Constructing within and between hospital physician social networks for modeling physician research participation.

BACKGROUND: Physician participation in clinical trials is essential for the progress of modern medicine. However, the demand for physician research partners is outpacing physicians' interest in participating in scientific studies. Understanding the factors that influence physician participation in research is crucial to addressing this gap. METHODS: In this study, we used a physician's social network, as constructed from patient billing data, to study if the research choices of a physician's immediate peers influence their likelihood to participate in scientific research. We analyzed data from 348 physicians across 40 hospitals. We used logistic regression models to examine the relationship between a physician's participation in clinical trials and the participation of their social network peers, adjusting for age, years of employment, and influences from other hospital facilities. RESULTS: We found that the likelihood of a physician participating in clinical trials increased dramatically with the proportion of their social network-defined colleagues at their primary hospital who were participating ([Formula: see text] for a 1% increase in the proportion of participating peers, [Formula: see text]). Additionally, physicians who work regularly at multiple facilities were more likely to participate ([Formula: see text], [Formula: see text]) and increasingly so as the extent to which they have social network ties to colleagues at hospitals other than their primary hospital increases ([Formula: see text], [Formula: see text]). These findings suggest an inter-hospital peer participation process. CONCLUSION: Our study provides evidence that the social structure of a physician's work-life is associated with their decision to participate in scientific research. The results suggest that interventions aimed at increasing physician participation in clinical trials could leverage the social networks of physicians to encourage participation. By identifying factors that influence physician participation in research, we can work towards closing the gap between the demand for physician research partners and the number of physicians willing to participate in scientific studies.

Redistribution of lamina-associated domains reshapes binding of pioneer factor FOXA2 in development of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in type 2 diabetes mellitus and the elderly, impacting 40% of individuals over 70. Regulation of heterochromatin at the nuclear lamina has been associated with aging and age-dependent metabolic changes. We previously showed that changes at the lamina in aged hepatocytes and laminopathy models lead to redistribution of lamina-associated domains (LADs), opening of repressed chromatin, and up-regulation of genes regulating lipid synthesis and storage, culminating in fatty liver. Here, we test the hypothesis that change in the expression of lamina-associated proteins and nuclear shape leads to redistribution of LADs, followed by altered binding of pioneer factor FOXA2 and by up-regulation of lipid synthesis and storage, culminating in steatosis in younger NAFLD patients (aged 21-51). Changes in nuclear morphology alter LAD partitioning and reduced lamin B1 signal correlate with increased FOXA2 binding before severe steatosis in young mice placed on a western diet. Nuclear shape is also changed in younger NAFLD patients. LADs are redistrubted and lamin B1 signal decreases similarly in mild and severe steatosis. In contrast, FOXA2 binding is similar in normal and NAFLD patients with moderate steatosis and is repositioned only in NAFLD patients with more severe lipid accumulation. Hence, changes at the nuclear lamina reshape FOXA2 binding with progression of the disease. Our results suggest a role for nuclear lamina in etiology of NAFLD, irrespective of aging, with potential for improved stratification of patients and novel treatments aimed at restoring nuclear lamina function.

Neonatal Intensive Care Variation in Medicaid-Insured Newborns: A Population-Based Study.

OBJECTIVE: To assess the contribution of maternal and newborn characteristics to variation in neonatal intensive care use across regions and hospitals. STUDY DESIGN: This was a retrospective population-based live birth cohort of newborn infants insured by Texas Medicaid in 2010-2014 with 2 subcohorts: very low birth weight (VLBW) singletons and late preterm singletons. Crude and risk-adjusted neonatal intensive care unit (NICU) admission rates, intensive and intermediate special care days, and imaging procedures were calculated across Neonatal Intensive Care Regions (n = 21) and hospitals (n = 100). Total Medicaid payments were calculated. RESULTS: Overall, 11.5% of live born, 91.7% of VLBW, and 37.6% of infants born late preterm were admitted to a NICU, receiving an average of 2 days, 58 days, and 5 days of special care with payments per newborn inpatient episode of $5231, $128 075, and $10 837, respectively. There was little variation across regions and hospitals in VLBW NICU admissions but marked variation for NICU admissions in late preterm newborn infants and for special care days and imaging rates in all cohorts. The variation decreased slightly after health risk adjustment. There was moderate substitution of intermediate for intensive care days across hospitals (Pearson r VLBW -0.63 P < .001; late preterm newborn -0.53 P < .001). CONCLUSIONS: Across all risk groups, the variation in NICU use was poorly explained by differences in newborn illness levels and is likely to indicate varying practice styles. Although the "right" rates are uncertain, it is unlikely that all of these use patterns represent effective and efficient care.

