Tumor Necrosis Factor Receptor-2 Signals Clear-Cell Renal Carcinoma Proliferation via Phosphorylated 4E Binding Protein-1 and Mitochondrial Gene Translation.

Clear-cell renal cell carcinoma (ccRCC), a tubular epithelial malignancy, secretes tumor necrosis factor (TNF), which signals ccRCC cells in an autocrine manner via two cell surface receptors, TNFR1 and TNFR2, to activate shared and distinct signaling pathways. Selective ligation of TNFR2 drives cell cycle entry of malignant cells via a signaling pathway involving epithelial tyrosine kinase, vascular endothelial cell growth factor receptor type 2, phosphatidylinositol-3-kinase, Akt, pSer727-Stat3, and mammalian target of rapamycin. In this study, phosphorylated 4E binding protein-1 (4EBP1) serine 65 (pSer65-4EBP1) was identified as a downstream target of this TNFR2 signaling pathway. pSer65-4EBP1 expression was significantly elevated relative to total 4EBP1 in ccRCC tissue compared with that in normal kidneys, with signal intensity increasing with malignant grade. Selective ligation of TNFR2 with the TNFR2-specific mutein increased pSer65-4EBP1 expression in organ cultures that co-localized with internalized TNFR2 in mitochondria and increased expression of mitochondrially encoded COX (cytochrome c oxidase subunit) Cox1, as well as nuclear-encoded Cox4/5b subunits. Pharmacologic inhibition of mammalian target of rapamycin reduced both TNFR2-specific mutein-mediated phosphorylation of 4EBP1 and cell cycle activation in tumor cells while increasing cell death. These results signify the importance of pSer65-4EBP1 in mediating TNFR2-driven cell-cycle entry in tumor cells in ccRCC and implicate a novel relationship between the TNFR2/pSer65-4EBP1/COX axis and mitochondrial function.

Long-term medication adherence and preventive vs reactive care utilization among older adults with diabetes.

OBJECTIVES: To assess long-term adherence to oral hypoglycemic agents (OHAs) and determine if adherence affects total health care expenditures of reactive vs preventive services. STUDY DESIGN: Retrospective cohort study. METHODS: This study measured adherence to OHAs using Medical Expenditure Panel Survey 2013-2017 data. Adults 65 years and older who had diabetes and were taking at least 1 OHA were included. Respondents with a medication possession ratio (MPR) of at least 80% were considered adherent. Health care utilization and expenditure were compared among adherent and nonadherent respondents for preventive and reactive services. Utilization data were analyzed using negative binomial regression and expenditure data using γ-family generalized linear regression models. RESULTS: Approximately 67% of the cohort (n = 1279) were adherent. The adherent group had greater health care expenditure overall than nonadherent respondents ($29,985 [95% CI, $27,161-$32,743] vs $24,623 [95% CI, $21,623-$28,122]; P < .05). Although expenditure was higher for prescription medications and office visits, mean emergency department expenditures were higher for adherent respondents. The utilization and proportion of expenditure on preventive vs reactive health care services did not differ by adherence as defined by an MPR of at least 80%. CONCLUSIONS: Increasing adherence provides an opportunity to improve CMS quality ratings. Our finding that adherence does not affect the financial burden of disease might be explained by the increased costs of preventive medication and increased comorbidity burden of these patients. Low adherence to OHAs encourages clinicians to be more proactive in ensuring that prescription medications are refilled regularly. By emphasizing equitable diabetes education and tailoring quality initiatives that minimize racial disparities, adherence can be better achieved.

Age Modifies Intracranial and Gastrointestinal Bleeding Risk from P2Y12 Inhibitors in Patients Receiving Dialysis.

