Academic cardiac electrophysiologists' perspectives on sleep apnea care.

PURPOSE: Obstructive sleep apnea syndrome (OSAS) is an important, modifiable risk factor in the pathophysiology of arrhythmias including atrial fibrillation (AF). The purpose of the study was to evaluate cardiac electrophysiologists' (EPs) perception of OSAS. METHODS: We designed a 27-item online Likert scale-based survey instrument entailing several domains: (1) relevance of OSAS in EP practice, (2) OSAS screening and diagnosis, (3) perception on treatments for OSAS, (4) opinion on the OSAS care model. The survey was distributed to 89 academic EP programs in the USA and Canada. While the survey instrument questions refer to the term sleep apnea (SA), our discussion of the diagnosis, management, and research on the sleep disorder is more accurately described with the term OSAS. RESULTS: A total of 105 cardiac electrophysiologists from 49 institutions responded over a 9-month period. The majority of respondents agreed that sleep apnea (SA) is a major concern in their practice (94%). However, 42% reported insufficient education on SA during training. Many (58%) agreed that they would be comfortable managing SA themselves with proper training and education and 66% agreed cardiac electrophysiologists should become more involved in management. Half of EPs (53%) were not satisfied with the sleep specialist referral process. Additionally, a majority (86%) agreed that trained advanced practice providers should be able to assess and manage SA. Time constraints, lack of knowledge, and the referral process are identified as major barriers to EPs becoming more involved in SA care. CONCLUSIONS: We found that OSAS is widely recognized as a major concern for EP. However, incorporation of OSAS care in training and routine practice lags. Barriers to increased involvement include time constraints and education. This study can serve as an impetus for innovation in the cardiology OSAS care model.

Quantitative assessment of Siglec-15 expression in lung, breast, head, and neck squamous cell carcinoma and bladder cancer.

Immune checkpoint blockade with programmed cell death (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors has resulted in significant progress in the treatment of various cancer types. However, not all patients respond to PD-1/PD-L1 blockade, underscoring the importance of identifying new potential targets for immunotherapy. One promising target is the immune system modulator Siglec-15. In this study, we assess Siglec-15 expression in solid tumors, with a focus on lung, breast, head and neck squamous and bladder cancers. Using quantitative immunofluorescence (QIF) with a previously validated antibody, we found increased Siglec-15 expression in both tumor and immune cells in all the four cancer types. Siglec-15 was seen to be predominantly expressed by the stromal immune cells (83% in lung, 70.1% in breast, 95.2% in head and neck squamous cell and 89% in bladder cancers). Considerable intra-tumoral heterogeneity was noted across cancer types. As previously described for non-small cell lung cancer (NSCLC), Siglec-15 expression was seen to be mutually exclusive to PD-L1 in all the four cancer types, although this differential expression was maintained but somewhat diminished in head and neck squamous cell carcinoma (HNSCC). Siglec-15 was not prognostic either for overall survival (OS) or progression-free survival (PFS). In summary, we show broad expression of this potential immune modulatory target in a wide range of cancer types. These data suggest potential future clinical trials in these tumor types.

Development of an immunohistochemical assay for Siglec-15.

Siglec-15, a member of sialic-acid binding immunoglobulin type lectins, is normally expressed by myeloid cells and upregulated in some human cancers and represents a promising new target for immunotherapy. While PD-L1 blockade is an important strategy for immunotherapy, its effectiveness is limited. The expression of Siglec-15 has been demonstrated to be predominantly mutually exclusive to PD-L1 in certain cancer histologies. Thus, there is significant opportunity for Siglec-15 as an immunotherapeutic target for patients that do not respond to PD-1/PD-L1 inhibition. The aim of this study was to prospectively develop an immunohistochemical (IHC) assay for Siglec-15 to be used as a companion diagnostic for future clinical trials. Here, we create and validate an IHC assay with a novel recombinant antibody to the cytoplasmic domain of Siglec-15. To find an enriched target, this antibody was first used in a quantitative fluorescence (QIF) assay to screen a broad range of tumor histologies to determine tumor types where Siglec-15 demonstrated high expression. Based on this and previous data, we focused on development of a chromogenic IHC assay for lung cancer. Then we developed a scoring system for this assay that has high concordance amongst pathologist readers. We then use this chromogenic IHC assay to test the expression of Siglec-15 in two cohorts of NSCLC. We found that this assay shows a higher level of staining in both tumor and immune cells compared to previous QIF assays utilizing a polyclonal antibody. However, similar to that study, only a small percentage of positive Siglec-15 cases showed high expression for PD-L1. This validated assay for Siglec-15 expression may support development of a companion diagnostic assay to enrich for patients expressing the Siglec-15 target for therapy.

