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ObjectiveLiver biopsy is still needed for fibrosis staging in many patients with non-alcoholic fatty liver disease. The aims of this study were to evaluate the individual diagnostic performance of liver stiffness measurement by vibration controlled transient elastography (LSM-VCTE), Fibrosis-4 Index (FIB-4) and NAFLD (non-alcoholic fatty liver disease) Fibrosis Score (NFS) and to derive diagnostic strategies that could reduce the need for liver biopsies.DesignIndividual patient data meta-analysis of studies evaluating LSM-VCTE against liver histology was conducted. FIB-4 and NFS were computed where possible. Sensitivity, specificity and area under the receiver operating curve (AUROC) were calculated. Biomarkers were assessed individually and in sequential combinations.ResultsData were included from 37 primary studies (n=5735; 45% women; median age: 54 years; median body mass index: 30 kg/m2; 33% had type 2 diabetes; 30% had advanced fibrosis). AUROCs of individual LSM-VCTE, FIB-4 and NFS for advanced fibrosis were 0.85, 0.76 and 0.73. Sequential combination of FIB-4 cut-offs (ConclusionSequential combinations of markers with a lower cut-off to rule-out advanced fibrosis and a higher cut-off to rule-in cirrhosis can reduce the need for liver biopsies.

BACKGROUND: Dilated cardiomyopathy (DCM) is a final common manifestation of heterogenous etiologies. Adverse outcomes highlight the need for disease stratification beyond ejection fraction. OBJECTIVES: The purpose of this study was to identify novel, reproducible subphenotypes of DCM using multiparametric data for improved patient stratification. METHODS: Longitudinal, observational UK-derivation (n = 426; median age 54 years; 67% men) and Dutch-validation (n = 239; median age 56 years; 64% men) cohorts of DCM patients (enrolled 2009-2016) with clinical, genetic, cardiovascular magnetic resonance, and proteomic assessments. Machine learning with profile regression identified novel disease subtypes. Penalized multinomial logistic regression was used for validation. Nested Cox models compared novel groupings to conventional risk measures. Primary composite outcome was cardiovascular death, heart failure, or arrhythmia events (median follow-up 4 years). RESULTS: In total, 3 novel DCM subtypes were identified: profibrotic metabolic, mild nonfibrotic, and biventricular impairment. Prognosis differed between subtypes in both the derivation (P < 0.0001) and validation cohorts. The novel profibrotic metabolic subtype had more diabetes, universal myocardial fibrosis, preserved right ventricular function, and elevated creatinine. For clinical application, 5 variables were sufficient for classification (left and right ventricular end-systolic volumes, left atrial volume, myocardial fibrosis, and creatinine). Adding the novel DCM subtype improved the C-statistic from 0.60 to 0.76. Interleukin-4 receptor-alpha was identified as a novel prognostic biomarker in derivation (HR: 3.6; 95% CI: 1.9-6.5; P = 0.00002) and validation cohorts (HR: 1.94; 95% CI: 1.3-2.8; P = 0.00005). CONCLUSIONS: Three reproducible, mechanistically distinct DCM subtypes were identified using widely available clinical and biological data, adding prognostic value to traditional risk models. They may improve patient selection for novel interventions, thereby enabling precision medicine. ispartof: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY vol:79 issue:22 pages:2219-2232 ispartof: location:United States status: published

Female physicians in academic medicine have faced barriers that potentially affect representation in different fields and delay promotion. Little is known about gender representation differences in United States academic radiology departments, particularly within the most pursued subspecialties.To determine whether gender differences exist in United States academic radiology departments across seven subspecialties with respect to academic ranks, departmental leadership positions, experience, and scholarly metrics.In this cross-sectional study from November 2018 to June 2020, a database of United States academic radiologists at 129 academic departments in seven subspecialties was created. Each radiologist's academic rank, departmental leadership position (executive-level - Chair, Director, Chief, and Department or Division Head vs vice-level - vice, assistant, or associate positions of executive level), self-identified gender, years in practice, and measures of scholarly productivity (number of publications, citations, and h-index) were compiled from institutional websites, Doximity, LinkedIn, Scopus, and official NPI profiles. The primary outcome, gender composition differences in these cohorts, was analyzed using ChiOverall, 5086 academic radiologists (34.7% women) with a median 14 years of practice (YOP) were identified and indexed. There were 919 full professors (26.1% women, p0.01) and 1055 executive-level leadership faculty (30.6% women, p0.01). Within all subspecialties except breast imaging, women were in the minority (35.4% abdominal, 79.1% breast, 12.1% interventional, 27.5% musculoskeletal, 22.8% neuroradiology, 45.1% pediatric, and 19.5% nuclear; p0.01). Relative to subspecialty gender composition, women full professors were underrepresented in abdominal, pediatric, and nuclear radiology (p0.05) and women in any executive-level leadership were underrepresented in abdominal and nuclear radiology (p0.05). However, after adjusting for h-index and YOP, gender did not influence rates of professorship or executive leadership. The strongest single predictors for professorship or executive leadership were h-index and YOP.Women academic radiologists in the United States are underrepresented among senior faculty members despite having similar levels of experience as men. Gender disparities regarding the expected number of women senior faculty members relative to individual subspecialty gender composition were more pronounced in abdominal and nuclear radiology, and less pronounced in breast and neuroradiology. Overall, h-index and YOP were the strongest predictors for full-professorship and executive leadership among faculty.● Though women comprise 34.7% of all academic radiologists, women are underrepresented among senior faculty members (26.1% of full professors and 30.6% of executive leadership) ● Women in junior faculty positions had higher median years of practice than their male counterparts (10 vs 8 for assistant professors, 21 vs 13 for vice leadership) ● Years of practice and h-index were the strongest predictors for full professorship and executive leadership.

The 2015 Magnetic Resonance Imaging in Multiple Sclerosis and 2016 Consortium of Multiple Sclerosis Centres guidelines on the use of MRI in diagnosis and monitoring of multiple sclerosis made an important step towards appropriate use of MRI in routine clinical practice. Since their promulgation, there have been substantial relevant advances in knowledge, including the 2017 revisions of the McDonald diagnostic criteria, renewed safety concerns regarding intravenous gadolinium-based contrast agents, and the value of spinal cord MRI for diagnostic, prognostic, and monitoring purposes. These developments suggest a changing role of MRI for the management of patients with multiple sclerosis. This 2021 revision of the previous guidelines on MRI use for patients with multiple sclerosis merges recommendations from the Magnetic Resonance Imaging in Multiple Sclerosis study group, Consortium of Multiple Sclerosis Centres, and North American Imaging in Multiple Sclerosis Cooperative, and translates research findings into clinical practice to improve the use of MRI for diagnosis, prognosis, and monitoring of individuals with multiple sclerosis. We recommend changes in MRI acquisition protocols, such as emphasising the value of three dimensional-fluid-attenuated inversion recovery as the core brain pulse sequence to improve diagnostic accuracy and ability to identify new lesions to monitor treatment effectiveness, and we provide recommendations for the judicious use of gadolinium-based contrast agents for specific clinical purposes. Additionally, we extend the recommendations to the use of MRI in patients with multiple sclerosis in childhood, during pregnancy, and in the post-partum period. Finally, we discuss promising MRI approaches that might deserve introduction into clinical practice in the near future.

