Predictive Modeling of Colonoscopic Findings in a Fecal Immunochemical Test-Based Colorectal Cancer Screening Program.

BACKGROUND: The fecal immunochemical test (FIT) is the primary modality used by the Los Angeles County Department of Health Services (LADHS) for colorectal cancer (CRC) screening in average-risk patients. Some patients referred for FIT-positive diagnostic colonoscopy have neither adenomas nor more advanced pathology. We aimed to identify predictors of false-positive FIT (FP-FIT) results in our largely disenfranchised, low socioeconomic status population. METHODS: We conducted a retrospective study of 596 patients who underwent diagnostic colonoscopy following a positive screening FIT. Colonoscopies showing adenomas (or more advanced pathology) were considered positive. We employed multiple logistic and linear regression as well as machine learning models (MLMs) to identify clinical predictors of FP-FIT (primary outcome) and the presence of advanced adenomas (secondary outcome). RESULTS: Overall, 268 patients (45.0%) had a FP-FIT. Female sex and hemorrhoids (odds ratios [ORs] 1.59 and 1.89, respectively) were associated with increased odds of FP-FIT and fewer advanced adenomas (ß = - 0.658 and - 0.516, respectively). Conversely, increasing age and BMI (ORs 0.94 and 0.96, respectively) were associated with decreased odds of FP-FIT and a greater number of advanced adenomas (ß = 0.073 and 0.041, respectively). MLMs predicted FP-FIT with high specificity (93.8%) and presence of advanced adenoma with high sensitivity (94.4%). CONCLUSION: Increasing age and BMI are associated with lower odds of FP-FIT and greater number of advanced adenomas, while female sex and hemorrhoids are associated with higher odds of FP-FIT and fewer advanced adenomas. The presence of the aforementioned predictors may inform the decision to proceed with diagnostic colonoscopy in FIT-positive patients.

Periplasmic stress contributes to a trade-off between protein secretion and cell growth in Escherichia coli Nissle 1917.

Maximizing protein secretion is an important target in the design of engineered living systems. In this paper, we characterize a trade-off between cell growth and per-cell protein secretion in the curli biofilm secretion system of Escherichia coli Nissle 1917. Initial characterization using 24-h continuous growth and protein production monitoring confirms decreased growth rates at high induction, leading to a local maximum in total protein production at intermediate induction. Propidium iodide (PI) staining at the endpoint indicates that cellular death is a dominant cause of growth reduction. Assaying variants with combinatorial constructs of inner and outer membrane secretion tags, we find that diminished growth at high production is specific to secretory variants associated with periplasmic stress mediated by outer membrane secretion and periplasmic accumulation of protein containing the outer membrane transport tag. RNA sequencing experiments indicate upregulation of known periplasmic stress response genes in the highly secreting variant, further implicating periplasmic stress in the growth-secretion trade-off. Overall, these results motivate additional strategies for optimizing total protein production and longevity of secretory engineered living systems Graphical Abstract.

Clinical Features and Outcomes of Patients with Pancreaticobiliary Malignancies in Los Angeles County and Their Association with CA 19-9 Levels.

Although CA 19-9 is a commonly used tumor marker in the management of PBMs, the literature describing outcomes in patients with PBMs who have undetectable or low (hereinafter "low") CA 19-9 levels remains scarce. In this study, we sought to compare clinical features and outcomes in patients with PBMs and low CA 19-9 levels to those with normal and elevated CA 19-9 levels. METHODS: We retrospectively collected data on patients with biopsy-confirmed PBMs and stratified patients into categories based on their CA 19-9 level at diagnosis. Survival curves were estimated for patients in each of the three aforementioned CA 19-9 groups using the Kaplan-Meier method and compared using a Cox proportional hazards regression model. RESULTS: Of the 283 patients identified, 23 (8.1%) had low, 70 (24.7%) had normal, and 190 (67.1%) had elevated CA 19-9 levels. After controlling for sex, age, BMI, the presence of metastases at the time of diagnosis, and treatment with curative intent, the hazard ratio for death in the elevated CA 19-9 group compared to the low CA 19-9 group was 1.993 (95% CI 1.089-3.648; p = 0.025). CONCLUSION: The elevated CA 19-9 level compared to the low CA 19-9 level and the presence of metastases were associated with an increased hazard of death, while treatment with curative intent was associated with a decreased hazard of death.

Gastrointestinal Manifestations of Coronavirus Disease 2019 Across the United States: A Multicenter Cohort Study.

