The Vascular Quality Initiative Cardiac Risk Index for prediction of myocardial infarction after vascular surgery
OBJECTIVE: The objective of this study was to develop and to validate the Vascular Quality Initiative (VQI) Cardiac Risk Index (CRI) for prediction of postoperative myocardial infarction (POMI) after vascular surgery.
METHODS: We developed risk models for in-hospital POMI after 88,791 nonemergent operations from the VQI registry, including carotid endarterectomy (CEA; n = 45,340), infrainguinal bypass (INFRA; n = 18,054), suprainguinal bypass (SUPRA; n = 2678), endovascular aneurysm repair (EVAR; n = 18,539), and open abdominal aortic aneurysm repair (OAAA repair; n = 4180). Multivariable logistic regression was used to create an all-procedure and four procedure-specific risk calculators based on the derivation cohort from 2012 to 2014 (N = 61,236). Generalizability of the all-procedure model was evaluated by applying it to each procedure subtype. The models were validated using a cohort (N = 27,555) from January 2015 to February 2016. Model discrimination was measured by area under the receiver operating characteristic curve (AUC), and performance was validated by bootstrapping 5000 iterations. The VQI CRI calculator was made available on the Internet and as a free smart phone app available through QxCalculate.
RESULTS: Overall POMI incidence was 1.6%, with variation by procedure type as follows: CEA, 0.8%; EVAR, 1.0%; INFRA, 2.6%; SUPRA, 3.1%; and OAAA repair, 4.3% (P < .001). Predictors of POMI in the all-procedure model included age, operation type, coronary artery disease, congestive heart failure, diabetes, creatinine concentration > 1.8 mg/dL, stress test status, and body mass index (AUC, 0.75; 95% confidence interval [CI], 0.73-0.76). The all-procedure model demonstrated only minimally reduced accuracy when it was applied to each procedure, with the following AUCs: CEA, 0.65 (95% CI, 0.59-0.70); INFRA, 0.69 (95% CI, 0.64-0.73); EVAR, 0.72 (95% CI, 0.65-0.80); SUPRA, 0.62 (95% CI, 0.52-0.72); and OAAA, 0.63 (95% CI, 0.56-0.70). Procedure-specific models had unique predictors and showed improved prediction compared with the all-procedure model, with the following AUCs: CEA, 0.69 (95% CI, 0.66-0.72); INFRA, 0.75 (95% CI, 0.73-0.78); EVAR, 0.76 (95% CI, 0.73-0.80); and OAAA, 0.72 (95% CI, 0.69-0.77). Bias-corrected AUC (95% CI) from internal validation for the models was as follows: all procedures, 0.75 (0.73-0.76); CEA, 0.68 (0.65-0.71); INFRA, 0.74 (0.72-0.76); EVAR, 0.73 (0.70-0.78); and OAAA repair, 0.68 (0.65-0.73).
CONCLUSIONS: The VQI CRI is a useful and valid clinical decision-making tool to predict POMI after vascular surgery. Procedure-specific models improve accuracy when they include unique risk factors.
Dynamics of dengue virus-specific B cells in the response to dengue virus-1 infections using flow cytometry with labeled virions
BACKGROUND: The development of reagents to identify and characterize antigen-specific B cells has been challenging.
METHODS: We recently developed Alexa Fluor-labeled dengue viruses (AF DENV) to characterize antigen-specific B cells in the peripheral blood of DENV-immune individuals.
RESULTS: In this study, we used AF DENV-1 together with AF DENV-2 on PBMC from children in Thailand undergoing acute primary or secondary DENV-1 infections to analyze the phenotypes of antigen-specific B cells that reflected their exposure or clinical diagnosis. DENV serotype-specific and cross-reactive B cells were identified in PBMC from all subjects. Frequencies of AF-DENV+ class switched memory B cells (IgD-CD27+ CD19+ cells) reached up to 8% during acute infection and early convalescence. AF DENV-labeled B cells expressed high levels of CD27 and CD38 during acute infection, characteristic of plasmablasts, and transitioned into memory B cells (CD38-CD27+) at the early convalescent time point. There was higher activation of memory B cells early during acute secondary infection suggesting reactivation from a previous DENV infection.
