Hypertension increases sympathetic neuron activity by enhancing intraganglionic cholinergic collateral connections.

Autonomic dysregulation, including sympathetic hyperactivity, is a common feature of hypertension (HT) and other cardiovascular diseases. The CNS plays a role in driving chronic sympathetic activation in disease, but several lines of evidence suggest that neuroplasticity in the periphery may also contribute. The potential contribution of postganglionic sympathetic neurons to sustained sympathetic hyperactivity is not well understood. We recently discovered that noradrenergic sympathetic neurons in the stellate ganglion (SG) have excitatory cholinergic collateral connections to other neurons within the ganglion. We hypothesize that remodelling of these neurons and increased cholinergic collateral transmission contributes to sustained sympathetic hyperactivity in cardiovascular diseases, including HT. To test that hypothesis, we examined the activity of sympathetic neurons in isolated SG under control conditions and after 1 week of HT induced by peripheral angiotensin II infusion, using whole-cell patch clamp recordings. Despite the absence of central inputs, we observed elevated spontaneous activity and synaptic transmission in sympathetic SG neurons from hypertensive mice that required generation of action potentials. Genetically disrupting cholinergic transmission in noradrenergic neurons decreased basal neuronal activity and prevented angiotensin II-mediated enhancement of activity. Similar changes in activity, driven by increased collateral transmission, were identified in cardiac projecting neurons and neurons projecting to brown adipose tissue. These changes were not driven by altered A-type K+ currents. This suggests that HT stimulates increased activity throughout the intraganglionic network of collateral connections, contributing to the sustained sympathetic hyperactivity characteristic in cardiovascular disease. KEY POINTS: Sympathetic neurons in ganglia isolated from angiotensin II-treated hypertensive mice are more active than neurons from control mice despite the absence of central activation. The enhanced activity is the result of a ganglionic network of cholinergic collaterals, rather than altered intrinsic excitability. Increased neuronal activity was observed in both cardiac neurons and brown adipose tissue-projecting neurons, which are not involved in cardiovascular homeostasis.

National trends in neoadjuvant chemotherapy utilization in patients with early-stage node-negative triple-negative breast cancer: the impact of the CREATE-X trial.

PURPOSE: Neoadjuvant chemotherapy (NAC) for triple-negative breast cancer (TNBC) allows for assessment of tumor pathological response and has survival implications. In 2017, the CREATE-X trial demonstrated survival benefit with adjuvant capecitabine in patients TNBC and residual disease after NAC. We aimed to assess national rates of NAC for cT1-2N0M0 TNBC before and after CREATE-X and examine factors associated with receiving NAC vs adjuvant chemotherapy (AC). METHODS: A retrospective cohort study of women with cT1-2N0M0 TNBC diagnosed from 2014 to 2019 in the National Cancer Database (NCDB) was performed. Variables were analyzed via ANOVA, Chi-squared, Fisher Exact tests, and a multivariate linear regression model was created. RESULTS: 55,633 women were included: 26.9% received NAC, 52.4% AC, and 20.7% received no chemotherapy (median ages 53, 59, and 71 years, p < 0.01). NAC utilization significantly increased over time: 19.5% in 2014-15 (n = 3,465 of 17,777), 27.1% in 2016-17 (n = 5,140 of 18,985), and 33.6% in 2018-19 (n = 6,337 of 18,871, p < 0.001). On multivariate analysis, increased NAC was associated with younger age (< 50), non-Hispanic white race/ethnicity, lack of comorbidities, cT2 tumors, care at an academic or integrated-network cancer program, and diagnosis post-2017 (p < 0.05 for all). Patients with government-provided insurance were less likely to receive NAC (p < 0.01). Women who traveled > 60 miles for treatment were more likely to receive NAC (p < 0.01). CONCLUSION: From 2014 to 2019, NAC utilization increased for patients with cT1-2N0M0 TNBC. Racial, socioeconomic, and access disparities were observed in who received NAC vs AC and warrants interventions to ensure equitable care.

Does Neoadjuvant Chemotherapy in Clinical T1-T2 N0 Triple-Negative Breast Cancer Increase the Extent of Axillary Surgery?

