Metformin reduces the clonal fitness of Dnmt3aR878H hematopoietic stem and progenitor cells by reversing their aberrant metabolic and epigenetic state.

Clonal hematopoiesis (CH) arises when a hematopoietic stem cell (HSC) acquires a mutation that confers a competitive advantage over wild-type (WT) HSCs, resulting in its clonal expansion. Individuals with CH are at an increased risk of developing hematologic neoplasms and a range of age-related inflammatory illnesses1-3. Therapeutic interventions that suppress the expansion of mutant HSCs have the potential to prevent these CH-related illnesses; however, such interventions have not yet been identified. The most common CH driver mutations are in the DNA methyltransferase 3 alpha (DNMT3A) gene with arginine 882 (R882) being a mutation hotspot. Here we show that murine hematopoietic stem and progenitor cells (HSPCs) carrying the Dnmt3aR878H/+ mutation, which is equivalent to human DNMT3AR882H/+, have increased mitochondrial respiration compared with WT cells and are dependent on this metabolic reprogramming for their competitive advantage. Importantly, treatment with metformin, an oral anti-diabetic drug with inhibitory activity against complex I in the electron transport chain (ETC), reduced the fitness of Dnmt3aR878H/+ HSCs. Through a multi-omics approach, we discovered that metformin acts by enhancing the methylation potential in Dnmt3aR878H/+ HSPCs and reversing their aberrant DNA CpG methylation and histone H3K27 trimethylation (H3K27me3) profiles. Metformin also reduced the fitness of human DNMT3AR882H HSPCs generated by prime editing. Our findings provide preclinical rationale for investigating metformin as a preventive intervention against illnesses associated with DNMT3AR882 mutation-driven CH in humans.

Large-scale efficient mid-wave infrared optoelectronics based on black phosphorus ink.

The mid-wave infrared (MWIR), ranging from 2 to 5 micrometers, is of substantial interest for chemical sensing, imaging, and spectroscopy. Black phosphorus (bP)-based MWIR light emitters and detectors have been shown to outperform the state-of-the-art for commercial devices due to the low Auger recombination coefficient of bP. However, the scalability of these devices remains a challenge. Here, we report a bP ink formula that preserves the exceptional MWIR optoelectronic properties of bP to deposit centimeter-scale, uniform, and pinhole free films with a photoluminescence quantum yield higher than competing III-V and II-VI semiconductors with similar bandgaps at high excitation regime. As a proof of concept, we use bP ink as a "phosphor" on a red commercial light-emitting diode to demonstrate bright MWIR light emission. We also show that these films can be integrated into heterostructure device architectures with electron and hole selective contacts for direct-injected light emission and detection in MWIR.

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.

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.

Anastomotic Stricture After Minimally Invasive Esophagectomy.

BACKGROUND: Despite improved outcomes, minimally invasive esophagectomy (MIE) continues to be associated with anastomotic strictures. Most resolve after a single dilation; however, some become refractory. Little is known about strictures after MIE in North America. METHODS: We performed a single-institution retrospective review of MIEs from 2015 to 2019. Primary outcomes were the proportion of patients requiring anastomotic dilation and the dilation rate per year. Univariate analyses of patients undergoing dilation by various risk factors were performed with nonparametric tests, and multivariate analyses of the dilation rate were conducted using generalized linear models. RESULTS: Of 391 included patients, 431 dilations were performed on 135 patients (34.5%, 3.2 dilations per patient who required at least 1 per patient). One complication occurred after dilation. Comorbidities, tumor histology, and tumor stage were not significantly associated with stricture. Three-field MIE was associated with a higher percentage of patients undergoing dilation (48.9% vs 27.1%, P < .001) and a higher rate of dilations (0.944 vs 0.441 dilations per year, P = .007) than 2-field MIE, and this association remained significant after controlling for covariates. When accounting for surgeon variability, this difference was no longer significant. Among patients with 1 or more dilations, those receiving dilation within 100 days of surgery needed more subsequent dilations (2.0 vs 0.6 dilations per year, P < .001). CONCLUSIONS: After controlling for multiple variables, a 3-field MIE approach was associated with a higher rate of repeat dilations in patients undergoing MIE. A shorter interval between esophagectomy and initial dilation is strongly associated with the need for repeated dilations.

Here it comes: Active forgetting triggered even just by anticipation of an impending event boundary.

