Transendothelial Migration of Human B Cells: Chemokine versus Antigen.

B cells, like T cells, can infiltrate sites of inflammation, but the processes and B cell subsets involved are poorly understood. Using human cells and in vitro assays, we find only a very small number of B cells will adhere to TNF-activated (but not to resting) human microvascular endothelial cells (ECs) under conditions of venular flow and do so by binding to ICAM-1 and VCAM-1. CXCL13 and, to a lesser extent, CXCL10 bound to the ECs can increase adhesion and induce transendothelial migration (TEM) of adherent naive and memory B cells in 10-15 min through a process involving cell spreading, translocation of the microtubule organizing center (MTOC) into a trailing uropod, and interacting with EC activated leukocyte cell adhesion molecule. Engagement of the BCR by EC-bound anti-κ L chain Ab also increases adhesion and TEM of κ+ but not λ+ B cells. BCR-induced TEM takes 30-60 min, requires Syk activation, is initiated by B cell rounding up and translocation of the microtubule organizing center to the region of the B cell adjacent to the EC, and also uses EC activated leukocyte cell adhesion molecule for TEM. BCR engagement reduces the number of B cells responding to chemokines and preferentially stimulates TEM of CD27+ B cells that coexpress IgD, with or without IgM, as well as CD43. RNA-sequencing analysis suggests that peripheral blood CD19+CD27+CD43+IgD+ cells have increased expression of genes that support BCR activation as well as innate immune properties in comparison with total peripheral blood CD19+ cells.

Discovery of small molecules that target a tertiary-structured RNA.

There is growing interest in therapeutic intervention that targets disease-relevant RNAs using small molecules. While there have been some successes in RNA-targeted small-molecule discovery, a deeper understanding of structure-activity relationships in pursuing these targets has remained elusive. One of the best-studied tertiary-structured RNAs is the theophylline aptamer, which binds theophylline with high affinity and selectivity. Although not a drug target, this aptamer has had many applications, especially pertaining to genetic control circuits. Heretofore, no compound has been shown to bind the theophylline aptamer with greater affinity than theophylline itself. However, by carrying out a high-throughput screen of low-molecular-weight compounds, several unique hits were identified that are chemically distinct from theophylline and bind with up to 340-fold greater affinity. Multiple atomic-resolution X-ray crystal structures were determined to investigate the binding mode of theophylline and four of the best hits. These structures reveal both the rigidity of the theophylline aptamer binding pocket and the opportunity for other ligands to bind more tightly in this pocket by forming additional hydrogen-bonding interactions. These results give encouragement that the same approaches to drug discovery that have been applied so successfully to proteins can also be applied to RNAs.

A Color-Tunable Alternating Current Organic Light Emitting Capacitor.

We demonstrate an alternating current (AC) driven light emitting capacitor in which the color of the emission spectra can be changed via an applied AC frequency. The device has a simple metal-oxide-semiconductor (MOS) capacitor structure with an organic emissive layer, enabling facile fabrication processing. The organic emissive layer comprises a thin, submonolayer low energy dye layer underneath a thick host matrix (∼30 nm) with higher energy emitting dyes. The emission of the lower energy dyes dominates at low frequency, while the higher energy emission of the host matrix dominates at high frequency. This simple color tunable device could be used for full-color displays and lighting in the future.

Persisting Type 2 Endoleaks Following EVAR for AAA Are Associated With AAA Expansion.

