Using implementation science to evaluate a population-wide genomic screening program: Findings from the first 20,000 In Our DNA SC participants.

We use the implementation science framework RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) to describe outcomes of In Our DNA SC, a population-wide genomic screening (PWGS) program. In Our DNA SC involves participation through clinical appointments, community events, or at home collection. Participants provide a saliva sample that is sequenced by Helix, and those with a pathogenic variant or likely pathogenic variant for CDC Tier 1 conditions are offered free genetic counseling. We assessed key outcomes among the first cohort of individuals recruited. Over 14 months, 20,478 participants enrolled, and 14,053 samples were collected. The majority selected at-home sample collection followed by clinical sample collection and collection at community events. Participants were predominately female, White (self-identified), non-Hispanic, and between the ages of 40-49. Participants enrolled through community events were the most racially diverse and the youngest. Half of those enrolled completed the program. We identified 137 individuals with pathogenic or likely pathogenic variants for CDC Tier 1 conditions. The majority (77.4%) agreed to genetic counseling, and of those that agreed, 80.2% completed counseling. Twelve clinics participated, and we conducted 108 collection events. Participants enrolled at home were most likely to return their sample for sequencing. Through this evaluation, we identified facilitators and barriers to implementation of our state-wide PWGS program. Standardized reporting using implementation science frameworks can help generalize strategies and improve the impact of PWGS.

Evaluation of a Telehealth-Enabled Pilot Program to Address Intensive Care Unit Health Care Worker Mental Health Distress.

Introduction: Health care workers (HCWs) are at heightened risk of adverse mental health events (AMHEs) and burnout with resultant impact on health care staffing, outcomes, and costs. We piloted a telehealth-enabled mental health screening and support platform among HCWs in the intensive care unit (ICU) setting at a tertiary care center. Methods: A survey consisting of validated screening tools was electronically disseminated to a potential cohort of 178 ICU HCWs. Participants were given real-time feedback on their results and those at risk were provided invitations to meet with resiliency clinicians. Participants were further invited to engage in a 3-month longitudinal assessment of their well-being through repeat surveys and a weekly text-based check-in coupled with self-help tips. Programmatic engagement was evaluated and associations between at-risk scores and engagement were assessed. Qualitative input regarding programmatic uptake and acceptance was gathered through key informant interviews. Results: Fifty (28%) HCWs participated in the program. Half of the participants identified as female, and most participants were white (74%) and under the age of 50 years (93%). Nurses (38%), physicians-in-training (24%), and faculty-level physicians (20%) engaged most frequently. There were 19 (38%) requests for an appointment with a resiliency clinician. The incidence of clinically significant symptoms of AMHEs and burnout was high but not clearly associated with engagement. Additional programmatic tailoring was encouraged by key informants while time was identified as a barrier to program engagement. Discussion: A telehealth-enabled platform is a feasible approach to screening at-risk HCWs for AMHEs and can facilitate engagement with support services.

Lessons Learned from the Pilot Phase of a Population-Wide Genomic Screening Program: Building the Base to Reach a Diverse Cohort of 100,000 Participants.

