Outcomes of Patients with Opioid-Related Diagnoses in Acute Coronary Syndrome: a National Inpatient Sample-Based Analysis.

BACKGROUND: Acute coronary syndrome (ACS) and opioid use are both major causes of morbidity and mortality globally. Although epidemiological studies point to increased risk of ACS in opioid users, in-hospital management and outcomes are unknown for this population when presenting with ACS. We sought to determine whether there are differences for in-hospital outcomes and management of ACS for those with and without opioid-related diagnoses (ORD). METHODS AND RESULTS: From the National Inpatient Sample database, we extracted patients hospitalized between 2012 and 2016 for ACS. The primary independent variable was ORD by International Classification of Diseases, 9th and 10th Revision, codes. The primary outcome was in-hospital mortality; secondary outcomes were cardiac arrest, receipt of angiogram, and percutaneous coronary intervention (PCI). Statistical comparisons were performed using χ2 test and Student's t test. Multivariable logistic regression was performed to determine the independent association between ORD and outcomes of interest. Among the estimated 5.8 million admissions for ACS, the proportion of patients with ORD increased over the study period (p for trend < 0.01). Compared to patients without ORD presenting with ACS, patients with ORD were younger with fewer cardiovascular risk factors. Yet, in-hospital mortality was higher in patients with ORD presenting with ACS (AOR 1.36, 95% CI 1.26-1.48). Patients with ORD were more likely to experience in-hospital cardiac arrest (AOR 1.42, 95% CI 1.23-1.63) and less likely to undergo angiogram (AOR 0.42, 95% CI 0.38-0.45) or PCI (AOR 0.30, 95% CI 0.28-0.32). CONCLUSION: Despite evidence of increased risk of mortality and cardiac arrest, patients with ORD admitted for ACS are less likely to receive ACS management.

Online case-based educational meetings can increase knowledge, skills, and widen access to surgical training:The nationwideVirtualTrauma & Orthopaedic Meetingseries.

BACKGROUND: Access to surgical training is challenging for undergraduate and early postgraduate trainees due to a greater focus on developing generic knowledge and skills, and a drive to recruit greater numbers into internal medicine and primary care. COVID-19 accelerated the declining access to surgical training environments. Our aims were to: 1) establish the feasibility of an online, specialty-specific, case-based surgical training series, and 2) evaluate its suitability for meeting the needs of trainees. METHODS: A nationwide audience of undergraduate and early postgraduate trainees were invited to a series of bespoke online case-based educational meetings in Trauma & Orthopaedics (T&O) over a six month period. The six sessions, which simulated real-world clinical meetings, were constructed by Consultant sub-specialists and involved the presentation of cases by registrars, followed by structured discussion of basic principles, radiological interpretation, and management strategies. Mixed qualitative and quantitative analyses were conducted. RESULTS: There were 131 participants (59.5% male), consisting mostly of doctors in training (58%) and medical students (37.4%). The mean quality rating was 9.0/10 (SD 1.06), further supported by qualitative analysis. 98% enjoyed the sessions, 97% reported improved knowledge of T&O, and 94% reported a direct benefit to clinical practice. There was a significant improvement in knowledge of T&O conditions, management plans, and radiological interpretation (p = <0.05). CONCLUSION: Structured virtual meetings, underpinned by bespoke clinical cases, may widen access to T&O training, increase flexibility and robustness of learning opportunities, and mitigate the effects of reduced exposure on preparation for surgical careers and recruitment.

Ageing and interferon gamma response drive the phenotype of neutrophils in the inflamed joint.

