Quality of Layperson CPR Instructions From Artificial Intelligence Voice Assistants.

This case series study evaluates responses from 4 artificial intelligence voice assistance on CPR questions from laypersons.

Visualizations throughout pharmacoepidemiology study planning, implementation, and reporting.

Transparency is increasingly promoted to instill trust in nonrandomized studies using real-world data. Graphics and data visualizations support transparency by aiding communication and understanding, and can inform study design and analysis decisions. However, other than graphical representation of a study design and flow diagrams (e.g., a Consolidated Standards of Reporting Trials [CONSORT] like diagram), specific standards on how to maximize validity and transparency with visualization are needed. This paper provides guidance on how to use visualizations throughout the life cycle of a pharmacoepidemiology study-from initial study design to final report-to facilitate rationalized and transparent decision-making about study design and implementation, and clear communication of study findings. Our intent is to help researchers align their practices with current consensus statements on transparency.

The EMS Modified Early Warning Score (EMEWS): A Simple Count of Vital Signs as a Predictor of Out-of-Hospital Cardiac Arrests.

Objective: For patients at risk for out-of-hospital cardiac arrest (OHCA) after Emergency Medical Services (EMS) arrival, outcomes may be mitigated by identifying impending arrests and intervening before they occur. Tools such as the Modified Early Warning Score (MEWS) have been developed to determine the risk of arrest, but involve relatively complicated algorithms that can be impractical to compute in the prehospital environment. A simple count of abnormal vital signs, the "EMS Modified Early Warning Score" (EMEWS), may represent a more practical alternative. We sought to compare to the ability of MEWS and EMEWS to identify patients at risk for EMS-witnessed OHCA.Methods: We conducted a retrospect analysis of the 2018 ESO Data Collaborative database of EMS encounters. Patients without cardiac arrest before EMS arrival were categorized into those who did or did not have an EMS-witnessed arrest. MEWS was evaluated without its temperature component (MEWS-T). The performance of MEWS-T and EMEWS in predicting EMS witnessed arrest was evaluated by comparing receiver-operating characteristic curves.Results: Of 369,064 included encounters, 4,651 were EMS witnessed arrests. MEWS-T demonstrated an area under the curve (AUC) of 0.79 (95% CI: 0.79 - 0.80), with 86.8% sensitivity and 51.0% specificity for MEWS-T ≥ 3. EMEWS demonstrated an AUC of 0.74 (95% CI: 0.73 - 0.75), with 81.3% sensitivity and 53.9% specificity for EMEWS ≥ 2.Conclusions: EMEWS showed a similar ability to predict EMS-witnessed cardiac arrest compared to MEWS-T, despite being significantly simpler to compute. Further study is needed to evaluate whether the implementation of EMEWS can aid EMS clinicians in anticipating and preventing OHCA.

Analyse d'ensemble des complications de la COVID-19 : étude d'auto-appariement pré- et post-exposition.

