Osimertinib Resistance via Histologic Transformation From Non-small Cell Lung Carcinoma to Carcinosarcoma.

Resistance to tyrosine kinase inhibitors (TKIs) in non-small cell lung carcinoma (NSCLC) remains a significant clinical challenge. Osimertinib, a third-generation TKI, has demonstrated efficacy in overcoming resistance, but novel resistance mechanisms continue to emerge. This case report presents a unique instance of histologic transformation from NSCLC to carcinosarcoma, representing a previously unreported manifestation of osimertinib resistance. We describe the clinical course of a 63-year-old female with epidermal growth factor receptor (EGFR)-mutant NSCLC who initially responded to osimertinib but eventually developed carcinosarcoma. The transformation was associated with additional EGFR mutations and alterations in RB and TP53. Despite aggressive treatment, the patient's condition deteriorated, emphasizing the limited therapeutic options for carcinosarcoma. This case underscores the need for further research to elucidate the molecular mechanisms behind histologic transformation and explore novel therapeutic strategies to address osimertinib resistance in NSCLC. Understanding and addressing these mechanisms are crucial for improving outcomes in patients facing this challenging form of resistance.

Dietary and Metabolic Approaches for Treating Autism Spectrum Disorders, Affective Disorders and Cognitive Impairment Comorbid with Epilepsy: A Review of Clinical and Preclinical Evidence.

Epilepsy often occurs with other neurological disorders, such as autism, affective disorders, and cognitive impairment. Research indicates that many neurological disorders share a common pathophysiology of dysfunctional energy metabolism, neuroinflammation, oxidative stress, and gut dysbiosis. The past decade has witnessed a growing interest in the use of metabolic therapies for these disorders with or without the context of epilepsy. Over one hundred years ago, the high-fat, low-carbohydrate ketogenic diet (KD) was formulated as a treatment for epilepsy. For those who cannot tolerate the KD, other diets have been developed to provide similar seizure control, presumably through similar mechanisms. These include, but are not limited to, the medium-chain triglyceride diet, low glycemic index diet, and calorie restriction. In addition, dietary supplementation with ketone bodies, polyunsaturated fatty acids, or triheptanoin may also be beneficial. The proposed mechanisms through which these diets and supplements work to reduce neuronal hyperexcitability involve normalization of aberrant energy metabolism, dampening of inflammation, promotion of endogenous antioxidants, and reduction of gut dysbiosis. This raises the possibility that these dietary and metabolic therapies may not only exert anti-seizure effects, but also reduce comorbid disorders in people with epilepsy. Here, we explore this possibility and review the clinical and preclinical evidence where available.

Pilot Study of the Effects of Paced Breathing on Measures of Convergent and Divergent Thinking.

BACKGROUND: The ability of the autonomic nervous system's stress response to impair aspects of cognitive flexibility is known. However, the ability to modulate the sympathetic response and improve these cognitive impairments via nonpharmacological intervention, such as paced breathing (PB), requires further investigation. OBJECTIVE: To better elucidate the effects of PB on cognition. METHOD: We employed a PB protocol in a total of 52 healthy men and women and measured performance on convergent and divergent cognitive tasks, perceived stress, and physiological measures (eg, blood pressure, heart rate). Participants attended two experimental sessions consisting of either PB or normal breathing followed by cognitive assessments including convergent (compound remote associate, anagram) and divergent (alternate use, fluency) tasks. Experiment 2 consisted of more difficult versions of cognitive tasks compared with Experiment 1. RESULTS: In Experiment 1, PB significantly reduced the female participants' systolic and diastolic blood pressure immediately after the breathing protocol without affecting their cognition. In Experiment 2, PB significantly reduced perceived stress immediately after the breathing protocol, regardless of sex. There was no effect on cognition in Experiment 2, but a correlation was observed between perceived stress change and anagram number solved change. CONCLUSION: While PB modulates sympathetic activity in females, there was a lack of improvement in cognitive flexibility performance. At least for a single trial of PB, cognitive flexibility did not improve.

Breastfeeding and Later-Life Cardiometabolic Health in Women With and Without Hypertensive Disorders of Pregnancy.