OBJECTIVE: Neutrophils are typically the most abundant leucocyte in arthritic synovial fluid. We sought to understand changes that occur in neutrophils as they migrate from blood to joint. METHODS: We performed RNA sequencing of neutrophils from healthy human blood, arthritic blood and arthritic synovial fluid, comparing transcriptional signatures with those from murine K/BxN serum transfer arthritis. We employed mass cytometry to quantify protein expression and sought to reproduce the synovial fluid phenotype ex vivo in cultured healthy blood neutrophils. RESULTS: Blood neutrophils from healthy donors and patients with active arthritis showed largely similar transcriptional signatures. By contrast, synovial fluid neutrophils exhibited more than 1600 differentially expressed genes. Gene signatures identified a prominent response to interferon gamma (IFN-γ), as well as to tumour necrosis factor, interleukin-6 and hypoxia, in both humans and mice. Mass cytometry confirmed that healthy and arthritic donor blood neutrophils are largely indistinguishable but revealed a range of neutrophil phenotypes in synovial fluid defined by downregulation of CXCR1 and upregulation of FcγRI, HLA-DR, PD-L1, ICAM-1 and CXCR4. Reproduction of key elements of this signature in cultured blood neutrophils required both IFN-γ and prolonged culture. CONCLUSIONS: Circulating neutrophils from patients with arthritis resemble those from healthy controls, but joint fluid cells exhibit a network of changes, conserved across species, that implicate IFN-γ response and ageing as complementary drivers of the synovial fluid neutrophil phenotype.

Going Bareback: Time and Aging in a Gay-for-Pay Porn Career.

This article explores a critical moment of going bareback in the career of arguably the biggest gay porn performer of the 2010s, Johnny Rapid. The analysis reveals a decidedly negative reception of Rapid, the promotion of bareback as event, and the quality of the bareback performance itself, all of which I read in accordance with what these narratives have to tell us about bareback at the time. Yet I also take the opportunity-writing several years after this critical moment in Rapid's career-to reflect on the success of the campaign. I read the case study in line with the concept of time, which has particular resonance with bareback. Through this reflection, I arrive at the conclusion that the time was right for an aging twink performer to be freshened-up by a transition to bareback-similar transitions of which have become widespread across the gay porn landscape in the intervening years between the 2015 Johnny Rapid Goes Bareback event and the present day, thanks in no small part to advancements in HIV prevention technologies.

Electronic health record risk score provides earlier prognostication of clinical outcomes in patients admitted to the cardiac intensive care unit.

In this observational study, we compared the prognostic ability of an electronic health record (EHR)-derived risk score, the Rothman Index (RI), automatically derived on admission, to the first 24-hour Sequential Organ Failure Assessment (SOFA) score for outcome prediction in the modern cardiac intensive care unit (CICU). We found that while the 24-hour SOFA score provided modestly superior discrimination for both in-hospital and CICU mortality, the RI upon CICU admission had better calibration for both outcomes. Given the ubiquitous nature of EHR utilization in the United States, the RI may become an important tool to rapidly risk stratify CICU patients within the ICU and improve resource allocation.

COVID-19 complicated by ST-segment elevation myocardial infarction in a 29-year-old patient.

We describe a case in which a 29-year-old male with no medical history presented with ST-segment elevation myocardial infarction as his presentation of coronavirus disease. During cardiac catheterization, he was found to have total occlusion of his left anterior descending artery by thrombus. Laboratory testing revealed markedly elevated inflammatory markers as well as evidence of a hypercoagulable state in the setting of severe acute respiratory syndrome coronavirus 2 infection, which was suspected to be the inciting factor for his acute coronary event.

Sea anemone model has a single Toll-like receptor that can function in pathogen detection, NF-κB signal transduction, and development.