Visual input arrives in a continuous stream, but we often experience the world as a sequence of discrete events - and the boundaries between events have important consequences for our mental lives. Perhaps the best example of this is that memory not only declines as a function of elapsed time, but is also impaired when crossing an event boundary - as when walking through a doorway. (This impairment may be adaptive, as when one "flushes" a cache in a computer program when completing a function.) But when exactly does this impairment occur? Existing work has not asked this question: based on a reasonable assumption that forgetting occurs when we cross event boundaries, memory has only been tested after this point. Here we demonstrate that even visual cues to an impending event boundary (that one has not yet crossed) suffice to trigger forgetting. Subjects viewed an immersive animation that simulated walking through a room. Before their walk, they saw a list of pseudo-words, and immediately after their walk, their recognition memory was tested. During their walk, some subjects passed through a doorway, while others did not (equating time and distance traveled). Memory was impaired (relative to the "no doorway" condition) not only when they passed through the doorway, but also when they were tested just before they would have crossed the doorway. Additional controls confirmed that this was due to the anticipation of event boundaries (rather than differential surprise or visual complexity). Visual processing may proactively "flush" memory to some degree in preparation for future events.

Highly multicolored light-emitting arrays for compressive spectroscopy.

Miniaturized, multicolored light-emitting device arrays are promising for applications in sensing, imaging, computing, and more, but the range of emission colors achievable by a conventional light-emitting diode is limited by material or device constraints. In this work, we demonstrate a highly multicolored light-emitting array with 49 different, individually addressable colors on a single chip. The array consists of pulsed-driven metal-oxide-semiconductor capacitors, which generate electroluminescence from microdispensed materials spanning a diverse range of colors and spectral shapes, enabling facile generation of arbitrary light spectra across a broad wavelength range (400 to 1400 nm). When combined with compressive reconstruction algorithms, these arrays can be used to perform spectroscopic measurements in a compact manner without diffractive optics. As an example, we demonstrate microscale spectral imaging of samples using a multiplexed electroluminescent array in conjunction with a monochrome camera.

Anomalous thickness dependence of photoluminescence quantum yield in black phosphorous.

Black phosphorus has emerged as a unique optoelectronic material, exhibiting tunable and high device performance from mid-infrared to visible wavelengths. Understanding the photophysics of this system is of interest to further advance device technologies based on it. Here we report the thickness dependence of the photoluminescence quantum yield at room temperature in black phosphorus while measuring the various radiative and non-radiative recombination rates. As the thickness decreases from bulk to ~4 nm, a drop in the photoluminescence quantum yield is initially observed due to enhanced surface carrier recombination, followed by an unexpectedly sharp increase in photoluminescence quantum yield with further thickness scaling, with an average value of ~30% for monolayers. This trend arises from the free-carrier to excitonic transition in black phosphorus thin films, and differs from the behaviour of conventional semiconductors, where photoluminescence quantum yield monotonically deteriorates with decreasing thickness. Furthermore, we find that the surface carrier recombination velocity of black phosphorus is two orders of magnitude lower than the lowest value reported in the literature for any semiconductor with or without passivation; this is due to the presence of self-terminated surface bonds in black phosphorus.

Performance comparisons of methylation and structural variants from low-input whole-genome methylation sequencing.

Aim: Whole-genome methylation sequencing carries both DNA methylation and structural variant information (single nucleotide variant [SNV]; copy number variant [CNV]); however, limited data is available on the reliability of obtaining this information simultaneously from low-input DNA using various library preparation and sequencing protocols. Methods: A HapMap NA12878 sample was sequenced with three protocols (EM-sequencing, QIA-sequencing and Swift-sequencing) and their performance was compared on CpG methylation measurement and SNV and CNV detection. Results: At low DNA input (10-25 ng), EM-sequencing was superior in almost all metrics except CNV detection where all protocols were similar. EM-sequencing captured the highest number of CpGs and true SNVs. Conclusion: EM-sequencing is suitable to detect methylation, SNVs and CNVs from single sequencing with low-input DNA.

Recalibration of a Deep Learning Model for Low-Dose Computed Tomographic Images to Inform Lung Cancer Screening Intervals.