Prenatal Programming of Infant Neurobehaviour in a Healthy Population.

BACKGROUND: Identifying the prenatal origins of mental conditions is of increasing interest, yet most studies have focused on high-risk populations and cannot disentangle prenatal and postnatal programming effects. Thus, we examined whether profiles of neurobehaviour indicative of future risk could be identified in healthy 1-3-day-old infants, and examined associations with perinatal risk factors. METHODS: Participants included 627 healthy mothers and term infants from a population-based US cohort. Neurobehaviour was assessed within 24-72 h after delivery with the NICU Network Neurobehavioural Scales (NNNS). A model-based clustering algorithm was used to derive neurobehavioural profiles from NNNS scores. Maternal health histories, pregnancy conditions and behaviours, labour/delivery factors, and infant attributes were examined in relation to the neurobehavioural profiles. RESULTS: Seven discrete neurobehavioural profiles were identified, including one average functioning profile, and two inversely patterned below and above average profiles. Higher pregnancy weight gain (OR 1.44, 95% CI 1.10, 1.88) and birthweight percentiles (OR 1.46, 95% CI 1.10, 1.95) were associated with greater odds of below average newborn neurobehaviour. Above average neurobehaviour was associated with experiencing longer gestations (OR 1.29, 95% CI 1.02, 1.64) and higher 5-min APGAR scores (OR 2.43, 95% CI 1.07, 5.52). Maternal pregnancy alcohol use (OR 0.54, 95% CI 0.33, 0.89), and fetal distress (OR 0.10, 95% CI 0.01, 0.72) were associated with lower likelihood of having average neurobehaviour. CONCLUSION: Distinct profiles of neurobehaviour can be derived in a healthy population of newborns, with different sets of perinatal factors predicting different patterns of neurobehaviour. These findings suggest a potential in utero origin for mental health risk.

Keeping up with the neighbor: a novel mechanism of call synchrony in Neoconocephalus ensiger katydids.

During solo calling, pulse periods gradually changed by up to 15% over several minutes. Pairs of calling males synchronized their pulses. The pulse rate (10-14 Hz) was considerably faster than the rate of synchronized signal units in other insects (0.5-3 Hz). Within each pulse cycle, males made only small adjustments to their pulse period, leading to regular switches of leader and follower roles. Large-scale timing adjustments only occurred in response to large delays. Stimulation with single pulses had no predictable effect on the timing of the male's next pulse, resulting in a flat phase response curve. When entrained to a stimulus with a faster pulse period, males briefly interrupted calling; they resumed calling largely synchronized with the stimulus. Throughout the stimulus, males made gradual changes to their pulse period, similar to those during pair calling. After the stimulus ended, pulse periods increased over several minutes, but did not return to their pre-stimulus values. Thus social context and intrinsic state of the males influenced pulse period in Neoconocephalus ensiger. These results indicate that N. ensiger males synchronize calls by adjusting their intrinsic pulse period, instead of adjusting the timing of individual pulses, as described in other synchronizing insects.

Sex-specific associations between placental leptin promoter DNA methylation and infant neurobehavior.

BACKGROUND: Leptin (LEP) is a hormone central for energy homeostasis and has been implicated in neurodevelopment. This adipokine is produced by the placenta and is epigenetically regulated by promoter DNA methylation. Recent evidence has suggested a role for LEP in behavioral development. In this study, we investigated associations between profiles of human newborn neurobehavior and placental LEP DNA methylation. METHODS: We determined LEP promoter methylation in 444 placental samples from healthy term infants and measured LEP gene expression in a random subset of these samples. Infant neurobehavior was assessed with the NICU Network Neurobehavioral Scales (NNNS) and we examined the relationship between LEP promoter methylation and profiles of infant neurobehavior derived from these scores generated using a hierarchical model-based clustering method. RESULTS: LEP methylation is negatively correlated with gene expression only in placentas from male infants (r=-0.6, P=0.006). A 10% increase in LEP DNA methylation was associated with membership in a profile of infant neurobehavior marked by increased lethargy and hypotonicity (OR=1.9; 95% CI: 1.07-3.4), and consistently with reduced risk of membership in a profile characterized by decreased lethargy and hypotonicity (OR=0.54; 95% CI: 0.3-0.94) only in male infants (n=223). No statistically significant associations were observed amongst female infants. DISCUSSION: These results suggest that increased placental LEP DNA methylation, related to reduced expression, may play a role in human newborn neurodevelopment, particularly in reactivity to various stimuli, but that these effects may be sexually dimorphic.