BACKGROUND: Current management strategies for early-stage triple-negative breast cancer (TNBC) include upfront surgery to determine pathologic stage to guide chemotherapy recommendations, or neoadjuvant chemotherapy (NAC) to de-escalate surgery, elucidate tumor response, and determine the role of adjuvant chemotherapy. However, patients who receive NAC with residual pathological nodal (pN) involvement require axillary lymph node dissection (ALND) as they are Z11/AMAROS ineligible. We aimed to evaluate the impact of NAC compared with upfront surgery on pN status and ALND rates in cT1-2N0 TNBC. METHODS: The National Cancer Database (NCDB) was queried for women with operable cT1-2N0 TNBC from 2014 to 2019. Demographic, clinicopathologic, and treatment data were collected. Multivariable linear regression analysis was performed to assess the odds of pN+ disease and undergoing ALND. RESULTS: Overall, 55,624 women were included: 26.9% (n = 14,942) underwent NAC and 73.1% (n = 40,682) underwent upfront surgery. The NAC cohort was younger (mean age 52.9 vs. 61.3 years; p < 0.001) with more cT2 tumors (71.6% vs. 31.0%; p < 0.001), and had lower ALND rates (4.3% vs. 5.5%; p < 0.001). The upfront surgery cohort was more likely to have one to three pathologically positive nodes (12.1% vs. 6.5%; odds ratio [OR] 2.37, 95% confidence interval (CI) 2.17-2.58; p < 0.001) but there was no difference in the likelihood of ALND (OR 1.1, 95% CI 0.99-1.24; p = 0.08). CONCLUSION: Patients who underwent upfront surgery were more likely to be pN+; however, ALND rates were similar between the two cohorts. Thus, the use of NAC does not result in a higher odds of ALND and the decision for NAC should be individualized and based on modern guidelines and systemic therapy benefits.

Trauma exposure correlates among patients receiving care in federally qualified health centers.

Over 80% of adults in the general population experience trauma. Rates of patients with posttraumatic stress disorder (PTSD) are high in primary care settings and are likely to be even higher in federally qualified health centers (FQHCs). Trauma exposure has been linked to psychiatric symptoms and physical health comorbidities, though little research has focused on FQHC patients. This study addresses this by examining clinical and sociodemographic correlates of specific trauma types among FQHC patients. We analyzed secondary data from patients who screened positive for PTSD and were receiving health care in FQHCs in a clinical trial (N = 978). Individuals who did versus did not experience a specific trauma type were compared using between-group tests. In the sample, 91.3% of participants were exposed to a DSM-5 Criterion A traumatic event, with 79.6% experiencing two or more trauma types. Witnessing a life-threatening event (57.3%) and physical assault (55.7%) were the most common traumatic experiences. Physical health comorbidities and worse physical health functioning were associated with a higher likelihood of exposure to all trauma types, with effect sizes larger than PTSD, ds = 0.78-1.35. Depressive and anxiety symptoms were also associated with a higher likelihood of experiencing nearly all trauma types to a lesser magnitude. People of color, OR = 2.45, and individuals experiencing financial inequities, OR = 1.73, had higher odds of experiencing serious accidents as well as other trauma types. The findings highlight the need for trauma-informed care, including routine trauma and PTSD screening, for FQHC patients.

National Trends in "Going Flat" After Mastectomy.

INTRODUCTION: The "Going Flat" movement became widely publicized in 2016 and provides information and support to women who choose to forego post-mastectomy breast reconstruction (PMBR). The objectives of this study were to evaluate temporal trends in PMBR to ascertain the potential impact of this movement and assess which factors are associated with going flat. METHODS: A retrospective cohort analysis was performed using the NCDB of women with non-metastatic breast cancer who underwent mastectomy between 2004 and 2019. Trends in going flat after mastectomy were examined and stratified by age (< 50, 50-69, ≥ 70). A multivariate logistic regression model was used to identify factors associated with going flat. RESULTS: 650,983 patients met the inclusion criteria: 244,201 (37.5%) underwent PMBR and 406,782 (62.5%) went flat. Among women < 70, rates of going flat steadily decreased from 2004 to 2015 and then stabilized after 2015, coinciding with the rise of the "Going Flat" movement. In multivariate analysis, non-White race, older age, increasing comorbidities, government provided insurance, treatment at a community program, radiotherapy, and adjuvant chemotherapy were associated with a higher likelihood of going flat (p < 0.001). CONCLUSION: In the first 2 years after the "Going Flat" movement, the number of women going flat after mastectomy has stabilized in women < 70 for the first time in over a decade. These trends suggest that the social and cultural impact of this movement may have contributed to the stabilization of PMBR rates.