To determine if history of mild traumatic brain injury (mTBI) is associated with advanced or accelerated brain aging among the United States (US) military Service Members and Veterans. Eight hundred and twenty-two participants (mean age = 40.4 years, 714 male/108 female) underwent MRI sessions at eight sites across the US. Two hundred and one participants completed a follow-up scan between five months and four years later. Predicted brain ages were calculated using T1-weighted MRIs and then compared with chronological ages to generate an Age Deviation Score for cross-sectional analyses and an Interval Deviation Score for longitudinal analyses. Participants also completed a neuropsychological battery, including measures of both cognitive functioning and psychological health. In cross-sectional analyses, males with a history of deployment-related mTBI showed advanced brain age compared to those without (t(884) = 2.1, p = .038), while this association was not significant in females. In follow-up analyses of the male participants, severity of posttraumatic stress disorder (PTSD), depression symptoms, and alcohol misuse were also associated with advanced brain age. History of deployment-related mTBI, severity of PTSD and depression symptoms, and alcohol misuse are associated with advanced brain aging in male US military Service Members and Veterans.

Urinary tract infections commonly occur in patients with spina bifida and pose a risk of renal scarring. Routine antibiotic prophylaxis has been utilized in newborns with spina bifida to prevent urinary tract infections. We hypothesized that prophylaxis can safely be withheld in newborns with spina bifida until clinical assessment allows for risk stratification.Newborns with myelomeningocele at 9 institutions were prospectively enrolled in the UMPIRE study and managed by a standardized protocol with a strict definition of urinary tract infection. Patient data were collected regarding details of reported urinary tract infection, baseline renal ultrasound findings, vesicoureteral reflux, use of clean intermittent catheterization and circumcision status in boys. Risk ratios and corresponding 95% confidence intervals were calculated using log-binomial models.From February 2015 through August 2019 data were available on 299 newborns (50.5% male). During the first 4 months of life, 48 newborns (16.1%) were treated for urinary tract infection with 23 (7.7%) having positive cultures; however, only 12 (4.0%) met the strict definition of urinary tract infection. Infants with grade 3-4 hydronephrosis had an increased risk of urinary tract infection compared to infants with no hydronephrosis (RR=10.1; 95% CI=2.8, 36.3). Infants on clean intermittent catheterization also had an increased risk of urinary tract infection (RR=3.3; 95% CI=1.0, 10.5).The incidence of a culture positive, symptomatic urinary tract infection among newborns with spina bifida in the first 4 months of life was low. Patients with high grades of hydronephrosis or those on clean intermittent catheterization had a significantly greater incidence of urinary tract infection. Our findings suggest that routine antibiotic prophylaxis may not be necessary for most newborns with spina bifida.

See Whyte and Turkstra (doi:10.1093/brain/awab210) for a scientific commentary on this article. In a randomized controlled trial, Mahncke et al. show that a self-administered computerized cognitive training program drove significant and enduring improvements in cognitive function in people with a history of mild traumatic brain injury and cognitive impairment, compared to an active control (computer games)., Clinical practice guidelines support cognitive rehabilitation for people with a history of mild traumatic brain injury (mTBI) and cognitive impairment, but no class I randomized clinical trials have evaluated the efficacy of self-administered computerized cognitive training. The goal of this study was to evaluate the efficacy of a self-administered computerized plasticity-based cognitive training programmes in primarily military/veteran participants with a history of mTBI and cognitive impairment. A multisite randomized double-blind clinical trial of a behavioural intervention with an active control was conducted from September 2013 to February 2017 including assessments at baseline, post-training, and after a 3-month follow-up period. Participants self-administered cognitive training (experimental and active control) programmes at home, remotely supervised by a healthcare coach, with an intended training schedule of 5 days per week, 1 h per day, for 13 weeks. Participants (149 contacted, 83 intent-to-treat) were confirmed to have a history of mTBI (mean of 7.2 years post-injury) through medical history/clinician interview and persistent cognitive impairment through neuropsychological testing and/or quantitative participant reported measure. The experimental intervention was a brain plasticity-based computerized cognitive training programme targeting speed/accuracy of information processing, and the active control was composed of computer games. The primary cognitive function measure was a composite of nine standardized neuropsychological assessments, and the primary directly observed functional measure a timed instrumental activities of daily living assessment. Secondary outcome measures included participant-reported assessments of cognitive and mental health. The treatment group showed an improvement in the composite cognitive measure significantly larger than that of the active control group at both the post-training [+6.9 points, confidence interval (CI) +1.0 to +12.7, P = 0.025, d = 0.555] and the follow-up visit (+7.4 points, CI +0.6 to +14.3, P = 0.039, d = 0.591). Both large and small cognitive function improvements were seen twice as frequently in the treatment group than in the active control group. No significant between-group effects were seen on other measures, including the directly-observed functional and symptom measures. Statistically equivalent improvements in both groups were seen in depressive and cognitive symptoms.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a common disease that is associated with increased morbidity and mortality, but treatment options are limited. The efficacy and safety of the glucagon-like peptide-1 receptor agonist semaglutide in patients with NASH is not known.METHODS: We conducted a 72-week, double-blind phase 2 trial involving patients with biopsy-confirmed NASH and liver fibrosis of stage F1, F2, or F3. Patients were randomly assigned, in a 3:3:3:1:1:1 ratio, to receive once-daily subcutaneous semaglutide at a dose of 0.1, 0.2, or 0.4 mg or corresponding placebo. The primary end point was resolution of NASH with no worsening of fibrosis. The confirmatory secondary end point was an improvement of at least one fibrosis stage with no worsening of NASH. The analyses of these end points were performed only in patients with stage F2 or F3 fibrosis; other analyses were performed in all the patients.RESULTS: In total, 320 patients (of whom 230 had stage F2 or F3 fibrosis) were randomly assigned to receive semaglutide at a dose of 0.1 mg (80 patients), 0.2 mg (78 patients), or 0.4 mg (82 patients) or to receive placebo (80 patients). The percentage of patients in whom NASH resolution was achieved with no worsening of fibrosis was 40% in the 0.1-mg group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in the placebo group (PCONCLUSIONS: This phase 2 trial involving patients with NASH showed that treatment with semaglutide resulted in a significantly higher percentage of patients with NASH resolution than placebo. However, the trial did not show a significant between-group difference in the percentage of patients with an improvement in fibrosis stage. (Funded by Novo Nordisk; ClinicalTrials.gov number, NCT02970942.).

ObjectiveTo evaluate whether a retinal spectral-domain optical coherence tomography (SD-OCT) assessment at baseline is associated with long-term disability worsening in people with multiple sclerosis (PwMS), we performed SD-OCT and Expanded Disability Status Scale (EDSS) assessments among 132 PwMS at baseline and at a median of 10 years later.MethodsIn this prospective, longitudinal study, participants underwent SD-OCT, EDSS, and visual acuity (VA) assessments at baseline and at follow-up. Statistical analyses were performed using generalized linear regression models, adjusted for age, sex, race, multiple sclerosis (MS) subtype, and baseline disability. We defined clinically meaningful EDSS worsening as an increase of ≥2.0 if baseline EDSS score was ResultsA total of 132 PwMS (mean age 43 years; 106 patients with relapsing-remitting MS) were included in analyses. Median duration of follow-up was 10.4 years. In multivariable models excluding eyes with prior optic neuritis, relative to patients with an average baseline ganglion cell + inner plexiform layer (GCIPL) thickness ≥70 µm (the mean GCIPL thickness of all eyes at baseline), an average baseline GCIPL thickness p = 0.02) and an almost 3-fold increased odds of low-contrast VA worsening (adjusted OR 2.93, 95% CI 1.40–6.13; p = 0.04).ConclusionsLower baseline GCIPL thickness on SD-OCT is independently associated with long-term disability worsening in MS. Accordingly, SD-OCT at a single time point may help guide therapeutic decision-making among individual PwMS.Classification of EvidenceThis study provides Class I evidence that lower baseline GCIPL thickness on SD-OCT is independently associated with long-term disability worsening in MS.

