Case definitions for inclusion and analysis of endpoints in clinical trials for nonalcoholic steatohepatitis through the lens of regulatory science.

Nonalcoholic steatohepatitis (NASH) is an important cause of liver-related morbidity and mortality. There are no approved therapies, and the results of clinical trials have been difficult to compare due to inconsistent definitions of relevant disease parameters in patients with NASH. The natural course of the disease has not been rigorously characterized, particularly with respect to the contributions of underlying obesity, type 2 diabetes, and other comorbidities and the treatments provided for these comorbidities. Efforts to perform analyses of pooled data are limited by heterogeneous case definitions used across studies to define disease states. There remains a major unmet need in the field to develop standardized definitions for populations for interventional trials. Such definitions are expected to impact how endpoints for clinical trials are constructed. The Liver Forum is a multistakeholder effort including US and European regulatory agencies, academic investigators, professional and patient representative organizations, and industry to catalyze therapeutic development for NASH by developing potential solutions to barriers to development. The Case Definitions Working Group was established by The Liver Forum to evaluate the validity of case definitions for populations to be included in clinical trials for NASH from a regulatory science perspective. Based on such analyses, specific recommendations are provided noting the strengths and weaknesses of the case definitions along with knowledge gaps that require additional study. (Hepatology 2018;67:2001-2012).

Centering Diverse Communities within Mindful Parenting Interventions in the U.S.: A Narrative Literature Review.

BACKGROUND: While mindfulness-based interventions targeted toward parents (and families) in the U.S. offer promise for the treatment and prevention of youth psychological disorders, current research has established the underrepresentation of diverse participants in the research literature. The full extent of inequalities in the demographics of participation in parent mindfulness intervention is less understood. OBJECTIVE: This study aimed to utilize a narrative literature review approach to examine and describe the degree to which research on mindful parenting interventions is inclusive of BIPOC (Black, Indigenous, and People of Color) communities, non-clinical samples (no diagnosed disorder), cultural adaptions, and skills specific to parenting. METHODS: An electronic database search of US-based studies was undertaken for empirical studies that primarily focused on parent mindfulness interventions, which reported outcomes related to either parenting behaviors or child mental health outcomes. After a full-text review, the search resulted in 34 articles. A narrative literature review of the 34 studies was conducted to assess the inclusion of BIPOC communities, non-clinical samples, cultural adaptions, and skills specific to parenting. RESULTS: This review found notable gaps in the degree to which mindful parenting research (1) included BIPOC populations in study samples; (2) focused on non-clinical samples; (3) adapted interventions to align with the cultural needs of participants; and (4) included the application of mindfulness to enhancing knowledge, skills, and behaviors specific to parenting. CONCLUSIONS: Given these gaps in the parent mindfulness literature, greater research attention is needed on mindful parenting interventions targeted toward BIPOC communities with no clinical diagnoses, interventions optimized by cultural adaptations, and explicit applications to parenting.

A Randomized Trial of Lipid Metabolism Modulation with Fenofibrate for Acute Coronavirus Disease 2019.

Background Abnormal cellular lipid metabolism appears to underlie SARS-CoV-2 cytotoxicity and may involve inhibition of peroxisome proliferator activated receptor alpha (PPARα). Fenofibrate, a PPAR-α activator, modulates cellular lipid metabolism. Fenofibric acid has also been shown to affect the dimerization of angiotensin-converting enzyme 2, the cellular receptor for SARS-CoV-2. Fenofibrate and fenofibric acid have been shown to inhibit SARS-CoV-2 replication in cell culture systems in vitro . Methods We randomly assigned 701 participants with COVID-19 within 14 days of symptom onset to 145 mg of fenofibrate (nanocrystal formulation with dose adjustment for renal function or dose-equivalent preparations of micronized fenofibrate or fenofibric acid) vs. placebo for 10 days, in a double-blinded fashion. The primary endpoint was a ranked severity score in which participants were ranked across hierarchical tiers incorporating time to death, duration of mechanical ventilation, oxygenation parameters, subsequent hospitalizations and symptom severity and duration. ClinicalTrials.gov registration: NCT04517396. Findings: Mean age of participants was 49 ± 16 years, 330 (47%) were female, mean BMI was 28 ± 6 kg/m 2 , and 102 (15%) had diabetes mellitus. A total of 41 deaths occurred. Compared with placebo, fenofibrate administration had no effect on the primary endpoint. The median (interquartile range [IQR]) rank in the placebo arm was 347 (172, 453) vs. 345 (175, 453) in the fenofibrate arm (P = 0.819). There was no difference in various secondary and exploratory endpoints, including all-cause death, across randomization arms. These results were highly consistent across pre-specified sensitivity and subgroup analyses. Conclusion Among patients with COVID-19, fenofibrate has no significant effect on various clinically relevant outcomes.

