescence. The study also provides support for the inclusion of parental/caregiver and community engagement in programs designed for VYAs. TRIAL REGISTRATION: Retrospectively registered on July 7th, 2020. NCT0445807.

The impact of genetic risk on liver fibrosis in non-alcoholic fatty liver disease as assessed by magnetic resonance elastography.

BACKGROUND: Variants in multiple genetic loci modify the risk of non-alcoholic fatty liver disease (NAFLD) and cirrhosis but there are limited data on the quantitative impact of variant copies on liver fibrosis. AIM: To investigate the effect of PNPLA3, TM6SF2, MBOAT7, GCKR and HSD17B13 genotype on liver fibrosis assessed by magnetic resonance elastography (MRE), a reproducible, accurate, continuous biomarker of liver fibrosis. METHODS: This is a cross-sectional analysis derived from a well-characterised cohort at risk for NAFLD who underwent genotyping and MRE assessment. Liver stiffness (LS) was estimated using MRE and advanced fibrosis was defined as liver stiffness ≥3.63 kilopascals (kPa). Univariable and multivariable linear and logistic regression analysis, were used to assess the association between genotype and MRE. RESULTS: Two hundred sixty-four patients (63% women) with a mean age 53 (±17) years, and 31% Hispanic ethnicity with genotyping and MRE were included. The odds of advanced fibrosis were 3.1 (95% CI: 1.1-8.9, P = 0.04) for CG and 6.5 (95% CI: 2.2-18.9, P < 0.01) for GG compared to CC PNPLA3 genotype. Each PNPLA3 risk variant copy was associated with 0.40 kPa (95% CI: 0.19-0.61, P < 0.01) increase in LS on MRE in analysis adjusted for age, sex and BMI and there was significant genotype-age interaction (P < 0.01). Conversely, the protective TA allele in HSD17B13 was associated with a -0.41 kPa (95% CI: -0.76 to -0.05, P = 0.03) decrease in liver stiffness on MRE multivariable analysis. CONCLUSION: Knowledge of PNPLA3 and HSD17B13 genotype may assist in the non-invasive risk stratification of NAFLD with closer monitoring recommended for those with high genetic risk.

RAMIC: Design of a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of ramipril in patients with COVID-19.

BACKGROUND AND AIMS: Retrospective studies have shown that angiotensin-converting-enzyme (ACE) inhibitors are associated with a reduced risk of complications and mortality in persons with novel coronavirus disease 2019 (COVID-19). Thus, we aimed to examine the efficacy of ramipril, an ACE-inhibitor, in preventing ICU admission, mechanical ventilation and/or mortality while also minimizing the risk of transmission and use of personal protective equipment (PPE). METHODS: RAMIC is a multicenter, randomized, double-blind, allocation-concealed, placebo-controlled trial comparing the efficacy of treatment with ramipril 2.5 mg orally daily compared to placebo for 14 days. The study population includes adult patients with COVID-19 who were admitted to a hospital or assessed in an emergency department or ambulatory clinic. Key exclusion criteria include ICU admission or need for mechanical ventilation at screening, use of an ACE inhibitor or angiotensin-receptor-II blocker within 7 days, glomerular filtration rate < 40 mL/min or a systolic blood pressure (BP) < 100 mmHg or diastolic BP < 65 mmHg. Patients are randomized 2:1 to receive ramipril (2.5 mg) or placebo daily. Informed consent and study visits occur virtually to minimize the risk of SARS-CoV-2 transmission and preserve PPE. The primary composite endpoint of ICU admission, invasive mechanical ventilation and death are adjudicated virtually. CONCLUSIONS: RAMIC is designed to assess the efficacy of treatment with ramipril for 14 days to decrease ICU admission, mechanical ventilator use and mortality in patients with COVID-19 and leverages virtual study visits and endpoint adjudication to mitigate risk of infection and to preserve PPE (ClinicalTrials.gov, NCT04366050).

Study Protocol of a Distance Learning Intervention to Support Social Emotional Learning and Identity Development for Adolescents Using Interactive Mobile Technology.

Background: The maturational period from age 10 to 14-often referred to as very young adolescents (VYAs)-represents a dynamic period of learning and neurobehavioral development as individuals transition from childhood to adolescence. This developmental period presents a window of opportunity for strategic investment to improve trajectories of health, education and well-being among young people. More specifically, neurodevelopmental changes during pubertal maturation influence neural circuitry involved in processing emotions, risks, rewards and social relationships. Technology can be leveraged to create social emotional learning experiences for VYAs and provide opportunities for flexible, distance learning in low-income countries. The aim of this study protocol is to detail how insights from developmental science can be used to inform the intervention design, implementation and evaluation of a distance learning, social emotional learning intervention for VYAs. Methods: This study will be delivered to 500 VYAs in Temeke District, Dar es salaam. Study participants will watch culturally-relevant, animated videos on social emotional mindsets and skills and content will be paired with experiential learning activities over a period of 10 weeks. A nested smart-phone based study will practice learning social emotional skills and mindsets through engagement with multi-media material via the WhatsApp messenger application. Surveys and in-depth interviews will be administered to adolescents, their parents/caregivers and teachers before and after the intervention to evaluate the effect of the intervention on study outcomes. Discussion: This study is among the first to provide results on how to effectively design a distance-learning intervention to promote social emotional learning and identity development within a low-resource context. The findings will provide substantial evidence to inform new intervention approaches that are effective in low-resource contexts and strategies to reach scale among similar programs invested in leveraging technology to support adolescent health and development. Clinical Trial registration: Study registered with ClinicalTrials.gov. Identifier number NCT0445807.