The CHORDS trial evaluated ocrelizumab (OCR) in patients with relapsing‐remitting multiple sclerosis who had a suboptimal response to previous disease‐modifying treatment. The objective of the present study was to assess the safety of shorter OCR infusions in a substudy of CHORDS. After completing four doses of OCR per initial US prescribing recommendations in the main study, participants in the substudy (N = 129) received a fifth dose over a 2‐h duration (vs. 3.5 h). Infusion‐related reactions occurred in 12.4% of patients. None were severe, life‐threatening or led to treatment discontinuation. Shorter infusion time did not change the safety profile of OCR. Clinicaltrials.gov (NCT0237856).

Background We aimed to characterize the spectrum of clinical features and examination findings in pediatric-onset stiff person syndrome. Methods Medical records were reviewed for all patients treated for stiff person syndrome with symptom onset in childhood at a tertiary medical center between March 2001 and February 2019. Results Of the 15 individuals who met inclusion criteria, 11 (73%) were female and 13 (87%) were Caucasian. Median age at symptom onset was 14.8 years (range 8.4 to 16.9), and median latency from symptom onset to diagnosis was 6.2 years (range 0.4 to 15.0). Nine individuals (60%) were not diagnosed until adulthood. The most common presenting features were painful spasms (n = 12, 80%), hyper-reflexia (n = 11, 73%), axial rigidity (n = =9, 60%), lower extremity rigidity or spasticity (n = 8, 53%), gait abnormalities (n = 6, 40%), and hyperlordosis (n = 6, 40%). Other noted features included anxiety (n = 5, 33%), dysautonomia (n = 3, 20%), and cranial neuropathies (n = 3, 20%). Personal (n = 9, 60%) and family history (n = 9, 60%) of autoimmune conditions was common. Serum antiglutamate decarboxylase 65 antibodies were found in 13 individuals (87%). Nearly all individuals received immunotherapy (n = 14, 93%), symptomatic medications (n = 15, 100%), and nonpharmacologic therapies (n = 14, 93%). However, most had persistent physical limitations, particularly impaired walking (n = 7, 47%) and inability to carry out previous activities (n = 14, 93%). Conclusions There is a wide spectrum of typical and less common features seen in individuals with pediatric-onset stiff person syndrome. Despite symptom onset in childhood, diagnosis is often delayed until adulthood, at which point disability accrual is frequently seen. Early recognition is vital to address symptoms and may potentially limit future disability.

Data on medium-term outcomes in indivduals with myocarditis after mRNA COVID-19 vaccination are scarce. We aimed to assess clinical outcomes and quality of life at least 90 days since onset of myocarditis after mRNA COVID-19 vaccination in adolescents and young adults.In this follow-up surveillance study, we conducted surveys in US individuals aged 12-29 years with myocarditis after mRNA COVID-19 vaccination, for whom a report had been filed to the Vaccine Adverse Event Reporting System between Jan 12 and Nov 5, 2021. A two-component survey was administered, one component to patients (or parents or guardians) and one component to health-care providers, to assess patient outcomes at least 90 days since myocarditis onset. Data collected were recovery status, cardiac testing, and functional status, and EuroQol health-related quality-of-life measures (dichotomised as no problems or any problems), and a weighted quality-of-life measure, ranging from 0 to 1 (full health). The EuroQol results were compared with published results in US populations (aged 18-24 years) from before and early on in the COVID-19 pandemic.Between Aug 24, 2021, and Jan 12, 2022, we collected data for 519 (62%) of 836 eligible patients who were at least 90 days post-myocarditis onset: 126 patients via patient survey only, 162 patients via health-care provider survey only, and 231 patients via both surveys. Median patient age was 17 years (IQR 15-22); 457 (88%) patients were male and 61 (12%) were female. 320 (81%) of 393 patients with a health-care provider assessment were considered recovered from myocarditis by their health-care provider, although at the last health-care provider follow-up, 104 (26%) of 393 patients were prescribed daily medication related to myocarditis. Of 249 individuals who completed the quality-of-life portion of the patient survey, four (2%) reported problems with self-care, 13 (5%) with mobility, 49 (20%) with performing usual activities, 74 (30%) with pain, and 114 (46%) with depression. Mean weighted quality-of-life measure (0·91 [SD 0·13]) was similar to a pre-pandemic US population value (0·92 [0·13]) and significantly higher than an early pandemic US population value (0·75 [0·28]; p0·0001). Most patients had improvements in cardiac diagnostic marker and testing data at follow-up, including normal or back-to-baseline troponin concentrations (181 [91%] of 200 patients with available data), echocardiograms (262 [94%] of 279 patients), electrocardiograms (240 [77%] of 311 patients), exercise stress testing (94 [90%] of 104 patients), and ambulatory rhythm monitoring (86 [90%] of 96 patients). An abnormality was noted among 81 (54%) of 151 patients with follow-up cardiac MRI; however, evidence of myocarditis suggested by the presence of both late gadolinium enhancement and oedema on cardiac MRI was uncommon (20 [13%] of 151 patients). At follow-up, most patients were cleared for all physical activity (268 [68%] of 393 patients).After at least 90 days since onset of myocarditis after mRNA COVID-19 vaccination, most individuals in our cohort were considered recovered by health-care providers, and quality of life measures were comparable to those in pre-pandemic and early pandemic populations of a similar age. These findings might not be generalisable given the small sample size and further follow-up is needed for the subset of patients with atypical test results or not considered recovered.US Centers for Disease Control and Prevention.

Spasticity occurs frequently in people with multiple sclerosis (PwMS) and may affect non-physical aspects of life. However, there is a paucity of data assessing the full impact of spasticity in PwMS.This survey of PwMS and spasticity (PwMSS) was undertaken to understand the impact of spasticity in physical, functional, emotional, and social domains.SEEN-MSS (Symptoms and Emotions Exploration Needed in Multiple Sclerosis Spasticity), an online survey, was developed in collaboration with three US-based MS organizations (conducted February-April 2021).Survey was completed by 1,177 PwMSS, 78% female, mean age 56.8yrs, 16.8yrs from MS diagnosis, 11.5yrs with spasticity. Considering day-to-day goals of treatment, respondents reported that managing symptoms(46%) was nearly as important as slowing disease progression(54%). Most reported spasticity was a constant reminder of their MS. Participants reported that spasticity limited daily activities (92%), caused pain (92%), impaired sleep (89%) and negatively impacted emotional well-being (87%). Spasticity fostered a sense of dependence (61%), isolation (40%), decline in self-confidence (75%), self-image (70%), and social connection (62%).Spasticity has wide-reaching negative impacts on multiple aspects of life, causing substantial burden for PwMSS. Results emphasize the need to fully understand the burden of spasticity and addressing individual needs of PwMSS.

© 2019 Elsevier Ltd. All rights reserved., Background: Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods: In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings: Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation: Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes.

