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G0 arrest (G0A) is widely recognized as a crucial factor contributing to tumor relapse. The role of genes related to G0A in lung adenocarcinoma (LUAD) was unclear. This study aimed to develop a gene signature based on for LUAD patients and investigate its relationship with prognosis, tumor immune microenvironment, and therapeutic response in LUAD. We use the TCGA-LUAD database as the discovery cohort, focusing specifically on genes associated with the G0A pathway. We used various statistical methods, including Cox and lasso regression, to develop the model. We validated the model using bulk transcriptome and single-cell transcriptome datasets (GSE50081, GSE72094, GSE127465, GSE131907 and EMTAB6149). We used GSEA enrichment and the CIBERSORT algorithm to gain insight into the annotation of the signaling pathway and the characterization of the tumor microenvironment. We evaluated the response to immunotherapy, chemotherapy, and targeted therapy in these patients. The expression of six genes was validated in cell lines by quantitative real-time PCR (qRT-PCR). Our study successfully established a six-gene signature (CHCHD4, DUT, LARP1, PTTG1IP, RBM14, and WBP11) that demonstrated significant predictive power for overall survival in patients with LUAD. It demonstrated independent prognostic value in LUAD. To enhance clinical applicability, we developed a nomogram based on this gene signature, which showed high reliability in predicting patient outcomes. Furthermore, we observed a significant association between G0A-related risk and tumor microenvironment as well as drug susceptibility, highlighting the potential of the gene signature to guide personalized treatment strategies. The expression of six genes were significantly upregulated in the LUAD cell lines. This signature holds the potential to contribute to improved prognostic prediction and new personalized therapies specifically for LUAD patients. [ABSTRACT FROM AUTHOR]

Notch ligands [jagged (JAG) and, delta-like (DLL) families] and receptors [NOTCH family] are key regulators of Notch signaling. NOTCH signaling contributes to vascular development, tissue homeostasis, angiogenesis, and cancer progression. To elucidate the universal functions of the JAG, DLL, and NOTCH families and their connections with various biological functions, we examined 15 types of cancer using The Cancer Genome Atlas clinical database. We selected the differentially expressed genes (DEGs), which were positively correlated to the JAG, DLL, and NOTCH families in each cancer. We selected positive and negative hallmark signatures across cancer types. These indicated biological features associated with angiogenesis, hypoxia, KRAS signaling, cell cycle, and MYC targets by gene ontology and gene set enrichment analyses using DEGs. Furthermore, we analyzed single-cell RNA sequencing data to examine the expression of JAG, DLL, and NOTCH families and enrichment of hallmark signatures. Positive signatures identified using DEGs, such as KRAS signaling and hypoxia, were enriched in clusters with high expression of JAG, DLL, and NOTCH families. We subsequently validated the correlation between the JAG, DLL, and NOTCH families and clinical stages, including treatment response, metastasis, and recurrence. In addition, we performed survival analysis to identify hallmark signatures that critically affect patient survival when combining the expression of JAG, DLL, and NOTCH families. By combining the DEG enrichment and hallmark signature enrichment in survival analysis, we suggested unexplored regulatory functions and synergistic effects causing synthetic lethality. Taken together, our observations demonstrate the functions of JAG, DLL, and NOTCH families in cancer malignancy and provide insights into their molecular regulatory mechanisms. [ABSTRACT FROM AUTHOR]

Electronic health records (EHR) data provides the researcher and physician with the opportunity to improve risk prediction by employing newer, more sophisticated modeling techniques. Rather than treating the impact of predictor variables on health trajectories as static, we explore the use of time-dependent variables in dynamically modeling time-to-event data through the use of landmarking (LM) data sets. We compare several different dynamic models presented in the literature that utilize LM data sets as the basis of their approach. These techniques include using pseudo-means, pseudo-survival probabilities, and the traditional Cox model. The models are primarily compared with their static counterparts using appropriate measures of model discrimination and calibration based on what summary measure is employed for the response variable. [ABSTRACT FROM AUTHOR]

Background: Studies on cross-informant agreement on adolescents' emotional and behavioral problems (EBPs) are sparse in low- and middle-income countries. This study aimed to assess parent-adolescent and teacher-adolescent agreement on EBPs and associated factors in Nepal. Methods: This cross-sectional survey included 1904 school-going adolescents aged 11–18, enrolled in government and private schools located in sixteen districts of Nepal. The Nepali versions of the Youth Self Report, Child Behavior Checklist, and Teacher's Report Form were administered to assess EBPs reported by adolescents, their parents, and teachers, respectively. Repeated measures analysis of variance (ANOVA) was done to assess mean differences in problem scores. Pearson's correlation was used to assess cross-informant agreement. Linear regression analysis was used to explore factors associated with cross-informant discrepancies in EBPs. Results: Adolescents reported significantly more problems than their parents and teachers. Mean Total Problem scores for the 90 common items in the adolescents' self-reports, parent reports, and teacher reports were 34.5 (standard deviation [SD]: 21.4), 24.1 (SD = 19.2), and 20.2 (SD = 17.5) respectively. Parent-adolescent agreement on Total Problems was moderate, whereas teacher-adolescent agreement was low. The parent-adolescent agreement was moderate to low for the two broadband scales and all syndrome scales, whereas the teacher-adolescent agreement was low for all scales. Female gender and ethnic minority status impacted both parent-adolescent and teacher-adolescent discrepancies. Family stress/conflicts impacted parent-adolescent discrepancies, while academic performance impacted teacher-adolescent discrepancies. Conclusions: Nepali adolescents reported more EBPs than their parents and teachers. The agreement between adolescents' self-reports and reports by their parents and teachers was moderate to low. Gender, caste/ethnicity, family stress/conflicts, and academic performance were associated with cross-informant discrepancies. It is crucial to collect information from different sources, consider context-specific needs, and discern factors influencing cross-informant discrepancies to accurately assess adolescents' EBPs and develop personalized approaches to treatment planning. [ABSTRACT FROM AUTHOR]

Advancing human induced pluripotent stem cell derived cardiomyocyte (hiPSC-CM) technology will lead to significant progress ranging from disease modeling, to drug discovery, to regenerative tissue engineering. Yet, alongside these potential opportunities comes a critical challenge: attaining mature hiPSC-CM tissues. At present, there are multiple techniques to promote maturity of hiPSC-CMs including physical platforms and cell culture protocols. However, when it comes to making quantitative comparisons of functional behavior, there are limited options for reliably and reproducibly computing functional metrics that are suitable for direct cross-system comparison. In addition, the current standard functional metrics obtained from time-lapse images of cardiac microbundle contraction reported in the field (i.e., post forces, average tissue stress) do not take full advantage of the available information present in these data (i.e., full-field tissue displacements and strains). Thus, we present "MicroBundleCompute," a computational framework for automatic quantification of morphology-based mechanical metrics from movies of cardiac microbundles. Briefly, this computational framework offers tools for automatic tissue segmentation, tracking, and analysis of brightfield and phase contrast movies of beating cardiac microbundles. It is straightforward to implement, runs without user intervention, requires minimal input parameter setting selection, and is computationally inexpensive. In this paper, we describe the methods underlying this computational framework, show the results of our extensive validation studies, and demonstrate the utility of exploring heterogeneous tissue deformations and strains as functional metrics. With this manuscript, we disseminate "MicroBundleCompute" as an open-source computational tool with the aim of making automated quantitative analysis of beating cardiac microbundles more accessible to the community. [ABSTRACT FROM AUTHOR]

People living with HIV are at three times greater risk for depressive symptoms. Inflammation is a notable predictor of depression, and people with HIV exhibit chronic inflammation despite antiretroviral therapy. We hypothesised that inflammatory biomarkers may mediate the association between HIV status and depressive symptoms. Participants (N = 60, 53% girls, median [interquartile range (IQR)] age 15.5 [15.0, 16.0] years, 70% living with HIV, of whom 90.5% were virally-suppressed) completed the nine-item Patient Health Questionnaire (PHQ-9). We measured choline and myo-inositol in basal ganglia, midfrontal gray matter, and peritrigonal white matter using magnetic resonance spectroscopy, and 16 inflammatory proteins in blood serum using ELISA and Luminex™ multiplex immunoassays. Using structural equation mediation modelling, we calculated standardised indirect effect estimates with 95% confidence intervals. Median [IQR] total PHQ-9 score was 3 [0, 7]. HIV status was significantly associated with total PHQ-9 score (B = 3.32, p = 0.022). Participants with HIV showed a higher choline-to-creatine ratio in the basal ganglia than those without HIV (β = 0.86, pFDR = 0.035). In blood serum, participants with HIV showed higher monocyte chemoattractant protein-1 (MCP-1, β = 0.59, pFDR = 0.040), higher chitinase-3 like-1 (YKL-40, β = 0.73, pFDR = 0.032), and lower interleukin-1beta (IL-1β, β = -0.67, pFDR = 0.047) than those without HIV. There were no significant associations of any biomarkers with total PHQ-9 score. None of the indirect effects were significant, mediating <13.1% of the association. Findings remained consistent when accounting for age, gender, and time between neuroimaging and PHQ-9 administration. Using a robust analytical approach in a community-based sample, we have shown that participants living with HIV reported greater depressive symptoms than those without HIV, but we did not find that neuroimaging and blood biomarkers of inflammation significantly mediated this association. Further studies with participants experiencing severe depression may help to elucidate the links between HIV, inflammation, and depression. [ABSTRACT FROM AUTHOR]

