Detyrosinated microtubules buckle and bear load in contracting cardiomyocytes
The microtubule (MT) cytoskeleton can transmit mechanical signals and resist compression in contracting cardiomyocytes. How MTs perform these roles remains unclear because of difficulties in observing MTs during the rapid contractile cycle. Here, we used high spatial and temporal resolution imaging to characterize MT behavior in beating mouse myocytes. MTs deformed under contractile load into sinusoidal buckles, a behavior dependent on posttranslational “detyrosination” of α-tubulin. Detyrosinated MTs associated with desmin at force-generating sarcomeres. When detyrosination was reduced, MTs uncoupled from sarcomeres and buckled less during contraction, which allowed sarcomeres to shorten and stretch with less resistance. Conversely, increased detyrosination promoted MT buckling, stiffened the myocyte, and correlated with impaired function in cardiomyopathy. Thus, detyrosinated MTs represent tunable, compression-resistant elements that may impair cardiac function in disease.
Detyrosinated microtubules buckle and bear load in contracting cardiomyocytes
Analysis. Medical error is not included on death certificates or in rankings of cause of death. Martin Makary and Michael Daniel assess its contribution to mortality and call for better reporting.
Risk literacy in medical decision-making – How can we better represent the statistical structure of risk?
Imagine that you have received a positive result on a routine cancer screening test. Follow-up biopsies were inconclusive, and the decision to treat aggressively or monitor conservatively is yours. Consider the following information: 0.1% of the population has a terminal version of this form of cancer, 99% of those people will appear positive on the test you have been administered, and 5% of those without terminal cancer will still have a benign condition that tests positive. Given your test result, what is the probability that you have terminal cancer and should treat it aggressively? When judging risks and trying to predict the future, how should you decide? We need to better understand the structure of risks and how the human mind creates representations of risk and probability.
Objectives To determine whether dietary pattern assessed by a simple self-administered food frequency questionnaire is associated with major adverse cardiovascular events (MACE) in high-risk patients with stable coronary artery disease.
Background A Mediterranean dietary pattern has been associated with lower cardiovascular (CV) mortality. It is less certain whether foods common in western diets are associated with CV risk.
Methods At baseline, 15 482 (97.8%) patients (mean age 67 ± 9 years) with stable coronary heart disease from 39 countries who participated in the Stabilisation of atherosclerotic plaque by initiation of darapladib therapy (STABILITY) trial completed a life style questionnaire which included questions on common foods. A Mediterranean diet score (MDS) was calculated for increasing consumption of whole grains, fruits, vegetables, legumes, fish, and alcohol, and for less meat, and a ‘Western diet score’ (WDS) for increasing consumption of refined grains, sweets and deserts, sugared drinks, and deep fried foods. A multi-variable Cox proportional hazards models assessed associations between MDS or WDS and MACE, defined as CV death, non-fatal myocardial infarction, or non-fatal stroke.
Results After a median follow-up of 3.7 years MACE occurred in 7.3% of 2885 subjects with an MDS ≥15, 10.5% of 4018 subjects with an MDS of 13–14, and 10.8% of 8579 subjects with an MDS ≤12. A one unit increase in MDS >12 was associated with lower MACE after adjusting for all covariates (+1 category HR 0.95, 95% CI 0.91, 0.98, P = 0.002). There was no association between WDS (adjusted model +1 category HR 0.99, 95% CI 0.97, 1.01) and MACE.
Conclusion Greater consumption of healthy foods may be more important for secondary prevention of coronary artery disease than avoidance of less healthy foods typical of Western diets.
Ralph A. H. Stewart1*, Lars Wallentin2, Jocelyne Benatar1, Nicolas Danchin3, Emil Hagstro¨m2, Claes Held2, Steen Husted4, Eva Lonn5, Amanda Stebbins6, Karen Chiswell6, Ola Vedin2, David Watson7, and Harvey D. White
Pioglitazone after Ischemic Stroke or Transient Ischemic Attack
BACKGROUND Patients with ischemic stroke or transient ischemic attack (TIA) are at increased risk for future cardiovascular events despite current preventive therapies. The identification of insulin resistance as a risk factor for stroke and myocardial infarction raised the possibility that pioglitazone, which improves insulin sensitivity, might benefit patients with cerebrovascular disease.
