Improvement in Renal Function and Reduction in Serum Uric Acid with Intensive Statin Therapy in Older Patients: A Post Hoc Analysis of the SAGE Trial.

BackgroundImprovement in renal function and decreases in serum uric acid (SUA) have been reported following prolonged high-intensity statin (HMG-CoA reductase inhibitor) therapy. This post hoc analysis of the SAGE trial examined the effect of intensive versus less intensive statin therapy on renal function, safety, and laboratory parameters, including SUA, in elderly coronary artery disease (CAD) patients (65-85 years) with or without chronic kidney disease (CKD).MethodsPatients were randomized to atorvastatin 80 mg/day or pravastatin 40 mg/day and treated for 12 months. Patients were stratified using Modification of Diet in Renal Disease (MDRD) estimated glomerular filtration rates (eGFRs) in CKD (eGFR <60 mL/min/1.73 m(2)) and non-CKD populations.ResultsOf the 893 patients randomized, 858 had complete renal data and 418 of 858 (49%) had CKD (99% Stage 3). Over 12 months, eGFR increased with atorvastatin and remained stable with pravastatin (+2.38 vs. +0.18 mL/min/1.73 m(2), respectively; p < 0.0001). MDRD eGFR improved significantly in both CKD treatment arms; however, the increased eGFR in patients without CKD was significantly greater with atorvastatin (+2.08 mL/min/1.73 m(2)) than with pravastatin (-1.04 mL/min/1.73 m(2)). Modest reductions in SUA were observed in both treatment arms, but a greater fall occurred with atorvastatin than with pravastatin (-0.52 vs. -0.09 mg/dL, p < 0.0001). Change in SUA correlated negatively with changes in eGFR and positively with changes in low-density lipoprotein cholesterol. Reports of myalgia were rare (3.6% CKD; 5.7% non-CKD), and there were no episodes of rhabdomyolysis. Elevated serum alanine and aspartate transaminase to >3 times the upper limit of normal occurred in 4.4% of atorvastatin- and 0.2% of pravastatin-treated patients.ConclusionIntensive management of dyslipidemia in older patients with stable coronary heart disease may have beneficial effects on renal function and SUA

The Ah receptor: adaptive metabolism, ligand diversity, and the xenokine model

Author Posting. © American Chemical Society, 2020. This is an open access article published under an ACS AuthorChoice License. The definitive version was published in Chemical Research in Toxicology, 33(4), (2020): 860-879, doi:10.1021/acs.chemrestox.9b00476.The Ah receptor (AHR) has been studied for almost five decades. Yet, we still have many important questions about its role in normal physiology and development. Moreover, we still do not fully understand how this protein mediates the adverse effects of a variety of environmental pollutants, such as the polycyclic aromatic hydrocarbons (PAHs), the chlorinated dibenzo-p-dioxins (“dioxins”), and many polyhalogenated biphenyls. To provide a platform for future research, we provide the historical underpinnings of our current state of knowledge about AHR signal transduction, identify a few areas of needed research, and then develop concepts such as adaptive metabolism, ligand structural diversity, and the importance of proligands in receptor activation. We finish with a discussion of the cognate physiological role of the AHR, our perspective on why this receptor is so highly conserved, and how we might think about its cognate ligands in the future.This review is dedicated in memory of the career of Alan Poland, one of the truly great minds in pharmacology and toxicology. This work was supported by the National Institutes of Health Grants R35-ES028377, T32-ES007015, P30-CA014520, P42-ES007381, and U01-ES1026127, The UW SciMed GRS Program, and The Morgridge Foundation. The authors would like to thank Catherine Stanley of UW Media Solutions for her artwork

An Attempt at Clarity: Understanding the Lives of Livia, Tanaquil, and Alexandra

This project looks at the lives of three women from antiquity, Livia, Tanaquil, and Alexandra, and determines what can and cannot be known about them. Livia, Tanaquil, and Alexandra were all powerful women during their time, but today, the stories of their lives are confusing and contradictory. Through the medium of fiction, this project brings Livia, Tanaquil, and Alexandra to life as characters in a story in order to highlight the problems that arise when studying these women. There are three essays that accompany the story, one for each of the women, which discuss the difficulties in interpreting the available historical evidence. Ultimately, this project serves as a reminder that Livia, Tanaquil, and Alexandra were real people, and the impact they had on the world deserves to be remembered

The WHO-DAS II: Psychometric Properties in the Measurement of Functional Health Status in Adults With Acquired Hearing Loss