CONCLUSIONS: AF DENV reveal changes in the phenotype of DENV serotype-specific and cross-reactive B cells during and after natural DENV infection and could be useful in analysis of the response to DENV vaccination.
Micronutrient Intake among Children in Puerto Rico: Dietary and Multivitamin-Multimineral Supplement Sources
BACKGROUND: Micronutrients are critical for healthy growth and development of children. Micro-nutrient intake from dietary sources is inadequate among some children and may be improved by use of multivitamin and multimineral (MVMM) supplements.
OBJECTIVE: To assess micronutrient intake from dietary and MVMM supplement sources among 12-year-old children in Puerto Rico.
METHODS: A representative sample of 732 children enrolled in an oral health study in Puerto Rico, who completed dietary and MVMM assessments through one 24-h recall, were included in this analysis. Micronutrient intake sources were described and compared to the Dietary Reference Intakes (DRIs) using the Estimated Average Requirement when available (used Adequate Intake for vitamin K and pantothenic acid). Micronutrient profiles of MVMM users and non-users were compared using t-tests.
RESULTS: Mean intakes of vitamins A, D, E, and K, pantothenic acid, cal-cium, and magnesium from food and beverage sources were below the DRIs. From food and beverage sources, MVMM users had higher intakes of riboflavin and folate compared to non-users (p < 0.05). When MVMM supplements were taken into account, users had higher in-takes of all nutrients except vitamin K. With the help of MVMM, users increased intake of vita-mins E, A, D, and pantothenic acid to IOM-recommended levels but calcium, magnesium, and vitamin K remained below guidelines.
CONCLUSION: Micronutrient intake from diet was below the IOM-recommended levels in the total sample. MVMM use improved intake of selected micronu-trients and facilitated meeting recommendations for some nutrients. Public health measures to improve micronutrient intake among children in Puerto Rico are needed.
Introduction: Latina mothers play a central role in raising and socializing their children; however, few studies have examined the cultural, socio-cognitive and neighborhood-related variables influencing the level of communication between Puerto Rican mothers and their children about sexuality and sexual health. This cross-sectional study sought to examine these influences.
Methods: Puerto Rican mothers with children aged 10-19 years (n = 193) were selected randomly for an ethnographic interview as part of a community participatory action research project in a U.S. urban northeastern community.
Results: Bivariate analyses found statistically significant associations between the child's age (p = 0.002), the mother's past communication about traditional gender role norms of women (marianismo) (p < 0.001), her positive outcome expectations for communications with her child (p < 0.025), and her perceptions of the physical condition (p < 0.001) and sexual health problems (p = 0.047) in the neighborhood. In a multivariate model, all of these variables remained significant except sexual health problems, and mother's attitudes toward the obligations of children to parents (familismo) emerged as a factor associated with a decrease in the number of sexual health topics that mothers raised with their children. No significant effects were found for mother's spiritual and religious experience (religiosidad).
Discussion: Our study highlights the importance of marianismo as a framework within which Puerto Rican mothers communicate sexual health information as well as the need to improve mothers' confidence discussing sexual health issues with their children. Future public health interventions to promote communication about sexuality and sexual health among Puerto Rican mothers should consider addressing this issue as a part of comprehensive neighborhood improvement projects.
Implementation of treat-to-target in rheumatoid arthritis through a Learning Collaborative: Rationale and design of the TRACTION trial
BACKGROUND/PURPOSE: Treat-to-target (TTT) is a recommended strategy in the management of rheumatoid arthritis (RA), but various data sources suggest that its uptake in routine care in the US is suboptimal. Herein, we describe the design of a randomized controlled trial of a Learning Collaborative to facilitate implementation of TTT.
METHODS: We recruited 11 rheumatology sites from across the US and randomized them into the following two groups: one received the Learning Collaborative intervention in Phase 1 (month 1-9) and the second formed a wait-list control group to receive the intervention in Phase 2 (months 10-18). The Learning Collaborative intervention was designed using the Model for Improvement, consisting of a Change Package with corresponding principles and action phases. Phase 1 intervention practices had nine learning sessions, collaborated using a web-based tool, and shared results of plan-do-study-act cycles and monthly improvement metrics collected at each practice. The wait-list control group sites had no intervention during Phase 1. The primary trial outcome is the implementation of TTT as measured by chart review, comparing the differences from baseline to end of Phase 1, between intervention and control sites.
