The role of nuclear receptor corepressor (NCoR) in thyroid hormone (TH) action has been difficult to discern because global deletion of NCoR is embryonic lethal. To circumvent this, we developed mice that globally express a modified NCoR protein (NCoRΔID) that cannot be recruited to the thyroid hormone receptor (TR). These mice present with low serum T(4) and T(3) concentrations accompanied by normal TSH levels, suggesting central hypothyroidism. However, they grow normally and have increased energy expenditure and normal or elevated TR-target gene expression across multiple tissues, which is not consistent with hypothyroidism. Although these findings imply an increased peripheral sensitivity to TH, the hypothalamic-pituitary-thyroid axis is not more sensitive to acute changes in TH concentrations but appears to be reset to recognize the reduced TH levels as normal. Furthermore, the thyroid gland itself, although normal in size, has reduced levels of nonthyroglobulin-bound T(4) and T(3) and demonstrates decreased responsiveness to TSH. Thus, the TR-NCoR interaction controls systemic TH sensitivity as well as the set point at all levels of the hypothalamic-pituitary-thyroid axis. These findings suggest that NCoR levels could alter cell-specific TH action that would not be reflected by the serum TSH.
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.
As anyone who has suffered through a head cold knows, food eaten when the olfactory system is impaired tastes “wrong”–an experience that leads many to conclude that taste stimuli are processed normally only when the olfactory system is unimpaired. Evidence that taste system function influences olfactory perception, meanwhile, has been vanishingly rare. Here, we demonstrate just such an influence, showing that if taste cortex is inactivated when an odor is first presented, later presentations are properly appreciated only if taste cortex is again inactivated.
IMPORTANCE Left ventricular assist devices (LVADs) improve outcomes in patients with advanced heart failure, but little is known about the role of neurohormonal blockade (NHB) in treating these patients.OBJECTIVE To analyze the association between NHB blockade and outcomes in patients with LVADs. DESIGN, SETTING, AND PARTICIPANTSThis retrospective cohort analysis of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) included patients from more than 170 centers across the United States and Canada with continuous flow LVADs from 2008 to 2016 who were alive with the device in place at 6 months after implant. The data were analyzed between February and November 2019.EXPOSURES Patients were stratified based on exposure to NHB and represented all permutations of the following drug classes: angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, β-blockers, and mineralocorticoid antagonists. MAIN OUTCOMES AND MEASURESThe outcomes of interest were survival at 4 years and quality of life at 2 years based on Kansas City Cardiomyopathy Questionnaire scores and a 6-minute walk test.RESULTS A total of 12 144 patients in INTERMACS met inclusion criteria, of whom 2526 (20.8% ) were women, 8088 (66.6%) were white, 3024 (24.9%) were African American, and 753 (6.2%) were Hispanic; the mean (SD) age was 56.8 (12.9) years. Of these, 10 419 (85.8%) were receiving NHB. Those receiving any NHB medication at 6 months had a better survival rate at 4 years compared with patients not receiving NHB (56.0%; 95% CI, 54.5%-57.5% vs 43.9%; 95% CI, 40.5%-47.7%). After sensitivity analyses with an adjusted model, this trend persisted with patients receiving triple therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, β-blocker, and mineralocorticoid antagonist having the lowest hazard of death compared with patients in the other groups (hazard ratio, 0.34; 95% CI, 0.28-0.41). Compared with patients not receiving NHB, use of NHB was associated with a higher Kansas City Cardiomyopathy Questionnaire score (66.6; bootstrapped 95% CI, bootstrapped 95% CI,; P = .02) and a 6-minute walk test (1103 ft; bootstrapped 95% CI, 1084-1123 ft vs 987 ft; bootstrapped 95% CI, 913-1060 ft; P < .001).CONCLUSIONS AND RELEVANCE Among patients with LVADs who tolerated NHB therapy, continued treatment was associated with improved survival and quality of life. The optimal heart failure regimen for patients after LVAD implant may be the initiation and continuation of guideline-directed medical therapy.
Background Previous studies examining the use of direct oral anticoagulants (DOACs) in atrial fibrillation (AF) have largely focused on patients newly initiating therapy. Little is known about the prevalence/patterns of switching to DOACs among AF patients initially treated with warfarin. Hypothesis To examine patterns of anticoagulation among patients chronically managed with warfarin upon the availability of DOACs and identify patient/practice‐level factors associated with switching from chronic warfarin therapy to a DOAC. Methods Prospective cohort study of AF patients in the NCDR PINNACLE registry prescribed warfarin between May 1, 2008 and May 1, 2015. Patients were followed at least 1 year (median length of follow‐up 375 days, IQR 154‐375) through May 1, 2016 and stratified as follows: continued warfarin, switched to DOAC, or discontinued anticoagulation. To identify significant predictors of switching, a three‐level multivariable hierarchical regression was developed. Results Among 383 008 AF patients initially prescribed warfarin, 16.3% (n = 62 620) switched to DOACs, 68.8% (n = 263 609) continued warfarin, and 14.8% (n = 56 779) discontinued anticoagulation. Among those switched, 37.6% received dabigatran, 37.0% rivaroxaban, 24.4% apixaban, and 1.0% edoxaban. Switched patients were more likely to be younger, women, white, and have private insurance (all P < .001). Switching was less likely with increased stroke risk (OR, 0.92; 95%CI, 0.91‐0.93 per 1‐point increase CHA 2 DS 2 ‐VASc), but more likely with increased bleeding risk (OR, 1.12; 95%CI, 1.10‐1.13 per 1‐point increase HAS‐BLED). There was substantial variation at the practice‐level (MOR, 2.33; 95%CI, 2.12‐2.58) and among providers within the same practice (MOR, 1.46; 95%CI, 1.43‐1.49). Conclusions Among AF patients treated with warfarin between October 1, 2010 and May 1, 2016, one in six were switched to DOACs, with differences across sociodemographic/clinical characteristics and substantial practice‐level variation. In the context of current guidelines which favor DOACs over warfarin, these findings help benchmark performance and identify areas of improvement.
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.
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