Clinical Research Network Research Articles

A model of weight-based stigma in health care and utilization outcomes: Evidence from the learning health systems network.

ObjectiveObesity is stigmatized and people with obesity report experiencing stigmatizing situations when seeking health care. The implications of these experiences are not well understood. This study tests an indirect effects model of negative care experiences as an intermediate variable between obesity and care avoidance/utilization and switching primary care doctors.MethodsA survey was completed by 2380 primary care patients in the Learning Health Systems Network (LHSNet) Clinical Data Research Network with a BMI >25 kg/m2. Measures included scales assessing stigmatizing situations, perceived patient‐centered communication, perceived respect, having delayed needed care, and having looked for a new primary doctor in the past 12 months. Sequential and serial indirect effects of care experiences and respect in the association between BMI and care utilization outcomes was modeled.ResultsThe hypothesized model was supported by findings. The associations between BMI and delaying needed care (OR = 1.06, p < 0.001) and attempting to switch primary doctors (OR = 1.02, p = 0.04) was mediated by both stigmatizing situations experienced in a health care context and lower patient‐centered communication. Lower perceived respect mediated the association between care experiences and utilization outcomes.ConclusionsPeople with higher BMIs may avoid care or switch doctors as a result of stigmatizing experiences and poor communication with doctors. These outcomes may contribute to morbidity in people with obesity if they delay or avoid care for health concerns when symptoms first present.

Early Impact of Severe Acute Respiratory Syndrome Coronavirus 2 on Pediatric Clinical Research: A Pan-European and Canadian Snapshot in Time

ObjectiveTo capture the early effects of the coronavirus disease 2019 (COVID-19) pandemic on pediatric clinical research.Study designPediatric clinical research networks from 20 countries and 50 of their affiliated research sites completed two surveys over one month from early May to early June 2020. Networks liaised with their affiliated sites and contributed to the interpretation of results through pan-European group discussions. Based on first detection dates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), countries formed 1 early detecting and 1 late detecting cluster. We tested the hypothesis that this clustering influenced clinical research.ResultsResearch sites were first impacted by the pandemic in mid-March 2020 (March 16 ± 10 days, the same date as lockdown initiation; P = .99). From first impact up until early June, site initiation and feasibility analysis processes were affected for >50% of the sites. Staff were redirected to COVID-19 research for 44% of the sites, and 75.5% of sites were involved in pediatric COVID-19 research (only 6.3% reported COVID-19 cases in their other pediatric trials). Mitigation strategies were used differently between the early and late detecting country clusters and between countries with and without a pediatric COVID-19 research taskforce. Positive effects include the development of teleworking capacities.ConclusionsThrough this collaborative effort from pediatric research networks, we found that pediatric trials were affected and conducted with a range of unequally applied mitigations across countries during the pandemic. The global impact might be greater than captured. In a context where clinical research is increasingly multinational, this report reveals the importance of collaboration between national networks.

Variation Among Infectious Diseases Pharmacists for the Treatment of Staphylococcus aureus Bacteremia

Introduction: Staphylococcus aureus bacteremia (SAB) remains complex, in that optimal treatment for patients, including complicated or persistent infection, remains unclear. Two recent surveys have demonstrated practice variations in SAB among infectious diseases (ID) physicians. Objectives: The purpose of this survey was to examine practice variations in SAB among ID pharmacists. Methods: A thirty-five-question survey was electronically distributed to the American College of Clinical Pharmacy (ACCP) Infectious Diseases Practice and Research Network (IDPRN) in Fall 2019 to determine differences in SAB management. Data were analyzed utilizing Pearson’s Chi-Square or Fisher’s Exact Test. Results: A total of 106 ID pharmacists responded. Only 28% of pharmacists practiced at hospitals with mandatory ID consultation for SAB. A majority (75%) had rapid diagnostic technology (RDT) for identifying SABSI, but 32% of those facilities with RDT did not notify pharmacy with results. Anti-staphylococcal penicillins were preferred for MSSA blood stream infections (BSI) in patients with central nervous system infection and endocarditis, whereas cefazolin was favored for other MSSA BSI. For persistent MRSA BSI, 34% selected daptomycin alone while 38% elected to combine daptomycin and ceftaroline. Pharmacists at hospitals less than 500 beds were more likely to use daptomycin, while those at larger hospitals were more likely to use daptomycin and ceftaroline for persistent MRSA BSI (P < .05). Conclusions: A survey of ID pharmacists showed variation in the management of SABs, as well as the definition and treatment of persistent SAB. Mandatory ID consultation and RDT use to improve SAB management have not been optimized.