Chief Residency Selection in Internal Medicine: Who Is Left Out?

Little progress has been made in improving racial, gender, or intersectional diversity within academic internal medicine (IM). Chief Residency fulfills a unique opportunity to target diversity efforts; Chief Residents (CR) are integral in creating an inclusive environment and support system for IM trainees, and the position serves as a steppingstone for future leadership positions within academia. However, the CR selection process often lacks transparency and includes steps that are fraught with bias, thereby disadvantaging underrepresented minority groups from gaining important experience needed to climb the academic ladder. We describe a more standardized selection process that will improve recruitment and selection of more diverse CRs and ultimately improve the recruitment, retention, and promotion of more diverse faculty within academic internal medicine. Key recommendations include an open call for applications, the use of standardized and structured interviews, and the formation of a diverse selection committee to conduct a transparent selection process based on explicitly defined criteria.

What is the optimal prophylaxis against postoperative deep vein thrombosis in the living donor to avoid complications and enhance recovery? - A systematic review of the literature and expert panel recommendations.

BACKGROUND: Deep venous thrombosis (DVT) prophylaxis is often employed to prevent the potentially serious complication of pulmonary embolism (PE). However, little data exist regarding the optimal DVT prophylaxis strategy for living donors undergoing hepatectomy for living donor liver transplantation. Here we present our consensus statement on DVT prophylaxis for living donors undergoing hepatectomy. OBJECTIVES: To identify the optimal DVT prophylaxis strategy, which reduces, risk of complications in living liver donors, and enhances recovery. METHODS: Systematic review following PRISMA guidelines and recommendations using the GRADE approach derived from an international expert panel. Of interest was the impact of DVT prophylaxis or lack of prophylaxis on living donors undergoing hepatectomy and subsequent rates of DVT, PE, and hemorrhagic complications. PROSPERO ID: CRD42021260720 RESULTS: The review of the literature identified three studies, which directly addressed thrombogenesis following living donor hepatectomy. All studies were observational in nature without randomization into treatments. The rate of DVT-PE in unscreened living donors with chemoprophylaxis was 5%. Furthermore, thromboelastography of living donors demonstrated sustained hypercoagulability for 50% of donors 10 days postoperatively. In line with CHEST (The American College of Chest Physicians) guidelines of chemoprophylaxis for surgical procedures with 3% or greater risk of DVT-PE, we conclude that a minimum of 10 days of postoperative chemoprophylaxis with unfractionated heparin or low-molecular weight heparin is recommended for patients undergoing living donor hepatectomy. The quality of evidence (QOE) for these recommendations based on the GRADE criteria is low, with a Grade of Recommendation of Strong. CONCLUSIONS: Chemoprophylaxis for DVT following living donor hepatectomy is associated with reduced adverse thrombotic events, (Quality of Evidence; Low | Grade of Recommendation; Strong).

Patient Safety During Anesthesia: 100 Years of Progress Documented in Anesthesia & Analgesia.

Anesthesiology has evolved to be a leader in addressing patient safety. Our specialty has overcome serious morbidities including explosions, fires, organ toxicity, fatal arrhythmias, and hypoxic brain damage. Anesthesia safety has been significantly improved due to modern drug development, technical advances, and a strong leadership willing to apply human factors and systems' research strategies, but patient safety concerns remain at the forefront as we strive to improve patient care even further. This year marks the centennial year since the publication of the first issue of Anesthesia & Analgesia. Today, the International Anesthesia Research Society (IARS) and Anesthesia & Analgesia continue to advance the boundaries of patient safety by disseminating practice standards, serving as a forum for novel ideas, and supporting research advancements. This review will discuss several topics published in Anesthesia & Analgesia that exemplify steady changes leading to the safe practices that we rely on currently as well as other IARS activities that have advocated and elevated patient safety within the specialty.

