Cystic fibrosis macrophage function and clinical outcomes after elexacaftor/tezacaftor/ivacaftor.

BACKGROUND: Abnormal macrophage function caused by dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) is a critical contributor to chronic airway infections and inflammation in people with cystic fibrosis (PWCF). Elexacaftor/tezacaftor/ivacaftor (ETI) is a new CFTR modulator therapy for PWCF. Host-pathogen and clinical responses to CFTR modulators are poorly described. We sought to determine how ETI impacts macrophage CFTR function, resulting effector functions and relationships to clinical outcome changes. METHODS: Clinical information and/or biospecimens were obtained at ETI initiation and 3, 6, 9 and 12 months post-ETI in 56 PWCF and compared with non-CF controls. Peripheral blood monocyte-derived macrophages (MDMs) were isolated and functional assays performed. RESULTS: ETI treatment was associated with increased CF MDM CFTR expression, function and localisation to the plasma membrane. CF MDM phagocytosis, intracellular killing of CF pathogens and efferocytosis of apoptotic neutrophils were partially restored by ETI, but inflammatory cytokine production remained unchanged. Clinical outcomes including increased forced expiratory volume in 1 s (+10%) and body mass index (+1.0 kg·m-2) showed fluctuations over time and were highly individualised. Significant correlations between post-ETI MDM CFTR function and sweat chloride levels were observed. However, MDM CFTR function correlated with clinical outcomes better than sweat chloride. CONCLUSION: ETI is associated with unique changes in innate immune function and clinical outcomes.

Police, courts, and corrections: Experiences of procedural injustice among Black adults.

Racial disparities and a corresponding lack of trust have been documented within the criminal legal system. In response, criminal legal system actors have sought to strengthen the legitimacy of their agencies. However, legitimizing these agencies can be problematic. Some argue that the current criminal legal system continues the legacy of slavery and Jim Crow as Blacks are disproportionately policed and incarcerated. As a framework, procedural injustice can offer a unique backdrop and interrogate ways in which the criminal legal system engages in delegitimizing actions that provoke noncompliance and enable social control. Using a procedural injustice lens, this study examines how justice-involved Black adults experience mistreatment by justice system actors. Semistructured interviews were conducted with 84 Black adults in Newark and Cleveland. Study findings offer a comprehensive account of how participants experience procedural injustice as arrestees, defendants, and incarcerated persons. More specifically, participant narratives describe deliberately antagonistic, abusive, and dehumanizing treatment by justice-system agents-often depicted as racially motivated. Participant accounts also describe this mistreatment as occurring in a context of coercion and powerlessness and as being institutionally sanctioned. Implications for the preservation of racial hierarchies, research, practice, and community psychology are discussed.

Mucus Plugs in Asthma at CT Associated with Regional Ventilation Defects at 3He MRI.

Background Airway mucus plugs in asthma are associated with exacerbation frequency, increased eosinophilia, and reduced lung function. The relationship between mucus plugs and spatially overlapping ventilation abnormalities observed at hyperpolarized gas MRI has not been assessed quantitatively. Purpose To assess regional associations between CT mucus plugs scored by individual bronchopulmonary segment and corresponding measurements of segmental ventilation defect percentage (VDP) at hyperpolarized helium 3 (3He) MRI. Materials and Methods In this secondary analysis of a Health Insurance Portability and Accountability Act-compliant prospective observational cohort, participants in the Severe Asthma Research Program (SARP) III (NCT01760915) between December 2012 and August 2015 underwent hyperpolarized 3He MRI to determine segmental VDP. Segmental mucus plugs at CT were scored by two readers, with segments scored as plugged only if both readers agreed independently. A linear mixed-effects model controlling for interpatient variability was then used to assess differences in VDP in plugged versus plug-free segments. Results Forty-four participants with asthma were assessed (mean age ± standard deviation, 47 years ± 15; 29 women): 19 with mild-to-moderate asthma and 25 with severe asthma. Mucus plugs were observed in 49 total bronchopulmonary segments across eight of 44 patients. Segments containing mucus plugs had a median segmental VDP of 25.9% (25th-75th percentile, 7.3%-38.3%) versus 1.4% (25th-75th percentile, 0.1%-5.2%; P < .001) in plug-free segments. Similarly, the model estimated a segmental VDP of 18.9% (95% CI: 15.7, 22.2) for mucus-plugged segments versus 5.1% (95% CI: 3.3, 7.0) for plug-free segments (P < .001). Participants with one or more mucus plugs had a median whole-lung VDP of 11.1% (25th-75th percentile, 7.1%-18.9%) versus 3.1% (25th-75th percentile, 1.1%-4.4%) in those without plugs (P < .001). Conclusion Airway mucus plugging at CT was associated with reduced ventilation in the same bronchopulmonary segment at hyperpolarized helium 3 MRI, suggesting that mucus plugging may be an important cause of ventilation defects in asthma. © RSNA, 2021 Online supplemental material is available for this article.