Phase I dose-escalation single centre clinical trial to evaluate the safety of infusion of memory T cells as adoptive therapy in COVID-19 (RELEASE)

BackgroundEffective treatments are still needed to reduce the severity of symptoms, time of hospitalization, and mortality of COVID-19. SARS-CoV-2 specific memory T-lymphocytes obtained from convalescent donors recovered can be used as passive cell immunotherapy.MethodsBetween September and November 2020 a phase 1, dose-escalation, single centre clinical trial was conducted to evaluate the safety and feasibility of the infusion of CD45RA− memory T cells containing SARS-CoV-2 specific T cells as adoptive cell therapy against moderate/severe cases of COVID-19. Nine participants with pneumonia and/or lymphopenia and with at least one human leukocyte antigen (HLA) match with the donor were infused. The first three subjects received the lowest dose (1 × 105 cells/kg), the next three received the intermediate dose (5 × 105 cells/kg) and the last three received the highest dose (1 × 106 cells/kg) of CD45RA− memory T cells. Clinicaltrials.gov registration: NCT04578210.FindingsAll participants’ clinical status measured by National Early Warning Score (NEWS) and 7-category point ordinal scales showed improvement six days after infusion. No serious adverse events were reported. Inflammatory parameters were stabilised post-infusion and the participants showed lymphocyte recovery two weeks after the procedure. Donor microchimerism was observed at least for three weeks after infusion in all patients.InterpretationThis study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using convalescent CD45RA− memory T cells is feasible and safe.FundingClinical Trial supported by Spanish Clinical Research Network PT17/0017/0013. Co-funded by European Regional Development Fund/European Social Fund. CRIS CANCER Foundation Grant to AP-M and Agencia Valenciana de Innovación Grant AVI-GVA COVID-19-68 to BS.

Impact of COVID-19 disease on clinical research in paediatric and congenital cardiology

BackgroundCOVID-19 triggered an unprecedented crisis affecting our society at every level. Clinical research in paediatric and congenital cardiology is currently in full development and may have been disrupted.AimsTo determine the impact of COVID-19 in paediatric and congenital cardiology clinical research and to analyse decision-making and adaptation processes, from a panel of on-going academic and industry-sponsored research at the time of the pandemic.MethodsThis observational study was carried out in April 2020, from a CHD clinical research network involving five tertiary care paediatric and congenital cardiology centres. Investigators and clinical research assistants from each participating research centre filled in an online survey questionnaire, and each principal investigator underwent a one-hour web-based videoconference interview.ResultsFrom a total of 34 study questionnaires and 288 enrolled patients at the time of the pandemic, 18 studies were declared as totally suspended. Upon investigator's decision, after discussion on ethical issues and with facilitating support from health authorities, 16 studies were resumed. The rate of study suspension in interventional research (53%) was similar to non-interventional research (56%). Logistical problems were predominantly reported in both continued and suspended trials. Research protocols were adapted, largely thanks to telemedicine, which in some cases even improved the course of the study.ConclusionsThe impact of the COVID-19 pandemic on clinical research in paediatric and congenital cardiology has been limited by a rapid adaptation of all research structures and an extensive use of telemedicine at all stages of the studies.

Genetic counselor roles in the undiagnosed diseases network research study: Clinical care, collaboration, and curation.

Genetic counselors (GCs) are increasingly filling important positions on research study teams, but there is limited literature describing the roles of GCs in these settings. GCs on the Undiagnosed Diseases Network (UDN) study team serve in a variety of roles across the research network and provide an opportunity to better understand genetic counselor roles in research. To quantitatively characterize the tasks regularly performed and professional fulfillment derived from these tasks, two surveys were administered to UDN GCs in a stepwise fashion. Responses from the first, free-response survey elicited the scope of tasks which informed development of a second structured, multiple-select survey. In survey 2, respondents were asked to select which roles they performed. Across 19 respondents, roles in survey 2 received a total of 947 selections averaging approximately 10 selections per role. When asked to indicate what roles they performed, respondent selected a mean of 50 roles (range 22-70). Survey 2 data were analyzed via thematic coding of responses and hierarchical cluster analysis to identify patterns in responses. From the thematic analysis, 20 non-overlapping codes emerged in seven categories: clinical interaction and care, communication, curation, leadership, participant management, research, and team management. Three themes emerged from the categories that represented the roles of GCs in the UDN: clinical care, collaboration, and curation. Cluster analyses showed that responses were more similar among individuals at the same institution than between institutions. This study highlights the ways GCs apply their unique skill set in the context of a clinical translational research network. Additionally, findings from this study reinforce the wide applicability of core skills that are part of genetic counseling training. Clinical literacy, genomics expertise and analysis, interpersonal, psychosocial and counseling skills, education, professional practice skills, and an understanding of research processes make genetic counselors well suited for such roles and poised to positively impact research experiences and outcomes for participants.