A randomized clinical trial of lipid metabolism modulation with fenofibrate for acute coronavirus disease 2019.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cytotoxicity may involve inhibition of peroxisome proliferator-activated receptor alpha. Fenofibrate activates peroxisome proliferator-activated receptor alpha and inhibits SARS-CoV-2 replication in vitro. Whether fenofibrate can be used to treat coronavirus disease 2019 (COVID-19) infection in humans remains unknown. Here, we randomly assigned inpatients and outpatients with COVID-19 within 14 d of symptom onset to 145 mg of oral fenofibrate nanocrystal formulation versus placebo for 10 d, in a double-blinded fashion. The primary endpoint was a severity score whereby participants were ranked across hierarchical tiers incorporating time to death, mechanical ventilation duration, oxygenation, hospitalization and symptom severity and duration. In total, 701 participants were randomized to fenofibrate (n = 351) or placebo (n = 350). The mean age of participants was 49 ± 16 years, 330 (47%) were female, mean body mass index was 28 ± 6 kg/m2 and 102 (15%) had diabetes. Death occurred in 41 participants. Compared with placebo, fenofibrate had no effect on the primary endpoint. The median (interquartile range) rank in the placebo arm was 347 (172, 453) versus 345 (175, 453) in the fenofibrate arm (P = 0.819). There was no difference in secondary and exploratory endpoints, including all-cause death, across arms. There were 61 (17%) adverse events in the placebo arm compared with 46 (13%) in the fenofibrate arm, with slightly higher incidence of gastrointestinal side effects in the fenofibrate group. Overall, among patients with COVID-19, fenofibrate has no significant effect on various clinically relevant outcomes ( NCT04517396 ).

Fruit-Promoting Smarter Lunchrooms Interventions: Results From a Cluster RCT.

INTRODUCTION: The Smarter Lunchrooms Movement was developed to provide schools with simple, low-cost solutions to encourage students to make healthier food choices at school. The objective of this study was to evaluate the impact of fruit-promoting Smarter Lunchroom interventions on middle school students' selection and consumption of fruits. DESIGN: A 9-week cluster RCT was conducted using a pre-test/post-test control group design in upstate New York in February-April 2014. SETTING/PARTICIPANTS: Ten middle schools (Grades 5-8) were recruited and randomized into a fruit intervention (n=4), vegetable intervention (n=3), or control group (n=3). This article focuses only on the fruit intervention and control groups. INTERVENTION: The fruit intervention group made changes to the convenience, visibility, and attractiveness of fruit in their lunchrooms for a period of 6 weeks. The control group made no changes, and were offered Smarter Lunchrooms training post-intervention. MAIN OUTCOME MEASURES: Selection and plate waste data were collected from February to April 2014, and analyzed in 2014-2015. Average selection, waste, and consumption of food items were computed, and the statistical differences between treatment and control groups were analyzed using t-test statistics and difference-in-difference analysis. RESULTS: Fruit selection increased overall by 36% (p<0.001), and fruit consumption increased overall by 23% (p<0.017). Vegetable selection and consumption and white milk selection also increased significantly in the treatment schools (p<0.001), though were not significant overall. CONCLUSIONS: The fruit intervention increased the selection and consumption of fruits overall, and increased the selection and consumption of vegetables and the selection of white milk in treatment schools. These findings provide evidence supporting the use of fruit-promoting Smarter Lunchrooms techniques in middle schools to increase the selection and consumption of healthy food items.

An outbreak of Escherichia coli O157 infection following exposure to a contaminated building.

CONTEXT: Infection with Escherichia coli O157 causes an estimated 70 000 diarrheal illnesses per year in the United States and can result in hemolytic-uremic syndrome and death. Environmental contamination with E coli O157 may be a public health problem. OBJECTIVES: To determine risk factors for E coli O157 infection during an outbreak investigation at a county fair and to evaluate environmental contamination as a possible cause of the outbreak. DESIGN, SETTING, AND PARTICIPANTS: Case-control study of 23 patients (median age, 15 years) and 53 age-matched controls who had attended the Lorain County, Ohio, fair between August 20 and August 26, 2001. Case-patients had laboratory-confirmed E coli O157 infection, hemolytic-uremic syndrome, or bloody diarrhea within 7 days of attending the fair; controls attended the fair and did not have diarrhea. MAIN OUTCOME MEASURES: Risk factors for infection and isolates of E coli O157 from environmental specimens. RESULTS: Six (26%) case-patients were hospitalized and 2 (9%) developed hemolytic-uremic syndrome. Case-patients were more likely than controls to have visited building A (a multipurpose community facility on the fairgrounds; matched odds ratio [MOR], 21.4 [95% confidence interval [CI], 2.7-170.7]). Among visitors to building A, illness was independently associated with attending a dance in the building (MOR, 7.5; 95% CI, 1.4-41.2), handling sawdust from the floor (MOR, 4.6; 95% CI, 1.1-20.0), or eating and/or drinking in the building (MOR, 4.5; 95% CI, 1.2-16.6). Twenty-four (44%) of 54 specimens collected from building A 6 weeks after the fair grew Shiga toxin-producing E coli O157. Isolates from sawdust, the rafters, and other surfaces were identical by molecular fingerprinting to patient isolates. Sawdust specimens collected 42 weeks after the fair also grew the same E coli O157 strain. CONCLUSIONS: Absence of evidence implicating specific food or beverage sources and the recovery of E coli O157 from the rafters suggest that airborne dispersion of bacteria contributed to the contamination. Because E coli O157 can survive in the environment for more than 10 months, humans may be at risk of infection long after an environment is initially contaminated.