Introduction: Interdisciplinary teams are often leveraged to improve quality of cancer care in the perioperative period. We aimed to identify the team structures and processes in interdisciplinary interventions that improve perioperative patient-reported outcomes for patients with cancer. Methods: We searched PubMed, EMBASE, and CINAHL for randomized control trials published at any time and screened 7,195 articles. To be included in our review, studies needed to report patient-reported outcomes, have interventions that occur in the perioperative period, include surgical cancer treatment, and include at least one non physician intervention clinical team member: advanced practice providers, including nurse practitioners and physician assistants, clinical nurse specialists, and registered nurses. We narratively synthesized intervention components, specifically roles assumed by intervention clinical team members and interdisciplinary team processes, to compare interventions that improved patient-reported outcomes, based on minimal clinically important difference and statistical significance. Results: We included 34 studies with a total of 4,722 participants, of which 31 reported a clinically meaningful improvement in at least one patient-reported outcome. No included studies had an overall high risk of bias. The common clinical team member roles featured patient education regarding diagnosis, treatment, coping, and pain/symptom management as well as postoperative follow up regarding problems after surgery, resource dissemination, and care planning. Other intervention components included six or more months of continuous clinical team member contact with the patient and involvement of the patient's caregiver. Conclusions: Future interventions might prioritize supporting clinical team members roles to include patient education, caregiver engagement, and clinical follow-up. [ABSTRACT FROM AUTHOR]

Background: In 2020 Globocan reported nearly 1.4 million new cases of gynaecology cancer worldwide. Cancer related fatigue has been identified as a symptom that can be present for gynaecology cancer patients many years after treatment. The current evidence around the management of this symptom suggests that exercise has the most positive outcome. However, some ambiguity remains around the evidence and whether it can address all areas of fatigue effectively. More recently, other interventions such as mindfulness have begun to show a favourable response to the management of symptoms for cancer patients. To date there has been little research that explores the feasibility of using both these interventions together in a gynaecology cancer population. This study aims to explore the feasibility of delivering an intervention that involves mindfulness and mindfulness and exercise and will explore the effect of this on fatigue, sleep, mood and quality of life. Methods/Design: This randomised control trial will assess the interventions outcomes using a pre and post design and will also include a qualitative process evaluation. Participants will be randomised into one of 2 groups. One group will undertake mindfulness only and the other group will complete exercise and mindfulness. Both groups will use a mobile application to complete these interventions over 8 weeks. The mobile app will be tailored to reflect the group the participants have drawn during randomisation. Self-reported questionnaire data will be assessed at baseline prior to commencing intervention and at post intervention. Feasibility will be assessed through recruitment, adherence, retention and attrition. Acceptability and participant perspective of participation (process evaluation), will be explored using focus groups. Discussion: This trial will hope to evidence and demonstrate that combination of two interventions such as mindfulness and exercise will further improve outcomes of fatigue and wellbeing in gynaecology cancer. The results of this study will be used to assess (i) the feasibility to deliver this type of intervention to this population of cancer patients using a digital platform; (ii) assist this group of women diagnosed with cancer to manage fatigue and other symptoms of sleep, mood and impact their quality of life. Trial registration: NCT05561413. [ABSTRACT FROM AUTHOR]

Background: Many studies analyze sexual and reproductive event data using descriptive life tables. Survival analysis has better power to estimate factors associated with age at first sex (AFS), but proportional hazards models may not be right model to use. This study used accelerated failure time (AFT) models, restricted Mean Survival time model (RMST) models, with semi and non-parametric methods to assess age at first sex (AFS), factors associated with AFS, and verify underlying assumptions for each analysis. Methods: Self-reported sexual debut data was used from respondents 15–24 years in eight cross-sectional surveys between 1994–2016, and from adolescents' survey in an observational community study (2019–2020) in northwest Tanzania. Median AFS was estimated in each survey using non-parametric and parametric models. Cox regression, AFT parametric models (exponential, gamma, generalized gamma, Gompertz, Weibull, log-normal and log-logistic), and RMST were used to estimate and identify factors associated with AFS. The models were compared using Akaike information criterion (AIC) and Bayesian information criterion (BIC), where lower values represent a better model fit. Results: The results showed that in every survey, the Cox regression model had higher AIC and BIC compared to the other models. Overall, AFT had the best fit in every survey round. The estimated median AFS using the parametric and non-parametric methods were close. In the adolescent survey, log-logistic AFT showed that females and those attending secondary and higher education level had a longer time to first sex (Time ratio (TR) = 1.03; 95% CI: 1.01–1.06, TR = 1.05; 95% CI: 1.02–1.08, respectively) compared to males and those who reported not being in school. Cell phone ownership (TR = 0.94, 95% CI: 0.91–0.96), alcohol consumption (TR = 0.88; 95% CI: 0.84–0.93), and employed adolescents (TR = 0.95, 95% CI: 0.92–0.98) shortened time to first sex. Conclusion: The AFT model is better than Cox PH model in estimating AFS among the young population. [ABSTRACT FROM AUTHOR]

Background: Nitrous oxide (N2O) with rapid analgesic effect is often used to relieve pain induced by diagnostic procedures. This review was conducted to evaluate the efficacy and safety of N2O in patients undergoing puncture biopsy. Methods: We systematically searched PubMed, Embase, the Cochrane Library, Web of Science, Scopus and the ClinicalTrials.gov up to March, 2022. Randomized controlled trials (RCTs) were included if they investigated the effect of N2O in adults undergoing puncture biopsy. The primary outcome was pain score. Secondary outcomes included anxiety score, patient satisfaction and side effects. Results: Twelve RCTs with 1070 patients were included in the qualitative review, of which eleven RCTs were included in the meta-analysis. Pooled analysis suggested that compared with the controls (placebo, lidocaine and midazolam), N2O had better analgesic effect (MD -1.12, 95% CI -2.12 to -0.13, P = 0.03; I2 = 94%). In addition, N2O significantly alleviated patient anxiety (MD = -1.79, 95% CI -2.41 to -1.18, P<0.00001; I2 = 0%) and improved patient satisfaction (MD 1.81, 95% CI 0.11 to 3.50, P = 0.04; I2 = 92%). There was no significant difference regrading the risk of nausea (RR 2.56; 95% CI 0.70 to 9.31, P = 0.15; I2 = 0%), headache (RR 0.62, 95% CI 0.17 to 2.33, P = 0.48; I2 = 46%), dizziness (RR 1.80, 95% CI 0.63 to 5.13, P = 0.27; I2 = 0%) or euphoria (RR 2.67, 95% CI 0.81 to 8.79, P = 0.11; I2 = 8%) between the N2O group and the control group. Conclusion: The present review suggested that N2O might be effective for pain management in patients undergoing puncture biopsy. [ABSTRACT FROM AUTHOR]

Background: Fast medical progress poses a significant challenge to doctors, who are asked to find the right balance between life-prolonging and palliative care. Literature indicates room for enhancing openness to discuss ethical sensitive issues within and between teams, and improving decision-making for benefit of the patient at end-of-life. Methods: Stepped wedge cluster randomized trial design, run across 10 different departments of the Ghent University Hospital between January 2022 and January 2023. Dutch speaking adult patients and one of their relatives will be included for data collection. All 10 departments were randomly assigned to start a 4-month coaching period. Junior and senior doctors will be coached through observation and debrief by a first coach of the interdisciplinary meetings and individual coaching by the second coach to enhance self-reflection and empowering leadership and managing group dynamics with regard to ethical decision-making. Nurses, junior doctors and senior doctors anonymously report perceptions of excessive treatment via the electronic patient file. Once a patient is identified by two or more different clinicians, an email is sent to the second coach and the doctor in charge of the patient. All nurses, junior and senior doctors will be invited to fill out the ethical decision making climate questionnaire at the start and end of the 12-months study period. Primary endpoints are (1) incidence of written do-not-intubate and resuscitate orders in patients potentially receiving excessive treatment and (2) quality of ethical decision-making climate. Secondary endpoints are patient and family well-being and reports on quality of care and communication; and clinician well-being. Tertiairy endpoints are quantitative and qualitative data of doctor leadership quality. Discussion: This is the first randomized control trial exploring the effects of coaching doctors in self-reflection and empowering leadership, and in the management of team dynamics, with regard to ethical decision-making about patients potentially receiving excessive treatment. [ABSTRACT FROM AUTHOR]

Purpose: Health disparities are driven by a complex interplay of determinants operating across multiple levels of influence. However, while recognized conceptually, much disparities research fails to capture this inherent complexity in study focus and/or design; little of such work accounts for the interplay across the multiple levels of influence from structural (contextual) to biological or clinical. We developed a novel modeling framework that addresses these challenges and provides new insights. Methods: We used data from the Florida Cancer Data System on endometrial cancer patients and geocoded-derived social determinants of health to demonstrate the applicability of a new modeling paradigm we term PRISM regression. PRISM is a new highly interpretable tree-based modeling framework that allows for automatic discovery of potentially non-linear hierarchical interactions between health determinants at multiple levels and differences in survival outcomes between groups of interest, including through a new specific area-level disparity estimate (SPADE) incorporating these multilevel influences. Results: PRISM demonstrates that hierarchical influences on racial disparity in endometrial cancer survival appear to be statistically relevant and that these better predict survival differences than only using individual level determinants. The interpretability of the models allows more careful inspection of the nature of these hierarchical effects on disparity. Additionally, SPADE estimates show distinct geographical patterns across census tracts in Florida. Conclusion: PRISM can provide a powerful new modeling framework with which to better understand racial disparities in cancer survival. [ABSTRACT FROM AUTHOR]