Cardiac point-of-care ultrasound publication trends.

INTRODUCTION: Cardiac point-of-care ultrasound (c-POCUS) is an increasingly implemented diagnostic tool with the potential to guide clinical management. We sought to characterize and analyze the existing c-POCUS literature with a focus on the temporal trends and differences across specialties. METHODS: A literature search for c-POCUS and related terms was conducted using Ovid (MEDLINE and Embase) and Web of Science databases through 2020. Eligible publications were classified by publication type and topic, author specialty, geographical region of senior author, and journal specialty. RESULTS: The initial search produced 1761 potential publications. A strict definition of c-POCUS yielded a final total of 574 cardiac POCUS manuscripts. A yearly increase in c-POCUS publications was observed. Nearly half of publications were original research (48.8%) followed by case report or series (22.8%). Most publications had an emergency medicine senior author (38.5%), followed by cardiology (20.8%), anesthesiology (12.5%), and critical care (12.5%). The proportion authored by emergency medicine and cardiologists has decreased over time while those by anesthesiology and critical care has generally increased, particularly over the last decade. First authorship demonstrated a similar trend. Articles were published in emergency medicine (24.4%) and cardiology journals (20.5%) with comparable frequency. CONCLUSION: The annual number of c-POCUS publications has steadily increased over time, reflecting the increased recognition and utilization of c-POCUS. This study can help inform clinicians of the current state of c-POCUS and augment the discussion surrounding barriers to continued adoption across all specialties.

Binding of the regulatory domain of MutL to the sliding ß-clamp is species specific.

The ß-clamp is a protein hub central to DNA replication and fork management. Proteins interacting with the ß-clamp harbor a conserved clamp-binding motif that is often found in extended regions. Therefore, clamp interactions have -almost exclusively- been studied using short peptides recapitulating the binding motif. This approach has revealed the molecular determinants that mediate the binding but cannot describe how proteins with clamp-binding motifs embedded in structured domains are recognized. The mismatch repair protein MutL has an internal clamp-binding motif, but its interaction with the ß-clamp has different roles depending on the organism. In Bacillus subtilis, the interaction stimulates the endonuclease activity of MutL and it is critical for DNA mismatch repair. Conversely, disrupting the interaction between Escherichia coli MutL and the ß-clamp only causes a mild mutator phenotype. Here, we determined the structures of the regulatory domains of E. coli and B. subtilis MutL bound to their respective ß-clamps. The structures reveal different binding modes consistent with the binding to the ß-clamp being a two-step process. Functional characterization indicates that, within the regulatory domain, only the clamp binding motif is required for the interaction between the two proteins. However, additional motifs beyond the regulatory domain may stabilize the interaction. We propose a model for the activation of the endonuclease activity of MutL in organisms lacking methyl-directed mismatch repair.

B7-H4 Modulates Regulatory CD4+ T Cell Induction and Function via Ligation of a Semaphorin 3a/Plexin A4/Neuropilin-1 Complex.

The potent immune regulatory function of an agonistic B7-H4-Ig fusion protein (B7-H4Ig) has been demonstrated in multiple experimental autoimmune models; however, the identity of a functional B7-H4 receptor remained unknown. The biological activity of B7-H4 is associated with decreased inflammatory CD4+ T cell responses as supported by a correlation between B7-H4-expressing tumor-associated macrophages and Foxp3+ T cells within the tumor microenvironment. Recent data indicate that members of the semaphorin (Sema)/plexin/neuropilin (Nrp) family of proteins both positively and negatively modulate immune cell function. In this study, we show that B7-H4 binds the soluble Sema family member Sema3a. Additionally, B7-H4Ig-induced inhibition of inflammatory CD4+ T cell responses is lost in both Sema3a functional mutant mice and mice lacking Nrp-1 expression in Foxp3+ T cells. These findings indicate that B7-H4Ig binds to Sema3a, which acts as a functional bridge to stimulate an Nrp-1/Plexin A4 heterodimer to form a functional immunoregulatory receptor complex resulting in increased levels of phosphorylated PTEN and enhanced regulatory CD4+ T cell number and function.

Assessment Scores of a Mock Objective Structured Clinical Examination Administered to 99 Anesthesiology Residents at 8 Institutions.