Minimal important difference metrics and test-retest reliability of the PTSD Checklist for DSM-5 with a primary care sample.

The PTSD Checklist for DSM-5 (PCL-5) is a measure of posttraumatic stress disorder (PTSD) symptom severity that is widely used for clinical and research purposes. Although previous work has examined metrics of minimal important difference (MID) of the PCL-5 in veteran samples, no work has identified PCL-5 MID metrics among adults in primary care in the United States. In this secondary analysis, data were evaluated from primary care patients (N = 971) who screened positive for PTSD and participated in a large clinical trial in federally qualified health centers in three U.S. states. Participants primarily self-identified as women (70.2%) and White (70.3%). We calculated test-retest reliability using clinic registry data and multiple distribution- and anchor-based metrics of MID using baseline and follow-up survey data. Test-retest reliability (Pearson's r, Spearman's ρ, intraclass correlation coefficient) ranged from adequate to excellent (.79-.94), with the shortest time lag demonstrating the highest reliability estimate. The MID for the PCL-5 was estimated using multiple approaches. Distribution-based approaches indicated an MID range of 8.5-12.5, and anchor-based approaches indicated an MID range of 9.8-11.7. Taken together, the MID metrics indicate that PCL-5 change scores of 9-12 likely reflect real change in PTSD symptoms and indicate at least an MID for patients, whereas PCL-5 change scores of 5 or less likely are not reliable. These findings can help inform clinicians using the PCL-5 in similar populations to track patient responses to treatment and help researchers interpret PCL-5 score changes in clinical trials.

Interpersonal communication-, education- and counselling-based interventions to support adherence to oral anticancer therapy: a systematic review.

Background. Many factors contribute to oral anti-cancer therapy adherence, including counselling and educational support. Objective. We systematically review the literature evaluating the effectiveness of interpersonal communication-, counselling- and education-based interventions on patient adherence to oral anticancer therapy. Methods. Using search terms pertaining to medication adherence, oral anticancer therapy, and communication, education, and counselling, we conducted a systematic search for full-text, original research articles prior to 3/13/20. Two reviewers independently reviewed each paper for inclusion and charted study information. Results. Twenty-four articles were included. All considered the use of oral anticancer therapy between two defined time points. Four studies also considered the length of time a patient persisted on therapy. Half (n = 12) of the studies reported a statistically significant relationship between the intervention and medication adherence, with no consistent pattern among intervention structure/content and effectiveness. Programmes offering in-person counselling and those targeting patients with chronic myeloid leukemia (CML), tended to report positive findings. Most studies faced substantial risk of bias, and only two reported using a behavioural theory to guide interventional content. Conclusions. Findings highlight the infancy of evidence base and need for rigorous and large-scale studies grounded in established behavioural theories to advance patient-targeted educational and counselling practices supporting adherence to oral anti-cancer therapy.

Knowledge about Treatment (KaT) in Mental Health Services.

This study developed and psychometrically evaluated a brief measure of mental health treatment knowledge (N = 726). Scores from Knowledge about Treatment (KaT) demonstrated a unidimensional measure with good model fit, internal consistency reliability, convergent and predictive validity, test-retest reliability, and measurement invariance across gender, ethnicity, education, and poverty status.

Antireflux surgery leads to durable improvement in laryngopharyngeal reflux symptoms.