Background Breastfeeding is associated with improved cardiometabolic profiles decades after pregnancy. Whether this association exists for women who experience hypertensive disorders of pregnancy (HDP) is unknown. The authors examined whether breastfeeding duration or exclusivity are associated with long-term cardiometabolic health, and whether this relationship differs by HDP status. Methods and Results Participants (N=3598) were from the UK ALSPAC (Avon Longitudinal Study of Parents and Children) cohort. HDP status was assessed by medical record review. Breastfeeding behaviors were assessed by contemporaneous questionnaires. Breastfeeding duration was categorized as never, <1, 1 to <3, 3 to <6, 6 to <9, and 9+ months. Breastfeeding exclusivity was categorized as never, <1, 1 to <3, and 3 to 6 months. Measures of cardiometabolic health (body mass index, waist circumference, C-reactive protein, insulin, proinsulin, glucose, lipids, blood pressure, mean arterial pressure, carotid intima-media thickness, and arterial distensibility) were measured 18 years after pregnancy. Analyses were conducted using linear regression adjusting for relevant covariates. Breastfeeding was associated with improved cardiometabolic health (lower body mass index, waist circumference, C-reactive protein, triglycerides, insulin, and proinsulin) in all women, but not for every breastfeeding duration. Interaction tests revealed additional benefits in women with a history of HDP, with the strongest benefit observed in the 6- to 9-month breastfeeding category (diastolic blood pressure, -4.87 mm Hg [95% CI, -7.86 to -1.88], mean arterial pressure -4.61 [95% CI, -7.45 to -1.77], and low-density lipoprotein cholesterol, -0.40 mmol/L [95% CI, -0.62 to -0.17 mmol/L]). Differences in C-reactive protein and low-density lipoprotein "survived" Bonferroni correction (P<0.001). Similar results were observed in the exclusive breastfeeding analyses. Conclusions Breastfeeding may be a mechanism to reduce the cardiovascular disease sequela associated with HDP; however, there is a need to establish whether associations reflect a causal effect.

Epigenomic Links Between Social Determinants of Health and Symptoms: A Scoping Review.

Social determinants of health (SDoH) impact health and wellness. The link between SDoH and adverse health outcomes, including symptom occurrence and severity, may be explained by an individual's physiologic response to one or more SDoH. One potential mechanism underlying this physiologic response linking SDoH and symptoms is the dynamic epigenome. The purpose of this scoping review of the literature was to examine differential susceptibility for symptoms by identifying and summarizing research linking SDoH and symptoms through epigenomic mechanisms. PubMed was searched to identify empirical research where at least one SDoH was an independent or dependent variable, at least one symptom was investigated, and the investigation included an epigenomic measure. Of the 484 articles initially retrieved, after thorough vetting, 41 articles met eligibility. The most studied symptom was depressive symptoms followed by anxiety, cognitive function, sleep dysfunction, and pain. The most frequently studied SDoH were: 1) stress, particularly early life stress and acculturative stress; and 2) trauma, predominantly childhood trauma. DNA methylation and telomere length were the most studied epigenomic measures. Four genes (SLC6A4, BDNF, NR3C1, OXTR) had evidence from multiple studies and across methodological approaches linking SDoH to symptoms. This review supports the inclusion of epigenomic approaches to better understand the link between SDoH and symptoms and provides evidence that SDoH impact telomere length and the methylation of genes involved in neurotransmitter signaling, neuronal survival, behavior, inflammation and stress response.

Dietary Inflammatory Index and sleep quality and duration among pregnant women with overweight or obesity.

STUDY OBJECTIVES: Sleep disturbances, which can worsen during pregnancy, have been linked to inflammatory processes. This study tested the hypothesis that more pro-inflammatory diets during pregnancy are associated with a decrease in sleep quality and shorter sleep duration. METHODS: The Health in Pregnancy and Postpartum study promoted a healthy lifestyle in pregnant women with pre-pregnancy overweight or obesity (n = 207). Data from <16 weeks and 32 weeks gestation were used. Sleep was measured using BodyMedia's SenseWear® armband. Diet was assessed using two 24-hr dietary recalls. Energy-density Dietary Inflammatory Index (E-DIITM) scores were calculated from micro and macronutrients. Linear mixed-effects models estimated the impact of the E-DII score on sleep parameters. RESULTS: Women with more pro-inflammatory diets, compared to those with more anti-inflammatory diets, were more likely to be nulliparous (51% vs. 25%, p = 0.03), frequent consumers of fast food (29% vs. 10% consuming on 4-6 days during the previous week, p = 0.01), ever-smokers (21% vs. 6%, p = 0.02), and younger (mean age 29.2 vs. 31.3 years, p = 0.02). For every one-unit increase (i.e., more pro-inflammatory) in the E-DII score, sleep latency increased by 0.69 min (p < 0.01). Among European Americans only, every one-unit higher E-DII was associated with a 2.92-min longer wake-after-sleep-onset (p = 0.02). CONCLUSION: An E-DII score that is 5 points lower (i.e., more anti-inflammatory) would equate to about 105 min of additional sleep per week among European American women. Anti-inflammatory diets may help to counteract detriments in sleep during pregnancy, especially among European American women. Additional work is needed among African American women. CLINICAL TRIALS IDENTIFIER: Name: Promoting Health in Pregnancy and Postpartum (HIPP); URL: https://clinicaltrials.gov/ct2/show/NCT02260518; Registration Identifier: NCT02260518.