Main objective: Sickness absence duration for shoulder lesion patients is difficult to prognosticate, and scientific evidence for the sick-listing practice is lacking. Our objective was to develop a clinically implementable prediction model for the duration of a sickness absence spell due to shoulder lesions. Methods: All new sickness absence spells due to shoulder lesions (ICD-10-code: M75) issued in the period January 2010—June 2012 that were longer than 14 days were identified through the nationwide sickness absence insurance register. Information on predictors was linked from four other nationwide registers. Piecewise-constant hazards regression models were fitted to predict duration of sickness absence. The model was developed and validated using split sample validation. Variable selection was based on log-likelihood loss ranking when excluding a variable from the model. The model was evaluated using calibration plots and the c-statistic. Results: 20 049 sickness absence spells were identified, of which 34% lasted >90 days. Predictors included in the model were age, sex, geographical region, occupational status, educational level, birth country, specialized healthcare at start of the spell, number of sickness absence days in the last 12 months, and specialized healthcare the last 12 months, before start date of the index sickness absence spell. The model was satisfactorily specified and calibrated. Overall c-statistic was 0.54 (95% CI 0.53–0.55). C-statistic for predicting durations >90, >180, and >365 days was 0.61, 0.66, and 0.74, respectively. Significance: The model can be used to predict the duration of sickness absence due to shoulder lesions. Covariates had limited predictive power but could discriminate the very long sickness absence spells from the rest. [ABSTRACT FROM AUTHOR]

Background and objective: The prognostic value of age and other non-hematological factors in predicting outcomes in older patients with newly diagnosed acute myeloid leukemia (AML) undergoing antileukemic therapy is not well understood. We performed a systematic review to determine the association between these factors and mortality and health-related quality of life or fatigue among these patients. Methods: We searched Medline and Embase through October 2021 for studies in which researchers quantified the relationship between age, comorbidities, frailty, performance status, or functional status; and mortality and health-related quality of life or fatigue in older patients with AML receiving antileukemic therapy. We assessed the risk of bias of the included studies using the Quality in Prognostic Studies tool, conducted random-effects meta-analyses, and assessed the quality of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation approach. Results: We included 90 studies. Meta-analysis showed that age (per 5-year increase, HR 1.16 95% CI 1.11–1.21, high-quality evidence), comorbidities (Hematopoietic Cell Transplantation-specific Comorbidity Index: 3+ VS less than 3, HR 1.60 95% CI 1.31–1.95, high-quality evidence), and performance status (Eastern Cooperative Oncology Group/ World Health Organization (ECOG/WHO): 2+ VS less than 2, HR 1.63 95% CI 1.43–1.86, high-quality evidence; ECOG/WHO: 3+ VS less than 3, HR 2.00 95% CI 1.52–2.63, moderate-quality evidence) were associated with long-term mortality. These studies provided inconsistent and non-informative results on short-term mortality (within 90 days) and quality of life. Conclusion: High-quality or moderate-quality evidence support that age, comorbidities, performance status predicts the long-term prognosis of older patients with AML undergoing antileukemic treatment. [ABSTRACT FROM AUTHOR]

Among non-dialysis-dependent chronic kidney disease (ND-CKD) patients, a low hematopoietic response to erythropoiesis-stimulating agents (ESAs) is a predictor for poor renal and cardiovascular outcome. To assess the method for evaluating hyporesponsiveness to ESA in patients with ND-CKD, a multicenter, prospective, observational study of 1,980 adult patients with ND-CKD with renal anemia was conducted. Darbepoetin alfa (DA) and iron supplement administrations were provided according to the recommendation of the attached document and the guidelines of JSDT (Japanese Society of Dialysis and Transplantation). The primary outcomes were progression of renal dysfunction and major adverse cardiovascular events. ESA responsiveness was assessed using pre-defined candidate formulae. During the mean follow-up period of 96 weeks, renal and cardiovascular disease (CVD) events occurred in 683 (39.6%) and 174 (10.1%) of 1,724 patients, respectively. Among pre-set candidate formulae, the one expressed by dividing the dose of DA by Hb level at the 12-week DA treatment was statistically significant in predicting renal (hazard ratio [HR], 1.449; 95% confidence interval [CI], 1.231–1.705; P<0.0001) and CVD events (HR, 1.719; 95% CI, 1.239–2.386; P = 0.0010). The optimum cut-off values for both events were close to 5.2. In conclusion, hyporesponsiveness to ESA in ND-CKD cases, which is associated with a risk for renal and CVD events, may be evaluated practicably as the dose of DA divided by the Hb level at the 12-week DA treatment, and the cut-off value of this index is 5.2. A search for the causes of poor response and measures for them should be recommended in such patients. Trial registration: ClinicalTrials. gov Identifier: NCT02136563; UMIN Clinical Trial Registry Identifier: UMIN000013464. [ABSTRACT FROM AUTHOR]

Background: Elevated blood lactate levels were reported as effective predictors of clinical outcome and mortality in ICU. However, there have been no studies simply comparing the timing of measuring lactates before vs. after ICU admission. Methods: A total of 19,226 patients with transfer time ≤ 24 hr were extracted from the Medical Information Mart for Intensive Care IV database (MIMIC-IV). After 1:1 propensity score matching, the patients were divided into two groups: measuring lactates within 3 hr before (BICU group, n = 4,755) and measuring lactate within 3 hr after ICU admission(AICU group, n = 4,755). The primary and secondary outcomes were hospital mortality, hospital 28-day mortality, ICU mortality, ICU length of stay (LOS), hospital LOS, and restricted mean survival time (RMST). Results: Hospital, hospital 28-day, and ICU mortality were significantly higher in AICU group (7.0% vs.9.8%, 6.7% vs. 9.4%, and 4.6% vs.6.7%, respectively, p<0.001 for all) Hospital LOS and ICU LOS were significantly longer in AICU group (8.4 days vs. 9.0 days and 3.0 days vs. 3.5 days, respectively, p<0.001 for both). After adjustment for predefined covariates, a significant association between the timing of measuring lactate and hospital mortality was observed in inverse probability treatment weight (IPTW) multivariate regression, doubly robust multivariate regression, and multivariate regression models (OR, 0.96 [95%CI, 0.95-0.97], OR 0.52 [95%CI, 0.46-0.60], OR 0.66 [95%CI, 0.56-0.78], respectively, p<0.001 for all), indicating the timing as a significant risk-adjusted factor for lower hospital mortality. The difference (BICU-AICU) of RMST at 28- days after ICU admission was 0.531 days (95%CI, 0.002-1.059, p<0.05). Placement of A-line and PA-catheter, administration of intravenous antibiotics, and bolus fluid infusion during the first 24-hr in ICU were significantly more frequent and faster in the BICU vs AICU group (67.6% vs. 51.3% and 126min vs.197min for A-line, 19.6% vs.13.2% and 182min vs. 274min for PA-catheter, 77.5% vs.67.6% and 109min vs.168min for antibiotics, and 57.6% vs.51.6% and 224min vs.278min for bolus fluid infusion, respectively, p<0.001 for all). Additionally, a significant indirect effect was observed in frequency (0.19879 [95% CI, 0.14061-0.25697] p<0.001) and time (0.07714 [95% CI, 0.22600-0.13168], p<0.01) of A-line replacement, frequency of placement of PA-catheter (0.05614 [95% CI, 0.04088-0.07140], p<0.001) and frequency of bolus fluid infusion (0.02193 [95%CI, 0.00303-0.04083], p<0.05). Conclusions: Measuring lactates within 3 hr prior to ICU might be associated with lower hospital mortality in unselected heterogeneous critically ill patients with transfer time to ICU ≤ 24hr, presumably due to more frequent and faster therapeutic interventions. [ABSTRACT FROM AUTHOR]

Expanded implementation of genetic sequencing has precipitously increased the discovery of germline and somatic variants. The direct benefit of identifying variants in actionable genes may lead to risk reduction strategies such as increased surveillance, prophylactic surgery, as well as lifestyle modifications to reduce morbidity and mortality. However, patients with African ancestry are more likely to receive inconclusive genetic testing results due to an increased number of variants of unknown significance decreasing the utility and impact on disease management and prevention. This study examines whole exome sequencing results from germline DNA samples in African American women with a family history of cancer including 37 cases that were diagnosed with breast cancer and 51 family members. Self-identified ancestry was validated and compared to the 1000 genomes population. The analysis of sequencing results was limited to 85 genes from three clinically available common genetic screening platforms. This target region had a total of 993 variants of which 6 (<1%) were pathogenic or likely pathogenic, 736 (74.1%) were benign, and 170 (17.1%) were classified as a variant of unknown significance. There was an average of 3.4±1.8 variants with an unknown significance per individual and 85 of 88 individuals (96.6%) harbored at least one of these in the targeted genes. Pathogenic or likely pathogenic variants were only found in 6 individuals for the BRCA1 (p.R1726fs, rs80357867), BRCA2 (p.K589fs, rs397507606 & p.L2805fs, rs397507402), RAD50 (p.E995fs, rs587780154), ATM (p.V2424G, rs28904921), or MUTYH (p.G396D, rs36053993) genes. Strategies to functionally validate the remaining variants of unknown significance, especially in understudied and hereditary cancer populations, are greatly needed to increase the clinical utility and utilization of clinical genetic screening platforms to reduce cancer incidence and mortality. [ABSTRACT FROM AUTHOR]

The dynamics of neuronal microtubules are essential for brain plasticity. Vesicular transport and synaptic transmission, additionally, requires acetylation of α-tubulin, and aberrant tubulin acetylation and neurobiological deficits are associated. Prolonged exposure to a stressor or consumption of drugs of abuse, like marihuana, lead to neurological changes and psychotic disorders. Here, we studied the effect of psychosocial stress and the administration of cannabinoid receptor type 1 drugs on α-tubulin acetylation in different brain regions of mice. We found significantly decreased tubulin acetylation in the prefrontal cortex in stressed mice. The impact of cannabinoid drugs on stress-induced microtubule disturbance was investigated by administration of the cannabinoid receptor agonist WIN55,212–2 and/or antagonist rimonabant. In both, control and stressed mice, the administration of WIN55,212–2 slightly increased the tubulin acetylation in the prefrontal cortex whereas administration of rimonabant acted antagonistically indicating a cannabinoid receptor type 1 mediated effect. The analysis of gene expression in the prefrontal cortex showed a consistent expression of ApoE attributable to either psychosocial stress or administration of the cannabinoid agonist. Additionally, ApoE expression inversely correlated with acetylated tubulin levels when comparing controls and stressed mice treated with WIN55,212–2 whereas rimonabant treatment showed the opposite. [ABSTRACT FROM AUTHOR]

