Use of non-steroidal anti-inflammatory drugs and pancreatic cancer risk in the Women's Health Initiative.

BACKGROUND: Pancreatic cancer is among the most fatal human cancers and the fourth leading cause of cancer death in the United States. Evidence suggests that chronic inflammation may play a role in pancreatic carcinogenesis, and its inhibition through non-steroidal anti-inflammatory drugs (NSAIDs) may reduce pancreatic cancer incidence. METHODS: We examined associations of total and individual NSAIDs with pancreatic cancer risk among postmenopausal women participating in the Women's Health Initiative observational study and clinical trials cohorts. Among 117,452 women, ages 55-79 years, 727 incident pancreatic cancer cases were reported over 18 years of follow-up. Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between NSAIDs and pancreatic cancer risk. RESULTS: Relative to non-use, consistent use of any NSAID was inversely associated with pancreatic cancer risk (HR 0.71, 95% CI: 0.59-0.87), primarily driven by strong associations for aspirin use (HR 0.67, 95% CI: 0.52-0.86). Use of total or individual non-aspirin NSAIDs were not associated with pancreatic cancer. Upon stratified analysis, we observed stronger associations for NSAIDs among participants with prevalent diabetes (HR 0.28, 95% CI: 0.10-0.75) relative to those without (HR 0.75, 95% CI: 0.61-0.92; P-interaction=0.03). CONCLUSIONS: Additional large prospective studies with careful measurement of NSAID type, dose, and frequency are needed to further investigate the possibility of added benefit among individuals diagnosed with diabetes. IMPACT: This study adds to existing evidence from prospective studies and clinical trials suggesting that use of aspirin may provide moderate benefit for pancreatic cancer prevention.

Impact of red blood cell transfusion on regional cerebral oxygen saturation during pediatric ECMO.

BACKGROUND: Low cerebral regional tissue oxygenation (crSO2) is associated with unfavorable neurological outcomes in children requiring extracorporeal membrane oxygenation (ECMO) support. Red blood cell (RBC) transfusion can improve brain oxygenation and crSO2 has been proposed as a noninvasive monitoring tool that could aid in RBC transfusion decision-making. However, how crSO2 responds to RBC transfusion is largely unknown. STUDY DESIGN AND METHODS: This was a retrospective, observational cohort study of all patients <21 years supported on ECMO at a single institution from 2011 to 2018. Transfusion events were grouped by pre-transfusion hemoglobin concentration (<10, 10- < 12, and ≥ 12 g/dL). Post- versus pre-transfusion crSO2 changes were analyzed using linear mixed-effects models. RESULTS: The final cohort included 830 transfusion events in 111 patients. Hemoglobin increased significantly post- versus pre-RBC transfusion (estimated mean increase of 0.47 g/dL [95% CI, 0.35-0.58], p < .001), as did crSO2 (estimated mean increase of 1.82 percentage points [95% CI, 1.23-2.40], p < .001). Larger improvements in crSO2 were associated with lower pre-transfusion crSO2 values (p < .001). There was no difference in mean change in crSO2 across the three hemoglobin groups in unadjusted analysis (p = .5) or after adjusting for age, diagnostic category, and pre-transfusion rSO2 (p = .15). Pre-transfusion crSO2 was <50% for 112 of 830 (13.5%) transfusion events, with only 30 (26.8%) crSO2 measurements noted to increase ≥50% post-transfusion. DISCUSSION: Among neonatal and pediatric patients on ECMO support, there was a statistically significant increase in crSO2 following RBC transfusion, although clinical significance needs to be investigated further. The effect was strongest among patients with lower crSO2 pre-transfusion.

Anxiety in pregnancy and stress responsiveness: An exploratory study of heart rate variability, cortisol, and alpha-amylase in the third trimester.

The present study aimed to explore the association between anxiety symptoms, including sleep, and physiological stress responsiveness in pregnant women with and without anxiety, as identified by psychiatric diagnosis. Fifty-four pregnant women with (n = 25) and without (n = 29) anxiety completed a laboratory cognitive stressor (the Stroop Color-Word Task) during the third trimester. Heart rate variability (HRV) (as the root mean square of successive differences, RMSSD) was recorded during baseline, stressor, and recovery periods. Salivary cortisol (sCORT) and alpha amylase (sAA) were measured at four timepoints surrounding the stressor task. Psychometric scales (Penn State Worry Questionnaire [PSWQ], Perceived Stress Scale [PSS], Spielberg Trait Anxiety Inventory Scale [STAI], and Pittsburgh Sleep Quality Index [PSQI]) were collected. Women in the anxiety group exhibited significantly less rebound in HRV (RMSSD, change of 4-ms difference, p = .025) from baseline to recovery following the Stroop than did those in the non-anxiety group. Neither neuroendocrine measure (sCORT, sAA) differed between groups at any measurement period. Across the recording period, lower reported sleep quality (PSQI, p = .0092) and higher subjective stress (PSS, p = .039) were associated with lower RMSSD. The findings suggest that women with and without anxiety in late pregnancy display differences in the degree of autonomic rebound as indicated by HRV following a stressor. In addition, levels of HRV over time were associated with subjective perceptions of increased stress and poor sleep. PREGNANCY AND ANXIOUS: The Role of the Immune and Endocrine Systems (NCT03664128).