Patterns of physical activity and sedentary behavior before and during pregnancy and cardiometabolic outcomes.

OBJECTIVE: To assess how physical activity and sedentary behavior change from pre-pregnancy to pregnancy, and if pre-pregnancy and pregnancy physical activity and sedentary behavior are related to gestational weight gain, blood pressure, or blood glucose across pregnancy. DESIGN: Secondary analysis of two prospective cohort studies. SETTING: Prenatal research centers in Pittsburgh, PA and Iowa City, IA. PARTICIPANTS: Pregnant individuals (n=131), 18-45 years old, of any BMI, with no medical condition limiting physical activity or use of hypertension/diabetes medications. METHODS: Participants self-reported physical activity and sedentary behavior pre-pregnancy and in each trimester using validated questionnaires. Blood pressure, blood glucose, and weight were obtained from study visits and/or electronic medical records. Multivariable regression examined associations between pre-pregnancy, trimester-specific, and changes in physical activity and sedentary behavior with weight gain and blood pressure outcomes in each trimester, and blood glucose in the second trimester. RESULTS: Compared to pre-pregnancy, physical activity was lower in each trimester, and sedentary behavior was higher in each trimester (p<0.05). Increasing physical activity from pre-pregnancy levels was associated with lower first trimester SBP (p<0.05). Unexpectedly, higher pre-pregnancy physical activity was associated with higher SBP in the first trimester (p=0.02) and higher weight gain in the third trimester (p=0.02). Higher and increasing sedentary behavior was associated with greater weight gain in the third trimester (p=0.03). CONCLUSION: Future research should investigate the opportune time (before or during pregnancy) to deliver behavior modification interventions that could prevent excessive gestational weight gain or elevated blood pressure to improve maternal health outcomes.

Grandmothers raising grandchildren: managing, balancing and maintaining family relationships.

Most grandparents raising grandchildren are embedded in a network of family members who either help them carry out the caregiving task or complicate that role. This study examined how grandmothers described family relationships, that is, with the grandchild's parents, grandmother's spouses/partners, and other relatives. Data were drawn from 457 weekly journal entries submitted by 129 grandmother caregivers. Using thematic analysis, a three-person team coded using NVIVO 12. Grandmothers described three overarching relationship themes: managing conflicted relationships with the grandchild's parents, balancing relationships with their spouse/partner, and maintaining relationships with other relatives. Implications for practice are provided.

Associations of objectively measured physical activity and sedentary time with pregnancy-specific health-related quality of life.

PURPOSE: To examine associations of objectively measured moderate-to-vigorous-intensity physical activity (MVPA) and sedentary behavior (SED) with pregnancy-specific health-related quality of life (QoL) across pregnancy trimesters. MATERIALS AND METHODS: Women (N=131, mean age 30.9 years ± 4.9) were recruited from two large health care systems in the United States. MVPA and SED were estimated using a waist-worn ActiGraph GT3X and thigh-worn activPAL3 micro, respectively, for seven days in each trimester of pregnancy. Questionnaires were administered in each trimester to assess pregnancy-specific health-related QoL using the Nausea and Vomiting of Pregnancy Specific health Related Quality of Life (NVPQoL) questionnaire. Mixed effects linear regression examined associations of MVPA and SED with the NVPQoL total score and domain-specific scores (physical symptoms, fatigue, emotions, and limitations) across trimesters. RESULTS: The NVPQoL total score and domain-specific scores significantly varied across trimesters, with highest scores (indicating worse QoL) observed in the first trimester and lowest scores (indicating better QoL) in the second trimester. A 1-standard deviation (SD) increment in MVPA (16.0 min/day or 1.8%) was associated with better QoL as indicated by the lower NVPQoL total score (ß=-4.06, p=0.024) and limitations score (ß = -2.80, p<0.001). A 1-SD increment in SED (1.5 hr/day or 10.0%) was associated with worse QoL as indicated by the higher fatigue score (ß = 0.82, p=0.041). CONCLUSIONS: Pregnancy-specific health-related QoL varies across trimesters. Both lower SED, and to a greater extent higher MVPA are potential behavioral targets for improving pregnancy-specific health-related QoL.

Demographic, Socioeconomic, and Health-Related Predictors of Objectively Measured Sedentary Time and Physical Activity During Pregnancy.