RESULTS: All intervention sites remained engaged in the Learning Collaborative throughout Phase 1, with a total of 38 providers participating. The primary trial outcome measures are currently being collected by the study team through medical record review.
CONCLUSIONS: If the Learning Collaborative is an effective means for improving implementation of TTT, this strategy could serve as a way of implementing disseminating TTT more widely.
Peripartum neuroactive steroid and gamma-aminobutyric acid profiles in women at-risk for postpartum depression
Neuroactive steroids (NAS) are allosteric modulators of the gamma-aminobutyric acid (GABA) system. NAS and GABA are implicated in depression. The peripartum period involves physiologic changes in NAS which may be associated with peripartum depression and anxiety. We measured peripartum plasma NAS and GABA in healthy comparison subjects (HCS) and those at-risk for postpartum depression (AR-PPD) due to current mild depressive or anxiety symptoms or a history of depression. We evaluated 56 peripartum medication-free subjects. We measured symptoms with the Hamilton Depression Rating Scale (HAM-D17), Hamilton Anxiety Rating Scale (HAM-A) and Spielberger State-Trait Anxiety Inventory-State (STAI-S). Plasma NAS and GABA were quantified by liquid chromatography-mass spectrometry. We examined the associations between longitudinal changes in NAS, GABA and depressive and anxiety symptoms using generalized estimating equation methods. Peripartum GABA concentration was 1.9+/-0.7ng/mL (p=0.004) lower and progesterone and pregnanolone were 15.8+/-7.5 (p=0.04) and 1.5+/-0.7ng/mL (p=0.03) higher in AR-PPD versus HCS, respectively. HAM-D17 was negatively associated with GABA (beta=-0.14+/-0.05, p=0.01) and positively associated with pregnanolone (beta=0.16+/-0.06, p=0.01). STAI-S was positively associated with pregnanolone (beta=0.11+/-0.04, p=0.004), allopregnanolone (beta=0.13+/-0.05, p=0.006) and pregnenolone (beta=0.02+/-0.01, p=0.04). HAM-A was negatively associated with GABA (beta=-0.12+/-0.04, p=0.004) and positively associated with pregnanolone (beta=0.11+/-0.05, p=0.05). Altered peripartum NAS and GABA profiles in AR-PPD women suggest that their interaction may play an important role in the pathophysiology of peripartum depression and anxiety.
OBJECTIVE: To evaluate the relevance, performance and potential usefulness of the Patient Assessment of cancer Communication Experiences (PACE) items.
METHODS: Items focusing on specific communication goals related to exchanging information, fostering healing relationships, responding to emotions, making decisions, enabling self-management, and managing uncertainty were tested via a retrospective, cross-sectional survey of adults who had been diagnosed with cancer. Analyses examined response frequencies, inter-item correlations, and coefficient alpha.
RESULTS: A total of 366 adults were included in the analyses. Relatively few selected Does Not Apply, suggesting that items tap relevant communication experiences. Ratings of whether specific communication goals were achieved were strongly correlated with overall ratings of communication, suggesting item content reflects important aspects of communication. Coefficient alpha was > /=.90 for each item set, indicating excellent reliability. Variations in the percentage of respondents selecting the most positive response across items suggest results can identify strengths and weaknesses.
CONCLUSION: The PACE items tap relevant, important aspects of communication during cancer care, and may be useful to cancer care teams desiring detailed feedback.
PRACTICE IMPLICATIONS: The PACE is a new tool for eliciting patients' perspectives on communication during cancer care. It is freely available online for practitioners, researchers and others.
Factors associated with patient activation in an older adult population with functional difficulties
OBJECTIVE: Patient activation, the patient's knowledge, skill, and confidence to manage his or her health, is an important indicator of future health and use of health care resources. Understanding factors associated with patient activation in an older population with functional difficulties may inform care in this population. This study aimed to determine whether patient activation is associated with depression, chronic conditions, family support, difficulties with activities of daily living (ADLs) and instrumental activities of daily living (IADLs), hospitalizations, education, and financial strain.
