Shear and hydrostatic stress regulate fetal heart valve remodeling through YAP-mediated mechanotransduction.

Clinically serious congenital heart valve defects arise from improper growth and remodeling of endocardial cushions into leaflets. Genetic mutations have been extensively studied but explain less than 20% of cases. Mechanical forces generated by beating hearts drive valve development, but how these forces collectively determine valve growth and remodeling remains incompletely understood. Here, we decouple the influence of those forces on valve size and shape, and study the role of YAP pathway in determining the size and shape. The low oscillatory shear stress promotes YAP nuclear translocation in valvular endothelial cells (VEC), while the high unidirectional shear stress restricts YAP in cytoplasm. The hydrostatic compressive stress activated YAP in valvular interstitial cells (VIC), whereas the tensile stress deactivated YAP. YAP activation by small molecules promoted VIC proliferation and increased valve size. Whereas YAP inhibition enhanced the expression of cell-cell adhesions in VEC and affected valve shape. Finally, left atrial ligation was performed in chick embryonic hearts to manipulate the shear and hydrostatic stress in vivo. The restricted flow in the left ventricle induced a globular and hypoplastic left atrioventricular (AV) valves with an inhibited YAP expression. By contrast, the right AV valves with sustained YAP expression grew and elongated normally. This study establishes a simple yet elegant mechanobiological system by which transduction of local stresses regulates valve growth and remodeling. This system guides leaflets to grow into proper sizes and shapes with the ventricular development, without the need of a genetically prescribed timing mechanism.

Hormonal milieu drives economic demand for cocaine in female rats.

There are substantial sex differences in drug abuse, and a key feature of cocaine addiction is pathologically high motivation for drug. We investigated the role of ovarian hormones on cocaine demand in female rats using a within-session threshold behavioral economics (BE) procedure, which allows us to compare motivation for drug across hormonal states and sex while controlling for differences in dose and intake. This approach quantifies demand elasticity (α) and free consumption (Q0, consumption at null effort) to determine motivation for cocaine. Overall, female rats showed greater motivation for cocaine compared to males. However, this difference was cycle phase-dependent - motivation for cocaine when females were in proestrus was lower compared to the same animals across cycle phases, and overall similar to that of males. Hormonal cycle phase accounted for 70% of the within-subject variance in demand elasticity, obscuring other individual differences in female demand. High serum progesterone (P4; e.g., in proestrus) predicted decreased cocaine motivation (high demand elasticity), whereas serum estradiol (E2) correlated to greater intake at null effort (Q0). However, individual differences were revealed across OVX females, who displayed a range of demand elasticity, as seen in males. E2 replacement in OVX females increased motivation for cocaine, whereas P4 replacement decreased motivation. We also found that as few as 4 weeks of cocaine self-administration accelerated estropause in female rats as young as 12 weeks old. By 13 weeks of self-administration, proestrus epochs were no longer observed, and cocaine demand was potentiated by persistent estrus in all females. Thus, P4 signaling is a key modulator of cocaine demand in females that may underlie previously observed sex differences in addiction phenotypes.

Local fluid shear stress operates a molecular switch to drive fetal semilunar valve extension.

BACKGROUND: While much is known about the genetic regulation of early valvular morphogenesis, mechanisms governing fetal valvular growth and remodeling remain unclear. Hemodynamic forces strongly influence morphogenesis, but it is unknown whether or how they interact with valvulogenic signaling programs. Side-specific activity of valvulogenic programs motivates the hypothesis that shear stress pattern-specific endocardial signaling controls the elongation of leaflets. RESULTS: We determined that extension of the semilunar valve occurs via fibrosa sided endocardial proliferation. Low OSS was necessary and sufficient to induce canonical Wnt/ß-catenin activation in fetal valve endothelium, which in turn drives BMP receptor/ligand expression, and pSmad1/5 activity essential for endocardial proliferation. In contrast, ventricularis endocardial cells expressed active Notch1 but minimal pSmad1/5. Endocardial monolayers exposed to LSS attenuate Wnt signaling in a Notch1 dependent manner. CONCLUSIONS: Low OSS is transduced by endocardial cells into canonical Wnt signaling programs that regulate BMP signaling and endocardial proliferation. In contrast, high LSS induces Notch signaling in endocardial cells, inhibiting Wnt signaling and thereby restricting growth on the ventricular surface. Our results identify a novel mechanically regulated molecular switch, whereby fluid shear stress drives the growth of valve endothelium, orchestrating the extension of the valve in the direction of blood flow.