Introduction: Over recent decades, the abundance and geographic ranges of wild ungulate species have expanded in many parts of Europe, including the UK. Populations are managed to mitigate their ecological impacts using interventions, such as shooting, fencing and administering contraception. Predicting how target species will respond to interventions is critical for developing sustainable, effective and efficient management strategies. However, the quantity and quality of evidence of the effects of interventions on ungulate species is unclear. To address this, we systematically mapped research on the effects of population management on wild ungulate species resident in the UK. Methods: We searched four bibliographic databases, Google Scholar and nine organisational websites using search terms tested with a library of 30 relevant articles. Worldwide published peer-reviewed articles were considered, supplemented by 'grey' literature from UK-based sources. Three reviewers identified and screened articles for eligibility at title, abstract and full-text levels, based on predefined criteria. Data and metadata were extracted and summarised in a narrative synthesis supported by structured graphical matrices. Results: A total of 123 articles were included in the systematic map. Lethal interventions were better represented (85%, n = 105) than non-lethal interventions (25%, n = 25). Outcomes related to demography and behaviour were reported in 95% of articles (n = 117), whereas effects on health, physiology and morphology were studied in only 11% of articles (n = 14). Well-studied species included wild pigs (n = 58), red deer (n = 28) and roe deer (n = 23). Conclusions: Evidence for the effects of population management on wild ungulate species is growing but currently limited and unevenly distributed across intervention types, outcomes and species. Priorities for primary research include: species responses to non-lethal interventions, the side-effects of shooting and studies on sika deer and Chinese muntjac. Shooting is the only intervention for which sufficient evidence exists for systematic review or meta-analysis. [ABSTRACT FROM AUTHOR]

Student Dropout Prediction (SDP) is pivotal in mitigating withdrawals in Massive Open Online Courses. Previous studies generally modeled the SDP problem as a binary classification task, providing a single prediction outcome. Accordingly, some attempts introduce survival analysis methods to achieve continuous and consistent predictions over time. However, the volatility and sparsity of data always weaken the models' performance. Prevailing solutions rely heavily on data pre-processing independent of predictive models, which are labor-intensive and may contaminate authentic data. This paper proposes a Survival Analysis based Volatility and Sparsity Modeling Network (SAVSNet) to address these issues in an end-to-end deep learning framework. Specifically, SAVSNet smooths the volatile time series by convolution network while preserving the original data information using Long-Short Term Memory Network (LSTM). Furthermore, we propose a Time-Missing-Aware LSTM unit to mitigate the impact of data sparsity by integrating informative missingness patterns into the model. A survival analysis loss function is adopted for parameter estimation, and the model outputs monotonically decreasing survival probabilities. In the experiments, we compare the proposed method with state-of-the-art methods in two real-world MOOC datasets, and the experiment results show the effectiveness of our proposed model. [ABSTRACT FROM AUTHOR]

Leadership in public health is necessary, relevant, and important as it enables the engagement, management, and transformation of complex public health challenges at a national level, as well as collaborating with internal stakeholders to address global public health threats. The research literature recommends exploring the journey of public health leaders and the factors influencing leadership development, especially in developing countries. Thus, we aimed to develop a grounded theory on individual leadership development in the Nepalese context. For this, we adopted constructivist grounded theory, and conducted 46 intensive interviews with 22 public health officials working under the Ministry of Health, Nepal. Data were analysed by adopting the principles of Charmaz's constructivist grounded theory. The theory developed from this study illustrates four phases of leadership development within an individual–initiation, identification, development, and expansion. The 'initial phase' is about an individual's wishes to be a leader without a formal role or acknowledgement, where family environment, social environment and individual characteristics play a role in influencing the actualisation of leadership behaviours. The 'identification phase' involves being identified as a public health official after having formal position in health-related organisations. The 'development' phase is about developing core leadership capabilities mostly through exposure and experiences. The 'expansion' phase describes expanding leadership capabilities and recognition mostly by continuous self-directed learning. The grounded theory provides insights into the meaning and actions of participants' professional experiences and highlighted the role of individual characteristics, family and socio-cultural environment, and workplace settings in the development of leadership capabilities. It has implications for academia to fulfill the absence of leadership theory in public health and is significant to fulfill the need of leadership models grounded in the local context of Asian countries. [ABSTRACT FROM AUTHOR]

Conventional frontline treatment for ovarian cancer consists of successive chemotherapy cycles of paclitaxel and platinum. Despite the initial favorable responses for most patients, chemotherapy resistance frequently leads to recurrent or refractory disease. New treatment strategies that circumvent or prevent mechanisms of resistance are needed to improve ovarian cancer therapy. We established in vitro paclitaxel-resistant ovarian cancer cell line and organoid models. Gene expression differences in resistant and sensitive lines were analyzed by RNA sequencing. We manipulated candidate genes associated with paclitaxel resistance using siRNA or small molecule inhibitors, and then screened the cells for paclitaxel sensitivity using cell viability assays. We used the Bliss independence model to evaluate the anti-proliferative synergy for drug combinations. ABCB1 expression was upregulated in paclitaxel-resistant TOV-21G (q < 1x10-300), OVCAR3 (q = 7.4x10-156) and novel ovarian tumor organoid (p = 2.4x10-4) models. Previous reports have shown some tyrosine kinase inhibitors can inhibit ABCB1 function. We tested a panel of tyrosine kinase inhibitors for the ability to sensitize resistant ABCB1-overexpressing ovarian cancer cell lines to paclitaxel. We observed synergy when we combined poziotinib or lapatinib with paclitaxel in resistant TOV-21G and OVCAR3 cells. Silencing ABCB1 expression in paclitaxel-resistant TOV-21G and OVCAR3 cells reduced paclitaxel IC50 by 20.7 and 6.2-fold, respectively. Furthermore, we demonstrated direct inhibition of paclitaxel-induced ABCB1 transporter activity by both lapatinib and poziotinib. In conclusion, lapatinib and poziotinib combined with paclitaxel synergizes to inhibit the proliferation of ABCB1-overexpressing ovarian cancer cells in vitro. The addition of FDA-approved lapatinib to second-line paclitaxel therapy is a promising strategy for patients with recurrent ovarian cancer. [ABSTRACT FROM AUTHOR]

Providing treatment sensitivity stratification at the time of cancer diagnosis allows better allocation of patients to alternative treatment options. Despite many clinical and biological risk markers having been associated with variable survival in cancer, assessing the interplay of these markers through Machine Learning (ML) algorithms still remains to be fully explored. Here, we present a Multi Learning Training approach (MuLT) combining supervised, unsupervised and self-supervised learning algorithms, to examine the predictive value of heterogeneous treatment outcomes for Multiple Myeloma (MM). We show that gene expression values improve the treatment sensitivity prediction and recapitulates genetic abnormalities detected by Fluorescence in situ hybridization (FISH) testing. MuLT performance was assessed by cross-validation experiments, in which it predicted treatment sensitivity with 68.70% of AUC. Finally, simulations showed numerical evidences that in average 17.07% of patients could get better response to a different treatment at the first line. [ABSTRACT FROM AUTHOR]

Objective: To characterize the evolution of central nervous system (CNS) inflammation in HIV-1 infection applying a panel of cerebrospinal fluid (CSF) inflammatory biomarkers to grouped subjects representing a broad spectrum of systemic HIV-1 immune suppression, CNS injury and viral control. Methods: This is a cross-sectional analysis of archived CSF and blood samples, assessing concentrations of 10 functionally diverse soluble inflammatory biomarkers by immunoassays in 143 HIV-1-infected subjects divided into 8 groups: untreated primary HIV-1 infection (PHI); four untreated groups defined by their blood CD4+ T lymphocyte counts; untreated patients presenting with subacute HIV-associated dementia (HAD); antiretroviral-treated subjects with ≥1 years of plasma viral suppression; and untreated elite controllers. Twenty HIV-1-uninfected controls were included for comparison. Background biomarkers included blood CD4+ and CD8+ T lymphocytes, CSF and blood HIV-1 RNA, CSF white blood cell (WBC) count, CSF/blood albumin ratio, CSF neurofilament light chain (NfL), and CSF t-tau. Findings: HIV-1 infection was associated with a broad compartmentalized CSF inflammatory response that developed early in its course and changed with systemic disease progression, development of neurological injury, and viral suppression. CSF inflammation in untreated individuals without overt HAD exhibited at least two overall patterns of inflammation as blood CD4+ T lymphocytes decreased: one that peaked at 200–350 blood CD4+ T cells/μL and associated with lymphocytic CSF inflammation and HIV-1 RNA concentrations; and a second that steadily increased through the full range of CD4+ T cell decline and associated with macrophage responses and increasing CNS injury. Subacute HAD was distinguished by a third inflammatory profile with increased blood-brain barrier permeability and robust combined lymphocytic and macrophage CSF inflammation. Suppression of CSF and blood HIV-1 infections by antiretroviral treatment and elite viral control were associated with reduced CSF inflammation, though not fully to levels found in HIV-1 seronegative controls. [ABSTRACT FROM AUTHOR]