BACKGROUND: Laryngopharyngeal reflux (LPR) symptoms are often present in patients with Gastroesophageal reflux disease (GERD). Whereas antireflux surgery (ARS) provides predictably excellent results in patients with typical GERD, those with atypical symptoms have variable outcomes. The goal of this study was to characterize the response of LPR symptoms to antireflux surgery. METHODS: Patients who underwent ARS between January 2009 and May 2020 were prospectively identified from a single institutional database. Patient-reported information on LPR symptoms was collected at standardized time points (preoperative and 2 weeks, 8 weeks, and 1 year postoperatively) using a validated Reflux Symptom Index (RSI) questionnaire. Patients were grouped by preoperative RSI score: ≤ 13 (normal) and > 13 (abnormal). Baseline characteristics were compared between groups using chi-square test or t-test. A mixed effects model was used to evaluate improvement in RSI scores. RESULTS: One hundred and seventy-six patients fulfilled inclusion criteria (mean age 57.8 years, 70% female, mean BMI 29.4). Patients with a preoperative RSI ≤ 13 (n = 61) and RSI > 13 (n = 115) were similar in age, BMI, primary reason for evaluation, DeMeester score, presence of esophagitis, and hiatal hernia (p > 0.05). The RSI > 13 group had more female patients (80 vs 52%, p = < 0.001), higher mean GERD-HRQL score, lower rates of PPI use, and normal esophageal motility. The RSI of all patients improved from a mean preoperative value of 19.2 to 7.8 (2 weeks), 6.1 (8 weeks), and 10.9 (1 year). Those with the highest preoperative scores (RSI > 30) had the best response to ARS. When analyzing individual symptoms, the most likely to improve included heartburn, hoarseness, and choking. CONCLUSIONS: In our study population, patients with LPR symptoms achieved a rapid and durable response to antireflux surgery. Those with higher preoperative RSI scores experienced the greatest improvement. Our data suggest that antireflux surgery is a viable treatment option for this patient population.

The immunorecognition, subcellular compartmentalization, and physicochemical properties of nucleic acid nanoparticles can be controlled by composition modification.

Nucleic acid nanoparticles (NANPs) have become powerful new platforms as therapeutic and diagnostic tools due to the innate biological ability of nucleic acids to identify target molecules or silence genes involved in disease pathways. However, the clinical application of NANPs has been limited by factors such as chemical instability, inefficient intracellular delivery, and the triggering of detrimental inflammatory responses following innate immune recognition of nucleic acids. Here, we have studied the effects of altering the chemical composition of a circumscribed panel of NANPs that share the same connectivity, shape, size, charge and sequences. We show that replacing RNA strands with either DNA or chemical analogs increases the enzymatic and thermodynamic stability of NANPs. Furthermore, we have found that such composition changes affect delivery efficiency and determine subcellular localization, effects that could permit the targeted delivery of NANP-based therapeutics and diagnostics. Importantly, we have determined that altering NANP composition can dictate the degree and mechanisms by which cell immune responses are initiated. While RNA NANPs trigger both TLR7 and RIG-I mediated cytokine and interferon production, DNA NANPs stimulate minimal immune activation. Importantly, incorporation of 2'F modifications abrogates RNA NANP activation of TLR7 but permits RIG-I dependent immune responses. Furthermore, 2'F modifications of DNA NANPs significantly enhances RIG-I mediated production of both proinflammatory cytokines and interferons. Collectively this indicates that off-target effects may be reduced and/or desirable immune responses evoked based upon NANPs modifications. Together, our studies show that NANP composition provides a simple way of controlling the immunostimulatory potential, and physicochemical and delivery characteristics, of such platforms.

Understanding Psychological Distress and Protective Factors Amongst Older Adults During the COVID-19 Pandemic.

OBJECTIVES: This study examined the emotional distress and loneliness during COVID-19 and the roles of resiliency and activities. DESIGN: A cross-sectional national survey. SETTING: Amazon Mechanical Turk (mTurk) and Prolific Research Platforms. PARTICIPANTS: Five hundred and one U.S. dwelling English-speaking adults 60 years old and older. MEASUREMENTS: Participants completed an online survey with the PHQ-9; GAD-7; Short Health Anxiety Inventory; 3-item UCLA Loneliness scale; PROMIS measures of global health, instrumental, and emotional support; 10-item Connor-Davidson Resilience Scale; and COVID-19 needs assessment. RESULTS: Across the sample 13% reported moderate depressive symptoms, 9% reported moderate anxiety symptoms, and 26% endorsed being "lonely." The emotionally distressed group endorsed more loneliness, lower resiliency, less physical exercise, and worse physical health. The low Socio-Economic Status group endorsed less loneliness, less likely to engage in physical exercise and worse physical health.The lonely group endorsed less resilience, less physical exercise, and worse physical health. A multiple logistic regression found that resilience, socioeconomic status, and physical health were significant predictors of loneliness, whereas global health was the best predictor of emotional distress. CONCLUSIONS: Even after prolonged social distancing, older adults in this study did not report greater psychological distress compared to earlier studies of older adults during COVID-19. Older adults with lower SES, worse physical health, and less resiliency, were more likely to report more loneliness. It is this group that should be the focus of intervention.