Hydrocephalus surveillance following shunt placement or endoscopic third ventriculostomy: a survey of surgeons in the Hydrocephalus Clinical Research Networks.

Late failure is a well-documented complication of cerebrospinal fluid shunt placement and, less commonly, endoscopic third ventriculostomy (ETV). However, standards regarding the frequency of clinical and radiological follow-up in these patients have not been defined. Here, the authors report on their survey of surgeons at sites for the Hydrocephalus Clinical Research Network (HCRN) or its implementation/quality improvement arm (HCRNq) to provide a cross-sectional overview of practice patterns. A 24-question survey was developed using the Research Electronic Data Capture (REDCap) platform and was distributed to the 138 pediatric neurosurgeons across 39 centers who participate in the HCRN or HCRNq. Survey questions were organized into three sections: 1) Demographics (5 questions), 2) Shunt Surveillance (12 questions), and 3) ETV Surveillance (7 questions). A total of 122 complete responses were obtained, for an overall response rate of 88%. The majority of respondents have been in practice for more than 10 years (58%) and exclusively treat pediatric patients (79%). Most respondents consider hydrocephalus to have stabilized 1 month (21%) or 3 months (39%) after shunt surgery, and once stability is achieved, 72% then ask patients to return for routine clinical follow-up annually. Overall, 83% recommend lifelong clinical follow-up after shunt placement. Additionally, 75% obtain routine imaging studies in asymptomatic patients, although the specific imaging modality and frequency of imaging vary. The management of an asymptomatic increase in ventricle size or an asymptomatic catheter fracture also varies widely. Many respondents believe that hydrocephalus takes longer to stabilize after ETV than after shunt placement, reporting that they consider hydrocephalus to have stabilized 3 (28%), 6 (33%), or 12 (28%) months after an ETV. Although 68% of respondents have patients return annually for routine clinical follow-up after an ETV, only 56% recommend lifelong follow-up. The proportion of respondents who perform lifelong follow-up increases with greater practice experience (p = 0.01). Overall, 67% of respondents obtain routine imaging studies in asymptomatic patients after an ETV, with "rapid" MRI the study of choice for most respondents. While there is a general consensus among pediatric neurosurgeons across North America that hydrocephalus patients should have long-term follow-up after shunt placement, radiological surveillance is characterized by considerable variety, as is follow-up after an ETV. Future work should focus on evaluating whether any one of these surveillance protocols is associated with improved outcomes.

Evaluating Sleep Disturbances in Children With Rare Genetic Neurodevelopmental Syndromes

BackgroundAdequate sleep is important for proper neurodevelopment and positive health outcomes. Sleep disturbances are more prevalent in children with genetically determined neurodevelopmental syndromes compared with typically developing counterparts. We characterize sleep behavior in Rett (RTT), Angelman (AS), and Prader-Willi (PWS) syndromes to identify effective approaches for treating sleep problems in these populations. We compared sleep-related symptoms across individuals with these different syndromes with each other, and with typically developing controls. MethodsChildren were recruited from the Rare Diseases Clinical Research Network consortium registries; unaffected siblings were enrolled as related controls. For each participant, a parent completed multiple sleep questionnaires including Pediatric Sleep Questionnaire (Sleep-Disordered Breathing), Children's Sleep Habits Questionnaire (CSHQ), and Pediatric Daytime Sleepiness Scale. ResultsSleep data were analyzed from 714 participants, aged two to 18 years. Young children with AS had more reported sleep problems than children with RTT or PWS. Older children with RTT had more reported daytime sleepiness than those with AS or PWS. Finally, all individuals with RTT had more evidence of sleep-disordered breathing when compared with individuals with PWS. Notably, typically developing siblings were also reported to have sleep problems, except for sleep-related breathing disturbances, which were associated with each of the genetic syndromes. ConclusionsIndividuals with RTT, AS, and PWS frequently experience sleep problems, including sleep-disordered breathing. Screening for sleep problems in individuals with these and other neurogenetic disorders should be included in clinical assessment and managements. These data may also be useful in developing treatment strategies and in clinical trials.