Background: Individuals aged ≥75 years are the fastest-growing population starting dialysis for end-stage kidney disease (ESKD) due to living longer with coronary artery disease. ESKD alone can increase bleeding risk, but P2Y12 inhibitor (P2Y12-I) antiplatelet medications prescribed for cardiovascular treatment can exacerbate this risk in patients with ESKD. The age-specific rates of bleeding complications in dialysis patients with ESKD on P2Y12-I remain unclear, as does how age modifies the bleeding risk from P2Y12-I use in these patients. Methods: In a retrospective cohort study, we collected data on 40,972 patients receiving maintenance hemo- or peritoneal dialysis who were newly prescribed P2Y12-I therapy between 2011 and 2015 from the USRDS registry. We analyzed the effect of age on the time to first bleed and the interactions between age and P2Y12-I type on modifying the effects of a bleed. Results: Twenty percent of the cohort were aged ≥75 years. There were 3096 (8%) gastrointestinal (GI) and 1298 (3%) intracranial (IC) bleeding events during a median follow-up of 1 year. Annual incidence rates for IC bleeds were 2% in those aged <55 years and 3% in those aged ≥75 years. Rates for GI bleeds were 4% in those aged <55 years and 9% in those aged ≥75 years. On clopidogrel, prasugrel, and ticagrelor, for every decade increase in age of the cohort members, the risk of IC bleed increased by 9%, 55%, and 59%, and the risk of GI bleed increased by 21%, 28%, and 39%, respectively. At age ≥75 years, prasugrel was associated with a greater risk of IC bleed than clopidogrel. At age ≥60 years, ticagrelor was associated with a greater risk of GI bleed than clopidogrel. Conclusions: More potent P2Y12-Is (prasugrel and ticagrelor) were associated with a disproportionately higher risk of IC bleed with increasing age compared with that of clopidogrel-prasugrel was much worse than clopidogrel at age ≥75 years. All three drugs were associated with only modest increase in the risk of GI bleed with every decade increase in age-ticagrelor was much worse than clopidogrel at ≥60 years of age. These results highlight the need for head-to-head clinical trials for the use of P2Y12-Is in patients with ESKD to determine age cutoffs where the risk of bleeding outweighs the benefits of thrombosis prevention.

ID proteins promote the survival and primed-to-naive transition of human embryonic stem cells through TCF3-mediated transcription.

Inhibition of DNA binding proteins 1 and 3 (ID1 and ID3) are important downstream targets of BMP signalling that are necessary for embryonic development. However, their specific roles in regulating the pluripotency of human embryonic stem cells (hESCs) remain unclear. Here, we examined the roles of ID1 and ID3 in primed and naive-like hESCs and showed that ID1 and ID3 knockout lines (IDs KO) exhibited decreased survival in both primed and naive-like state. IDs KO lines in the primed state also tended to undergo pluripotent dissolution and ectodermal differentiation. IDs KO impeded the primed-to-naive transition (PNT) of hESCs, and overexpression of ID1 in primed hESCs promoted PNT. Furthermore, single-cell RNA sequencing demonstrated that ID1 and ID3 regulated the survival and pluripotency of hESCs through the AKT signalling pathway. Finally, we showed that TCF3 mediated transcriptional inhibition of MCL1 promotes AKT phosphorylation, which was confirmed by TCF3 knockdown in KO lines. Our study suggests that IDs/TCF3 acts through AKT signalling to promote survival and maintain pluripotency of both primed and naive-like hESCs.

Assessing coprescription of opioids with central nervous system depressants for nonmalignant chronic musculoskeletal pain management in the outpatient setting.

OBJECTIVES: To determine annual prescribing trends of opioids and coprescription of central nervous system (CNS) depressants in nonmalignant chronic musculoskeletal pain from the National Ambulatory Medical Care Survey (NAMCS). To determine patient and provider characteristics associated with coprescription opioids and CNS depressants. DESIGN: The cross-sectional study analyzed NAMCS data from 2014 to 2016. Pain medications and CNS depressants were determined using Multum drug classification categories. All 30 medication entries were scanned in order to capture the maximum number of entries compared to previous studies. Multivariate logistic regressions were used to determine characteristics associated with opioid and CNS depressant coprescribing. PARTICIPANTS: Adults (18 years and older) with nonmalignant chronic musculoskeletal pain diagnosis based on ICD-9 codes were identified as the reason for visit. RESULTS: A total of 47,973,413 weighted visits with nonmalignant chronic musculoskeletal pain were reported in the US ambulatory setting from 2014 to 2016. Amongst these patients, 31 percent were on opioids, of which 26 percent were also prescribed benzodiazepines, 8 percent NBSH, and 22 percent gabapentinoids. The annual prescribing rate of opioids decreased significantly in 2016 compared to 2014 (OR: 0.63, 95 percent CI: 0.43-0.94). Polypharmacy and tobacco use were associated with higher odds of having opioids and concurrent opioid with CNS depressants. CONCLUSION: Our study results are in agreement with previous studies that found a steady decline in opioid prescribing even with the inclusion of all 30 medications in our study. Likewise, as previous studies have found, certain patient characteristics continue to be significant for receiving opioid and CNS depressant prescriptions.