Adolescent, caregiver and community experiences with a gender transformative, social emotional learning intervention.

BACKGROUND: Inequitable gender norms, beliefs and behaviors, are shaped by learning experiences during key developmental stages in an individual's life course, and can have negative impacts on health and well-being outcomes. Very early adolescence represents one stage when formative learning experiences about gender inequity can have the potential to support or hinder more equitable gender norms, beliefs and behaviors. The aim of this qualitative study was to evaluate the effect of a gender transformative, social emotional learning intervention for very young adolescents (VYAs) that included experiential learning with peers, parents/caregivers and community members. METHODS: This study examined the effects of an intervention designed to provide social emotional learning opportunities for adolescents ages 10-11 in Dar es Salaam, Tanzania. The qualitative sample included 279 participants. Qualitative methods included 102 in-depth interviews with VYAs, 22 focus groups with 117 VYAs, 60 in-depth interviews with parents/caregivers and 54 participant observations. A grounded theory approach was used to identify emergent themes. RESULTS: Participants reported growth in targeted areas of social emotional mindsets and skills, including a shift in gender norms, beliefs and behaviors. VYAs reported that experiential learning in mixed gender teams provided opportunities to actively practice and reflect on gender norms, beliefs and behaviors. VYAs also reported active practice of social emotional mindsets and skills with peers, parents/caregivers and the community. Parents/caregivers reported changes in VYAs' social emotional mindsets and skills within the home, with the community and with siblings and peers. Both adolescents and parent/caregivers reported positive change towards more equitable gender norms, beliefs and behaviors through participation in experiential learning activities and reflective discussions. CONCLUSIONS: These findings suggest that an intervention providing social and emotional experiential learning opportunities during the developmental window of very young adolescence can be effective in transforming gender norms, beliefs and behaviors. Involvement of peers, parents/caregivers and community members was effective at supporting learning social emotional mindsets and skills in VYAs. Findings encourage local and global adolescent programming to include gender transformative content paired with social emotional experiential learning with peers, family and the community and can stimulate positive change in gender norms, beliefs and behaviors to promote gender equity.

The role of anxiety sensitivity in exercise tolerance and anxiety and depressive symptoms among individuals seeking treatment in cardiopulmonary rehabilitation.

The aim of the current cross-sectional study was to examine the effects of specific anxiety sensitivity (AS) dimensions (AS -Physical, -Cognitive, and -Social concerns) on exercise tolerance (i.e. 6-minute walk test) and factors that interfere with cardiopulmonary rehabilitation (CPR) and exercise adherence (i.e. depression and anxiety symptoms) among individuals seeking treatment in cardiopulmonary rehabilitation (CPR). Participants were 69 individuals (65.2% male, Mage = 63.60, SD = 12.55, Range = 27-85 years) with various cardiovascular or pulmonary conditions meeting criteria for CPR entry, who presented for an intake appointment at an outpatient phase 2 CPR clinic. Higher levels of AS-Physical and-Social concerns were significantly associated with poorer exercise tolerance and greater generalized anxiety symptoms, respectively. Though none of the AS dimensions were significant individual predictors, they were collectively associated with greater depressive symptoms. Future work should assess whether it may be useful to target AS in some patients prior to or throughout CPR.

MRE combined with FIB-4 (MEFIB) index in detection of candidates for pharmacological treatment of NASH-related fibrosis.

OBJECTIVE: Patients with non-alcoholic fatty liver disease (NAFLD) with ≥stage 2 fibrosis are at increased risk for liver-related mortality and are candidates for pharmacological therapies for treatment of NAFLD. The aim of this prospective cohort study is to examine the diagnostic accuracy of MR elastography (MRE) combined with fibrosis-4 (FIB-4) in diagnosing ≥stage 2 fibrosis (candidates for pharmacological therapies). DESIGN: This is a cross-sectional analysis of a prospective cohort (University of California at San Diego (UCSD)-NAFLD) including 238 consecutive patients with contemporaneous MRE and biopsy-proven NAFLD. Non-alcoholic steatohepatitis-Clinical Research Network-Histologic Scoring System was used to assess histology. The radiologist and pathologist were blinded to clinical, pathological and imaging data, respectively. Receiver operating characteristics (ROCs) were determined to examine the diagnostic accuracy of MRE and FIB-4 for diagnosis of ≥stage 2 fibrosis in NAFLD. We then validated these findings in an independent validation cohort derived from Yokohama City University in Japan (Japan-NAFLD Cohort; N=222 patients). RESULTS: In the UCSD-NAFLD (training) Cohort, MRE demonstrated a clinically significant diagnostic accuracy for the detection of ≥stage 2 fibrosis with an area under the ROC curve (AUROC) of 0.93 (95% CI 0.90 to 0.97) vs FIB-4 with an AUROC of 0.78 (95% CI 0.71 to 0.85), which was both clinically and statistically significant (p<0.0001). We then combined MRE with FIB-4 (MRE ≥3.3 kPa and FIB-4 ≥1.6) to develop a clinical prediction rule to rule in ≥stage 2 fibrosis patients which had positive predictive value (PPV) of 97.1% (p<0.02) in the UCSD-NAFLD cohort (AUROC of 0.90 (95% CI 0.85 to 0.95)) which remained significant at PPV of 91.0% (p<0.003) in the Japan-NAFLD Cohort (AUROC of 0.84 (95% CI 0.78 to 0.89)). CONCLUSION: MRE combined with FIB-4 (MEFIB) index may be used for non-invasive identification of candidates for (≥stage 2 fibrosis) pharmacological therapy among patients with NAFLD with a high PPV.