BACKGROUND: Sedentary behavior (SED) and moderate-to-vigorous intensity physical activity (MVPA) have important implications for health; however, little is known about predictors of these behaviors during pregnancy. METHODS: This cohort study measured SED (activPAL) and MVPA (GT3X) in each trimester of pregnancy. Univariate associations of demographic, socioeconomic, and pregnancy health-related factors with SED or MVPA were calculated. Associations with P < .10 were included in stepwise linear regression models to determine independent predictors in each trimester. RESULTS: Pregnant women (n = 127) were age 31.0 (4.9) years and 78% white. In regression models across trimesters, fewer children ≤ age 5 in the household (P < .04) and primarily sitting job activity (P < .008) were related to higher SED and use of assisted reproductive technology (P < .05) was associated with higher MVPA. In at least one trimester, younger age was related to higher SED (P = .014); no history of pregnancy loss (P < .04), being married (P = .003), employed (P < .004, full time or student), white race (P = .006), and higher education (P = .010) were associated with higher MVPA. CONCLUSIONS: Predictors of SED in pregnancy were more consistent, and differed from predictors of MVPA. These findings may help identify women at risk of high SED or low MVPA, though future research in larger samples is needed.

Successful and Cost-Effective Facebook Recruitment: Is It Possible? Results From a Longitudinal Randomized Clinical Trial in Grandmother Caregivers.

Facebook is often cited in health-related research as a practical option to recruit participants into research studies, but issues with recruiting verifiable and qualified participants and unpredictable costs exist. The purpose of this paper is to describe a social network theory-guided, no-cost, Facebook recruitment strategy in comparison to a traditional recruitment campaign for a national online intervention study for grandmother caregivers (n = 348); 211 participants were recruited via Facebook, and 137 through traditional techniques. Participation rates did not vary by recruitment method. Facebook participants were slightly older, higher income, and more likely to be white and married, but did not differ in education levels. Our strategy quickly obtained an engaged and committed participant base. The application of social network theory to traditional recruitment strategies represents a novel way for researchers to recruit through Facebook and yield viable and engaged participants without investing in Facebook ads.

Longitudinal Assessment of Relationships Between Health Behaviors and IL-6 in Overweight and Obese Pregnancy.

BACKGROUND: Inflammation is a common factor in adverse pregnancy outcomes (APOs). Behavioral factors influence inflammatory markers and APOs but rarely have been investigated simultaneously in pregnancy. Our purpose was to determine how diet, physical activity, and obesity are associated with interleukin (IL)-6 in early and late pregnancy. METHODS: We conducted a secondary analysis of 49 overweight/obese pregnant women. Health behavior data, including diet quality using the Dietary Inflammatory Index (DII®); physical activity (Leisure Time Physical Activity scale); body mass index (BMI); and plasma IL-6 concentrations were collected at 13-16 weeks (early pregnancy) and 34-36 weeks (late pregnancy) gestation. Multiple linear regression analyses were used to determine the amount of variance explained in early and late pregnancy IL-6 concentrations by early and late pregnancy diet, physical activity, and BMI. RESULTS: Early diet and early BMI were the strongest predictors of early IL-6 concentrations (R2 = 0.43; p < .001) and late IL-6 concentrations (R2 = 0.30; p < .001). Late BMI predicted late IL-6 (R2 = .11; p = .02). Change in diet over pregnancy predicted late IL-6 (R2 = 0.17; p = .03). CONCLUSION: These findings suggest that maternal diet and BMI in early pregnancy, which likely reflects prepregnancy status, may have a greater impact on inflammatory processes than factors later in pregnancy. Future work should assess if behavioral factors before pregnancy produce similar relationships to those reported here, which may clarify the timing and type of lifestyle interventions to effectively reduce APOs.

Theoretical and Operational Consideration of Mindfulness, Resilience, and Resourcefulness.

Mindfulness, resilience, and resourcefulness are theoretically distinct but related constructs critical for improving psychosocial well-being outcomes for informal caregivers and others. Our aims were to evaluate the theoretical and operational distinctions among these constructs. Measures of mindfulness (Decentering Scale), resilience (Connor-Davidson Scale) and resourcefulness (Resourcefulness Scale) were collected from a national sample of 348 grandmother caregivers. We conducted exploratory factor analysis and examined correlation patterns. Inter-correlations ranged from r= .26 (resourcefulness and resilience) to r= .73 (resilience and mindfulness). Factor analyses and scree plots indicated unidimensional factors for resilience and for mindfulness, and two factors for resourcefulness (personal and social). When items from all measures were analyzed together, the four factors remained. Distinct relationships were found between mindfulness, resilience, and resourcefulness with relevant external variables. Our results support the conceptual distinctions among the constructs, providing support for interventions targeting these constructs to improve psychosocial outcomes in caregivers.