Atrial fibrillation (AF) in hypertrophic cardiomyopathy (HC) is associated with significant symptomatic deterioration, heart failure, and thromboembolic disease. There is a need for better mechanistic insight and improved identification of at risk patients. We used cardiovascular magnetic resonance (CMR) to assess predictors of AF in HC, in particular the role of myocardial fibrosis. Consecutive patients with HC referred for CMR 2003 to 2013 were prospectively enrolled. CMR parameters including left ventricular volumes, presence and percentage of late gadolinium enhancement in the left ventricle (%LGE) and left atrial volume index (LAVi) were measured. Overall, 377 patients were recruited (age 62 ± 14 years, 73% men). Sixty-two patients (16%) developed new-onset AF during a median follow up of 4.5 (interquartile range 2.9 to 6.0) years. Multivariable analysis revealed %LGE (hazard ratio [HR] 1.3 per 10% (confidence interval: 1.0 to 1.5; p = 0.02), LAVi (HR 1.4 per 10 mL/m 2[1.2 to 1.5; p < 0.001]), age at HC diagnosis, nonsustained ventricular tachycardia and diabetes to be independent predictors of AF. We constructed a simple risk prediction score for future AF based on the multivariable model with a Harrell's C-statistic of 0.73. In conclusion, the extent of ventricular fibrosis and LA volume independently predicted AF in patients with HC. This finding suggests a mechanistic relation between fibrosis and future AF in HC. CMR with quantification of fibrosis has incremental value over LV and LA measurements in risk stratification for AF. A risk prediction score may be used to identify patients at high risk of future AF who may benefit from more intensive rhythm monitoring and a lower threshold for oral anticoagulation.

Background & Aims Volixibat is an inhibitor of the apical sodium-dependent bile acid transporter (ASBT) that has been hypothesized to improve non-alcoholic steatohepatitis (NASH) by blocking bile acid reuptake and stimulating hepatic bile acid production. We studied the safety, tolerability and efficacy of volixibat in patients with NASH. Methods In this double-blind, phase II dose-finding study, adults with ≥5% steatosis and NASH without cirrhosis (N = 197) were randomized to receive volixibat (5, 10 or 20 mg) or placebo once daily for 48 weeks. The endpoints of a predefined interim analysis (n = 80), at week 24, were: ≥5% reduction in MRI-proton density fat fraction and ≥20% reduction in serum alanine aminotransferase levels. The primary endpoint was a ≥2-point reduction in non-alcoholic fatty liver disease activity score without worsening fibrosis at week 48. Results Volixibat did not meet either interim endpoint; the study was terminated owing to lack of efficacy. In participants receiving any volixibat dose, mean serum 7-alpha-hydroxy-4-cholesten-3-one (C4; a biomarker of bile acid synthesis) increased from baseline to week 24 (+38.5 ng/ml [SD 53.18]), with concomitant decreases in serum total cholesterol (−14.5 mg/dl [SD 28.32]) and low-density lipoprotein cholesterol (−16.1 mg/dl [SD 25.31]). These changes were generally dose-dependent. On histological analysis, a greater proportion of participants receiving placebo (38.5%, n = 5/13) than volixibat (30.0%, n = 9/30) met the primary endpoint. Treatment-emergent adverse events (TEAEs) were mainly mild or moderate. No serious TEAEs were related to volixibat. Diarrhoea was the most common TEAE overall and the most common TEAE leading to discontinuation. Conclusions Increased serum C4 and decreased serum cholesterol levels provide evidence of target engagement. However, inhibition of ASBT by volixibat did not elicit a liver-related therapeutic benefit in adults with NASH. Lay summary A medicine called volixibat has previously been shown to reduce cholesterol levels in the blood. This study investigated whether volixibat could reduce the amount of fat in the liver and reduce liver injury in adults with an advanced form of non-alcoholic fatty liver disease. Volixibat did not reduce the amount of fat in the liver, nor did it have any other beneficial effect on liver injury. Participants in the study generally tolerated the side effects of volixibat and, as in previous studies, the main side effect was diarrhoea. These results show that volixibat is not an effective treatment for people with fatty liver disease. Clinical trial identifier NCT02787304 .

Purpose To determine predictors of survival after transarterial radioembolization of hepatic metastases from breast cancer. Materials and Methods Twenty-four patients with chemotherapy-refractory hepatic metastases from breast cancer who underwent radioembolization from 2013 to 2018 were evaluated based on various demographic and clinical factors before and after treatment. Overall survival (OS) was estimated by Kaplan–Meier method. Log-rank analysis was performed to determine predictors of prolonged OS from the time of first radioembolization and first hepatic metastasis diagnosis. Results Median OS times were 35.4 and 48.6 months from first radioembolization and time of hepatic metastasis diagnosis, respectively. Radioembolization within 6 months of hepatic metastasis diagnosis was a positive predictor of survival from first radioembolization, with median OS of 38.9 months vs 22.1 months for others (P = .033). Estrogen receptor (ER)–positive status predicted prolonged survival (38.6 months for ER+ vs 5.4 months for ER−; P = .005). The presence of abdominal pain predicted poor median OS: 12.8 months vs 38.6 months for others (P Conclusions In patients with metastatic breast cancer, radioembolization within 6 months of hepatic metastasis diagnosis and ER+ status appear to be positive predictors of prolonged survival. Conversely, baseline abdominal pain, baseline ascites, and treatment-related grade ≥ 2 toxicity at 3 months after treatment appear to be negative predictors of OS.

To investigate timing of Yttrium-90 radioembolization (Y90) during treatment course, genomics, and other clinical factors as predictors of overall survival (OS) in colorectal liver metastasis (CRLM) that have progressed on at least one line of chemotherapy. This was a retrospective study from 2013 to 2018 of patients with CRLM and genomic analysis prior to Y90 at a multihospital tertiary referral center. OS from liver metastasis diagnosis and predictors of OS were analyzed using Kaplan–Meier estimation with log-rank and Cox regression analyses. Overall, 58 patients with CRLM who progressed on at least one line of chemotherapy who had genomic analysis prior to Y90 were identified. Median OS after hepatic metastasis was 29.9 months. Of these, 16 (28%) patients received Y90 after failure of the first-line systemic chemotherapy. There was significantly prolonged OS in patients receiving Y90 immediately following failure of the first-line chemotherapy folinic acid, fluorouracil, oxaliplatin ((FOLFOX) ± bevacizumab) versus following multiple lines of chemotherapy (median OS of 46.3 vs. 26.6 months, P = 0.005). The presence of genetic mutation in tumor, MAPK pathway wild type, left-sided primary tumor, low MELD score, and non-diffuse unilobar disease were also found to be predictors prolonged survival on log-rank analysis (P’s

Purpose To explore receptivity of and preferences for risk-reducing health behavior changes among African American survivors of early-stage lung cancer and their family members. Participants & setting 26 African American non-small cell lung cancer survivor-family member dyads were recruited from two cancer programs in the southeastern United States. Methodologic approach Social cognitive theory principles guided the design and implementation of focus groups. Descriptive statistics were used to summarize the data, and thematic analysis was used to interpret the transcripts from the focus groups. Findings The following four themes were identified. Implications for nursing Participants emphasized the need for improved provider communication. Pragmatic communication interventions for providers, survivors, and family members may facilitate behavior change and improve outcomes among underserved populations.

