Single-nucleotide polymorphism-based genetic risk score and patient age at prostate cancer diagnosis

Importance: Few studies have evaluated the association between a single-nucleotide polymorphism-based genetic risk score (GRS) and patient age at prostate cancer (PCa) diagnosis. Objectives: To test the association between a GRS and patient age at PCa diagnosis and to compare the performance of a GRS with that of family history (FH) in PCa risk stratification. Design, Setting, and Participants: A cohort study of 3225 white men was conducted as a secondary analysis of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) chemoprevention trial, a 4-year, randomized, double-blind, placebo-controlled multicenter study conducted from March 2003 to April 2009 to evaluate the safety and efficacy of dutasteride in reducing PCa events. Participants were confirmed to be cancer free by prostate biopsy (6-12 cores) within 6 months prior to the study and underwent 10 core biopsies every 2 years per protocol. The dates for performing data analysis were from July 2016 to October 2019. Interventions: A well-established, population-standardized GRS was calculated for each participant based on 110 known PCa risk-associated single-nucleotide polymorphisms, which is a relative risk compared with the general population. Men were classified into 3 GRS risk groups based on predetermined cutoff values: low (\u3c0.50), average (0.50-1.49), and high (≥1.50). Main Outcomes and Measures: Prostate cancer diagnosis-free survival among men of different risk groups. Results: Among 3225 men (median age, 63 years [interquartile range, 58-67 years]) in the study, 683 (21%) were classified as low risk, 1937 (60%) as average risk, and 605 (19%) as high risk based on GRS alone. In comparison, 2789 (86%) were classified as low or average risk and 436 (14%) as high risk based on FH alone. Men in higher GRS risk groups had a PCa diagnosis-free survival rate that was worse than that of those in the lower GRS risk group (χ2 = 53.3; P \u3c .001 for trend) and in participants with a negative FH of PCa (χ2 = 45.5; P \u3c .001 for trend). Combining GRS and FH further stratified overall genetic risk, indicating that 957 men (30%) were at high genetic risk (either high GRS or positive FH), 1667 men (52%) were at average genetic risk (average GRS and negative FH), and 601 men (19%) were at low genetic risk (low GRS and negative FH). The median PCa diagnosis-free survival was 74 years (95% CI, 73-75 years) for men at high genetic risk, 77 years (95% CI, 75 to \u3e80 years) for men at average genetic risk, and more than 80 years (95% CI, \u3e80 to \u3e80 years) for men at low genetic risk. In contrast, the median PCa diagnosis-free survival was 73 years (95% CI, 71-76 years) for men with a positive FH and 77 years (95% CI, 76-79 years) for men with a negative FH. Conclusions and Relevance: This study suggests that a GRS is significantly associated with patient age at PCa diagnosis. Combining FH and GRS may better stratify inherited risk than FH alone for developing personalized PCa screening strategies

Pastoral Influences on the Relief of Poverty and their Metrics

I am writing this paper from two perspectives, one to argue whether public policy can reduce or end poverty and then to argue why it is appropriate for policy makers to try. I plan to use the conclusions to state avidly, poverty is not a fixed product of civilized life. To even try to believe this, we are taught, is a sin. Yet somehow our targets for eradicating poverty lag. I intend to look at the reasons we do not feel compelled to use our rich amounts of time and resources to reduce the burden of poverty on the poor and create a modern population of more educated, stable, higher incoming earning persons, and how failure to succeed violates the spirit of government

“The hierarchy is your constraint:” a qualitative investigation of social workers’ moral distress across a U.S. health system

This paper reports findings from a qualitative study on the triggers of hospital social workers’ moral distress at a large southern U.S. health system. Moral distress occurs when ethical conflict cannot be resolved in a way that aligns with an individual’s personal and professional values and ethics. Participants indicated that moral distress derives from both individual interactions and the culture and climate of health systems. For example, participants expressed how sources of moral distress derived from client-centered decisions, such as end-of-life care and patient autonomy; interpersonal dynamics, including team or supervisory conflict; structural issues, such as insurance barriers or internal hospital policies; and organizational values, such as perceptions of institutional support and validation. Implications of this research suggest that health systems need to foster positive ethical environments that nurture clinicians’ health and mental health through programs that aim to increase moral resilience, promote empowerment, and foster wellness

‘Have They Talked About Us At All?’ The Moral Distress of Healthcare Social Workers during the COVID-19 Pandemic: A Qualitative Investigation in the State of Texas

Amid the ongoing pandemic, as overburdened and underfunded health systems are requiring health care social workers (HSWs) to assume responsibilities beyond their scope of practice, institutional constraints have undoubtedly heightened encounters of moral distress (MD). MD is the psychological disequilibrium that arises when institutional factors obligate an individual to carry out a task that violates their professional and/or personal ethics. Our qualitative study investigated HSWs’ (n = 43) MD in Texas during the 2019 COVID-19 pandemic. Findings from our study indicate that MD occurs across five levels: (i) patient care decisions; (ii) personal care decisions; (iii) team/unit decisions; (iv) organisational decisions; and (v) social justice decisions. MD is rooted in systems that disproportionately impact historically excluded populations, including social inequities such as financial instability, homelessness and substance use. Organisations need to explicitly consider social justice initiatives that seek to identify growing disparities in care that have been at the forefront of the pandemic; macro-level perspectives that expand MD must address social and health inequities that impede daily tasks of all health care workers. MD encounters that are rooted in social determinants of health can inform supervision, education and practice to ameliorate HSWs’ value conflict

