AI-based histologic scoring enables automated and reproducible assessment of enrollment criteria and endpoints in NASH clinical trials.

Clinical trials in nonalcoholic steatohepatitis (NASH) require histologic scoring for assessment of inclusion criteria and endpoints. However, guidelines for scoring key features have led to variability in interpretation, impacting clinical trial outcomes. We developed an artificial intelligence (AI)-based measurement (AIM) tool for scoring NASH histology (AIM-NASH). AIM-NASH predictions for NASH Clinical Research Network (CRN) grades of necroinflammation and stages of fibrosis aligned with expert consensus scores and were reproducible. Continuous scores produced by AIM-NASH for key histological features of NASH correlated with mean pathologist scores and with noninvasive biomarkers and strongly predicted patient outcomes. In a retrospective analysis of the ATLAS trial, previously unmet pathological endpoints were met when scored by the AIM-NASH algorithm alone. Overall, these results suggest that AIM-NASH may assist pathologists in histologic review of NASH clinical trials, reducing inter-rater variability on trial outcomes and offering a more sensitive and reproducible measure of patient therapeutic response.

Human-interpretable image features derived from densely mapped cancer pathology slides predict diverse molecular phenotypes.

Computational methods have made substantial progress in improving the accuracy and throughput of pathology workflows for diagnostic, prognostic, and genomic prediction. Still, lack of interpretability remains a significant barrier to clinical integration. We present an approach for predicting clinically-relevant molecular phenotypes from whole-slide histopathology images using human-interpretable image features (HIFs). Our method leverages >1.6 million annotations from board-certified pathologists across >5700 samples to train deep learning models for cell and tissue classification that can exhaustively map whole-slide images at two and four micron-resolution. Cell- and tissue-type model outputs are combined into 607 HIFs that quantify specific and biologically-relevant characteristics across five cancer types. We demonstrate that these HIFs correlate with well-known markers of the tumor microenvironment and can predict diverse molecular signatures (AUROC 0.601-0.864), including expression of four immune checkpoint proteins and homologous recombination deficiency, with performance comparable to 'black-box' methods. Our HIF-based approach provides a comprehensive, quantitative, and interpretable window into the composition and spatial architecture of the tumor microenvironment.

The Effects of Acute Exercise on Short- and Long-Term Memory: Considerations for the Timing of Exercise and Phases of Memory.

The specific questions addressed from this research include: (1) Does high-intensity acute exercise improve memory?, (2) If so, do the mechanisms occur via encoding, consolidation, or retrieval? and (3) If acute exercise occurs in multiple phases of memory (e.g., before encoding and during consolidation), does this have an additive effect on memory? Three experimental, within-subject, counterbalanced studies were conducted among young adults. High-intensity exercise involved a 20-minutes bout of exercise at 75% of heart rate reserve. Memory was evaluated from a word-list task, including multiple evaluations out to 24-hours post-encoding. The timing of the exercise and memory assessments were carefully positioned to evaluate whether any improvements in memory were driven by mechanisms related to encoding, consolidation, and/or retrieval. We demonstrated that high-intensity acute exercise enhanced memory. This effect was robust (repeatable) and occurred through encoding, consolidation and retrieval-based mechanisms. Further, incorporating acute exercise into multiple phases of memory additively enhanced memory function.

Breast cancer survivors' preferences for social support features in technology-supported physical activity interventions: findings from a mixed methods evaluation.