PURPOSE: To determine the evolution of abdominal aortic aneurysm (AAA) diameter in the presence of persisting type 2 endoleaks (pEL2) following endovascular abdominal aortic aneurysm repair (EVAR). MATERIALS AND METHODS: This is a retrospective, single-center, case-control study. All patients with pEL2 (pEL2 group, persisting for > 12 months) between 2004 and 2018 were identified and compared with a 1:1 age- and gender-matched control with no endoleak (control group). Primary outcome measures were freedom from AAA expansion and freedom from AAA shrinkage over time. AAA diameter measurements were performed on computed tomography angiography (CTA). Secondary outcome measures were survival, AAA-related mortality, reinterventions for pEL2, incidence of secondary type 1 endoleaks (EL1), and infrarenal aortic branch vessel anatomy. RESULTS: A total of 773 patients were treated with EVAR for AAA between 2004 and 2018. Of them, 286 patients demonstrated type 2 endoleaks (EL2) in postoperative CTA or intraoperative angiography (37%). Forty-five of 286 EL2 (15.7%) were pEL2 (pEL2 group). Freedom from AAA expansion in the pEL2 group was 100%, 96.7%, 85.2%, and 54.3% after 1, 2, 3, and 4 years, respectively, compared with 100% after 1, 2, 3, and 4 years in the control group (p<0.01). Freedom from AAA shrinkage in the pEL2 group after 1, 2, 3, and 4 years was 95.5%, 90.4%, 90.4%, and 79.1%, respectively, compared with 86.7%, 34.8%, 19.3%, and 19.3% in the control group (p<0.01). Overall survival at 1, 2, 3, and 4 years was 100%, 97.6%, 95.0% and 95.0% in the pEL2 group and 100% at 1, 2, 3, and 4 years in the control group (p=0.17). There were no AAA-related deaths in either group. Patients with pEL2 had a significantly increased number of infrarenal aortic branches (p<0.05, respectively). Eighteen patients (40.0%) in the pEL2 group underwent 34 reinterventions for pEL2, with a median follow-up (FU) of 925 days (0-4173). Clinical success was achieved in 9 patients (50.0%). Four patients (8.9%) with pEL2 developed secondary EL1 after a median FU of 1278 days (662-2121). CONCLUSION: pEL2 are associated with AAA expansion during midterm FU. Further studies are warranted to evaluate the association of AAA expansion due to pEL2 with clinical outcomes to allow recommendations with regard to treatment indications.

Presence of refractory GERD-like symptoms following laparoscopic fundoplication is rarely indicative of true recurrent GERD.

BACKGROUND: Laparoscopic fundoplication (LF) is the gold standard for gastroesophageal reflux disease (GERD). Recurrent GERD is a known complication; however, the incidence of recurrent GERD-like symptoms and long-term fundoplication failure is rarely reported. Our objective was to identify the rate of recurrent pathologic GERD in patients with GERD-like symptoms following fundoplication. We hypothesized that patients with recurrent GERD-like symptoms refractory to medical management do not have evidence of fundoplication failure as indicated by a positive ambulatory pH study. METHODS: This is a retrospective cohort study of 353 consecutive patients undergoing LF for GERD between 2011 and 2017. Baseline demographics, objective testing, GERD-HRQL scores, and follow-up data were collected in a prospective database. Patients with return visits to clinic following routine post-operative visits were identified (n = 136, 38.5%), and those with a primary complaint of GERD-like symptoms (n = 56, 16%) were included. The primary outcome was the proportion of patients with a positive post-operative ambulatory pH study. Secondary outcomes included proportion of patients with symptoms managed with acid-reducing medications, time to return to clinic, and need for reoperation. P values < 0.05 were considered significant. RESULTS: Fifty-six (16%) patients returned during the study period for an evaluation of recurrent GERD-like symptoms with a median interval of 51.2 (26.2-74.7) months. Twenty-four patients (42.9%) were successfully managed expectantly or with acid-reducing medications. Thirty two (57.1%) presented with GERD-like symptoms and failure of management with medical acid suppression and underwent repeat ambulatory pH testing. Of these, only 5 (9%) were found to have a DeMeester score of > 14.7, and three (5%) underwent recurrent fundoplication. CONCLUSION: Following LF, the incidence of GERD-like symptoms refractory to PPI therapy is much higher than the incidence of recurrent pathologic acid reflux. Few patients with recurrent GI symptoms require surgical revision. Evaluation, including objective reflux testing, is critical to evaluating these symptoms.

