Harvard T.H. Chan School of Public Health

Focus Areas: Integrative Approaches to Care, Experiential Workshop This session will highlight two of the most important, yet frequently overlooked, determinants of heart health: mind-body interactions and nutrition. These areas will be explored through didactic and experiential learning. The session will begin with a short presentation by Dr Adi Haramati on the physiology of stress and the scientific basis for mind-body approaches to de-stress, followed by an experiential autogenic exercise that will allow participants to track their own vascular response to a relaxation exercise (using skin thermistors). Dr David Eisenberg will then provide a short presentation on national and global trends in the areas of nutrition, obesity, and diabetes and will discuss the relationship between health professionals’ personal self-care behaviors and the frequency with which they advise their patients about these same behaviors. A cooking demonstration will showcase simple techniques that healthcare professionals can use and share with their patients to convey the fact that healthy foods can also be easy to make, convenient, affordable, and “craveably” delicious. Dr Stephen Devries will complete the presentation with a review of recent clinical studies highlighting the efficacy of nutrition and mind-body interventions on heart health. Practical recommendations for incorporating integrative strategies into heart care will be emphasized.

HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10−8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.

The epidemic of HIV-1C in southern Africa is characterized by a sustained prevalence that is substantially higher than for other epidemics of HIV/AIDS. Perhaps the best correlate of transmission is high viral load (HVL), which we target to prevent spread of HIV in a community randomization trial based on antiretroviral treatment (ART) as prevention (TasP). Designed for over 100,000 adults in 30 randomized villages in Botswana, this trial also utilizes other prevention interventions such as HIV testing, male circumcision, clinical linkage and ART chemoprophylaxis during pregnancy. Viral phylogenetics is used to estimate the proportion of incident infections originating in test villages, and thus the relative contribution of TasP for preventing transmissions. Analysis of results through modeling includes estimating cost effectiveness and estimations of contributions for different prevention interventions.

Acute salicylate overdose in pregnancy is potentially fatal for both the mother and fetus and presents a unique challenge in intensive care management. While suggested thresholds exist for hemodialysis in adults with toxic salicylate ingestion, it is unclear if these thresholds remain appropriate for the gravid patient, particularly given that medications such as acetylsalicylic acid may cross the placental barrier and accumulate in the fetal bloodstream. We describe a case of a gravid patient at ∼37 weeks gestational age with a self-reported acetylsalicylic acid ingestion of 32.5 g and review prior cases of both acute and chronic salicylate ingestion in pregnancy in order to determine the clinical precedent for hemodialysis in this situation.

Objective. To examine body mass index (BMI) changes among pediatric multidisciplinary weight management participants and nonparticipants. Design. In this retrospective database analysis, we used multivariable mixed effect models to compare 2-year BMI z-score trajectories among 583 eligible overweight or obese children referred to the One Step Ahead program at the Boston Children's Primary Care Center between 2003 and 2009. Results. Of the referred children, 338 (58%) attended the program; 245 (42%) did not participate and were instead followed by their primary care providers within the group practice. The mean BMI z-score of program participants decreased modestly over a 2-year period and was lower than that of nonparticipants. The group-level difference in the rate of change in BMI z-score between participants and nonparticipants was statistically significant for 0–6 months (P = 0.001) and 19–24 months (P = 0.008); it was marginally significant for 13–18 months (P = 0.051) after referral. Younger participants (<5 years) had better outcomes across all time periods examined. Conclusion. Children attending a multidisciplinary program experienced greater BMI z-score reductions compared with usual primary care in a real world practice; younger participants had significantly better outcomes. Future research should consider early intervention and cost-effectiveness analyses.

The November 2014 midterm election was the first election since key coverage provisions of the Affordable Care Act (ACA) were implemented, including the Medicaid expansion and creation of the health insurance exchanges. The pre-election variability in the states’ implementation of these provisions coupled with the large number of states selecting their next governor made the election important at the state level. To better understand the role of health care in the recent gubernatorial elections, we analyzed health policy content presented by 71 candidates for governor on their campaign Web sites. Nearly 80% of all candidates discussed health policy on their Web site, including the subset of the 36 winning governors. The predominant focus of health policy content was on the ACA as a whole or its provisions. Medicaid was discussed more often by candidates in non-expansion states than those from expansion states. Based on the statements of winning governors, we expect serious consideration of the Medicaid expansion to occur in at least 4 states, whereas 2 states may make efforts to reverse course. Relatively few winning governors (33%) mentioned the exchanges. Only 1 expressed interest in switching from the federal exchange to a state exchange, which has particular relevance given the Supreme Court’s pending decision on King v. Burwell that could invalidate tax credits on the federal exchange. The prominence of health care in the gubernatorial campaigns strengthens the likelihood that governors will play an influential role in the health system’s future, especially as the ACA undergoes further federal debate.

