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Context: Whether a healthy lifestyle may be associated with longer telomere length is largely unknown. Objectives: To examine healthy lifestyle practices, which are primary prevention measures against major age-related chronic diseases, in relation to leukocyte telomere length. Design and Setting: Cross-sectional analysis in the Nurses' Health Study (NHS). Participants: The population consisted of 5,862 women who participated in multiple prospective case-control studies within the NHS cohort. Z scores of leukocyte telomere length were derived within each case-control study. Based on prior work, we defined low-risk or healthy categories for five major modifiable factors assessed in 1988 or 1990: non-current smoking, maintaining a healthy body weight (body mass index in 18.5-24.9 kg/m²), engaging in regular moderate or vigorous physical activities (≥150 minutes/week), drinking alcohol in moderation (1 drink/week to <2 drinks/day), and eating a healthy diet (Alternate Healthy Eating Index score in top 50%). We calculated difference (%) of the z scores contrasting low-risk groups with reference groups to evaluate the association of interest. Results: Although none of the individual low-risk factors was significantly associated with larger leukocyte telomere length z scores, we observed a significant, positive relationship between the number of low-risk factors and the z scores. In comparison with women who had zero low-risk factors (1.9% of the total population) and were, therefore, considered the least healthy group, the leukocyte telomere length z scores were 16.4%, 22.1%, 28.7%, 22.6%, and 31.2% (P for trend = 0.015) higher for women who had 1 to 5 low-risk factors, respectively. Conclusions: Adherence to a healthy lifestyle, defined by major modifiable risk factors, was associated with longer telomere length in leukocytes. [ABSTRACT FROM AUTHOR]

For a fixed amount of time engaged in physical activity, activity choice may affect body weight differently depending partly on other activities’ displacement. Typical models used to evaluate effects of physical activity on body weight do not directly address these substitutions. An isotemporal substitution paradigm was developed as a new analytic model to study the time-substitution effects of one activity for another. In 1991–1997, the authors longitudinally examined the associations of discretionary physical activities, with varying activity displacements, with 6-year weight loss maintenance among 4,558 healthy, premenopausal US women who had previously lost >5% of their weight. Results of isotemporal substitution models indicated widely heterogeneous relations with each physical activity type (P < 0.001) depending on the displaced activities. Notably, whereas 30 minutes/day of brisk walking substituted for 30 minutes/day of jogging/running was associated with weight increase (1.57 kg, 95% confidence interval: 0.33, 2.82), brisk walking was associated with lower weight when substituted for slow walking (−1.14 kg, 95% confidence interval: −1.75, −0.53) and with even lower weight when substituted for TV watching. Similar heterogeneous relations with weight change were found for each activity type (TV watching, slow walking, brisk walking, jogging/running) when displaced by other activities across these various models. The isotemporal substitution paradigm may offer new insights for future public health recommendations [ABSTRACT FROM AUTHOR]

Background: Merkel cell carcinoma (MCC) is a rare and highly aggressive form of skin cancer. However, there is limited research on the clinicopathological features of early-onset MCC (EOMCC) and the differences between EOMCC and late-onset MCC (LOMCC). Our objective was to evaluate the clinicopathological features and cancer-specific survival (CSS) of EOMCC., Methods: Our cohort study analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database from January 1, 2018, to December 31, 2020. Data from 1941 patients who were diagnosed with primary cutaneous MCC were included. We then divided the patients with MCC into two groups: those with EOMCC (526 patients) and those with LOMCC (1415 patients). CSS is used as the primary outcome., Results: The EOMCC group exhibited trends toward advanced tumor progression, an expanded surgical scope, increased lymph node retrieval, intensified radiotherapy, greater utilization of systemic therapy, and a better prognosis. Multivariate analysis revealed that LOMCC (HR 3.305 [2.002-5.456], P < 0.001), advanced T stage (HR 1.430 [1.139-1.797], P = 0.002), advanced N stage (HR 1.522 [1.221-1.897], P < 0.001), M1 stage (HR 2.587 [1.480-4.521], P < 0.001), and radiation (HR 0.586 [0.410-0.837], P = 0.003) were significantly associated with CSS. Among these factors, EOMCC/LOMCC was most strongly associated with CSS, indicating that LOMCC is an independent risk factor for CSS. Interestingly, we found that regional EOMCC and localized or in situ LOMCC had almost completely overlapping survival curves (P log-rank  = 0.620). Additionally, we observed that the TNM staging + age model was a more accurate predictor of CSS among MCC patients than using TNM staging alone., Conclusions: We found that EOMCC has distinct clinicopathological features compared to LOMCC. EOMCC is associated with better CSS. The combination of TNM staging and age was more accurate for predicting patient outcomes than TNM staging alone., (© 2024 the International Society of Dermatology.)

