CYP8B1 downregulation mediates the metabolic effects of vertical sleeve gastrectomy in mice.

BACKGROUND AND AIMS: Although the benefits of vertical sleeve gastrectomy (VSG) surgery are well known, the molecular mechanisms by which VSG alleviates obesity and its complications remain unclear. We aim to determine the role of CYP8B1 (cytochrome P450, family 8, subfamily B, polypeptide 1) in mediating the metabolic benefits of VSG. APPROACH AND RESULTS: We found that expression of CYP8B1, a key enzyme in controlling the 12α-hydroxylated (12α-OH) bile acid (BA) to non-12α-OH BA ratio, was strongly downregulated after VSG. Using genetic mouse models of CYP8B1 overexpression, knockdown, and knockout, we demonstrated that overexpression of CYP8B1 dampened the metabolic improvements associated with VSG. In contrast, short hairpin RNA-mediated CYP8B1 knockdown improved metabolism similar to those observed after VSG. Cyp8b1 deficiency diminished the metabolic effects of VSG. Further, VSG-induced alterations to the 12α-OH/non-12α-OH BA ratio in the BA pool depended on CYP8B1 expression level. Consequently, intestinal lipid absorption was restricted, and the gut microbiota (GM) profile was altered. Fecal microbiota transplantation from wild type-VSG mice (vs. fecal microbiota transplantation from wild-type-sham mice) improved metabolism in recipient mice, while there were no differences between mice that received fecal microbiota transplantation from knockout-sham and knockout-VSG mice. CONCLUSIONS: CYP8B1 is a critical downstream target of VSG. Modulation of BA composition and gut microbiota profile by targeting CYP8B1 may provide novel insight into the development of therapies that noninvasively mimic bariatric surgery to treat obesity and its complications.

A Phase II Clinical Trial of Pembrolizumab and Enobosarm in Patients with Androgen Receptor-Positive Metastatic Triple-Negative Breast Cancer.

LESSONS LEARNED: The combination of enobosarm and pembrolizumab was well tolerated and showed a modest clinical benefit rate of 25% at 16 weeks. Future trials investigating androgen receptor-targeted therapy in combination with immune checkpoint inhibitors are warranted. BACKGROUND: Luminal androgen receptor is a distinct molecular subtype of triple-negative breast cancer (TNBC) defined by overexpression of androgen receptor (AR). AR-targeted therapy has shown modest activity in AR-positive (AR+) TNBC. Enobosarm (GTx-024) is a nonsteroidal selective androgen receptor modulator (SARM) that demonstrates preclinical and clinical activity in AR+ breast cancer. The current study was designed to explore the safety and efficacy of the combination of enobosarm and pembrolizumab in patients with AR+ metastatic TNBC (mTNBC). METHODS: This study was an open-label phase II study for AR+ (≥10%, 1+ by immunohistochemistry [IHC]) mTNBC. Eligible patients received pembrolizumab 200 mg intravenous (IV) every 3 weeks and enobosarm 18 mg oral daily. The primary objective was to evaluate the safety of enobosarm plus pembrolizumab and determine the response rate. Peripheral blood, tumor biopsies, and stool samples were collected for correlative analysis. RESULTS: The trial was stopped early because of the withdrawal of GTx-024 drug supply. Eighteen patients were enrolled, and 16 were evaluable for responses. Median age was 64 (range 36-81) years. The combination was well tolerated, with only a few grade 3 adverse events: one dry skin, one diarrhea, and one musculoskeletal ache. The responses were 1 of 16 (6%) complete response (CR), 1 of 16 (6%) partial response (PR), 2 of 16 (13%) stable disease (SD), and 12 of 16 (75%) progressive disease (PD). Response rate (RR) was 2 of 16 (13%). Clinical benefit rate (CBR) at 16 weeks was 4 of 16 (25%). Median follow-up was 24.9 months (95% confidence interval [CI], 17.5-30.9). Progression-free survival (PFS) was 2.6 months (95% CI, 1.9-3.1) and overall survival (OS) was 25.5 months (95% CI, 10.4-not reached [NR]). CONCLUSION: The combination of enobosarm and pembrolizumab was well tolerated, with a modest clinical benefit rate of 25% at 16 weeks in heavily pretreated AR+ TNBC without preselected programmed death ligand-1 (PD-L1). Future clinical trials combining AR-targeted therapy with immune checkpoint inhibitor (ICI) for AR+ TNBC warrant investigation.