Coagulation factor V is a T-cell inhibitor expressed by leukocytes in COVID-19.

Clotting Factor V (FV) is primarily synthesized in the liver and when cleaved by thrombin forms pro-coagulant Factor Va (FVa). Using whole blood RNAseq and scRNAseq of peripheral blood mononuclear cells, we find that FV mRNA is expressed in leukocytes, and identify neutrophils, monocytes, and T regulatory cells as sources of increased FV in hospitalized patients with COVID-19. Proteomic analysis confirms increased FV in circulating neutrophils in severe COVID-19, and immunofluorescence microscopy identifies FV in lung-infiltrating leukocytes in COVID-19 lung disease. Increased leukocyte FV expression in severe disease correlates with T-cell lymphopenia. Both plasma-derived and a cleavage resistant recombinant FV, but not thrombin cleaved FVa, suppress T-cell proliferation in vitro. Anticoagulants that reduce FV conversion to FVa, including heparin, may have the unintended consequence of suppressing the adaptive immune system.

Co-Expression and Functional Interactions of Death Receptor 3 and E-Selectin in Clear Cell Renal Cell Carcinoma.

Similar to the behavior of inflamed tubular epithelial cells, clear cell renal cell carcinoma (ccRCC) cells express death receptor 3 (DR3 or TNFSFR25) in situ, and expression increases with tumor grade. Surprisingly, E-selectin, which can be induced in endothelial cells by DR3 signaling, is also expressed by ccRCC cells and increases with tumor grade. In ccRCC organ cultures, addition of tumor necrosis factor-like 1A (TL1A or TNFSF15), the ligand for DR3, activates NF-κB and mitogen-activated protein kinases, induces both DR3 and E-selectin expression in an NF-κB-dependent manner, and promotes cell cycle entry. DR3 immunoprecipitated from ccRCC tissue contains sialyl Lewis X moieties (the ligand recognized by E-selectin), proximity ligation assays reveal DR3, and E-selectin interacts on ccRCC cells. Similar to that with the addition of TL1A, the addition of soluble E-selectin to ccRCC organ cultures activates NF-κB and mitogen-activated protein kinases in ccRCC cells and increases both DR3 and E-selectin expression and cell-cycle entry. In contrast, normal renal tubular epithelium, which poorly expresses DR3, is minimally responsive to either of these ligands. These data suggest a functional role for autocrine/paracrine DR3/E-selectin interactions in ccRCC and its progression, revealing a potential new target for therapeutic intervention.

Cost of Traditional Herbal Medicines for Noncommunicable Diseases in Rural and Urban Communities in South Africa.

OBJECTIVES: This study assessed traditional herbal medicine (THM) and conventional medicine (CM) utilization among participants with noncommunicable disease in South Africa. METHODS: A cross-sectional study of the Prospective Urban and Rural Epidemiological study collected data through face-to-face interviews using structured questionnaires in 2014. Descriptive, bivariate, and multivariate logistic regression were used to determine the effect of sociodemographic and economic factors on THM and CM use. All statistical analyses were conducted using the statistical computing and graphics language "R." RESULTS: Of the total 417 randomly selected participants in this study, 85% were females, 95% with no health insurance, and 81% with monthly incomes of <2000 rand (R) ($137 equivalent) per month. Moreover, 73% spend 5% of their income on THM, and 10% say they are willing to pay >R500 per year on THM to feel better. Age was significantly associated with different spending patterns after controlling for other demographic factors, given that older adults were 82% (odds ratio 0.18; 95% confidence interval 0.02-0.93) less likely to pay >R100 for THM whereas younger adults were 59% (odds ratio 0.41; 95% confidence interval 0.17-0.97) less likely to pay for CM. CONCLUSIONS: The cost of using THM and CM largely differed by age. The economic insight into this study reveals individuals more willing to pay for THM to payors, which can ultimately clue payors into areas for medication optimization from potential drug-drug interactions and adverse events and, therefore, reduce healthcare costs.

Accurate Medication Adherence Measurement Using Administrative Data for Frequently Hospitalized Patients.