Background: Exposure to maternal stress in utero is associated with a range of adverse outcomes. We previously observed an association between maternal stress and white matter microstructure in a sample of infants born prematurely. In this study, we aimed to investigate the relationship between maternal trait anxiety, stressful life events and brain volumes. Methods: 221 infants (114 males, 107 females) born prematurely (median gestational age = 30.43 weeks [range 23.57–32.86]) underwent magnetic resonance imaging around term-equivalent age (mean = 42.20 weeks, SD = 1.60). Brain volumes were extracted for the following regions of interest: frontal lobe, temporal lobe, amygdala, hippocampus, thalamus and normalized to total brain volume. Multiple linear regressions were conducted to investigate the relationship between maternal anxiety/stress and brain volumes, controlling for gestational age at birth, postmenstrual age at scan, socioeconomic status, sex, days on total parenteral nutrition. Additional exploratory Tensor Based Morphometry analyses were performed to obtain voxel-wise brain volume changes from Jacobian determinant maps. Results and conclusion: In this large prospective study, we did not find evidence of a relationship between maternal prenatal stress or trait anxiety and brain volumes. This was the case for both the main analysis using a region-of-interest approach, and for the exploratory analysis using Jacobian determinant maps. We discuss these results in the context of conflicting evidence from previous studies and highlight the need for further research on premature infants, particularly including term-born controls. [ABSTRACT FROM AUTHOR]

Purpose: The aim is to determine whether serial post-systolic shortening (PSS) using speckle tracking echocardiography (STE) could predict major adverse cardiovascular events (MACE), especially symptom-driven infarct-related artery (IRA) revascularization and improvement in segmental function in post-myocardial infarction patients. Methods/Results: Ninety-four patients (average age 61.1 ± 12.5 y, 84 [84.9%] male) with new-onset acute myocardial infarction were enrolled. Serial echocardiography was performed during the initial presentation, and at 3, 6 and 12 months after admission. PSS, strain and systolic strain rate were calculated using STE. Improvement in segmental function was defined as a decrease of ≧1 grade in wall motion score. During the follow-up (29.4 ± 12.7months), 22 patients (23.4%) had MACE and 17 patients had symptom-driven IRA revascularization. In multivariate model, PSS at 3 months was independently predictive for symptom-driven IRA revascularization (Hazard ratio (HR) = 0.5, 95% CI = 0.26–0.97) and for MACE (HR = 0.4, 95% CI = 0.24–0.67) (p < 0.05). Segmental function improvements were found in 255 segments (66.1%) and ROC curve analyses showed that AUC (95% CI) of the initial PSS was 0.7(0.65–0.77) (cut-off values = -1.08, sensitivity = 58%, specificity = 73% specificity). Conclusions: Post-systolic shortening at 3 months is an independent predictor for symptom-driven IRA revascularization and MACE. Regional wall motion recovery also could be predicted by initial PSS. Serial assessment of two-dimensional STE should be investigated in post-myocardial infarction patients in the future. [ABSTRACT FROM AUTHOR]

Primary focal hyperhidrosis (PFH, OMIM %144110) is a genetically influenced condition characterised by excessive sweating. Prevalence varies between 1.0–6.1% in the general population, dependent on ethnicity. The aetiology of PFH remains unclear but an autosomal dominant mode of inheritance, incomplete penetrance and variable phenotypes have been reported. In our study, nine pedigrees (50 affected, 53 non-affected individuals) were included. Clinical characterisation was performed at the German Hyperhidrosis Centre, Munich, by using physiological and psychological questionnaires. Genome-wide parametric linkage analysis with GeneHunter was performed based on the Illumina genome-wide SNP arrays. Haplotypes were constructed using easyLINKAGE and visualised via HaploPainter. Whole-exome sequencing (WES) with 100x coverage in 31 selected members (24 affected, 7 non-affected) from our pedigrees was achieved by next generation sequencing. We identified four genome-wide significant loci, 1q41-1q42.3, 2p14-2p13.3, 2q21.2-2q23.3 and 15q26.3-15q26.3 for PFH. Three pedigrees map to a shared locus at 2q21.2-2q23.3, with a genome-wide significant LOD score of 3.45. The chromosomal region identified here overlaps with a locus at chromosome 2q22.1-2q31.1 reported previously. Three families support 1q41-1q42.3 (LOD = 3.69), two families share a region identical by descent at 2p14-2p13.3 (LOD = 3.15) and another two families at 15q26.3 (LOD = 3.01). Thus, our results point to considerable genetic heterogeneity. WES did not reveal any causative variants, suggesting that variants or mutations located outside the coding regions might be involved in the molecular pathogenesis of PFH. We suggest a strategy based on whole-genome or targeted next generation sequencing to identify causative genes or variants for PFH. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to assess time on treatment with abiraterone and enzalutamide, two androgen receptor targeted (ART) drugs, the impact on time on treatment of time interval without drug supply between prescription fillings, and adherence to treatment. Material and methods: By use of data from The National Prostate Cancer Register, The Prescribed Drug Registry and the Patient Registry, time on treatment with the abiraterone and enzalutamide was analyzed in all men with castration resistant prostate cancer (CRPC) in Sweden 2015–2019. Three time intervals between consecutive fillings, i.e. time without drug supply, were assessed. Adherence to the treatment was evaluated by use of the Medication Possession Ratio. Kaplan Meier analysis and multivariable Cox regression model were used to assess factors affecting time on treatment. Results: Between January 2015 and October 2019, 1803 men filled a prescription for abiraterone and 4 534 men filled a prescription for enzalutamide. With a time interval of 30 days or less between two fillings, median time on treatment was 4.9 months (IQR 2.6–11.7) for abiraterone and 8.0 months (IQR 3.6–16.4) for enzalutamide. In sensitivity analyses, allowing for no more than 14 days without drug supply between fillings, median time on treatment was 3.9 months (IQR 2.1–9.0) for abiraterone and 5.9 months (IQR 2.8–12.1) for enzalutamide. Allowing for any time period without drug between fillings, median time on treatment was 5.7 months (IQR 2.7–14.0) for abiraterone and 9.8 months (IQR 4.4–21.0) for enzalutamide. Adherence to treatment was above 90% for both drugs. Conclusion: Time on treatment with abiraterone and enzalutamide was shorter in clinical practice than in randomized controlled trials and varied almost two-fold with time interval without drug. Adherence to treatment was high. The main limitation of our study was the lack of data on use of chemotherapy. [ABSTRACT FROM AUTHOR]

Despite considerable evidence demonstrating that waist circumference (WC) is independently associated with cardiovascular disease (CVD) and/or all-cause mortality, whether the addition of WC improves risk prediction models is unclear. The objective was to evaluate the improvement in risk prediction with the addition of WC, alone or in combination with BMI, to the Framingham Risk Score (FRS) and a population specific model. 34,377 men and 9,477 women aged 20 to 79 years who completed a baseline examination at the Cooper Clinic (Dallas, TX) during 1977–2003 and enrolled in the Aerobics Center Longitudinal Study (ACLS). WC was measured at the level of the umbilicus and expressed as a continuous variable. Deaths among participants were identified using the National Center for Health Statistics National Death Index. A total of 728 fatal cardiovascular disease (CVD) events occurred over a mean follow-up period of 13.1 ± 7.5 years. WC was significantly higher in CVD decedents (P =.002). The FRS C-statistic for fatal CVD in men was 0.836 (0.816–0.855) and 0.883 (0.851–0.915) in women. The addition of WC did not improve the C-statistic in men (0.831 (0.809–0.853)) or women (0.883 (0.850–0.916)). Similar findings were observed for non-fatal CVD and all-cause mortality, and when WC was added to a population specific model. Upon adding WC, the net-reclassification index was 0.024 with an integrated discrimination improvement of -0.0004. The addition of WC, alone or in combination with BMI, did not substantively improve risk prediction for CVD or all-cause mortality compared to the Framingham Risk Score or a population specific model. [ABSTRACT FROM AUTHOR]

Detailed information about the lives and deaths of children in antiquity is often in short supply. Childhood dietary histories are, however, recorded and maintained in the teeth of both juveniles and adults. Primary tooth dentinal collagen does not turn over, preserving a sequential record of dietary changes. The use of nitrogen (δ15N) and carbon (δ13C) isotope values of incrementally sampled dentin are used in the study of breastfeeding practices but evidence for the addition of weaning foods, both in terms of mode and, particularly, duration, has remained analytically inaccessible to date. Here, we demonstrate how the novel use hydrogen isotope (δ2H) values of sequentially micro-sampled dentin collagen, measured from individuals excavated from a Punic cemetery, in Sardinia, Italy, can serve as a proxy for weaning food type and duration in ancient childhood diet. The weaning rate and age, based on the decline in δ15N and δ13C values of permanent first molars and the concomitant increase in δ2H, appears to be broadly similar among six individuals. Hydrogen isotopes vary systematically from a low value soon after birth, rising through early childhood. The early post-birth values can be explained by the influence of 2H-depleted lipids from mother's breastmilk and the later δ2H rise is consistent with, among other things, a substantial portion of boiled foodstuffs, such as the higher δ2H values observed in porridge. Overall δ2H in dentin shows great promise to elucidate infant and childhood feeding practices, and especially the introduction of supplementary foods during the weaning process. [ABSTRACT FROM AUTHOR]

Deer overabundance is a contributing factor in the degradation of plant communities and ecosystems worldwide. The management and conservation of the deer-affected ecosystems requires us to urgently grasp deer population trends and to identify the factors that affect them. In this study, we developed a Bayesian state–space model to estimate the population dynamics of sika deer (Cervus nippon) in a cool-temperate forest in Japan, where wolves (Canis lupus hodophilax) are extinct. The model was based on field data collected from block count surveys, road count surveys by vehicles, mortality surveys during the winter, and nuisance control for 12 years (2007–2018). We clarified the seasonal and annual fluctuation of the deer population. We found a peak of deer abundance (2010) over 12 years. In 2011 the estimated deer abundance decreased drastically and has remained at a low level then. The deer abundance gradually increased from April to December during 2013–2018. The seasonal fluctuation we detected could reflect the seasonal migration pattern of deer and the population recruitment through fawn births in early summer. In our model, snowfall accumulation, which can be a lethal factor for deer, may have slightly affected their mortality during the winter. Although we could not detect a direct effect of snow on population dynamics, snowfall decrease due to global warming may decelerate the winter migration of deer; subsequently, deer staying on-site may intensively forage evergreen perennial plants during the winter season. The nuisance control affected population dynamics. Even in wildlife protection areas and national parks where hunting is regulated, nuisance control could be effective in buffering the effect of deer browsing on forest ecosystems. [ABSTRACT FROM AUTHOR]