Generational differences in beliefs about COVID-19 vaccines.

Vaccine uptake variation across demographic groups remains a public health barrier to overcome the coronavirus pandemic despite substantial evidence demonstrating the effectiveness of COVID-19 vaccines against severe illness and death. Generational cohorts differ in their experience with historical and public health events, which may contribute to variation in beliefs about COVID-19 vaccines. Nationally representative longitudinal data (December 20, 2020 to July 23, 2021) from the Understanding America Study (UAS) COVID-19 tracking survey (N = 7279) and multilevel logistic regression were used to investigate whether generational cohorts differ in COVID-19 vaccine beliefs. Regression models adjusted for wave, socioeconomic and demographic characteristics, political affiliation, and trusted source of information about COVID-19. Birth-year cutoffs define the generational cohorts: Silent (1945 and earlier), Boomer (1946-1964), Gen X (1965-1980), Millennial (1981-1996), and Gen Z (1997-2012). Compared to Boomers, Silents had a lower likelihood of believing that COVID-19 vaccines have many known harmful side effects (OR = 0.52, 95%CI = 0.35-0.74) and that they may lead to illness and death (OR = 0.53, 95%CI = 0.37-0.77). Compared to Boomers, Silents had a higher likelihood of believing that the vaccines provide important benefits to society (OR = 2.27, 95%CI = 1.34-3.86) and that they are useful and effective (OR = 1.97, 95%CI = 1.17-3.30). Results for Gen Z are similar to those reported for Silents. Beliefs about COVID-19 vaccines markedly differ across generations. This is consistent with the idea of generational imprinting-the idea that some beliefs may be resistant to change through adulthood. Policy strategies other than vaccine education may be needed to overcome this pandemic and future public health challenges.

Association between COVID-19 vaccine hesitancy and trust in the medical profession and public health officials.

One's personal physician, national and state or local public health officials, and the broader medical profession play important roles in encouraging vaccine uptake for COVID-19. However, the relationship between trust in these experts and vaccine hesitancy has been underexplored, particularly among racial/minority groups where historic medical mistrust may reduce uptake. Using an April 2021 online sample of US adults (n = 3041) that explored vaccine hesitancy, regression models estimate levels of trust in each of these types of experts and between trust in each of these experts and the odds of being COVID-19 vaccine takers vs refusers or hesitaters. Interaction terms assess how levels of trust in the medical profession by race/ethnicity are associated with vaccine hesitancy. Trust in each expert is positively associated with trust in other experts, except for trust in the medical profession. Only trust in one's own doctor was associated with trust in the medical profession, as measured by factor scores derived from a validated scale. Lower levels of trust in experts were significantly associated with being either a hesitater or a refuser compared to being a taker. Black respondents had higher odds of being either a hesitater or a refuser compared to white respondents but the interaction with trust was insignificant. For Hispanic respondents only, the odds of being a hesitater declined significantly when trust in the medical profession rose. Mistrust in the medical profession, one's doctor and national experts contributes to vaccine hesitancy. Mobilizing personal physicians to speak to their own patients may help.

Are recommended dietary patterns equitable?