Background and Objectives: Genomic information is increasingly relevant for disease prevention and risk management at the individual and population levels. Screening healthy adults for Tier 1 conditions of hereditary breast and ovarian cancer, Lynch syndrome, and familial hypercholesterolemia using a population-based approach can help identify the 1−2% of the US population at increased risk of developing diseases associated with these conditions and tailor prevention strategies. Our objective is to report findings from an implementation science study that evaluates multi-level facilitators and barriers to implementation of the In Our DNA SC population-wide genomic screening initiative. Methods: We established an IMPACTeam (IMPlementAtion sCience for In Our DNA SC Team) to evaluate the pilot phase using principles of implementation science. We used a parallel convergent mixed methods approach to assess the Reach, Implementation, and Effectiveness outcomes from the RE-AIM implementation science framework during the pilot phase of In Our DNA SC. Quantitative assessment included the examination of frequencies and response rates across demographic categories using chi-square tests. Qualitative data were audio-recorded and transcribed, with codes developed by the study team based on the semi-structured interview guide. Results: The pilot phase (8 November 2021, to 7 March 2022) included recruitment from ten clinics throughout South Carolina. Reach indicators included enrollment rate and representativeness. A total of 23,269 potential participants were contacted via Epic's MyChart patient portal with 1976 (8.49%) enrolled. Black individuals were the least likely to view the program invitation (28.9%) and take study-related action. As a result, there were significantly higher enrollment rates among White (10.5%) participants than Asian (8.71%) and Black (3.46%) individuals (p < 0.0001). Common concerns limiting reach and participation included privacy and security of results and the impact participation would have on health or life insurance. Facilitators included family or personal history of a Tier 1 condition, prior involvement in genetic testing, self-interest, and altruism. Assessment of implementation (i.e., adherence to protocols/fidelity to protocols) included sample collection rate (n = 1104, 55.9%) and proportion of samples needing recollection (n = 19, 1.7%). There were no significant differences in sample collection based on demographic characteristics. Implementation facilitators included efficient collection processes and enthusiastic clinical staff. Finally, we assessed the effectiveness of the program, finding low dropout rates (n = 7, 0.35%), the identification of eight individuals with Tier 1 conditions (0.72% positive), and high rates of follow-up genetic counseling (87.5% completion). Conclusion: Overall, Asian and Black individuals were less engaged, with few taking any study-related actions. Strategies to identify barriers and promoters for the engagement of diverse populations are needed to support participation. Once enrolled, individuals had high rates of completing the study and follow-up engagement with genetic counselors. Findings from the pilot phase of In Our DNA SC offer opportunities for improvement as we expand the program and can provide guidance to organizations seeking to begin efforts to integrate population-wide genomic screening.

Poor Sleep Quality Is Associated with Higher Hemoglobin A1c in Pregnant Women: A Pilot Observational Study.

We hypothesized that poor sleep quality exacerbates glucose intolerance manifested as elevated glycosylated hemoglobin (HbA1c), which increases the risk for gestational diabetes. To test this, 38 pregnant and 22 non-pregnant (age, 18⁻35 years; body-mass index, 20⁻35 kg/m²) otherwise healthy women were enrolled in the study. Sleep quality was assessed during gestational week 24 (pregnant), or outside of the menstrual period (non-pregnant), using qualitative (Pittsburgh Sleep Quality Index) and objective (actigraphic wrist-watch) measures. Blood glucose, total cortisol, and depression status were evaluated. Eight pregnant and one non-pregnant women were lost to follow-up, or withdrew from the study. There was a higher incidence of poor sleep quality in pregnant (73%) relative to non-pregnant women (43%). Although actigraphic data revealed no differences in actual sleep hours between pregnant and non-pregnant women, the number of wake episodes and sleep fragmentation were higher in pregnant women. Poor sleep quality was positively correlated with higher HbA1c in both pregnant (r = 0.46, n = 26, p = 0.0151) and non-pregnant women (r = 0.50, n = 19, p = 0.0217), reflecting higher average blood glucose concentrations. In contrast, poor sleep was negatively correlated with cortisol responses in pregnant women (r = -0.46, n = 25, p = 0.0167). Three pregnant women had elevated one-hour oral glucose tolerance test results (>153 mg/dL glucose). These same pregnant women exhibited poor sleep quality. These results support the suggestion that poor sleep quality is an important risk factor that is associated with glucose intolerance and attendant health complications in pregnancy.

Chronic methamphetamine exposure produces a delayed, long-lasting memory deficit.

Methamphetamine (METH) is a highly addictive and neurotoxic psychostimulant. Its use in humans is often associated with neurocognitive impairment. Whether this is due to long-term deficits in short-term memory and/or hippocampal plasticity remains unclear. Recently, we reported that METH increases baseline synaptic transmission and reduces LTP in an ex vivo preparation of the hippocampal CA1 region from young mice. In the current study, we tested the hypothesis that a repeated neurotoxic regimen of METH exposure in adolescent mice decreases hippocampal synaptic plasticity and produces a deficit in short-term memory. Contrary to our prediction, there was no change in the hippocampal plasticity or short-term memory when measured after 14 days of METH exposure. However, we found that at 7, 14, and 21 days of drug abstinence, METH-exposed mice exhibited a deficit in spatial memory, which was accompanied by a decrease in hippocampal plasticity. Our results support the interpretation that the deleterious cognitive consequences of neurotoxic levels of METH exposure may manifest and persist after drug abstinence. Therefore, therapeutic strategies should consider short-term as well as long-term consequences of methamphetamine exposure.