Cigarette smoking is among the leading risk factors for mortality and morbidity. While men have a higher smoking prevalence, mechanistic experiments suggest that women are at higher risk for health problems due to smoking. Moreover, the comparison of smoking effects on multiple conditions and mortality for men and women has not yet been done in a population-based group with race/ethnic diversity. We used proportional hazards models and restricted mean survival time to assess differences in smoking effects by sex for multiple health outcomes using data from the U.S. Health and Retirement Study (HRS), a population-representative cohort of individuals aged 50+ (n = 22,708, 1992–2014). Men had experienced more smoking pack-years than women (22.0 vs 15.6 average pack-years). Age of death, onset of lung disorders, heart disease, stroke, and cancer showed dose-dependent effects of smoking for both sexes. Among heavy smokers (>28 pack-years) women had higher risk of earlier age of death (HR = 1.3, 95%CI:1.03–1.65) and stroke (HR = 1.37, 95%CI:1.02–1.83). Risk of cancer and heart disease did not differ by sex for smokers. Women had earlier age of onset for lung disorders (HR = 2.83, 95%CI:1.74–4.6), but men risk due to smoking were higher (Smoking-Sex interaction P<0.02) than women. Passive smoke exposure increased risk of earlier heart disease (HR = 1.33, 95%CI:1.07–1.65) and stroke (HR:1.54, 95%CI:1.07–2.22) for non-smokers, mainly in men. Smoking cessation after 15 years partially attenuated the deleterious smoking effects for all health outcomes. In sum, our results suggest that women are more vulnerable to ever smoking for earlier death and risk of stroke, but less vulnerable for lung disorders. From an epidemiological perspective, sex differences in smoking effects are important considerations that could underlie sex differences in health outcomes. These findings also encourage future mechanistic experiments to resolve potential mechanisms of sex-specific cigarette smoke toxicity. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is a major healthcare challenge contributing to high morbidity and mortality. Treatment options are still limited, mainly due to insufficient understanding of the underlying pathophysiology. Further research and the development of reliable animal models resembling the human disease phenotype is therefore necessary to develop novel, innovative and ideally causal therapies. Since ischaemic heart failure (IHF) is a major cause for AF in patients we investigated AF in the context of IHF in a close-to-human porcine ischaemia-reperfusion model. Myocardial infarction (AMI) was induced in propofol/fentanyl/midazolam-anaesthetized pigs by occluding the left anterior descending artery for 90 minutes to model ischaemia with reperfusion. After 30 days ejection fraction (EF) was significantly reduced and haemodynamic parameters (pulmonary capillary wedge pressure (PCWP), right atrial pressure (RAP), left ventricular enddiastolic pressure (LVEDP)) were significantly elevated compared to age/weight matched control pigs without AMI, demonstrating an IHF phenotype. Electrophysiological properties (sinus node recovery time (SNRT), atrial/AV nodal refractory periods (AERP, AVERP)) did not differ between groups. Atrial burst pacing at 1200 bpm, however, revealed a significantly higher inducibility of atrial arrhythmia episodes including AF in IHF pigs (3/15 vs. 10/16, p = 0.029). Histological analysis showed pronounced left atrial and left ventricular fibrosis demonstrating a structural substrate underlying the increased arrhythmogenicity. Consequently, selective ventricular infarction via LAD occlusion causes haemodynamic alterations inducing structural atrial remodeling which results in increased atrial fibrosis as the arrhythmogenic atrial substrate in pigs with IHF. [ABSTRACT FROM AUTHOR]

Cathepsins are the major lysosomal proteases that maintain intracellular homeostasis. Herein, we investigated the alterations in myocardial cathepsin expression during aging, cardiac hypertrophy, and sudden cardiac death (SCD). Cardiac tissue and blood were sampled from autopsy cases. Subjects were classified into three groups: SCD with cardiac hypertrophy (SCH), compensated cardiac hypertrophy (CCH), and control. Immunoblotting was performed for the major cardiac cathepsins and their targets: cathepsin B, D, and L (CTSB/D/L), p62, ATP synthase subunit c (ATPSC), and α-synuclein (ASNC). Immunohistochemical analysis and ELISA using serum samples were performed for CTSD. Cardiac CTSB and CTSD were upregulated with age (r = 0.63 and 0.60, respectively), whereas the levels of CTSL, p62, ATPSC, and ASNC remained unchanged. In age-matched groups, cardiac CTSD was significantly downregulated in SCH (p = 0.006) and CTSL was moderately downregulated in CCH (p = 0.021); however, p62, ATPSC, and ASNC were not upregulated in cardiac hypertrophy. Immunohistochemistry also revealed decreased myocardial CTSD levels in SCH, and serum CTSD levels were relatively lower in SCH cases. Overall, these results suggest that upregulation of cardiac CTSB and CTSD with age may compensate for the elevated proteolytic demand, and that downregulation of CTSD is potentially linked to SCH. [ABSTRACT FROM AUTHOR]

Due to differential treatment responses of patients to pharmacotherapy, drug development and practice in medicine are concerned with personalized medicine, which includes identifying subgroups of population that exhibit differential treatment effect. For time–to–event data, available methods only focus on detecting and testing treatment–by–covariate interactions and may not consider multiplicity. In this work, we introduce the Bayesian credible subgroups approach for time–to–event endpoints. It provides two bounding subgroups for the true benefiting subgroup: one which is likely to be contained by the benefiting subgroup and one which is likely to contain the benefiting subgroup. A personalized treatment effect is estimated by two common measures of survival time: the hazard ratio and restricted mean survival time. We apply the method to identify benefiting subgroups in a case study of prostate carcinoma patients and a simulated large clinical dataset. [ABSTRACT FROM AUTHOR]

Background: External validation of prognostic risk models is essential before they are implemented in clinical practice. This study evaluated the recently developed MEGNA score for survival prediction after resection of intrahepatic cholangiocarcinoma (ICC), with a focus on the direct comparison of its prognostic value to that of the current International Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC) Cancer staging system. Material and methods: Between 1997 and 2018, 417 consecutive patients with ICC were referred to our tertiary care centre and were retrospectively identified out of a dedicated clinical database. Of this group, 203 patients underwent surgical resection and met the inclusion criteria. Multivariate analysis was performed to assess the predictors of the recently proposed MEGNA score regarding overall survival (OS). Concordance indices (C-indices) and integrated Brier scores (IBS) were calculated to assess the ability of both the MEGNA score and the current (8th) edition of the UICC/AJCC Cancer staging system to predict individual patient outcome. Results: Stratification according to the MEGNA score resulted in a median OS of 34.5 months, 26.1 months, 21.5 months, and 16.6 months for MEGNA scores 0, 1, 2, and ≥3, respectively (log rank p < 0.001). However, of the five factors that contribute to the MEGNA score, age > 60 years was not a predictor for poor OS in our cohort. The C-index for the MEGNA score was 0.58, the IBS was 0.193. The 8th edition of the UICC/AJCC system performed slightly better, with a C-index of 0.61 and an IBS of 0.186. Conclusion: The ability of the MEGNA score to predict individual patient outcome was only moderate in this external validation. Its prognostic value did not reach that of the more widely known and used UICC/AJCC system. However, neither scoring system performed well enough to support clear-cut clinical decisions. [ABSTRACT FROM AUTHOR]

Background: Despite advancements in pharmacological and device-based treatment, heart failure (HF) continues to impose an enormous burden for health care system worldwide. Decompensation of HF is one of the main causes of hospitalization, therefore the identification of patients with the highest risk of such complication is still of great clinical importance. The prognostic significance and utility of global longitudinal strain (GLS) has been previously studied in patients with the broad spectrum of cardiovascular diseases in various endpoints, however its role in assessing the risk of hospitalization due to HF exacerbation of optimally treated outpatients has not been fully explored. Therefore, the aim of the study was to verify whether the GLS of the left ventricle (LV) derived by 2D speckle tracking echocardiography has, independently of other well-known clinical parameters, an additional impact on the risk of HF decompensation in stable patients with LV systolic dysfunction of ischemic origin. Methods: In 193 clinically stable HF outpatients with LV ejection fraction (LVEF) ≤ 50%, GLS, additionally to other clinical parameters, was analyzed. During 34 (14–71) months of follow-up, 58 patients were hospitalized due to HF decompensation (EVENT). Results: EVENT was significantly associated with age, QRS width, NYHA functional class, left atrium diameter, LV systolic and diastolic volume, LVEF, hemoglobin, brain natriuretic peptide, diuretic treatment, absence of beta-blockers, impaired renal function and history of diabetes in univariate Cox analyzes. GLS with pre-specified cut-off value of -9.4% was also significantly associated with the EVENT (HR 15.16; 95% CI 1.81–126.91). After adjusting for above-mentioned parameters GLS was still a significant predictor of hospitalization due to HF decompensation. Conclusions: GLS measurement can provide incremental information on the risk of HF decompensation in stable outpatients with LV systolic dysfunction of ischemic origin. [ABSTRACT FROM AUTHOR]