Ventilation defects on hyperpolarized helium-3 MRI in asthma are predictive of 2-year exacerbation frequency.

BACKGROUND: There is an unmet need for an objective biomarker to predict asthma exacerbations. OBJECTIVE: Our aim was to assess the ventilation defect percent (VDP) on hyperpolarized helium-3 magnetic resonance imaging as a predictor of exacerbation frequency following imaging. METHODS: Subjects underwent hyperpolarized helium-3 and conventional clinical measurements, including pulmonary function tests, during a period of disease stability, and exacerbations were recorded prospectively over the following 2 years. We used a Poisson regression tree model to estimate an optimal VDP threshold for classifying subjects into high- versus low-exacerbation groups and then used statistical regression to compare this VDP threshold against conventional clinical measures as predictors of exacerbations. RESULTS: A total of 67 individuals with asthma (27 males and 40 females, 28 with mild-to-moderate asthma and 39 with severe asthma) had a median VDP of 3.75% (1.2% [first quartile]-7.9% [third quartile]). An optimal VDP threshold of 4.28% was selected on the basis of the maximum likelihood estimation of the regression tree model. Subjects with a VDP greater than 4.28% (n = 32) had a median of 1.5 exacerbations versus 0.0 for subjects with a VDP less than 4.28% (n = 35). In a stepwise multivariate regression model, a VDP greater than 4.28% was associated with an exacerbation incidence rate ratio of 2.5 (95% CI = 1.3-4.7) versus a VDP less than or equal to 4.28%. However, once individual medical history was included in the model, VDP was no longer significant. Nonetheless, VDP may provide an objective and complementary quantitative marker of individual exacerbation risk that is useful for monitoring individual change in disease status, selecting patients for therapy, and assessing treatment response. CONCLUSION: VDP measured with magnetic resonance imaging shows promise as a biomarker of prospective asthma exacerbations.

Intraperitoneal nanotherapy for metastatic ovarian cancer based on siRNA-mediated suppression of DJ-1 protein combined with a low dose of cisplatin.

Herein, we report an efficient combinatorial therapy for metastatic ovarian cancer based on siRNA-mediated suppression of DJ-1 protein combined with a low dose of cisplatin. DJ-1 protein modulates, either directly or indirectly, different oncogenic pathways that support and promote survival, growth, and invasion of ovarian cancer cells. To evaluate the potential of this novel therapy, we have engineered a cancer-targeted nanoplatform and validated that DJ-1 siRNA delivered by this nanoplatform after intraperitoneal injection efficiently downregulates the DJ-1 protein in metastatic ovarian cancer tumors and ascites. In vivo experiments revealed that DJ-1 siRNA monotherapy outperformed cisplatin alone by inhibiting tumor growth and increasing survival of mice with metastatic ovarian cancer. Finally, three cycles of siRNA-mediated DJ-1 therapy in combination with a low dose of cisplatin completely eradicated ovarian cancer tumors from the mice, and there was no cancer recurrence detected for the duration of the study, which lasted 35 weeks.

Alzheimer's disease and type 2 diabetes: what is the connection?