BACKGROUND: Objective Structured Clinical Examinations (OSCEs) are used in a variety of high-stakes examinations. The primary goal of this study was to examine factors influencing the variability of assessment scores for mock OSCEs administered to senior anesthesiology residents. METHODS: Using the American Board of Anesthesiology (ABA) OSCE Content Outline as a blueprint, scenarios were developed for 4 of the ABA skill types: (1) informed consent, (2) treatment options, (3) interpretation of echocardiograms, and (4) application of ultrasonography. Eight residency programs administered these 4 OSCEs to CA3 residents during a 1-day formative session. A global score and checklist items were used for scoring by faculty raters. We used a statistical framework called generalizability theory, or G-theory, to estimate the sources of variation (or facets), and to estimate the reliability (ie, reproducibility) of the OSCE performance scores. Reliability provides a metric on the consistency or reproducibility of learner performance as measured through the assessment. RESULTS: Of the 115 total eligible senior residents, 99 participated in the OSCE because the other residents were unavailable. Overall, residents correctly performed 84% (standard deviation [SD] 16%, range 38%-100%) of the 36 total checklist items for the 4 OSCEs. On global scoring, the pass rate for the informed consent station was 71%, for treatment options was 97%, for interpretation of echocardiograms was 66%, and for application of ultrasound was 72%. The estimate of reliability expressing the reproducibility of examinee rankings equaled 0.56 (95% confidence interval [CI], 0.49-0.63), which is reasonable for normative assessments that aim to compare a resident's performance relative to other residents because over half of the observed variation in total scores is due to variation in examinee ability. Phi coefficient reliability of 0.42 (95% CI, 0.35-0.50) indicates that criterion-based judgments (eg, pass-fail status) cannot be made. Phi expresses the absolute consistency of a score and reflects how closely the assessment is likely to reproduce an examinee's final score. Overall, the greatest (14.6%) variance was due to the person by item by station interaction (3-way interaction) indicating that specific residents did well on some items but poorly on other items. The variance (11.2%) due to residency programs across case items was high suggesting moderate variability in performance from residents during the OSCEs among residency programs. CONCLUSIONS: Since many residency programs aim to develop their own mock OSCEs, this study provides evidence that it is possible for programs to create a meaningful mock OSCE experience that is statistically reliable for separating resident performance.

Rapid adaptation to foreign-accented speech and its transfer to an unfamiliar talker.

How fast can listeners adapt to unfamiliar foreign accents? Clarke and Garrett [J. Acoust. Soc. Am. 116, 3647-3658 (2004)] (CG04) reported that native-English listeners adapted to foreign-accented English within a minute, demonstrating improved processing of spoken words. In two web-based experiments that closely follow the design of CG04, the effects of rapid accent adaptation are examined and its generalization is explored across talkers. Experiment 1 replicated the core finding of CG04 that initial perceptual difficulty with foreign-accented speech can be attenuated rapidly by a brief period of exposure to an accented talker. Importantly, listeners showed both faster (replicating CG04) and more accurate (extending CG04) comprehension of this talker. Experiment 2 revealed evidence that such adaptation transferred to a different talker of a same accent. These results highlight the rapidity of short-term accent adaptation and raise new questions about the underlying mechanism. It is suggested that the web-based paradigm provides a useful tool for investigations in speech adaptation.

Differences in the subgingival microbial population of chronic periodontitis in subjects with and without type 2 diabetes mellitus-a systematic review.