Parents' Desire to Change Phone Use: Associations with Objective Smartphone Use and Feelings About Problematic Use and Distraction.

We examined objective smartphone use (via a mobile sensing application) and self-reported desire to change phone use among a sample of 268 U.S. parents of infants. Using the Transtheoretical Stages of Change model as a conceptual foundation, we contextualized their attitudes and behaviors and explored how phone use and desire to change relate to perceptions of distraction and problematic phone use around their child. Latent profile analysis of parents' precontemplation, contemplation, and action scores revealed two classes-precontemplators (15%) and contemplators (85%). Contemplators-those considering or desiring change-showed more bedtime phone use and general social networking than precontemplors; however, there were no significant differences between groups on other objective use measures (e.g., total daily duration of phone use, phone use around child, etc.). Contemplators also showed greater perceptions of problematic use around their child and parenting distraction. Moreover, parents' problematic use and distraction were predictive of higher contemplation scores, even after controlling for demographic and objective phone use variables. Taken together, these results suggest that perceptions of phone use as problematic may be more important than actual phone habits, especially total phone use duration, for desire to change. Suggestions for future research and intervention are provided.

A CRISPR-enhanced metagenomic NGS test to improve pandemic preparedness.

The lack of preparedness for detecting and responding to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen (i.e., COVID-19) has caused enormous harm to public health and the economy. Testing strategies deployed on a population scale at day zero, i.e., the time of the first reported case, would be of significant value. Next-generation sequencing (NGS) has such capabilities; however, it has limited detection sensitivity for low-copy-number pathogens. Here, we leverage the CRISPR-Cas9 system to effectively remove abundant sequences not contributing to pathogen detection and show that NGS detection sensitivity of SARS-CoV-2 approaches that of RT-qPCR. The resulting sequence data can also be used for variant strain typing, co-infection detection, and individual human host response assessment, all in a single molecular and analysis workflow. This NGS work flow is pathogen agnostic and, therefore, has the potential to transform how large-scale pandemic response and focused clinical infectious disease testing are pursued in the future.

Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial.

Previous studies have suggested that the gut microbiome influences the response to checkpoint inhibitors (CPIs) in patients with cancer. CBM588 is a bifidogenic live bacterial product that we postulated could augment CPI response through modulation of the gut microbiome. In this open-label, single-center study (NCT03829111), 30 treatment-naive patients with metastatic renal cell carcinoma with clear cell and/or sarcomatoid histology and intermediate- or poor-risk disease were randomized 2:1 to receive nivolumab and ipilimumab with or without daily oral CBM588, respectively. Stool metagenomic sequencing was performed at multiple timepoints. The primary endpoint to compare the relative abundance of Bifidobacterium spp. at baseline and at 12 weeks was not met, and no significant differences in Bifidobacterium spp. or Shannon index associated with the addition of CBM588 to nivolumab-ipilimumab were detected. Secondary endpoints included response rate, progression-free survival (PFS) and toxicity. PFS was significantly longer in patients receiving nivolumab-ipilimumab with CBM588 than without (12.7 months versus 2.5 months, hazard ratio 0.15, 95% confidence interval 0.05-0.47, P = 0.001). Although not statistically significant, the response rate was also higher in patients receiving CBM588 (58% versus 20%, P = 0.06). No significant difference in toxicity was observed between the study arms. The data suggest that CBM588 appears to enhance the clinical outcome in patients with metastatic renal cell carcinoma treated with nivolumab-ipilimumab. Larger studies are warranted to confirm this clinical observation and elucidate the mechanism of action and the effects on microbiome and immune compartments.