OBJECTIVE: Dietary recommendations (DR) in the USA may be inadequate at improving diets in racial/ethnic minority communities and may require redesign of the systems driving their development over the long term. Meanwhile, cultural adaptation of evidence-based DR may be an important strategy for mitigating nutrition disparities, but less is known about the adaptability of these recommendations to meet the needs of diverse groups. We examined the content and origin of major DRs - aspects that provide context on their potential universality across populations and evaluated their potential for cultural adaptation. DESIGN: Case studies of Dietary Approaches to Stop Hypertension (DASH), the Mediterranean diet (MD), the EAT-Lancet diet (EAT) and the NOVA classification system. SETTING: United States. PARTICIPANTS: Racial/ethnic minority populations. RESULTS: Current DR differ in their origin/evolution but are similar in their reductionist emphasis on physical health. DASH has been successfully adapted for some cultures but may be challenged by the need for intensive resources; MD may be more beneficial if applied as part of a broader set of food procurement/preparation practices than as just diet alone; EAT-Lancet adaptation may not honor existing country-specific practices that are already beneficial to human and environmental health (e.g. traditional/plant-based diets); evidence for cultural adaptation is limited with NOVA, but classification of levels of food processing has potential for widespread application. CONCLUSIONS: For DR to equitably support diverse populations, they must move beyond a Eurocentric or 'general population' framing, be more inclusive of cultural differences and honour social practices to improve diet and reduce disparities.

Identification of MFGE8 and KLK5/7 as mediators of breast tumorigenesis and resistance to COX-2 inhibition.

BACKGROUND: Cyclooxygenase 2 (COX-2) promotes stemness in triple negative breast cancer (TNBC), highlighting COX-2 as a promising therapeutic target in these tumors. However, to date, clinical trials using COX-2 inhibitors in breast cancer only showed variable patient responses with no clear significant clinical benefits, suggesting underlying molecular mechanisms contributing to resistance to COX-2 inhibitors. METHODS: By combining in silico analysis of human breast cancer RNA-seq data with interrogation of public patient databases and their associated transcriptomic, genomic, and clinical profiles, we identified COX-2 associated genes whose expression correlate with aggressive TNBC features and resistance to COX-2 inhibitors. We then assessed their individual contributions to TNBC metastasis and resistance to COX-2 inhibitors, using CRISPR gene knockout approaches in both in vitro and in vivo preclinical models of TNBC. RESULTS: We identified multiple COX-2 associated genes (TPM4, RGS2, LAMC2, SERPINB5, KLK7, MFGE8, KLK5, ID4, RBP1, SLC2A1) that regulate tumor lung colonization in TNBC. Furthermore, we found that silencing MFGE8 and KLK5/7 gene expression in TNBC cells markedly restored sensitivity to COX-2 selective inhibitor both in vitro and in vivo. CONCLUSIONS: Together, our study supports the establishment and use of novel COX-2 inhibitor-based combination therapies as future strategies for TNBC treatment.

Views on the need to implement restriction policies to be able to address COVID-19 in the United States.

Several restriction policies implemented in many states in the United States have demonstrated their effectiveness in mitigating the spread of the coronavirus disease (COVID-19), but less is known about the differences in views on the restriction policies among different population segments. This study aimed to understand which different population groups of adults in the United States consider several key restriction policies as necessary to combat COVID-19. Survey data from Wave 64 (March 19-24, 2020) of the Pew Research Center's American Trends Panel (n=10,609) and logistic regression were used to evaluate the association between socioeconomic and demographic characteristics, employment status, political party affiliation, news exposure, census region, and opinions about COVID-19 restriction policies. The policies included restricting international travel, imposing business closures, banning large group gatherings, cancelling entertainment events, closing schools, limiting restaurants to carry-out only, and postponing state primary elections. Most survey respondents viewed COVID-19 restriction policies as necessary. Views on each restriction policy varied substantially across some population segments such as age, race, and ethnicity. Regardless of population segments, those who followed news closely or considered themselves Democrat/lean Democrat were more likely to consider all the policies as necessary than those not following the news closely or those who considered themselves Republican/lean Republican. The effectiveness of key COVID-19 restriction policies is likely to vary substantially across population groups given that views on the need to implement these policies vary widely. Tailored health messages may be needed for some population segments given divergent views on COVID-19 restriction policies.

The infectious complications of atopic dermatitis.