Background: Advance Care Planning via Group Visits (ACP-GV) is a patient-centered intervention facilitated by a clinician using a group modality to promote healthcare decision-making among veterans. Participants in the group document a "Next Step" to use in planning for their future care needs. The next step may include documentation of preferences in an advance directive, discussing plans with family, or anything else to fulfill their ACP needs. This evaluation seeks to determine whether there are identifiable subgroups of group participants with differing needs prior to delivery of the ACP-GV program and, if so, to use information about the subgroups to enhance the program offered to veterans in United States Department of Veterans Affairs (VA) healthcare settings., Methods: We conducted a secondary analysis of national data from a quality improvement evaluation. Patient- and provider-level data from administrative healthcare records for VA users in all 50 states, territories, and the District of Columbia provides data on veterans attending ACP-GV during federal fiscal years 2018-2022 (N = 26,857). Latent class analysis seeks to identify the various subgroups of veterans based on their level of ACP self-efficacy before attending ACP-GV and any demographic differences across the resulting subgroups of veterans attending ACP-GV. ACP self-efficacy is derived from seven items obtained from a participant worksheet used during the group., Results: Analysis revealed two distinct groups of veterans, distinguishable by their pre-ACP-GV levels of one aspect of ACP self-efficacy: prior knowledge of ACP. Veterans with higher prior knowledge of ACP are associated with an identified next step focused on checking their current AD status and updating it, and veterans with lower ACP prior knowledge are associated with identifying a next step to discuss ACP more fully with family. Differences in age, sex, race, ethnicity, and marital status exist across subgroups of veterans., Conclusion: Greater attention must be paid to ACP and veterans' prior knowledge of ACP to consistently encourage annual review and status updates., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: The association between the Triglyceride-Glucose (TyG) Index and mortality rates in patients with cardiovascular disease (CVD) remains unclear. This study investigates the association between the TyG index and the incidence of all-cause and CVD-specific mortality among individuals with a history of CVD., Design: Population-based cohort study., Setting: Data were sourced from the US National Health and Nutrition Examination Survey (2007-2018) and linked mortality data, with follow-up continuing until 31 December 2019., Participants: The study population comprised 3422 individuals aged 20 years or older with a documented history of CVD., Outcome Measures: We examined the association between the TyG index and the risk of all-cause and cardiovascular mortality., Results: Over a median follow-up of 5.79 years, 1030 deaths occurred, including 339 due to CVD. Cox regression analysis, adjusted for multiple confounders, showed that individuals in the highest TyG index quartile, compared with those in the lowest, had HRs of 0.76 (95% CI: 0.60 to 0.96) for all-cause mortality and 0.58 (95% CI: 0.39 to 0.89) for CVD mortality. There was a significant inverse relationship between higher TyG index levels and lower mortality risks. For each unit increase in the TyG index, the adjusted HRs for all-cause and CVD mortality decreased by 18% (HR 0.82; 95% CI: 0.71 to 0.94) and 27% (HR 0.73; 95% CI: 0.57 to 0.92), respectively., Conclusions: TyG index values are negatively associated with all-cause and CVD mortality risks among individuals with previous CVD. Further interventional studies are needed to clarify the impact of TyG levels on cardiovascular health., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Although in vitro experiments have demonstrated the potential of flavonoid compounds in regulating blood pressure, there is still a lack of evidence from large population studies. We conducted a cross-sectional study using the National Health and Nutrition Examination Survey to investigate the relationship between flavonoid intake levels (natural log transformation) and hypertension events. A total of 15 752 participants aged over 20 years were included, and a weighted multivariable logistic regression analysis was performed to explore the relationship between total flavonoids, five sub types intake, and hypertension events. Smooth curve fitting was used to explore potential nonlinear relationships. Higher total flavonoids intake was associated with a lower risk of hypertension than the lowest group. The adjusted odds ratios (95% CIs) were 0.79 (0.70-0.88) for total flavonoids intake. Elevated total flavonoids intake levels were significantly and linearly associated with a lower risk of hypertension. For each unit increase in the total flavonoids intake level, the adjusted ORs for risk of hypertension decrease by 5% (OR 0.95; 95% CI, 0.92-0.98). In addition, in restricted cubic spline regression, we found that flavan-3-ols, anthocyanidins, and flavonols intake were linearly and negatively related to prevalence of hypertension. Flavones intake showed nonlinear associations with prevalence of hypertension with inflection points of -1.90. Within a certain range, a negative correlation exists between flavonoids intake and hypertension events. This finding provides insights into dietary modifications in the prevention of hypertension., (© 2024 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Background: Serum prostate-specific antigen (PSA) is a primary metric for diagnosis and prognosis of prostate cancer (PCa). Exposure to heavy metals, such as lead, cadmium, mercury, and zinc can impact PSA levels in PCa patients. However, it is unclear whether this effect also occurs in men without PCa, which may lead to the overdiagnosis of PCa., Method: Data on a total of 5089 American men who had never been diagnosed with PCa were obtained from the National Health and Nutrition Examination Survey performed from 2003-2010. The relationship between serum PSA levels (dependent variable) and concentrations of lead (μmol/L), cadmium (nmol/L), and mercury (μmol/L) were investigated with dietary zinc intake being used as a potential modifier or covariate in a weighted linear regression model and a generalized additive model. A series of bootstrapping analyses were performed to evaluate sensitivity and specificity using these models., Results: Regression analyses suggested that, in general, lead, cadmium, or mercury did not show an association with PSA levels, which was consistent with the results of the bootstrapping analyses. However, in a subgroup of participants with a high level of dietary zinc intake (≥14.12 mg/day), a significant positive association between cadmium and serum PSA was identified (1.06, 95% CI, P = 0.0268, P for interaction=0.0249)., Conclusions: With high-level zinc intake, serum PSA levels may rise in PCa-free men as the exposure to cadmium increases, leading to a potential risk of an overdiagnosis of PCa and unnecessary treatment. Therefore, environmental variables should be factored in the current diagnostic model for PCa that is solely based on PSA measurements. Different criteria for PSA screening are necessary based on geographical variables. Further investigations are needed to uncover the biological and biochemical relationship between zinc, cadmium, and serum PSA levels to more precisely diagnose PCa., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Hospitalized older adults spend as much as 95% of their time in bed, which can result in adverse events and delay recovery while increasing costs. Observational studies have shown that general mobility interventions (e.g., ambulation) can mitigate adverse events and improve patients' functional status. Mobility technicians (MTs) may address the need for patients to engage in mobility interventions without overburdening nurses. There is no data, however, on the effect of MT-assisted ambulation on adverse events or functional status, or on the cost tradeoffs if a MT were employed. The AMBULATE study aims to determine whether MT-assisted ambulation improves mobility status and decreases adverse events for older medical inpatients. It will also include analyses to identify the patients that benefit most from MT-assisted mobility and assess the cost-effectiveness of employing a MT., Methods: The AMBULATE study is a multicenter, single-blind, parallel control design, individual-level randomized trial. It will include patients admitted to a medical service in five hospitals in two regions of the USA. Patients over age 65 with mild functional deficits will be randomized using a block randomization scheme. Those in the intervention group will ambulate with the MT up to three times daily, guided by the Johns Hopkins Mobility Goal Calculator. The intervention will conclude at hospital discharge, or after 10 days if the hospitalization is prolonged. The primary outcome is the Short Physical Performance Battery score at discharge. Secondary outcomes are discharge disposition, length of stay, hospital-acquired complications (falls, venous thromboembolism, pressure ulcers, and hospital-acquired pneumonia), and post-hospital functional status., Discussion: While functional decline in the hospital is multifactorial, ambulation is a modifiable factor for many patients. The AMBULATE study will be the largest randomized controlled trial to test the clinical effects of dedicating a single care team member to facilitating mobility for older hospitalized patients. It will also provide a useful estimation of cost implications to help hospital administrators assess the feasibility and utility of employing MTs., Trial Registration: Registered in the United States National Library of Medicine clinicaltrials.gov (# NCT05725928). February 13, 2023., (© 2023. The Author(s).)