CONTEXTE: De nombreuses études sur les complications de la maladie à coronavirus 2019 (COVID-19) ont reposé sur des séries de cas et de petites cohortes qui ne permettaient pas d'établir un lien causal avec la COVID-19 ni d'estimer les risques dans les différents milieux de soins. Nous avons voulu étudier toutes les complications possibles de la COVID-19 afin de confirmer les complications précédemment déclarées et d'identifier de potentielles complications encore inconnues. MÉTHODES: À partir des données sur les demandes de remboursement de frais médicaux aux États-Unis, nous avons comparé la fréquence de tous les codes de diagnostic de la Classification internationale des maladies, 10 e révision, modification clinique (CIM-10-MC) enregistrés avant et après le déclenchement de la pandémie de COVID-19 dans un modèle d'auto-appariement pré- et post-exposition. Nous avons inclus les patients ayant reçu un diagnostic de COVID-19 entre le 1er mars 2020 et le 30 avril 2020, et calculé les estimations de risque et les rapports de cotes (RC) pour le lien avec la COVID-19 de chaque code de diagnostic de la CIM-10-MC. RÉSULTATS: Sur les 1724 codes de diagnostic de la CIM-10-MC attribués à 70 288 patients atteints de COVID-19, 69 étaient significativement liés à la COVID-19. Les diagnostics étroitement liés à la COVID-19 et comportant un risque absolu élevé comprenaient la pneumonie virale (RC 177,63; intervalle de confiance [IC] à 95 % 147,19­214,37; risque absolu 27,6 %), l'insuffisance respiratoire (RC 11,36; IC à 95 % 10,74­12,02; risque absolu 22,6 %), l'insuffisance rénale aiguë (RC 3,50; IC à 95 % 3,34­3,68; risque absolu 11,8 %) et la sepsie (RC 4,23; IC à 95 % 4,01­4,46; risque absolu 10,4 %). Les diagnostics étroitement liés à la COVID-19, mais comportant un risque absolu faible comprenaient la myocardite (RC 8,17; IC à 95 % 3,58­18,62; risque absolu 0,1 %), la coagulation intravasculaire disséminée (RC 11,83; IC à 95 % 5,26­26,62; risque absolu 0,1 %) et le pneumothorax (RC 3,38; IC à 95 % 2,68­4,26; risque absolu 0,4 %). INTERPRÉTATION: Nous avons confirmé et établi les estimations du risque de plusieurs complications de la COVID-19. Ces résultats pourraient orienter le pronostic, les décisions thérapeutiques et les conseils aux patients.

Real-world evidence of bariatric surgery and cardiovascular benefits using electronic health records data: A lesson in bias.

AIM: To reproduce and correct studies on bariatric surgery and the reduction in major adverse cardiovascular events (MACE) among patients with obesity and type 2 diabetes (T2D). METHODS: We used electronic healthcare records (EHR) from in and outpatient facilities around the United States to identify a cohort of patients with T2D, aged 18 to 80 years and with a body mass index (BMI) of 30 kg/m2 or higher undergoing bariatric surgery. We compared against hip/knee arthroplasty to establish an active comparison group that reduced bias from differential information and confounding. The main outcome was six-point MACE. Pre-exposure characteristics were adjusted in propensity score (PS) models with 1:2 matching plus high-dimensional PS matching. RESULTS: After a range of exclusions, the final cohort included 344 bariatric surgery patients (65% female; mean age 58 years) and 551 PS-matched patients undergoing arthroplasty (65% female; 59 years). Median follow-up was 2.5 years in both groups. Bariatric surgery patients showed a sustained 20% weight reduction and an HbA1c reduction by 1% point. We found no benefits of bariatric surgery for six-point MACE (HR = 0.99; 95% CI 0.76-1.30). We observed known increases in risks for vitamin B12 deficiency anaemia (HR = 3.06; 1.10-8.49) and cholelithiasis (HR = 1.72; 0.94-3.13). CONCLUSIONS: This real-world evidence study found reductions in HbA1c and BMI following bariatric surgery similar to trials, and no meaningful cardiovascular benefit compatible with the underpowered trials but in contrast to earlier EHR studies. We showed how information bias typical in EHR analyses and confounding may cause substantial bias.

Diagnosis-wide analysis of COVID-19 complications: an exposure-crossover study.