Background: Pharmacy administrative claims data remain an accessible and efficient source to measure medication adherence for frequently hospitalized patient populations that are systematically excluded from the landmark drug trials. Published pharmacotherapy studies use medication possession ratio (MPR) and proportion of days covered (PDC) to calculate medication adherence and usually fail to incorporate hospitalization and prescription overlap/gap from claims data. To make the cacophony of adherence measures clearer, this study created a refined hospital-adjusted algorithm to capture pharmacotherapy adherence among patients with end-stage renal disease (ESRD). Methods: The United States Renal Data System (USRDS) registry of ESRD was used to determine prescription-filling patterns of those receiving new prescriptions for oral P2Y12 inhibitors (P2Y12-I) between 2011 and 2015. P2Y12-I-naïve patients were followed until death, kidney transplantation, discontinuing medications, or loss to follow-up. After flagging/censoring key variables, the algorithm adjusted for hospital length of stay (LOS) and medication overlap. Hospital-adjusted medication adherence (HA-PDC) was calculated and compared with traditional MPR and PDC methods. Analyses were performed with SAS software. Results: Hospitalization occurred for 78% of the cohort (N = 46 514). The median LOS was 12 (interquartile range [IQR] = 2-34) days. MPR and PDC were 61% (IQR = 29%-94%) and 59% (IQR = 31%-93%), respectively. After applying adjustments for overlapping coverage days and hospital stays independently, HA-PDC adherence values changed in 41% and 52.7% of the cohort, respectively. When adjustments for overlap and hospital stay were made concurrently, HA-PDC adherence values changed in 68% of the cohort by 5.8% (HA-PDC median = 0.68, IQR = 0.31-0.93). HA-PDC declined over time (3M-6M-9M-12M). Nearly 48% of the cohort had a ≥30 days refill gap in the first 3 months, and this increased over time (P < .0001). Conclusions: Refill gaps should be investigated carefully to capture accurate pharmacotherapy adherence. HA-PDC measures increased adherence substantially when adjustments for hospital stay and medication refill overlaps are made. Furthermore, if hospitalizations were ignored for medications that are included in Medicare quality measures, such as Medicare STAR program, the apparent reduction in adherence might be associated with lower quality and health plan reimbursement.

Health Disparities of Coronavirus Disease 2019 in Texas, March-July 2020.

OBJECTIVES: Although disparities in coronavirus disease 2019 (COVID-19) prevalence are known, knowledge of the recent surge of COVID-19 in Texas and factors affecting fatality rates is limited. Understanding the health disparities associated with COVID-19 can help healthcare professionals determine the populations that are most in need of COVID-19 preventive care and treatment. The aim of this study was to assess COVID-19-related case and mortality rates. METHODS: Our cross-sectional analysis used Texas Department of State Health Services COVID-19 case surveillance counts. Case, hospitalization, and mortality counts were obtained from March to July 2020. RESULTS: From March to July 2020, there were 420,397 COVID-19-related cases and 6954 deaths in Texas. There were 3277 new cases and 104 deaths in March, and 261,876 new cases and 3660 deaths in July. The number of new COVID-19 cases was the highest from March to April (relative risk 1.77, 95% confidence interval [CI] 1.76-1.78). Although the death rate in June was a 30% increase over the rate in May, death rates nearly tripled by the end of July, for a total of 3660 deaths. Of the 3958 deaths, demographic data were available for 753 deaths. Of these, 440 were male, 16 Asian, 95 Black, 221 Hispanic, 325 White, and 96 were "Other" or "Unknown." Males were associated with a slightly higher chance of acquiring COVID-19 than females (odds ratio [OR] 1.11, 95% CI 1.09-1.14) and nearly a 29% higher chance of dying of COVID-19 compared with females (OR 1.29, 95% CI 1.11-1.49). Bivariate analysis revealed that the probability of acquiring COVID-19 was 12% higher in older adults compared with individuals younger than 65 years old (OR 1.12, 95% CI 1.08-1.16), and older adults had an 18.8 times higher risk of death when compared with the rate of younger individuals (OR 18.79, 95% CI 15.93-22.15). Hispanics and Blacks were 70% and 48%, respectively, more likely to contract COVID-19 than Whites. All races had lower significant chance of death when compared with Whites. At the end of July, there was a total of 430,485 Texas COVID-19 cases and 6387 fatalities (8.8% of all cases and 4% of all deaths in the United States.). Case fatality ratios were the highest in older adults. As we continued to observe data, in contrast to previous study time points, we found that Asians and Hispanics had no significant difference in COVID mortality rates and were comparable in terms of mortality odds and death case ratios when compared with Whites. CONCLUSIONS: This time period represents the highest COVID-19 surge time in Texas. Although our data consist of a short time period of population-level data in an ongoing pandemic and are limited by information reported to the Texas Department of State Health Services, older age, male sex, Hispanics, and Blacks are currently associated with higher infection rates, whereas older age, male sex, and Whites are associated with higher mortality rates. Clinicians and decision makers should be aware of the COVID-19 health disparities and risk factors for mortality to better promote targeted interventions and allocate resources accordingly.

