Sex-differences in human liver gene expression were characterized on a genome-wide scale using a large liver sample collection, allowing for detection of small expression differences with high ...statistical power. 1,249 sex-biased genes were identified, 70% showing higher expression in females. Chromosomal bias was apparent, with female-biased genes enriched on chrX and male-biased genes enriched on chrY and chr19, where 11 male-biased zinc-finger KRAB-repressor domain genes are distributed in six clusters. Top biological functions and diseases significantly enriched in sex-biased genes include transcription, chromatin organization and modification, sexual reproduction, lipid metabolism and cardiovascular disease. Notably, sex-biased genes are enriched at loci associated with polygenic dyslipidemia and coronary artery disease in genome-wide association studies. Moreover, of the 8 sex-biased genes at these loci, 4 have been directly linked to monogenic disorders of lipid metabolism and show an expression profile in females (elevated expression of ABCA1, APOA5 and LDLR; reduced expression of LIPC) that is consistent with the lower female risk of coronary artery disease. Female-biased expression was also observed for CYP7A1, which is activated by drugs used to treat hypercholesterolemia. Several sex-biased drug-metabolizing enzyme genes were identified, including members of the CYP, UGT, GPX and ALDH families. Half of 879 mouse orthologs, including many genes of lipid metabolism and homeostasis, show growth hormone-regulated sex-biased expression in mouse liver, suggesting growth hormone might play a similar regulatory role in human liver. Finally, the evolutionary rate of protein coding regions for human-mouse orthologs, revealed by dN/dS ratio, is significantly higher for genes showing the same sex-bias in both species than for non-sex-biased genes. These findings establish that human hepatic sex differences are widespread and affect diverse cell metabolic processes, and may help explain sex differences in lipid profiles associated with sex differential risk of coronary artery disease.
Abstract Neuropathological and neuroimaging studies have consistently demonstrated degeneration of monoamine systems, especially the serotonin system, in normal aging and Alzheimer's disease. The ...evidence for degeneration of the serotonin system in mild cognitive impairment is limited. Thus, the goal of the present study was to measure the serotonin transporter in vivo in mild cognitive impairment and healthy controls. The serotonin transporter is a selective marker of serotonin terminals and of the integrity of serotonin projections to cortical, subcortical and limbic regions, as well as the cell bodies of origin (raphe nuclei). Twenty-eight participants with mild cognitive impairment (age 66.6 ± 6.9, 16 males) and 28 healthy, cognitively normal, demographically matched controls (age 66.2 ± 7.1, 15 males) underwent magnetic resonance imaging for measurement of grey matter volumes and high-resolution positron emission tomography with well-established radiotracers for the serotonin transporter and regional cerebral blood flow. Beta-amyloid imaging was performed to describe, in combination with the neuropsychological testing, the likelihood of subsequent cognitive decline in the participants with mild cognitive impairment. The following hypotheses were tested: 1) the serotonin transporter would be lower in mild cognitive impairment compared to controls in cortical and limbic regions, 2) in mild cognitive impairment relative to controls, serotonin transporter would be lower to a greater extent and more widespread than lower grey matter volumes or regional cerebral blood flow and 3) lower cortical and limbic serotonin transporters would be correlated with greater deficits in auditory-verbal and visual-spatial memory in mild cognitive impairment, not in controls. Reduced serotonin transporter availability was observed in mild cognitive impairment compared to controls in cortical and limbic areas typically affected by Alzheimer's disease pathology, as well as in sensory and motor areas, striatum and thalamus that are relatively spared in Alzheimer's disease. The reduction of the serotonin transporter in mild cognitive impairment was greater than grey matter atrophy or reductions in regional cerebral blood flow compared to controls. Lower cortical serotonin transporters were associated with worse performance on tests of auditory-verbal and visual-spatial memory in mild cognitive impairment, not in controls. The serotonin system may represent an important target for prevention and treatment of MCI, particularly the post-synaptic receptors (5-HT4 and 5-HT6), which may not be as severely affected as presynaptic aspects of the serotonin system.