Association of Early Antibiotic Exposure With Childhood Body Mass Index Trajectory Milestones

Past studies have showed associations between antibiotic exposure and child weight outcomes. Few, however, have documented alterations to body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) trajectory milestone patterns during childhood after early-life antibiotic exposure. To examine the association of antibiotic use during the first 48 months of life with BMI trajectory milestones during childhood in a large cohort of children. This retrospective cohort study used electronic health record data from 26 institutions participating in the National Patient-Centered Clinical Research Network from January 1, 2009, to December 31, 2016. Participant inclusion required at least 1 valid set of same-day height and weight measurements at each of the following age periods: 0 to 5, 6 to 11, 12 to 23, 24 to 59, and 60 to 131 months (183 444 children). Data were analyzed from June 1, 2019, to June 30, 2020. Antibiotic use at 0 to 5, 6 to 11, 12 to 23, 24 to 35, and 36 to 47 months of age. Age and magnitude of BMI peak and BMI rebound. Of 183 444 children in the study (mean age, 3.3 years [range, 0-10.9 years]; 95 228 [51.9%] were boys; 80 043 [43.6%] were White individuals), 78.1% received any antibiotic, 51.0% had at least 1 episode of broad-spectrum antibiotic exposure, and 65.0% had at least 1 episode of narrow-spectrum antibiotic exposure at any time before 48 months of age. Exposure to any antibiotics at 0 to 5 months of age (vs no exposure) was associated with later age (β coefficient, 0.05 months [95% CI, 0.02-0.08 months]) and higher BMI (β coefficient, 0.09 [95% CI, 0.07-0.11]) at peak. Exposure to any antibiotics at 0 to 47 months of age (vs no exposure) was associated with an earlier age (-0.60 months [95% CI, -0.81 to -0.39 months]) and higher BMI at rebound (β coefficient, 0.02 [95% CI, 0.01-0.03]). These associations were strongest for children with at least 4 episodes of antibiotic exposure. Effect estimates for associations with age at BMI rebound were larger for those exposed to antibiotics at 24 to 35 months of age (β coefficient, -0.63 [95% CI, -0.83 to -0.43] months) or 36 to 47 (β coefficient, -0.52 [95% CI, -0.72 to -0.31] months) than for those exposed at 0 to 5 months of age (β coefficient, 0.26 [95% CI, 0.01-0.51] months) or 6 to 11 (β coefficient, 0.00 [95% CI, -0.20 to 0.20] months). In this cohort study, antibiotic exposure was associated with statistically significant, but small, differences in BMI trajectory milestones in infancy and early childhood. The small risk of an altered BMI trajectory milestone pattern associated with early-life antibiotic exposure is unlikely to be a key factor during prescription decisions for children.

Diabetic Retinopathy Clinical Research Retina Network Protocols in the Management of Diabetic Macular Edema

The Diabetic Retinopathy Clinical Research Network (DRCR) retina network was formed in 2002 through a United States National Eye Institute and National Institute of Diabetes and Digestive and Kidney Diseases-sponsored cooperative agreement with the objective of creating a collaborative network for multicenter clinical trials focusing on diabetic retinopathy (DR) and its associated complications. The DRCR Retina Network has initiated and completed 30 multicenter studies in over 350 clinical sites. The goals of the DRCR was to design, implement, and report clinical studies that would answer important questions related to clinical practice and management of DR as well as DME. Diabetic macular edema (DME) is the leading cause of vision loss in the working age population and until the turn of the century the treatment options were limited to macular laser. This review aims to summarize the major DME studies completed by the DRCR The current review covers the major clinical trials that have helped help establish the current standard of care in the management of DME including protocols A, B, I, T, U and V.