Comparative Effectiveness and Safety of Oral P2Y12 Inhibitors in Patients on Chronic Dialysis.

INTRODUCTION: Although oral P2Y12 inhibitors (P2Y12-Is) are one of the most commonly prescribed medication classes in patients with end stage kidney disease on dialysis (ESKD), scarce data exist regarding their benefits and risks. METHODS: We compared effectiveness and safety of clopidogrel, prasugrel, and ticagrelor in a longitudinal study using the United States Renal Data System registry of Medicare beneficiaries with ESKD. Individuals who filled new P2Y12-I prescriptions between 2011 and 2015 were included and followed until death or censoring. The primary exposure variable was P2Y12-I assignment. The primary outcome variable was death. Secondary outcomes included cardiovascular (CV) death, coronary revascularization, and gastrointestinal (GI) hemorrhage. Survival analyses were performed after propensity matching. RESULTS: Of 44,619 patients with ESKD who received P2Y12-Is, 95% received clopidogrel (n = 42,523), 3% prasugrel (n = 1205), and 2% ticagrelor (n = 891). To balance baseline differences, propensity-matching was performed: 1:6 for prasugrel (n = 1189) versus clopidogrel (n = 7134); 1:4 for ticagrelor (n = 880) versus clopidogrel (n = 3520); and 1:1 for ticagrelor versus prasugrel (n = 880). Prasugrel was associated with a reduced risk for death versus clopidogrel and ticagrelor (adjusted hazard ratio [HR] = 0.82; 95% CI: 0.73-0.93 and 0.78; 95% CI: 0.64-0.95). Compared with clopidogrel, prasugrel reduced risk for coronary revascularization (HR = 0.91; 95% CI: 0.86-0.96). There were no differences in GI hemorrhage between P2Y12-Is. CONCLUSION: In patients with ESKD, prasugrel compared with others reduced risk of death possibly by reducing risk for coronary revascularizations and without worsening gastrointestinal hemorrhage. Future trials are imperative to compare efficacy and safety of P2Y12-Is in patients with ESKD.

Impact of Fall Risk and Direct Oral Anticoagulant Treatment on Quality-Adjusted Life-Years in Older Adults with Atrial Fibrillation: A Markov Decision Analysis.

BACKGROUND AND OBJECTIVE: The decision to initiate anticoagulation in older adults with atrial fibrillation is complicated by the benefit of ischemic stroke prevention vs the risk of falls resulting in major bleeds. The objective of this study was to assess the impact of different treatments including direct oral anticoagulants on quality-adjusted life-years (QALYs) in patients aged 75 years and older with atrial fibrillation in the context of falls. METHODS: A Markov decision process was constructed for older patients with atrial fibrillation taking no anti-thrombotic, aspirin, warfarin, rivaroxaban, and apixaban. Input probabilities for clinical events were estimated from the available literature. One-way and two-way sensitivity analyses were performed by measuring the impact of varying input probabilities of clinical events on QALY outcomes. RESULTS: The base-case scenario estimated that older adults treated with no anti-thrombotic, aspirin, warfarin, rivaroxaban, and apixaban had QALYs of 8.03, 8.69, 10.38, 11.02, and 11.56, respectively. The sensitivity analysis estimated that an older adult would need to fall over 45 (rivaroxaban) and 458 (apixaban) times per year for the QALY of a direct oral anticoagulant to be lower than that of aspirin. CONCLUSIONS: Older adults with atrial fibrillation benefit from stroke protection of anticoagulants, especially direct oral anticoagulants, even if they are at high risk of falls. Clinicians should not consider fall risk as a deciding factor for withholding anticoagulation in this population of patients.

Polypharmacy and Cognition Function Among Rural Adults.