Changes in the nutritional status of free-ranging animals have a strong influence on individual fitness, yet it remains challenging to monitor longitudinally. Nitrogen (δ15N) and carbon (δ13C) isotope values measured chronologically along the length of metabolically inert keratinous tissues can be used as a nutritional biomarker to retrospectively reconstruct the foraging ecology and eco-physiology of consumers. We quantitatively describe the physiological effects of fasting on amino acid metabolism using sequentially measured bulk tissue and amino acid δ15N values along the length of whiskers sampled from free-ranging juvenile, subadults, adult female, and male southern elephant seals (SES; Mirounga leonina) on Marion Island in the Southern Ocean. For both juveniles and adult females, whisker segments representing fasting had significantly higher bulk tissue δ15N values of 0.6 ± 0.5‰ and 1.3–1.8‰, respectively, in comparison to segments unaffected by fasting. We also found a large increase (2–6‰) in δ15N values for most glucogenic amino acids and a simultaneous depletion (2–3‰) of alanine in segments reflecting fasting, which enabled us to accurately predict (74%) the nutritional status of our model species. We hypothesize that the glucose-alanine cycle is the mechanism driving the observed depletion of alanine δ15N values during fasting. We demonstrated that keratinaceous tissues can be used as a longitudinal nutritional biomarker to detect changes in the nitrogen balance of an individual. Moreover, it is evident that physiological factors have an important influence on tissue δ15N values and can lead to erroneous bulk tissue or amino acid isotope-based reconstructions of foraging habits.

Aims:\ud There is an important need for better biomarkers to predict left ventricular (LV) remodelling in dilated cardiomyopathy (DCM). We undertook a comprehensive assessment of cardiac structure and myocardial composition to determine predictors of remodelling.\ud \ud Methods and results:\ud Prospective study of patients with recent‐onset DCM with cardiovascular magnetic resonance (CMR) assessment of ventricular structure and function, extracellular volume (T1 mapping), myocardial strain, myocardial scar (late gadolinium enhancement) and contractile reserve (dobutamine stress). Regression analyses were used to evaluate predictors of change in LV ejection fraction (LVEF) over 12 months. We evaluated 56 participants (34 DCM patients, median LVEF 43%; 22 controls). Absolute LV contractile reserve predicted change in LVEF (1% increase associated with 0.4% increase in LVEF at 12 months, P = 0.02). Baseline myocardial strain (P = 0.39 global longitudinal strain), interstitial myocardial fibrosis (P = 0.41), replacement myocardial fibrosis (P = 0.25), and right ventricular contractile reserve (P = 0.17) were not associated with LV reverse remodelling. There was a poor correlation between contractile reserve and either LV extracellular volume fraction (r = −0.22, P = 0.23) or baseline LVEF (r = 0.07, P = 0.62). Men were more likely to experience adverse LV remodelling (P = 0.01) but age (P = 0.88) and disease‐modifying heart failure medication (beta‐blocker, P = 0.28; angiotensin‐converting enzyme inhibitor, P = 0.92) did not predict follow‐up LVEF.\ud \ud Conclusions:\ud Substantial recovery of LV function occurs within 12 months in most patients with recent‐onset DCM. Women had the greatest improvement in LVEF. A low LV contractile reserve measured by dobutamine stress CMR appears to identify patients whose LVEF is less likely to recover.

BACKGROUND: Patient outcomes are poor for aggressive B-cell non-Hodgkin's lymphomas not responding to or progressing within 12 months after first-line therapy. Tisagenlecleucel is an anti-CD19 chimeric antigen receptor T-cell therapy approved for diffuse large B-cell lymphoma after at least two treatment lines. METHODS: We conducted an international phase 3 trial involving patients with aggressive lymphoma that was refractory to or progressing within 12 months after first-line therapy. Patients were randomly assigned to receive tisagenlecleucel with optional bridging therapy (tisagenlecleucel group) or salvage chemotherapy and autologous hematopoietic stem-cell transplantation (HSCT) (standard-care group). The primary end point was event-free survival, defined as the time from randomization to stable or progressive disease at or after the week 12 assessment or death. Crossover to receive tisagenlecleucel was allowed if a defined event occurred at or after the week 12 assessment. Other end points included response and safety. RESULTS: A total of 322 patients underwent randomization. At baseline, the percentage of patients with high-grade lymphomas was higher in the tisagenlecleucel group than in the standard-care group (24.1% vs. 16.9%), as was the percentage with an International Prognostic Index score (range, 0 to 5, with higher scores indicating a worse prognosis) of 2 or higher (65.4% vs. 57.5%). A total of 95.7% of the patients in the tisagenlecleucel group received tisagenlecleucel; 32.5% of the patients in the standard-care group received autologous HSCT. The median time from leukapheresis to tisagenlecleucel infusion was 52 days. A total of 25.9% of the patients in the tisagenlecleucel group had lymphoma progression at week 6, as compared with 13.8% of those in the standard-care group. The median event-free survival in both groups was 3.0 months (hazard ratio for event or death in the tisagenlecleucel group, 1.07; 95% confidence interval, 0.82 to 1.40; P = 0.61). A response occurred in 46.3% of the patients in the tisagenlecleucel group and in 42.5% in the standard-care group. Ten patients in the tisagenlecleucel group and 13 in the standard-care group died from adverse events. CONCLUSIONS: Tisagenlecleucel was not superior to standard salvage therapy in this trial. Additional studies are needed to assess which patients may obtain the most benefit from each approach. (Funded by Novartis; BELINDA ClinicalTrials.gov number, NCT03570892.).

In May 2020, Westat, in partnership with Stanford University School of Medicine, conducted a nationally-representative household survey of American attitudes and behaviors regarding COVID-19. In this article, we examine what the Coronavirus Attitudes and Behaviors Survey tells us about the impact of COVID-19 on financial status and how this impact varies by demographic characteristics, the presence of health risk factors, and financial status (including employment factors). The survey reveals significant inequality in financial impact, as those who were most financially vulnerable prior to the pandemic found themselves under greater financial strain, while those who were more financially secure have experienced a neutral or even positive impact of the pandemic on household finances. These findings have important implications for public policy as policymakers seek to target aid to those who need it most.

The population prevalence of high-risk non-alcoholic steatohepatitis (NASH), defined as nonalcoholic fatty liver disease activity score ≥4 and fibrosis stage ≥2, is unknown. The FibroScan-AST (FAST) score, calculated using liver stiffness measurement and controlled attenuation parameter values from FibroScan and aspartate aminotransferase levels, is a validated algorithm to identify individuals with high-risk NASH. We estimated the prevalence of high-risk NASH using the FAST score in the United States population.Data were derived from the National Health and Nutrition Examination Surveys 2017-2018, which included a total of 4218 adults with valid elastography measurements. FAST scores of ≥0.35 (sensitivity, 90%) and ≥0.67 (specificity, 90%) were used to identify adults with high-risk NASH in the general population.At 90% sensitivity for the FAST score, the prevalence of age-adjusted high-risk NASH was 5.8% and was higher among men (8.2% vs 3.6% in women) and in Hispanics (9.2% vs. 5.8% non-Hispanic (N.H.) Asians, 5.2% in N.H. whites, and 3.8% in N.H. blacks). The prevalence of high-risk NASH was 11.7% in those with metabolic syndrome and 22.5% in individuals with type 2 diabetes mellitus (T2DM). At 90% specificity for the FAST score, the prevalence of age-adjusted high-risk NASH was 1.2% and was higher among men (1.7% vs 0.8% in women) and in Hispanics (2.2% vs 1.0% in N.H. Asians, 0.9% in N.H. whites, and 0.4% in N.H. blacks). The prevalence of high-risk NASH was 3.4% in those with metabolic syndrome and 8.7% in adults with T2DM.We estimate at least 2 million adults have high-risk NASH in the United States. Moreover, the prevalence of high-risk NASH among individuals with T2DM is higher, ranging between 8.7% and 22.5%, supporting the case for coordinated case-finding and management.