Genistein attenuates the hypertensive effects of dietary NaCl in hypertensive male rats.

Diets high in polyphenols may protect estrogen-depleted women and rats from hypertension, but there is little evidence for this beneficial effect in males. On a polyphenol-free diet, ovariectomized spontaneously hypertensive rats (SHRs), high dietary NaCl increases arterial pressure, and this effect is greatly blunted by a soy-based diet. High NaCl diets also elevate arterial pressure in male SHRs, and pilot studies indicated that soy polyphenols blunt this effect. The present studies tested the hypothesis that genistein (the primary polyphenol in soy) reduces NaCl-sensitive hypertension in young, male stroke-prone SHRs (SHR-SP, a very NaCl-sensitive strain of SHR). Seven-week-old male SHR-SPs were placed on polyphenol-free diets with or without normal dietary amounts of genistein [0.06% (wt/wt)] and containing high (4%), moderate (2%), or basal (0.7%) NaCl. SHR-SP on the genistein-free diet displayed a dose-related increase in arterial pressure in response to dietary NaCl, and dietary genistein blunted this response. Ganglionic blockade with hexamethonium reduced arterial pressure to similar levels in all six groups, suggesting that the antihypertensive effects of genistein are influenced by the autonomic nervous system. We further hypothesized that genistein, like estrogen, would improve insulin sensitivity and lipid profiles. Thus, in study 2, 7-wk-old male SHR-SP were placed on high (6%) or basal (0.7%) NaCl diets with or without genistein (0.06%). Dietary genistein reduced plasma insulin and insulin resistance in SHR-SP on a high NaCl diet and decreased plasma cholesterol and triglycerides in SHR-SP on the basal NaCl diet. Thus, in male SHR-SP, dietary genistein blunts NaCl-sensitive hypertension, and these effects may be regulated, in part, by the autonomic nervous system and/or metabolic mechanisms.

Antihypertensive and cognitive effects of grape polyphenols in estrogen-depleted, female, spontaneously hypertensive rats.

Both endogenous and dietary estrogens reduce hypertension and enhance cognitive abilities in estrogen-depleted female spontaneously hypertensive rats (SHR). Many of the beneficial effects of estrogens/phytoestrogens also appear to be provided by other polyphenols (e.g., proanthocyanidins) in grape seed, which lack appreciable estrogenic receptor binding. The present study tested the hypothesis that similar to phytoestrogens, proanthrocyanidins in grape seed polyphenols reduce salt-sensitive hypertension in young, estrogen-depleted SHR. SHR were ovariectomized at 4 wk of age and placed on phytoestrogen-free diets with or without 0.5% grape seed extract added and with high (8.0%) or basal (0.6%) NaCl. After 10 wk on the diets, grape proanthrocyanidin supplementation significantly reduced arterial pressure in the rats fed the basal (10 mmHg) and high (26 mmHg)-NaCl diet, compared with the nonsupplemented controls. In vitro superoxide production was significantly reduced (23%) by the grape seed polyphenols. Spatial learning (8-arm-radial maze) in the SHR on the basal NaCl diets was improved by dietary grape seed polyphenols. These results indicate that grape seed polyphenols decrease arterial pressure in SHR, probably via an antioxidant mechanism.

Age-related decreases in gonadal hormones in Long-Evans rats: relationship to rise in arterial pressure.