METHODS: (N=277), We administered surveys measuring patient activation, financial strain, depressive symptoms, family support, and chronic conditions to an older adult population. We tested association through multivariate linear regressions controlling for race, sex, and age.
RESULTS: Patient activation is significantly (p < 0.05), positively associated with family support and self-rated overall health, and significantly (p < 0.05), negatively associated with depressive symptoms and difficulties with ADLs and IADLs. We found no association between patient activation and financial stress, hospitalizations, and education.
CONCLUSIONS: Older age, depressive symptoms, and difficulties with ADLs and IADLs were associated with decreased patient activation.
PRACTICE IMPLICATIONS: Developing interventions tailored to older adults' level of patient activation has the potential to improve outcomes for this population.
Deficiency in mevalonate kinase (MVK) causes systemic inflammation. However, the molecular mechanisms linking the mevalonate pathway to inflammation remain obscure. Geranylgeranyl pyrophosphate, a non-sterol intermediate of the mevalonate pathway, is the substrate for protein geranylgeranylation, a protein post-translational modification that is catalyzed by protein geranylgeranyl transferase I (GGTase I). Pyrin is an innate immune sensor that forms an active inflammasome in response to bacterial toxins. Mutations in MEFV (encoding human PYRIN) result in autoinflammatory familial Mediterranean fever syndrome. We found that protein geranylgeranylation enabled Toll-like receptor (TLR)-induced activation of phosphatidylinositol-3-OH kinase (PI(3)K) by promoting the interaction between the small GTPase Kras and the PI(3)K catalytic subunit p110delta. Macrophages that were deficient in GGTase I or p110delta exhibited constitutive release of interleukin 1beta that was dependent on MEFV but independent of the NLRP3, AIM2 and NLRC4 inflammasomes. In the absence of protein geranylgeranylation, compromised PI(3)K activity allows an unchecked TLR-induced inflammatory responses and constitutive activation of the Pyrin inflammasome.
Racial/Ethnic Disparities in Meeting 5-2-1-0 Recommendations among Children and Adolescents in the United States
OBJECTIVE: To evaluate racial/ethnic disparities among children and adolescents in meeting the 4 daily 5-2-1-0 nutrition and activity targets in a nationally representative sample. The 5-2-1-0 message summarizes 4 target daily behaviors for obesity prevention: consuming > /=5 servings of fruit and vegetables, engaging in < /=2 hours of screen time, engaging in > /=1 hour of physical activity, and consuming 0 sugar-sweetened beverages daily. STUDY DESIGN: The National Health and Nutrition Examination Survey (2011-2012) data were used. The study sample included Hispanic (n = 608), non-Hispanic black (n = 609), Asian (n = 253), and non-Hispanic white (n = 484) youth 6-19 years old. The 5-2-1-0 targets were assessed using 24-hour dietary recalls, the Global Physical Activity Questionnaire, and sedentary behavior items. Outcomes included meeting all targets, no targets, and individual targets. Multivariable logistic regression models accounting for the complex sampling design were used to evaluate the association of race/ethnicity with each outcome among children and adolescents separately. RESULTS: None of the adolescents and <1% of children met all 4 of the 5-2-1-0 targets, and 19% and 33%, of children and adolescents, respectively, met zero targets. No racial/ethnic differences in meeting zero targets were observed among children. Hispanic (aOR, 1.76 [95% CI, 1.04-2.98]), non-Hispanic black (aOR, 1.82 [95% CI, 1.04-3.17]), and Asian (aOR, 1.48 [95% CI, 1.08-2.04]) adolescents had greater odds of meeting zero targets compared with non-Hispanic whites. Racial/ethnic differences in meeting individual targets were observed among children and adolescents. CONCLUSIONS: Despite national initiatives, youth in the US are far from meeting 5-2-1-0 targets. Racial/ethnic disparities exist, particularly among adolescents.