Background: Isolated diastolic hypertension (IDH) is recognized as a risk factor for cardiovascular disease, yet its clinical epidemiology remains poorly understood due to insufficient recognition. This study aims to describe the trend in the prevalence, awareness, and treatment of IDH in the United States from 2001 to 2018., Methods: This cross-sectional study utilized data from the National Health and Nutrition Examination Survey (NHANES) conducted in nine consecutive two-year cycles from 2001-2002 to 2017-2018, comprising a sample of 48,742 adults aged over 18 years. IDH was defined as a diastolic blood pressure ≥ 80 mm Hg with a systolic BP < 130 mm Hg by the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines., Results: In the nationally representative dataset, 8.9% of participants had IDH in 2017-2018, a decreased of 3.6% (95% confidence interval [CI], -2.6% to -5.0%, P<0.0002) since 2001-2002. IDH prevalence was highest among Mexican American (10.5%), individuals aged 40-59 (12.3%), increased with body mass index (BMI) (11.2% among those BMI ≥30.0 kg/m 2 ), and tended to be higher in men (12.3%). A multiple regression analysis showed that men, white race/ethnicity, young and middle-aged people (aged 18-59), and increasing BMI were independently associated with increased risks of IDH. Among IDH patients, there was a modest increase in awareness (P<0.0002), from 22.4% (95%CI, 18.4% to 27.1%) in 2001-2002 to 35.0% (95%CI, 28.2% to 42.5%) in 2017-2018, with the largest percentage increases among non-Hispanic white and men. IDH treatment increased by 7.6% (95%CI, 3.1% to 12.1%) between 2001-2002 and 2017-2018, with the greatest increases occurring in Mexican American and men., Conclusion: IDH prevalence is decreasing from 2001-2002 to 2017-2018 in the United States. Despite the significantly increased in both awareness and treatment, they remain below 50%., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: Intracerebral haemorrhage (ICH) is the most devastating form of stroke causing high morbidity and mortality. We aimed to develop a novel clinical score incorporating multisystem markers to predict functional dependence at 90 days after ICH., Methods: We analysed data from Chinese Cerebral Hemorrhage: Mechanism and Intervention study. Multivariable logistic regression analysis was used to identify the factors associated with 90-day functional dependency (the modified Rankin Scale ≥3) after ICH and develop the ADVISING scoring system. To test the scoring system, a total of 2111 patients from Hubei province were included as the training cohort, and 733 patients from other three provinces in China were included as an external validation cohort., Results: We found nine variables to be significantly associated with functional dependency and included in the ADVISING score system: age, deep location of haematoma, volume of haematoma, National Institutes of Health Stroke Scale, aspartate transaminase, international normalised ratio, neutrophil-lymphocyte ratio, fasting blood glucose and glomerular filtration rate. Individuals were divided into 12 different categories by using these nine potential predictors. The proportion of patients who were functionally dependent increased with higher ADVISING scores, which showed good discrimination and calibration in both the training cohort (C-statistic, 0.866; p value of Hosmer-Lemeshow test, 0.195) and validation cohort (C-statistic, 0.884; p value of Hosmer-Lemeshow test, 0.853). The ADVISING score also showed better discriminative performance compared with the other five existing ICH scores (p<0.001)., Conclusions: ADVISING score is a reliable tool to predict functional dependency at 90 days after ICH., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Joint arthroplasties are among the most commonly performed elective surgeries in the United States. Surgical outcomes are known to improve with volume but it is unclear whether this has led to consolidation among elective surgeries. We examined trends in volumes per surgeon and hospital to assess whether the known volume-outcome relationship has led to consolidation in elective joint arthroplasty and to determine if there exist volume thresholds above which outcomes do not change., Methods: Among Medicare beneficiaries who underwent either total knee or total hip arthroplasty from 2009 through 2015, we described volume trends and used mixed-effect models to relate annual surgeon and hospital volumes with 30-day complications or mortality. We tested for optimal volume cut points at both the hospital and surgeon level., Results: Adjusted annual complication rates were inversely associated with volume for both procedures at both the surgeon level and hospital level, but there was minimal consolidation between 2009 and 2015. Complications no longer declined after volumes of each case exceeded 260 per year. The vast majority of cases (around 93% of hip and 88% of knee arthroplasties) were performed by surgeons operating at suboptimal volumes., Conclusion: More than 2 decades after the volume-outcome relationship was established for joint arthroplasty, many cases continue to be performed by low-volume surgeons, with far more cases performed by surgeons operating at suboptimal volumes. Further improvement could be expected through consolidation at both the hospital and surgeon level, with a target of at least 260 cases per surgeon annually for each operation. Payers seem best-equipped to drive consolidation., (Copyright © 2022 Elsevier Inc. All rights reserved.)

(1) Background: Increasing evidence indicates that lipid metabolism may influence the concentration of prostate-specific antigen (PSA). However, the association between triglycerides and PSA remains unclear and complicated. Hence, we evaluated the correlation between triglycerides and PSA based on the U.S. National Health and Nutrition Examination Survey (NHANES) database. (2) Methods: A total of 2910 participants out of 41,156 participants fit into our study after conducting the screening from the 2003 to 2010 NHANES survey. Serum triglycerides were the independent variable of our study, and PSA was the dependent variable; (3) Results: In our study, the average age of chosen participants was 59.7 years (±12.7). After adjusting for covariates, the result indicated that for each additional unit of serum triglyceride (mg/dL), the PSA concentrations were reduced by 0.0043 ng/mL (-0.0082, -0.0005) with a statistical difference. Furthermore, we used machine learning of the XGBoost model to determine the relative importance of selected variables as well as constructed a smooth curve based on the fully adjusted model to investigate the possible linear relationship between the triglyceride and PSA concentrations. (4) Conclusions: The serum triglyceride is independently and negatively correlated with PSA among American males, which may make it hard to detect asymptomatic prostate cancer and diagnose at an advance stage with higher triglycerides due to detection bias.

Purpose: Studies have supported the use of packaging interventions such as pillboxes or blister packs to improve medication adherence but have not evaluated the efficacy of these interventions in a population of low socioeconomic status. The aim of this study was to assess the effect of home-delivered pill packs on medication adherence in a low-income Black American population with Medicaid insurance., Methods: This study was an open-label, randomized, controlled trial. The patient population studied included 80 patients followed by primary care physicians at the Cleveland Clinic. Patients were randomized to a study group who received delivery of their multidrug medical therapy, defined as a minimum of 4 medications daily, in prepackaged blisters or a control group who obtained their prescriptions from their routine pharmacy., Results: The primary analysis compared the mean percentage of missed pills between the 2 groups using t-test analysis. The percentage of missed pills in the study group was significantly lower than in the control group (mean [SD]: 3.7% [6.0%] vs 17.4% [16.6%] missed daily pills; P < 0.001). The number of daily missed doses was also significantly lower in the study group (0.3 [0.5] vs 0.7 [0.6]; P = 0.002). Patients were on a mean of 8.1 (SD, 2.3) and 8.1 (SD, 2.6) medications in the study and control groups, respectively (P = 0.96)., Conclusion: Delivery of prepackaged medications in a low-income Black American community was demonstrated to improve medication adherence. The use of prepackaged blisters for medication home delivery is a model that can be utilized on a larger scale for patients on multidrug medical therapy., (© American Society of Health-System Pharmacists 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Over one third of American adults are at high risk for developing diabetes, which can be delayed or prevented using interventions such as medical nutrition therapy (MNT) or metformin. Physicians' self-reported rates of prediabetes treatment are improving, but patterns of actual referral, prescription, and MNT visits are unknown., Objective: To characterize treatment of prediabetes in primary care., Design: We conducted a retrospective cohort study using electronic health record data. We described patterns of treatment and used multivariable logistic regression to evaluate the association of patient factors and PCP-specific treatment rate with patient treatment., Patients: We included overweight or obese outpatients who had a first prediabetes-range hemoglobin A1c (HbA1c) during 2011-2018 and had primary care provider (PCP) follow-up within a year., Main Measures: We collected patient characteristics and the following treatments: metformin prescription; referral to MNT, diabetes education, endocrinology, or bariatric medicine; and MNT visit. We did not capture within-visit physician counseling., Key Results: Of 16,713 outpatients with prediabetes, 20.4% received treatment, including metformin prescriptions (7.8%) and MNT referrals (11.3%), but only 7.4% of referred patients completed a MNT visit. The strongest predictor of treatment was the patient's PCP's treatment rate. Some PCPs never treated prediabetes, but two treated more than half of their patients; 62% had no patients complete a MNT visit. Being younger or female and having higher body mass index or HbA1c were also positively associated with treatment. Compared to white patients, black patients were more likely to receive MNT referral and less likely to receive metformin., Conclusions: Almost 80% of patients with new prediabetes never received treatment, and those who did receive referrals had very poor visit completion. Treatment rates appear to reflect provider rather than patient preferences.