METHODS In this multicenter, double-blind trial, we randomly assigned 3876 patients who had had a recent ischemic stroke or TIA to receive either pioglitazone (target dose, 45 mg daily) or placebo. Eligible patients did not have diabetes but were found to have insulin resistance on the basis of a score of more than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index. The primary outcome was fatal or nonfatal stroke or myocardial infarction.
RESULTS By 4.8 years, a primary outcome had occurred in 175 of 1939 patients (9.0%) in the pioglitazone group and in 228 of 1937 (11.8%) in the placebo group (hazard ratio in the pioglitazone group, 0.76; 95% confidence interval [CI], 0.62 to 0.93; P=0.007). Diabetes developed in 73 patients (3.8%) and 149 patients (7.7%), respectively (hazard ratio, 0.48; 95% CI, 0.33 to 0.69; P<0.001). There was no significant between-group difference in all-cause mortality (hazard ratio, 0.93; 95% CI, 0.73 to 1.17; P=0.52). Pioglitazone was associated with a greater frequency of weight gain exceeding 4.5 kg than was placebo (52.2% vs. 33.7%, P<0.001), edema (35.6% vs. 24.9%, P<0.001), and bone fracture requiring surgery or hospitalization (5.1% vs. 3.2%, P=0.003).
CONCLUSIONS In this trial involving patients without diabetes who had insulin resistance along with a recent history of ischemic stroke or TIA, the risk of stroke or myocardial infarction was lower among patients who received pioglitazone than among those who received placebo. Pioglitazone was also associated with a lower risk of diabetes but with higher risks of weight gain, edema, and fracture. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT00091949.)
W.N. Kernan, C.M. Viscoli, K.L. Furie, L.H. Young, S.E. Inzucchi, M. Gorman, P.D. Guarino, A.M. Lovejoy, P.N. Peduzzi, R. Conwit, L.M. Brass,* G.G. Schwartz, H.P. Adams, Jr., L. Berger, A. Carolei, W. Clark, B. Coull, G.A. Ford, D. Kleindorfer, J.R. O’Leary, M.W. Parsons, P. Ringleb, S. Sen, J.D. Spence, D. Tanne, D. Wang, and T.R. Winder
N Engl J Med 2016;374:1321-31. DOI: 10.1056/NEJMoa1506930 Copyright © 2016 Massachusetts Medical Society
Healthcare has no doubt made giant strides in patient safety in recent years: According to an HHS report released in December, hospital-acquired condition rates dropped 17 percent from 2010 to 2014, leading to 87,000 fewer patient deaths in hospitals.
Becker’s Hospital Review, January 12, 2016
Shannon Barnet, Max Green and Heather Punke
Hospital readmission rates following surgery are increasingly being used as a marker of quality of care and are used in pay-for-performance metrics. To our knowledge, comprehensive data on readmissions to the initial hospital or a different hospital after emergency general surgery (EGS) procedures do not exist.
Objective To define readmission rates and identify risk factors for readmission after common EGS procedures.
Design, Setting, and Participants Patients undergoing EGS, as defined by the American Association for the Surgery of Trauma, were identified in the California State Inpatient Database (2007-2011) on January 15, 2015. Patients were 18 years and older. We identified the 5 most commonly performed EGS procedures in each of 11 EGS diagnosis groups. Patient demographics (sex, age, race/ethnicity, and insurance type) as well as Charlson Comorbidity Index score, length of stay, complications, and discharge disposition were collected. Factors associated with readmission were determined using multivariate logistic regression models analysis.
Main Outcomes and Measures Thirty-day hospital readmission.