Aspirin, nonaspirin nonsteroidal anti-inflammatory drug, and acetaminophen use and risk of invasive epithelial ovarian cancer: a pooled analysis in the Ovarian Cancer Association Consortium.

BACKGROUND: Regular aspirin use is associated with reduced risk of several malignancies. Epidemiologic studies analyzing aspirin, nonaspirin nonsteroidal anti-inflammatory drug (NSAID), and acetaminophen use and ovarian cancer risk have been inconclusive. METHODS: We analyzed pooled data from 12 population-based case-control studies of ovarian cancer, including 7776 case patients and 11843 control subjects accrued between 1992 and 2007. Odds ratios (ORs) for associations of medication use with invasive epithelial ovarian cancer were estimated in individual studies using logistic regression and combined using random effects meta-analysis. Associations between frequency, dose, and duration of analgesic use and risk of ovarian cancer were also assessed. All statistical tests were two-sided. RESULTS: Aspirin use was associated with a reduced risk of ovarian cancer (OR = 0.91; 95% confidence interval [CI] = 0.84 to 0.99). Results were similar but not statistically significant for nonaspirin NSAIDs, and there was no association with acetaminophen. In seven studies with frequency data, the reduced risk was strongest among daily aspirin users (OR = 0.80; 95% CI = 0.67 to 0.96). In three studies with dose information, the reduced risk was strongest among users of low dose (<100 mg) aspirin (OR = 0.66; 95% CI = 0.53 to 0.83), whereas for nonaspirin NSAIDs, the reduced risk was strongest for high dose (≥500 mg) usage (OR = 0.76; 95% CI = 0.64 to 0.91). CONCLUSIONS: Aspirin use was associated with a reduced risk of ovarian cancer, especially among daily users of low-dose aspirin. These findings suggest that the same aspirin regimen proven to protect against cardiovascular events and several cancers could reduce the risk of ovarian cancer 20% to 34% depending on frequency and dose of use.

Area-level attributes and esophageal adenocarcinoma in surveillance, epidemiology and end results registries.

PURPOSE: To examine the associations between area-level socioeconomic attributes and stage of esophageal adenocarcinoma diagnoses in 16 SEER cancer registries during 2000-2007. METHODS: Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable logistic regression models to assess the relationship between distant-stage esophageal adenocarcinoma and individual, census tract, and county-level attributes. RESULTS: Among cases with data on birthplace, no significant association was seen between reported birth within versus outside the United States and distant-stage cancer (adjusted OR=1.02, 95% CI: 0.85-1.22). Living in an area with a higher percentage of residents born outside the United States than the national average was associated with distant-stage esophageal adenocarcinoma; census tract level: >11.8%, (OR=1.10, 95% CI:1.01-1.19), county level: >11.8%, (OR=1.14, 95% CI:1.05-1.24). No association was observed between median household income and distant-stage cancer at either census tract or county levels. CONCLUSION: The finding of greater odds of distant-stage esophageal adenocarcinoma among cases residing in SEER areas with higher proportion of non-U.S. Natives suggests local areas where esophageal cancer control efforts might be focused. Missing data at the individual level was a limitation of the present study. Furthermore, inconsistent associations with foreign birth at individual- versus area-levels cautions against using area-level attributes as proxies for case attributes.

Tubal ligation, hysterectomy and epithelial ovarian cancer in the New England Case-Control Study.

Previous studies have observed that tubal ligation and hysterectomy are associated with a decreased risk of ovarian cancer; however, little is known about whether these associations vary by surgical characteristics, individual characteristics or tumor histology. We used logistic regression to examine tubal ligation, simple hysterectomy and hysterectomy with unilateral oophorectomy in relation to risk of epithelial ovarian cancer in the New England Case-Control Study. Our primary analysis included 2,265 cases and 2,333 controls. Overall, tubal ligation was associated with a lower risk of epithelial ovarian cancer [odds ratio (OR) = 0.82, 95% confidence interval (CI): 0.68-0.97], especially for endometrioid tumors (OR = 0.45, 95% CI: 0.29-0.69). The inverse association between tubal ligation and ovarian cancer risk was stronger for women who had undergone the procedure at the time of last delivery (OR = 0.60, 95% CI: 0.42-0.84) rather than at a later time (OR = 0.93, 95% CI: 0.75-1.15). Overall, simple hysterectomy was not associated with ovarian cancer risk (OR: 1.09, 95% CI: 0.83-1.42), although it was associated with a nonsignificant decreased risk of ovarian cancer among women who underwent the procedure at age 45 or older (RR: 0.64, 95% CI: 0.40-1.02) or within the last 10 years (OR = 0.65, 95% CI: 0.38-1.13). Overall, women who had a hysterectomy with a unilateral oophorectomy had significantly lower risk of ovarian cancer (OR = 0.65, 95% CI: 0.45-0.94). In summary, tubal ligation and hysterectomy with unilateral oophorectomy were inversely associated with ovarian cancer risk in a large population-based case-control study. Additional research is necessary to understand the potential biologic mechanisms by which these procedures may reduce ovarian cancer risk.