Chronic graft-versus-host disease (cGVHD) remains a common threat after allogeneic hematopoietic cell transplantation (allo-HSCT), and ocular manifestations occur in up to 60% to 90% of cGVHD patients. We sought to reveal major metabolic dysregulation and to determine tear metabolites as potential biomarkers for ocular cGVHD. Twenty-three ocular cGVHD and 16 control tear samples were collected for this study. Differential metabolites were identified using a liquid chromatography-mass spectrometry system. Spearman's test was used to analyze the correlation between metabolites and ophthalmic indexes (National Institutes of Health [NIH] eye score, fluorescein tear film break-up time [T-BUT], corneal fluorescein staining [CFS], and Schirmer's test). Receiver operating characteristic (ROC) curve was analyzed to evaluate the prediction potential of identified metabolites for ocular cGVHD. Differential metabolites were mainly observed in lipid metabolites, and we highlighted the lipid dysregulation in glycerophospholipid metabolism, sphingolipid metabolism, and biosynthesis of unsaturated fatty acids. In glycerophospholipid metabolism, phosphatidylcholine (34:1) (PC [34:1]) exhibited the strongest correlation with NIH eye score (r = 0.80), T-BUT (r = 0.79), CFS (r = 0.77), and Schirmer's test (r = 0.69). In sphingolipid metabolism, sphingomyelin (SM) was the most consistent with T-BUT (r = 0.74) and CFS (r = 0.71), whereas lactosylceramide (LacCer) was the most consistent with NIH eye score (r = 0.76) and Schirmer's test (r = 0.64). In biosynthesis of unsaturated fatty acids, docosahexaenoic acid (DHA) had the highest correlation with NIH eye score (r = 0.73), T-BUT (r = 0.60), CFS (r = 0.67) and Schirmer's test (r = 0.67) (P < .0001 for all). ROC analysis revealed that area under the curve (AUC) values for PC (34:1) (AUC = 0.967), LacCer (AUC = 0.946), SM (AUC = 0.932), and DHA (AUC = 0.929) were significantly correlated with cGVHD (P < .0001 for all). Our study identified PC (34:1), SM, LacCer, and DHA as promising tear biomarkers to indicate metabolic dysregulation and ophthalmic manifestations in ocular cGVHD., (Copyright © 2020 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Kinase inhibitors (KIs) represent an important class of anti-cancer drugs. Although cardiotoxicity is a serious adverse event associated with several KIs, the reasons remain poorly understood, and its prediction remains challenging. We obtain transcriptional profiles of human heart-derived primary cardiomyocyte like cell lines treated with a panel of 26 FDA-approved KIs and classify their effects on subcellular pathways and processes. Individual cardiotoxicity patient reports for these KIs, obtained from the FDA Adverse Event Reporting System, are used to compute relative risk scores. These are then combined with the cell line-derived transcriptomic datasets through elastic net regression analysis to identify a gene signature that can predict risk of cardiotoxicity. We also identify relationships between cardiotoxicity risk and structural/binding profiles of individual KIs. We conclude that acute transcriptomic changes in cell-based assays combined with drug substructures are predictive of KI-induced cardiotoxicity risk, and that they can be informative for future drug discovery.

Background: Existing imaging techniques have a low ability to detect lymph node metastasis (LNM) of gallbladder cancer (GBC). Gallbladder removal by laparoscopic cholecystectomy can provide pathological information regarding the tumor itself for incidental gallbladder cancer (IGBC). The purpose of this study was to identify the risk factors associated with LNM of IGBC and to establish a nomogram to improve the ability to predict the risk of LNM for IGBC., Methods: A total of 796 patients diagnosed with stage T1/2 GBC between 2004 and 2015 who underwent surgery and lymph node evaluation were enrolled in this study. We randomly divided the dataset into a training set (70%) and a validation set (30%). A logistic regression model was used to construct the nomogram in the training set and then was verified in the validation set. Nomogram performance was quantified with respect to discrimination and calibration., Results: The rates of LNM in T1a, T1b and T2 patients were 7, 11.1 and 44.3%, respectively. Tumor diameter, T stage, and tumor differentiation were independent factors affecting LNM. The C-index and AUC of the training set were 0.718 (95% CI, 0.676-0.760) and 0.702 (95% CI, 0.659-0.702), respectively, demonstrating good prediction performance. The calibration curves showed perfect agreement between the nomogram predictions and actual observations. Decision curve analysis showed that the LNM nomogram was clinically useful when the risk was decided at a possibility threshold of 2-63%. The C-index and AUC of the validation set were 0.73 (95% CI: 0.665-0.795) and 0.692 (95% CI: 0.625-0.759), respectively., Conclusion: The nomogram established in this study has good prediction ability. For patients with IGBC requiring re-resection, the model can effectively predict the risk of LNM and make up for the inaccuracy of imaging.