OBJECTIVE: Atopic dermatitis (AD) is a chronic inflammatory skin disease that is complicated by an increased risk for skin and systemic infections. Preventive therapy for AD is based on skin barrier improvement and anti-inflammatory treatments, whereas overt skin and systemic infections require antibiotics or antiviral treatments. This review updates the pathophysiology, diagnosis, management, controversy of antibiotic use, and potential treatments of infectious complications of AD. DATA SOURCES: Published literature obtained through PubMed database searches and clinical pictures. STUDY SELECTIONS: Studies relevant to the mechanisms, diagnosis, management, and potential therapy of infectious complications of AD. RESULTS: Skin barrier defects, type 2 inflammation, Staphylococcusaureus colonization, and cutaneous dysbiosis are the major predisposing factors for the increased infections in AD. Although overt infections require antibiotics, the use of antibiotics in AD exacerbation remains controversial. CONCLUSION: Infectious complications are a comorbidity of AD. Although not common, systemic bacterial infections and eczema herpeticum can be life-threatening. Preventive therapy of infections in AD emphasizes skin barrier improvement and anti-inflammatory therapy. The use of antibiotics in AD exacerbation requires further studies.

Expectations versus reality: trainee participation on the robotic console in academic surgery.

INTRODUCTION: Trainees underestimate the amount of operative autonomy they receive, whereas faculty overestimate; this has not been studied in robotics. We aimed to assess the perceptions and expectations of our general surgery trainees and faculty on robotic console participation in academic surgery. METHODS: A survey was administered to general surgery robotic faculty and trainees eligible to sit at the console. Participants estimated the average percentage of trainee console participation time (CPT) per case for robotic cholecystectomies (CCY) and inguinal hernia repairs (IHR) from January to June 2019. Trainees were additionally asked what CPT they expected according to their training level (novice or senior). Expected CPTs were compared to actual CPTs extracted from robotic console logs during the same time frame. RESULTS: Survey response rate was 80% for faculty (4 of 5) and 65% for trainees (15 of 23). Novices expected a higher CPT than they perceived in CCY (42.8% ± 14.8% vs 19.0% ± 17.2%, p = 0.03) and IHR (36.1% ± 17.6% vs. 10.7% ± 13.7%, p = 0.01), but in actuality, they did more CPT than perceived (by 34.9% in CCY, p < 0.01; 14% in IHR, p = 0.10). Senior trainees accurately perceived their CPT in IHR, but expected a higher CPT by 15.9% (p = 0.04). In CCY, seniors perceived a 23.8% higher CPT than in reality (p = 0.04). Faculty generally overperceived trainee CPT by 12.8-16.3% (p > 0.05). Compared to faculty, novices perceived lower CPTs in both CCY by 29.9% (p = 0.16) and IHR by 26.8% (p = 0.07), but seniors tended to agree with the faculty-perceived CPTs (p > 0.05). CONCLUSION: Our robotic trainees expect to do more on the console than they perceive. Faculty think they allow their trainees more participation than in reality. Compared to faculty perception, novice trainees perceive a much lower level of trainee participation than senior trainees do. Expectation setting and standardizing learning curves are important for robotic surgery training.

Tobacco use is not associated with increased risk of recurrent reflux 5 years after laparoscopic anti-reflux surgery.