Type 2 diabetes, fuelled by the obesity epidemic, is an escalating worldwide cause of personal hardship and public cost. Diabetes incidence increases with age, and many studies link the classic senescence and ageing protein p16(INK4A) to diabetes pathophysiology via pancreatic islet biology. Genome-wide association studies (GWASs) have unequivocally linked the CDKN2A/B locus, which encodes p16 inhibitor of cyclin-dependent kinase (p16(INK4A)) and three other gene products, p14 alternate reading frame (p14(ARF)), p15(INK4B) and antisense non-coding RNA in the INK4 locus (ANRIL), with human diabetes risk. However, the mechanism by which the CDKN2A/B locus influences diabetes risk remains uncertain. Here, we weigh the evidence that CDKN2A/B polymorphisms impact metabolic health via islet biology vs effects in other tissues. Structured in a bedside-to-bench-to-bedside approach, we begin with a summary of the evidence that the CDKN2A/B locus impacts diabetes risk and a brief review of the basic biology of CDKN2A/B gene products. The main emphasis of this work is an in-depth look at the nuanced roles that CDKN2A/B gene products and related proteins play in the regulation of beta cell mass, proliferation and insulin secretory function, as well as roles in other metabolic tissues. We finish with a synthesis of basic biology and clinical observations, incorporating human physiology data. We conclude that it is likely that the CDKN2A/B locus influences diabetes risk through both islet and non-islet mechanisms.
PURPOSE: The purpose of this study is to describe characteristics of middle-age inpatients' (ages 45-64) fallers and their fall and fall injury risk factors.
BACKGROUND: Middle-age falls were 42-46% of inpatient falls. Studies related to inpatient falls have not targeted this population.
METHODS: A 439 retrospective chart review was performed. Middle-age fall and injury rates were compared with ages 21-44 and 65-90.
RESULTS: The mean age was 55.75years (SD 5.26). 28.7% (n=126) of falls resulted in injury. Individual fallers (n=386) had a mean of four comorbidities (SD 1.843), including hypertension (46.5%), anxiety/depression (40.2%), and alcohol and drug abuse (32.9%). There was no significant difference (p=.637) in fall rates per 1,000 patient days between ages 45-64 and 65-90.
CONCLUSION: Middle-age inpatients' acute illness makes them as vulnerable for fall and injury as the older population. They should not be overlooked for fall prevention measures.
A comparison of the CHARGE-AF and the CHA2DS2-VASc risk scores for prediction of atrial fibrillation in the Framingham Heart Study
BACKGROUND: Atrial fibrillation (AF) affects more than 33 million individuals worldwide and increases risks of stroke, heart failure, and death. The CHARGE-AF risk score was developed to predict incident AF in three American cohorts and it was validated in two European cohorts. The CHA2DS2-VASc risk score was derived to predict risk of stroke, peripheral embolism, and pulmonary embolism in individuals with AF, but it has been increasingly used for AF risk prediction. We compared CHARGE-AF risk score versus CHA2DS2-VASc risk score for incident AF risk in a community-based cohort.
METHODS AND RESULTS: We studied Framingham Heart Study participants aged 46 to 94 years without prevalent AF and with complete covariates. We predicted AF risk using Fine-Gray proportional sub-distribution hazards regression. We used the Wald chi(2) statistic for model fit, C-statistic for discrimination, and Hosmer-Lemeshow (HL) chi(2) statistic for calibration. We included 9722 observations (mean age 63.9 +/- 10.6 years, 56% women) from 4548 unique individuals: 752 (16.5%) developed incident AF and 793 (17.4%) died. The mean CHARGE-AF score was 12.0 +/- 1.2 and the sub-distribution hazard ratio (sHR) for AF per unit increment was 2.15 (95% CI, 99-131%; P < .0001). The mean CHA2DS2-VASc score was 2.0 +/- 1.5 and the sHR for AF per unit increment was 1.43 (95% CI, 37%-51%; P < .0001). The CHARGE-AF model had better fit than CHA2DS2-VASc (Wald chi(2) = 403 vs 209, both with 1 df), improved discrimination (C-statistic = 0.75, 95% CI, 0.73-0.76 vs C-statistic = 0.71, 95% CI, 0.69-0.73), and better calibration (HL chi(2) = 5.6, P = .69 vs HL chi(2) = 28.5, P < .0001).