PSY6-5 Challenges of gynecologic cancer research with Asian countries

With growing and aging populations and the economic development, the need for cancer treatment development is increasing in Asian countries. There are some cancer types and histological types that are rare in the West but common in Asia. However, these cancers may fall outside the main scope of Western-led therapy development. Among gynecologic cancers, cervical cancer and ovarian clear cell carcinoma are common in Asian countries but rare in the west. For the development of cancer treatment in these Asian countries, it is necessary to develop not only the cancer treatment in Asia, but also to develop the infrastructure for advanced medicine such as genomic medicine. National Cancer Center Hospital, Tokyo is launching ATLAS (Asian clinical TriaLs network for cAncerS) project to establish a clinical research network across Asia. With partners in Malaysia, Viet Nam, Thailand, the Philippines and Indonesia, a framework for international clinical trials will be created. This project is aiming advance cancer genomic medicine and both investigators-initiated and industry-sponsored trials to achieve regulatory approval. The project will improve oncology drug access in Asia, where available drugs are limited, with establishment of cancer genomic medicine, and drug development. As a part of the ATLAS project, we are preparing following project: TEAL trial, A-TRAIN, MASTER KEY Asia. TEAL trial is an international investigator-initiated clinical trial for cervical cancer in Asian countries. A-TRAIN is a study comprehensively investigating circulating tumor DNA for metastatic / recurrent solid tumors including gynecologic cancers. MASTER KEY is a platform study to promote treatment development for rare cancers including a registry study, and multiple clinical trials in Japan. In MASTER KEY Asia, registration from Asian partner sites are planned in Asian counties. Of these projects, this presentation will focus on efforts against gynecologic cancer.

Treatment strategies for hydrocephalus related to Dandy-Walker syndrome: evaluating procedure selection and success within the Hydrocephalus Clinical Research Network.

Treating Dandy-Walker syndrome-related hydrocephalus (DWSH) involves either a CSF shunt-based or endoscopic third ventriculostomy (ETV)-based procedure. However, comparative investigations are lacking. This study aimed to compare shunt-based and ETV-based treatment strategies utilizing archival data from the Hydrocephalus Clinical Research Network (HCRN) registry. A retrospective review of prospectively collected and maintained data on children with DWSH, available from the HCRN registry (14 sites, 2008-2018), was performed. The primary outcome was revision-free survival of the initial surgical intervention. The primary exposure was either shunt-based (i.e., cystoperitoneal shunt [CPS], ventriculoperitoneal shunt [VPS], and/or dual-compartment) or ETV-based (i.e., ETV alone or with choroid plexus cauterization [CPC]) initial surgical treatment. Primary analysis included multivariable Cox proportional hazards models. Of 8400 HCRN patients, 151 (1.8%) had DWSH. Among these, the 102 patients who underwent shunt placement (79 VPSs, 16 CPSs, 3 other, and 4 multiple proximal catheter) were younger (6.6 vs 18.8 months, p < 0.001) and more frequently had 1 or more comorbidities (37.3% vs 14.3%, p = 0.005) than the 49 ETV-treated children (28 ETV-CPC). Fifty percent of the shunt-based and 51% of the ETV-based treatments failed. Notably, 100% (4/4) of the dual-compartment shunts failed. Adjusting for age, baseline ventricular size, and comorbidities, ETV-based treatment was not significantly associated with earlier failure compared with shunt-based treatment (HR for failure 1.32, 95% CI 0.77-2.26; p = 0.321). Complication rates were low: 4.9% and 6.1% (p = 0.715) for shunt- and ETV-based procedures, respectively. There was no difference in survival between ETV-CPC- and ETV-based treatment when adjusting for age (HR for failure 0.86, 95% CI 0.29-2.55, p = 0.783). In this North American, multicenter, prospective database review, shunt-based and ETV-based primary treatment strategies of DWSH appear similarly durable. Pediatric neurosurgeons can reasonably consider ETV-based initial treatment given the similar durability and the low complication rate. However, given the observational nature of this study, the treating surgeon might need to consider subgroups that were too small for a separate analysis. Very young children with comorbidities were more commonly treated with shunts, and older children with fewer comorbidities were offered ETV-based treatment. Future studies may determine preoperative characteristics associated with ETV treatment success in this population.