Incidental findings: A practical protocol for reporting elevated depressive symptoms in behavioral health research.

Intervention studies conducted in caregivers often focus on improving mental health. Consequently, researchers may discover incidental findings like elevated depressive symptoms. Researchers have an ethical obligation to report incidental findings to participants, but no protocols exist for reporting behavioral health symptoms. The purpose of this paper was to describe a protocol for reporting elevated depressive symptoms to participants, based on the protocol used in a national randomized clinical trial of stress-reduction methods for 348 grandmothers raising grandchildren. Each questionnaire included the CES-D scale, and was scored immediately after completion. We established a cut-off score of 30 based on previous research. A registered nurse on the research team called participants with scores over 30 and ascertained whether the participant 1) was aware of the problem and 2) had sought help, and then offered additional resources. Overall, 94 (27%) participants had a CES-D score > 30. The majority (91%) were aware of the problem. About a third of the participants were on medication for their symptoms, and a third were seeing a therapist. Nine participants were not aware they had depressive symptoms. This paper outlines the ethical premise for developing our protocol, details of protocol development, and discussion for how research teams can apply this protocol to their work.

"Take an opportunity whenever you get it": Information Sharing among African-American Women with Hypertension.

Nearly half of African-American women have hypertension, which increases their risk for cardiovascular disease and stroke. A plethora of consumer health information products and services exist to inform people with hypertension and to promote self-management among them. Promotion of information sharing by African-American women represents a promising, culturally-applicable strategy for consumer health information services focused on hypertension self-management. Yet, how African-American women share hypertension information with others is unclear. The purpose of this qualitative, descriptive study was to examine practices of information sharing in African-American women with hypertension. Thirteen women (mean age = 73, SD = 9.87) participated in one of two focus groups held at an urban community health center. Thematic analysis revealed that the women shared information about how they self-managed their blood pressure 1) with female family members and friends, 2) about ways in which they adapted self-management strategies to work for them, 3) mostly in group settings, and 4) because they wanted to prevent others from suffering and reinforce their own knowledge about hypertension self-management. New findings emerged regarding assessing "readiness" for information. Study findings will be used to inform the design of an information sharing intervention to support self-management of hypertension in African-American women.

Is There an Association of Physical Activity with Brain Volume, Behavior, and Day-to-day Functioning? A Cross Sectional Design in Prodromal and Early Huntington Disease.

BACKGROUND: Huntington disease (HD) is a genetic neurodegenerative disease leading to progressive motor, cognitive, and behavioral decline. Subtle changes in these domains are detectable up to 15 years before a definitive motor diagnosis is made. This period, called prodromal HD, provides an opportunity to examine lifestyle behaviors that may impact disease progression. THEORETICAL FRAMEWORK: Physical activity relates to decreased rates of brain atrophy and improved cognitive and day-to-day functioning in Alzheimer disease and healthy aging populations. Previous research has yielded mixed results regarding the impact of physical activity on disease progression in HD and paid little attention to the prodromal phase. METHODS: We conducted analyses of associations among current physical activity level, current and retrospective rate of change for hippocampus and striatum volume, and cognitive, motor, and day-to-day functioning variables. Participants were 48 gene-expanded cases with prodromal and early-diagnosed HD and 27 nongene-expanded control participants. Participants wore Fitbit Ultra activity monitors for three days and completed the self-reported International Physical Activity Questionnaire (IPAQ). Hippocampal and striatal white matter volumes were measured using magnetic resonance imaging. Cognitive tests included the Stroop Color and Word Test, and the Symbol Digit Modalities Test (SDMT). Motor function was assessed using the Unified Huntington's Disease Rating Scale total motor score (TMS). Day-to-day functioning was measured using the World Health Organization Disability Assessment Schedule (WHODAS) version 2.0. RESULTS: Higher Fitbit activity scores were significantly related to better scores on the SDMT and WHODAS in case participants but not in controls. Fitbit activity scores tracked better with TMS scores in the group as a whole, though the association did not reach statistical significance in the case participants. Higher Fitbit activity scores related to less day-to-day functioning decline in retrospective slope analyses. Fitbit activity scores did not differ significantly between cases and controls. CONCLUSIONS: This is the first known study examining the associations between activity level and imaging, motor, cognitive, and day-to-day functioning outcomes in prodromal and early HD. Preliminary results suggest physical activity positively correlates with improved cognitive and day-to-day functioning and possibly motor function in individuals in the prodromal and early phase of the condition.