BACKGROUND: Polypharmacy (using≥5 medications) is associated with poor health outcomes. Mixed results from past studies surrounding chronic medication use, control of chronic conditions, and their effects on cognitive performance warrant further attention. OBJECTIVE: Investigate a link between polypharmacy and cognition function in rural-dwelling adults in Texas, USA. METHODS: Project FRONTIER (Facing Rural Obstacles to Healthcare Now Through Intervention, Education & Research) is a cross-sectional epidemiological study using community-based participatory research in three counties of Texas. Residents age > 40 were eligible for inclusion. The primary outcome is cognitive impairment, and exposures of interest are polypharmacy; comorbidities; and diabetes, hypertension, and depression medication. Logistic regression was used to assess association. RESULTS: Six hundred eighty-nine individuals participated; the mean age was 61, and the majority were female (68.7%).The median number of medications taken by participants was 3.3 (IQR: 0-5); the rate of polypharmacy was 29.6%. Anti-hypertensive agents were the most common medications (15%) used. Polypharmacy users were 2.84 times more likely to have cognitive impairment [OR: 2.84, 95%CI (1.32-6.09)] than those using < 5 medications. Participants on hypertensive medications had 1.85 times higher odds [OR: 1.85, 95%CI (1.14-3.01)] of having cognitive impairment than those who did not have cognitive impairment. CONCLUSION: Polypharmacy increases the odds of cognitive impairment. The odds of presenting with cognitive impairment increased as the number of medications increased. Additionally, we identified a large, concerning number of participants with pharmacotherapy and poor chronic disease management. A larger study should examine medication adherence among rural elders to manage chronic disease and any healthcare barriers to adherence.

Shorter length of hospital stay for hip fracture in those with dementia and without a known diagnosis of osteoporosis in the USA.

BACKGROUND: About 50% of all hospitalized fragility fracture cases in older Americans are hip fractures. Approximately 3/4 of fracture-related costs in the USA are attributable to hip fractures, and these are mostly covered by Medicare. Hip fracture patients with dementia, including Alzheimer's disease, have worse health outcomes including longer hospital length of stay (LOS) and charges. LOS and hospital charges for dementia patients are usually higher than for those without dementia. Research describing LOS and acute care charges for hip fractures has mostly focused on these outcomes in trauma patients without a known pre-admission diagnosis of osteoporosis (OP). Lack of documented diagnosis put patients at risk of not having an appropriate treatment plan for OP. Whether having a diagnosis of OP would have an effect on hospital outcomes in dementia patients has not been explored. We aim to investigate whether having a diagnosis of OP, dementia, or both has an effect on LOS and hospital charges. In addition, we also report prevalence of common comorbidities in the study population and their effects on hospital outcomes. METHODS: We conducted a cross-sectional analysis of claims data (2012-2013) for 2175 Medicare beneficiaries (≥65 years) in the USA. RESULTS: Compared to those without OP or dementia, patients with demenia only had a shorter LOS (by 5%; P = .04). Median LOS was 6 days (interquartile range [IQR]: 5-7), and the median hospital charges were $45,100 (IQR: 31,500 - 65,600). In general, White patients had a shorter LOS (by 7%), and those with CHF and ischemic heart disease (IHD) had longer LOS (by 7 and 4%, respectively). Hospital charges were 6% lower for women, and 16% lower for White patients. CONCLUSION: This is the first study evaluating LOS in dementia in the context of hip fracture which also disagrees with previous reporting about longer LOS in dementia patients. Patients with CHF and IHD remains at high risk for longer LOS regardless of their diagnosis of dementia or OP.

Greater Changes in Drug Burden Index (DBI) during Hospitalization and Increased 30-Day Readmission Rates among Older In-Hospital Fallers.

A higher drug burden index (DBI) is known to be associated with pre-admission falls leading to hospitalization. We investigated whether a mean difference in DBI (ΔDBI) between the events of in-hospital falls and hospital admission was associated with 30-day readmission in 113 patients ≥50 years who fell during their hospital stays between 2007 and 2014. A greater ΔDBI (≥0.09) was positively associated with higher 30-day readmission rates (incident rate ratio: 2.02; 95% confidence interval: 1.49-2.74). An effort to keep DBI low may thus decrease 30-day readmissions for older in-hospital fallers.

The Efficacy of Sunitinib Treatment of Renal Cancer Cells Is Associated with the Protein PHAX In Vitro.

