Loss of DNA Mismatch Repair Imparts a Selective Advantage in Planarian Adult Stem Cells

Lynch syndrome (LS) leads to an increased risk of early-onset colorectal and other types of cancer and is caused by germline mutations in DNA mismatch repair (MMR) genes. Loss of MMR function results in a mutator phenotype that likely underlies its role in tumorigenesis. However, loss of MMR also results in the elimination of a DNA damage-induced checkpoint/apoptosis activation barrier that may allow damaged cells to grow unchecked. A fundamental question is whether loss of MMR provides pre-cancerous stem cells an immediate selective advantage in addition to establishing a mutator phenotype. To test this hypothesis in an in vivo system, we utilized the planarian Schmidtea mediterranea which contains a significant population of identifiable adult stem cells. We identified a planarian homolog of human MSH2, a MMR gene which is mutated in 38% of LS cases. The planarian Smed-msh2 is expressed in stem cells and some progeny. We depleted Smed-msh2 mRNA levels by RNA-interference and found a striking survival advantage in these animals treated with a cytotoxic DNA alkylating agent compared to control animals. We demonstrated that this tolerance to DNA damage is due to the survival of mitotically active, MMR-deficient stem cells. Our results suggest that loss of MMR provides an in vivo survival advantage to the stem cell population in the presence of DNA damage that may have implications for tumorigenesis

Smoking cessation and counseling: A mixed methods study of pediatricians and parents.

ObjectivePediatric providers play an important role in parental and youth smoking cessation. The goal of this study was to understand smoking cessation attitudes of parents and the behaviors, confidence and self-efficacy of pediatricians related to providing smoking cessation counseling to parents and youth.MethodsA mixed methods study was conducted in a convenience sample of families (n = 1,549) and pediatric primary care clinicians (n = 95) in Connecticut using surveys and focus groups from April, 2016 to January, 2017.ResultsThe smoking rate (cigarettes or electronic cigarettes) among all households surveyed was 21%. Interest in quitting smoking was high (71%) and did not differ based on smoking amount, duration, type of community of residence (urban, rural, etc), or race/ethnicity. For example, compared to participants who smoked for ConclusionsClinicians frequently screen parents about their smoking behaviors, but rarely provide smoking cessation counseling and express low confidence in this activity. Clinicians are more confident counseling youth than parents. Clinicians also recognize the dangers of electronic cigarettes, yet they infrequently counsel youth about these dangers

Smoking cessation and counseling: A mixed methods study of pediatricians and parents.

OBJECTIVE Pediatric providers play an important role in parental and youth smoking cessation. The goal of this study was to understand smoking cessation attitudes of parents and the behaviors, confidence and self-efficacy of pediatricians related to providing smoking cessation counseling to parents and youth. METHODS A mixed methods study was conducted in a convenience sample of families (n = 1,549) and pediatric primary care clinicians (n = 95) in Connecticut using surveys and focus groups from April, 2016 to January, 2017. RESULTS The smoking rate (cigarettes or electronic cigarettes) among all households surveyed was 21%. Interest in quitting smoking was high (71%) and did not differ based on smoking amount, duration, type of community of residence (urban, rural, etc), or race/ethnicity. For example, compared to participants who smoked for <10 years, those who smoked ≥20 years had a similar interest in quitting (OR = 1.12; 95% CI: 0.85-1.48). Ninety percent of clinicians surveyed asked parents about their smoking behavior at least annually but 36% offered no smoking cessation counseling services or referral. Clinicians almost always reported counseling youth about the dangers of nicotine and tobacco use (99%), were more confident about counseling youth than parents (p<0.01) and reported low self-efficacy about smoking cessation and prevention counseling of parents and youth. Ninety-three percent of clinicians opined that electronic cigarettes were equally or more dangerous than cigarettes but 34% never counseled youth about the dangers of electronic cigarettes. CONCLUSIONS Clinicians frequently screen parents about their smoking behaviors, but rarely provide smoking cessation counseling and express low confidence in this activity. Clinicians are more confident counseling youth than parents. Clinicians also recognize the dangers of electronic cigarettes, yet they infrequently counsel youth about these dangers