Elucidating measures of systemic racism to mitigate racial disparities in kidney transplantation.

PURPOSE OF REVIEW: Given recent national attention to the role of racism in perpetuating racial inequities in society and health, this review provides a timely and relevant summary of key measures of systemic racism in kidney transplantation. More specifically, the review identifies current and promising interventions, whereas highlighting the need for more sustainable and impactful interventions. RECENT FINDINGS: Racial disparities persist in kidney transplantation. Black and Hispanic individuals are less likely to receive a kidney transplant than non-Hispanic Whites despite disproportionately higher rates of kidney failure. Studies demonstrate that socioeconomic factors do not fully explain existing racial disparities in transplantation. Systemic racism at all levels, individual, interpersonal, institutional, and structural, is at the core of racial disparities, and current interventions are insufficient in mitigating their effects. Thus, targeted and sustainable interventions must be implemented to mitigate systemic racism in kidney transplantation. SUMMARY: Systemic racism in all its forms continues to influence disparities at all stages of kidney transplantation. This paper highlights recent findings that shed light on how racism contributes to racial disparities in kidney transplantation. Using these findings to identify targets and strategies for mitigation, relevant interventions and policies that show promise are detailed.

Long-term dysphagia resolution following POEM versus Heller myotomy for achalasia patients.

BACKGROUND: Heller myotomy (HM) has historically been considered the gold standard treatment for achalasia. Peroral endoscopic myotomy (POEM) is a less-invasive procedure and offers a quicker recovery. Although some studies have compared short-term outcomes of HM and POEM, predictors of long-term dysphagia resolution remain unclear. The objective of this study was to evaluate patient-reported outcomes for achalasia patients who underwent either POEM or HM over a 9-year period. METHODS: Data from our single academic institutional foregut database were used to identify achalasia patients who underwent HM or POEM from 2009 to 2018. Electronic health record data were reviewed to obtain patient characteristics and operative data. Achalasia severity stages were established for each patient using esophagram findings from an attending radiologist blinded to the procedure type. Postoperative outcomes were assessed via telephone for patients with at least 9 months of follow-up using Eckardt dysphagia scores. Patient age, sex, type of operation, and duration of follow-up were included in a multivariable linear regression model with Eckardt score as the outcome. RESULTS: Our cohort included 141 patients (97 HM and 44 POEM). Eighty-two patients completed a phone survey at the 9 months or greater time interval (response rate = 58%). Mean Eckardt scores were 2.98 and 2.53 at a median follow-up of 3 years and 1 year for HM and POEM patients, respectively (an Eckardt score ≤ 3 is considered a successful myotomy). Lower stages of achalasia on esophagram (e.g., Stage 0 vs. Stage 4) were associated with greater dysphagia improvement. On multivariable analysis, operative approach was not associated with a statistically significant difference in dysphagia outcomes. CONCLUSIONS: POEM and HM were associated with similar rates of dysphagia resolution for achalasia patients at a median of 2 years of follow-up. Both procedures appear to be durable options for achalasia treatment.

The use of national collaborative to promote advanced practice registered nurse-led high-value care initiatives.

BACKGROUND: High-value healthcare focuses on improving healthcare to produce cost effective care, however limited information on the role of advanced practice registered nurses (APRNs) exists. PURPOSE: This descriptive report describes APRN-led initiatives implemented as part of a national collaborative promoting the Choosing Wisely® campaign and high-value care measures. METHOD: An APRN national collaborative focuses on developing and implementing high-value care initiatives. Monthly calls, podcasts, and a file sharing platform are used to facilitate the work of the national collaborative. FINDINGS: A total of 16 APRN teams from 14 states are participating and have implemented a number of initiatives to reduce unnecessary testing and treatments, promote appropriate antibiotic use, and promote optimal clinical practices such as mobility for hospitalized elderly patients, among others. DISCUSSION: A national collaborative has proven to be a successful way to engage APRN teams to focus on targeting high-value care and promoting evidence-based practices in clinical care.