Alzheimer's disease (AD) is a progressive neurodegenerative condition primarily affecting individuals 65 years of age and older. There are few therapies available, and the disease is eventually fatal. Although the molecular mechanisms responsible for the development of AD remain unknown, a strong correlation between insulin dysfunction in type 2 diabetes mellitus and AD has recently been established. This has led to innovative research in the prevention and treatment of AD. Currently the most promising antidiabetic treatment options for AD are intranasal insulin and liraglutide, both of which are being investigated in ongoing clinical trials. Intranasal insulin showed promise in a pilot human trial, and while initial results appear positive, the clinical significance is unknown. Whereas current treatments only slow disease progression for a relatively short time, these new therapies may be able to reverse damage that has already occurred and potentially restore neurological function.

Comparison of hyperpolarized 3He-MRI, CT based parametric response mapping, and mucus scores in asthmatics.

Purpose: The purpose of this study was to anatomically correlate ventilation defects with regions of air trapping by whole lung, lung lobe, and airway segment in the context of airway mucus plugging in asthma. Methods: A total of 34 asthmatics [13M:21F, 13 mild/moderate, median age (range) of 49.5 (36.8-53.3) years and 21 severe, 56.1 (47.1-62.6) years] and 4 healthy subjects [1M:3F, 38.5 (26.6-52.2) years] underwent HP 3He MRI and CT imaging. HP 3He MRI was assessed for ventilation defects using a semi-automated k-means clustering algorithm. Inspiratory and expiratory CTs were analyzed using parametric response mapping (PRM) to quantify markers of emphysema and functional small airways disease (fSAD). Segmental and lobar lung masks were obtained from CT and registered to HP 3He MRI in order to localize ventilation defect percent (VDP), at the lobar and segmental level, to regions of fSAD and mucus plugging. Spearman's correlation was utilized to compare biomarkers on a global and lobar level, and a multivariate analysis was conducted to predict segmental fSAD given segmental VDP (sVDP) and mucus score as variables in order to further understand the functional relationships between regional measures of obstruction. Results: On a global level, fSAD was correlated with whole lung VDP (r = 0.65, p < 0.001), mucus score (r = 0.55, p < 0.01), and moderately correlated (-0.60 ≤ r ≤ -0.56, p < 0.001) to percent predicted (%p) FEV1, FEF25-75 and FEV1/FVC, and more weakly correlated to FVC%p (-0.38 ≤ r ≤ -0.35, p < 0.001) as expected from previous work. On a regional level, lobar VDP, mucus scores, and fSAD were also moderately correlated (r from 0.45-0.66, p < 0.01). For segmental colocalization, the model of best fit was a piecewise quadratic model, which suggests that sVDP may be increasing due to local airway obstruction that does not manifest as fSAD until more extensive disease is present. sVDP was more sensitive to the presence of a mucus plugs overall, but the prediction of fSAD using multivariate regression showed an interaction in the presence of a mucus plugs when sVDP was between 4% and 10% (p < 0.001). Conclusion: This multi-modality study in asthma confirmed that areas of ventilation defects are spatially correlated with air trapping at the level of the airway segment and suggests VDP and fSAD are sensitive to specific sources of airway obstruction in asthma, including mucus plugs.

A polypill for all? Critical review of the polypill literature for primary prevention of cardiovascular disease and stroke.

OBJECTIVE: To evaluate the efficacy and safety of the polypill for prevention of cardiovascular disease (CVD) and stroke and to present literature related to the polypill components (statin, aspirin, antihypertensive) for primary prevention of CVD and stroke. DATA SOURCES: A literature search was conducted in MEDLINE (1948-January 2011) and EMBASE (1974-January 2011) using the terms polypill and Polycap. When limited to clinical trials, systematic reviews, or meta-analyses, 7 studies were identified. Bibliographies of pertinent review articles and studies were scanned for additional references. A similar search was conducted to identify literature related to the use of polypill components for primary prevention of CVD and stroke. STUDY SELECTION AND DATA EXTRACTION: Studies that evaluated the hypothetical benefits of a polypill and controlled trials that assessed a formulation of the polypill related to prevention of CVD and stroke were included. Studies were assessed for efficacy, safety, drug interactions, and clinical pharmacokinetics. DATA SYNTHESIS: An initial study to predict benefit estimated that a hypothetical polypill would reduce diastolic blood pressure by 11 mm Hg and low-density lipoprotein cholesterol (LDL-C) by 70 mg/dL, thus reducing the relative risks of CVD and stroke by 88% and 80%, respectively. One clinical trial in patients at low risk for CVD and stroke found that diastolic blood pressure was reduced by 1.6 mm Hg and LDL-C was reduced by 17.7 mg/dL, correlating with 44% and 21% reduction in the relative risks of CVD and stroke, respectively. Studies in higher risk patients reported reductions in systolic blood pressure of up to 28.8 mm Hg and in LDL-C of up to 54 mg/dL, correlating with 62% and 60% relative reduction in risks of CVD and stroke, respectively. CONCLUSIONS: Polypill study results have been more modest than originally theorized. However, results show promise in patients at higher risk for CVD and stroke.