Visualization of clinical teaching citations using social network analysis

BackgroundAnalyzing the previous research literature in the field of clinical teaching has potential to show the trend and future direction of this field. This study aimed to visualize the co-authorship networks and scientific map of research outputs of clinical teaching and medical education by Social Network Analysis (SNA).MethodsWe Identified 1229 publications on clinical teaching through a systematic search strategy in the Scopus (Elsevier), Web of Science (Clarivate Analytics) and Medline (NCBI/NLM) through PubMed from the year 1980 to 2018.The Ravar PreMap, Netdraw, UCINet and VOSviewer software were used for data visualization and analysis.ResultsBased on the findings of study the network of clinical teaching was weak in term of cohesion and the density in the co-authorship networks of authors (clustering coefficient (CC): 0.749, density: 0.0238) and collaboration of countries (CC: 0.655, density: 0.176). In regard to centrality measures; the most influential authors in the co-authorship network was Rosenbaum ME, from the USA (0.048). More, the USA, the UK, Canada, Australia and the Netherlands have central role in collaboration countries network and has the vertex co-authorship with other that participated in publishing articles in clinical teaching. Analysis of background and affiliation of authors showed that co-authorship between clinical researchers in medicine filed is weak. Nineteen subject clusters were identified in the clinical teaching research network, seven of which were related to the expected competencies of clinical teaching and three related to clinical teaching skills.ConclusionsIn order to improve the cohesion of the authorship network of clinical teaching, it is essential to improve research collaboration and co-authorship between new researchers and those who have better closeness or geodisk path with others, especially those with the clinical background. To reach to a dense and powerful topology in the knowledge network of this field encouraging policies to be made for international and national collaboration between clinicians and clinical teaching specialists. In addition, humanitarian and clinical reasoning need to be considered in clinical teaching as of new direction in the field from thematic aspects.

Development and prognostic relevance of a histologic grading and staging system for alcohol-related liver disease

The SALVE Histopathology Group (SHG) developed and validated a grading and staging system for the clinical and full histological spectrum of alcohol-related liver disease (ALD) and evaluated its prognostic utility in a multinational cohort of 445 patients. SALVE grade was described by semiquantitative scores for steatosis, activity (hepatocellular injury and lobular neutrophils) and cholestasis. The histological diagnosis of steatohepatitis due to ALD (histological ASH, hASH) was based on the presence of hepatocellular ballooning and lobular neutrophils. Fibrosis staging was adapted from the Clinical Research Network staging system for non-alcoholic fatty liver disease and the Laennec staging system and reflects the pattern and extent of ALD fibrosis. There are 7 SALVE fibrosis stages (SFS) ranging from no fibrosis to severe cirrhosis. Interobserver κ-value for each grading and staging parameter was >0.6. In the whole study cohort, long-term outcome was associated with activity grade and cholestasis, as well as cirrhosis with very broad septa (severe cirrhosis) (p <0.001 for all parameters). In decompensated ALD, adverse short-term outcome was associated with activity grade, hASH and cholestasis (p= 0.038, 0.012 and 0.001, respectively), whereas in compensated ALD, hASH and severe fibrosis/cirrhosis were associated with decompensation-free survival (p= 0.011 and 0.001, respectively). On multivariable analysis, severe cirrhosis emerged as an independent histological predictor of long-term survival in the whole study cohort. Severe cirrhosis and hASH were identified as independent predictors of short-term survival in decompensated ALD, and also as independent predictors of decompensation-free survival in compensated ALD. The SALVE grading and staging system is a reproducible and prognostically relevant method for the histological assessment of disease activity and fibrosis in ALD. Patients with alcohol-related liver disease (ALD) may undergo liver biopsy to assess disease severity. We developed a system to classify ALD under the microscope by grading ALD activity and staging the extent of liver scarring. We validated the prognostic performance of this system in 445 patients from 4 European centers.

Histological severity of nonalcoholic fatty liver disease is associated with 10-year risk for atherosclerotic cardiovascular disease.

Nonalcoholic fatty liver disease (NAFLD) is associated with atherosclerotic cardiovascular disease (ASCVD). However, few studies have investigated the association between the histological severity of NAFLD and ASCVD. Therefore, we investigated whether the histological severity of NAFLD is associated with ASCVD risk. We performed cross-sectional analysis of prospectively enrolled, biopsy-proven NAFLD patients. The 10-year ASCVD risk was assessed using the Korean Risk Prediction Model. The histological spectrum of NAFLD was classified by the nonalcoholic steatohepatitis (NASH) clinical research network histological scoring system. The association between each histological subgroup and ASCVD risk was analyzed using logistic regression analysis. This study included 398 Korean subjects (mean age, 57.9years; male, 44.2%) with biopsy-proven NAFLD and 102 no-NALFD controls. Subjects with ASCVD risk ≥ 10% showed more severe grades of hepatocellular ballooning and more advanced stages of fibrosis when compared with subjects with ASCVD risk < 10% (p < 0.05 for each). The presence of NASH (odds ratio [OR] 4.07; 95% confidence interval [CI] 1.40-11.88) or advanced fibrosis (OR 8.11; 95% CI 1.83-35.98) was independently associated with a higher risk of ASCVD even after adjustment for age, sex, body mass index, blood pressure, lipids, liver enzymes, systemic inflammation, and insulin resistance. Patients with NASH or advanced fibrosis are at an increased risk of developing ASCVD compared with no-NAFLD controls or subjects with NAFL, independent of conventional metabolic risk factors for CVD. Histological information on NAFLD may be helpful to promote our understanding of extrahepatic complications, such as ASCVD, resulting from NAFLD progression.