The Impact of Extended Delayed Surgery for Indolent Lung Cancer or Part-Solid Ground Glass Nodules.

BACKGROUND: During the COVID-19 pandemic, patients with lung cancer may experience treatment delays. The objective of this study was to evaluate the impact of extended treatment delays on survival among patients with stage I typical bronchopulmonary carcinoid (BC), lepidic predominant adenocarcinoma (LPA) or invasive adenocarcinoma with a lepidic component (ADL). METHODS: Using National Cancer Database data (2004-2015), multivariable Cox regression analysis with penalized smoothing splines was performed to examine the association between treatment delay and all-cause mortality for stage I BC, LPA, and ADL. Propensity score-matched analyses compared the overall survival of patients who received "early" vs "delayed" surgery (ie, 0-30 vs 90-120 days after diagnosis) across the different histologic subtypes. RESULTS: During the study period, patients with stage I BC (n = 4947), LPA (n = 5340), and ADL (n = 6816) underwent surgery. Cox regression analysis of these cohorts showed a gradual steady increase in the hazard ratio the longer treatment is delayed. However, in propensity score-matched analyses that created cohorts of patients who underwent early and delayed surgery that were well-balanced in patient characteristics, no significant differences in 5-year survival were found between early and delayed surgery for stage I BC (87% [95% CI:77%-93%] vs 89% [95% CI: 80%-94%]), stage I LPA (73% [95% CI: 64%-80%] vs 77% [95% CI: 68%-83%]), and stage I ADL (71% [95% CI: 64%-76%] vs 69% [95% CI: 60%-76%]). CONCLUSIONS: During the COVID-19 pandemic, for early-stage indolent lung tumors and part-solid ground glass lung nodules, a delay of surgery by 3-4 months after diagnosis can be considered.

Use of Industrial Filters by Health Care Workers During Shortages of N95 Respirators in Pandemic Times.

The coronavirus disease 2019 (COVID-19) pandemic has led to a significant shortage of personal protective equipment in multiple health care facilities around the world, with the highest impact on N95 respirator masks. The N95 respirator is a mask that blocks at least 95% of very small (0.3 µm) particles and is considered a standard for enhanced respiratory precautions. The N95 mask shortage has created a need for other options for nasal and oral respiratory protection with similar filtration efficiency and "medical-grade" clearance, which can be used in health care settings. However, the literature around various filter types, their filtration capabilities, and the organizations certifying their use is dense, confusing, and not easily accessible to the public. Here, we synthesize relevant literature to analyze and disseminate information on (1) alternative viable filter options to N95s, (2) the National Institute for Occupational Safety and Health certification process, (3) the relationship of National Institute for Occupational Safety and Health certification to Food and Drug Administration certification of filtration devices and surgical masks, and (4) how this relationship may affect future filtration usage in the medical community during a pandemic. Analysis of these standards is meant to inform regarding evidence of respirator efficacy but does not imply any official endorsement of these alternatives. With this article, we illuminate viable alternative respirator options during the COVID-19 pandemic to help alleviate the dependency on N95 face masks.

Stereotactic Body Radiotherapy Versus Delayed Surgery for Early-stage Non-small-cell Lung Cancer.