BACKGROUND: Many studies reporting coronavirus disease 2019 (COVID-19) complications have involved case series or small cohorts that could not establish a causal association with COVID-19 or provide risk estimates in different care settings. We sought to study all possible complications of COVID-19 to confirm previously reported complications and to identify potential complications not yet known. METHODS: Using United States health claims data, we compared the frequency of all International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) diagnosis codes occurring before and after the onset of the COVID-19 pandemic in an exposure-crossover design. We included patients who received a diagnosis of COVID-19 between Mar. 1, 2020, and Apr. 30, 2020, and computed risk estimates and odds ratios (ORs) of association with COVID-19 for every ICD-10-CM diagnosis code. RESULTS: Among 70 288 patients with COVID-19, 69 of 1724 analyzed ICD-10-CM diagnosis codes were significantly associated with COVID-19. Disorders showing both strong association with COVID-19 and high absolute risk included viral pneumonia (OR 177.63, 95% confidence interval [CI] 147.19-214.37, absolute risk 27.6%), respiratory failure (OR 11.36, 95% CI 10.74-12.02, absolute risk 22.6%), acute kidney failure (OR 3.50, 95% CI 3.34-3.68, absolute risk 11.8%) and sepsis (OR 4.23, 95% CI 4.01-4.46, absolute risk 10.4%). Disorders showing strong associations with COVID-19 but low absolute risk included myocarditis (OR 8.17, 95% CI 3.58-18.62, absolute risk 0.1%), disseminated intravascular coagulation (OR 11.83, 95% CI 5.26-26.62, absolute risk 0.1%) and pneumothorax (OR 3.38, 95% CI 2.68-4.26, absolute risk 0.4%). INTERPRETATION: We confirmed and provided risk estimates for numerous complications of COVID-19. These results may guide prognosis, treatment decisions and patient counselling.

Evidence-based crisis standards of care for out-of-hospital cardiac arrests in a pandemic.

BACKGROUND & PURPOSE: Pandemics such as COVID-19 can lead to severe shortages in healthcare resources, requiring the development of evidence-based Crisis Standard of Care (CSC) protocols. A protocol that limits the resuscitation of out-of-hospital cardiac arrests (OHCA) to events that are more likely to result in a positive outcome can lower hospital burdens and reduce emergency medical services resources and infection risk, although it would come at the cost of lives lost that could otherwise be saved. Our primary objective was to evaluate candidate OHCA CSC protocols involving known predictors of survival and identify the protocol that results in the smallest resource burden, as measured by the number of hospitalizations required per favorable OHCA outcome achieved. Our secondary objective was to describe the effects of the CSC protocols in terms of health outcomes and other measures of resource burden. METHODS: We conducted a retrospective cohort study of adult patients in the Cardiac Arrest Registry to Enhance Survival (CARES) database. Non-traumatic OHCA events from 2018 were included (n = 79,533). Candidate CSC protocols involving combinations of known predictors of good survival for OHCA were applied to the existing dataset to measure the resulting numbers of resuscitation attempts, transportations to hospital, hospital admissions, and favorable neurological outcomes. These outcomes were also assessed under Standard Care, defined as no CSC protocol applied to the data. RESULTS: The CSC protocol with the smallest number of hospitalizations per survivor with a favorable neurological outcome was that an OHCA resuscitation should only be attempted if the arrest was witnessed by emergency medical services or the first monitored rhythm was shockable (number of hospitalizations: 2.26 [95% CI: 2.21-2.31] vs. 3.46 [95% CI: 3.39-3.53] under Standard Care). This rule resulted in significant reductions in resource utilization (46.1% of hospitalizations and 29.2% of resuscitation attempts compared to Standard Care) while still preserving 70.5% of the favorable neurological outcomes under Standard Care. For every favorable neurological outcome lost under this CSC protocol, 6.3 hospital beds were made free that could be used to treat other patients. CONCLUSION: In a pandemic scenario, pre-hospital CSC protocols that might not otherwise be considered have the potential to greatly improve overall survival, and this study provides an evidence-based approach towards selecting such a protocol. As this study was performed using data generated before the COVID-19 pandemic, future studies incorporating pandemic-era data will further help develop evidence-based CSC protocols.