Glycemic Control Predicts Severity of Hepatocyte Ballooning and Hepatic Fibrosis in Nonalcoholic Fatty Liver Disease.

Background and AimsWhether glycemic control, as opposed to diabetes status, is associated with the severity of NAFLD is open for study. We aimed to evaluate whether degree of glycemic control in the years preceding liver biopsy predicts the histological severity of NASH.Approach and ResultsUsing the Duke NAFLD Clinical Database, we examined patients with biopsy‐proven NAFLD/NASH (n = 713) and the association of liver injury with glycemic control as measured by hemoglobin A1c (HbA1c). The study cohort was predominantly female (59%) and White (84%) with median (interquartile range) age of 50 (42, 58) years; 49% had diabetes (n = 348). Generalized linear regression models adjusted for age, sex, race, diabetes, body mass index, and hyperlipidemia were used to assess the association between mean HbA1c over the year preceding liver biopsy and severity of histological features of NAFLD/NASH. Histological features were graded and staged according to the NASH Clinical Research Network system. Group‐based trajectory analysis was used to examine patients with at least three HbA1c (n = 298) measures over 5 years preceding clinically indicated liver biopsy. Higher mean HbA1c was associated with higher grade of steatosis and ballooned hepatocytes, but not lobular inflammation. Every 1% increase in mean HbA1c was associated with 15% higher odds of increased fibrosis stage (OR, 1.15; 95% CI, 1.01, 1.31). As compared with good glycemic control, moderate control was significantly associated with increased severity of ballooned hepatocytes (OR, 1.74; 95% CI, 1.01, 3.01; P = 0.048) and hepatic fibrosis (HF; OR, 4.59; 95% CI, 2.33, 9.06; P < 0.01).ConclusionsGlycemic control predicts severity of ballooned hepatocytes and HF in NAFLD/NASH, and thus optimizing glycemic control may be a means of modifying risk of NASH‐related fibrosis progression.

Noninvasive measure of treatment response in non-alcoholic steatohepatitis: Insights from EMMINENCE and meta-analysis.

Background and AimLiver histology changes are the current gold standard for evaluating non‐alcoholic steatohepatitis (NASH), but are limited by their invasiveness and variability for sampling and interpretation. We evaluated noninvasive biomarkers as an indication of histologic changes in NASH.MethodsAssociations between 12‐month biomarker and NASH Clinical Research Network histologic score changes in 339 patients with NASH in the EMMINENCE trial was examined with multivariable models and partial canonical correlation. A meta‐analysis of 17 NASH trials including 3717 patients examined associations between these same changes and histologic response within treatment groups, and treatment effects on biomarkers and on liver histology. Biopsy measures assessed were changes in ballooning, steatosis, inflammation, and fibrosis, NASH improvement without worsening of fibrosis, and fibrosis improvement without worsening of NASH. All analytic methods suggest that a combination of aspartate aminotransferase (AST), cytokeratin‐18 (CK‐18 [M30 or M65]), and hemoglobin A1C (HbA1c) changes best predicts overall liver biopsy changes in response to interventions.ResultsThe weighted average of standardized mean changes (0.403 × AST, 0.314 × CK‐18, 0.283 × HbA1c) facilitated comparisons of within‐group responses and treatment effects among studies included in the meta‐analysis. This composite in EMMINENCE discriminated between patients with and without NASH resolution without worsening fibrosis with area under the receiver‐operator characteristic curve of 0.7880, and for fibrosis improvement without NASH worsening of 0.7553.ConclusionA composite score based on changes in AST, HbA1c, and CK‐18 could serve as a surrogate for liver histologic improvement and an effective objective, noninvasive tool for comparative assessment of treatment effects of novel interventions.