Anti-angiogenic agents, such as the multi-tyrosine kinase inhibitor sunitinib, are key first line therapies for metastatic clear cell renal cell carcinoma (ccRCC), but their mechanism of action is not fully understood. Here, we take steps towards validating a computational prediction based on differential transcriptome network analysis that phosphorylated adapter RNA export protein (PHAX) is associated with sunitinib drug treatment. The regulatory impact factor differential network algorithm run on patient tissue samples suggests PHAX is likely an important regulator through changes in genome-wide network connectivity. Immunofluorescence staining of patient tumours showed strong localisation of PHAX to the microvasculature consistent with the anti-angiogenic effect of sunitinib. In normal kidney tissue, PHAX protein abundance was low but increased with tumour grade (G1 vs. G3/4; p < 0.01), consistent with a possible role in cancer progression. In organ culture, ccRCC cells had higher levels of PHAX protein expression than normal kidney cells, and sunitinib increased PHAX protein expression in a dose dependent manner (untreated vs. 100 µM; p < 0.05). PHAX knockdown in a ccRCC organ culture model impacted the ability of sunitinib to cause cancer cell death (p < 0.0001 untreated vs. treated), suggesting a role for PHAX in mediating the efficacy of sunitinib.

Tumor necrosis factor receptor-2 signaling pathways promote survival of cancer stem-like CD133+ cells in clear cell renal carcinoma.

Clear cell renal cell carcinoma (ccRCC) contains cancer stem-like cells (CSCs) that express CD133 (ccRCC-CD133+). CSCs are rarely in cell cycle and, as nonproliferating cells, resist most chemotherapeutic agents. Previously, we reported that tumor necrosis factor receptor-2 (TNFR2) signaling promotes the cell cycle entry of ccRCC-CD133+CSCs, rendering them susceptible to cell-cycle-dependent chemotherapeutics. Here, we describe a TNFR2-activated signaling pathway in ccRCC-CD133+CSCs that is required for cell survival. Wild-type (wt)TNF or R2TNF but not R1TNF (TNF muteins that selectively bind to TNFR2 and TNFR1) induces phosphorylation of signal transducer and activator of transcription 3 (STAT3) on serine727 but not tyrosine705, resulting in pSTAT3Ser727 translocation to and colocalization with TNFR2 in mitochondria. R2TNF signaling activates a kinase cascade involving the phosphorylation of VEGFR2, PI-3K, Akt, and mTORC. Inhibition of any of the kinases or siRNA knockdown of TNFR2 or STAT3 promotes cell death associated with mitochondrial morphological changes, cytochrome c release, generation of reactive oxygen species, and TUNEL+cells expressing phosphorylated mixed lineage kinase-like (MLKL). Pretreatment with necrostatin-1 is more protective than z-VAD.fmk, suggesting that most death is necroptotic and TNFR2 signaling promotes cell survival by preventing mitochondrial-mediated necroptosis. These data suggest that a TNFR2 selective agonist may offer a potential therapeutic strategy for ccRCC.

Signaling through tumor necrosis receptor 2 induces stem cell marker in CD133+ regenerating tubular epithelial cells in acute cell-mediated rejection of human renal allografts.

Tumor necrosis factor receptor 2 (TNFR2) is strongly upregulated on renal tubular epithelial cells by acute cell-mediated rejection (ACR. In human kidney organ culture, TNFR2 signaling both upregulates TNFR2 expression and promotes cell cycle entry of tubular epithelial cells. We find significantly more cells express CD133 mRNA and protein, a putative stem cell marker, in allograft biopsy samples with ACR compared to acute tubular injury without rejection or pretransplant "normal kidney" biopsy samples. Of CD133+ cells, ~85% are within injured tubules and ~15% are interstitial. Both populations express stem cell marker TRA-1-60 and TNFR2, but only tubular CD133+ cells express proximal tubular markers megalin and aquaporin-1. TNFR2+ CD133+ cells in tubules express proliferation marker phospho-histone H3S10 (pH3S10 ). Tubular epithelial cells in normal kidney organ cultures respond to TNFR2 signaling by expressing CD133 mRNA and protein, stem cell marker TRA-1-60, and pH3S10 within 3 hours of treatment. This rapid response time suggests that CD133+ cells in regenerating tubules of kidneys undergoing ACR represent proliferating tubular epithelial cells with TNFR2-induced stem cell markers rather than expansion of resident stem cells. Infiltrating host mononuclear cells are a likely source of TNF as these changes are absent in acute tubular injury .

Motivational Interviewing to Encourage Quit Attempts Among Smokers Not Ready to Quit: A Trial-Based Economic Analysis.

