Does the prescriptive lifestyle of Seventh-Day Adventists provide \u27immunity\u27 from the secular effects of changes in BMI?

Objective: To examine the effect of Seventh-day Adventist (SDA) membership on &lsquo;immunity&rsquo; to the secular effects of changes in BMI.Design: Three independent, cross-sectional, screening surveys conducted by Sydney Adventist Hospital in 1976, 1986 and 1988 and a survey conducted among residents of Melbourne in 2006.Subjects: Two hundred and fifty-two SDA and 464 non-SDA in 1976; 166 SDA and 291 non-SDA in 1986; 120 SDA and 300-non SDA in 1988; and 251 SDA and 294 non-SDA in 2006.Measurements: Height and weight measured by hospital staff in 1976, 1986 and 1988; self-reported by respondents in 2006.Results: The mean BMI of non-SDA men increased between 1986 and 2006 (P &lt; 0&middot;001) but did not change for SDA men or non-SDA women. Despite small increases in SDA women&rsquo;s mean BMI (P = 0&middot;030) between 1988 and 2006, this was no different to that of SDA men and non-SDA women in 2006. The diet and eating patterns of SDA men and women were more &lsquo;prudent&rsquo; than those of non-SDA men and women, including more fruit, vegetables, grains, nuts and legumes, and less alcohol, meat, sweetened drinks and coffee. Many of these factors were found to be predictors of lower BMI.Conclusion: The &lsquo;prudent&rsquo; dietary and lifestyle prescriptions of SDA men appear to have &lsquo;immunised&rsquo; them to the secular effects of changes that occurred among non-SDA men&rsquo;s BMI. The dietary and lifestyle trends of SDA women did not reflect the increase in their BMI observed in 2006.<br /

An epigenetic switch regulates the ontogeny of AXL-positive/EGFR-TKi-resistant cells by modulating miR-335 expression.

Despite current advancements in research and therapeutics, lung cancer remains the leading cause of cancer-related mortality worldwide. This is mainly due to the resistance that patients develop against chemotherapeutic agents over the course of treatment. In the context of non-small cell lung cancers (NSCLC) harboring EGFR-oncogenic mutations, augmented levels of AXL and GAS6 have been found to drive resistance to EGFR tyrosine kinase inhibitors such as Erlotinib and Osimertinib in certain tumors with mesenchymal-like features. By studying the ontogeny of AXL-positive cells, we have identified a novel non-genetic mechanism of drug resistance based on cell-state transition. We demonstrate that AXL-positive cells are already present as a subpopulation of cancer cells in Erlotinib-naïve tumors and tumor-derived cell lines and that the expression of AXL is regulated through a stochastic mechanism centered on the epigenetic regulation of miR-335. The existence of a cell-intrinsic program through which AXL-positive/Erlotinib-resistant cells emerge infers the need of treating tumors harboring EGFR-oncogenic mutations upfront with combinatorial treatments targeting both AXL-negative and AXL-positive cancer cells

Adjusting a cancer mortality-prediction model for disease status-related eligibility criteria

<p>Abstract</p> <p>Background</p> <p>Volunteering participants in disease studies tend to be healthier than the general population partially due to specific enrollment criteria. Using modeling to accurately predict outcomes of cohort studies enrolling volunteers requires adjusting for the bias introduced in this way. Here we propose a new method to account for the effect of a specific form of healthy volunteer bias resulting from imposing disease status-related eligibility criteria, on disease-specific mortality, by explicitly modeling the length of the time interval between the moment when the subject becomes ineligible for the study, and the outcome.</p> <p>Methods</p> <p>Using survival time data from 1190 newly diagnosed lung cancer patients at MD Anderson Cancer Center, we model the time from clinical lung cancer diagnosis to death using an exponential distribution to approximate the length of this interval for a study where lung cancer death serves as the outcome. Incorporating this interval into our previously developed lung cancer risk model, we adjust for the effect of disease status-related eligibility criteria in predicting the number of lung cancer deaths in the control arm of CARET. The effect of the adjustment using the MD Anderson-derived approximation is compared to that based on SEER data.</p> <p>Results</p> <p>Using the adjustment developed in conjunction with our existing lung cancer model, we are able to accurately predict the number of lung cancer deaths observed in the control arm of CARET.</p> <p>Conclusions</p> <p>The resulting adjustment was accurate in predicting the lower rates of disease observed in the early years while still maintaining reasonable prediction ability in the later years of the trial. This method could be used to adjust for, or predict the duration and relative effect of any possible biases related to disease-specific eligibility criteria in modeling studies of volunteer-based cohorts.</p

Relative survival: a useful tool to assess generalisability in longitudinal studies of health in older persons

Generalisability of longitudinal studies is threatened by issues such as choice of sampling frame, representativeness of the initial sample, and attrition. To determine representativeness, cohorts are often compared with the population of interest at baseline on demographic and health characteristics. This study illustrates the use of relative survival as a tool for assessing generalisability of results from a cohort of older people among whom death is a potential threat to generalisability.The authors used data from the 1921-26 cohort (n = 12,416, aged 70-75 in 1996) of the Australian Longitudinal Study on Women's Health (ALSWH). Vital status was determined by linkage to the National Death Index, and expected deaths were derived using Australian life tables. Relative survival was estimated using observed survival in the cohort divided by expected survival among women of the same age and State or Territory.Overall, the ALSWH women showed relative survival 9.5% above the general population. Within States and Territories, the relative survival advantage varied from 6% to 23%. The interval-specific relative survival remained relatively constant over the 12 years (1996-2008) under review, indicating that the survival advantage of the cohort has not diminished over time.This study demonstrates that relative survival can be a useful measure of generalisability in a longitudinal study of the health of the general population, particularly when participants are older

