Diabetic nephropathy (DN) is a major cause of end-stage renal disease. Yet the pathogenic mechanisms underlying the development of DN are not fully defined, partially due to lack of suitable models that mimic the complex pathogenesis of renal disease in diabetic patients. In this study, we describe early and late renal manifestations of DN and renal responses to long-term treatments with rosiglitazone or high-dose enalapril in ZSF1 rats, a model of metabolic syndrome, diabetes, and chronic renal disease. At 8 weeks of age, obese ZSF1 rats developed metabolic syndrome and diabetes (hyperglycemia, glucosuria, hyperlipidemia, and hypertension) and early signs of renal disease (proteinuria, glomerular collagen IV deposition, tubulointerstitial inflammation, and renal hypertrophy). By 32 weeks of age, animals developed renal histopathology consistent with DN, including mesangial expansion, glomerulosclerosis, tubulointerstitial inflammation and fibrosis, tubular dilation and atrophy, and arteriolar thickening. Rosiglitazone markedly increased body weight but reduced food intake, improved glucose control, and attenuated hyperlipidemia and liver and kidney injury. In contrast, rosiglitazone markedly increased cardiac hypertrophy via a blood pressure-independent mechanism. High-dose enalapril did not improve glucose homeostasis, but normalized blood pressure, and nearly prevented diabetic renal injury. The ZSF1 model thus detects the clinical observations seen with rosiglitazone and enalapril in terms of primary and secondary endpoints of cardiac and renal effects. This and previous reports indicate that the obese ZSF1 rat meets currently accepted criteria for progressive experimental diabetic renal disease in rodents, suggesting that this may be the best available rat model for simulation of human DN.

BackgroundDiagnostic error is commonly defined as a missed, delayed or wrong diagnosis and has been described as among the most important patient safety hazards. Diagnostic errors also account for the largest category of medical malpractice high severity claims and total payouts. Despite a large literature on the incidence of inpatient adverse events, no systematic review has attempted to estimate the prevalence and nature of harmful diagnostic errors in hospitalised patients.MethodsA systematic literature search was conducted using Medline, Embase, Web of Science and the Cochrane library from database inception through 9 July 2019. We included all studies of hospitalised adult patients that used physician review of case series of admissions and reported the frequency of diagnostic adverse events. Two reviewers independently screened studies for inclusion, extracted study characteristics and assessed risk of bias. Harmful diagnostic error rates were pooled using random-effects meta-analysis.ResultsTwenty-two studies including 80 026 patients and 760 harmful diagnostic errors from consecutive or randomly selected cohorts were pooled. The pooled rate was 0.7% (95% CI 0.5% to 1.1%). Of the 136 diagnostic errors that were described in detail, a wide range of diseases were missed, the most common being malignancy (n=15, 11%) and pulmonary embolism (n=13, 9.6%). In the USA, these estimates correspond to approximately 249 900 harmful diagnostic errors yearly.ConclusionBased on physician review, at least 0.7% of adult admissions involve a harmful diagnostic error. A wide range of diseases are missed, including many common diseases. Fourteen diagnoses account for more than half of all diagnostic errors. The finding that a wide range of common diagnoses are missed implies that efforts to improve diagnosis must target the basic processes of diagnosis, including both cognitive and system-related factors.PROSPERO registration numberCRD42018115186.

2-Methoxyestradiol (2ME) is a major nonestrogenic metabolite of estradiol. Our previous studies suggest that 2ME, in several models of cardiac and/or vascular injury, strongly inhibits cardiac and vascular remodeling. Furthermore, our most recent study shows that in male rats, 2ME attenuates the development and retards the progression of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH), and in female rats, 2ME eliminates the exacerbation of PAH and the increased mortality due to ovariectomy. The current standard of care of patients with PAH includes treatment with an endothelin receptor antagonist (eg, bosentan) or a phosphodiesterase5 inhibitor (eg, sildenafil). Moreover, combination therapy is often prescribed. Therefore, in the present study, we compared the efficacy of 2ME (10 μg · kg(-1) · h(-1), 2ME-10) to the effects of bosentan (200 mg/kg; BOS), sildenafil (50 mg/kg; SIL), and their respective combinations with 2ME-10 (2ME + BOS and 2ME + SIL groups, respectively). Treatments were initiated 12 days after administration of MCT (60 mg/kg). Twenty-eight days after MCT administration, right ventricular peak systolic pressure was measured and morphometric analysis was conducted. 2ME exhibited beneficial effects in pulmonary hypertensive animals and had efficacy comparable to that of BOS and SIL. Importantly, combination treatments had favorable effects on survival, vascular remodeling, and inflammatory response, and the 2ME + SIL combination was significantly more efficacious than any other treatment. These results indicate that 2ME is effective in experimental PAH and suggests that 2ME may provide additional therapeutic benefit over existing drugs used for the treatment of pulmonary hypertension.

BACKGROUND:The number of preventable inpatient deaths in the USA is commonly estimated as between 44,000 and 98,000 deaths annually. Because many inpatient deaths are believed to be preventable, mortality rates are used for quality measures and reimbursement. We aimed to estimate the proportion of inpatient deaths that are preventable. METHODS: A systematic literature search of Medline, Embase, Web of Science, and the Cochrane Library through April 8, 2019, was conducted. We included case series of adult patients who died in the hospital and were reviewed by physicians to determine if the death was preventable. Two reviewers independently performed data extraction and study quality assessment. The proportion of preventable deaths from individual studies was pooled using a random-effects model. RESULTS: Sixteen studies met inclusion criteria. Eight studies of consecutive or randomly selected cohorts including 12,503 deaths were pooled. The pooled rate of preventable mortality was 3.1% (95% CI 2.2-4.1%). Two studies also reported rates of preventable mortality limited to patients expected to live longer than 3 months, ranging from 0.5 to 1.0%. In the USA, these estimates correspond to approximately 22,165 preventable deaths annually and 7150 deaths for patients with greater than 3month life expectancy. DISCUSSION: The number of deaths due to medical error is lower than previously reported and the majority occur in patients with less than 3-month life expectancy. The vast majority of hospital deaths are due to underlying disease. Our results have implications for the use of hospital mortality rates for quality reporting and reimbursement.