The World Health Organization\u27s (WHO) Disability Assessment Scale II (WHO-DAS II) is a generic health-status instrument firmly grounded in the WHO\u27s International Classification of Functioning, Disability and Health (WHO-ICF). As such, it assesses functioning for six domains: communication, mobility, self-care, interpersonal, life activities, and participation. Domain scores aggregate to a total score. Because the WHO-DAS II contains questions relevant to hearing and communication, it has good face validity for use as an outcome measure for audiologic intervention. The purpose of the present study was to determine the psychometric properties of the WHO-DAS II on a sample of individuals with adult-onset hearing loss, including convergent validity, internal consistency, and test-retest stability. Convergent validity was established by examining correlations between the WHO-DAS II (domain and total scores) and the Abbreviated Profile of Hearing Aid Benefit (APHAB) and the Hearing Aid Handicap for the Elderly (HHIE), two disease-specific measures, as well as with the Short Form-36 for veterans (SF-36V), a second generic measure. Data on all four measures were collected from 380 older individuals with adult-onset hearing loss who were not hearing aid users. The results of the convergent validity analysis revealed that the WHO-DAS II communication domain score was moderately and significantly correlated with scores on the APHAB and the HHIE. WHO-DAS II interpersonal and participation domain scores and the total scores were also moderately and significantly correlated with HHIE scores. These findings support the validity of using the WHO-DAS II for assessing activity limitations and participation restrictions of adult-onset hearing loss. Several WHO-DAS II domain scores and the total score were also significantly and moderately-markedly correlated with scores from the SF-36V. These findings support the validity of the WHO-DAS II as a generic health-status instrument. Internal consistency reliability for all the domain scores was adequate for all but the interpersonal domain. Test-retest stability for all the domain scores was adequate. Critical difference values were calculated for use in clinical application of the WHO-DAS II. From these findings, we concluded that the WHO-DAS II communication, participation, and total scores can be used to examine the effects of adult-onset hearing loss on functional health status. Further work examining the utility of the WHO-DAS II as an outcome measure for hearing aid intervention is warranted

Reasons for placement and replacement of crowns in general dental practice

Objectives The aim of this study was to investigate the reasons for placement and replacement of crowns in general dental practice. Methods Forty general dental practitioners recorded the principal reason for the provision of new (initial) and replacement crowns for a maximum of up to 20 patients over a 20-week period. Results A total of 664 patients received 783 crowns during the period of this study. Of these, 69% (n = 542) were new (initial) placements and 31% (n = 241) were replacements. Overall, tooth fracture (45%, n = 241) was the most frequently reported reason for new/ initial crown placements. Aesthetics (21%, n = 53) and secondary/recurrent caries (20%; n = 47) were the most frequent reasons for crown replacement. Maxillary premolars (27%, n = 145) and mandibular molars (25%, n = 137) were the teeth that received most initial crown placements. In contrast, maxillary incisors (50%, n = 115) were the most common teeth to receive a replacement crown. Dentists were more likely to replace a crown if they had not placed the original crown: 74% of replacement crowns (n = 178) were placed by a different dentist. Most patients had only one crown placed or replaced per course of treatment (n = 611; 90%). Conclusions The results of this study reveal the prescribing habits of dentists in relation to provision of initial and replacement crowns. The vast majority of patients had only one crown provided per course of treatment, which is probably a reflection of funding schemes and changing patterns of oral health. This sample reported fewer replacement crowns than previous studies. In keeping with existing literature, crowns were more frequently replaced when the treating dentist had not placed the initial crown. However, against this, more replacements were provided for more long-standing patients (5+ years attendance) compared to those with shorter attendance history (<5 years). In an area where high quality evidence is lacking, further consensus on the need for placement and replacement crowns is needed. Such information would assist dentists to provide high-quality care and commissioners in developing an evidence-based service

Functional disruptions of the brain in low back pain: A potential imaging biomarker of functional disability

Chronic low back pain (LBP) is one of the leading causes of disability worldwide. While LBP research has largely focused on the spine, many studies have demonstrated a restructuring of human brain architecture accompanying LBP and other chronic pain states. Brain imaging presents a promising source for discovering noninvasive biomarkers that can improve diagnostic and prognostication outcomes for chronic LBP. This study evaluated graph theory measures derived from brain resting-state functional connectivity (rsFC) as prospective noninvasive biomarkers of LBP. We also proposed and tested a hybrid feature selection method (Enet-subset) that combines Elastic Net and an optimal subset selection method. We collected resting-state functional MRI scans from 24 LBP patients and 27 age-matched healthy controls (HC). We then derived graph-theoretical features and trained a support vector machine (SVM) to classify patient group. The degree centrality (DC), clustering coefficient (CC), and betweenness centrality (BC) were found to be significant predictors of patient group. We achieved an average classification accuracy of 83.1%