Background Several chronic inflammatory diseases co-exist with and accelerate sarcopenia (reduction in muscle strength, function and mass) and negatively impact on both morbidity and mortality. There is currently limited research on the extent of sarcopenia in such conditions, how to accurately assess it and whether there are generic or disease-specific mechanisms driving sarcopenia. Therefore, this study aims to identify potential mechanisms driving sarcopenia within chronic inflammatory disease via a multi-modal approach; in an attempt to help define potential interventions for future use. Methods This prospective cohort study will consist of a multi-modal assessment of sarcopenia and its underlying mechanisms. Recruitment will target three chronic inflammatory diseases: chronic liver disease (CLD) (n=50), with a subset of NAFLD (n=20), inflammatory bowel disease (IBD) (n=50) and rheumatoid arthritis (RA) (n=50) both before and after therapeutic intervention. In addition, 20 age and sex matched healthy individuals will be recruited for comparison. Participants will undergo 4 assessment visits at weeks 0, 2, 12 and 24. Visits will consist of the following assessments: blood tests, anthropometrics, functional assessment, quadriceps muscle imaging, actigraphy, quality of life questionnaires, food diary collection and muscle biopsy of the vastus lateralis (at weeks 2 and 24 only). In addition, stool and urine samples will be collected for future microbiome and metabolomics analysis. Discussion This is the first study to use a multi-modal assessment model to phenotype sarcopenia in these chronic inflammatory diseases. We hope to identify generic as well as disease-specific mechanisms driving sarcopenia. We appreciate that these cohorts do require separate standards of care treatments which limit comparison between groups. Ethics and dissemination The study is approved by the Health Research Authority - West Midlands Solihull Research Ethics Service Committee Authority (REC reference: 18/WM/0167). Recruitment commenced in January 2019 and will continue until July 2021. The study was halted in March 2020 and again in January 2021 with the COVID-19 pandemic. The findings will be disseminated through peer-reviewed publications and conference presentations. All data will be stored on a secure server. Trial registration ClinicalTrials.gov Identifier: NCT04734496

Background Despite the benefits of genetic counseling and testing, uptake of cancer genetic services is generally low and Black/African American (Black) women are substantially less likely to receive genetic services than non-Hispanic White women. Our team developed a culturally sensitive, narrative decision aid video to promote uptake of genetic counseling among Black women at risk for a hereditary breast cancer syndrome that can be incorporated in conjunction with population-based cancer risk assessment in a clinical setting. We report here a pilot study to demonstrate changes in intention to access genetic counseling and intervention satisfaction. Methods Black women who were personally unaffected by breast cancer and were recommended for genetic counseling based on family history screening in a mammography center were recruited at the time of the mammogram. A prospective, pre-post survey study design, guided by theoretical constructs, was used to evaluate baseline and immediate post-intervention psychosocial factors, including intention to participate in genetic counseling and intervention satisfaction. Results Pilot recruitment goals were met (n = 30). Pre-intervention, 50% of participants indicated that they were extremely likely to make a genetic counseling appointment, compared with 70% post-intervention (p = 0.05). After watching the intervention, 50% of participants indicated that the video changed their mind regarding genetic counseling. Conclusions This study demonstrated cultural satisfaction with a decision aid intervention designed to motivate Black women with hereditary breast cancer risk to attend a genetic counseling appointment. Our study showed that intention may be a specific and key construct to target in interventions designed to support decision-making about genetic services. Study results informed the design of a subsequent large scale, randomized implementation study. Trial registration Trial registration: Clinicaltrials.govNCT04082117. Registered September 9, 2019. Retrospectively registered.

We describe a woman with a history of relapsing acute optic neuritis and perineuritis. Testing failed to confirm a specific diagnosis; hence, she was diagnosed with seronegative neuromyelitis optica spectrum disorder and treated with the immunotherapy rituximab, later in conjunction with mycophenolate mofetil. She achieved a durable remission for 9 years until she presented with paresthesia affecting her left fifth digit, right proximal thigh, and left foot, while also reporting a 25-pound weight loss over the prior 3 months. New imaging demonstrated a longitudinally extensive and enhancing optic nerve, in conjunction with multifocal enhancing lesions within the spinal cord, in a skip-like distribution. The differential diagnosis is discussed.

Summary Background No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor 1,5 modulator, on disability progression in patients with SPMS. Methods This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18–60 years) with SPMS and an Expanded Disability Status Scale score of 3·0–6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials.gov, number NCT01665144. Findings 1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65–0·95; relative risk reduction 21%; p=0·013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups. Interpretation Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS. Funding Novartis Pharma AG.

The aim of this study is to investigate the gender distribution of first and senior authors in the most highly cited original research studies published in the top 10 surgical journals from 2015 to 2020 to identify disparities and changes over time.A retrospective study analyzing the gender distribution of first and senior authors in the top 10 most cited studies from the top 10 surgical journals from 2015 to 2020. The genders of the first and senior authors of each study were assessed using National Provider Identifier (NPI) numbers or pronouns from institutional biographies or news articles.The genders of 1200 first and senior authors from 600 original research studies were assessed. First author gender distribution consisted of 71.8% men, 22.3% women, 0% non-binary, and 5.8% unknown. Senior author gender distribution was 82.3% men, 14.3% women, 0% non-binary, and 3.3% unknown. Studies published by first authors who are women received more citations than those published by first authors that are men in 2015 (169.1 versus 112.9, P = 0.002) and 2016 (144.2 versus 101.5, P = 0.011). There was an increase in first authorship among men from 2015 to 2020 (P = 0.035).Men represent a significantly higher proportion of both first and senior authorships in top surgical research and the gap has widened from 2015 to 2020. However, studies written by women first authors received significantly more citations than those written by men.

A 31-year-old woman presented with fever, ataxia, double vision, confusion, and auditory hallucinations, preceded by 2 weeks of cough, increased oral secretions, and dermatomal rash. Her medical history was unremarkable. Her family history was notable for first-degree relatives with autoimmune

Objectives To compare abnormal call rates (ACR), cancer detection rates (CDR), positive predictive values (PPVs), and annual return to screen recommendations after switching from digital mammography (DM) to digital breast tomosynthesis plus DM (DBT + DM) for breast cancer screening. Setting The Alberta Breast Cancer Screening Program collects screening data from clinics throughout the province of Alberta, Canada. Methods This study retrospectively collected data, between 2015 and 2018, on women aged 40+ who underwent breast cancer screening at two large volume multisite radiology groups to compare metrics one year prior and one year after DBT + DM implementation. Comparisons between modalities were carried out within age groups, within breast density categories, and for initial vs. subsequent screens. Results A total of 125,432 DM and 128,912 DBT + DM screening exams were performed. For women aged 50–74, the DBT + DM group had a higher ACR ( p Conclusion All metrics improved or stayed the same after switching to DBT + DM except for ACR. However, the increase in ACR could be attributed to a trend already occurring prior to the switch. Longer term monitoring is needed to confirm these findings.