Comparison of sociodemographic and health-related characteristics of UK Biobank participants with the general population

UK Biobank is a population-based cohort of 500,000 participants recruited between 2006 and 2010. Approximately 9.2 million individuals aged 40-69 years who lived within 25 miles of the 22 assessment centres in England, Wales and Scotland were invited, and 5.4% participated in the baseline assessment. The representativeness of the UK Biobank cohort was investigated by comparing demographic characteristics between non-responders and responders. Sociodemographic, physical, lifestyle and health-related characteristics of the cohort were compared with nationally representative data sources. UK Biobank participants were more likely to be older, women and to live in less socioeconomically deprived areas than non-participants. Compared with the general population, participants were less likely to be obese, smoke, drink alcohol on a daily basis and had fewer self-reported health outcomes. Rates of all-cause mortality and total cancer incidence (at age 70-74 years) were 46.2% and 11.8% lower in men, and 55.5% and 18.1% lower in women, respectively, than the general population of the same age. UK Biobank is not representative of the sampling population, with evidence of a ‘healthy volunteer’ selection bias. Nonetheless, the valid assessment of exposure-disease relationships may be widely generalizable and does not require participants to be representative of the population at large

Efficacy of Sym004 in Patients With Metastatic Colorectal Cancer With Acquired Resistance to Anti-EGFR Therapy and Molecularly Selected by Circulating Tumor DNA Analyses: A Phase 2 Randomized Clinical Trial.

IMPORTANCE: Acquired resistance to anti-EGFR therapy (epidermal growth factor receptor) is frequently due to RAS and EGFR extracellular domain (ECD) mutations in metastatic colorectal cancer (mCRC). Some anti-EGFR-refractory patients retain tumor EGFR dependency potentially targetable by agents such as Sym004, which is a mixture of 2 nonoverlapping monoclonal antibodies targeting EGFR. OBJECTIVE: To determine if continuous blockade of EGFR by Sym004 has survival benefit. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, phase 2, randomized, clinical trial comparing 2 regimens of Sym004 with investigator's choice from March 6, 2014, through October 15, 2015. Circulating tumor DNA (ctDNA) was analyzed for biomarker and tracking clonal dynamics during treatment. Participants had wild-type KRAS exon 2 mCRC refractory to standard chemotherapy and acquired resistance to anti-EGFR monoclonal antibodies. INTERVENTIONS: Participants were randomly assigned in a 1:1:1 ratio to Sym004, 12 mg/kg/wk (arm A), Sym004, 9 mg/kg loading dose followed by 6 mg/kg/wk (arm B), or investigator's choice of treatment (arm C). MAIN OUTCOMES AND MEASURES: Overall survival (OS). Secondary end points included preplanned exploratory biomarker analysis in ctDNA. RESULTS: A total of 254 patients were randomized (intent-to-treat [ITT] population) (median age, 63 [range, 34-91] years; 63% male; n\u2009=\u2009160). Median OS in the ITT population was 7.9 months (95% CI, 6.5-9.9 months), 10.3 months (95% CI, 9.0-12.9 months), and 9.6 months (95% CI, 8.3-12.2 months) for arms A, B, and C, respectively (hazard ratio [HR], 1.31; 95% CI, 0.92-1.87 for A vs C; and HR, 0.97; 95% CI, 0.68-1.40 for B vs C). The ctDNA revealed high intrapatient genomic heterogeneity following anti-EGFR therapy. Sym004 effectively targeted EGFR ECD-mutated cancer cells, and a decrease in EGFR ECD ctDNA occurred in Sym004-treated patients. However, this did not translate into clinical benefit in patients with EGFR ECD mutations, likely owing to co-occurring resistance mechanisms. A subgroup of patients was defined by ctDNA (RAS/BRAF/EGFR ECD-mutation negative) associated with improved OS in Sym004-treated patients in arm B compared with arm C (median OS, 12.8 and 7.3 months, respectively). CONCLUSIONS AND RELEVANCE: Sym004 did not improve OS in an unselected population of patients with mCRC and acquired anti-EGFR resistance. A prospective clinical validation of Sym004 efficacy in a ctDNA molecularly defined subgroup of patients with refractory mCRC is warranted. TRIAL REGISTRATION: clinicaltrialsregister.eu Identifier: 2013-003829-29

The Association of Health Literacy and Blood Pressure Reduction in a Cohort of Patients with Hypertension: The Heart Healthy Lenoir Trial

OBJECTIVE: Lower health literacy is associated with poorer health outcomes. Few interventions poised to mitigate the impact of health literacy in hypertensive patients have been published. We tested if a multilevel quality improvement intervention could differentially improve Systolic Blood Pressure (SBP) more so in patients with low vs. higher health literacy. METHODS: We conducted a non-randomized prospective cohort trial of 525 patients referred with uncontrolled hypertension. Stakeholder informed and health literacy sensitive strategies were implemented at the practice and patient level. Outcomes were assessed at 0, 6, 12, 18 and 24 months. RESULTS: At 12 months, the low and higher health literacy groups had statistically significant decreases in mean SBP (6.6 and 5.3 mmHg, respectively), but the between group difference was not significant (Δ 1.3 mm Hg, P=.067). At 24 months, the low and higher health literacy groups reductions were 8.1 and 4.6 mm Hg, respectively, again the between group difference was not significant (Δ 3.5 mm Hg, p = 0.25). CONCLUSIONS/PRACTICE IMPLICATIONS: A health literacy sensitive multi-level intervention may equally lower SBP in patients with low and higher health literacy. Practical health literacy appropriate tools and methods can be implemented in primary care settings using a quality improvement approach