Experiencing Moral Distress Within the Intimate Partner Violence & Sexual Assault Workforce

PURPOSE: Moral distress (MD) refers to the psychological disequilibrium that emerges when institutional policies and/or practices conflict with an individual\u27s professional values and ethics. MD has been interrogated frequently in health care and ancillary medical settings, and has been identified as a critical barrier to enhanced organizational climate and patient care. However, little work has investigated experiences of MD among members of the intimate partner violence (IPV) and sexual violence (SV) workforce. METHODS: This study investigates MD in a sample of IPV and SV service providers via secondary analysis of 33 qualitative interviews conducted with service providers in the summer and fall of 2020 as the COVID-19 pandemic response was unfolding. RESULTS: Qualitative content analysis revealed multiple overlapping vectors of MD experienced by IPV and SV service providers related to institutional resource constraints, providers working beyond their capacity and/or competency, shifting responsibilities within service agencies creating burdens among staff; and breakdowns in communication. Impacts of these experiences at individual, organizational, and client levels were identified by participants. CONCULSIONS: The study uncovers the need for further investigation of MD as a framework within the IPV/SV field, as well as potential lessons from similar service settings which could support IPV and SV agencies in addressing staff experiences of MD

Combined Hyperglycemia and Hyperinsulinemia-induced Insulin Resistance in Adipocytes is associated with Dual Signaling Defects mediated by PKC-ζ

A hyperglycemic and hyperinsulinemic environment characteristic of type 2 diabetes causes insulin resistance. In adipocytes, defects in both insulin sensitivity and maximum response of glucose transport have been demonstrated. To investigate the molecular mechanisms, freshly isolated rat adipocytes were incubated in control (5.6 mM glucose, no insulin) and high glucose (20 mM)/high insulin (100 nM) (HG/HI) for 18 h to induce insulin resistance. Insulin resistant adipocytes manifested decreased sensitivity of glucose uptake associated with defects in IRS-1 Tyr phosphorylation, association of p85 subunit of phosphatidylinositol-3-kinase, AktSer473 and Thr308 phosphorylation accompanied by impaired glucose transporter 4 translocation. In contrast, PKC-ζ activity was augmented by chronic HG/HI. Inhibition of PKC-ζ with a specific cell permeable peptide reversed the signalling defects and insulin sensitivity of glucose uptake. Transfection of dominant-negative kinase-inactive PKC-ζ blocked insulin resistance, while constitutively-active PKC-ζ recapitulated the defects. The HG/HI incubation was associated with stimulation of IRS-1Ser318 and AktThr34 phosphorylation, targets of PKC-ζ. Transfection of IRS-1S318A and AktT34A each partially corrected, while combined transfection of both completely normalized insulin signaling. In vivo hyperglycemia/hyperinsulinemia in rats, for 48h similarly resulted in activation of PKC-ζ and increased phosphorylation of IRS-1 Ser318 and AktThr 34. These data indicate that impairment of insulin signaling by chronic HG/HI is mediated by dual defects at IRS-1 and Akt mediated by PKC-ζ.</p

Rosiglitazone Prevents High Glucose-Induced Vascular Endothelial Growth Factor and Collagen IV Expression in Cultured Mesangial Cells

Peroxisome proliferator-activated receptor (PPARγ), a ligand-dependent transcription factor, negatively modulates high glucose effects. We postulated that rosiglitazone (RSG), an activator of PPARγ prevents the upregulation of vascular endothelial growth factor (VEGF) and collagen IV by mesangial cells exposed to high glucose. Primary cultured rat mesangial cells were growth-arrested in 5.6 mM (NG) or 25 mM D-glucose (HG) for up to 48 hours. In HG, PPARγ mRNA and protein were reduced within 3 h, and enhanced ROS generation, expression of p22phox, VEGF and collagen IV, and PKC-ζ membrane association were prevented by RSG. In NG, inhibition of PPARγ caused ROS generation and VEGF expression that were unchanged by RSG. Reduced AMP-activated protein kinase (AMPK) phosphorylation in HG was unchanged with RSG, and VEGF expression was unaffected by AMPK inhibition. Hence, PPARγ is a negative modulator of HG-induced signaling that acts through PKC-ζ but not AMPK and regulates VEGF and collagen IV expression by mesangial cells

Exploiting p53 Status to Enhance Effectiveness of Chemotherapy by Lowering Associated Toxicity

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Active sensing coating for early detection of corrosion processes

A corrosion sensing coating based on specially developed polymeric microcapsules with a pH-indicator is reported. The synthesis of the microcapsules is designed in a way to ensure their optimal compatibility with the polyurethane protective coatings and to allow release of the indicator at higher pH values. The obtained polyurea microcapsules have a regular and microsized morphology and a loading content of 12 wt%. The developed sensing coating applied on aluminium and magnesium alloys is able to indicate initiation of corrosion processes through a pink coating coloration, as a result of local pH increase in the cathodic areas