Exposure to secondhand smoke and asthma severity among children in Connecticut

<div><p>Objective</p><p>To determine whether secondhand smoke (SHS) exposure is associated with greater asthma severity in children with physician-diagnosed asthma living in CT, and to examine whether area of residence, race/ethnicity or poverty moderate the association.</p><p>Methods</p><p>A large childhood asthma database in CT (Easy Breathing) was linked by participant zip code to census data to classify participants by area of residence. Multinomial logistic regression models, adjusted for enrollment date, sex, age, race/ethnicity, area of residence, insurance type, family history of asthma, eczema, and exposure to dogs, cats, gas stove, rodents and cockroaches were used to examine the association between self-reported exposure to SHS and clinician-determined asthma severity (mild, moderate, and severe persistent vs. intermittent asthma).</p><p>Results</p><p>Of the 30,163 children with asthma enrolled in Easy Breathing, between 6 months and 18 years old, living in 161 different towns in CT, exposure to SHS was associated with greater asthma severity (adjusted relative risk ratio (aRRR): 1.07 [1.00, 1.15] and aRRR: 1.11 [1.02, 1.22] for mild and moderate persistent asthma, respectively). The odds of Black and Puerto Rican/Hispanic children with asthma being exposed to SHS were twice that of Caucasian children. Though the odds of SHS exposure for publicly insured children with asthma were three times greater than the odds for privately insured children (OR: 3.02 [2.84,3,21]), SHS exposure was associated with persistent asthma only among privately insured children (adjusted odds ratio (aOR): 1.23 [1.11,1.37]).</p><p>Conclusion</p><p>This is the first large-scale pragmatic study to demonstrate that children exposed to SHS in Connecticut have greater asthma severity, clinically determined using a systematic approach, and varies by insurance status.</p></div

Design, methods, and baseline characteristics of a pilot, randomized, controlled trial of the effects of an electronic monitoring device on medication adherence in children with asthma

Current methods of assessing adherence are inaccurate. Electronic monitoring devices (EMDs) may more accurately assess adherence, but are not currently used in practice. The design, methods, and participant baseline characteristics are described for a pilot trial of the effects of an EMD on asthma medication adherence in a pediatric population. This was a pilot, randomized, controlled trial of children with persistent asthma managed with daily inhaled corticosteroids (ICS). Seventy-five children were randomized 2:1 to receive either two EMDs (one for ICS and one for rescue) linked via Bluetooth to a mobile application (app) or standard of care (controls). EMDs recorded dates and times of inhaler actuations and the app sent daily medication reminders to participants. Controls were provided standard care. Medication adherence was measured using pharmacy refill records and self-report, whereas EMD data were used to measure adherence in the intervention group. Secondary outcomes included asthma control, pulmonary function, and quality of life. One hundred sixty children were screened for eligibility, with 123 individuals excluded. Seventy-five children were enrolled, with 25 allocated to the control group and 50 to the intervention. The mean age of participants is 12 years old (±2.9), with equal proportions of male and female children; 45% are Latinx and 19% African-American; 77% report Medicaid or CHIP coverage. Half of participants have moderate persistent asthma and 48% had marginally controlled asthma at time of enrollment. There were no significant inter-group differences in baseline sociodemographic characteristics. This pilot successfully reached target populations and met recruitment and enrollment goals. It is addressing an important knowledge gap by evaluating the effects of an EMD with a mobile app on adherence rates, findings which could prove useful in determining whether routine use of EMDs in clinical practice help children achieve better asthma control and outcomes. NCT03734861

Risk of exposure to SHS among children with asthma using Logistic Regression with Complete Case analysis.

<p>Risk of exposure to SHS among children with asthma using Logistic Regression with Complete Case analysis.</p

Main Effects Analysis on Asthma Severity using Multinomial Logistic Regression with Multiple Imputation (N = 30163).

<p>Main Effects Analysis on Asthma Severity using Multinomial Logistic Regression with Multiple Imputation (N = 30163).</p