Actionable Real-World Evidence to Improve Health Outcomes and Reduce Medical Spending Among Risk-Stratified Patients with Diabetes.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a chronic condition with a high economic burden as well as drug treatments that have not all demonstrated effects on longevity. Managed care organizations want to improve health outcomes in these complex patients but lack actionable evidence to make informed decisions on which therapies are most effective among their members and may also control total health care spending. OBJECTIVE: To produce actionable evidence by identifying antidiabetic treatments that are effective and may reduce total cost of care in various risk groups of patients with T2DM, using insurance claims data that includes medical claims and pharmacy dispensing data among members of Horizon Blue Cross Blue Shield of New Jersey with T2DM. METHODS: We identified patients with T2DM in longitudinal claims data from Horizon between 2014 and 2017 with demographic and enrollment information, inpatient and outpatient diagnoses and procedures, and pharmacy dispensing. Outcomes included myocardial infarction, heart failure (HF), stroke, percutaneous revascularization, health care services utilization, and plan costs (i.e., medical, pharmacy, and total cost of care). After propensity score decile adjustment on over 20 covariates, we evaluated the effectiveness and safety of second-line antidiabetic treatment that included sodium-glucose co-transporter-2 (SGLT-2) inhibitors, sulfonylureas (SUs), dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists. RESULTS: Among 115,308 members with T2DM, the most common comorbidities were cardiovascular risk factors, including hyperlipidemia (56%), hypertension (50%), and existing cardiovascular disease (CVD; 55%). Among members receiving dual antidiabetic treatment (n = 20,204), the most prevalent treatments were metformin plus the following second-line medications: SUs (42%), DPP-4 inhibitors (29%), SGLT-2 inhibitors (10%), or GLP-1 receptor agonists (3%). Approximately 20% of members accounted for 79% of total cost of care, with an average of $9,605 per member per year (PMPY). Compared with SU initiation and after propensity score decile adjustment, new users of SGLT-2 inhibitors had a reduced risk for HF hospitalization (HR = 0.35, 95% CI = 0.13-0.89), hypoglycemia, albuminuria, microvascular disease, and metabolic failure. Among SGLT-2 inhibitor initiators with established CVD, the savings in total cost of care compared with SU initiators was $5,520 per member over an average treatment duration of 6 months and an approximate savings of $11,000 PMPY if patients persisted on treatment for 12 months. CONCLUSIONS: In the Horizon membership, we confirmed that SGLT-2 inhibitors reduce HF hospitalizations, resulting in reduced medical spending and savings in total cost of care. Regulatory-grade analytics of local data provided the confidence to encourage increased SGLT-2 inhibitor use to produce better outcomes and save total cost of care despite higher pharmacy spending. DISCLOSURES: This research did not receive outside funding; however, Aetion has since begun a contractual relationship with Horizon Blue Cross Blue Shield of New Jersey. Garry, Petruski-Ivleva, Cheever, and Rajan are employees of and have stock options in Aetion, a company that makes software for the analysis of real-world data. Eapen was an employee of Aetion during the implementation of this study. Rassen is an employee of and has ownership interest in Aetion. Murk is a consultant to Aetion of which he owns equity. Schneeweiss is a consultant to WHISCON and to Aetion, of which he also owns equity. He is the principal investigator of investigator-initiated grants to the Brigham and Women's Hospital from Bayer, Genentech, Boehringer Ingelheim, and Vertex. Gambino is an employee and officer at Horizon Blue Cross and Blue Shield of New Jersey. He was recently appointed to a board observer position at Aetion, as Horizon has small equity interest in Aetion. Jan is an employee of Rutgers State University and Horizon Blue Cross Blue Shield of New Jersey and has no conflict of interest or association with Aetion or any pharmaceutical company. Jang and Rubin are employees of Horizon Blue Cross and Blue Shield of New Jersey and have no conflict of interest or association with Aetion. This work was presented as a poster at AMCP Nexus 2018, October 22-25, 2018, in Orlando, FL; as part of a continuing education session at the AMCP Managed Care & Specialty Pharmacy 2019 Annual Meeting in San Diego, CA, March 25-28, 2019; as invited podium presenter at the Blue Cross Blue Shield 2019 National Summit conference in Grapevine, TX, April 29-May 2, 2019; and was accepted for a podium presentation at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 2019 annual conference in New Orleans, LA, May 18-22, 2019, where it won an award for Best Podium Presentation.

Graphical Depiction of Longitudinal Study Designs in Health Care Databases.