Results Among 177 511 patients meeting inclusion criteria, 57.1% were white, 48.8% were privately insured, and most were 45 years and older (51.3%). Laparoscopic appendectomy (35.2%) and laparoscopic cholecystectomy (19.3%) were the most common procedures. The overall 30-day readmission rate was 5.91%. Readmission rates ranged from 4.1% (upper gastrointestinal) to 16.8% (cardiothoracic). Of readmitted patients, 16.8% were readmitted at a different hospital. Predictors of readmission included Charlson Comorbidity Index score of 2 or greater (adjusted odds ratio: 2.26 [95% CI, 2.14-2.39]), leaving against medical advice (adjusted odds ratio: 2.24 [95% CI, 1.89-2.66]), and public insurance (adusted odds ratio: 1.55 [95% CI, 1.47-1.64]). The most common reasons for readmission were surgical site infections (16.9%), gastrointestinal complications (11.3%), and pulmonary complications (3.6%).
Conclusions and Relevance Readmission after EGS procedures is common and varies widely depending on patient factors and diagnosis categories. One in 5 readmitted patients will go to a different hospital, causing fragmentation of care and potentially obscuring the utility of readmission as a quality metric. Assisting socially vulnerable patients and reducing postoperative complications, including infections, are targets to reduce readmissions.
Low-Dose Acetylsalicylic Acid Treatment and Impact on Short-Term Mortality in Staphylococcus aureus Bloodstream Infection: A Propensity Score–Matched Cohort Study
Objectives: Staphylococcus aureus bloodstream infection is associated with considerable mortality. Experimental models suggest a direct antistaphylococcal effect of acetylsalicylic acid, but evidence from human studies is scarce. We aimed to estimate the effect of low-dose acetylsalicylic acid therapy on mortality in bloodstream infections caused by S. aureus compared with Escherichia coli.
Design: Retrospective cohort study based on observational data from 838 and 602 episodes of S. aureus and E. coli bloodstream infection, respectively. Setting: Swiss tertiary referral center. Patients: Adult patients with S. aureus and E. coli bloodstream infection, respectively, categorized according to low-dose acetylsalicylic acid therapy as outpatient or inpatient before bacteremia.
Measurements and Main Results: Thirty-day all-cause mortality was analyzed in a total of 314 propensity score-matched S. aureus bloodstream infection and in 268 E. coli bloodstream infection patients, respectively (1:1 match of low-dose acetylsalicylic acid users and nonusers). S. aureus bloodstream infection cases and controls were equally matched for relevant confounders except treatment with statins, which was strongly associated with a low-dose acetylsalicylic acid use (p < 0.001). At day 30, 12.1% of cases and 27.4% of controls had died (hazard ratio, 0.40; p < 0.001). Low-dose acetylsalicylic acid use was associated with a reduced 30-day all-cause mortality in multivariate analysis (hazard ratio, 0.38; 95% CI, 0.21-0.69; p = 0.001) of matched patients and also of the entire cohort (n = 689) after adjustment for the propensity score (hazard ratio, 0.58, 95% CI, 0.34-0.98; p = 0.04). In contrast, low-dose acetylsalicylic acid use was not associated with the primary endpoint in patients with E. coli bloodstream infection (hazard ratio, 0.78; 95% CI, 0.40-1.55; p = 0.8).
Conclusions: Low-dose acetylsalicylic acid at the time of bloodstream infection was strongly associated with a reduced short-term mortality in patients with S. aureus bloodstream infection. Future studies are required to investigate if early low-dose acetylsalicylic acid is a suitable treatment in patients with S. aureus bloodstream infection.
Osthoff, Michael MD; Sidler, Jan A. MD; Lakatos, Botond MD; Frei, Reno MD; Dangel, Marc MPH; Weisser, Maja MD; Battegay, Manuel MD; Widmer, Andreas F. MD, MS
Copyright (C) by 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Importance Children living in poverty generally perform poorly in school, with markedly lower standardized test scores and lower educational attainment. The longer children live in poverty, the greater their academic deficits. These patterns persist to adulthood, contributing to lifetime-reduced occupational attainment.
Objective To determine whether atypical patterns of structural brain development mediate the relationship between household poverty and impaired academic performance.
Design, Setting, and Participants Longitudinal cohort study analyzing 823 magnetic resonance imaging scans of 389 typically developing children and adolescents aged 4 to 22 years from the National Institutes of Health Magnetic Resonance Imaging Study of Normal Brain Development with complete sociodemographic and neuroimaging data. Data collection began in November 2001 and ended in August 2007. Participants were screened for a variety of factors suspected to adversely affect brain development, recruited at 6 data collection sites across the United States, assessed at baseline, and followed up at 24-month intervals for a total of 3 periods. Each study center used community-based sampling to reflect regional and overall US demographics of income, race, and ethnicity based on the US Department of Housing and Urban Development definitions of area income. One-quarter of sample households reported the total family income below 200% of the federal poverty level. Repeated observations were available for 301 participants.