Local referrals as a strategy for increasing value of surgical care among medicare patients undergoing liver and pancreatic surgery.

BACKGROUND: The focus of the current Medicare payment reform is to increase value - i.e. improve health care quality while lowering costs. This study sought to define cost variation and surgical quality among hospitals within small geographic areas typical of work commute patterns. METHODS: Medicare Provider Analysis and Review (MEDPAR) Inpatient Files was used to identify patients undergoing elective liver and pancreatic surgery between 2013 and 2015. Hospitals were assigned to combined statistical areas (CSAs) based on zip codes. Average price-standardized Medicare payments were used to identify highest- and lowest-cost hospitals within CSAs, and clinical outcomes were compared. RESULTS: The study included 12,016 patients. Medicare payments for index hospitalization were 45% ($12,580), 42% ($16,831), 44% ($12,901) and 50% ($18,605) higher for the highest-vs. lowest-cost hospitals for non-complex pancreatic procedures, complex pancreatic procedures, non-complex liver procedures, and complex liver procedures, respectively. Surgical quality was worse at highest-vs. lowest-cost hospitals, demonstrated by higher rates of complications, prolonged LOS and 90-day mortality. CONCLUSION: There was a significant variation in surgical cost for each procedure between CSAs, and within CSAs. Highest-cost hospitals demonstrated worse quality metrics than the lowest-cost hospitals. Local referrals to low-cost hospitals represent an opportunity for increasing value of surgical care.

Hot spotting surgical patients undergoing hepatopancreatic procedures.

BACKGROUND: The burden of health care spending in the United States is a major concern, as health care costs have exponentially increased during the last three decades. The objective of the current study was to investigate the degree of cost-concentration among Medicare patients undergoing liver and pancreatic surgery. METHODS: Medicare claims data from 2013 to 2015 were used to identify patients undergoing elective liver and pancreatic resections. Patients were divided into four groups: 1) non-complex pancreatic procedures; 2) complex pancreatic procedures; 3) non-complex liver procedures; and 4) complex liver procedures. Unadjusted price-standardized Medicare payments were calculated and payments were divided into quintiles. Patient-level factors associated with payments were analyzed by multivariable linear regression. RESULTS: A total of 17,125 patients were included in the study. Patients in the top quintile of spending accounted for over 40% of payments for all liver and pancreatic procedures. Patients with comorbidity scores ≥5, male sex, open surgical approach and a diagnosis of congestive heart failure were associated with higher costs. CONCLUSION: Patients undergoing liver and pancreatic resections on the top 20% of payments were responsible for a disproportionate share of Medicare payments - over 40% of total expenditures. Overall hospital surgical volume was lower among the highest quintile of payments.

Programmable Nucleic Acid Based Polygons with Controlled Neuroimmunomodulatory Properties for Predictive QSAR Modeling.

In the past few years, the study of therapeutic RNA nanotechnology has expanded tremendously to encompass a large group of interdisciplinary sciences. It is now evident that rationally designed programmable RNA nanostructures offer unique advantages in addressing contemporary therapeutic challenges such as distinguishing target cell types and ameliorating disease. However, to maximize the therapeutic benefit of these nanostructures, it is essential to understand the immunostimulatory aptitude of such tools and identify potential complications. This paper presents a set of 16 nanoparticle platforms that are highly configurable. These novel nucleic acid based polygonal platforms are programmed for controllable self-assembly from RNA and/or DNA strands via canonical Watson-Crick interactions. It is demonstrated that the immunostimulatory properties of these particular designs can be tuned to elicit the desired immune response or lack thereof. To advance the current understanding of the nanoparticle properties that contribute to the observed immunomodulatory activity and establish corresponding designing principles, quantitative structure-activity relationship modeling is conducted. The results demonstrate that molecular weight, together with melting temperature and half-life, strongly predicts the observed immunomodulatory activity. This framework provides the fundamental guidelines necessary for the development of a new library of nanoparticles with predictable immunomodulatory activity.