Incorporating peer and professional social support features into remotely delivered, technology-supported physical activity interventions may increase their effectiveness. However, very little is known about survivors' preferences for potential social features. This study explored breast cancer survivors' preferences for both traditional (e.g., coaching calls and peer support) and innovative (i.e., message boards and competitions) social support features within remotely delivered, technology-supported physical activity interventions. Survivors [N = 96; Mage = 55.8 (SD = 10.2)] self-reported demographic and disease characteristics and physical activity. A subset (n = 28) completed semistructured phone interviews. Transcribed interviews were evaluated using a thematic content analysis approach and consensus review. Following interviews, the full sample self-reported preferences for social features for remotely delivered physical activity interventions via online questionnaires. Questionnaire data were analyzed using descriptive statistics. Four themes emerged from interview data: (a) technology increases social connectedness; (b) interest in professional involvement/support; (c) connecting with similar survivors; and (d) apprehension regarding competitive social features. Quantitative data indicated that most survivors were interested in social features including a coach (77.1 per cent), team (66.7 per cent), and exercise buddy (57.3 per cent). Survivors endorsed sharing their activity data with their team (80.0 per cent) and buddy (76.6 per cent), but opinions were mixed regarding a progress board ranking their activity in relation to other participants' progress. Survivors were interested in using a message board to share strategies to increase activity (74.5 per cent) and motivational comments (73.4 per cent). Social features are of overall interest to breast cancer survivors, yet preferences for specific social support features varied. Engaging survivors in developing and implementing remotely delivered, technology-supported social features may enhance their effectiveness.

A qualitative exploration of social and environmental factors affecting diet and activity in knee replacement patients.

AIMS AND OBJECTIVES: To examine perceived social and environmental barriers and facilitators for healthy eating and activity before and after knee replacement. BACKGROUND: Many patients undergoing knee replacement surgery are overweight or obese. While obesity treatment guidelines encourage diet and activity modifications, gaps exist in understanding social and environmental determinants of these behaviours for knee replacement patients. Identifying these determinants is critical for treatment, as they are likely amplified due to patients' mobility limitations, the nature of surgery and reliance on others during recovery. DESIGN: This qualitative study used semi-structured interviews. METHODS: Twenty patients (M = 64.7 ± 9.8 years, 45% female, 90% Caucasian, body mass index 30.8 ± 5.5 kg/m2 ) who were scheduled for or had recently undergone knee replacement were interviewed. Participants were asked to identify social and environmental factors that made it easier or harder to engage in healthy eating or physical activity. Deidentified transcripts were analysed via constant comparative analysis to identify barriers and facilitators to healthy eating and activity. This paper was written in accordance with COnsolidated criteria for REporting Qualitative research standards. RESULTS: Identified social and environmental healthy eating barriers included availability of unhealthy food and attending social gatherings; facilitators included availability of healthy food, keeping unhealthy options "out of sight," and social support. Weather was the primary activity barrier, while facilitators included access to physical activity opportunities and social support. CONCLUSIONS: Results provide salient factors for consideration by clinicians and behavioural programmes targeting diet, activity, and weight management, and patient variables to consider when tailoring interventions. RELEVANCE TO CLINICAL PRACTICE: Practitioners treating knee replacement patients would be aided by an understanding of patients' perceived social and environmental factors that impede or facilitate surgical progress. Particularly for those directly interacting with patients, like nurses, physiotherapists, or other professionals, support from health professionals appears to be a strong facilitator of adherence to diet and increased activity.

Phenotypic and genotypic differences in colorectal carcinoma among Caucasians, Asians, and Hispanics lack statistical significance.

Colorectal carcinoma (CRC) has been shown to have both genetic and environmental factors that can promote carcinoma development. Previous studies have found ethnic differences in the distribution of molecular phenotypes of CRC. Very little specific data exist regarding Hispanic CRC, and these data primarily focus on epidemiology or location of carcinoma. Our retrospective study analyzed 562 Caucasian, Asian, and Hispanic CRC patients at the UCI Medical Center from 2004 to 2012. The results showed that there were no statistically significant differences with respect to mean age, gender or site of carcinoma among the three ethnic groups. There were no statistically significant differences among the three ethnicities with respect to rates of MSI, mutated BRAF, and mutated KRAS. The Caucasian group had a non-significant higher rate of MSI (15%) and BRAF mutation (12%) than the Asian and Hispanic groups. Hispanics had a non-significant higher rate of KRAS mutation (59%) than Caucasians (38%) and Asians (37%). The results of this study demonstrated a higher rate of MSI and BRAF mutation in the Caucasian group and a higher rate of KRAS mutation in the Hispanic group, however differences were not statistically significant.