Background Diagnostic errors cause substantial preventable harm, but national estimates vary widely from 40,000 to 4 million annually. This cross-sectional analysis of a large medical malpractice ...claims database was the first phase of a three-phase project to estimate the US burden of serious misdiagnosis-related harms. Methods We sought to identify diseases accounting for the majority of serious misdiagnosis-related harms (morbidity/mortality). Diagnostic error cases were identified from Controlled Risk Insurance Company (CRICO)'s Comparative Benchmarking System (CBS) database (2006-2015), representing 28.7% of all US malpractice claims. Diseases were grouped according to the Agency for Healthcare Research and Quality (AHRQ) Clinical Classifications Software (CCS) that aggregates the International Classification of Diseases diagnostic codes into clinically sensible groupings. We analyzed vascular events, infections, and cancers (the "Big Three"), including frequency, severity, and settings. High-severity (serious) harms were defined by scores of 6-9 (serious, permanent disability, or death) on the National Association of Insurance Commissioners (NAIC) Severity of Injury Scale. Results From 55,377 closed claims, we analyzed 11,592 diagnostic error cases median age 49, interquartile range (IQR) 36-60; 51.7% female. These included 7379 with high-severity harms (53.0% death). The Big Three diseases accounted for 74.1% of high-severity cases (vascular events 22.8%, infections 13.5%, and cancers 37.8%). In aggregate, the top five from each category (n = 15 diseases) accounted for 47.1% of high-severity cases. The most frequent disease in each category, respectively, was stroke, sepsis, and lung cancer. Causes were disproportionately clinical judgment factors (85.7%) across categories (range 82.0-88.8%). Conclusions The Big Three diseases account for about three-fourths of serious misdiagnosis-related harms. Initial efforts to improve diagnosis should focus on vascular events, infections, and cancers.
•Previous studies show serotonin degeneration in transgenic amyloid mouse models.•A pattern of decreased 5-HTT and increased amyloid distinguishes MCIs from controls.•Decreased 5-HTT and increased ...amyloid is correlated with memory deficits in MCI.
Degeneration of the serotonin system has been observed in Alzheimer’s disease (AD) and in mild cognitive impairment (MCI). In transgenic amyloid mouse models, serotonin degeneration is detected prior to widespread cortical beta-amyloid (Aβ) deposition, also suggesting that serotonin degeneration may be observed in preclinical AD.
The differences in the distribution of serotonin degeneration (reflected by the loss of the serotonin transporter, 5-HTT) relative to Aβ deposition was measured with positron emission tomography in a group of individuals with MCI and a group of healthy older adults. A multi-modal partial least squares (mmPLS) algorithm was applied to identify the spatial covariance pattern between 5-HTT availability and Aβ deposition.
Forty-five individuals with MCI and 35 healthy older adults were studied, 22 and 27 of whom were included in the analyses who were “amyloid positive” and “amyloid negative”, respectively. A pattern of lower cortical, subcortical and limbic 5-HTT availability and higher cortical Aβ deposition distinguished the MCI from the healthy older control participants. Greater expression of this pattern was correlated with greater deficits in memory and executive function in the MCI group, not in the control group.
A spatial covariance pattern of lower 5-HTT availability and Aβ deposition was observed to a greater extent in an MCI group relative to a control group and was associated with cognitive impairment in the MCI group. The results support the application of mmPLS to understand the neurochemical changes associated with Aβ deposition in the course of preclinical AD.
2 Educational approaches should not only improve knowledge but also enhance skills and behaviors, encouraging putting antimicrobial stewardship into practice.3 A review showed that interactive ...practice-based seminars, online modules, motivational interviewing, academic detailing, social media engagement, and engagement of learners from different and training levels have been helpful in reducing antibiotic use.4 Education strategies focused on a specific antimicrobial stewardship goal (for example, multifaceted or syndrome-specific interventions) can be successful.5 Facility-specific practice guidelines with a strong implementation and dissemination plan are also recommended as an education-based approach to antimicrobial stewardship.1 Innovative curricula have been particularly effective. An interactive educational seminar for family practitioners focused on communication strategies reduced antibiotic prescribing for respiratory tract infections for 3.5 years.6 An initiative focused on clinicians at multiple training levels led to a sustained improvement in antibiotic prescribing 20 months after the intervention.7 The initiative included second year medical students (a tool kit, simulated patient cases, antibiograms, and an app), internal medicine residents (case-based lectures and antibiograms), infectious diseases fellows (interactive antimicrobial stewardship cases in a workshop), and internal medicine attending physicians (a tool allowing internal medicine attending physicians to be antimicrobial stewardship extenders).7 These innovative curricula demonstrate that educational interventions can be important antimicrobial stewardship interventions. Enhanced communication skills and C-reactive protein point-of-care testing for respiratory tract infection: 3.5-year follow-up of a cluster randomized trial.