OBJECTIVE: To evaluate the overall survival of patients with operable stage IA non-small-cell lung cancer (NSCLC) who undergo "early" SBRT (within 0-30 days after diagnosis) versus "delayed" surgery (90-120 days after diagnosis). SUMMARY OF BACKGROUND DATA: During the COVID-19 pandemic, national guidelines have recommended patients with operable stage IA NSCLC to consider delaying surgery by at least 3 months or, alternatively, to undergo SBRT without delay. It is unknown which strategy is associated with better short- and long-term outcomes. METHODS: Multivariable Cox proportional hazards modeling and propensity score-matched analysis was used to compare the overall survival of patients with stage IA NSCLC in the National Cancer Data Base from 2004 to 2015 who underwent "early" SBRT (0-30 days after diagnosis) versus that of patients who underwent "delayed" wedge resection (90-120 days after diagnosis). RESULTS: During the study period, 570 (55%) patients underwent early SBRT and 475 (45%) underwent delayed wedge resection. In multivariable analysis, delayed resection was associated with improved survival [adjusted hazard ratio 0.61; (95% confidence interval (CI): 0.50-0.76)]. Propensity-score matching was used to create 2 groups of 279 patients each who received early SBRT or delayed resection that were well-matched with regard to baseline characteristics. The 5-year survival associated with delayed resection was 53% (95% CI: 45%-61%) which was better than the 5-year survival associated with early SBRT (31% [95% CI: 24%-37%]). CONCLUSION: In this national analysis, for patients with stage IA NSCLC, extended delay of surgery was associated with improved survival when compared to early treatment with SBRT.

Changes of gut microbiota between different weight reduction programs.

BACKGROUND: Gut microbiota may induce obesity, diabetes, and metabolic syndrome. Different weight reduction programs may induce different changes in gut microbiota. OBJECTIVES: To assess the changes in gut microbiota between obese adults who participated in 2 different weight reduction programs, the dietary counseling (DC) group and sleeve gastrectomy (SG) group, for 3 months. SETTING: A University Hospital. METHODS: Ten obese participants from each group were matched according to sex, age, and body mass index. Gut microbiota compositions were determined by metagenomics using next-generation sequencing before and after treatment. Anthropometric indices, metabolic factors, and gut microbiota were compared between and within groups. RESULTS: After 3 months of treatment, compared with subjects in DC group, subjects in SG group experienced a greater reduction in body weight, body mass index, body fat, waist and hip circumference, diastolic blood pressure, hemoglobin, insulin, insulin resistance, glutamate pyruvate transaminase, blood urine nitrogen, and glycated hemoglobin (HbA1C). A total of 8, 17, and 46 species experienced significant abundance changes in DC, in SG, and between the 2 groups, respectively. Diversity of the gut flora increased in SG and between the 2 groups after treatment. The weight change over the course of the weight loss program was further adjusted and only 4 species, including Peptoniphilus lacrimalis 315 B, Selenomonas 4 sp., Prevotella 2 sp., and Pseudobutyrivibrio sp., were found to be significantly different between the 2 weight loss programs. These 4 species may be the different gut microbiota change between internal and surgical weight reduction programs. CONCLUSIONS: There are significant differences not only in anthropometric indices and metabolic factors but also in gut microbiota change between the 2 programs.

Right-Sided Versus Left-Sided Pneumonectomy After Induction Therapy for Non-Small Cell Lung Cancer.

BACKGROUND: A right-sided pneumonectomy after induction therapy for non-small cell lung cancer (NSCLC) has been shown to be associated with significant perioperative risk. We examined the effect of laterality on long-term survival after induction therapy and pneumonectomy using the National Cancer Data Base. METHODS: Perioperative and long-term outcomes of patients who underwent pneumonectomy after induction chemotherapy, with or without radiotherapy, from 2004 to 2014 in the National Cancer Data Base were evaluated using multivariable Cox proportional hazards modeling and propensity score-matched analysis. RESULTS: During the study period, 1,465 patients (right, 693 [47.3%]; left, 772 [52.7%]) met inclusion criteria. Right-sided pneumonectomy was associated with significantly higher 30-day (8.2% [57 of 693] vs 4.2% [32 of 772], p < 0.01) and 90-day mortality (13.6% [94 of 693] vs 7.9% [61 of 772], p < 0.01), and right-sided pneumonectomy was a predictor of higher 90-day mortality (odds ratio, 2.23; p < 0.01). However, overall 5-year survival between right and left pneumonectomy was not significantly different in unadjusted (37.6% [95% confidence interval {CI}, 0.34 to 0.42] vs 35% [95% CI, 0.32 to 0.39], log-rank p = 0.94) or multivariable analysis (hazard ratio, 1.07; 95% CI, 0.92 to 1.25; p = 0.40). A propensity score-matched analysis of 810 patients found no significant differences in 5-year survival between the right-sided versus left-sided groups (34.7% [95% CI, 0.30 to 0.40] vs 34.1%, [95% CI, 0.29 to 0.39], log-rank p = 0.86). CONCLUSIONS: In this national analysis, right-sided pneumonectomy after induction therapy was associated with a significantly higher perioperative but not worse long-term mortality compared to a left-sided procedure.