Approximately 25% of colorectal cancer patients in sub-Saharan Africa are younger than 40 years, and hereditary factors may contribute. We investigated the frequency and patterns of inherited colorectal cancer among black Zimbabweans. A population-based cross-sectional study of ninety individuals with a new diagnosis of colorectal cancer was carried out in Harare, Zimbabwe between November 2012 and December 2015. Phenotypic data was obtained using interviewer administered questionnaires, and reviewing clinical and pathology data. Cases were screened for mismatch repair deficiency by immunohistochemistry and/or microsatellite instability testing, and for MLH1, MSH2 and EPCAM deletions using multiplex ligation-dependent probe amplification. Next generation sequencing using a 16-gene panel was performed for cases with phenotypic features consistent with familial colorectal cancer. Variants were assessed for pathogenicity using the mean allele frequency, phenotypic features and searching online databases. Three Lynch syndrome cases were identified: MSH2 c.2634G>A pathogenic mutation, c.(1896+1_1897–1)_(*193_?)del , and one fulfilling the Amsterdam criteria, with MLH1 and PMS2 deficiency, but no identifiable pathogenic mutation. Two other cases had a strong family history of cancers, but the exact syndrome was not identified. The prevalence of Lynch syndrome was 3·3% (95% CI 0·7–9·4), and that of familial colorectal cancer was 5·6% (95% CI, 1·8–12·5). Identifying cases of inherited colorectal cancer in sub-Saharan Africa is feasible, and our findings can inform screening guidelines appropriate to this setting. [ABSTRACT FROM AUTHOR]

To investigate the issues of the NNT based on the absolute risk reduction (ARR), namely NNTARR; and to propose an alternative definition and an estimation procedure based on the restricted mean survival time (RMST), namely NNTRMST, for RCTs. Three recent clinical trials with survival endpoints, representing different scenarios, were selected to compare the performance of the NNTARR and NNTRMST. For each trial, both versions of NNT were estimated using the reconstructed individual-level data, and the average life gain (ALG) was derived to show the differences between the NNTARR and NNTRMST. Four hypothetical scenarios were constructed to further explore the advantages and disadvantages of each definition of the NNT for survival endpoints. For the illustrative trial examples, the NNTARR failed to capture the profile of the treatment effect over time as it is calculated at a specific time point. Sometimes it may even result in misinterpretations of the treatment benefit. In particular, when either the observed event rates are low, the two survival curves cross, or a mixture of survival patterns exist. In contrast, the NNTRMST based on the average survival (or event-free) time can quantify the treatment effect more accurately and its interpretation is more intuitive and clinically meaningful. The NNTRMST can be used as an alternative measure for quantifying treatment effect in RCTs, especially so in the case of the ALG, which helps practitioners to better understand the magnitude of the benefit conferred by treatment. [ABSTRACT FROM AUTHOR]

Incidentally discovered solitary pulmonary nodules (SPN) caused by nontuberculous mycobacteria (NTM) is uncommon, and its optimal treatment strategy remains uncertain. This cohort study determined the clinical characteristics and outcome of asymptomatic patients with NTM-SPN after surgical resection. Resected SPNs with culture-positive for NTM in six hospitals in Taiwan during January, 2010 to January, 2017 were identified. Asymptomatic patients without a history of NTM-pulmonary disease (PD) or same NTM species isolated from the respiratory samples were selected. All were followed until May 1, 2019. A total of 43 patients with NTM-SPN were enrolled. Mycobacterium avium complex (60%) and M. kansasii (19%) were the most common species. The mean age was 61.7 ± 13.4. Of them, 60% were female and 4% had history of pulmonary tuberculosis. The NTM-SPN was removed by wedge resection in 38 (88%), lobectomy in 3 (7%) and segmentectomy in 2 (5%). Caseating granuloma was the most common histologic feature (58%), while chronic inflammation accounts for 23%. Mean duration of the follow-up was 5.2 ± 2.8 years (median: 4.2 years [2.5–7.0]), there were no mycobacteriology recurrence or NTM-PD development. In conclusion, surgical resection is likely to curative for incidentally discovered NTM-SPN in asymptomatic patients without culture evidence of the same NTM species from respiratory specimens, and routine mycobacterium culture for resected SPN might be necessary for differentiating pulmonary tuberculosis and NTM because further treatment differs. [ABSTRACT FROM AUTHOR]

Background: A20 protein has ubiquitin-editing activities and acts as a key regulator of inflammation and immunity. Previously, our group showed that A20 promotes tumor metastasis through multi-monoubiquitylation of SNAIL1 in basal-like breast cancer. Here, we investigated survival outcomes in patients with breast cancer according to A20 expression. Patients and methods: We retrospectively collected tumor samples from patients with breast cancer. Immunohistochemistry (IHC) with an A20-specific antibody was performed, and survival outcomes were analyzed. Results: A20 expression was evaluated in 442 patients. High A20 expression was associated with advanced anatomical stage and young age. High A20 expression showed significantly inferior recurrence-free-survival and overall-survival (P<0.001 and P<0.001, respectively). Multivariate analysis showed that A20 was an independent prognostic marker for RFS (HRs: 2.324, 95% CIs: 1.446–3.736) and OS (HRs: 2.629, 95% CIs: 1.585–4.361). In human epidermal growth factor receptor 2 (HER2)-positive and triple negative breast cancer (TNBC) subtypes, high A20 levels were associated with poor OS. Conclusion: We found that A20 expression is a poor prognostic marker in breast cancer. The prognostic impact of A20 was pronounced in aggressive tumors, such as HER2-positive and TNBC subtypes. Our findings suggested that A20 may be a valuable target in patients with aggressive breast cancer. [ABSTRACT FROM AUTHOR]

Background: To determine the incidence of acute cerebral infarction or space occupying lesion (SOL) among patients with isolated vertigo or dizziness (IVD) and to evaluate the role of cerebellar function test (CFT) and D-dimer to discriminate ACI/SOL and non-ACI/SOL. Methods: A retrospective study of consecutive emergency department (ED) patients with IVD during one year was conducted. ACI was based on the diffusion-weighted magnetic resonance imaging (DW-MRI), and SOL was based on the concurrent MRI sequences. A sensitivity analysis of CFT and D-dimer was also performed. Results: Among the 468 patients enrolled, 13 patients (2.8%) had ACI, 11 at cerebellum, 1 at occipital lobe, and 1 at centrum semiovale. Twenty-five patients (5.3%) had SOL. Aneurysm is most frequent (n = 7), followed by meningioma (n = 4) and venous anomaly (n = 4). In total, ACI/SOL was found in 8.1% (n = 38). Abnormal findings in finger-to-nose (FN), heel-to-shin (HTS), and rapid alternative movement (RAM) tests were significantly higher in ACI or ACI/SOL group, while gait disturbance, tandem gait abnormality, and Romberg’s test were not. CFT sensitivities were low for ACI as well as for ACI/SOL, but specificities were high for ACI and ACI/SOL. D-dimer level showed a sensitivity of 100% at >0.18 mg/L for ACI and >0.15 mg/L for ACI/SOL. However, specificity was low at corresponding D-dimer level. Among the subgroup (n = 411) who did not show any abnormality in CFT, 9 patients (2.2%) had ACI, and 33 patients (8.0%) had ACI/SOL. Conclusion: The present study reports a clinically significant incidence of ACI/SOL among ED patients with IVD. D-dimer showed high sensitive and low specificity, while CFT showed low sensitivity and high specificity. [ABSTRACT FROM AUTHOR]

Purpose: Normalized emphysema score is a protocol-robust CT biomarker of mortality. We aimed to improve mortality prediction by including the emphysema score progression rate–its change over time–into the models. Method and materials: CT scans from 6000 National Lung Screening Trial CT arm participants were included. Of these, 1810 died (445 lung cancer-specific). The remaining 4190 survivors were sampled with replacement up to 24432 to approximate the full cohort. Three overlapping subcohorts were formed which required participants to have images from specific screening rounds. Emphysema scores were obtained after resampling, normalization, and bullae cluster analysis of the original images. Base models contained solely the latest emphysema score. Progression models included emphysema score progression rate. Models were adjusted by including baseline age, sex, BMI, smoking status, smoking intensity, smoking duration, and previous COPD diagnosis. Cox proportional hazard models predicting all-cause and lung cancer mortality were compared by calculating the area under the curve per year follow-up. Results: In the subcohort of participants with baseline and first annual follow-up scans, the analysis was performed on 4940 participants (23227 after resampling). Area under the curve for all-cause mortality predictions of the base and progression models 6 years after baseline were 0.564 (0.564 to 0.565) and 0.569 (0.568 to 0.569) when unadjusted, and 0.704 (0.703 to 0.704) to 0.705 (0.704 to 0.705) when adjusted. The respective performances predicting lung cancer mortality were 0.638 (0.637 to 0.639) and 0.643 (0.642 to 0.644) when unadjusted, and 0.724 (0.723 to 0.725) and 0.725 (0.725 to 0.726) when adjusted. Conclusion: Including emphysema score progression rate into risk models shows no clinically relevant improvement in mortality risk prediction. This is because scan normalization does not adjust for an overall change in lung density. Adjusting for changes in smoking behavior is likely required to make this a clinically useful measure of emphysema progression. [ABSTRACT FROM AUTHOR]