OBJECTIVES: The purpose of this systematic review was to evaluate the available evidence in the literature in regard to the subgingival microbial population of chronic periodontitis in subjects with type 2 diabetes mellitus (T2DM+PD) compared to non-diabetic subjects (NDM+PD). MATERIALS AND METHODS: A literature search was conducted at Ovid MEDLINE and EMBASE database from 1980 to 2016, supplemented by hand searching as needed. Studies presenting with at least one of the primary outcomes (presence of any subgingival microorganisms, proportion and/or the amount of any subgingival plaque bacteria in T2DM+PD versus NDM+PD) were included. Screening, data extraction and quality assessment were conducted independently and in duplicate. RESULTS: From 611 citations, 19 full-text papers were screened and 11 articles were included for critical appraisal by both reviewers. Some evidence of a difference in the microbial profile between chronic PD subjects with and without T2DM was identified. The strength of evidence is strongest in Tannerella forthysia (T .forsythia) which was reported to be less frequent in the diabetic (T2DM+PD) group in five of the studies, followed by a weaker strength of evidence for other periodontal pathogens such as Porphyromonas gingivalis (P. gingivalis) and Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans), which were also found less frequent in the diabetic (T2DM+PD) group . CONCLUSION: Only few studies have compared T2DM+PD with NDM+PD. It is therefore strongly recommended that further studies which include four distinct groups of participants (NDM+PD, T2DM+PD, NDM+NPD, T2DM+NPD) instead of using intra-subject comparisons between healthy and diseased sites of the same subjects. CLINICAL RELEVANCE: Differences in bacterial populations of T2DM+PD in comparison to NDM+PD subjects may indicate the need of different protocols for the treatment of the diabetic patients with periodontal disease.

Current knowledge and perspectives of Paenibacillus: a review.

Isolated from a wide range of sources, the genus Paenibacillus comprises bacterial species relevant to humans, animals, plants, and the environment. Many Paenibacillus species can promote crop growth directly via biological nitrogen fixation, phosphate solubilization, production of the phytohormone indole-3-acetic acid (IAA), and release of siderophores that enable iron acquisition. They can also offer protection against insect herbivores and phytopathogens, including bacteria, fungi, nematodes, and viruses. This is accomplished by the production of a variety of antimicrobials and insecticides, and by triggering a hypersensitive defensive response of the plant, known as induced systemic resistance (ISR). Paenibacillus-derived antimicrobials also have applications in medicine, including polymyxins and fusaricidins, which are nonribosomal lipopeptides first isolated from strains of Paenibacillus polymyxa. Other useful molecules include exo-polysaccharides (EPS) and enzymes such as amylases, cellulases, hemicellulases, lipases, pectinases, oxygenases, dehydrogenases, lignin-modifying enzymes, and mutanases, which may have applications for detergents, food and feed, textiles, paper, biofuel, and healthcare. On the negative side, Paenibacillus larvae is the causative agent of American Foulbrood, a lethal disease of honeybees, while a variety of species are opportunistic infectors of humans, and others cause spoilage of pasteurized dairy products. This broad review summarizes the major positive and negative impacts of Paenibacillus: its realised and prospective contributions to agriculture, medicine, process manufacturing, and bioremediation, as well as its impacts due to pathogenicity and food spoilage. This review also includes detailed information in Additional files 1, 2, 3 for major known Paenibacillus species with their locations of isolation, genome sequencing projects, patents, and industrially significant compounds and enzymes. Paenibacillus will, over time, play increasingly important roles in sustainable agriculture and industrial biotechnology.

Facilitators and Barriers of Heart Surgery Discharge: Patients' and Nurses' Narrative Accounts.

BACKGROUND: Optimal patient recovery from open-heart surgery relies on effective discharge planning and education. However, the nature of the discharge experience has not been clearly described. OBJECTIVE: The study purpose is to explore patients' and nurses' narrative accounts of the facilitators and barriers of heart surgery discharge. METHODS: A qualitative study was employed using a narrative methodology that elicited and analyzed stories. This research was conducted in a large, urban hospital in Ontario, Canada. A total of 17 patients and nurses were recruited. Five female and 5 male patients were recruited from a preoperative clinic. Ages ranged from 37 to 80 years. Seven nurses were recruited from inpatient cardiovascular units. They had 2 to 19 years of cardiovascular nursing experience. Semistructured, narrative-based interviews were conducted. Two interviews were conducted with each patient at 1 week after discharge and at 4 to 6 weeks. One interview was conducted with each nurse. RESULTS: Findings indicate that although the preoperative period was identified as an effective time for discharge preparation, the patient's cognitive capacity was limited during the postoperative phase of surgery. Both nurses and patients also found that insufficient time impeded the discharge process and limited individualized discussions. The structured and standardized delivery of discharge information affected patients' capacity to apply it to the particularities in their own lives and homes. The fostering of therapeutic relationships created a space where patients felt comfortable sharing their concerns and nurses learned more about patients and thus could better tailor the discharge approach. CONCLUSIONS: Study recommendations include group and scenario-based education in which patients and nurses brainstorm about how to apply the discharge information to the particularities of patients' lives and homes. Provision of support needs to be bolstered during the home period, where patients have timely opportunities to discuss their concerns and questions with practitioners or possibly peers.