INTRODUCTION: Tobacco use worsens gastrointestinal reflux disease (GERD). Smoking cessation improves GERD symptoms, but its impact on the efficacy of laparoscopic anti-reflux surgery (LARS) is unclear. In this retrospective cohort study, we hypothesized that non-smokers would demonstrate greater long-term improvements in disease-specific quality of life than active smokers. METHODS: Data were maintained in an IRB-approved prospective database, and patients were stratified according to tobacco use. Postoperative follow-up occurred in clinic and long-term follow-up via telephone interview. Outcomes measured were gastroesophageal health-related quality of life (GERD-HRQL) and GERD symptom scale (GERSS) scores, proton pump inhibitor (PPI) cessation, and satisfaction with surgery. RESULTS: Two hundred and thirty-five patients underwent primary LARS, and 31 (13%) were active smokers with 18 median pack-years [10-30]. Baseline PPI use (96% vs. 94%, p = 0.64), presence of a hiatal hernia (79% vs. 68%, p = 0.13), esophagitis (28% vs. 45%, p = 0.13), and DeMeester score (41.9 vs. 33.6, p = 0.47) were similar. Baseline GERD-HRQL and GERSS scores and their post-surgical decreases were also similar between groups. PPI cessation was achieved in 92% of non-smokers and 94% of smokers (p = 0.79), and GERD-HRQL scores decreased to 4 [1-7] and 5 [0-12], respectively (p = 0.53). After 59 [25-74] months, GERD-HRQL scores were 5 [2-11] and 2 [0-13] (p = 0.61) and PPI cessation was maintained in 69% and 79% of patients (p = 0.59). Satisfaction with surgery was similar between smokers and non-smokers (88% vs. 87%, p = 0.85). Female gender was significantly associated with increased improvements in GERD-HRQL (p < 0.01) and GERSS scores (p = 0.04) postoperatively but not at long-term follow-up. Patients without a hiatal hernia were less likely to achieve long-term PPI cessation compared to those with a hernia (OR 0.23, p < 0.01). CONCLUSIONS: After 5 years, smokers demonstrate similar symptom resolution, PPI cessation rates, and satisfaction with surgery as non-smokers. Active smoking does not appear to negatively impact long-term symptomatic outcomes of LARS.

Influence of sociodemographic variables on weight loss outcomes up to 3-years following primary bariatric surgery.

BACKGROUND: Our group has previously demonstrated that low socioeconomic status (SES) independently predicts ≤ 25th percentile weight-loss following bariatric surgery (BS). Given that sociodemographic metrics can be separated into income, education, and race, we sought to investigate how each metric independently impacted weight loss following BS. METHODS: Patients from a single academic institution who underwent bariatric surgery from 2014 to 2016 were retrospectively reviewed. Patients were stratified by income (low/high), education (≤ high school/ ≥ college), and race (black/white) then compared using univariate analysis. Variables significant on univariate analyses were subsequently used for a greedy 1:3 propensity score match with a caliper of 0.2. After matching, groups were balanced on demographics, social/medical/psychological history, and surgery type. Percent excess body weight loss for each post-operative time point was compared using appropriate univariate analyses. A p-value ≤ 0.05 was considered statistically significant. RESULTS: 571 patients were included. Unmatched race analysis demonstrated black patients were significantly younger (p = 0.05), single (p < 0.0001), in a lower income bracket (p < 0.0001), and experienced less weight loss at 2- (p = 0.01), 6- (p = 0.007), 12- (p = 0.008) and 24- (p = 0.007) months post-op. After matching, black patients continued to experience less weight loss at 2- (p = 0.01) and 6- (p = 0.03) months, which trended at 1 year (p = 0.06). Initial income analysis demonstrated patients in the low-income group (LIG) were more likely to be black (p < 0.0001), have ≤ high school education (p = 0.004), a higher preoperative BMI (p = 0.008), and lower postoperative weight loss at 2- (p = 0.001), 6- (p = 0.01), and 12- (p = 0.04) months after surgery. After matching, no differences were observed up to 3-years post-op. Analysis of education demonstrated no effect on weight loss in both unmatched and matched analyses. CONCLUSION: Unmatched analysis demonstrated that low income and race impact short-term weight loss after BS. After matching, however, race, not socioeconomic status, predicted weight loss outcomes up to 1-year.

Use of the MMPI-2 personality profile in predicting 30-day ED-visits and readmissions following primary bariatric surgery.