Hospitalization and antimicrobial resistance in Salmonella outbreaks, 1984-2002.

Few studies have evaluated the health consequences of antimicrobial-resistant Salmonella strains associated with outbreaks. Among 32 outbreaks occurring in the United States from 1984 to 2002, 22% of 13,286 persons in 10 Salmonella-resistant outbreaks were hospitalized, compared with 8% of 2,194 persons in 22 outbreaks caused by pansusceptible Salmonella strains (p<0.01).

Non-O157 Shiga toxin-producing Escherichia coli infections in the United States, 1983-2002.

BACKGROUND: Shiga toxin-producing Escherichia coli (STEC) O157:H7 is a well-recognized cause of bloody diarrhea and hemolytic-uremic syndrome (HUS). Non-O157 STEC contribute to this burden of illness but have been underrecognized as a result of diagnostic limitations and inadequate surveillance. METHODS: Between 1983 and 2002, 43 state public health laboratories submitted 940 human non-O157 STEC isolates from persons with sporadic illnesses to the Centers for Diseases Control and Prevention reference laboratory for confirmation and serotyping. RESULTS: The most common serogroups were O26 (22%), O111 (16%), O103 (12%), O121 (8%), O45 (7%), and O145 (5%). Non-O157 STEC infections were most frequent during the summer and among young persons (median age, 12 years; interquartile range, 3-37 years). Virulence gene profiles were as follows: 61% stx(1) but not stx(2); 22% stx(2) but not stx(1); 17% both stx(1) and stx(2); 84% intimin (eae); and 86% enterohemolysin (E-hly). stx(2) was strongly associated with an increased risk of HUS, and eae was strongly associated with an increased risk of bloody diarrhea. STEC O111 accounted for most cases of HUS and was also the cause of 3 of 7 non-O157 STEC outbreaks reported in the United States. CONCLUSIONS: Non-O157 STEC can cause severe illness that is comparable to the illness caused by STEC O157. Strains that produce Shiga toxin 2 are much more likely to cause HUS than are those that produce Shiga toxin 1 alone. Improving surveillance will more fully elucidate the incidence and pathological spectrum of these emerging agents. These efforts require increased clinical suspicion, improved clinical laboratory isolation, and continued serotyping of isolates in public health laboratories.

Isomers of C(20): an energy profile.

Semiempirical calucaltions, at the PM 3 level, are used to geometrically optimize and determine the absolute energies (heats of formation) of a variety of C(20) isomers. Based on the geometrically optimized Cartesian coordinates of the ring and the bowl isomers, and the subsequent saddle-point calculation, a two-dimensional energy profile between these two isomers is generated. Performing geometry optimization on the Cartesian coordinates that correspond to energy minima within the ring-bowl profile, we have been able to identify several more isomers of C(20) that are predicted to be energitically stable. With these additional stable structures, we have identified pairs of isomers that lie adjacent to one another on the potential energy surface, as is evidenced by the form of their respective energy profiles. These adjacent pairs of isomers establish a step-wise transformation between the ring and the bowl. This process, which extends out over the three-dimensional surface, is predicted to require less energy than that of the direct, two-dimensional transformation predicted in the ring-bowl profile.

Toxigenic Vibrio cholerae serogroup O141-associated cholera-like diarrhea and bloodstream infection in the United States.

Toxigenic Vibrio cholerae serogroup O141 has been associated with sporadic cholera-like diarrhea and bloodstream infection in the United States. Consumption of seafood and proximity to the coast may increase the risk of infection. All V. cholerae isolates recovered from stool samples of patients with diarrhea or from a normally sterile site should be serogrouped and assessed for cholera toxin production. Improved surveillance and case-control studies are needed to further characterize illness and risk factors for V. cholerae O141 infection.