Sex steroids modify sexual behavior and autonomic function. The gradual decline in circulating levels is correlated with several diseases in humans and animals. However, little is known about age-related changes that occur in the availability of these steroids. In the current studies, we characterized age-related changes in (1) circulating levels of estradiol (females) or testosterone (males), (2) reproductive function (estrous cyclicity in females; erectile reflexes in males), and (3) blood pressure in a longitudinal study. In a separate study, we characterized the estrous cyclicity of sex steroids in female, and diurnal periodicity in male, Long-Evans rats. Young females exhibit regular estrous cycles, transition to irregular cycles at about 10 mo of age, then to cycles characterized by extended periods of estrous, and to persistent estrous. Despite the loss of cyclicity, circulating 17beta-estradiol in middle-aged females was maintained at levels similar to those in young females during diestrous. Males display an age-related decline in testosterone, circulating levels decrease by about 25% during the period from 8 to 16 mo of age. Also, during any 24 h period testosterone levels in young males vary from a peak of about 3.5 ng/mL (late light period) to a trough of 0.7 ng/mL (early dark period). In middle-aged males the rhythm amplitude is greatly blunted (1.4 to 0.7 ng/mL). Males exhibit age-related decrements in erectile reflexes. In females and males systolic blood pressure is relatively stable until 8 mo of age, but significantly increases during the next 5 mo of age. In males, the increase in arterial pressure is gradual from about 8 mo of age. Young females have lower blood pressures than age-matched males, but by 14 mo of age this sex-related advantage is lost. Thus, by middle age, male and female rats are exposed to less gonadal hormone/altered patterns of availability, exhibit decrements in reproductive function, and display an increase in systolic blood pressure.

Estrogen depletion differentially affects blood pressure depending on age in Long-Evans rats.

Normotensive female rats exhibit age-related decreases in estrous cyclicity and increases in blood pressure. In spontaneously hypertensive rats, estrogens, including dietary phytoestrogens, prevent or attenuate the increased blood pressure associated with estrogen depletion. The present studies examine the effects of ovariectomy (OVX) at either 3 or 10 mo of age. Although blood pressure increases from 3 to 9 mo, OVX at 3 mo of age has no added effect--despite the fact that OVX (compared to ovary-intact) rats weighed significantly more. In contrast, aging from 10 to 16 mo is associated with a further increase in blood pressure, which is potentiated by estrogen depletion. Removal of dietary phytoestrogens exacerbated the hypertensive effects of OVX in these middle-aged rats. As in younger rats, estrogen depletion at 10 mo of age was associated with greater weight gain. Whereas estrogen depletion at 3 mo of age was without effect on fluid intake over the next 6 mo, OVX at 10 mo of age was associated with decreased fluid intake. In a final study, rats were OVX at 3 mo of age with estradiol (E2) treatment initiated at 10 mo of age. Long-term OVX ( >10 mo) was associated with increased blood pressure and mortality at 14-16 mo of age. Circulating levels of E2 were decreased by OVX. Plasma aldosterone was increased by OVX, an effect which was prevented by either E2 or phytoestrogens. Neither E2 nor aldosterone was affected by age. These data indicate that (a) the physiological effects of estrogen depletion vary with age; (b) phytoestrogens in the diet exert some protective effects; and (c) long-term OVX in the absence of hormone re-placement is associated with premature mortality. We suggest that chronic increases in aldosterone and sympathetic tone underlie the hypertensive effects of estrogen depletion.

Estrogen depletion increases blood pressure and hypothalamic norepinephrine in middle-aged spontaneously hypertensive rats.

In male spontaneously hypertensive rats (SHR) a high NaCl diet increases arterial pressure via a reduction in anterior hypothalamic nucleus norepinephrine release. Young female SHR are relatively well protected from this NaCl-sensitive hypertension, but depletion of both endogenous and dietary estrogens greatly exacerbates NaCl-sensitive hypertension. This study tests the hypothesis that estrogen also protects late middle-aged female SHR from NaCl-sensitive hypertension and that this effect is mediated by an estrogen-related effect on hypothalamic norepinephrine release. Ten-month-old female SHR were ovariectomized and placed on a phytoestrogen-free diet containing either basal or high NaCl. Each rat was implanted with a silastic tube containing 17beta estradiol or vehicle. Three months later, arterial pressure and hypothalamic norepinephrine metabolite levels (MOPEG) were measured. On the basal NaCl diet, estrogen-depleted rats displayed increased arterial pressure (12 mm Hg) and decreased anterior hypothalamic nucleus MOPEG (20%). Both effects were reversed by estrogen treatment. In all groups, the high NaCl diet increased arterial pressure by over 35 mm Hg and reduced anterior hypothalamic nucleus MOPEG by >60%. Across all groups, there was a significant inverse correlation between arterial pressure and anterior hypothalamic nucleus MOPEG. These data suggest that both dietary NaCl excess and estrogen depletion raise arterial pressure in middle-aged female SHR by a decreasing hypothalamic norepinephrine.