The Bioinformatics Open Source Conference (BOSC) is organized by the Open Bioinformatics Foundation (OBF), a nonprofit group dedicated to promoting the practice and philosophy of open source software development and open science within the biological research community. Since its inception in 2000, BOSC has provided bioinformatics developers with a forum for communicating the results of their latest efforts to the wider research community. BOSC offers a focused environment for developers and users to interact and share ideas about standards; software development practices; practical techniques for solving bioinformatics problems; and approaches that promote open science and sharing of data, results, and software. BOSC is run as a two-day special interest group (SIG) before the annual Intelligent Systems in Molecular Biology (ISMB) conference. BOSC 2015 took place in Dublin, Ireland, and was attended by over 125 people, about half of whom were first-time attendees. Session topics included “Data Science;” “Standards and Interoperability;” “Open Science and Reproducibility;” “Translational Bioinformatics;” “Visualization;” and “Bioinformatics Open Source Project Updates”. In addition to two keynote talks and dozens of shorter talks chosen from submitted abstracts, BOSC 2015 included a panel, titled “Open Source, Open Door: Increasing Diversity in the Bioinformatics Open Source Community,” that provided an opportunity for open discussion about ways to increase the diversity of participants in BOSC in particular, and in open source bioinformatics in general. The complete program of BOSC 2015 is available online at http://www.open-bio.org/wiki/BOSC_2015_Schedule.

Circadian rhythms modulate the biology of many human tissues, including brain tissues, and are driven by a near 24-hour transcriptional feedback loop. These rhythms are paralleled by 24-hour rhythms of large portions of the transcriptome. The role of dynamic DNA methylation in influencing these rhythms is uncertain. While recent work in Neurospora suggests that dynamic site-specific circadian rhythms of DNA methylation may play a role in modulating the fungal molecular clock, such rhythms and their relationship to RNA expression have not, to our knowledge, been elucidated in mammalian tissues, including human brain tissues. We hypothesized that 24-hour rhythms of DNA methylation exist in the human brain, and play a role in driving 24-hour rhythms of RNA expression. We analyzed DNA methylation levels in post-mortem human dorsolateral prefrontal cortex samples from 738 subjects. We assessed for 24-hour rhythmicity of 420,132 DNA methylation sites throughout the genome by considering methylation levels as a function of clock time of death and parameterizing these data using cosine functions. We determined global statistical significance by permutation. We then related rhythms of DNA methylation with rhythms of RNA expression determined by RNA sequencing. We found evidence of significant 24-hour rhythmicity of DNA methylation. Regions near transcription start sites were enriched for high-amplitude rhythmic DNA methylation sites, which were in turn time locked to 24-hour rhythms of RNA expression of nearby genes, with the nadir of methylation preceding peak transcript expression by 1–3 hours. Weak ante-mortem rest-activity rhythms were associated with lower amplitude DNA methylation rhythms as were older age and the presence of Alzheimer's disease. These findings support the hypothesis that 24-hour rhythms of DNA methylation, particularly near transcription start sites, may play a role in driving 24-hour rhythms of gene expression in the human dorsolateral prefrontal cortex, and may be affected by age and Alzheimer's disease.

Background: Vitamin D deficiency may be involved in the development of atherosclerosis and coronary heart disease in humans.Methods: We assessed prospectively whether plasma 25-hydroxyvitamin D (25[OH]D) concentrations are associated with risk of coronary heart disease. A nested case-control study was conducted in 18 225 men in the Health Professionals Follow-up Study; the men were aged 40 to 75 years and were free of diagnosed cardiovascular disease at blood collection. The blood samples were returned between April 1, 1993, and November 30, 1999; 99% were received between April 1, 1993, and November 30, 1995. During 10 years of follow-up, 454 men developed nonfatal myocardial infarction or fatal coronary heart disease. Using risk set sampling, controls (n=900) were selected in a 2: 1 ratio and matched for age, date of blood collection, and smoking status.Results: After adjustment for matched variables, men deficient in 25(OH)D (<= 15 ng/mL [to convert to nano-moles per liter, multiply by 2.496]) were at increased risk for MI compared with those considered to be sufficient in 25(OH)D ( >= 30 ng/mL) (relative risk [RR], 2.42; 95% confidence interval [CI], 1.53-3.84; P <.001 for trend). After additional adjustment for family history of myocardial infarction, body mass index, alcohol consumption, physical activity, history of diabetes mellitus and hypertension, ethnicity, region, marine omega-3 intake, low- and high-density lipoprotein cholesterol levels, and triglyceride levels, this relationship remained significant (RR, 2.09; 95% CI, 1.24-3.54 P=.02 for trend). Even men with intermediate 25(OH)D levels were at elevated risk relative to those with sufficient 25(OH)D levels (22.6-29.9 ng/mL: RR, 1.60 [95% CI, 1.10-2.32]; and 15.0-22.5 ng/mL: RR, 1.43 [95% CI, 0.96-2.13], respectively).Conclusion: Low levels of 25 (OH) D are associated with higher risk of myocardial infarction in a graded manner, even after controlling for factors known to be associated with coronary artery disease.