Effect of High Sucrose Diet on Histopathological Indicators Associated With Nonalcoholic Fatty Liver Disease in Male and Female C57bl/6N Mice

Abstract Objectives To evaluate the effect of a high sucrose diet on the histopathological indicators related to NAFLD in male and female mice of the C57bl/6N strain. Methods Forty male and female mice of the C57bl/6N strain were randomly divided into four experimental groups: Control male (CMG) and female groups (CFG) with a standard diet (Rodent Chow) and tap water, as well as sucrose male (SMG) and female groups (SFG) which received standard diet and a 50% sucrose water solution. All the groups were fed ad libitum to one of the two different diets for 20 weeks. After 20 weeks, mice were sacrificed. Blood, hepatic and adipose tissues were collected for analyses. Hepatic tissues were sectioned and stained with hematoxylin and eosin. Samples were examined by light microscopy to analyze liver damage. The non-alcoholic steatohepatitis (NASH) degree was determined according to the histological score system proposed by the clinical research network of NASH. Results In hepatic histological samples of MCG, a normal parenchyma formed by hepatocytes with a conserved architecture was observed, in which the cytoplasm and the nucleus can be appreciated. According to the histological score system of the clinical research network of NASH, it was not considered into any NASH grade. FCG showed few microvesicles in parenchyma, developing grade 1 of NASH, with microvesicular steatosis, not considered pathological. Compared to sucrose groups, in MSG were observed presence of moderate microvesicular steatosis, moderate metabolic stress, and glycogen condensation. No presence of inflammatory infiltrate, inflammation, or granulomas, developing grade 4 of NASH. On the other hand, FSG showed a wide spread of macrovesicular steatosis (zones 1, 2 and 3 of liver acinus), presence of inflammatory infiltrate and granulomas in the liver parenchyma. High metabolic stress in the three zones and glycogen condensation, with the loss of histological architecture, positioning in grade 6 of NASH. Conclusions A high sucrose diet contributed to develop NAFLD in mice of the C57bl/6n strain. MSG showed light to moderate degree of NAFLD, whereas FSG showed a moderate to a high degree of NAFLD (steatosis and NASH) related to sucrose consumption. Funding Sources This work was supported by the Universidad Autónoma de Sinaloa.

The UPTAKE study: a cross-sectional survey examining the insights and beliefs of the UK population on COVID-19 vaccine uptake and hesitancy

ObjectiveA key challenge towards a successful COVID-19 vaccine uptake is vaccine hesitancy. We examine and provide novel insights on the key drivers and barriers towards COVID-19 vaccine uptake.DesignThis study involved...

Patient Recruitment Into a Multicenter Clinical Cohort Linking Electronic Health Records From 5 Health Systems: Cross-sectional Analysis

BackgroundThere is growing interest in identifying and recruiting research participants from health systems using electronic health records (EHRs). However, few studies have described the practical aspects of the recruitment process or compared electronic recruitment methods to in-person recruitment, particularly across health systems.ObjectiveThe objective of this study was to describe the steps and efficiency of the recruitment process and participant characteristics by recruitment strategy.MethodsEHR-based eligibility criteria included being an adult patient engaged in outpatient primary or bariatric surgery care at one of 5 health systems in the PaTH Clinical Research Network and having ≥2 weight measurements and 1 height measurement recorded in their EHR within the last 5 years. Recruitment strategies varied by site and included one or more of the following methods: (1) in-person recruitment by study staff from clinical sites, (2) US postal mail recruitment letters, (3) secure email, and (4) direct EHR recruitment through secure patient web portals. We used descriptive statistics to evaluate participant characteristics and proportion of patients recruited (ie, efficiency) by modality.ResultsThe total number of eligible patients from the 5 health systems was 5,051,187. Of these, 40,048 (0.8%) were invited to enter an EHR-based cohort study and 1085 were enrolled. Recruitment efficiency was highest for in-person recruitment (33.5%), followed by electronic messaging (2.9%), including email (2.9%) and EHR patient portal messages (2.9%). Overall, 779 (65.7%) patients were enrolled through electronic messaging, which also showed greater rates of recruitment of Black patients compared with the other strategies.ConclusionsWe recruited a total of 1085 patients from primary care and bariatric surgery settings using 4 recruitment strategies. The recruitment efficiency was 2.9% for email and EHR patient portals, with the majority of participants recruited electronically. This study can inform the design of future research studies using EHR-based recruitment.