INTRODUCTION: This study used data from a randomized controlled trial evaluating the efficacy of motivational interviewing (MI) relative to health education (HE) and brief advice (BA) to encourage quit attempts and cessation in order to determine their relative cost-effectiveness. AIMS AND METHODS: Urban community residents (n = 255) with low desire to quit smoking were randomized to MI, HE, or BA which differed in communication style and/or number of treatment sessions. Incremental cost-effectiveness ratios were used to compare the intensive interventions (MI and HE) to BA for facilitating quit attempts and smoking cessation. Costs were calculated from the perspective of an agency that might engage in program delivery. Sensitivity analysis examined different assumptions for MI training and pharmacotherapy costs. RESULTS: Total intervention delivery time costs per participant for MI, HE, and BA were $46.63, $42.87, and $2.4, respectively. Cost-effectiveness ratios per quit attempt at 24 weeks were $380 for MI, $272 for HE, and $209 for BA. The cost per additional quit attempt for MI and HE relative to BA was $508 and $301, respectively. The cost per additional quit for MI and HE relative to BA was $2030 and $752, respectively. Four separate sensitivity analyses conducted in our study did not change the conclusion the HE had a lower Incremental Cost-Effectiveness Ratio for both quit attempts and cessation. CONCLUSIONS: HE was the most cost-effective of the three types of smoking cessation induction therapies and therefore may be preferable for smokers who are less motivated to quit. Providing valuable cost information in choosing different clinical methods for motivating smokers to quit. IMPLICATIONS: All direct costs and activity-based time costs associated with delivering the intervention were analyzed from the perspective of an agency that may wish to replicate these strategies. A randomized controlled trial evaluating the efficacy of MI relative to HE and BA to encourage quit attempts and cessation determined their relative cost-effectiveness. HE was the most cost-effective of the three types of smoking cessation induction therapies and therefore may be preferable. Despite guideline recommendations, MI may not be the best approach to encourage quit attempts in diverse populations. Rather, a structured, intensive HE intervention might be the most cost-effective alternative.

Trends for and Clinical Factors Associated with Choice of Oral P2Y12 Inhibitors for Patients on Chronic Dialysis.

BACKGROUND: Trends and clinical factors associated with prescribing choices for oral P2Y12 inhibitors (P2Y12-I) remain unknown for patients on chronic dialysis, i.e., with end-stage renal disease (ESRD). METHODS: From 2011-2014 U.S. Renal Data System registry, we identified 36,542 ESRD patients who received new prescriptions for P2Y12-I (median age 64.0 years and 54% males). Of the cohort, 93% were receiving hemodialysis and 7% on peritoneal dialysis. We analyzed trends and investigated clinical factors associated with specific P2Y12-I prescribed. RESULTS: Clopidogrel was prescribed for 95%, prasugrel for 3%, and ticagrelor for 2%. Clopidogrel was favored for those ≥75 years (18% of cohort). Compared to Caucasians, African Americans (36% of cohort) and Hispanics (19% of cohort) were less likely to receive prasugrel and ticagrelor (P<0.05). Patients receiving hemodialysis versus peritoneal dialysis were less likely to receive prasugrel over clopidogrel, adjusted odds ratio (aOR) 0.67 (0.55-0.82). Each additional year of dialysis decreased the odds of receiving prasugrel over clopidogrel, aOR 0.91 (0.85-0.98). History of atrial fibrillation reduced the odds of receiving ticagrelor or prasugrel over clopidogrel, aOR 0.69 (0.54-0.89) and 0.73 (0.60-0.89), respectively. Concomitant oral anticoagulant use was not associated with choice of P2Y12-I. Occurrence of non-ST segment elevation myocardial infarction or percutaneous coronary intervention within the 6-month period prior to the index date favored ticagrelor over prasugrel, aOR 1.31 (1.06-1.62) and 1.29 (1.01-1.66), respectively. However, prescribing trends favoring ticagrelor over prasugrel were not observed for deployment of drug-eluting, or multiple coronary stents. CONCLUSION: Between 2011 and 2014, clopidogrel remained the most common P2Y12-I whereas ticagrelor and prasugrel remained underutilized in ESRD patients. Prescribing practices for these drugs were based upon clinically approved indication for their use in the general population as well as perceived complexity of an ESRD patient including demographics, dialysis-related factors and comorbidities. Comparative effectiveness studies involving ESRD patients are needed to prove that ticagrelor and prasugrel are just as safe and effective as clopidogrel before clinicians can make informed decisions for choice of P2Y12-I in this patient population.