Background: Most patients with low-grade upper tract urothelial cancer are treated by radical nephroureterectomy. We aimed to assess the safety and activity of a non-surgical treatment using instillation of UGN-101, a mitomycin-containing reverse thermal gel., Methods: In this open-label, single-arm, phase 3 trial, participants were recruited from 24 academic sites in the USA and Israel. Patients (aged ≥18 years) with primary or recurrent biopsy-proven, low-grade upper tract urothelial cancer (measuring 5-15 mm in maximum diameter) and an Eastern Cooperative Oncology Group performance status score of less than 3 (Karnofsky Performance Status score >40) were registered to receive six instillations of once-weekly UGN-101 (mitomycin 4 mg per mL; dosed according to volume of patient's renal pelvis and calyces, maximum 60 mg per instillation) via retrograde catheter to the renal pelvis and calyces. All patients had a planned primary disease evaluation 4-6 weeks after the completion of initial therapy, in which the primary outcome of complete response was assessed, defined as negative 3-month ureteroscopic evaluation, negative cytology, and negative for-cause biopsy. Activity (complete response, expected to occur in >15% of patients) and safety were assessed by the investigator in all patients who received at least one dose of UGN-101. Data presented are from the data cutoff on May 22, 2019. This study is registered with ClinicalTrials.gov, NCT02793128., Findings: Between April 6, 2017, and Nov 26, 2018, 71 (96%) of 74 enrolled patients received at least one dose of UGN-101. 42 (59%, 95% CI 47-71; p<0·0001) patients had a complete response at the primary disease evaluation visit. The median follow-up for patients with a complete response was 11·0 months (IQR 5·1-12·4). The most frequently reported all-cause adverse events were ureteric stenosis in 31 (44%) of 71 patients, urinary tract infection in 23 (32%), haematuria in 22 (31%), flank pain in 21 (30%), and nausea in 17 (24%). 19 (27%) of 71 patients had study drug-related or procedure-related serious adverse events. No deaths were regarded as related to treatment., Interpretation: Primary chemoablation of low-grade upper tract urothelial cancer with intracavitary UGN-101 results in clinically significant disease eradication and might offer a kidney-sparing treatment alternative for these patients., Funding: UroGen Pharma., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background/aim: Episodes of non-severe hypoglycemia can be captured through diagnoses documented in the electronic medical record. We aimed to create a clinically useful prediction model for a severe hypoglycemia event, requiring an emergency department visit or hospitalization, in patients with Type 2 diabetes with a history of non-severe hypoglycemia., Methods: Using electronic medical record data from 50,439 patients with Type 2 diabetes in one health system, number of severe hypoglycemia events and associated patient characteristics from 2006 to 2015 were previously defined. Using the landmarking method, a dynamic prediction model was built using the subset of 1876 patients who had a documented non-severe hypoglycemia diagnosis code, using logistic regression to obtain landmark-specific odds of severe hypoglycemia in this group. For model performance, the bootstrap procedure was employed for internal validation and area under the curve (AUC) and index of prediction accuracy (IPA) were calculated., Results: Glycosylated hemoglobin (HbA1c) less than 7% (53 mmol/mol) was associated with increased odds ratio (OR) of severe hypoglycemia at 3 months (OR 1.92 95% Confidence Interval (CI) 1.19-3.10 at HbA1c 5% (31 mmol/mol) and OR 1.21, CI 1.03-1.41 at HbA1c 6%(42 mmol/mol).) History of non-severe hypoglycemia within the past 3 months increased odds for severe hypoglycemia (OR 2.58 95% CI 1.80-3.70) as did Black race, insulin use with the past 3 months, and comorbidities. Metformin and sulfonlylurea use in the past 3 months, increasing age and body mass index had lower odds of a future severe hypoglycemia event. For the prediction model for 3 month risk of severe hypoglycemia, the AUC was 0.890 (CI 0.843-0.907) and the IPA was 10.8% (CI 4.4% - 12.4%)., Conclusion: In patients with a documented diagnosis of non-severe hypoglycemia, a dynamic prediction model identifies patients with Type 2 diabetes with 3-month increased risk of severe hypoglycemia, allowing for preventive efforts, such as medication changes, at the point of care., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Objectives: Previous study has reported phosphorus intake is associated prostate cancer (PCa), but the association between phosphorus intake and serum prostate specific antigen (PSA) levels hasn't been reported in non-history of PCa population. Therefore, we performed a secondary data analysis based on existing data from the public Nutrition Examination Survey (NHANES) (2003-2010) database., Methods and Study Design: Totally 6403 participants were selected from NHANES (2003-2010) database. The interested independent and dependent variables were considered as dietary phosphorus intake and PSA level, respectively. Covariates included demographic data, dietary data, physical examination data, and comorbidities. Weighted linear regression and generalized additive models were used to addressing the linear and non-linear link of phosphorus intake to PSA level., Results: Linear association between phosphorus intake and PSA was not detected [β=0.016 (95% Confidence Interval (CI) -0.012, 0.045)]. But we found an existing nonlinearity. By the recursive algorithm, the inflection point was 1151 mg. On the left side of the inflection point, we did not find the correlation between dietary phosphorus intake (per 100 change) and PSA level [β=-0.04 (95% CI -0.11, 0.02), p=0.2155], while dietary phosphorus intake (per 100 change) positively associated with PSA [β=0.05 (95% CI 0.01, 0.09) p=0.0293] on the right side of inflection point., Conclusions: There is a non-linear correlation between dietary phosphorus intake and PSA. Dietary phosphorus intake was positively associated with increased PSA when dietary phosphorus intake is beyond 1151 mg after adjusting other covariates. Over 1151 mg per day dietary phosphorus intake may be the risk factor for PSA increasing.

Objectives: To identify factors associated with 30-day all-cause readmission rates in surgical patients discharged to skilled nursing facilities (SNFs), and derive and validate a risk score., Design: Retrospective cohort., Setting and Participants: Patients admitted to 1 tertiary hospital's surgical services between January 1, 2011, and December 31, 2014 and subsequently discharged to 110 SNFs within a 25-mile radius of the hospital. The first 2 years were used for the derivation set and the last 2 for validation., Methods: Data were collected on 30-day all cause readmissions, patient demographics, procedure and surgical service, comorbidities, laboratory tests, and prior health care utilization. Multivariate regression was used to identify risk factors for readmission., Results: During the study period, 2405 surgical patients were discharged to 110 SNFs, and 519 (21.6%) of these patients experienced readmission within 30 days. In a multivariable regression model, hospital length of stay [odds ratio (OR) per day: 1.03, 95% confidence interval (CI) 1.02-1.04], number of hospitalizations in past year (OR 1.24 per hospitalization, 95% CI 1.18-1.31), nonelective surgery (OR 1.33, 95% CI 1.18-1.65), low-risk service (orthopedic/spine service) (OR 0.32, 95% CI 0.25-0.42), and intermediate-risk service (cardiothoracic surgery/urology/gynecology/ear, nose, throat) (OR 0.69, 95% CI 0.53-0.88) were associated with all-cause readmissions. The model had a C index of 0.71 in the validation set. Using the following risk score [0.8 × (hospital length of stay) + 7 × (number of hospitalizations in past year) +10 for nonelective surgery, +36 for high-risk surgery, and +20 for intermediate-risk surgery], a score of >40 identified patients at high risk of 30-day readmission (35.8% vs 12.6%, P < .001)., Conclusions/implications: Among surgical patients discharged to an SNF, a simple risk score with 4 parameters can accurately predict the risk of 30-day readmission., (Copyright © 2019 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to compare the outcomes of thoracic endovascular aortic repair (TEVAR) without and with left subclavian artery (LSA) revascularization using the Nationwide Inpatient Sample (NIS) database., Methods: NIS records from 2005 to 2013 were retrospectively analyzed to identify patients undergoing TEVAR without and with LSA revascularization. Perioperative outcomes were compared between the two groups. The LSA revascularization group was further subdivided to compare perioperative outcomes if the revascularization was performed pre- or post-TEVAR or if the revascularization was performed open versus endovascular. Comparisons were examined using univariable analysis and multivariable logistic regression. Multivariable models were constructed using a forward selection approach with P < 0.05 required for model entry. Odds ratios are expressed per standard deviation change for continuous covariates. Continuous variables were compared between different groups using t-test, and categorical variables were compared using the chi-squared test. All statistical analyses were performed using R (cran.r-project.org)., Results: 7,773 TEVAR patients were included in this study. 6,411 (82.5%) were performed without and 1,362 (17.5%) with LSA revascularization. The rate of revascularization for LSA coverage during TEVAR doubled after the Society for Vascular Surgery Guidelines recommending revascularization were published in 2009. Groups were not significantly different in age (65.5 ± 15.8 and 66.1 ± 14.4 years old, respectively), gender, or race. Multivariable analysis showed that although rates of spinal cord ischemia and upper extremity ischemia were similar, perioperative cardiac complications (OR 1.5, 95% CI [1.2, 1.9], P = 0.025), stroke (OR 2.1, 95% CI [1.6, 2.8], P = 0.001), and pulmonary complications (OR 1.9, 95% CI [1.7, 2.3], P < 0.001) were significantly higher in the patients undergoing TEVAR with LSA revascularization than those without. Of the 1,362 patients with LSA revascularization, 1,251 (91.9%) were performed pre-TEVAR and 111 (8.1%) were performed post-TEVAR. Among the 1,251 patients with pre-TEVAR LSA revascularization, 583 had open surgery and 553 had stenting. In 115 patients, LSA revascularization was coded as both open and endovascular. Compared with pre-TEVAR revascularization, post-TEVAR revascularization was associated with higher risks of pulmonary complications and spinal cord ischemia. Endovascular LSA revascularization had lower pulmonary and stroke morbidity versus open LSA revascularization. The perioperative outcomes for the LSA revascularization subgroups are summarized., Conclusions: TEVAR with LSA revascularization is associated with significantly increased rates of perioperative stroke and cardiopulmonary complications. LSA revascularization before TEVAR, compared with post-TEVAR revascularization, had lower perioperative complications. In high-risk patients, endovascular LSA revascularization may be recommended over open surgery., (Published by Elsevier Inc.)