Preferences and motivation for weight loss among knee replacement patients: implications for a patient-centered weight loss intervention.

BACKGROUND: Most knee replacement patients are overweight/obese, yet are commonly excluded from evidence-based weight loss programs due to mobility limitations and barriers faced around the time of surgery. The purpose of this study was to identify knee replacement patient preferences for weight loss programs and qualitatively understand previous motives for weight loss attempts as well as strategies used to facilitate behavior changes. METHODS: Patients who were either scheduled to have knee replacement or had one recently completed within the last 3 months were recruited to participate. Patients completed a brief weight loss program preference questionnaire assessing preferred components of a weight loss program (i.e. self-monitoring, educational topics, program duration). Qualitative interviews were completed to identify motives for and strategies used during past weight loss attempts. All interviews were transcribed, de-identified, and analyzed using constant comparative analysis. RESULTS: Twenty patients (11 pre-operative and 9 post-operative) between 47 and 79 years completed the study (55% male, 90% White, and 85% with a BMI ≥25 kg/m2). Patients reported a preference for a weight loss program that starts before surgery, is at least 6 months in duration, and focuses both on diet and exercise. The majority of patients preferred to have a telephone-based program and wanted to track diet and physical activity on a smartphone application. The most common motive for weight loss mentioned by patients related to physical appearance (including how clothing fit), followed by wanting to lose weight to improve knee symptoms or to prevent or delay knee replacement. Strategies that patients identified as helpful during weight loss attempts included joining a formal weight loss program, watching portion sizes, and self-monitoring their dietary intake, physical activity, or weight. CONCLUSIONS: This study provides a preliminary examination into the motives for weight loss, strategies utilized during past weight loss attempts, and preferences for future weight loss programs as described by knee replacement patients. These results will help guide the development and adaptation of future patient-centered weight loss programs as well as help clinicians recommend targeted weight programs based on the specific preferences of the knee replacement population.

Physical activity: a synopsis and comment on "community-wide interventions for increasing physical activity".

In this synopsis, we summarize and comment on Baker and colleagues' Cochrane review of studies on the population-level impact of community-wide physical activity (PA) interventions. Insufficient PA remains a major public health problem. Community-wide interventions offer an opportunity to extend reach by increasing the proportion of the population experiencing the intervention. A previous Cochrane review of community-wide PA interventions concluded that evidence for effectiveness was mixed. Hence, Baker and colleagues incorporated new data about community-based PA interventions. This Cochrane review concluded there is an overall lack of evidence that community-wide interventions improve PA outcomes at the population level. Recommendations are that future research should use high quality research design, more explicitly test ways to increase reach, and utilize objective measurements of PA to increase validity. We suggest that future research should first optimize the intervention by systematically evaluating treatment components and selecting a maximally efficient and effective treatment package.

Acceptability of smartphone technology to interrupt sedentary time in adults with diabetes.

Breaking up sitting time with light- or moderate-intensity physical activity may help to alleviate some negative health effects of sedentary behavior, but few studies have examined ways to effectively intervene. This feasibility study examined the acceptability of a new technology (NEAT!) developed to interrupt prolonged bouts (≥20 min) of sedentary time among adults with type 2 diabetes. Eight of nine participants completed a 1-month intervention and agreed that NEAT! made them more conscious of sitting time. Most participants (87.5 %) expressed a desire to use NEAT! in the future. Sedentary time decreased by 8.1 ± 4.5 %, and light physical activity increased by 7.9 ± 5.5 % over the 1-month period. The results suggest that NEAT! is an acceptable technology to intervene on sedentary time among adults with type 2 diabetes. Future studies are needed to examine the use of the technology among larger samples and determine its effects on glucose and insulin levels.