Nitrogen isotope (δ

OBJECTIVES 1) Identify factors that influence African American physicians to choose a career in otolaryngology; 2) determine the predominant practice setting for African American otolaryngologists who can be role models; and 3) determine if the presence of an African American otolaryngologist in academic setting influences career choice. METHODS Survey methodology included a 15-item survey to determine trends in practice and factors that influenced choice of specialty. RESULTS The results were reviewed for trends influencing career choice and practice location and stratified by age group. Most African American otolaryngologists are in academic practice and have subspecialty fellowship training. Enjoying medical student clerkship was the most frequently cited reason why African Americans chose otolaryngology as a career regardless of age. Early exposure was a driving factor in those 30 to 40 years old. Receiving mentorship was less influential in career choice for all age groups, but there was a positive association between those who were mentored in training and those who mentor faculty. CONCLUSION The findings suggest the continued need for initiatives to increase African Americans in our specialty. Encouraging early exposure, intentional mentoring of students, and development of African American role models who can be mentors may help increase the number of African American otolaryngologist faculty. This can help our specialty achieve racial parity in a percentage that matches the number of African Americans in the United States workforce. LEVEL OF EVIDENCE 5 Laryngoscope, 130:2336-2342, 2020.

Healthy older adults show impaired relational learning, but improved transitive expression when inferences are made across pre-experimentally known premise relations. Here, we used the transitivity paradigm to ask whether the organizational structure within schemas facilitates the bridging of relations for novel inference for otherwise healthy older adults who are exhibiting early signs of cognitive decline ("at-risk" older adults), and individuals with single- or multiple-domain amnestic mild cognitive impairment (aMCI). Relational learning was impaired in the two older adult groups, but transitive expression was facilitated by prior semantic knowledge of relations. Prior semantic knowledge did not improve novel inference for aMCI individuals. Schematic scaffolding can successfully support inference in preclinical cognitive decline, but such cognitive support may no longer be useful later in the disease process when dysfunction in neural circuitry may be too severe. The findings encourage future work of semantic knowledge and inference in larger samples of aMCI cases.

Rationale and Objectives Requests for gastrostomy tube placement in patients on aspirin (ASA) 325 mg are common, particularly in patients following reconstructive surgery for head and neck cancer, but periprocedural guidelines and recommendations regarding management of high dose aspirin are inconsistent. The purpose of this study was to assess the bleeding risk of percutaneous gastrostomy tube placement in patients on ASA 325 mg. Materials and Methods This retrospective study of 213 patients who underwent image-guided “push” percutaneous gastrostomy tube placement compared rates of significant bleeding and other secondary outcomes (including all-cause mortality within 30 days, procedure-related mortality, bowel perforation, abdominal abscess, peritonitis, aspiration pneumonia, intraprocedural airway complications, and tube dislodgement) between patients maintained on ASA 325 mg and patients not on antiplatelet or anticoagulation therapy. Results No significant bleeding episodes occurred in patients on ASA 325 mg, compared to three episodes in patients not on ASA 325 mg (p = 0.37). A patient in each group had aspiration pneumonia possibly related to tube placement. There were no other notable secondary outcomes, including intraprocedural airway complications in this population with complex head and neck anatomy. Conclusion These findings suggest that holding ASA 325 mg in patients undergoing percutaneous gastrostomy tube placement is not necessary, especially in patients in whom holding ASA would pose considerable risk. Further multi-institutional longitudinal study is warranted to validate these results.

A variety of chemicals have been linked to occupational liver diseases, including several solvents and mixtures thereof, pesticides, and metals. Workplace exposures have been associated with virtually the entire spectrum of acute and chronic liver diseases. However, their prevalence is inadequately quantified and their epidemiology limited. Occupational liver diseases may result from high accidental or from prolonged lower level exposures. Whereas the former is uncommon and easily recognised, the latter are relatively more frequent but often overlooked because they may display normal values of conventional markers, have an insidious onset and be asymptomatic or be obfuscated and confounded by concurrent conditions. In addition, specific tests of toxicity are not available, histopathology may not be revealing and the assessment of internal dose of chemicals is usually not decisive. Given these circumstances, the diagnosis of these liver disorders is challenging, one of exclusion and often requires an interdisciplinary approach. These recommendations offer a classification of the type of liver injuries associated with occupational exposures - based in part on the criteria for drug-induced liver injury - a grading of their severity, and the diagnostic and preventive criteria for chemically induced occupational liver disease.

Objective Lung shunt fraction studies using technetium-99 m macro aggregated albumin are routinely performed before yttrium-90 radioembolization regardless of underlying liver malignancy type. This study evaluates the role of lung shunt fraction studies in hepatocellular carcinoma compared to non-hepatocellular carcinoma liver tumors. Methods A single-institution retrospective analysis of all pre-yttrium-90 technetium-99 m macro aggregated albumin lung shunt fraction studies between November 2012 to March 2018 was performed. Patient variables including age, underlying malignancy, laboratory values, lung shunt fraction, and severity of liver disease were compared between hepatocellular carcinoma and non-hepatocellular carcinoma cases. Results A total of 734 technetium-99 m macro aggregated albumin studies were identified in 653 patients. Among these cases, the liver tumor was hepatocellular carcinoma in 368 (50.1%), colorectal cancer in 112 (15.3%), neuroendocrine tumor in 89 (12.1%), cholangiocarcinoma in 59 (8.0%), breast cancer in 27 (3.7%), and other metastatic malignancies in 79 (10.7%). The mean lung shunt fraction for non-hepatocellular carcinoma cases was 7.4%, which was significantly lower than the mean lung shunt fraction, 11.7%, for hepatocellular carcinoma cases (P = 0.0001). In only one non-hepatocellular carcinoma case was yttrium-90 radioembolization not pursued due to high lung shunt fraction (69.3%), wherein large scale shunting was grossly apparent on angiography in a patient with metastatic gastrointestinal stromal tumor. In comparison, the lung shunt fraction was too high to pursue radioembolization in 37 hepatocellular carcinoma cases (mean lung shunt fraction 35.1%). Conclusion Lung shunt fraction appears low among patients with non-hepatocellular carcinoma liver malignancies. Further analysis examining the necessity of pre-Y90 technetium-99 m macro aggregated albumin lung shunt fraction studies in patients with non-hepatocellular carcinoma malignancies is warranted, since a consolidated yttrium-90 radioembolization without prior lung shunt fraction evaluation could reduce resource consumption, improve workflows, and patient access.

An autoimmune response against myelin protein is considered one of the key pathogenic processes that initiates multiple sclerosis (MS). The currently available MS disease modifying therapies have demonstrated to reduce the frequency of inflammatory attacks. However, they appear limited in preventing disease progression and neurodegeneration. Hence, novel therapeutic approaches targeting both inflammation and neuroregeneration are urgently needed. A new pregnancy derived synthetic peptide, synthetic PreImplantation Factor (sPIF), crosses the blood-brain barrier and prevents neuro-inflammation. We report that sPIF reduces paralysis and de-myelination of the brain in a clinically-relevant experimental autoimmune encephalomyelitis mice model. These effects, at least in part, are due to post-translational modifications, which involve cyclic AMP dependent protein kinase (PKA), calcium-dependent protein kinase (PKC), and immune regulation. In terms of potential MS treatment, sPIF was successfully tested in neurodegenerative animal models of perinatal brain injury and experimental autoimmune encephalitis. Importantly, sPIF received a FDA Fast Track Approval for first in human trial in autommuninty (completed).