Background: The lack of evidence-based guidelines on the use of prophylactic inferior vena cava filters (IVCFs) in patients after trauma has led to variation of its application. We seek to understand the national trend of the use of prophylactic IVCF in trauma population., Methods: A retrospective review of the National Trauma Databank (2002-2014) was performed to identify patients who received an IVCF after trauma. Those without a preexisting venous thromboembolism or discharge diagnosis of VTE were classified as receiving prophylactic IVCF. Multivariable logistic regression analysis was used to examine associations between the use of prophylactic IVCF and risk factors for VTE. P value ≤0.05 was considered statistically significant., Results: Among the 2,189,994 patients evaluated, 41,155 (2%) received a prophylactic IVCF. The rate of overall IVCF placement (2.9% in 2002-2006 to 1.6% in 2014, P < 0.001) and prophylactic IVCF placement (2.5% in 2002-2006 to 1.2% in 2014, P < 0.001) decreased over the study period. In multivariable analysis, significant risk factors associated with the use of prophylactic IVCF were male gender (OR 1.2, 95% CI 1.1-1.2), African-American race (OR 1.2, 95% CI 1.1-1.2), injury severity score ≥ 24 (OR 4.4, 95% CI 4.2-4.5), Glasgow Coma Scale <8 (OR 1.4, 95% CI 1.4-1.5), spinal cord injury with paraplegia (OR 5.1, 95% CI 4.7-5.6), pelvic fracture (OR 2.9, 95% CI 2.7-3.0), long bone fracture (OR 1.3, 95% CI 1.3-1.4), and solid organ injury (OR 1.2, 95% CI 1.2-1.3) (P < 0.001). Patients who were treated at a level-II trauma center (OR 1.1, 95% CI 1.1-1.2, P < 0.001), at a facility with ≥200 beds (OR 1.3, 95% CI 1.2-1.4, P < 0.001), and those with medical insurance coverage (OR 1.4, 95% CI 1.6-1.8, P < 0.001) were also more likely to receive a prophylactic IVCF., Conclusions: The utilization of prophylactic IVCF in trauma patients has decreased over time between 2008 and 2014. Considerable variation exists in its use, which is not fully accounted for by the VTE rate. Further study is required to evaluate appropriate indications for placement of prophylactic IVCF in trauma patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: To review the contribution of the Nurses' Health Study (NHS) to our understanding of the complex relationship between exogenous hormones and health outcomes in women., Methods: We performed a narrative review of the publications of the NHS and NHS II from 1976 to 2016., Results: Oral contraceptive and postmenopausal hormone use were studied in relation to major health outcomes, including cardiovascular disease and cancer. Current or recent oral contraceptive use is associated with a higher risk of cardiovascular disease (mainly among smokers), melanoma, and breast cancer, and a lower risk of colorectal and ovarian cancer. Although hormone therapy is not indicated primarily for chronic disease prevention, findings from the NHS and a recent analysis of the Women's Health Initiative indicate that younger women who are closer to menopause onset have a more favorable risk-benefit profile than do older women from use of hormone therapy for relief of vasomotor symptoms., Conclusions: With updated information on hormone use, lifestyle factors, and other variables, the NHS and NHS II continue to contribute to our understanding of the complex relationship between exogenous hormones and health outcomes in women.

Importance: The prevalence and short-term outcomes of hypertensive urgency (systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg) are unknown. Guidelines recommend achieving blood pressure control within 24 to 48 hours. However, some patients are referred to the emergency department (ED) or directly admitted to the hospital, and whether hospital management is associated with better outcomes is unknown., Objectives: To describe the prevalence of hypertensive urgency and the characteristics and short-term outcomes of these patients, and to determine whether referral to the hospital is associated with better outcomes than outpatient management., Design, Setting, and Participants: This retrospective cohort study with propensity matching included all patients presenting with hypertensive urgency to an office in the Cleveland Clinic Healthcare system from January 1, 2008, to December 31, 2013. Pregnant women and patients referred to the hospital for symptoms or treatment of other conditions were excluded. Final follow-up was completed on June 30, 2014, and data were assessed from October 31, 2014, to May 31, 2015., Exposures: Hospital vs ambulatory blood pressure management., Main Outcomes and Measures: Major adverse cardiovascular events (MACE) consisting of acute coronary syndrome and stroke or transient ischemic attack, uncontrolled hypertension (≥140/90 mm Hg), and hospital admissions., Results: Of 2 199 019 unique patient office visits, 59 836 (4.6%) met the definition of hypertensive urgency. After excluding 851 patients, 58 535 were included. Mean (SD) age was 63.1 (15.4) years; 57.7% were women; and 76.0% were white. Mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) was 31.1 (7.6); mean (SD) systolic blood pressure, 182.5 (16.6) mm Hg; and mean (SD) diastolic blood pressure, 96.4 (15.8) mm Hg. In the propensity-matched analysis, the 852 patients sent home were compared with the 426 patients referred to the hospital, with no significant difference in MACE at 7 days (0 vs 2 [0.5%]; P = .11), 8 to 30 days (0 vs 2 [0.5%]; P = .11), or 6 months (8 [0.9%] vs 4 [0.9%]; P > .99). Patients sent home were more likely to have uncontrolled hypertension at 1 month (735 of 852 [86.3%] vs 349 of 426 [81.9%]; P = .04) but not at 6 months (393 of 608 [64.6%] vs 213 of 320 [66.6%]; P = .56). Patients sent home had lower hospital admission rates at 7 days (40 [4.7%] vs 35 [8.2%]; P = .01) and at 8 to 30 days (59 [6.9%] vs 48 [11.3%]; P = .009)., Conclusions and Relevance: Hypertensive urgency is common, but the rate of MACE in asymptomatic patients is very low. Visits to the ED were associated with more hospitalizations, but not improved outcomes. Most patients still had uncontrolled hypertension 6 months later.

Evaluation of time trends in dietary quality and their relation to disease burden provides essential feedback for policy making. We used an index titled the Alternate Healthy Eating Index 2010 to evaluate trends in dietary quality among 33,885 US adults. From 1999 to 2012 the index increased from 39.9 to 48.2 (perfect score = 110). Gaps in performance on the index across socioeconomic groups persisted or widened. Using data relating index scores to health outcomes in two large cohorts, we estimated that the improvements in dietary quality from 1999 to 2012 prevented 1.1 million premature deaths. Also, this improvement in diet quality resulted in 8.6 percent fewer cardiovascular disease cases, 1.3 percent fewer cancer cases, and 12.6 percent fewer type 2 diabetes cases. Although the steady improvement in dietary quality likely accounted for substantial reductions in disease burden from 1999 to 2012, overall dietary quality in the United States remains poor. Policy initiatives are needed to ensure further improvements., (Project HOPE—The People-to-People Health Foundation, Inc.)