A Serpin shapes the extracellular environment to prevent influenza A virus maturation

Interferon-stimulated genes (ISGs) act in concert to provide a tight barrier against viruses. Recent studies have shed light on the contribution of individual ISG effectors to the antiviral state, but most have examined those acting on early, intracellular stages of the viral life cycle. Here, we applied an image-based screen to identify ISGs inhibiting late stages of influenza A virus (IAV) infection. We unraveled a directly antiviral function for the gene SERPINE1, encoding plasminogen activator inhibitor 1 (PAI-1). By targeting extracellular airway proteases, PAI-1 inhibits IAV glycoprotein cleavage, thereby reducing infectivity of progeny viruses. This was biologically relevant for IAV restriction in vivo. Further, partial PAI-1 deficiency, attributable to a polymorphism in human SERPINE1, conferred increased susceptibility to IAV in vitro. Together, our findings reveal that manipulating the extracellular environment to inhibit the last step in a virus life cycle is an important mechanism of the antiviral response

Comparing single-best-answer and very-short-answer questions for the assessment of applied medical knowledge in 20 UK medical schools: Cross-sectional study.

OBJECTIVES: The study aimed to compare candidate performance between traditional best-of-five single-best-answer (SBA) questions and very-short-answer (VSA) questions, in which candidates must generate their own answers of between one and five words. The primary objective was to determine if the mean positive cue rate for SBAs exceeded the null hypothesis guessing rate of 20%. DESIGN: This was a cross-sectional study undertaken in 2018. SETTING: 20 medical schools in the UK. PARTICIPANTS: 1417 volunteer medical students preparing for their final undergraduate medicine examinations (total eligible population across all UK medical schools approximately 7500). INTERVENTIONS: Students completed a 50-question VSA test, followed immediately by the same test in SBA format, using a novel digital exam delivery platform which also facilitated rapid marking of VSAs. MAIN OUTCOME MEASURES: The main outcome measure was the mean positive cue rate across SBAs: the percentage of students getting the SBA format of the question correct after getting the VSA format incorrect. Internal consistency, item discrimination and the pass rate using Cohen standard setting for VSAs and SBAs were also evaluated, and a cost analysis in terms of marking the VSA was performed. RESULTS: The study was completed by 1417 students. Mean student scores were 21 percentage points higher for SBAs. The mean positive cue rate was 42.7% (95% CI 36.8% to 48.6%), one-sample t-test against ≤20%: t=7.53, p<0.001. Internal consistency was higher for VSAs than SBAs and the median item discrimination equivalent. The estimated marking cost was £2655 ($3500), with 24.5 hours of clinician time required (1.25 s per student per question). CONCLUSIONS: SBA questions can give a false impression of students' competence. VSAs appear to have greater authenticity and can provide useful information regarding students' cognitive errors, helping to improve learning as well as assessment. Electronic delivery and marking of VSAs is feasible and cost-effective

Redox changes during the cell cycle in the embryonic root meristem of Arabidopsis thaliana

Aims: The aim of this study was to characterize redox changes in the nuclei and cytosol occurring during the mitotic cell cycle in the embryonic roots of germinating Arabidopsis seedlings, and to determine how redox cycling was modified in mutants with a decreased capacity for ascorbate synthesis. Results: Using an in vivo reduction-oxidation (redox) reporter (roGFP2), we show that transient oxidation of the cytosol and the nuclei occurred at G1 in the synchronized dividing cells of the Arabidopsis root apical meristem, with reduction at G2 and mitosis. This redox cycle was absent from low ascorbate mutants in which nuclei were significantly more oxidized than controls. The cell cycle-dependent increase in nuclear size was impaired in the ascorbate-deficient mutants, which had fewer cells per unit area in the root proliferation zone. The transcript profile of the dry seeds and size of the imbibed seeds was strongly influenced by low ascorbate but germination, dormancy release and seed aging characteristics were unaffected. Innovation: These data demonstrate the presence of a redox cycle within the plant cell cycle and that the redox state of the nuclei is an important factor in cell cycle progression. Conclusions: Controlled oxidation is a key feature of the early stages of the plant cell cycle. However, sustained mild oxidation restricts nuclear functions and impairs progression through the cell cycle leading to fewer cells in the root apical meristem