Citations

Ischemia-reperfusion injury (IRI) due to hypotension is a common cause of human acute kidney injury (AKI). Hypoxia-inducible transcription factors (HIFs) orchestrate a protective response in renal endothelial and epithelial cells in AKI models. As human mucin 1 (MUC1) is induced by hypoxia and enhances HIF-1 activity in cultured epithelial cells, we asked whether mouse mucin 1 (Muc1) regulates HIF-1 activity in kidney tissue during IRI. Whereas Muc1 was localized on the apical surface of the thick ascending limb, distal convoluted tubule, and collecting duct in the kidneys of sham-treated mice, Muc1 appeared in the cytoplasm and nucleus of all tubular epithelia during IRI. Muc1 was induced during IRI, and Muc1 transcripts and protein were also present in recovering proximal tubule cells. Kidney damage was worse and recovery was blocked during IRI in Muc1 knockout mice compared with congenic control mice. Muc1 knockout mice had reduced levels of HIF-1α, reduced or aberrant induction of HIF-1 target genes involved in the shift of glucose metabolism to glycolysis, and prolonged activation of AMP-activated protein kinase, indicating metabolic stress. Muc1 clearly plays a significant role in enhancing the HIF protective pathway during ischemic insult and recovery in kidney epithelia, providing a new target for developing therapies to treat AKI. Moreover, our data support a role specifically for HIF-1 in epithelial protection of the kidney during IRI as Muc1 is present only in tubule epithelial cells.

Background/Aims: Depressive disorders (DEP) are often comorbid with other chronic conditions. Bidirectional associations between DEP and these conditions are poorly understood. In this study, we aimed to identify chronic conditions with the greatest influence on the DEP diagnosis. Methods: A validated electronic health record-based algorithm was applied to identify DEP patients receiving primary care at Mayo Clinic between 2000 and 2013. Cases were identified on the basis of having > 2 DEP-related ICD-9 diagnosis codes, > 1 antidepressant prescription, and > 3 mentions of in- or outpatient clinical notes for DEP. Controls were matched on birth year (± 2 years), sex and outpatient clinic visits at the same year. We ascertained 26 chronic condition categories, as defined by Chronic Conditions Data Warehouse, using the 5 years of medical records prior to the DEP diagnosis. For each age group at diagnosis (60 years), gradient boosting machine models were applied to estimate relative influence (RI) of the chronic conditions on the DEP diagnosis. Results: A total of 11,219 DEP cases were identified (median age at DEP diagnosis 44 years, 34% male and 89% white). The proportion of subjects with at least one co-occurring condition increased with older age and was higher in DEP cases compared to controls (9.5% vs. 6.9% for subjects 60 years). For subjects aged ≤ 45 years, diabetes mellitus (RI=19.6%) was identified as the most influential condition contributing to the risk of DEP, followed by asthma (RI=11.6%) and rheumatoid arthritis (RI=11.0%). For subjects aged 46–60 years, the most influential condition was rheumatoid arthritis (RI=13.2%) followed by diabetes mellitus (RI=12.9%). For subjects older than 60 years, dementia (RI=10.7%) and rheumatoid arthritis (RI=10.2%) showed similar relative contribution to the risk of DEP. Discussion: Among nonelderly adults who received primary care at Mayo Clinic (2000–2013), diabetes mellitus and rheumatoid arthritis were the strongest risk predictors for a diagnosis of depression among 26 chronic conditions considered. Our results suggest that certain chronic conditions may play a role in exacerbating, precipitating or increasing longitudinal risk of medically significant depression.