B7-DC-Ig enhances vaccine effect by a novel mechanism dependent on PD-1 expression level on T cell subsets.

Programmed death receptor 1 (PD-1) is an important signaling molecule often involved in tumor-mediated suppression of activated immune cells. Binding of this receptor to its ligands, B7-H1 (PD-L1) and B7-DC (PD-L2), attenuates T cell activation, reduces IL-2 and IFN-γ secretion, decreases proliferation and cytotoxicity, and induces apoptosis. B7-DC-Ig is a recombinant protein that binds and targets PD-1. It is composed of an extracellular domain of murine B7-DC fused to the Fc portion of murine IgG2a. In this study, we demonstrate that B7-DC-Ig can enhance the therapeutic efficacy of vaccine when combined with cyclophosphamide. We show that this combination significantly enhances Ag-specific immune responses and leads to complete eradication of established tumors in 60% of mice and that this effect is CD8 dependent. We identified a novel mechanism by which B7-DC-Ig exerts its therapeutic effect that is distinctly different from direct blocking of the PD-L1-PD-1 interaction. In this study, we demonstrate that there are significant differences between levels and timing of surface PD-1 expression on different T cell subsets. We found that these differences play critical roles in anti-tumor immune effect exhibited by B7-DC-Ig through inhibiting proliferation of PD-1(high) CD4 T cells, leading to a significant decrease in the level of these cells, which are enriched for regulatory T cells, within the tumor. In addition, it also leads to a decrease in PD-1(high) CD8 T cells, tipping the balance toward nonexhausted functional PD-1(low) CD8 T cells. We believe that the PD-1 expression level on T cells is a crucial factor that needs to be considered when designing PD-1-targeting immune therapies.

Extrinsic Positive End-Expiratory Pressure due to Failure of the Positive-Pressure Relief Valve Within the Scavenging System: A Case Report.

The anesthesia gas scavenging system (AGSS) removes waste gases from the anesthesia machine. Within the AGSS, safety features prevent excessive pressures from affecting ventilation. Although the literature contains reports describing failures of the AGSS, we found no reports of positive-pressure relief valve (PPRV) malfunctions. We encountered 2 cases of extrinsic positive end-expiratory pressure (PEEP) resulting from a malfunctioning PPRV. Both cases suffered delayed identification intraoperatively but patients did not experience postoperative complications. These cases highlight the importance of daily scavenger system prechecks, the potential physiologic implications of AGSS malfunctions, and the importance of preplanned contingencies for machine failure.

Bisphosphonate therapy in the management of diffuse sclerosing osteomyelitis of the mandible: a systematic review and narrative synthesis.

Background: Diffuse sclerosing osteomyelitis (DSO) affecting the mandible is an uncommon condition characterised by recurrent pain and functional disturbances. Traditional treatments involving antibiotics, steroids, and analgesics have generally yielded unsatisfactory results. Numerous articles have proposed the utilisation of bisphosphonate therapy as an alternative approach to achieve sustained symptom relief. This study aims to consolidate the available evidence on the effectiveness of bisphosphonate therapy in managing DSO. Methods: A systematic review protocol was registered with PROSPERO and reported in accordance with the Preferred Reporting for Items for Systematic Reviews and Meta-Analyses. Comprehensive electronic search strategies were devised, and studies were screened based on predefined inclusion and exclusion criteria. Results: Ten articles met the eligibility criteria, encompassing a total of 135 patients diagnosed with DSO who received bisphosphonate treatment. All included studies consistently reported a reduction in pain levels and swelling, along with a decrease in the cumulative use of analgesics. The majority of patients reported long-lasting symptom improvement with bisphosphonate therapy. Notably, four studies documented improvements in maximal mouth opening, with one study reporting a mean increase of 9.6mm. Furthermore, six studies observed improvements in panoramic radiographs and cone beam computed tomography scans, with one publication describing two patients exhibiting near-normal bone architecture. Importantly, all studies reported the absence of long-term complications. Conclusions: Bisphosphonate therapy emerges as a promising treatment modality for DSO, exhibiting efficacy in symptom alleviation and radiological enhancement while conferring lasting benefits. Nevertheless, further prospective studies are warranted to refine treatment protocols and substantiate these findings.