Vitamin D Supplementation to Treat Statin-Associated Muscle Symptoms: A Review.

For the past 15 years, cardiovascular disease (CVD) has been the leading cause of death for both men and women in the United States and worldwide. With an aging population, there has been increasing use of statin therapy to reduce the risk of CVD. However, statin-associated muscle symptoms (SAMS) remain an obstacle to this treatment, leading to discontinuation and nonadherence to statin therapy. Signs and symptoms of SAMS include muscle pain, tenderness, and increased serum creatine kinase. Despite the idiopathic pathophysiology of SAMS, some studies have shown an association between vitamin D deficiency and SAMS; the use of vitamin D supplements can lead to relief of these symptoms. The purpose of this review was to critique evidence for the association between low serum vitamin D and SAMS and the use of vitamin D supplementation for treatment.

Detecting aberrant opioid behavior in the emergency department: a prospective study using the screener and Opioid Assessment for Patients with Pain-Revised (SOAPP®-R), Current Opioid Misuse Measure (COMM)™, and provider gestalt.

Emergency department (ED) providers have limited time to evaluate patients at risk for opioid misuse. A validated tool to assess the risk for aberrant opioid behavior may mitigate adverse sequelae associated with prescription opioid misuse. We sought to determine if SOAPP-R, COMM, and provider gestalt were able to identify patients at risk for prescription opioid misuse as determined by pharmacy records at 12 months. We conducted a prospective observational study of adult patients in a high volume US ED. Patients completed the SOAPP-R and COMM, and treating EM providers evaluated patients' opioid misuse risk. We performed variable-centered, person-centered, and hierarchical cluster analyses to determine whether provider gestalt, SOAPP-R, or COMM, or a combination, predicted higher misuse risk. The primary outcome was the number of opioid prescriptions at 12 months according to pharmacy records. For 169 patients (mean age 43 years, 51% female, 73% white), correlation analysis showed a strong relationship between SOAPP-R and COMM with predicting the number of opioid prescriptions dispensed at 12 months. Provider scores estimating opioid misuse were not related to SOAPP-R and only weakly associated with COMM. In our adjusted regression models, provider gestalt and SOAPP-R uniquely predicted opioid prescriptions at 6 and 12 months. Using designated cutoff scores, only SOAPP-R detected a difference in the number of opioid prescriptions. Cluster analysis revealed that provider gestalt, SOAPP-R, and COMM scores jointly predicted opioid prescriptions. Provider gestalt and self-report instruments uniquely predicted the number of opioid prescriptions in ED patients. A combination of gestalt and self-assessment scores can be used to identify at-risk patients who otherwise miss the cutoff scores for SOAPP-R and COMM.

Adaptation and Validation of the Fresno Test of Competence in Evidence-Based Medicine in Doctor of Pharmacy Students.

Objective. To adapt and validate an instrument assessing competence in evidence-based medicine (EBM) in Doctor of Pharmacy students. Methods. The Fresno test was validated in medical residents. We adapted it for use in pharmacy students. A total of 120 students and faculty comprised the validation set. Internal reliability, item difficulty, and item discrimination were assessed. Construct validity was assessed by comparing mean total scores of students to faculty, and comparing proportions of students and faculty who passed each item. Results. Cronbach's alpha was acceptable, and no items had a low item-total correlation. All of the point-biserial correlations were acceptable. Item difficulty ranged from 0% to 60%. Faculty had higher total scores and also scored higher than students on most items, and 8 of 11 of these differences were statistically significant. Conclusion. The Pharm Fresno is a reliable and valid instrument to assess competence in EBM in pharmacy students. Future research will focus on further refining the instrument.