There is limited information on the prevalence of the potent mutagen 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) in U.S. water supplies. We measured MX concentrations and mutagenic activity in tap water samples from 36 surface water systems throughout Massachusetts. We found MX levels much higher (up to 80 ng/L) than previously reported in the United States. We also evaluated the role of water treatment on mutagenic activity and disinfection by-product formation. After adjusting for other covariates, chloramination and filtration were the most important treatment options for reducing mutagenic activity and disinfection by-product formation. Multiple chlorine application (before and after filtration) was associated with increased mutagenicity. Chlorine dose, pH, and total organic carbon were also associated with mutagenicity, MX, and total trihalomethane (TTHM) concentration. Seasonal variation was evident for MX and mutagenic activity, with higher levels occurring in the spring compared to the fall. In contrast, TTHM concentrations were greater in the fall.

Cell invasion through a dense three-dimensional (3D) matrix is believed to depend on the ability of cells to generate traction forces. To quantify the role of cell tractions during invasion in 3D, we present a technique to measure the elastic strain energy stored in the matrix due to traction-induced deformations. The matrix deformations around a cell were measured by tracking the 3D positions of fluorescent beads tightly embedded in the matrix. The bead positions served as nodes for a finite element tessellation. From the strain in each element and the known matrix elasticity, we computed the local strain energy in the matrix surrounding the cell. We applied the technique to measure the strain energy of highly invasive MDA-MB-231 breast carcinoma and A-125 lung carcinoma cells in collagen gels. The results were compared to the strain energy generated by non-invasive MCF-7 breast and A-549 lung carcinoma cells. In all cases, cells locally contracted the matrix. Invasive breast and lung carcinoma cells showed a significantly higher contractility compared to non-invasive cells. Higher contractility, however, was not universally associated with higher invasiveness. For instance, non-invasive A-431 vulva carcinoma cells were the most contractile cells among all cell lines tested. As a universal feature, however, we found that invasive cells assumed an elongated spindle-like morphology as opposed to a more spherical shape of non-invasive cells. Accordingly, the distribution of strain energy density around invasive cells followed patterns of increased complexity and anisotropy. These results suggest that not so much the magnitude of traction generation but their directionality is important for cancer cell invasion.

Background: Debates exist over whether health inequities are bound to rise as population health improves, due to health improving more quickly among the better off, with most analyses focused on mortality data. Methods: We analysed 50 years of socioeconomic inequities in measured health status among US-born Black and White Americans, using data from the National Health Examination Surveys (NHES) I-III (1959–70), National Health and Nutrition Examination Surveys (NHANES) I-III (1971–94) and NHANES 1999–2008. Results: Absolute US socioeconomic health inequities for income percentile and education variously decreased (serum cholesterol; childhood height), stagnated [systolic blood pressure (SBP)], widened [body mass index (BMI), waist circumference (WC)] and in some cases reversed (age at menarche), even as on-average values rose (BMI, WC), idled (childhood height) and fell (SBP, serum cholesterol, age at menarche), with patterns often varying by race/ethnicity and socioeconomic measure; similar results occurred for relative inequities. For example, for WC, the adverse 20th (low) vs 80th (high) income percentile gap increased only among Whites (NHES I: 0.71 cm [95% confidence interval (CI) −0.74, 2.16); NHANES 2005–08: 2.10 (95% CI 0.96, 3.62)]. By contrast, age at menarche for girls in the 20th vs 80th income percentile among Black girls remained consistently lower, by 0.34 years (95% CI 0.12, 0.55) whereas among White girls the initial null difference became inverse [NHANES 2005–08: −0.49 years (95% CI −0.86, −0.12; overall P = 0.0015)]. Adjusting for socioeconomic position only modestly altered Black/White health inequities. Conclusions: Health inequities need not rise as population health improves.

Genetic studies of blood pressure (BP) to date have mainly analysed common variants (minor allele frequency, MAF>0.05). In a meta-analysis of up to >1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (MAF≤0.01) variant-BP associations (P<5x10-8) of which, 32 were in new BP-associated loci and 55 were independent BP-associated SNVs within known BP-associated regions. Rare variants, 44% of which were coding, on average had effects ~8 times larger than the mean effects of common variants and indicate potential candidate causal genes at new and known loci e.g. GATA5, PLCB3. BP-associated variants (including rare and common) were enriched in regions of active chromatin in foetal tissues, potentially linking foetal development with BP regulation in later life. Multivariable Mendelian randomisation highlighted inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.