Pharmacoepidemiologic and pharmacoeconomic analysis of health care databases has become a vital source of evidence to support health care decision making and efficient management of health care organizations. However, decision makers often consider studies done in nonrandomized health care databases more difficult to review than randomized trials because many design choices need to be considered. This is perceived as an important barrier to decision making about the effectiveness and safety of medical products. Design flaws in longitudinal database studies are avoidable but can be unintentionally obscured in the convoluted prose of methods sections, which often lack specificity. We propose a simple framework of graphical representation that visualizes study design implementations in a comprehensive, unambiguous, and intuitive way; contains a level of detail that enables reproduction of key study design variables; and uses standardized structure and terminology to simplify review and communication to a broad audience of decision makers. Visualization of design details will make database studies more reproducible, quicker to review, and easier to communicate to a broad audience of decision makers.

Measuring prevalence and incidence of chronic conditions in claims and electronic health record databases.

BACKGROUND: Health care databases are natural sources for estimating prevalence and incidence of chronic conditions, but substantial variation in estimates limits their interpretability and utility. We evaluated the effects of design choices when estimating prevalence and incidence in claims and electronic health record databases. METHODS: Prevalence and incidence for five chronic diseases at increasing levels of expected frequencies, from cystic fibrosis to COPD, were estimated in the Clinical Practice Research Datalink (CPRD) and MarketScan databases from 2011 to 2014. Estimates were compared using different definitions of lookback time and contributed person-time. RESULTS: Variation in lookback time substantially affected estimates. In 2014, for CPRD, use of an all-time vs a 1-year lookback window resulted in 4.3-8.3 times higher prevalence (depending on disease), reducing incidence by 1.9-3.3 times. All-time lookback resulted in strong temporal trends. COPD prevalence between 2011 and 2014 in MarketScan increased by 25% with an all-time lookback but stayed relatively constant with a 1-year lookback. Varying observability did not substantially affect estimates. CONCLUSION: This framework draws attention to the underrecognized potential for widely varying incidence and prevalence estimates, with implications for care planning and drug development. Though prevalence and incidence are seemingly straightforward concepts, careful consideration of methodology is required to obtain meaningful estimates from health care databases.

The extracellular signal-regulated kinase 1/2 triggers angiogenesis in human ectopic endometrial implants by inducing angioblast differentiation and proliferation.

PROBLEM: The role of extracellular signal-regulated kinase (ERK)1/2-mediated angiogenesis during endometriotic nidation is unknown. We posit that ERK1/2-induced angioblast differentiation and proliferation promotes ectopic endometrial angiogenesis. METHODS OF STUDY: Human eutopic and ectopic endometria were immunostained for total- (T-) or phosphorylated- (P-) ERK1/2 or double-immunostained for P-ERK1/2-CD34 and PCNA-CD34. Estradiol (E2 ), cytokines, normal peritoneal fluid (NPF) or endometriotic peritoneal fluid (EPF) ±PD98059, an ERK1/2 inhibitor, treaded primary human endometrial endothelial cells (HEECs) were evaluated by T-/P-ERK1/2 immunoblotting, MTT viability and tube formation assays. RESULTS: HEECs exhibited higher endothelial P-ERK1/2 immunoreactivity in ectopic vs eutopic endometria. Double-immunostained ectopic endometria displayed abundant CD34-positive angioblasts exhibiting strong P-ERK1/2 and PCNA immunoreactivity. EPF and vascular growth factor (VEGF)-A significantly increased HEEC proliferation and P-ERK1/2 levels. PD98059 reduced basal, EPF, and VEGF-induced HEEC proliferation and promoted vascular stabilization following tube formation. CONCLUSION: Enhanced ERK1/2 activity in angioblasts by such peritoneal factors as VEGF, E2 induces proliferation to trigger ectopic endometrial angiogenesis.

A new media without animal component for sperm cryopreservation: motility and various attributes affecting paternal contribution of sperm.