Background and Aims: Gastrointestinal (GI) symptoms occur among patients diagnosed with coronavirus disease 2019 (COVID-19), and there is clear evidence that SARS-CoV-2, the causative pathogen, infects the GI tract. In this large, multicenter cohort study, we evaluated variations in gastrointestinal and hepatic manifestations of COVID-19 throughout the United States (US). Methods: Patients hospitalized with a positive COVID-19 test prior to October 2020 were identified at 7 US academic centers. Demographics, presenting symptoms, laboratory data, and hospitalization outcomes were abstracted. Descriptive and regression analyses were used to evaluate GI manifestations and their potential predictors. Results: Among 2031 hospitalized patients with COVID-19, GI symptoms were present in 18.9%; diarrhea was the most common (15.2%), followed by nausea and/or vomiting (12.6%) and abdominal pain (6.0%). GI symptoms were less common in the Western cohort (16.0%) than the Northeastern (25.6%) and Midwestern (26.7%) cohorts. Compared to nonintensive care unit (ICU) patients, ICU patients had a higher prevalence of abnormal aspartate aminotransferase (58.1% vs 37.3%; P < .01), alanine aminotransferase (37.5% vs 29.3%; P = .01), and total bilirubin (12.7% vs 9.0%; P < .01). ICU patients also had a higher mortality rate (22.7% vs 4.7%; P < .01). Chronic liver disease was associated with the development of GI symptoms. Abnormal aspartate aminotransferase or alanine aminotransferase was associated with an increased risk of ICU admission. Conclusion: We present the largest multicenter cohort of patients with COVID-19 across the United States. GI manifestations were common among patients hospitalized with COVID-19, although there was significant variability in prevalence and predictors across the United States.

Decline of hippocampal stress reactivity and neuronal ensemble coherence in a mouse model of depression.

Dysregulations of stress systems, especially the hypothalamo-pituitary-adrenal (HPA) axis, have been commonly reported in major depression. Consistent results emphasized the role of the hippocampus in regulating stress systems and restoring an operative control on HPA axis following antidepressant treatments. However, very little is known about how the hippocampus integrates stress-related information and reacts to stressors beforehand. We therefore aimed to assess activations of hippocampal neuronal ensembles during stress-related experiences and evaluated the effects of a mouse model of depression, the Unpredictable Chronic Mild Stress (UCMS), and an antidepressant treatment (fluoxetine, 20mgkg(-1)day(-1), ip) in BALB/cByJ mice. The UCMS induced a depression-like syndrome characterized by a reduced weight gain, a progressive deterioration of the coat, an altered stress-coping strategy in behavioural tests and HPA axis dysregulations. Chronic fluoxetine had no effect in control non-stressed mice per se but reversed the syndrome induced by the UCMS, including an improvement of the HPA-system alterations. Neuronal activation was then assessed by immediate early-gene (c-fos) expression in different subfields of the CA3 and dentate gyrus (DG) along the dorso-ventral axis of the hippocampus, as they can support different computational functions. Our results showed that the hippocampus reacts to stressors by adjusting activations of cell ensembles. A pre-treatment with dexamethasone (DEX), a glucocorticoid receptor (GR) agonist that produced a delayed inhibition of the HPA axis activity, reduced novelty-related activations in the proximal CA3 (CA3c) and the DG of the dorsal hippocampus. All these effects were compromised by the UCMS, particularly by altering activation coherences within the dorsal CA3-DG network, but were rescued by chronic fluoxetine. Our study indicates therefore that variations of CA3-DG cell ensemble activation may contribute to stress integration in the hippocampus and that dysfunctions of this process may foster HPA-system dysregulations and depression-related states. It suggests that pharmacological interventions aiming to consolidate CA3-DG neural network might improve stress reactivity and possibly benefit to patients with major depression.

Inhibition of IKKß Reduces Ethanol Consumption in C57BL/6J Mice.

Proinflammatory pathways in neuronal and non-neuronal cells are implicated in the acute and chronic effects of alcohol exposure in animal models and humans. The nuclear factor-κB (NF-κB) family of DNA transcription factors plays important roles in inflammatory diseases. The kinase IKKß mediates the phosphorylation and subsequent proteasomal degradation of cytosolic protein inhibitors of NF-κB, leading to activation of NF-κB. The role of IKKß as a potential regulator of excessive alcohol drinking had not previously been investigated. Based on previous findings that the overactivation of innate immune/inflammatory signaling promotes ethanol consumption, we hypothesized that inhibiting IKKß would limit/decrease drinking by preventing the activation of NF-κB. We studied the systemic effects of two pharmacological inhibitors of IKKß, TPCA-1 and sulfasalazine, on ethanol intake using continuous- and limited-access, two-bottle choice drinking tests in C57BL/6J mice. In both tests, TPCA-1 and sulfasalazine reduced ethanol intake and preference without changing total fluid intake or sweet taste preference. A virus expressing Cre recombinase was injected into the nucleus accumbens and central amygdala to selectively knock down IKKß in mice genetically engineered with a conditional Ikkb deletion (IkkbF/F ). Although IKKß was inhibited to some extent in astrocytes and microglia, neurons were a primary cellular target. Deletion of IKKß in either brain region reduced ethanol intake and preference in the continuous access two-bottle choice test without altering the preference for sucrose. Pharmacological and genetic inhibition of IKKß decreased voluntary ethanol consumption, providing initial support for IKKß as a potential therapeutic target for alcohol abuse.