CONCLUSION: The CHARGE-AF risk score performed better than the CHA2DS2-VASc risk score at predicting AF in a community-based cohort.
OBJECTIVE: Culturally appropriate tools for patient assessment are needed to train psychiatric residents. An objective structured clinical examination (OSCE) can be a helpful tool for evaluating trainees in the psychiatry milestones pertaining to cultural competency.
METHODS: Seventeen psychiatry residents and fellows at the University of Massachusetts participated in two small-group OSCE exercises to learn cultural interviewing using the DSM-5 Cultural Formulation Interview. Trainee groups presented a cultural formulation and received feedback. Participants were surveyed about their comfort with cultural interviewing before and after the exercise.
RESULTS: Paired t tests (N = 16) showed that mean level of comfort with the Cultural Formulation Interview increased by a mean of 0.5 points after training (t = 3.16, df = 15, p < 01 95 % CI = 163-837).
DISCUSSION: The UMass culturally appropriate assessment OSCE enhanced psychiatric trainees' comfort with culturally appropriate interviewing using the Cultural Formulation Interview.
Practice Patterns and Outcomes Associated With Use of Anticoagulation Among Patients With Atrial Fibrillation During Sepsis
Importance: Atrial fibrillation (AF) during sepsis is associated with an increased risk of ischemic stroke during hospitalization, but risks and benefits associated with anticoagulation for AF during sepsis are unclear.
Objective: To determine clinician practice patterns and patient risk of stroke and bleeding associated with use of anticoagulation for AF during sepsis.
Design, Setting, and Participants: A retrospective cohort study using enhanced administrative claims data from approximately 20% of patients hospitalized in the United States July 1, 2010, to June 30, 2013, examined patients with AF during sepsis who did not have additional indications for therapeutic anticoagulation. Propensity score and instrumental variable analyses were used to evaluate risks of in-hospital stroke and bleeding associated with anticoagulation during sepsis.
Exposures: Parenteral anticoagulants administered in doses greater than those used for prophylaxis of venous thromboembolism.
Main Outcomes and Measures: Ischemic stroke and clinically significant bleeding events during hospitalization.
Results: Of 113511 patients hospitalized with AF and sepsis, 38582 were included in our primary analysis (18976 men and 19606 women; mean [SD] age, 74.9 [11.7] years). A total of 13611 patients (35.3%) received parenteral anticoagulants, while 24971 (64.7%) did not. Hospital utilization rates of parenteral anticoagulants for AF during sepsis varied (median, 33%; 25th-75th percentile, 25%-43%). CHA2DS2VASc scores (congestive heart failure, hypertension, age > /=75 years [doubled], type 1 or type 2 diabetes, stroke or transient ischemic attack or thromboembolism [doubled], vascular disease [prior myocardial infarction, peripheral artery disease, or aortic plaque], age 65-75 years, sex category [female]) poorly discriminated the risk of ischemic stroke during sepsis (C statistic, 0.526). Among 27010 propensity score-matched patients, rates of in-hospital ischemic stroke events did not differ significantly between patients who did (174 of 13505 [1.3%]) and did not (185 of 13505 [1.4%]) receive parenteral anticoagulation (relative risk [RR], 0.94; 95% CI, 0.77-1.15). Clinically significant bleeding occurred more often among patients who received parenteral anticoagulation (1163 of 13505 [8.6%]) than patients who did not receive parenteral anticoagulation (979 of 13505 [7.2%]; RR, 1.21; 95% CI, 1.10-1.32). Risk of ischemic stroke associated with parenteral anticoagulation did not differ significantly between patients with preexisting (RR, 1.12; 95% CI, 0.86-1.44) or newly diagnosed AF (RR, 0.85; 95% CI 0.57-1.27; P = .31 for interaction). Results were robust to multiple sensitivity analyses, including hospital utilization rates of parenteral anticoagulation for AF as an instrument for anticoagulation exposure (RR for stroke, 1.08; 95% CI, 0.62-1.90; RR for bleeding, 1.23; 95% CI, 0.88-1.72).