Objective: The arteriovenous graft (AVG) is most often used in hemodialysis patients when an autogenous fistula is not feasible. The optimal location (forearm or upper arm) and configuration (loop or straight) of AVGs are not known. To evaluate relationships of AVG location and configuration with patency, we conducted a secondary analysis using data from a randomized, placebo-controlled trial of dipyridamole plus aspirin for newly placed AVG., Methods: Participants of the Dialysis Access Consortium (DAC) Graft Study with newly placed upper extremity prosthetic grafts involving the brachial artery were studied. Multivariable analyses adjusting for trial treatment group, center, gender, race, body mass index, diabetes, current treatment with chronic dialysis, and prior arteriovenous vascular access or central venous catheter were performed to compare outcomes of forearm (fAVG) and upper arm (uAVG) grafts, including loss of primary unassisted patency (LPUP) and cumulative primary graft failure (CGF). Subgroup analyses of graft configuration and outflow vein used were also conducted., Results: A total of 508 of the 649 participants (78%) enrolled in the trial had an upper extremity brachial artery graft placed, 255 with fAVG and 253 with uAVG. Participants with fAVG were less often male (33% vs 43%; P = .03), African American (62% vs 78%; P < .001), and receiving dialysis at the time of surgery (62% vs 80%; P < .001). Participants with fAVG had a higher mean body mass index (33 vs 29; P < .001). The LPUP (fAVG 70% vs uAVG 78%; P = .07) and CGF (33% vs 36%; P = .91) were similar between fAVG and uAVG at 1-year follow-up. In multivariable analysis, AVG location (uAVG vs fAVG) was not associated with LPUP (hazard ratio, 1.21; 95% confidence interval, 0.90-1.63; P = .20) or CGF (hazard ratio, 1.36; 95% confidence interval, 0.94-1.97; P = .10). LPUP did not differ significantly between fAVG and uAVG among subgroups based on AVG configuration (P = 1.00) or outflow vein used (P = .16)., Conclusions: Patency was comparable between fAVG and uAVG despite the larger caliber veins often encountered in the upper arm in carefully selected patients. Our findings support the traditional view that, in order to preserve a maximal number of access sites, the forearm location should be considered first before resorting to an upper arm graft., (Copyright © 2015 Society for Vascular Surgery. All rights reserved.)

Objectives: We investigated Black-White differences in the association between average alcohol drinking patterns and all-cause mortality., Methods: We pooled nationally representative samples of 152 180 adults in the National Health Interview Survey from 1997 to 2002 with mortality follow-up through 2006. Usual drinking days per week and level of alcohol consumed per day were based on self-report. We used race- and gender-specific Cox proportional hazards regression analyses to adjust for physical activity, smoking status, and other potential confounders., Results: Over 9 years, 13 366 deaths occurred from all causes. For men, the lowest multivariable-adjusted hazard ratio (HR) for total mortality among drinkers was 0.81 among White men who consumed 1 to 2 drinks 3 to 7 days per week (compared with abstainers) and Black men who abstained. For women, the lowest mortality risk was among White women (HR = 0.71) consuming 1 drink per day 3 to 7 days per week and Black women (HR = 0.72) consuming 1 drink on 2 or fewer days per week., Conclusions: Risks and benefits of alcohol consumption in relation to mortality risk were dependent on race- and gender-specific drinking patterns.

With the integration of electronic health records (EHRs), health data has become easily accessible and abounded. The EHR has the potential to provide important healthcare information to researchers by creating study cohorts. However, accessing this information comes with three major issues: 1) Predictor variables often change over time, 2) Patients have various lengths of follow up within the EHR, and 3) the size of the EHR data can be computationally challenging. Landmark analyses provide a perfect complement to EHR data and help to alleviate these three issues. We present two examples that utilize patient birthdays as landmark times for creating dynamic datasets for predicting clinical outcomes. The use of landmark times help to solve these three issues by incorporating information that changes over time, by creating unbiased reference points that are not related to a patient's exposure within the EHR, and reducing the size of a dataset compared to true time-varying analysis. These techniques are shown using two example cohort studies from the Cleveland Clinic that utilized 4.5 million and 17,787 unique patients, respectively.

Purpose: Long-standing diabetes is a risk factor for pancreatic cancer, and recent-onset diabetes in the several years before diagnosis is a consequence of subclinical pancreatic malignancy. However, the impact of diabetes on survival is largely unknown., Patients and Methods: We analyzed survival by diabetes status among 1,006 patients diagnosed from 1986 to 2010 from two prospective cohort studies: the Nurses' Health Study (NHS) and Health Professionals Follow-Up Study (HPFS). We validated our results among 386 patients diagnosed from 2004 to 2013 from a clinic-based case series at Dana-Farber Cancer Institute (DFCI). We estimated hazard ratios (HRs) for death using Cox proportional hazards models, with adjustment for age, sex, race/ethnicity, smoking, diagnosis year, and cancer stage., Results: In NHS and HPFS, HR for death was 1.40 (95% CI, 1.15 to 1.69) for patients with long-term diabetes (> 4 years) compared with those without diabetes (P < .001), with median survival times of 3 months for long-term diabetics and 5 months for nondiabetics. Adjustment for a propensity score to reduce confounding by comorbidities did not change the results. Among DFCI patient cases, HR for death was 1.53 (95% CI, 1.07 to 2.20) for those with long-term diabetes compared with those without diabetes (P = .02), with median survival times of 9 months for long-term diabetics and 13 months for nondiabetics. Compared with nondiabetics, survival times were shorter for long-term diabetics who used oral hypoglycemics or insulin. We observed no statistically significant association of recent-onset diabetes (< 4 years) with survival., Conclusion: Long-standing diabetes was associated with statistically significantly decreased survival among patients with pancreatic cancer enrolled onto three longitudinal studies., (© 2014 by American Society of Clinical Oncology.)

Context: Statistical methods to identify symptom clusters (SC) have varied between studies. The optimal statistical method to identify SC is unknown., Objectives: Our primary objective was to explore whether eight different statistical techniques applied to a single data set produced different SC. A secondary objective was to investigate whether SC identified by these techniques resembled those from our original study., Methods: We reanalyzed a symptom data set of 1000 patients with advanced cancer. Eight separate cluster analyses were conducted on both prevalence and severity of 38 symptoms. Hierarchical cluster analysis identified clusters at r-values of 0.6, 0.5, and 0.4. For prevalence and severity, the Spearman correlation and Kendall tau-b correlation, respectively, measured the similarity (distance) between symptom pairs. Sensitivity analysis of the prevalence data was done with Cohen kappa coefficient as a similarity measure. The K-means clustering method validated clusters., Results: Hierarchical cluster analysis identified similar cluster configurations from the 38 symptoms using an r-value of 0.6, 0.5, or 0.4. A cutoff point of 0.6 yielded seven clusters. Five of them were identical at all three r-values used: (1) fatigue/anorexia-cachexia: anorexia, dry mouth, early satiety, fatigue, lack of energy, taste changes, weakness, and weight loss (>10%); (2) gastrointestinal: belching, bloating, dyspepsia, and hiccough; (3) nausea/vomiting: nausea and vomiting; (4) aerodigestive: cough, dysphagia, dyspnea, hoarseness, and wheeze; (5) neurologic: confusion, hallucinations, and memory problems. Regardless of the threshold, there were always some symptoms (e.g., pain) that did not cluster with any others. Seven clusters were validated by K-means analysis., Conclusion: Seven SC identified from both prevalence and severity data were consistently present irrespective of the statistical analysis used. There were only minor variations in the number of clusters and their symptom composition between analytical techniques. All seven clusters originally identified were confirmed. Four consistent SC were found in all analyses: aerodigestive, fatigue/anorexia-cachexia, nausea/vomiting, and upper GI. Our results support the clinical importance of the SC concept., (Published by Elsevier Inc.)