PURPOSE: Our aim was the development of a safe sperm cryopreservation New Media (NM), composed of consistent and reproducible components devoid of any animal origin, and evaluation of NM in terms of its effect on sperm structure and function as compared to regularly used yolk media (TYM) (Irvine Scientific). METHODS: We evaluated patient semen samples and cryopreserved them in duplicates in either NM or TYM. The samples were cryopreserved for either a short term of 1 week or long term of 1 month prior to thawing. The parameters investigated include sperm motility via computer-assisted semen analysis (CASA), sperm concentration, and sperm biomarkers that promote paternal contribution of spermatozoa to fertilization including hyaluronic acid binding, chromatin maturity, apoptotic markers, cytoplasmic retention, and sperm DNA integrity. RESULTS: As compared to TYM, NM was equally capable of sperm cryopreservation with both short-term and long-term storage in media, and after freeze-thaw and gradient processing of sperm. HA binding of sperm was comparable post thaw in both NM and yolk media. There are also no differences observed between the samples cryopreserved in NM or TYM in terms of their aniline blue staining, CK immunocytochemistry, caspase 3 immunostaining, or DNA nick translation. CONCLUSIONS: NM has the advantage of being xeno-free, yet in preservation of sperm motility and other sperm attributes, the NM is as effective as the TYM.

Genome-wide search identifies a gene-gene interaction between 20p13 and 2q14 in asthma.

BACKGROUND: Many studies have attempted to identify gene-gene interactions affecting asthma susceptibility. However, these studies have typically used candidate gene approaches in limiting the genetic search space, and there have been few searches for gene-gene interactions on a genome-wide scale. We aimed to conduct a genome-wide gene-gene interaction study for asthma, using data from the GABRIEL Consortium. RESULTS: A two-stage study design was used, including a screening analysis (N = 1625 subjects) and a follow-up analysis (N = 5264 subjects). In the screening analysis, all pairwise interactions among 301,547 SNPs were evaluated, encompassing a total of 4.55 × 10(10) interactions. Those with a screening interaction p-value < 10(-5) were evaluated in the follow-up analysis. No interaction selected from the screening analysis met strict statistical significance in the follow-up (p-value < 1.45 × 10(-7)). However, the top-ranked interaction (rs910652 [20p13] × rs11684871 [2q14]) in the follow-up (p-value = 1.58 × 10(-6)) was significant in one component of a replication analysis. This interaction was notable in that rs910652 is located within 78 kilobases of ADAM33, which is one of the most well studied asthma susceptibility genes. In addition, rs11684871 is located in or near GLI2, which may have biologically relevant roles in asthma. CONCLUSIONS: Using a genome-wide approach, we identified and found suggestive evidence of replication for a gene-gene interaction in asthma involving loci that are potentially highly relevant in asthma pathogenesis.

Exhaustive Genome-Wide Search for SNP-SNP Interactions Across 10 Human Diseases.

The identification of statistical SNP-SNP interactions may help explain the genetic etiology of many human diseases, but exhaustive genome-wide searches for these interactions have been difficult, due to a lack of power in most datasets. We aimed to use data from the Resource for Genetic Epidemiology Research on Adult Health and Aging (GERA) study to search for SNP-SNP interactions associated with 10 common diseases. FastEpistasis and BOOST were used to evaluate all pairwise interactions among approximately N = 300,000 single nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) ≥ 0.15, for the dichotomous outcomes of allergic rhinitis, asthma, cardiac disease, depression, dermatophytosis, type 2 diabetes, dyslipidemia, hemorrhoids, hypertensive disease, and osteoarthritis. A total of N = 45,171 subjects were included after quality control steps were applied. These data were divided into discovery and replication subsets; the discovery subset had > 80% power, under selected models, to detect genome-wide significant interactions (P < 10(-12)). Interactions were also evaluated for enrichment in particular SNP features, including functionality, prior disease relevancy, and marginal effects. No interaction in any disease was significant in both the discovery and replication subsets. Enrichment analysis suggested that, for some outcomes, interactions involving SNPs with marginal effects were more likely to be nominally replicated, compared to interactions without marginal effects. If SNP-SNP interactions play a role in the etiology of the studied conditions, they likely have weak effect sizes, involve lower-frequency variants, and/or involve complex models of interaction that are not captured well by the methods that were utilized.