Comparing Self-Management Programs with and without Peer Support among Patients with Chronic Obstructive Pulmonary Disease: A Clinical Trial.

Rationale: Self-management support (SMS) is an essential component of care for patients who have chronic obstructive pulmonary disease (COPD), but there is little evidence on how to provide SMS most effectively to these patients. Peer support (i.e., support provided by a person with a similar medical condition) has been successfully used to promote self-management among patients with various chronic conditions, yet no randomized studies have focused on testing its effects for patients with COPD. Objectives: To assess whether adding peer support to healthcare professional (HCP) support to help patients with COPD self-management results in better health-related quality of life (HRQoL) and less acute care use. Methods: A two-arm randomized controlled trial was performed at one academic and one community hospital and their affiliate clinics. The study population included patients aged ⩾40 years who had been diagnosed with COPD by a physician and were currently receiving daily treatment for it. Two self-management support strategies were compared over 6 months. One strategy relied on the HCP for COPD self-management (HCP support); the other used a dual approach involving both HCPs and peer supporters (HCP Plus Peer). The primary outcome was change in HRQoL measured by the St. George's Respiratory Questionnaire at 6 months (range, 0-100, lower is better; four-point meaningful difference). Secondary outcomes included COPD-related and all-cause hospitalizations and emergency department visits. Analysis was conducted under intention to treat. Results: The number of enrolled participants was 292. Mean age was 67.7 (standard deviation, 9.4) years; 70.9% of participants were White, and 61.3% were female. St. George's Respiratory Questionnaire scores were not significantly different between the study arms at 6 months. HCP Plus Peer arm participants had fewer COPD-related acute care events at 3 months (incidence rate ratio, 0.68; 95% confidence interval [CI], 0.50-0.93) and 6 months (incidence rate ratio, 0.84; 95% CI, 0.71-0.99). Conclusions: Adding peer support to HCP support to help patients self-manage COPD did not further improve HRQoL in this study. However, it did result in fewer COPD-related acute care events during the 6-month intervention period. Clinical trial registered with www.clinicaltrials.gov (NCT02891200).

Sterol and lipid analyses identifies hypolipidemia and apolipoprotein disorders in autism associated with adaptive functioning deficits.

An improved understanding of sterol and lipid abnormalities in individuals with autism spectrum disorder (ASD) could lead to personalized treatment approaches. Toward this end, in blood, we identified reduced synthesis of cholesterol in families with ≥2 children with ASD participating with the Autism Genetic Resource Exchange (AGRE), as well as reduced amounts of high-density lipoprotein cholesterol (HDL), apolipoprotein A1 (ApoA1) and apolipoprotein B (ApoB), with 19.9% of the subjects presenting with apolipoprotein patterns similar to hypolipidemic clinical syndromes and 30% with either or both ApoA1 and ApoB less than the fifth centile. Subjects with levels less than the fifth centile of HDL or ApoA1 or ApoA1 + ApoB had lower adaptive functioning than other individuals with ASD, and hypocholesterolemic subjects had apolipoprotein deficits significantly divergent from either typically developing individuals participating in National Institutes of Health or the National Health and Nutrition Examination Survey III.

Adjuvant therapy for early stage, endometrial cancer with lymphovascular space invasion: Is there a role for chemotherapy?