Optimization of remotely delivered intensive lifestyle treatment for obesity using the Multiphase Optimization Strategy: Opt-IN study protocol.

BACKGROUND: Obesity-attributable medical expenditures remain high, and interventions that are both effective and cost-effective have not been adequately developed. The Opt-IN study is a theory-guided trial using the Multiphase Optimization Strategy (MOST) to develop an optimized, scalable version of a technology-supported weight loss intervention. OBJECTIVE: Opt-IN aims to identify which of 5 treatment components or component levels contribute most meaningfully and cost-efficiently to the improvement of weight loss over a 6 month period. STUDY DESIGN: Five hundred and sixty obese adults (BMI 30-40 kg/m(2)) between 18 and 60 years old will be randomized to one of 16 conditions in a fractional factorial design involving five intervention components: treatment intensity (12 vs. 24 coaching calls), reports sent to primary care physician (No vs. Yes), text messaging (No vs. Yes), meal replacement recommendations (No vs. Yes), and training of a participant's self-selected support buddy (No vs. Yes). During the 6-month intervention, participants will monitor weight, diet, and physical activity on the Opt-IN smartphone application downloaded to their personal phone. Weight will be assessed at baseline, 3, and 6 months. SIGNIFICANCE: The Opt-IN trial is the first study to use the MOST framework to develop a weight loss treatment that will be optimized to yield the best weight loss outcome attainable for $500 or less.

Mobile health: a synopsis and comment on "Increasing physical activity with mobile devices: a meta-analysis".

We offer a synopsis and commentary on J. Fanning and colleagues' article "Increasing Physical Activity with Mobile Devices: A Meta-Analysis" published in the Journal of Medical Internet Research. Although regular physical activity has a range of benefits, very few adults in the USA meet recommended guidelines for daily physical activity. The meta-analysis of Fanning et al. (2012) aimed to synthesize the results of research using mobile devices to increase physical activity. Their review identified 11 studies that used mobile technologies, including short message service (SMS), apps, or personal digital assistant (PDA) to improve physical activity behaviors among participants. Fanning et al. conclude that while literature in this area is limited to date, there is initial support for the efficacy of mobile-based interventions for improving physical activity. Included studies varied greatly, and the majority used only SMS to influence physical behaviors, meaning generalization of results to other forms of mobile technologies may be premature. This review does, however, provide a foundation for understanding how mobile-based interventions may be used efficaciously for the development of future interventions to improve health behaviors.

e-Health intervention development: a synopsis and comment on "What Design Features are Used in Effective e-Health Interventions? A Review Using Techniques From Critical Interpretive Synthesis".

In this synopsis and commentary on the Morrison and colleagues article published in Telemedicine and e-Health (18:2, 137-144, 2012), we provide a brief review of effective design features of e-Health interventions as well as a discussion on future directions. The Internet is being used more frequently to deliver health behavior interventions; however, it is unclear which design features contribute to intervention outcomes. Morrison and colleagues conducted a review using critical interpretive synthesis techniques to identify design features that mediate the effects of e-Health intervention outcomes. A total of four design features were identified (social context and support, contacts with intervention, tailoring, and self-management) that may mediate the effect of the intervention on outcomes. This review provides a preliminary conceptual framework to guide future evaluations of the effects of e-Health design features on intervention outcomes. Future research should target optimizing e-Health interventions to determine which design features should be included as well as how they contribute to outcomes.

Macrophage-produced IL-12p70 mediates hemorrhage-induced damage in a complement-dependent manner.

Hemorrhage and hemorrhagic shock instigate intestinal damage and inflammation. Multiple components of the innate immune response, including complement and neutrophil infiltration, are implicated in this pathology. To investigate the interaction of complement activation and other components of the innate immune response during hemorrhage, we treated mice after hemorrhage with CR2-fH, a targeted inhibitor of the alternative complement pathway and assessed intestinal damage and inflammation 2 h after hemorrhage. In wild-type mice, CR2-fH attenuated hemorrhage-induced, midjejunal damage and inflammation as determined by decreased mucosal damage, macrophage infiltration, leukotriene B4, IL-12p40, and TNF-[alpha] production. The critical nature of intestinal macrophage infiltration and activation in the response to hemorrhage was further determined using mice pretreated with clodronate-containing liposomes. The absence of either macrophages or IL-12p70 attenuated intestinal damage. These data suggest that complement activation and macrophage infiltration with IL-12p70 production are critical to hemorrhage-induced midjejunal damage and inflammation.