Liver cirrhosis is a major cause of death worldwide and is characterized by extensive fibrosis. There are currently no effective antifibrotic therapies available. To obtain a better understanding of the cellular and molecular mechanisms involved in disease pathogenesis and enable the discovery of therapeutic targets, here we profile the transcriptomes of more than 100,000 single human cells, yielding molecular definitions for non-parenchymal cell types that are found in healthy and cirrhotic human liver. We identify a scar-associated TREM2+CD9+ subpopulation of macrophages, which expands in liver fibrosis, differentiates from circulating monocytes and is pro-fibrogenic. We also define ACKR1+ and PLVAP+ endothelial cells that expand in cirrhosis, are topographically restricted to the fibrotic niche and enhance the transmigration of leucocytes. Multi-lineage modelling of ligand and receptor interactions between the scar-associated macrophages, endothelial cells and PDGFRα+ collagen-producing mesenchymal cells reveals intra-scar activity of several pro-fibrogenic pathways including TNFRSF12A, PDGFR and NOTCH signalling. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides a conceptual framework for the discovery of rational therapeutic targets in liver cirrhosis. Single-cell RNA sequencing is used to characterize and compare the functional diversity of cells from liver biopsies of human scarred and normal liver, and identifies markers for scar-associated macrophages and endothelial cells.

Background Obesity and type 2 diabetes are drivers of non-alcoholic fatty liver disease (NAFLD). Glucagon-like peptide-1 analogues effectively treat obesity and type 2 diabetes and may offer potential for NAFLD treatment. Aim To evaluate the effect of the glucagon-like peptide-1 analogue, semaglutide, on alanine aminotransferase (ALT) and high-sensitivity C-reactive protein (hsCRP) in subjects at risk of NAFLD. Methods Data from a 104-week cardiovascular outcomes trial in type 2 diabetes (semaglutide 0.5 or 1.0 mg/week) and a 52-week weight management trial (semaglutide 0.05-0.4 mg/day) were analysed. Treatment ratios vs placebo were estimated for ALT (both trials) and hsCRP (weight management trial only) using a mixed model for repeated measurements, with or without adjustment for change in body weight. Results Elevated baseline ALT (men >30 IU/L; women >19 IU/L) was present in 52% (499/957) of weight management trial subjects. In this group with elevated ALT, end-of-treatment ALT reductions were 6%-21% (P= 0.2 mg/day) and hsCRP reductions 25%-43% vs placebo (P < 0.05 for 0.2 and 0.4 mg/day). Normalisation of elevated baseline ALT occurred in 25%-46% of weight management trial subjects, vs 18% on placebo. Elevated baseline ALT was present in 41% (1325/3268) of cardiovascular outcomes trial subjects. In this group with elevated ALT, no significant ALT reduction was noted at end-of-treatment for 0.5 mg/week, while a 9% reduction vs placebo was seen for 1.0 mg/week (P = 0.0024). Treatment ratios for changes in ALT and hsCRP were not statistically significant after adjustment for weight change. Conclusions Semaglutide significantly reduced ALT and hsCRP in clinical trials in subjects with obesity and/or type 2 diabetes.

PurposeThe purpose of this study was to develop and validate a novel medication regimen complexity–intensive care unit (MRC-ICU) scoring tool in critically ill patients and to correlate MRC with illness severity and patient outcomes.MethodsThis study was a single-center, retrospective observational chart review of adults admitted to the medical ICU (MICU) between November 2016 and June 2017. The primary aim was the development and internal validation of the MRC-ICU scoring tool. Secondary aims included external validation of the MRC-ICU and exploration of relationships between medication regimen complexity and patient outcomes. Exclusion criteria included a length of stay of less than 24 hours in the MICU, active transfer, or hospice orders at 24 hours. A total of 130 patient medication regimens were used to test, modify, and validate the MRC-ICU tool.ResultsThe 39-line item medication regimen complexity scoring tool was validated both internally and externally. Convergent validity was confirmed with total medications (p < 0.0001). Score discriminant validity was confirmed by lack of association with age (p = 0.1039) or sex (p = 0.7829). The MRC-ICU score was significantly associated with ICU length of stay (p = 0.0166), ICU mortality (p = 0.0193), and patient acuity (p < 0.0001).ConclusionThe MRC-ICU scoring tool was validated and found to correlate with length of stay, inpatient mortality, and patient acuity.

Nonalcoholic steatohepatitis (NASH) is an increasingly prevalent indication for liver transplantation (LT) across the world. The relative outcomes following transplantation are poorly described in this cohort. We aimed to analyze the incidence and outcome of LT for NASH as compared with other indications.This is a retrospective analysis of 513 patients who underwent deceased-donor, adult LT between 2002 and 2012 as recorded at the Medical University of Innsbruck, Austria.The prevalence of NASH cirrhosis as indication for liver transplantation was 12.7% (65/513). Patient survival in patients with NASH was comparable to other indications, including alcohol-induced liver steatosis (ALD) and hepatitis C virus (HCV) (P=0.208). Patients with NASH were older, had a higher model of end-stage liver disease score and a higher BMI, but patient survival and graft survival were equivalent to other indications. Patients with hepatocellular carcinoma (HCC) as primary indication for liver transplantation showed significantly inferior overall survival as compared with the other indications (P=0.003). Patients with NASH had coexisting HCC in 53.7% of cases, whereas HCC in ALD, HCV and other indications was prevalent in 31.2, 47.7, and 34.5%, respectively (P0.0001). Patients with NASH had a higher incidence of advanced HCCs (outside the Milan criteria) than patients with ALD, HCV, and other indications (P=0.034). Postoperative complications were significantly higher in the NASH cohort (P=0.048).In this single-center LT database analysis, patients with NASH have a higher incidence and a more rapid progression of HCC as well as an increased incidence of postoperative complications. Our findings warrant confirmation by others.

The purpose of this study is to compare the motivations of interventional radiology (IR) residency, IR fellowship, and diagnostic radiology (DR) applicants.A questionnaire was distributed to IR integrated residency and IR fellowship applicants for the 2018 National Resident Matching Program (NRMP) Match. Survey respondents scored the influence of 13 aspects of IR on their career decision. These results were combined with a previously published survey of DR residency applicants from 2016 who were asked the same questions. Pairwise comparisons to survey responses were made between IR residency and IR fellowship as well as IR residency and DR residency respondents.There were 202 of 657 DR residency respondents (response rate 30.7%), 114 of 295 IR residency respondents (response rate 38.6%), and 70 of 169 IR fellowship respondents (response rate 41.4%). Compared with DR respondents, IR residency respondents rated the following factors more positively: influence of a mentor (P = .030), perceived job satisfaction (P.001), job market (P .001), salary (P.001), intellectual stimulation (P = .030), the use of emerging or advanced technology (P.001), and the visual nature of the field (P .001). In contrast, DR residency respondents rated flexible work hours (P.001), physics (P.001), and competitiveness of the application process (P.001) more positively than IR respondents. Compared with IR fellowship respondents, IR residency respondents rated flexible work hours (P = .002), the job market (P = .020), physics (P.001), and salary (P.001) more positively, and competitiveness (P = .002) was felt to be more negative for residency applicants.The motivations for pursuing IR residency differ from both DR residency and IR fellowship. Understanding these motivations can help to recruit top quality IR residency applicants.