Abstract Objectives Antibiotic prophylaxis (AP) administration prior to invasive dental procedures has been a leading focus of infective endocarditis prevention. However, there have been long-standing concerns about the risk of adverse drug reactions as a result of this practice. The objective of this study was to identify the incidence and nature of adverse reactions to amoxicillin and clindamycin prophylaxis to prevent infective endocarditis. Methods We obtained AP prescribing data for England from January 2004 to March 2014 from the NHS Business Services Authority, and adverse drug reaction data from the Medicines and Healthcare Products Regulatory Agency's Yellow Card reporting scheme for prescriptions of the standard AP protocol of a single 3 g oral dose of amoxicillin or a single 600 mg oral dose of clindamycin for those allergic to penicillin. Results The reported adverse drug reaction rate for amoxicillin AP was 0 fatal reactions/million prescriptions (in fact 0 fatal reactions for nearly 3 million prescriptions) and 22.62 non-fatal reactions/million prescriptions. For clindamycin, it was 13 fatal and 149 non-fatal reactions/million prescriptions. Most clindamycin adverse drug reactions were Clostridium difficile infections. Conclusions AP adverse drug reaction reporting rates in England were low, particularly for amoxicillin, and lower than previous estimates. This suggests that amoxicillin AP is comparatively safe for patients without a history of amoxicillin allergy. The use of clindamycin AP was, however, associated with significant rates of fatal and non-fatal adverse drug reactions associated with C. difficile infections. These were higher than expected and similar to those for other doses, durations and routes of clindamycin administration.

Purpose: Cellulitis in obese patients is associated with increased rates of treatment failure compared to those with normal body mass index (BMI); however, patients have not been extensively studied in the outpatient environment or stratified based on range of obesity and associated risk factors. This study looked at antibiotic dosing and treatment failure in the obese population from the primary care perspective and accounts for BMI range, weight, comorbid diabetes, and tobacco use. Methods: This study was a retrospective chart review of 637 adult primary care patients designed to evaluate rates of treatment failure of outpatient cellulitis among patients of varying BMI. Treatment failure was defined as ( a) hospital admission for intravenous antibiotics, ( b) prolonged antibiotic course, or ( c) requiring a different antibiotic after initial course. Results: Adverse outcomes were not statistically significant between normal BMI and those with BMI ≥40 kg/m 2 . A subset of patients with a BMI ≥50 kg/m 2 was noted to have approximately twice the rate of adverse outcomes as the normal BMI group. While controlling for age, gender, race, diagnosis of diabetes mellitus, and tobacco use, a BMI of ≥50 kg/m 2 and a weight ≥120 kg was associated with adverse outcomes with an odds ratio of 2.440 (95% CI, 1.260-4.724; P = .008) and 2.246 (95% CI, 1.154-4.369; P = .017), respectively. Conclusions: Patients with cellulitis weighing >120kg or with a BMI ≥50 kg/m 2 were at greatest risk for treatment failure in the outpatient setting, even when controlling for comorbid diabetes and tobacco use. As morbid obesity continues to become more prevalent, it becomes imperative that primary care physicians have better antibiotic dosing guidelines to account for the physiologic effects of obesity to minimize the risk of increased morbidity, health care costs, and antibiotic resistance.

Objectives To assess whether HOUSES (HOUsing-based index of socioeconomic status (SES)) is associated with risk of and mortality after rheumatoid arthritis (RA). Design We conducted a population-based case–control study which enrolled population-based RA cases and their controls without RA. Setting The study was performed in Olmsted County, Minnesota. Participants Study participants were all residents of Olmsted County, Minnesota, with RA identified using the 1987 American College of Rheumatology criteria for RA from 1 January 1988, to 31 December 2007, using the auspices of the Rochester Epidemiology Project. For each patient with RA, one control was randomly selected from Olmsted County residents of similar age and gender without RA. Primary and secondary outcome measure The disease status was RA cases and their matched controls in relation to HOUSES as an exposure. As a secondary aim, post-RA mortality among only RA cases was an outcome event. The associations of SES measured by HOUSES with the study outcomes were assessed using logistic regression and Cox models. HOUSES, as a composite index, was formulated based on a summed z-score for housing value, square footage and number of bedrooms and bathrooms. Results Of the eligible 604 participants, 418 (69%) were female; the mean age was 56±15.6 years. Lower SES, as measured by HOUSES, was associated with the risk of developing RA (0.5±3.8 for controls vs −0.2±3.1 for RA cases, p=0.003), adjusting for age, gender, calendar year of RA index date, smoking status and BMI. The lowest quartile of HOUSES was significantly associated with increased post-RA mortality compared to higher quartiles of HOUSES (HR 1.74; 95% CI 1.10 to 2.74; p=0.017) in multivariate analysis. Conclusions Lower SES, as measured by HOUSES, is associated with increased risk of RA and mortality after RA. HOUSES may be a useful tool for health disparities research concerning rheumatological outcomes when conventional SES measures are unavailable.