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Motivation: Cell fate decisions, such as apoptosis or proliferation, are communicated via signaling pathways. The pathways are heavily intertwined and often consist of sequential interaction of proteins (kinases). Information integration takes place on the protein level via n -to-1 interactions. A state-of-the-art procedure to quantify information flow (edges) between signaling proteins (nodes) is network inference. However, edge weight calculation typically refers to 1-to-1 interactions only and relies on mean protein phosphorylation levels instead of single cell distributions. Information theoretic measures such as the mutual information (MI) have the potential to overcome these shortcomings but are still rarely used., Results: This work proposes a Bayesian nearest neighbor-based MI estimator (BannMI) to quantify n -to-1 kinase dependency in signaling pathways. BannMI outperforms the state-of-the-art MI estimator on protein-like data in terms of mean squared error and Pearson correlation. Using BannMI, we analyze apoptotic signaling in phosphoproteomic cancerous and noncancerous breast cell line data. Our work provides evidence for cooperative signaling of several kinases in programmed cell death and identifies a potential key role of the mitogen-activated protein kinase p38., Availability and Implementation: Source code and applications are available at: https://github.com/zuiop11/nn_info and can be downloaded via Pip as Python package: nn-info., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press.)

Objective: Obstructive sleep apnea (OSA) is associated with an increased risk of mortality and cardiometabolic diseases. The STOP-Bang questionnaire is a tool to screen populations at risk of OSA and prioritize complementary studies. Our objective was to evaluate the clinical utility of this questionnaire in identifying patients at an increased risk of mortality after discharge in a cohort of hospitalized patients., Methods: This was a prospective cohort study involving consecutive patients admitted to an internal medicine unit between May and June of 2017 who were reevaluated three years after discharge. At baseline, we collected data on comorbidities (hypertension, obesity, diabetes, and fasting lipid profile) and calculated STOP-Bang scores, defining the risk of OSA (0-2 score, no risk; ≥ 3 score, risk of OSA; and ≥ 5 score, risk of moderate-to-severe OSA), which determined the study groups. We also recorded data regarding all-cause and cardiovascular mortality at the end of the follow-up period., Results: The sample comprised 435 patients. Of those, 352 (80.9%) and 182 (41.8%) had STOP-Bang scores ≥ 3 and ≥ 5, respectively. When compared with the group with STOP-Bang scores of 0-2, the two groups showed higher prevalences of obesity, hypertension, diabetes, and dyslipidemia. Multivariate analysis showed an independent association between cardiovascular mortality and STOP-Bang score ≥ 5 (adjusted hazard ratio = 3.12 [95% CI, 1.39-7.03]; p = 0.01). Additionally, previous coronary heart disease was also associated with cardiovascular mortality., Conclusions: In this cohort of hospitalized patients, STOP-Bang scores ≥ 5 were able to identify patients at an increased risk of cardiovascular mortality three years after discharge.

Background: Supplementation of vitamin B12 in older adults is a common practice to avoid vitamin B12 insufficiency. However, there is a paucity of information about the effects of cobalamin excess., Aim: To asses any potential effects of high levels vitamin B12 on mortality on adults aged ≥ 65 years admitted to an internal medicine service., Material and Methods: We Prospectively studied patients admitted to an internal medicine service of an academic hospital from September 2017 to September 2018, who were able to give their consent and answer questionnaires. We tabulated age, gender, medical history, comorbidity index (Charlson), frailty score (Fried scale), admission diagnosis and blood tests performed within 48 hours of admission. The primary outcome was death by any cause in less of 30 days or after one of year follow up, determined according to death certificates., Results: We included 93 patients aged 65 to 94 years (53% males). Fifteen patients died during the year of follow up (five within 30 days of admission). Those who died had higher cobalamin levels than survivors (1080.07 ± 788.09 and 656.68 ± 497.33 pg/mL respectively, p = 0.02). Patients who died had also a significantly lower corrected serum calcium, sodium (p = 0.04) and a medical history of chronic liver disease (p = 0.03). In the multivariable analysis, only vitamin B12 preserved the association with mortality (p = 0.009)., Conclusions: There was a significant association between high levels of cobalamin and all-cause mortality in this group of patients aged ≥ 65 years-old.

Background: The purpose of this study was to establish a quantitative standardized RT-PCR for the detection of Prostate Specific Membrane Antigen (PSMA)-expressing circulating cells and to evaluate clinical relevance in patients undergoing radical retropubic prostatectomy (RRP) for clinically localized prostate cancer (PCa)., Materials and Methods: An external standard molecule (PSMA MIMIC) was constructed for standardization of PSMA RT-PCR reactions. It has the same sequence as endogenous PSMA, except for a central 85 bp deletion, allowing the amplification of both targets simultaneously with nearly the same amplification characteristics as in a nested PCR. PSMA RT-PCR was performed from peripheral blood samples of 73 patients with clinically localized PCa, 4 with metastatic PCa, 27 with benign prostatic hyperplasia (BPH) and 27 controls. Pre, intra- and postoperative blood samples were tested for circulating PSMA expressing cells in 54 out of 73 patients with clinically localized PCa. We also tested intraoperative blood samples of 19 BPH patients treated by transurethral or open surgery., Results: Endogenous PSMA signals from PCa patients varied between 850 and 9900 transcript molecules, corresponding to 2-20 PSMA-expressing cells/ml blood. Standardized RT-PCR using the PSMA MIMIC molecule revealed a significant decrease of "false-positives" in cancer-free controls (p = 0.004). Controls could clearly be distinguished from prostate cancer patients based on PSMA PCR positivity (p = 0.003). Thirty-two % of patients with localized prostate cancer, 11% of BPH patients and 7% of healthy controls were positive in standardized assays compared to 48%, 30% and 27% without PSMA MIMIC, respectively. Preoperatively, a correlation with tumor stage (p = 0.030), grade (p = 0.035) and Gleason Score (p = 0.03) could be demonstrated in clinically localized PCa patients. Dissemination of prostate cells during surgery occurred in 32% of the RRPs and 21% of BPH patients. Positive PCR signals from intraoperative blood samples correlated with positive lymph node status (p = 0.007) and tumor grade (p = 0.005). Postoperative positive results correlated with grade (p = 0.012) and Gleason Score (p = 0.035)., Conclusion: Counseling the patient with clinically localized prostate cancer can be challenging. Surgery may be, in retrospect, inappropriate in a number of patients due to preoperative understaging. This newly constructed external standard allows quantitative detection of circulating prostate cells, and therefore may open new perspectives for PSMA RT-PCR techniques as diagnostic assays and tools for post-therapeutic follow-up.