To summarize the state of evidence related to undergraduate medical education (UME) accreditation internationally, describe from whom and where the evidence has come, and identify opportunities for ...further investigation.
The authors searched Embase, ERIC, PubMed, and Scopus from inception through January 31, 2018, without language restrictions, to identify peer-reviewed articles on UME accreditation. Articles were classified as scholarship if all Glassick's criteria were met and as nonscholarship if not all were met. Author, accrediting agency, and study characteristics were analyzed.
Database searching identified 1,379 nonduplicate citations, resulting in 203 unique, accessible articles for full-text review. Of these and with articles from hand searching added, 36 articles were classified as scholarship (30 as research) and 85 as nonscholarship. Of the 36 scholarship and 85 nonscholarship articles, respectively, 21 (58%) and 44 (52%) had an author from the United States or Canada, 8 (22%) and 11 (13%) had an author from a low- or middle-income country, and 16 (44%) and 43 (51%) had an author affiliated with a regulatory authority. Agencies from high-income countries were featured most often (scholarship: 28/60 47%; nonscholarship: 70/101 69%). Six (17%) scholarship articles reported receiving funding. All 30 research studies were cross-sectional or retrospective, 12 (40%) reported only analysis of accreditation documents, and 5 (17%) attempted to link accreditation with educational outcomes.
Limited evidence exists to support current UME accreditation practices or guide accreditation system creation or enhancement. More research is required to optimize UME accreditation systems' value for students, programs, and society.
Diagnostic errors cause substantial preventable harms worldwide, but rigorous estimates for total burden are lacking. We previously estimated diagnostic error and serious harm rates for key dangerous ...diseases in major disease categories and validated plausible ranges using clinical experts.
We sought to estimate the annual US burden of serious misdiagnosis-related harms (permanent morbidity, mortality) by combining prior results with rigorous estimates of disease incidence.
Cross-sectional analysis of US-based nationally representative observational data. We estimated annual incident vascular events and infections from 21.5 million (M) sampled US hospital discharges (2012-2014). Annual new cancers were taken from US-based registries (2014). Years were selected for coding consistency with prior literature. Disease-specific incidences for 15 major vascular events, infections and cancers ('Big Three' categories) were multiplied by literature-based rates to derive diagnostic errors and serious harms. We calculated uncertainty estimates using Monte Carlo simulations. Validity checks included sensitivity analyses and comparison with prior published estimates.
Annual US incidence was 6.0 M vascular events, 6.2 M infections and 1.5 M cancers. Per 'Big Three' dangerous disease case, weighted mean error and serious harm rates were 11.1% and 4.4%, respectively. Extrapolating to all diseases (including non-'Big Three' dangerous disease categories), we estimated total serious harms annually in the USA to be 795 000 (plausible range 598 000-1 023 000). Sensitivity analyses using more conservative assumptions estimated 549 000 serious harms. Results were compatible with setting-specific serious harm estimates from inpatient, emergency department and ambulatory care. The 15 dangerous diseases accounted for 50.7% of total serious harms and the top 5 (stroke, sepsis, pneumonia, venous thromboembolism and lung cancer) accounted for 38.7%.
An estimated 795 000 Americans become permanently disabled or die annually across care settings because dangerous diseases are misdiagnosed. Just 15 diseases account for about half of all serious harms, so the problem may be more tractable than previously imagined.
To assess if having a mental health and/or substance use disorder is associated with a missed acute myocardial infarction diagnosis in the emergency department (ED).
This was a retrospective cohort ...analysis (2009 to 2017) of adult ED encounters at Kaiser Permanente Southern California. We used the validated symptom-disease pair analysis of diagnostic error methodological approach to “look back” and “look forward” and identify missed acute myocardial infarctions within 30 days of a treat-and-release ED visit. We use adjusted logistic regression to report the odds of missed acute myocardial infarction among patients with a history of mental health and/or substance use disorders.