Conclusions and Relevance: Among patients with AF during sepsis, parenteral anticoagulation was not associated with reduced risk of ischemic stroke and was associated with higher bleeding rates.
Relations of Arterial Stiffness and Brachial Flow-Mediated Dilation With New-Onset Atrial Fibrillation: The Framingham Heart Study
The relations of measures of arterial stiffness, pulsatile hemodynamic load, and endothelial dysfunction to atrial fibrillation (AF) remain poorly understood. To better understand the pathophysiology of AF, we examined associations between noninvasive measures of vascular function and new-onset AF. The study sample included participants aged >/=45 years from the Framingham Heart Study offspring and third-generation cohorts. Using Cox proportional hazards regression models, we examined relations between incident AF and tonometry measures of arterial stiffness (carotid-femoral pulse wave velocity), wave reflection (augmentation index), pressure pulsatility (central pulse pressure), endothelial function (flow-mediated dilation), resting brachial arterial diameter, and hyperemic flow. AF developed in 407/5797 participants in the tonometry sample and 270/3921 participants in the endothelial function sample during follow-up (median 7.1 years, maximum 10 years). Higher augmentation index (hazard ratio, 1.16; 95% confidence interval, 1.02-1.32; P=0.02), baseline brachial artery diameter (hazard ratio, 1.20; 95% confidence interval, 1.01-1.43; P=0.04), and lower flow-mediated dilation (hazard ratio, 0.79; 95% confidence interval, 0.63-0.99; P=0.04) were associated with increased risk of incident AF. Central pulse pressure, when adjusted for age, sex, and hypertension (hazard ratio, 1.14; 95% confidence interval, 1.02-1.28; P=0.02) was associated with incident AF. Higher pulsatile load assessed by central pulse pressure and greater apparent wave reflection measured by augmentation index were associated with increased risk of incident AF. Vascular endothelial dysfunction may precede development of AF. These measures may be additional risk factors or markers of subclinical cardiovascular disease associated with increased risk of incident AF.
Trajectories of Risk Factors and Risk of New-Onset Atrial Fibrillation in the Framingham Heart Study
The associations of long-term patterns of risk factors and the risk of incident atrial fibrillation (AF) are incompletely characterized. Among 4351 Framingham Study participants (mean age 50+/-11 years at baseline examination, 57% women) from the original and offspring cohorts, we defined longitudinal patterns, referred to as trajectories, of AF risk factors and a composite AF risk score using approximately 16 years of data. We used Cox proportional hazards models to examine the association of trajectories to 15-year risk of AF. During follow-up, 719 participants developed AF. Five distinct trajectory groups were identified for systolic blood pressure (BP): groups 1 and 2 (normotensive throughout), group 3 (prehypertensive), group 4 (hypertensive initially with decreasing BP), and group 5 (hypertensive and increasing BP). In multivariable-adjusted analyses, compared with group 1, groups 4 (hazard ratio 2.05; 95% confidence interval 1.24-3.37) and 5 (hazard ratio 1.95; 95% confidence interval 1.08-3.49) were associated with incident AF. Three trajectory groups were identified for antihypertensive treatment. Compared with the group with no treatment throughout, the other 2 groups were associated with increased risk of incident AF. Distinct trajectories for diastolic BP, smoking, diabetes mellitus, and the composite risk score were not associated with increased 15-year risk of AF. Longitudinal trajectories may distinguish how exposures related to AF contribute toward prospective AF risk. Distinct trajectory groups with persistently elevated systolic BP and longer antihypertensive treatment are associated with increased risk of incident AF.
OBJECTIVES: Higher body mass index (BMI) is an important risk factor for atrial fibrillation (AF). The adipokines leptin, adiponectin and resistin are correlates of BMI, but their association with incident AF is not well known. We explored this relationship in a large cohort of postmenopausal women.