Emergency medicine providers' opioid prescribing practices stratified by gender, age, and years in practice.

BACKGROUND: Emergency medicine providers (EMPs) prescribe about 25% of opioids, but the effect of EMP risk perception on decisions to prescribe opioids is unknown. This study was undertaken to identify factors that influence EMP risk and opioid prescribing practices. METHODS: We distributed an anonymous questionnaire to EMPs at a military trauma and referral center. Response frequencies and distributions were assessed for independence using the Chi-square test. RESULTS: Eighty-nine EMPs completed the questionnaire (100% response). Respondents were primarily younger male physicians (80%) in practice under five years (55%). Male EMPs were more likely to prescribe more opioid tablets than female ones both when and when not concerned for opioid misuse (P<0.001, P<0.007, respectively). Of the providers, 70% stated that patient age would influence their prescribing decisions. Hydrocodone and oxycodone were the opioids prescribed most frequently. About 60% of the providers reported changing their prescribing behavior would not prevent opioid misuse. Additionally, 40% of the providers believed at least 10% of patients seen at this military ED misused opioids. CONCLUSION: Female EM providers reported prescribing fewer opioid tablets. Patient age influenced prescribing behavior, but the effect is unknown. Finally, EM providers reported that altering their prescribing behavior would not prevent prescription opioid misuse.

Impact of pharmacy student and resident-led discharge counseling on heart failure patients.

PURPOSE: Many health systems have implemented interventions to reduce the rate of heart failure readmissions. Pharmacists have the training and expertise to provide effective medication-related education. However, few studies have examined the impact of discharge education provided by pharmacy students and residents on patients hospitalized with heart failure exacerbations. METHODS: This was a nonrandomized intervention study evaluating the impact of a pharmacy student and resident-led discharge counseling program on heart failure readmissions. The primary end point was the 30-day heart failure readmission rate. Secondary end points included self-reported patient understanding of medications, number of medication errors documented, and estimated associated cost avoidance. RESULTS: A total of 86 and 94 patients were enrolled into the intervention and control groups, respectively. No statistically significant difference in readmission rates was detected between the intervention and the control groups. Thirty-four medication errors and discrepancies were documented, or 1 for every 2.5 patients counseled, resulting in an estimated cost avoidance of $4241 for the institution. Eighty-nine percent of patients who received discharge counseling agreed they had a better understanding of their medications after speaking with a pharmacy resident or student. CONCLUSIONS: There was no statistically significant difference in readmission rates; however, several medication errors were prevented, and a large percentage of patients expressed an improved understanding of their medications.

Pharmacy student impact on inappropriate prescribing of acid suppressive therapy.

OBJECTIVE: To examine the impact that having pharmacy students on internal medicine patient care teams had on inappropriate prescribing of acid suppressive therapy (AST). METHODS: In this observational cohort study, internal medicine patients who received care from teams with a pharmacy student were compared to patients who received care from teams without a pharmacy student. The primary endpoint was proportion of patients on inappropriate AST. RESULTS: The overall proportion of patients receiving inappropriate AST was 24.4%. There was no significant difference between patients seen by teams with a pharmacy student and those seen by teams without a pharmacy student. The proportion of patients discharged with new inappropriate AST prescriptions was lower after pharmacy student review, though not significantly (6.1% vs. 9.4%, p = 0.07). Pharmacy student reviews shortened the median duration of inappropriate AST by 1.5 days (6 vs. 8.5 days, p = 0.025). CONCLUSIONS: Patient care teams on which pharmacy students performed medication reviews had a reduced duration of inappropriate use of AST in patients.

Food-entrained rhythmic expression of apolipoprotein E expression in the hypothalamus of rats.