SUMMARY Dipeptidyl peptidase IV (DPPIV) inhibitors enhance renovascular responses to angiotensin II (Ang) in spontaneously hypertensive rats (SHR) but not Wistar-Kyoto rats. Because DPPIV inhibitors are often used in the metabolic syndrome, it is important to determine whether in this setting DPPIV inhibition enhances renovascular responses to Ang. Six-week-old Lean-ZSF1 rats (harbor SHR genes; do not have the metabolic syndrome; n=11) and Obese-ZSF1 rats (harbor SHR genes; express the metabolic syndrome; n=10) were obtained from Charles River (Wilmington, MA). At 7 weeks of age, compared to Lean-ZSF1, Obese-ZSF1 demonstrated significant (p<0.05) increases in body weight (262±8 versus 310±13 g), plasma glucose (112±4 versus 153±9 mg/dl), hemoglobin A1c (4.7±0.1 versus 5.8±0.4 %), urinary glucose excretion (0.02±0.003 versus 6.70±1.80 g/kg body weight/24 hours) and urinary protein excretion (100±7 versus 313±77 mg/kg body weight/24 hours). Mean blood pressure was high (133±7 mmHg) in both strains. At 8 weeks of age, kidneys were isolated and perfused. In Lean-ZSF1, renovascular responses (changes in perfusion pressure) to physiological levels of Ang (0.1 nmol/L) were 3.4±1.3 (n=5) and 18.2±5.9 (n=6) mmHg in untreated versus sitagliptin-treated (1 µmol/L) kidneys, respectively. In Obese-ZSF1, renovascular responses to Ang were 5.5±1.3 (n=4) and 17.8±8.2 (n=6) mmHg in untreated versus sitagliptin-treated kidneys, respectively. Analysis of variance revealed a significant (p=0.0367) effect of sitagliptin on renovascular responses to Ang that was strain independent. Conclusion: Sitagliptin enhances renovascular responses to Ang in rats harboring SHR genes, and this effect persists in rats with diabetic nephropathy and the metabolic syndrome.

Pulmonary hypertension (PH) is emerging as a serious complication associated with hemolytic disorders, and plexiform lesions (PXL) have been reported in patients with sickle cell disease (SCD). We hypothesized that repetitive hemolysis per se induces PH and angioproliferative vasculopathy and evaluated a new mechanism for hemolysis-associated PH (HA-PH) that involves the release of adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) from erythrocytes. In healthy rats, repetitive administration of hemolyzed autologous blood (HAB) for 10 days produced reversible pulmonary parenchymal injury and vascular remodeling and PH. Moreover, the combination of a single dose of Sugen-5416 (SU, 200 mg/kg) and 10-day HAB treatment resulted in severe and progressive obliterative PH and formation of PXL (Day 26, right ventricular peak systolic pressure (mmHg): 26.1 ± 1.1, 41.5 ± 0.5 and 85.1 ± 5.9 in untreated, HAB treated and SU+HAB treated rats, respectively). In rats, repetitive administration of HAB increased plasma ADA activity and reduced urinary adenosine levels. Similarly, SCD patients had higher plasma ADA and PNP activity and accelerated adenosine, inosine, and guanosine metabolism than healthy controls. Our study provides evidence that hemolysis per se leads to the development of angioproliferative PH. We also report the development of a rat model of HA-PH that closely mimics pulmonary vasculopathy seen in patients with HA-PH. Finally, this study suggests that in hemolytic diseases released ADA and PNP may increase the risk of PH, likely by abolishing the vasoprotective effects of adenosine, inosine and guanosine. Further characterization of this new rat model of hemolysis-induced angioproliferative PH and additional studies of the role of purines metabolism in HA-PH are warranted.

Objectives: Approximately 3.7% of patients experience adverse events in health care facilities, many of which are preventable. Patient safety requires effective training and an interprofessional culture of safety, but few studies compare the safety skills of different hospital professions. We sought to assess skills in safety hazards identification among staff from different health care disciplines with a pilot study.

Objectives: Little is known about whether improving the quality of written discharge instructions can result in improved readmission rates and whether there are differences in the quality of discharge instructions based on provider and patient characteristics. We set out to determine provider characteristics associated with high quality discharge instructions and whether redesigned discharge instructions would lead to improvement in their quality and reduce hospital readmission rates. Methods:We instituted sequential interventions of educational outreach and a redesigned discharge instructions template and evaluated their quality using 11 metrics based on established best practices and subsequent 30-day readmission rates.Results: In total, 225 randomly selected charts were reviewed during a 15-month period. An average of 5.36 quality metrics were completed before our interventions, which increased to 5.61 after educational outreach and 7.16 after the template was redesigned. The risk standardized 30-day readmission rate fluctuated from a baseline of 10.48% to 12.71% and 10.97% following each intervention, respectively. Medical students completed significantly more quality metrics than interns, residents, or attendings (P < 0.05 for all) and residents completed significantly more than attendings (P = 0.014).Conclusions: Although an education intervention was ineffective in improving discharge instruction quality, a redesigned discharge instructions template did improve the quality of patient discharge instructions. Neither intervention led to a meaningful change in readmission rates. We also found significant differences in the quality of discharge instructions based on the level of training of the author of the discharge instructions.