Importance: Annual low-dose computed tomographic (LDCT) screening reduces lung cancer mortality, but harms could be reduced and cost-effectiveness improved by reusing the LDCT image in conjunction with deep learning or statistical models to identify low-risk individuals for biennial screening. Objective: To identify low-risk individuals in the National Lung Screening Trial (NLST) and estimate, had they been assigned a biennial screening, how many lung cancers would have been delayed 1 year in diagnosis. Design, Setting, and Participants: This diagnostic study included participants with a presumed nonmalignant lung nodule in the NLST between January 1, 2002, and December 31, 2004, with follow-up completed on December 31, 2009. Data were analyzed for this study from September 11, 2019, to March 15, 2022. Exposures: An externally validated deep learning algorithm that predicts malignancy in current lung nodules using LDCT images (Lung Cancer Prediction Convolutional Neural Network [LCP-CNN]; Optellum Ltd) was recalibrated to predict 1-year lung cancer detection by LDCT for presumed nonmalignant nodules. Individuals with presumed nonmalignant lung nodules were hypothetically assigned annual vs biennial screening based on the recalibrated LCP-CNN model, Lung Cancer Risk Assessment Tool (LCRAT + CT [a statistical model combining individual risk factors and LDCT image features]), and the American College of Radiology recommendations for lung nodules, version 1.1 (Lung-RADS). Main Outcomes and Measures: Primary outcomes included model prediction performance, the absolute risk of a 1-year delay in cancer diagnosis, and the proportion of people without lung cancer assigned a biennial screening interval vs the proportion of cancer diagnoses delayed. Results: The study included 10 831 LDCT images from patients with presumed nonmalignant lung nodules (58.7% men; mean [SD] age, 61.9 [5.0] years), of whom 195 were diagnosed with lung cancer from the subsequent screen. The recalibrated LCP-CNN had substantially higher area under the curve (0.87) than LCRAT + CT (0.79) or Lung-RADS (0.69) to predict 1-year lung cancer risk (P < .001). If 66% of screens with nodules were assigned to biennial screening, the absolute risk of a 1-year delay in cancer diagnosis would have been lower for recalibrated LCP-CNN (0.28%) than LCRAT + CT (0.60%; P = .001) or Lung-RADS (0.97%; P < .001). To delay only 10% of cancer diagnoses at 1 year, more people would have been safely assigned biennial screening under LCP-CNN than LCRAT + CT (66.4% vs 40.3%; P < .001). Conclusions and Relevance: In this diagnostic study evaluating models of lung cancer risk, a recalibrated deep learning algorithm was most predictive of 1-year lung cancer risk and had least risk of 1-year delay in cancer diagnosis among people assigned biennial screening. Deep learning algorithms could prioritize people for workup of suspicious nodules and decrease screening intensity for people with low-risk nodules, which may be vital for implementation in health care systems.

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.

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.

Assessment of Herb-Drug Interaction Potential of Five Common Species of Licorice and Their Phytochemical Constituents.

The dried roots and rhizomes of Glycyrrhiza species (G. glabra, G. uralensis and G. inflata), commonly known as licorice, have long been used in traditional medicine. In addition, two other species, G. echinata and G. lepidota are also considered "licorice" in select markets. Currently, licorice is an integral part of several botanical drugs and dietary supplements. To probe the botanicals' safety, herb-drug interaction potential of the hydroethanolic extracts of five Glycyrrhiza species and their key constituents was investigated by determining their effects on pregnane X receptor, aryl hydrocarbon receptor, two major cytochrome P450 isoforms (CYP3A4 and CYP1A2), and the metabolic clearance of antiviral drugs. All extracts enhanced transcriptional activity of PXR and AhR (>2-fold) and increased the enzyme activity of CYP3A4 and CYP1A2. The highest increase in CYP3A4 was seen with G. echinata (4-fold), and the highest increase in CYP1A2 was seen with G. uralensis (18-fold) and G. inflata (16-fold). Among the constituents, glabridin, licoisoflavone A, glyasperin C, and glycycoumarin activated PXR and AhR, glabridin being the most effective (6- and 27-fold increase, respectively). Licoisoflavone A, glyasperin C, and glycycoumarin increased CYP3A4 activity while glabridin, glyasperin C, glycycoumarin, and formononetin increased CYP1A2 activity (>2-fold). The metabolism of antiretroviral drugs (rilpivirine and dolutegravir) was increased by G. uralensis (2.0 and 2.5-fold) and its marker compound glycycoumarin (2.3 and 1.6-fold). The metabolism of dolutegravir was also increased by G. glabra (2.8-fold) but not by its marker compound, glabridin. These results suggest that licorice and its phytochemicals could affect the metabolism and clearance of certain drugs that are substrates of CYP3A4 and CYP1A2.Supplemental data for this article is available online at https://doi.org/10.1080/19390211.2022.2050875 .