Design and use of an ex vivo peripheral simulating bioreactor system for pharmacokinetic analysis of a drug coated stent.

Currently, there are no ex vivo systems that can model the motion of peripheral arteries and allow for the evaluation of pharmacokinetics (PK) of endovascular devices. The objective of this study was to develop a novel peripheral simulating bioreactor system to evaluate drug pharmacokinetics of stents. We utilized 3D-printed and off-the-shelf components to construct a peripheral-simulating bioreactor system capable of mimicking the motion of peripheral arteries. Servo motors were primarily used to shorten/elongate, twist, and bend explanted porcine carotid arteries. To evaluate the pharmacokinetics in the bioreactor, drug-eluting stents were deployed within explanted arteries and subjected to vascular motion along with pulsatile flow conditions. Following 30 min and 24 h, the arteries were removed, and paclitaxel levels were measured. Scanning electron microscopy was also performed to evaluate the stent surface. Arterial paclitaxel levels of the stent-treated arteries were found to be higher at 30 min than at 24 h following pulsatile and no vascular motion and even higher at 24 h following pulsatile flow and vascular motion. The residual drug on the stent significantly decreased from 30 min to 24 h. Scanning electron microscopy confirmed the loss of paclitaxel coating at 24 h and greater disturbance in stents under peripheral motion versus pulsatile only. This system represents the first ex vivo system to determine the PK of drug-eluting stents under physiological flow and vascular motion conditions. This work provides a novel system for a quick and inexpensive preclinical tool to study acute drug tissue concentration kinetics of drug-releasing interventional vascular devices designed for peripheral applications.

Up-regulated PLA2G10 in cancer impairs T cell infiltration to dampen immunity.

T cells are often absent from human cancer tissues during both spontaneously induced immunity and therapeutic immunotherapy, even in the presence of a functional T cell-recruiting chemokine system, suggesting the existence of T cell exclusion mechanisms that impair infiltration. Using a genome-wide in vitro screening platform, we identified a role for phospholipase A2 group 10 (PLA2G10) protein in T cell exclusion. PLA2G10 up-regulation is widespread in human cancers and is associated with poor T cell infiltration in tumor tissues. PLA2G10 overexpression in immunogenic mouse tumors excluded T cells from infiltration, resulting in resistance to anti-PD-1 immunotherapy. PLA2G10 can hydrolyze phospholipids into small lipid metabolites, thus inhibiting chemokine-mediated T cell mobility. Ablation of PLA2G10's enzymatic activity enhanced T cell infiltration and sensitized PLA2G10-overexpressing tumors to immunotherapies. Our study implicates a role for PLA2G10 in T cell exclusion from tumors and suggests a potential target for cancer immunotherapy.

Integrating multiple 'omics' analyses identifies serological protein biomarkers for preeclampsia.

BACKGROUND: Preeclampsia (PE) is a pregnancy-related vascular disorder which is the leading cause of maternal morbidity and mortality. We sought to identify novel serological protein markers to diagnose PE with a multi-'omics' based discovery approach. METHODS: Seven previous placental expression studies were combined for a multiplex analysis, and in parallel, two-dimensional gel electrophoresis was performed to compare serum proteomes in PE and control subjects. The combined biomarker candidates were validated with available ELISA assays using gestational age-matched PE (n=32) and control (n=32) samples. With the validated biomarkers, a genetic algorithm was then used to construct and optimize biomarker panels in PE assessment. RESULTS: In addition to the previously identified biomarkers, the angiogenic and antiangiogenic factors (soluble fms-like tyrosine kinase (sFlt-1) and placental growth factor (PIGF)), we found 3 up-regulated and 6 down-regulated biomakers in PE sera. Two optimal biomarker panels were developed for early and late onset PE assessment, respectively. CONCLUSIONS: Both early and late onset PE diagnostic panels, constructed with our PE biomarkers, were superior over sFlt-1/PIGF ratio in PE discrimination. The functional significance of these PE biomarkers and their associated pathways were analyzed which may provide new insights into the pathogenesis of PE.