BACKGROUND: Minnesota Multiphasic Personality Inventory-2 (MMPI-2) is used for psychological screening of bariatric surgery (BS) candidates. To date, no studies have analyzed the relationship between MMPI-2 and early returns to hospital. The aim of this study was to determine whether high T scores on the MMPI-2 clinical scales were associated with early return to hospital after primary bariatric surgery. METHODS: Patients who completed an MMPI-2 evaluation, undergoing primary BS from 2014 to 2016 were evaluated. T score for the tested scales were collected and stratified into a high T score (T > 65) vs not (T < 65). The optimal 'cut-point' (specific number of high T scores predicting likelihood for 30-day ED-visit/hospital readmission) was calculated using Youden's Index (J) = Max(c) [sensitivity (c) + specificity (c) - 1], where c = number of scales with a T score > 65. Patients were stratified based on the optimal cut-point which was determined to be ≥ 4 high T scores. Univariate and multivariate logistic regression analyses were used to identify differences between groups and predictors for early ED-visits and hospital readmissions. RESULTS: 375 patients had psychological evaluations available for review. Patients were divided into those with ≥ 4 high T scores (Scr(≥4); n = 86) versus not (Scr (<4); n = 289). Multivariate analysis showed Scr(≥ 4) (aOR 2.99, CI 1.20-7.47; p = 0.019), bipolar disorder (aOR 4.82, CI 1.25-18.83; p = 0.022), and urgent hospital complications (aOR 6.81, CI 2.02-22.91; p = 0.002), were significant independent predictors of 30-day readmissions. Early ED-visits were significantly predicted by public insurance (aOR 3.30, CI 1.22-8.91; p = 0.019), but the effect of the Scr(≥4) profile (aOR 2.42, CI 0.97-6.09; p = 0.06), while influential, did not reach significance. CONCLUSION: Differences in personality traits may be associated increased 30-day readmissions following primary bariatric surgery. Our study represents a novel application of the MMPI-2.

Survey of the Preparation of Cardiovascular Emergency Medications for Adult Cardiovascular Anesthesia.

OBJECTIVES: To describe current practices and safety concerns regarding cardiac emergency medications in cardiac anesthesia. DESIGN: An anonymous survey with multiple-choice questions. SETTINGS: Online survey using Opinio platform. PARTICIPANTS: Cardiac anesthesiologists from United States and Canada. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Response rate was 12% (n = 320), with 78% of respondents from the United States and 22% from Canada. The majority of the respondents were experienced (66%), academic (60%), and worked in large cardiac institutions (81%). Most cardiac emergency medications were prepared in the operating room (53.4%), followed by the pharmacy (34%) and industry (8.2%). American respondents had more medications prepared by a pharmacy (53%) versus Canadian (10%, p < 0.001). The majority (85%) considered expiration time of cardiac medications prepared in the operating room to be more than 12 hours. Familiarity with the American Society of Anesthesiologists guidelines on labeling was 58%, other medication safety guidelines 25%, and 34% were not familiar with any guidelines. The majority used color-coded labeling (95%), and a minority (11%) used bar-code systems. Most respondents (69%) agreed that lack of availability of preprepared medications could compromise patient safety. Having to prepare medications by themselves was a concern for respondents based on distractions (66%), lack of availability for emergencies (53%), labeling errors (41%), incorrect concentration (36%), sterility (33%), and stability (30%). CONCLUSION: This survey found that cardiac emergency medications commonly are prepared in the operating room. The authors identified gaps in familiarity with parenteral medications safety guidelines. Most safety concerns could be addressed with the application of current medication safety guidelines.

Mathematical modeling and digital design of an intensified filtration-washing-drying unit for pharmaceutical continuous manufacturing.

This paper introduces a comprehensive mathematical model of a novel integrated filter-dryer carousel system, designed for continuously filtering, washing and drying a slurry stream into a crystals cake. The digital twin includes models for dead-end filtration, cake washing and convective cake drying, based on dynamic multi-component mass, energy and momentum balances. For set of feed conditions and control inputs, the model allows tracking the solvents and impurities content in the cake (critical quality attributes, CQAs) throughout the whole process. The model parameters were identified for the isolation of paracetamol from a multi-component slurry, containing a non-volatile impurity. The calibrated model was used for identifying the probabilistic design space and maximum throughput for the process, expressing the combinations of the carousel feed conditions and control inputs for which the probability of meeting the target CQAs is acceptable.