Techno-economic analysis of dynamic, end-to-end optimal pharmaceutical campaign manufacturing using PharmaPy.

Increased interest in the pharmaceutical industry to transition from batch to continuouos manufacturing motivates the use of digital frameworks that allow systematic comparison of candidate process configurations. This paper evaluates the technical and economic feasibility of different end-to-end optimal process configurations, viz. batch, hybrid and continuous, for small-scale manufacturing of an active pharmaceutical ingredient. Production campaigns were analyzed for those configurations containing continuous equipment, where significant start-up effects are expected given the relatively short campaign times considered. Hybrid operating mode was found to be the most attractive process configuration at intermediate and large annual production targets, which stems from combining continuous reactors and semi-batch vaporization equipment. Continuous operation was found to be more costly, due to long stabilization times of continuous crystallization, and thermodynamic limitations of flash vaporization. Our work reveals the benefits of systematic digital evaluation of process configurations that operate under feasible conditions and compliant product quality attributes.

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.

Accelerating integration of tobacco use treatment in the context of lung cancer screening: Relevance and application of implementation science to achieving policy and practice.

Based on the findings from the National Lung Screening Trial, the U.S. Preventive Services Task Force recommends annual low dose computed tomography (LDCT) lung cancer screening (LCS) among high-risk adults. Approximately 54% of individuals seeking LCS report current cigarette smoking. Effective smoking cessation interventions, offered at the time of LCS, enhances the health benefits of screening that are attributable to reductions in lung cancer overall and tobacco-related mortality. Considering these data, the Centers for Medicare & Medicaid Services' (CMS) 2015 decision to cover LCS with LDCT required that radiology imaging facilities make tobacco cessation interventions available for people who smoke. In February 2022, CMS reversed their 2015 coverage requirement for delivering tobacco use treatment at the time of LDCT; CMS retained the requirement for counseling during the shared decision-making visit prior to the exam. The policy change does not diminish the importance of offering high-quality tobacco cessation services in conjunction with routine LDCT for LCS. However, LCS programs face a range of barriers to implementing tobacco use treatment in their settings. As a result, implementation has lagged. Closing the "evidence to practice" gap is the focus of implementation science, a field that offers a set of rigorous methods and a systematic approach to identifying and overcoming contextual barriers to implementing evidence-based guidelines in a range of clinical settings. In this paper, we describe how implementation science frameworks and methods can be used to help guide LCS programs in their efforts to integrate tobacco use treatment and discuss policy changes needed to further facilitate the delivery of TUT as an essential component of the LCS process.

Lung cancer is the leading cause of cancer death in the United States. There is strong evidence, from a large number of international studies, that lung cancer screening for people who meet specific criteria, can reduce lung cancer-related deaths. Based on these findings, the Centers for Medicare and Medicaid decided to provide insurance coverage for lung cancer screening for eligible patients. This includes people aged 50­80 years who have a 20 pack-year smoking history and currently smoke or have quit within the past 15 years. Over 50% of people who seek lung cancer screening report current cigarette smoking. Studies show that offering these smokers support to quit at the time of screening can further increase survival rates by reducing both deaths from lung cancer and other tobacco-related diseases. Unfortunately, lung cancer screening programs do not consistently provide effective treatments to help smokers quit. This is a missed opportunity to engage smokers in quitting when the health risk of tobacco use is most salient, and therefore smokers may be more willing to engage in tobacco use treatment. This paper provides detailed guidance on how programs can implement high quality tobacco use treatment services in conjunction with lung cancer screening.

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.

Costimulators expressed on human endothelial cells modulate antigen-dependent recruitment of circulating T lymphocytes.