Attenuated cocaine-seeking after oxytocin administration in male and female rats.

RATIONALE: Initial drug abstinence (modeled here as Extinction Day 1, ED1) is a critical time point in the progression of addiction that is strongly influenced by stress and sex. ED1 induces corticosterone release in both sexes, and cocaine-seeking during ED1 can be mitigated by corticotrophin-releasing factor (CRF) antagonists more effectively in female rats. Oxytocin (OXT) is a neuropeptide that has several biological functions, including regulation of stress pathways. METHODS: To investigate a relationship between OXT, sex, and cocaine-seeking, we examined Fos on ED1 in OXT neurons of paraventricular (PVN) and supraoptic nuclei (SON) compared to homecage (cocaine experienced) or naïve male and female rats. We also administered OXT 30 min prior to ED1 testing or cued reinstatement testing. RESULTS: OXT neurons had decreased activity (as reflected by Fos protein) in PVN and SON on withdrawal day 1 (homecage) compared to naïve rats. Fos in OXT neurons was further decreased on ED1, compared to homecage controls, in both males and females even though in SON, cocaine exposure increased the number of OXT-expressing neurons. In addition, systemically administered OXT reduced cocaine-seeking during ED1 and cue-induced reinstatement of cocaine-seeking but delayed extinction, similarly among male and female rats. CONCLUSIONS: These data indicate that OXT neurons in PVN and SON may be involved in cocaine-seeking during ED1 and support OXT as a possible therapeutic to decrease cocaine-seeking during initial abstinence and in response to cocaine-associated cues.

The prevalence of obesity and metabolic syndrome in Tibetan immigrants living in high altitude areas in Ladakh, India.

OBJECTIVE: To examine the prevalence of obesity and related cardiovascular disease risk factors among Tibetan immigrants living in high altitude areas. RESEARCH METHODS & PROCEDURES: A total of 149 Tibetan immigrants aged 20 years and over were recruited in 2016 in Ladakh, India. Anthropometric indices and biochemical factors were measured. Using the provided Asia-Pacific criteria from the World Health Organization, overweight and obese status were determined. Metabolic syndrome (MetS) was defined according to the American Heart Association. RESULTS: In general, men were older, taller, and had a greater amount of fasting glucose, and uric acid when compared to women. The prevalence of overweight, general obesity, and central obesity was 23.4, 42.6, and 42.6% in men and 7.8, 64.7, and 69.6% in women, respectively. The prevalence of MetS was 10.6% in men and 33.3% in women, respectively. In older subjects, the prevalence of obesity and MetS was found to be greater. In both genders, the prevalence of hypertension, central obesity, and MetS was significantly different among these body mass index (BMI) groups. Compared to the non-central obesity group, the central obesity group has higher weight, BMI, body fat, hip circumference, systolic and diastolic BP, and prevalence of hypertension. No relationship was found between the prevalence of diabetes and fasting glucose and BMI groups or central obesity groups in both genders. CONCLUSIONS: Among this group of Tibetan immigrants living in high altitude areas, women have a higher prevalence of obesity and MetS than men. No relationship was found between diabetes and obesity.