PharmaPy: An object-oriented tool for the development of hybrid pharmaceutical flowsheets.

Process design and optimization continue to provide computational challenges as the chemical engineering and process optimization communities seek to address more complex and larger scale applications. Software tools for digital design and flowsheet simulation are readily available for traditional chemical processing applications such as in commodity chemicals and hydrocarbon processing; however, tools for pharmaceutical manufacturing are much less well developed. This paper introduces, PharmaPy, a Python-based modelling platform for pharmaceutical manufacturing systems design and optimization. The versatility of the platform is demonstrated in simulation and optimization of both continuous and batch processes. The structure and features of a Python-based modeling platform, PharmaPy are presented. Illustrative examples are shown to highlight key features of the platform and framework.

Divergent TCR-Initiated Calcium Signals Govern Recruitment versus Activation of Human Alloreactive Effector Memory T Cells by Endothelial Cells.

Early human allograft rejection can be initiated when circulating human host versus graft Ag-specific CD8 and CD4 effector memory T cells directly recognize MHC class I and II, respectively, expressed on the luminal surface by endothelium lining graft blood vessels. TCR engagement triggers both graft entry (TCR-driven transendothelial migration or TEM) and production of proinflammatory cytokines. Both TCR-driven TEM and cytokine expression are known to depend on T cell enzymes, myosin L chain kinase, and calcineurin, respectively, that are activated by cytoplasmic calcium and calmodulin, but whether the sources of calcium that control these enzymes are the same or different is unknown. Using superantigen or anti-CD3 Ab presented by cultured human dermal microvascular cells to freshly isolated peripheral blood human effector memory T cells under conditions of flow (models of alloantigen recognition in a vascularized graft), we tested the effects of pharmacological inhibitors of TCR-activated calcium signaling pathways on TCR-driven TEM and cytokine expression. We report that extracellular calcium entry via CRAC channels is the dominant contributor to cytokine expression, but paradoxically these same inhibitors potentiate TEM. Instead, calcium entry via TRPV1, L-Type Cav, and pannexin-1/P2X receptors appear to control TCR-driven TEM. These data reveal new therapeutic targets for immunosuppression.

Disparities in Sources of Added Sugars and High Glycemic Index Foods in Diets of US Children, 2011-2016.

INTRODUCTION: Added sugars and high glycemic index (GI) foods might play a role in cardiometabolic pathogenesis. Our study aimed to describe the top sources of added sugars and types of high GI foods in diets of children by race/ethnicity. METHODS: We examined data for 3,112 children, aged 6 to 11 years from the National Health and Nutrition Examination Survey (NHANES), 2011 to 2016. Mean intake was estimated and linear regression models tested for differences by race/ethnicity. Population proportions for food sources were created and ranked, accounting for survey weighting when appropriate. RESULTS: Asian American and Mexican American children had the lowest reported added sugar intake. Cereals were observed to contribute highly to added sugar intake. Soft drinks did not contribute as much added sugar intake for Asian American children as it did for children of other races/ethnicities. Asian American children consumed significantly more high GI foods than other groups. Types of high GI foods differed meaningfully across racial/ethnic groups (ie, Mexican American: burritos/tacos; other Hispanic, White, and Black: pizza; Asian American: rice). Rice accounted for 37% of total high GI foods consumed by Asian American children. CONCLUSIONS: Sources of added sugars and types of high GI foods in children's diets vary across racial/ethnic groups. Targeting foods identified as top sources of added sugars for all race/ethnicities and focusing on substitution of whole grains may reduce obesity, diabetes, and related cardiometabolic risk more equitably.