CR2+ marginal zone B cell production of pathogenic natural antibodies is C3 independent.

Intestinal ischemia-reperfusion (IR)-induced damage requires complement receptor 2 (CR2) for generation of the appropriate natural Ab repertoire. Pathogenic Abs recognize neoantigens on the ischemic tissue, activate complement, and induce intestinal damage. Because C3 cleavage products act as ligands for CR2, we hypothesized that CR2(hi) marginal zone B cells (MZBs) require C3 for generation of the pathogenic Abs. To explore the ability of splenic CR2(+) B cells to generate the damaging Ab repertoire, we adoptively transferred either MZBs or follicular B cells (FOBs) from C57BL/6 or Cr2(-/-) mice into Rag-1(-/-) mice. Adoptive transfer of wild type CR2(hi) MZBs but not CR2(lo) FOBs induced significant damage, C3 deposition, and inflammation in response to IR. In contrast, similarly treated Rag-1(-/-) mice reconstituted with either Cr2(-/-) MZB/B1 B cells (B1Bs) or FOBs lacked significant intestinal damage and displayed limited complement activation. To determine whether C3 cleavage products are critical in CR2-dependent Ab production, we evaluated the ability of the natural Ab repertoire of C3(-/-) mice to induce damage in response to IR. Infusion of C3(-/-) serum into Cr2(-/-) mice restored IR-induced tissue damage. Furthermore, Rag-1(-/-) mice sustained significant damage after infusion of Abs from C3(-/-) but not Cr2(-/-) mice. Finally, adoptive transfer of MZBs from C3(-/-) mice into Rag-1(-/-) mice resulted in significant tissue damage and inflammation. These data indicate that CR2 expression on MZBs is sufficient to induce the appropriate Abs required for IR-induced tissue damage and that C3 is not critical for generation of the pathogenic Abs.

Helicobacter infection alters MyD88 and Trif signalling in response to intestinal ischaemia-reperfusion.

Ischaemia-reperfusion-induced intestinal injury requires both Toll-like receptor 4 (TLR4) signalling through myeloid differentiation primary response gene (88) (MyD88) and complement activation. As a common Gram-negative intestinal pathogen, Helicobacter hepaticus signals through TLR4 and upregulates the complement inhibitor, decay accelerating factor (DAF; CD55). Since ischaemia-reperfusion (IR) injury is complement dependent, we hypothesized that Helicobacter infection may alter IR-induced intestinal damage. Infection increased DAF transcription and subsequently decreased complement activation in response to IR without altering intestinal damage in wild-type mice. Ischaemia-reperfusion induced similar levels of DAF mRNA expression in uninfected wild-type, MyD88(-/-) or TIR-domain-containing adaptor-inducing interferon-ß (Trif)-deficient mice. However, during infection, IR-induced DAF transcription was significantly attenuated in Trif-deficient mice. Likewise, IR-induced intestinal damage, complement component 3 deposition and prostaglandin E(2) production were attenuated in Helicobacter-infected, Trif-deficient but not MyD88(-/-) mice. While infection attenuated IR-induced cytokine production in wild-type and MyD88(-/-) mice, there was no further decrease in Trif-deficient mice. These data indicate distinct roles for MyD88 and Trif in IR-induced inflammation and suggest that chronic, undetected infections, such as Helicobacter, alter the use of the adaptor proteins to induce damage.

Natural Helicobacter infection modulates mouse intestinal muscularis macrophage responses.