Background: Defensive medicine represents one cause of economic losses in healthcare. Studies that measured its cost have produced conflicting results., Objective: To directly measure the proportion of primary care costs attributable to defensive medicine., Research Design and Methods: Six-week prospective study of primary care physicians from four outpatient practices. On 3 distinct days, participants were asked to rate each order placed the day before on the extent to which it represented defensive medicine, using a 5-point scale from 0 (not at all defensive) to 4 (entirely defensive)., Main Outcome Measures: This study calculated the order defensiveness score for each order (the defensiveness/4) and the physician defensive score (the mean of all orders defensiveness scores). Each order was assigned a weighted cost by multiplying the total cost of that order (based on Medicare reimbursement rates) by the order defensiveness score. The proportion of total cost attributable to defensive medicine was calculated by dividing the weighted cost of defensive orders by the total cost of all orders., Results: Of 50 eligible physicians, 23 agreed to participate; 21 returned the surveys and rated 1234 individual orders on 347 patients. Physicians wrote an average of 3.6 ± 1.0 orders/visit with an associated total cost of $72.60 ± 18.5 per order. Across physicians, the median physician defensive score was 0.018 (IQR = [0.008, 0.049]) and the proportion of costs attributable to defensive medicine was 3.1% (IQR = [0.5%, 7.2%]). Physicians with defensive scores above vs below the median had a similar number of orders and total costs per visit. Physicians were more likely to place defensive orders if trained in community hospitals vs academic centers (OR = 4.29; 95% CI = 1.55-11.86; p = 0.01)., Conclusions: This study describes a new method to directly quantify the cost of defensive medicine. Defensive medicine appears to have minimal impact on primary care costs.

We report the results of an International Nosocomial Infection Control Consortium (INICC) surveillance study from January 2007-December 2012 in 503 intensive care units (ICUs) in Latin America, Asia, Africa, and Europe. During the 6-year study using the Centers for Disease Control and Prevention's (CDC) U.S. National Healthcare Safety Network (NHSN) definitions for device-associated health care-associated infection (DA-HAI), we collected prospective data from 605,310 patients hospitalized in the INICC's ICUs for an aggregate of 3,338,396 days. Although device utilization in the INICC's ICUs was similar to that reported from ICUs in the U.S. in the CDC's NHSN, rates of device-associated nosocomial infection were higher in the ICUs of the INICC hospitals: the pooled rate of central line-associated bloodstream infection in the INICC's ICUs, 4.9 per 1,000 central line days, is nearly 5-fold higher than the 0.9 per 1,000 central line days reported from comparable U.S. ICUs. The overall rate of ventilator-associated pneumonia was also higher (16.8 vs 1.1 per 1,000 ventilator days) as was the rate of catheter-associated urinary tract infection (5.5 vs 1.3 per 1,000 catheter days). Frequencies of resistance of Pseudomonas isolates to amikacin (42.8% vs 10%) and imipenem (42.4% vs 26.1%) and Klebsiella pneumoniae isolates to ceftazidime (71.2% vs 28.8%) and imipenem (19.6% vs 12.8%) were also higher in the INICC's ICUs compared with the ICUs of the CDC's NHSN., (Copyright © 2014 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Mosby, Inc. All rights reserved.)

Background: The prognostic significance of venous involvement and tumour thrombus level in renal cell carcinoma (RCC) remains highly controversial. In 2010, the American Joint Committee on Cancer (AJCC) and the Union International Centre le Cancer (UICC) revised the RCC staging system (7th edition) based on tumour thrombus level, differentiating the T stage of tumours limited to renal-vein-only involvement., Objective: We aimed to evaluate the impact of tumour thrombus extension in a multi-institutional cohort of patients., Design, Setting, and Participants: An international consortium of 11 institutions was established to retrospectively review a combined cohort of 1215 patients undergoing radical nephrectomy and tumour thrombectomy for RCC, including 585 patients with inferior vena cava (IVC) involvement or higher., Measurements: Predictive factors of survival, including histology, tumour thrombus level, nodal status, Fuhrman grade, and tumour size, were analysed., Results and Limitations: A total of 1122 patients with complete data were reviewed. The median follow-up for all patients was 24.7 mo, with a median survival of 33.8 mo. The 5-yr survival was 43.2% (renal vein involvement), 37% (IVC below the diaphragm), and 22% with caval involvement above the diaphragm. On multivariate analysis, tumour size (hazard ratio [HR]: 1.64 [range: 1.03-2.59]; p=0.036), Fuhrman grade (HR: 2.26 [range: 1.65-3.1]; p=0.000), nodal metastasis (HR: 1.32 [range: 1.09-1.67]; p=0.005), and tumour thrombus level (HR: 2.10 [range: 1.53-3.0]; p=0.00) correlated independently with survival., Conclusions: Based on analysis of the largest known cohort of patients with RCC along with IVC and atrial thrombus involvement, tumour thrombus level is an independent predictor of survival. Our findings support the changes to the latest AJCC/UICC staging system., (Copyright © 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

A rice mini-core collection consisting of 217 accessions has been developed to represent the USDA core and whole collections that include 1,794 and 18,709 accessions, respectively. To improve the efficiency of mining valuable genes and broadening the genetic diversity in breeding, genetic structure and diversity were analyzed using both genotypic (128 molecular markers) and phenotypic (14 numerical traits) data. This mini-core had 13.5 alleles per locus, which is the most among the reported germplasm collections of rice. Similarly, polymorphic information content (PIC) value was 0.71 in the mini-core which is the highest with one exception. The high genetic diversity in the mini-core suggests there is a good possibility of mining genes of interest and selecting parents which will improve food production and quality. A model-based clustering analysis resulted in lowland rice including three groups, aus (39 accessions), indica (71) and their admixtures (5), upland rice including temperate japonica (32), tropical japonica (40), aromatic (6) and their admixtures (12) and wild rice (12) including glaberrima and four other species of Oryza. Group differentiation was analyzed using both genotypic distance Fst from 128 molecular markers and phenotypic (Mahalanobis) distance D(2) from 14 traits. Both dendrograms built by Fst and D(2) reached similar-differentiative relationship among these genetic groups, and the correlation coefficient showed high value 0.85 between Fst matrix and D(2) matrix. The information of genetic and phenotypic differentiation could be helpful for the association mapping of genes of interest. Analysis of genotypic and phenotypic diversity based on genetic structure would facilitate parent selection for broadening genetic base of modern rice cultivars via breeding effort.

Summary: Rapid advances in pharmaceutical sciences have brought ever-increasing interests in combined therapies for better clinical efficacy and safety, especially in cases of complicated and refractory diseases. Innovative experimental technologies and theoretical frameworks are being actively developed for multicomponent drug research. In this work, we present the Drug Combination Database, with aims to facilitate analyses of known drug combinations, to summarize patterns of beneficial drug interactions, and to provide a basis for theoretical modeling and simulation of such drug interactions. Its current version (1.0) collected 499 approved or investigational drug combinations, including 40 unsuccessful drug combinations, involving 485 individual drugs, from >6000 references.