METHODS: We studied an ethnically diverse cohort of community-dwelling postmenopausal women aged 50-79 who were nationally recruited at 40 clinical centres as part of the Women's Health Initiative investigation. Participants underwent measurements of baseline serum leptin, adiponectin and resistin levels and were followed for incident AF. Adipokine levels were log transformed and normalised using inverse probability weighting. Cox proportional hazard regression models were used to estimate associations with adjustment for known AF risk factors.
RESULTS: Of the 4937 participants included, 892 developed AF over a follow-up of 11.1 years. Those with AF had higher mean leptin (14.9 pg/mL vs 13.9 pg/mL), adiponectin (26.3 ug/mL vs 24.5 ug/mL) and resistin (12.9 ng/mL vs 12.1 ng/mL) levels. After multivariable adjustment, neither log leptin nor log adiponectin levels were significantly associated with incident AF. However, log resistin levels remained significantly associated with incident AF (HR=1.57 per 1 log (ng/mL) increase, p=0.006). Additional adjustment for inflammatory cytokines only partially attenuated the association between resistin and incident AF (HR=1.43, p=0.06 adjusting for C-reactive protein (CRP); HR=1.39, p=0.08 adjusting for IL-6). Adjusting for resistin partially attenuated the association between BMI and incident AF (HR=1.14 per 5 kg/m(2), p=0.006 without resistin; HR=1.12, p=0.02 with resistin).
CONCLUSIONS: In women, elevated levels of serum resistin are significantly associated with higher rates of incident AF and partially mediate the association between BMI and AF. In the same population, leptin and adiponectin levels are not significantly associated with AF.
Factors influencing survival among Kenyan children diagnosed with endemic Burkitt lymphoma between 2003 and 2011: A historical cohort study
Discovering how to improve survival and establishing clinical reference points for children diagnosed with endemic Burkitt lymphoma (eBL) in resource-constrained settings has recaptured international attention. Using multivariate analyses, we evaluated 428 children with eBL in Kenya for age, gender, tumor stage, nutritional status, hemoglobin, lactate dehydrogenase (LDH), Epstein-Barr virus (EBV) and Plasmodium falciparum prior to induction of chemotherapy (cyclophosphamide, vincristine, methotrexate and doxorubicin) to identify predictive and prognostic biomarkers of survival. During this 10 year prospective study period, 22% died in-hospital and 78% completed six-courses of chemotherapy. Of those, 16% relapsed or died later; 31% achieved event-free-survival; and 31% were lost to follow-up; the overall one-year survival was 45%. After adjusting for covariates, low hemoglobin ( < 8 g/dL) and high LDH ( > 400 mU/ml) were associated with increased risk of death (adjusted Hazard Ratio (aHR) = 1.57 [0.97-2.41]) and aHR = 1.84, [0.91-3.69], respectively). Anemic children with malaria were 3.55 times more likely to die [1.10-11.44] compared to patients without anemia or malarial infection. EBV load did not differ by tumor stage nor was it associated with survival. System-level factors can also contribute to poor outcomes. Children were more likely to die when inadvertently overdosed by more than 115% of the correct dose of cyclophosphamide (a HR = 1.43 [0.84-2.43]) or doxorubicin (a HR = 1.25, [0.66-2.35]), compared with those receiving accurate doses of the respective agent in this setting. This study codifies risk factors associated with poor outcomes for eBL patients in Africa and provides a benchmark by which to assess improvements in survival for new chemotherapeutic approaches.
Inflammation Mediated by JNK in Myeloid Cells Promotes the Development of Hepatitis and Hepatocellular Carcinoma
The cJun NH2-terminal kinase (JNK) signaling pathway is required for the development of hepatitis and hepatocellular carcinoma. A role for JNK in liver parenchymal cells has been proposed, but more recent studies have implicated non-parenchymal liver cells as the relevant site of JNK signaling. Here, we tested the hypothesis that myeloid cells mediate this function of JNK. We show that mice with myeloid cell-specific JNK deficiency exhibit reduced hepatic inflammation and suppression of both hepatitis and hepatocellular carcinoma. These data identify myeloid cells as a site of pro-inflammatory signaling by JNK that can promote liver pathology. Targeting myeloid cells with a drug that inhibits JNK may therefore provide therapeutic benefit for the treatment of inflammation-related liver disease.