Randomized trial assessing impact of probiotic supplementation on gut microbiome and clinical outcome from targeted therapy in metastatic renal cell carcinoma.

Studies suggest a link between the gut microbiome and metastatic renal cell carcinoma (mRCC) outcomes, including evidence that mRCC patients possess a lower abundance of Bifidobacterium spp. compared to healthy adults. We sought to assess if a Bifidobacterium-containing yogurt product could modulate the gut microbiome and clinical outcome from vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKIs). mRCC patients initiating VEGF-TKIs, regardless of the line of therapy, were randomized to probiotic-supplemented (two 4 oz. servings of the probiotic yogurt product daily) or probiotic-restricted arms. Stool samples were collected prior to therapy and at weeks 2, 3, 4, and 12. Microbiome composition was assessed using whole-metagenome sequencing. A total of 20 patients were randomized. Bifidobacterium animalis, the active ingredient of the probiotic supplement, reached detectable levels in all patients in the probiotic-supplemented arm versus two patients in the probiotic-restricted arm. Clinical benefit rate was similar in probiotic-supplemented versus probiotic-restricted arms (70% vs. 80%, p = 0.606). Linear discriminant analysis (LDA) effect size analysis of MetaPhIAn2 abundance data predicted 25 enriched species demonstrating an LDA score >3 in either clinical benefit or no clinical benefit. In patients with clinical benefit (vs. no clinical benefit), Barnesiella intestinihominis and Akkermansia muciniphila were significantly more abundant (p = 7.4 × 10-6 and p = 5.6 × 10-3 , respectively). This is the first prospective randomized study demonstrating modulation of the gut microbiome with a probiotic in mRCC. Probiotic supplementation successfully increased the Bifidobacterium spp. levels. Analysis of longitudinal stool specimens identified an association between B. intestinihominis, A. muciniphila, and clinical benefit with therapy. Trial Registration: NCT02944617.

Analysis of Gut Microbiome Using Explainable Machine Learning Predicts Risk of Diarrhea Associated With Tyrosine Kinase Inhibitor Neratinib: A Pilot Study.

Neratinib has great efficacy in treating HER2+ breast cancer but is associated with significant gastrointestinal toxicity. The objective of this pilot study was to understand the association of gut microbiome and neratinib-induced diarrhea. Twenty-five patients (age ≥ 60) were enrolled in a phase II trial evaluating safety and tolerability of neratinib in older adults with HER2+ breast cancer (NCT02673398). Fifty stool samples were collected from 11 patients at baseline and during treatment. 16S rRNA analysis was performed and relative abundance data were generated. Shannon's diversity was calculated to examine gut microbiome dysbiosis. An explainable tree-based approach was utilized to classify patients who might experience neratinib-related diarrhea (grade ≥ 1) based on pre-treatment baseline microbial relative abundance data. The hold-out Area Under Receiver Operating Characteristic and Area Under Precision-Recall Curves of the model were 0.88 and 0.95, respectively. Model explanations showed that patients with a larger relative abundance of Ruminiclostridium 9 and Bacteroides sp. HPS0048 may have reduced risk of neratinib-related diarrhea and was confirmed by Kruskal-Wallis test (p ≤ 0.05, uncorrected). Our machine learning model identified microbiota associated with reduced risk of neratinib-induced diarrhea and the result from this pilot study will be further verified in a larger study. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT02673398.

Involving patients as key stakeholders in the design of cardiovascular implantable electronic device data dashboards: Implications for patient care.