OBJECTIVES: Lymphovascular space invasion (LVSI) is an independent risk factor for recurrence and poor survival in early-stage endometrioid endometrial cancer (EEC), but optimal adjuvant treatment is unknown. We aimed to compare the survival of women with early-stage EEC with LVSI treated postoperatively with observation (OBS), radiation (RAD, external beam and/or vaginal brachytherapy), or chemotherapy (CHEMO)+/-RAD. METHODS: This was a multi-institutional, retrospective cohort study of women with stage I or II EEC with LVSI who underwent hysterectomy+/-lymphadenectomy from 2005 to 2015 and received OBS, RAD, or CHEMO+/-RAD postoperatively. Progression-free survival and overall survival were evaluated using Kaplan-Meier estimates and Cox proportional hazards models. RESULTS: In total, 478 women were included; median age was 64 years, median follow-up was 50.3 months. After surgery, 143 (30%) underwent OBS, 232 (48.5%) received RAD, and 103(21.5%) received CHEMO+/-RAD (95% of whom received RAD). Demographics were similar among groups, but those undergoing OBS had lower stage and grade. A total of 101 (21%) women recurred. Progression-free survival (PFS) was improved in both CHEMO+/-RAD (HR = 0.18, 95% CI: 0.09-0.39) and RAD (HR = 0.31, 95% CI: 0.18-0.54) groups compared to OBS, though neither adjuvant therapy was superior to the other. However, in grade 3 tumors, the CHEMO+/-RAD group had superior PFS compared to both RAD (HR 0.25; 95% CI: 0.12-0.52) and OBS cohorts (HR = 0.10, 95% CI: 0.03-0.32). Overall survival did not differ by treatment. CONCLUSIONS: In early-stage EEC with LVSI, adjuvant therapy improved PFS compared to observation alone. In those with grade 3 EEC, adjuvant chemotherapy with or without radiation improved PFS compared to observation or radiation alone.

Explanation of observational data engenders a causal belief about smoking and cancer.

Most researchers do not deliberately claim causal results in an observational study. But do we lead our readers to draw a causal conclusion unintentionally by explaining why significant correlations and relationships may exist? Here we perform a randomized controlled experiment in a massive open online course run in 2013 that teaches data analysis concepts to test the hypothesis that explaining an analysis will lead readers to interpret an inferential analysis as causal. We test this hypothesis with a single example of an observational study on the relationship between smoking and cancer. We show that adding an explanation to the description of an inferential analysis leads to a 15.2% increase in readers interpreting the analysis as causal (95% confidence interval for difference in two proportions: 12.8%-17.5%). We then replicate this finding in a second large scale massive open online course. Nearly every scientific study, regardless of the study design, includes an explanation for observed effects. Our results suggest that these explanations may be misleading to the audience of these data analyses and that qualification of explanations could be a useful avenue of exploration in future research to counteract the problem. Our results invite many opportunities for further research to broaden the scope of these findings beyond the single smoking-cancer example examined here.

Graph theoretic analysis of structural connectivity across the spectrum of Alzheimer's disease: The importance of graph creation methods.

Graph theory is increasingly being used to study brain connectivity across the spectrum of Alzheimer's disease (AD), but prior findings have been inconsistent, likely reflecting methodological differences. We systematically investigated how methods of graph creation (i.e., type of correlation matrix and edge weighting) affect structural network properties and group differences. We estimated the structural connectivity of brain networks based on correlation maps of cortical thickness obtained from MRI. Four groups were compared: 126 cognitively normal older adults, 103 individuals with Mild Cognitive Impairment (MCI) who retained MCI status for at least 3 years (stable MCI), 108 individuals with MCI who progressed to AD-dementia within 3 years (progressive MCI), and 105 individuals with AD-dementia. Small-world measures of connectivity (characteristic path length and clustering coefficient) differed across groups, consistent with prior studies. Groups were best discriminated by the Randic index, which measures the degree to which highly connected nodes connect to other highly connected nodes. The Randic index differentiated the stable and progressive MCI groups, suggesting that it might be useful for tracking and predicting the progression of AD. Notably, however, the magnitude and direction of group differences in all three measures were dependent on the method of graph creation, indicating that it is crucial to take into account how graphs are constructed when interpreting differences across diagnostic groups and studies. The algebraic connectivity measures showed few group differences, independent of the method of graph construction, suggesting that global connectivity as it relates to node degree is not altered in early AD.

An estimate of the science-wise false discovery rate and application to the top medical literature.

The accuracy of published medical research is critical for scientists, physicians and patients who rely on these results. However, the fundamental belief in the medical literature was called into serious question by a paper suggesting that most published medical research is false. Here we adapt estimation methods from the genomics community to the problem of estimating the rate of false discoveries in the medical literature using reported $P$-values as the data. We then collect $P$-values from the abstracts of all 77 430 papers published in The Lancet, The Journal of the American Medical Association, The New England Journal of Medicine, The British Medical Journal, and The American Journal of Epidemiology between 2000 and 2010. Among these papers, we found 5322 reported $P$-values. We estimate that the overall rate of false discoveries among reported results is 14% (s.d. 1%), contrary to previous claims. We also found that there is no a significant increase in the estimated rate of reported false discovery results over time (0.5% more false positives (FP) per year, $P = 0.18$) or with respect to journal submissions (0.5% more FP per 100 submissions, $P = 0.12$). Statistical analysis must allow for false discoveries in order to make claims on the basis of noisy data. But our analysis suggests that the medical literature remains a reliable record of scientific progress.