Ovarian cancer risk factors by tumor dominance, a surrogate for cell of origin.

Differentiating ovarian tumors based on developmental pathway may further enhance our understanding of the disease. Traditionally, ovarian cancers were thought to arise from the ovarian surface epithelium; however, recent evidence suggests that some tumors originate in the fallopian tube. We classified cases in a population-based case-control study (New England Case-Control [NECC] Study) and two cohort studies (Nurses' Health Study [NHS]/Nurses' Health Study II [NHSII]) by tumor dominance, a proxy for tissue of origin. Dominant tumors (likely ovarian origin) are restricted to one ovary or are at least twice as large on one ovary compared to the other. Ovarian cancer risk factors were evaluated in relation to dominant and nondominant tumors (likely tubal origin) using polytomous logistic regression (NECC) or competing risks Cox models (NHS/NHSII). Results were combined using random-effects meta-analyses. Among 1,771 invasive epithelial ovarian cancer cases, we observed 1,089 tumors with a dominant mass and 682 with no dominant mass. Dominant tumors were more likely to be mucinous, endometrioid or clear cell, whereas nondominant tumors were more likely to be serous. Tubal ligation, two or more births, endometriosis and age were more strongly associated with dominant tumors (rate ratio [RR] = 0.60, 0.83, 1.58 and 1.37, respectively) than nondominant tumors (RR = 1.03, 0.93, 0.84 and 1.14, respectively; p-difference = 0.0001, 0.01, 0.0003 and 0.01, respectively). These data suggest that risk factors for tumors putatively arising from ovarian versus fallopian tube sites may differ; in particular, reproductive factors may be more important for ovarian-derived tumors. As this is the first study to evaluate ovarian cancer risk factors by tumor dominance, these results need to be validated by other studies.

Non-steroidal anti-inflammatory drug use and ovarian cancer risk: findings from the NIH-AARP Diet and Health Study and systematic review.

BACKGROUND: Chronic inflammation has been proposed as a risk factor for ovarian cancer. Some data suggest that anti-inflammatory medications may be protective against ovarian cancer; however, results have been inconsistent. METHODS: We evaluated the risk of epithelial ovarian cancer with regular use of NSAIDs prospectively in the NIH-AARP Diet and Health Study, using Cox proportional hazard models. We also examined the risk of common subtypes of epithelial ovarian cancer (serous, mucinous, endometrioid, clear cell, and other epithelial) with regular use of NSAIDs. In addition, we performed meta-analyses summarizing the risk of ovarian cancer with "regular use" of NSAIDs in previously published studies. RESULTS: We did not observe a significant association between regular use of NSAIDs with ovarian cancer risk in the AARP cohort (aspirin: RR 1.06, 95 % CI 0.87-1.29; non-aspirin NSAIDs: RR 0.93, 95 % CI 0.74-1.15); however, summary estimates from prospective cohort studies demonstrated that use of non-aspirin NSAIDs may reduce the risk of ovarian cancer (RR 0.88, 95 % CI 0.77-1.01). Although not significant, we found that mucinous tumors were inversely associated with non-aspirin NSAID use (RR 0.69, 95 % CI 0.23-2.10) in the AARP cohort, which was supported by the meta-analysis (RR 0.69, CI 0.50-0.94.) CONCLUSION: Although results from the NIH-AARP cohort study were not statistically significant, our meta-analysis suggests that non-aspirin NSAIDs may be protective against ovarian cancer. Additional analyses, focusing on dose, duration, and frequency of NSAID use and accounting for ovarian cancer heterogeneity are necessary to further elucidate the association between NSAID use and ovarian cancer risk.

Tubal ligation, hysterectomy and ovarian cancer: A meta-analysis.