Genome-Wide Gene by Environment Interaction Analysis Identifies Common SNPs at 17q21.2 that Are Associated with Increased Body Mass Index Only among Asthmatics.

Asthmatics have an increased risk of being overweight/obese. Although the underlying mechanisms of this are unclear, genetic factors are believed to play an essential role. To identify common genetic variants that are associated with asthma-related BMI increase, we performed a genome-wide gene by environment (asthma) interaction analysis for the outcome of BMI in the Multi-Ethnic Study of Atherosclerosis (MESA) study (N = 2474 Caucasians, 257 asthmatics), and replicated findings in the Framingham Heart Study (FHS) offspring cohort (N = 1408 Caucasians, 382 asthmatics). The replicable tagging SNP, rs2107212, was further examined in stratified analyses. Seven SNPs clustered in 17q21.2 were identified to be associated with higher BMI among asthmatics (interaction p < 5×10-7 in MESA and p < 0.05 in FHS). In both MESA and FHS asthmatics, subjects carrying the A allele on rs2107212 had significantly higher odds of obesity than non-carriers, which was not the case for non-asthmatics. We further examined BMI change subsequent to asthma diagnosis over a period of 26 years in FHS and demonstrated greater BMI increase among asthmatics compared to non-asthmatics. Asthmatics carrying the A allele at rs2107212 had significantly greater net BMI increase over the 26-year period compared to non-asthmatics. In this study, we found that common genetic variants on 17q21.2 are associated with post-asthma BMI increase among Caucasians. This finding will help elucidate pathways involved in the comorbidity of asthma and obesity.

Racial Disparities in Knowledge of Pelvic Floor Disorders Among Community-Dwelling Women.

OBJECTIVE: To evaluate racial and ethnic differences in knowledge about preventative and curative treatments for pelvic floor disorders (PFD). METHODS: The is a secondary analysis of responses from 416 community-dwelling women, aged 19 to 98 years, living in New Haven County, CT, who completed the Prolapse and Incontinence Knowledge Questionnaire. Associations between race/ethnicity (categorized as white, African American, and other women of color [combined group of Hispanic, Asian or "other" women] and knowledge proficiency about modifiable risk factors and treatments for PFD were evaluated. Associations were adjusted for age, marital status, socioeconomic status, education, working in a medical field, and PFD history. RESULTS: Compared to white women, African American women were significantly less likely to recognize childbirth as a risk factor for urinary incontinence (UI) and pelvic organ prolapse (POP), to know that exercises can help control leakage, and to recognize pessaries as a treatment option for POP. Other women of color were also significantly less likely to know about risk factors, preventative strategies, and curative treatment options for POP and UI; however, these findings may not be generalizable given the heterogeneity and small size of this group. CONCLUSIONS: Significant racial disparities exist in women's baseline knowledge regarding risk factors and treatment options for POP and UI. Targeted, culturally sensitive educational interventions are essential to enhancing success in reducing the personal and economic burden of PFD, which have proven negative effects on women's quality of life.

Confronting the missing epistasis problem: on the reproducibility of gene-gene interactions.

Epistasis (gene-gene interaction) is thought to play an integral role in the genetic basis of complex traits, and a significant amount of research has been invested into identifying this phenomenon in human disease. However, the overall success of empirical studies of epistasis in humans is unclear, as such studies are rarely systematically evaluated. Here, we have selected asthma as an example of a well-studied, complex human disease, and provide a critical analysis and replication attempt of nearly all prior reports of epistasis for this disease. Of 191 previously reported interactions, we find that 39.8% were not originally identified using an explicit test for interaction and thus may not have been true epistatic effects to begin with. Moreover, directions of effect were not described for 46.1% of the interactions, which prevents their rigorous replication. In the original studies, attempts at replication were made for 15.2% of the interactions, and 7.3% were actually replicated. In the current study, we were able to evaluate 85.9% of the interactions using a large asthma dataset from the GABRIEL Consortium. None of these interactions could be replicated based on strict criteria. However, we found nominally significant (p < 0.05) evidence in support of 23.8% of the evaluated interactions. Although many reports of epistasis are not robustly supported in the published literature, our results suggest that at least some of these reports may have been true-positive examples of epistasis. In general, improvements in empirical studies of epistasis are called for, in order to better understand the importance of this phenomenon in human disease.