Apolipoprotein E (apoE) is a protein mainly synthesized in the liver and brain. To further understand the role of brain apoE in the management of daily food intake, we have examined the circadian pattern of hypothalamic apoE gene and protein expression in freely-fed (FF) and food-restricted (RF, food provided 4 h daily between 1000 h and 1400 h) rats sacrificed at 3-h intervals throughout the light-dark cycle. In FF rats, hypothalamic apoE mRNA and protein levels fluctuated with peaks occuring during the dark phase and the nadirs occuring during the light phase. This pattern was altered in RF rats, which had a marked increase in hypothalamic apoE mRNA and protein levels during the 4-h feeding period in the light phase. Although corticosterone (CORT) levels temporally coincided with the increasing phase of apoE in the hypothalamus in both FF and RF rats, depletion of CORT by adrenalectomy (ADX) did not significantly influence the hypothalamic apoE levels during either period, implying that the circadian pattern of hypothalamic apoE is regulated by factors other than circulating CORT. The finding that hypothalamic apoE and food intake are positively associated during the normal circadian cycle as well as in the period of restricted feeding suggests that hypothalamic apoE is food-entrained and likely involved in the physiological regulation of daily food intake.

Effect of intraperitoneal and intravenous administration of cholecystokinin-8 and apolipoprotein AIV on intestinal lymphatic CCK-8 and apo AIV concentration.

CCK and apolipoprotein AIV (apo AIV) are gastrointestinal satiety signals whose synthesis and secretion by the gut are stimulated by fat absorption. Intraperitoneally administered CCK-8 is more potent in suppressing food intake than a similar dose administered intravenously, but the reason for this disparity is unclear. In contrast, both intravenous and intraperitoneally administered apo AIV are equally as potent in inhibiting food intake. When we compared the lymphatic concentration of CCK-8 and apo AIV, we found that neither intraperitoneally nor intravenously administered CCK-8 or apo AIV altered lymphatic flow rate. Interestingly, intraperitoneal administration of CCK-8 produced a significantly higher lymphatic concentration at 15 min than did intravenous administration. Intraperitoneal injection of apo AIV also yielded a higher lymphatic concentration at 30 min than did intravenous administration. Intraperitoneal administration of CCK-8 and apo AIV also resulted in a much longer period of elevated CCK-8 and apo AIV peptide concentration in lymph than intravenous administration. Furthermore, enzymatic activity of dipeptidyl peptidase IV (DPPIV) and aminopeptidase was higher in plasma than in lymph during fasting, and so, satiation peptides, such as CCK-8 and apo AIV in the lymph, are protected from degradation by the significantly lower DPPIV and aminopeptidase activity levels in lymph than in plasma. Therefore, the higher potency of intraperitoneally administered CCK-8 compared with intravenously administered CCK-8 in inhibiting food intake may be explained by both its higher concentration in lymph and the prolonged duration of its presence in the lamina propria.

Brain apolipoprotein E: an important regulator of food intake in rats.

OBJECTIVE: The worldwide prevalence of obesity is increasing at an alarming rate, along with the associated increased rates of type 2 diabetes, heart disease, and some cancers. While efforts to address environmental factors responsible for the recent epidemic must continue, investigation into the anorectic functions of potential molecules we present here, such as apolipoprotein (apo)E, offers exciting possibilities for future development of successful anti-obesity therapies. RESEARCH DESIGN AND METHODS: Changes in feeding behavior after intracerebroventricular injection of apoE, the regulation of hypothalamic apoE gene expression by energy status, and the interaction of hypothalamic apoE with other neuropeptides were studied. RESULTS: Intracerebroventricular apoE significantly decreased food intake without causing malaise, whereas intracerebroventricular infusion of apoE antiserum stimulated feeding, implying that endogenous apoE tonically inhibits food intake. Consistent with this, apoE was present in the hypothalamus, a brain site intimately involved in the integration of signals for energy homeostasis. Fasted rats exhibited significantly decreased apoE gene expression in the hypothalamus, and refeeding of these rats for 4 h evoked a significant increase of hypothalamic apoE mRNA levels. Both genetically obese (ob/ob) mice and rats with high-fat diet-induced obesity had significantly reduced hypothalamic apoE mRNA levels compared with their lean control counterparts, suggesting that decreased apoE may contribute to hyperphagia in these obese animals. Additionally, apoE-stimulated hypothalamic proopiomelanocortin gene expression and SHU9119, a melanocortin 3/4 receptor antagonist, attenuated the inhibitory function of apoE on feeding. CONCLUSIONS: These data demonstrate that apoE suppresses food intake via a mechanism enhancing melanocortin signaling in the hypothalamus.