PURPOSE: The purpose of this meta-analysis was to determine the strength of the association between gynecologic surgeries, tubal ligation and hysterectomy, and ovarian cancer. METHODS: We searched the PubMed, Web of Science, and Embase databases for all English-language articles dated between 1969 through March 2011 using the keywords "ovarian cancer" and "tubal ligation" or "tubal sterilization" or "hysterectomy." We identified 30 studies on tubal ligation and 24 studies on hysterectomy that provided relative risks for ovarian cancer and a p-value or 95% confidence interval (CI) to include in the meta-analysis. Summary RRs and 95% CIs were calculated using a random-effects model. RESULTS: The summary RR for women with vs. without tubal ligation was 0.70 (95%CI: 0.64, 0.75). Similarly, the summary RR for women with vs. without hysterectomy was 0.74 (95%CI: 0.65, 0.84). Simple hysterectomy and hysterectomy with unilateral oophorectomy were associated with a similar decrease in risk (summery RR = 0.62, 95%CI: 0.49-0.79 and 0.60, 95%CI: 0.47-0.78, respectively). In secondary analyses, the association between tubal ligation and ovarian cancer risk was stronger for endometrioid tumors (summary RR = 0.45, 95%CI: 0.33, 0.61) compared to serous tumors. CONCLUSION: Observational epidemiologic evidence strongly supports that tubal ligation and hysterectomy are associated with a decrease in the risk of ovarian cancer, by approximately 26-30%. Additional research is needed to determine whether the association between tubal ligation and hysterectomy on ovarian cancer risk differs by individual, surgical, and tumor characteristics.

Ovarian cancer risk factors by histologic subtypes in the NIH-AARP Diet and Health Study.

Data suggest that risk factors for ovarian carcinoma vary by histologic type, but findings are inconsistent. We prospectively evaluated risk factors by histological subtypes of incident ovarian cancer (n = 849) in a cohort of 169,391 women in the NIH-AARP Diet and Health Study. We constructed Cox models of individual exposures by comparing case subtypes to the entire non-case group and assessed p-heterogeneity in case-case comparisons using serous as the reference category. Substantial risk differences between histologic subtypes were observed for menopausal hormone therapy (MHT) use, oral contraceptive (OC) use, parity and body mass index (p-heterogeneity = 0.01, 0.03, 0.05, 0.03, respectively). MHT users were at increased risk for all histologic subtypes except for mucinous carcinomas, where risk was reduced (relative risk (RR) = 0.37; 95% confidence interval (CI): 0.18, 0.80). OC users were only at significantly decreased risk for serous cancers (RR = 0.69; 95% CI: 0.55, 0.85). Although parity was inversely associated with risk of all subtypes, the RRs ranged from 0.28 (clear cell) to 0.83 (serous). Obesity was a significant risk factor only for endometrioid cancers (RR = 1.64; 95% CI: 1.00, 2.70). Our findings support a link between etiological factors and histological heterogeneity in ovarian carcinoma.

Frequency of mismatch repair deficiency in ovarian cancer: a systematic review This article is a US Government work and, as such, is in the public domain of the United States of America.

Loss of mismatch repair (MMR) capacity may represent an important tumor initiating mechanism in ovarian cancer. We conducted a systematic review to analyze the frequency of microsatellite instability (MSI), immunohistochemical (IHC) staining for MMR proteins, and hypermethylation of the MLH1 promoter region in ovarian cancers. Studies examining MSI, loss of MMR gene expression by IHC staining and MLH1 promoter hypermethylation in ovarian cancer were identified by a systematic literature search of the PubMed electronic database through August 31, 2009. Pertinent data was extracted from eligible studies and estimates for pooled proportions were computed using random effects models. The pooled proportion of MSI detection was 0.10 (95% CI, 0.06-0.14) among 1,234 cases in 22 studies. Dinonucleotide markers had a higher frequency of instability than mononucleotide markers. The pooled proportion of MLH1 or MSH2 staining loss was 0.06 (95% CI, 0.01-0.17) among 474 cases in three studies, with a higher frequency of loss in MLH1. The pooled proportion of MLH1 methylation was 0.10 (95% CI, 0.06-0.15) among 672 cases in seven studies. Data reporting MSI and loss of MMR staining in the same cases was limited. Although MMR deficiency was found in all histologic subtypes, endometrioid cancers had the highest proportion. Approximately 10% of unselected ovarian cancers are related to MMR deficiency. While MMR deficiency is associated with improved survival in other MMR-deficiency related cancer sites, epidemiological and clinical factors related to the MMR-deficient phenotype have not been adequately studied in ovarian cancer to date.