Endothelial cells (ECs) can present antigens to circulating effector memory T cells (TEM) and to regulatory T cells (T regs), triggering antigen-specific extravasation at specific sites where foreign antigens are introduced, e.g. by infection or transplantation. We model human antigen-induced transendothelial migration (TEM) using presentation of superantigen by cultured human dermal microvascular (HDM)ECs to isolated resting human peripheral blood T cell subpopulations or to T effector cells activated in vitro. T cell receptor (TCR)-mediated cytokine synthesis, a common assay of T cell activation by antigen, is modulated by antigen-independent signals provided by various positive or negative costimulator proteins (the latter known as checkpoint inhibitors) expressed by antigen presenting cells, including ECs. We report here that some EC-expressed costimulators also modulate TCR-TEM, but effects differ between TEM and cytokine production and among some T cell types. Blocking EC LFA-3 interactions with TEM CD2 boosts TEM but reduces cytokine production. Blocking EC ICOS-L interactions with TEM CD28 (but not ICOS) reduces both responses but these involve distinct CD28-induced signals. Activated CD4+ T effector cells no longer undergo TCR-TEM. Engagement of T cell CD28 by EC ICOS-L increases TCR-TEM by activated CD8 effectors while engagement of OX40 promotes TCR-TEM by activated CD4 T regs. B7-H3 mostly affects TEM of resting TEM and some checkpoint inhibitors affect cytokine synthesis or TEM depending upon subtype. Our data suggest that blockade or mimicry of costimulators/checkpoint inhibitors in vivo, clinically used to modulate immune responses, may act in part by modulating T cell homing.

Development of a Mobile App for Clinical Research: Challenges and Implications for Investigators.

Advances in mobile app technologies offer opportunities for researchers to feasibly collect a large amount of patient data that were previously inaccessible through traditional clinical research methods. Collection of data via mobile devices allows for several advantages, such as the ability to continuously gather data outside of research facilities and produce a greater quantity of data, making these data much more valuable to researchers. Health services research is increasingly incorporating mobile health (mHealth), but collecting these data in current research institutions is not without its challenges. Our paper uses a specific example to depict specific challenges of mHealth research and provides recommendations for investigators looking to incorporate digital app technologies and patient-collected digital data into their studies. Our experience describes how clinical researchers should be prepared to work with variable software and mobile app development timelines; research institutions that are interested in participating in mHealth research need to invest in supporting information technology infrastructures in order to be a part of the growing field of mHealth and gain access to valuable patient-collected data.

A Biohybrid Material With Extracellular Matrix Core and Polymeric Coating as a Cell Honing Cardiovascular Tissue Substitute.

Objective: To investigate the feasibility of a hybrid material in which decellularized pericardial extracellular matrix is functionalized with polymeric nanofibers, for use as a cardiovascular tissue substitute. Background: A cardiovascular tissue substitute, which is gradually resorbed and is replaced by host's native tissue, has several advantages. Especially in children and young adults, a resorbable material can be useful in accommodating growth, but also enable rapid endothelialization that is necessary to avoid thrombotic complications. In this study, we report a hybrid material, wherein decellularized pericardial matrix is functionalized with a layer of polymeric nanofibers, to achieve the mechanical strength for implantation in the cardiovascular system, but also have enhanced cell honing capacity. Methods: Pericardial sacs were decellularized with sodium deoxycholate, and polycaprolactone-chitosan fibers were electrospun onto the matrix. Tissue-polymer interaction was evaluated using spectroscopic methods, and the mechanical properties of the individual components and the hybrid material were quantified. In-vitro blood flow loop studies were conducted to assess hemocompatibility and cell culture methods were used to assess biocompatibility. Results: Encapsulation of the decellularized matrix with 70 µm thick matrix of polycaprolactone-chitosan nanofibers, was feasible and reproducible. Spectroscopy of the cross-section depicted new amide bond formation and C-O-C stretch at the interface. An average peel strength of 56.13 ± 11.87 mN/mm2 was measured, that is sufficient to withstand a high shear of 15 dynes/cm2 without delamination. Mechanical strength and extensibility ratio of the decellularized matrix alone were 18,000 ± 4,200 KPa and 0.18 ± 0.03% whereas that of the hybrid was higher at 20,000 ± 6,600 KPa and 0.35 ± 0.20%. Anisotropy index and stiffness of the biohybrid were increased as well. Neither thrombus formation, nor platelet adhesion or hemolysis was measured in the in-vitro blood flow loop studies. Cellular adhesion and survival were adequate in the material. Conclusion: Encapsulating a decellularized matrix with a polymeric nanofiber coating, has favorable attributes for use as a cardiovascular tissue substitute.