The look-back analysis identified 44,473 acute myocardial infarction hospital encounters; 574 (1.3%) diagnoses were missed. The odds of missed diagnoses were higher in patients with mental health disorders (odds ratio OR 1.48, 95% confidence interval CI 1.23 to 1.77) but not in those with substance abuse disorders (OR 1.22, 95% CI 0.91 to 1.62). The highest risk was observed in those with co-occurring disorders (OR 1.90, 95% CI 1.30 to 2.76). The look-forward analysis identified 325,088 chest pain/dyspnea ED encounters; 508 (0.2%) were missed acute myocardial infarctions. No significant associations of missed acute myocardial infarction were revealed in either group (mental health disorder: OR 0.92, 95% CI 0.71 to 1.18; substance use disorder: OR 1.22, 95% CI 0.80 to 1.85).
The look-back analysis identified patients with mental illness at increased risk of missed acute myocardial infarction diagnosis, with the highest risk observed in those with a history of comorbid substance abuse. Having substance use disorders alone did not increase this risk in either cohort. The look-forward analysis revealed challenges in prospectively identifying high-risk patients to target for improvement.
Background: Health care quality is frequently described with measures representing the overall performance of a health care system. Despite the growing attention to overuse of health care resources, ...there is little experience with aggregate measures of overuse. Objective: To identify a set of possible indicators of overuse that can be operationalized with claims data and to describe variation in these indicators across the hospital referral regions (HRRs). Design: Using an environmental scan, we identified published descriptions of overused procedures. We assessed each procedure's feasibility for measurement with claims and developed algorithms for occurrences of procedures in patients unlikely to benefit. Using a 5% sample of Medicare claims from 2008, we calculated summary statistics to illustrate variance in the use across HRRs. Results: A total of 613 procedures were identified as overused; 20 had abundant frequency and variance to be possible measures of systematic overuse. These included 13 diagnostic tests, 2 tests for screening, 1 for monitoring, and 4 therapeutic procedures. The usage varied markedly across HRRs. For illustration, 1 HRR used computed tomography for rhinosinusitis diagnosis in 80 of 1000 beneficiaries (mean usage across HRRs was 14/1000). Among 1,451,142 beneficiaries, 14% had at least one overuse event (range, 8.4%–27%). Conclusions: We identified a set of overused procedures that may be used as measures of overuse and that demonstrate significant variance in their usage. The implication is that an index of overuse might be built from these indicators that would reveal systematic patterns of overuse within regions. Alternatively, these indicators may be valuable in the quality improvement efforts.
BACKGROUND:Overuse can be defined as use of a service when the risk of harm exceeds its likely benefit. Yet, there has been little work with composite measures of overuse.
OBJECTIVE:Our goal was to ...create a composite measure of overuse with claims data.
DESIGN:Observational study using 5% of Medicare claims from 2008.
SETTING:All inpatient and outpatient settings of care, excluding nursing homes.
PARTICIPANTS:Older Americans receiving health care services in hospitals or outpatient settings.
MEASURES:We applied algorithms to identify specific cases of overuse across 20 previously identified procedures and used multilevel modeling techniques to examine variation in overuse across all procedures. Included in the model were patient-level factors and both procedure and regional fixed effects for the 306 hospital referral regions (HRR). These estimated regional fixed effects, representing the systematic, region variation in overuse across all measures, was then normalized compared with the overall average to generate a Z score for each HRR. The resulting “Overuse Index” was then compared with total costs, 30-day postdischarge mortality, and total mortality at the HRR level, graphically, and associations were tested using Spearman ρ.
RESULTS:The Overuse Index varied markedly across regions, but 23 were higher than the average (P<0.05). The Index was positively associated with total costs (ρ=0.28, P<0.0001). It was positively correlated with 30-day postdischarge mortality (ρ=0.18 P≤0.005), and neither positively or negatively correlated with total mortality.
CONCLUSIONS:This study confirms previous research hypothesizing that systematic regional variation in overuse exists and is measurable. Addition research is needed to validate index and to test its predictive and concurrent validity in panel data.
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