Helicobacter species are common laboratory pathogens which induce intestinal inflammation and disease in susceptible mice. Since in vitro studies indicate that Helicobacter products activate macrophages, we hypothesized that in vivo Helicobacter infection regulates the inflammatory response of intestinal muscularis macrophages from C57Bl/6 mice. Helicobacter hepaticus infection increased surface expression of macrophage markers F4/80, CD11b and MHC-II within whole intestinal muscle mounts. However, constitutive cytokine and chemokine production by macrophages isolated from infected mice significantly decreased compared to macrophages from uninfected mice despite no detectable bacterial products in the cultures. In addition, muscularis macrophages from infected mice up-regulated FIZZ-1 and SK-1 gene expression, suggesting the macrophages had an anti-inflammatory phenotype. Corresponding with increased anti-inflammatory gene expression, macrophages from infected mice were more phagocytic but did not produce cytokines after stimulation with LPS and IFN-γ or immune complexes and IL-4. Therefore, the presence of Helicobacter infection matures intestinal muscularis macrophages, modulating the constitutive macrophage response to become more anti-inflammatory and resistant to secondary stimulation.

Domain V peptides inhibit beta2-glycoprotein I-mediated mesenteric ischemia/reperfusion-induced tissue damage and inflammation.

Reperfusion of ischemic tissue induces significant tissue damage in multiple conditions, including myocardial infarctions, stroke, and transplantation. Although not as common, the mortality rate of mesenteric ischemia/reperfusion (IR) remains >70%. Although complement and naturally occurring Abs are known to mediate significant damage during IR, the target Ags are intracellular molecules. We investigated the role of the serum protein, ß2-glycoprotein I as an initiating Ag for Ab recognition and ß2-glycoprotein I (ß2-GPI) peptides as a therapeutic for mesenteric IR. The time course of ß2-GPI binding to the tissue indicated binding and complement activation within 15 min postreperfusion. Treatment of wild-type mice with peptides corresponding to the lipid binding domain V of ß2-GPI blocked intestinal injury and inflammation, including cellular influx and cytokine and eicosanoid production. The optimal therapeutic peptide (peptide 296) contained the lysine-rich region of domain V. In addition, damage and most inflammation were also blocked by peptide 305, which overlaps with peptide 296 but does not contain the lysine-rich, phospholipid-binding region. Importantly, peptide 296 retained efficacy after replacement of cysteine residues with serine. In addition, infusion of wild-type serum containing reduced levels of anti-ß2-GPI Abs into Rag-1(-/-) mice prevented IR-induced intestinal damage and inflammation. Taken together, these data suggest that the serum protein ß2-GPI initiates the IR-induced intestinal damage and inflammatory response and as such is a critical therapeutic target for IR-induced damage and inflammation.

Complement regulates TLR4-mediated inflammatory responses during intestinal ischemia reperfusion.

Innate immune responses including TLR4 and complement activation are required for mesenteric ischemia/reperfusion (IR)-induced tissue damage. We examined the regulation of TLR4 and complement activation in a mouse model of intestinal IR. Intestinal IR-induced C3 deposition in a TLR4 dependent manner. In addition, in wild-type but not TLR4 deficient mice, IR significantly increased C3 and Factor B (FB) mRNA expression within the intestine. To further examine the role of TLR4 and complement, we administered the complement inhibitor, CR2-Crry, to target local complement activation in wild-type C57Bl/10, and TLR4 deficient B10/ScN mice. TLR4 deficient mice sustained less damage and inflammation after IR than wild-type mice, but administration of CR2-Crry did not further reduce tissue damage. In contrast, CR2-Crry treatment of wild-type mice was accompanied by a reduction in complement activation and in C3 and FB transcription in response to IR. CR2-Crry also significantly decreased intestinal IL-6 and IL-12p40 production in both the wild-type and TLR4 deficient mice. These data indicate that TLR4 regulates extrahepatic complement production while complement regulates TLR4-mediated cytokine production during intestinal IR.