Interferon-γ protects first-trimester decidual cells against aberrant matrix metalloproteinases 1, 3, and 9 expression in preeclampsia.

Human extravillous trophoblast (EVT) invades the decidua via integrin receptors and subsequently degrades extracellular matrix proteins. In preeclampsia (PE), shallow EVT invasion elicits incomplete spiral artery remodeling, causing reduced uteroplacental blood flow. Previous studies show that preeclamptic decidual cells, but not interstitial EVTs, display higher levels of extracellular matrix-degrading matrix metalloproteinase (MMP)-9, but not MMP-2. Herein, we extend our previous PE-related assessment of MMP-2 and MMP-9 to include MMP-1, which preferentially degrades fibrillar collagens, and MMP-3, which can initiate a local proteolytic cascade. In human first-trimester decidual cells incubated with estradiol, tumor necrosis factor-α (TNF-α) significantly enhanced MMP-1, MMP-3, and MMP-9 mRNA and protein levels and activity measured by real-time quantitative RT-PCR, ELISA, immunoblotting, and zymography, respectively. In contrast, interferon γ (IFN-γ) reversed these effects and medroxyprogesterone acetate elicited further reversal. Immunoblotting revealed that p38 mitogen-activated protein kinase signaling mediated TNF-α enhancement of MMP-1, MMP-3, and MMP-9, whereas IFN-γ inhibited p38 mitogen-activated protein kinase phosphorylation. Unlike highly regulated MMP-1, MMP-3, and MMP-9, MMP-2 mRNA and protein expression was constitutive in decidual cells. Because inflammation underlies PE-associated shallow EVT invasion, these results suggest that excess macrophage-derived TNF-α augments expression of MMP-1, MMP-3, and MMP-9 in decidual cells to interfere with normal stepwise EVT invasion of the decidua. In contrast, decidual natural killer cell-derived IFN-γ reverses such TNF-α-induced MMPs to protect against PE.

Knowledge of pelvic floor disorders in a population of community-dwelling women.

OBJECTIVE: The objective of the study was to investigate baseline knowledge and demographic factors associated with a lack of knowledge about urinary incontinence (UI) and pelvic organ prolapse (POP). STUDY DESIGN: This study was a community-based, cross-sectional survey of 431 racially and socioeconomically diverse women aged 19-98 years. The Prolapse and Incontinence Knowledge Questionnaire was used to assess participants' knowledge. Primary endpoints were the total number of correct responses on the UI and POP scales, respectively. Percentages of individuals answering each item or group of items correctly were explored as secondary outcomes. RESULTS: All women lacked knowledge proficiency about UI and POP, although knowledge about UI was slightly greater than knowledge about POP. Overall, 71.2% of subjects lacked UI proficiency (<80% correct), whereas 48.1% lacked proficiency in POP knowledge (<50% correct). Black women demonstrated significantly less knowledge about UI and POP than white women, both before and after adjustment for age, education, and household income. When combined into 1 group, Asian, Hispanic, and other women also showed significantly less UI and POP knowledge than white women. Most women who reported symptoms of UI had not received treatment for their problems. CONCLUSION: There is a global lack of knowledge about UI and POP among community-dwelling women, with more pronounced knowledge gaps among nonwhite women. UI and POP are chronic medical conditions that should be included in routine screening questions for well-woman care. Further studies are needed to explore how best to educate and improve women's awareness of these prevalent pelvic floor disorders.