Exposure Household poverty measured by family income and adjusted for family size as a percentage of the federal poverty level.
Main Outcomes and Measures Children’s scores on cognitive and academic achievement assessments and brain tissue, including gray matter of the total brain, frontal lobe, temporal lobe, and hippocampus.
Results Poverty is tied to structural differences in several areas of the brain associated with school readiness skills, with the largest influence observed among children from the poorest households. Regional gray matter volumes of children below 1.5 times the federal poverty level were 3 to 4 percentage points below the developmental norm (P < .05). A larger gap of 8 to 10 percentage points was observed for children below the federal poverty level (P < .05). These developmental differences had consequences for children’s academic achievement. On average, children from low-income households scored 4 to 7 points lower on standardized tests (P < .05). As much as 20% of the gap in test scores could be explained by maturational lags in the frontal and temporal lobes.
Conclusions and Relevance The influence of poverty on children’s learning and achievement is mediated by structural brain development. To avoid long-term costs of impaired academic functioning, households below 150% of the federal poverty level should be targeted for additional resources aimed at remediating early childhood environments.
Nicole L. Hair, PhD; Jamie L. Hanson, PhD; Barbara L. Wolfe, PhD; Seth D. Pollak, PhD
JAMA Pediatr. 2015;169(9):822-829. doi:10.1001/jamapediatrics.2015.1475.
Association Between Treatment at a High-Volume Facility and Improved Survival for Radiation-Treated Men With High-Risk Prostate Cancer
Purpose: Although the association between higher hospital volume and improved outcomes has been well-documented in surgery, there is little data about whether this effect exists for radiation-treated patients. We investigated whether treatment at a radiation facility that treats a high volume of prostate cancer patients is associated with improved survival for men with high-risk prostate cancer. Methods and Materials: We used the National Cancer Database (NCDB) to identity patients diagnosed with prostate cancer from 2004 to 2006. The radiation case volume (RCV) of each hospital was based on its number of radiation-treated prostate cancer patients. We used propensity-score based analysis to compare the overall survival (OS) of high-risk prostate cancer patients in high versus low RCV hospitals. Primary endpoint is overall survival. Covariates adjusted for were tumor characteristics, sociodemographic factors, radiation type, and use of androgen deprivation therapy (ADT). Results: A total of 19,565 radiation-treated high-risk patients were identified. Median follow-up was 81.0 months (range: 1-108 months). When RCV was coded as a continuous variable, each increment of 100 radiation-managed patients was associated with improved OS (adjusted hazard ratio [AHR]: 0.97; 95% confidence interval [CI]: 0.95- 0.98; P<.0001) after adjusting for known confounders. For illustrative purposes, when RCV was dichotomized at the 80th percentile (43 patients/year), high RCV was associated with improved OS (7-year overall survival 76% vs 74%, log-rank test PZ.0005; AHR: 0.91, 95% CI: 0.86-0.96, PZ.0005). This association remained significant when RCV was dichotomized at 75th (37 patients/year), 90th (60 patients/year), and 95th (84 patients/year) percentiles but not the 50th (19 patients/year). Conclusions: Our results suggest that treatment at centers with higher prostate cancer radiation case volume is associated with improved OS for radiation-treated men with high-risk prostate cancer.
Int J Radiation Oncol Biol Phys, Vol. 94, No. 4, pp. 683e690, 2016
Copyright: 2016 The Authors
Yu-Wei Chen, MD, MS, Brandon A. Mahal, MD, Vinayak Muralidhar, MSc, Michelle Nezolosky, BA, Clair J. Beard, MD, Robert B. Den, MD, Felix Y. Feng, MD,Karen E. Hoffman, MD, MPH, MHSc, Neil E. Martin, MD, MPH, Peter F. Orio, DO, MS, and Paul L. Nguyen, MD