BACKGROUND: Data from remote monitoring (RM) of cardiovascular implantable electronic devices (CIEDs) currently are not accessible to patients despite demand. The typical RM report contains multiple pages of data for trained technicians to read and interpret and requires a patient-centered approach to be curated to meet individual user needs. OBJECTIVE: The purpose of this study was to understand which RM data elements are important to patients and to gain design insights for displaying meaningful data in a digital dashboard. METHODS: Adults with implantable cardioverter-defibrillators (ICDs) and pacemakers (PMs) participated in this 2-phase, user-centered design study. Phase 1 included a card-sorting activity to prioritize device data elements. Phase 2 included one-on-one design sessions to gather insights and feedback about a visual display (labels and icons). RESULTS: Twenty-nine adults (mean age 71.8 ± 11.6 years; 51.7% female; 89.7% white) participated. Priority data elements for both ICD and PM groups in phase 1 (n = 19) were related to cardiac episodes, device activity, and impedance values. Recommended replacement time for battery was high priority for the PM group but not the ICD group. Phase 2 (n = 10) revealed that patients would like descriptive, nontechnical terms to depict the data and icons that are intuitive and informative. CONCLUSION: This user-centered design study demonstrated that patients with ICDs and PMs were able to prioritize specific data from a comprehensive list of data elements that they had never seen before. This work contributes to the goal of sharing RM data with patients in a way that optimizes the RM feature of CIEDs for improving patient outcomes and clinical care.

Stool Microbiome Profiling of Patients with Metastatic Renal Cell Carcinoma Receiving Anti-PD-1 Immune Checkpoint Inhibitors.

Preclinical models and early clinical data suggest an interplay between the gut microbiome and response to immunotherapy in solid tumors including metastatic renal cell carcinoma (mRCC). We sought to characterize the stool microbiome of mRCC patients receiving a checkpoint inhibitor (CPI) and to assess treatment-related changes in microbiome composition over the course of CPI therapy. Stool was collected from 31 patients before initiation of nivolumab (77%) or nivolumab plus ipilimumab (23%) therapy, of whom 58% experienced clinical benefit. Greater microbial diversity was associated with clinical benefit from CPI therapy (p = 0.001), and multiple species were associated with clinical benefit or lack thereof. Temporal profiling of the microbiome indicated that the relative abundance of Akkermansia muciniphila increased in patients deriving clinical benefit from CPIs. This study substantiates results from previous CPI-related microbiome profiling studies in mRCC. Temporal changes in microbiome composition suggest potential utility in modulating the microbiome for more successful CPI outcomes. PATIENT SUMMARY: We compared the composition and diversity of the gut microbiome in patients receiving immunotherapy for renal cell carcinoma. We found that higher microbial diversity is associated with better treatment outcomes. Treatment response is characterized by changes in microbial species over the course of treatment.

Teens Using Screens for Help: Impact of Suicidal Ideation, Anxiety, and Depression Levels on Youth Preferences for Telemental Health Resources.

BACKGROUND: High rates of mental illness, stress, and suicidality among teens constitute a major public health concern in the United States. However, treatment rates remain low, partially because of barriers that could be mitigated with tech-based telemental health (TMH) resources, separate from or in addition to traditional care. OBJECTIVE: This study aimed to analyze TMH resource usage by high school students to establish current user characteristics and provide a framework for future development. METHODS: A total of 2789 students were surveyed regarding demographics, recent anxiety and depression symptoms, suicidality, and stress; people with whom they could openly and honestly discuss stress or problems, and prior TMH use. Logistic regression models and a general linear model were used to test relationships between variables. RESULTS: Overall, 30.58% (853/2789) and 22.91% (639/2789) of students reported moderate to severe anxiety and depression symptoms, respectively, in the past 2 weeks; 16.24% (414/2550) had seriously considered suicide in the past year, consistent with national averages. Meanwhile, 16.03% (447/2789) of students had previously used at least 1 of 4 types of TMH resources (ie, self-help, anonymous chat, online counselor, or crisis text line). Teens reporting depression symptoms, higher stress, or suicidality were less likely to talk to a parent about stress or problems and more likely to tell no one. Suicidality was related to the use of all 4 types of TMH resources. Depression symptoms were related to the use of anonymous chat and crisis text line, and those with higher stress were more likely to have used an online counselor. Those reporting anxiety symptoms were less likely to have no one to talk to and more likely to have used a self-help resource. CONCLUSIONS: Youth struggling with mental health symptoms, some of whom lack real-life confidants, are using existing TMH support, with resource preferences related to symptoms. Future research should consider these preferences and assist in the creation of specialized, evidence-based TMH resources.