Aims: Elevated levels of high-sensitivity cardiac troponin T (hsTnT) are associated with adverse outcomes in numerous patient populations. Their value in prediction of stroke risk in patients with atrial fibrillation (AF) is in debate. Methods: The study population included 2898 consecutive patients presenting with AF to the emergency department of the Department of Cardiology, Heidelberg University Hospital. Associations between hsTnT and stroke risk were assessed using multivariable Cox regression. Results: Elevated hsTnT levels (>14 ng/L) were associated with increased risk of stroke. Even after adjustment for various risk factors, elevated hsTnT remained independently associated with stroke risk in patients with AF, adjusted hazard ratio 2.35 [95% confidence interval (CI): 1.26–4.36] (P = 0.007). These results were consistent across important subgroups (age, renal function, ejection fraction, CHA2DS2-VASc score and main admission diagnosis). For hsTnT, area under the receiver-operating-characteristic curve (AUC) was 0.659 [95% CI: 0.575–0.742], compared to 0.610 [95% CI: 0.526–0.694] for the CHA2DS2-VASc score. Inclusion of hsTnT in the multivariable model for stroke risk prediction consisting of all variables of the CHA2DS2-VASc score was associated with a significant improvement of its discriminatory power. Conclusion: Elevated hsTnT levels are significantly associated with higher risk of stroke and provide prognostic information independent of CHA2DS2-VASc score variables. Measurement of hsTnT may improve prediction of stroke risk in patients presenting to an emergency department with AF as compared to risk stratification based only on clinical variables. [ABSTRACT FROM AUTHOR]

Initially, the function of the fat mass and obesity associated (Fto) gene seemed to be primarily the regulation of the body weight. Here we show that loss of Fto results in a hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis. In consequence, Fto-/- mice display an anxiety-like behavior and impairments in working memory. Furthermore, differentiation of neurons is affected in the hippocampus. As a cause of these impairments we identified a processing defect of the neurotrophin BDNF which is most likely the result of a reduced expression of MMP-9. Therefore, we propose FTO as a possible new target to develop novel approaches for the treatment of diseases associated with hippocampal disorders. In parallel, we also would like to make the point that any anti-obesity therapy via blocking FTO function can have negative effects on the proper function of the hippocampus. [ABSTRACT FROM AUTHOR]

The effects of social hierarchies (dominant/subordinate individuals), such as aggressiveness, feeding order, and territoriality, are some of the characteristics used for describing fish behaviour. Social hierarchy patterns are still poorly understood in European-reared sea bass (Dicentrarchus labrax). In this work, we examine the social interactions among captive fish integrating behavioural and physiological profiles. Groups of three fish with EMG (electromyogram) radio transmitters were monitored for two weeks via video recording. Plasma levels of cortisol, glucose, lactate and lysozyme as well as haematological parameters such as haemoglobin, haematocrit and RBCC (red blood cell count) were measured at the beginning and end of the experiments. Behaviour and muscle activity were monitored daily. The results highlighted that the social hierarchic order was established after one to two days, and it was maintained throughout the experimental period. Dominant and subordinate fish (ß and γ) showed significant differences in muscle activity, hormonal profile (cortisol), aspecific immunity (lysozyme), carbohydrate metabolism (lactate) and behavioural patterns (food order and aggressiveness). This holistic approach helps to provide insights into the physiological status of the subordinate (ß and γ) and dominant individuals. These data have wide implications for aquaculture practice. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to evaluate predictors of residual tumor and clinical prognosis in T1a-T1b (incidental) prostate cancer by analysis of specimens from men undergoing surgery for benign prostatic hyperplasia. Materials and methods: We retrospectively reviewed medical records of incidental prostate cancer patients who had undergone radical prostatectomy. Patients whose tumor statuses were further confirmed by prostate biopsy, or who had used androgen deprivation therapy before radical prostatectomy, were excluded. Clinical and pathological parameters were analyzed to evaluate residual tumor and clinical prognosis. We used univariate and multivariate logistic regression analyses, as well as receiver operator characteristics, to predict residual tumor (pT0). Results: The final analysis included 95 patients. Among these patients, 67 (70.53%) exhibited residual tumor, whereas 28 (29.47%) did not (pT0). Pathology findings showed that 44 (65.67%), 16 (23.88%), and 7 patients (10.45%) exhibited Gleason scores of G6, G7, and ≥G8, respectively. Fifty-seven and 10 patients exhibited pathologic T stages T2 and T3, respectively. Mean follow-up duration was 70.26 (±34.67) months. Biochemical recurrence was observed in 11 patients; none were pT0 patients. Multivariate logistic regression showed that low prostate-specific antigen density after benign prostatic hyperplasia surgery and invisible lesion on multiparametric magnetic resonance imaging were significantly associated with pT0. Additionally, a combination of these factors showed an increase in the diagnostic accuracy of pT0, compared with mpMRI alone (AUC 0.805, 0.767, respectively); this combination showed sensitivity, specificity, and positive predictive values of 71.6%, 89.3%, and 94.1%, respectively. Conclusion: Our results suggest that patients with incidental prostate cancer who have both prostate-specific antigen density ≤0.08 after benign prostatic hyperplasia surgery as well as invisible cancer lesion on multiparametric magnetic resonance imaging should be considered for active surveillance. [ABSTRACT FROM AUTHOR]

Categorizing the archaeological remains of Sus scrofa as domesticated “pigs” or wild “boars” is often difficult because of their morphological and genetic similarities. For this purpose, we tested whether feeding ecological change of S. scrofa that accompanied their domestication can be detected based on the three-dimensional texture created on the tooth enamel surface by mastication. We scanned the lower tooth surface of one wild and one stall-fed populations of modern S. s. leucomystax and one wild population of S. s. riukiuanus by using a confocal laser microscope. The average body weight of S. s. leucomystax is twice as heavier as that of S. s. riukiuanus. The textures were quantified using the industrial “roughness” standard, ISO 25178, to prevent inter-observer errors and to distinguish small differences that were difficult to detect by two dimensional image observation. The values of parameters related to height and volume were significantly larger in the stall-fed population. Twenty parameters differed significantly between the stall-fed and wild population of S. s. leucomystax, which indicated that the feeding ecological difference affected the ISO parameters of the two boar populations. Six parameters also differed between the wild populations of S. s. leucomystax and S. s. riukiuanus. Surprisingly, no parameter differed between the populations of stall-fed S. s. leucomystax and wild S. s. riukiuanus. Consumption of hard nuts and/or agricultural fruits and crops by the wild population of S. s. riukiuanus may have produced a tooth surface texture similar to that of the stall-fed population of S. s. leucomystax. Further analysis of S. s. riukiuanus with a known diet is necessary to conclude whether ISO parameters reflect the dietary transition accompanying the domestication of Sus (e.g., wild, semi-domestic, and domestic). Until then, caution is needed in discriminating domesticated populations from wild populations that mainly feed on hard objects. [ABSTRACT FROM AUTHOR]

Background: Genetic programming (GP) is an evolutionary computing methodology capable of identifying complex, non-linear patterns in large data sets. Despite the potential advantages of GP over more typical, frequentist statistical approach methods, its applications to survival analyses are rare, at best. The aim of this study was to determine the utility of GP for the automatic development of clinical prediction models. Methods: We compared GP against the commonly used Cox regression technique in terms of the development and performance of a cardiovascular risk score using data from the SMART study, a prospective cohort study of patients with symptomatic cardiovascular disease. The composite endpoint was cardiovascular death, non-fatal stroke, and myocardial infarction. A total of 3,873 patients aged 19–82 years were enrolled in the study 1996–2006. The cohort was split 70:30 into derivation and validation sets. The derivation set was used for development of both GP and Cox regression models. These models were then used to predict the discrete hazards at t = 1, 3, and 5 years. The predictive ability of both models was evaluated in terms of their risk discrimination and calibration using the validation set. Results: The discrimination of both models was comparable. At time points t = 1, 3, and 5 years the C-index was 0.59, 0.69, 0.64 and 0.66, 0.70, 0.70 for the GP and Cox regression models respectively. At the same time points, the calibration of both models, which was assessed using calibration plots and the generalization of the Hosmer-Lemeshow test statistic, was also comparable, but with the Cox model being better calibrated to the validation data. Conclusion: Using empirical data, we demonstrated that a prediction model developed automatically by GP has predictive ability comparable to that of manually tuned Cox regression. The GP model was more complex, but it was developed in a fully automated way and comprised fewer covariates. Furthermore, it did not require the expertise normally needed for its derivation, thereby alleviating the knowledge elicitation bottleneck. Overall, GP demonstrated considerable potential as a method for the automated development of clinical prediction models for diagnostic and prognostic purposes. [ABSTRACT FROM AUTHOR]

International Guidelines for mineral bone disorders recommend that in Non Dialytic-Chronic Kidney Disease (ND-CKD) clinical decisions should be based on the trend of serum PTH changes over time rather than on a single value. However, the prognostic impact of these changes in ND-CKD patients remains unknown. We performed a multicenter cohort study in ND-CKD patients (stage 1–5) followed for 36 months in 24 Italian Nephrology Units. PTH changes (ΔPTH) were defined as the absolute differences between all available PTH measurements following the first control and basal value. Primary endpoint in this subanalysis was renal death (End-Stage Renal Disease (ESRD) or all-causes death before ESRD). Association between renal death and ΔPTH was assessed by time-dependent Cox model for repeated measurements. Out of the original cohort (N = 884), we selected 543 patients (66.3±15.4 ys, 58.4% males) with at least two serum PTH measurements. At baseline, eGFR was 36 (IQR: 22.4–56.8) mL/min/1.73m2 and serum PTH 46 (IQR: 28–81) pg/mL. ΔPTH was in median 0 (IQR:-18/18) pg/mL. Basal predictors of longitudinal PTH increments were higher serum phosphate, more advanced CKD stages and lower serum PTH. Fully adjusted Cox model with ΔPTH quartiles as discrete time-dependent covariate showed a significant risk of renal death in the highest quartile (HR: 1.91; 95%CI:1.08–3.38; P = 0.026). Considering ΔPTH as continuous time-dependent variable, (HR:1.02; 95%C.I.: 1.01–1.04; P = 0.004), risk of renal death progressively rose as ΔPTH increased. An increment in serum PTH over time is associated with a worse prognosis in ND-CKD patients, independently from baseline or any absolute concentration of serum PTH and phosphate. [ABSTRACT FROM AUTHOR]