In organisms from insects to vertebrates, Toll-like receptors (TLRs) are primary pathogen detectors that activate downstream pathways, specifically those that direct expression of innate immune effector genes. TLRs also have roles in development in many species. The sea anemone Nematostella vectensis is a useful cnidarian model to study the origins of TLR signaling because its genome encodes a single TLR and homologs of many downstream signaling components, including the NF-κB pathway. We have characterized the single N. vectensis TLR (Nv-TLR) and demonstrated that it can activate canonical NF-κB signaling in human cells. Furthermore, we show that the intracellular Toll/IL-1 receptor (TIR) domain of Nv-TLR can interact with the human TLR adapter proteins MAL and MYD88. We demonstrate that the coral pathogen Vibrio coralliilyticus causes a rapidly lethal disease in N. vectensis and that heat-inactivated V. coralliilyticus and bacterial flagellin can activate a reconstituted Nv-TLR-to-NF-κB pathway in human cells. By immunostaining of anemones, we show that Nv-TLR is expressed in a subset of cnidocytes and that many of these Nv-TLR-expressing cells also express Nv-NF-κB. Additionally, the nematosome, which is a Nematostella-specific multicellular structure, expresses Nv-TLR and many innate immune pathway homologs and can engulf V. coralliilyticus Morpholino knockdown indicates that Nv-TLR also has an essential role during early embryonic development. Our characterization of this primitive TLR and identification of a bacterial pathogen for N. vectensis reveal ancient TLR functions and provide a model for studying the molecular basis of cnidarian disease and immunity.

Evolutionary Origins of Toll-like Receptor Signaling.

Toll-like receptors (TLRs) are transmembrane pattern recognition receptors that are best known for their roles in innate immunity for the detection of and defense against microbial pathogens. However, TLRs also have roles in many nonimmune processes, most notably development. TLRs direct both immune and developmental programs by activation of downstream signaling pathways, often by activation of the NF-κB pathway. There are two primary TLR subtypes: 1) TLRs with multiple cysteine clusters in their ectodomain (mccTLRs) and 2) TLRs with a single cysteine cluster in their ectodomain (sccTLRs). For some time, it has been known that TLRs and the biological processes that they control are conserved in organisms from insects to mammals. However, genome and transcriptome sequencing has revealed that many basal metazoans also have TLRs and downstream NF-κB signaling components. In this review, we discuss what is known about the structure, biological function, and downstream signaling pathways of TLRs found in phyla from Porifera through Annelida. From these analyses, we hypothesize that mccTLRs emerged in the phylum Cnidaria, that sccTLRs evolved in the phylum Mollusca, and that TLRs have dual immune and developmental biological functions in organisms as ancient as cnidarians.

Association of Physician Certification in Interventional Cardiology With In-Hospital Outcomes of Percutaneous Coronary Intervention.

BACKGROUND: The value of American Board of Internal Medicine certification has been questioned. We evaluated the Association of Interventional Cardiology certification with in-hospital outcomes of patients undergoing percutaneous coronary intervention (PCI) in 2010. METHODS AND RESULTS: We identified physicians who performed ≥10 PCIs in 2010 in the CathPCI Registry and determined interventional cardiology (ICARD) certification status using American Board of Internal Medicine data. We compared in-hospital outcomes of patients treated by certified and noncertified physicians using hierarchical multivariable models adjusted for differences in patient characteristics and PCI volume. Primary end points were all-cause in-hospital mortality and bleeding complications. Secondary end points included emergency coronary artery bypass grafting, vascular complications, and a composite of any adverse outcome. With 510,708 PCI procedures performed by 5175 physicians, case mix and unadjusted outcomes were similar among certified and noncertified physicians. The adjusted risks of in-hospital mortality (odds ratio, 1.10; 95% confidence interval, 1.02-1.19) and emergency coronary artery bypass grafting (odds ratio, 1.32; 95% confidence interval, 1.12-1.56) were higher in the non-ICARD-certified group, but the risks of bleeding and vascular complications and the composite end point were not statistically significantly different between groups. CONCLUSIONS: We did not observe a consistent association between ICARD certification and the outcomes of PCI procedures. Although there was a significantly higher risk of mortality and emergency coronary artery bypass grafting in patients treated by non-ICARD-certified physicians, the risks of vascular complications and bleeding were similar. Our findings suggest that ICARD certification status alone is not a strong predictor of patient outcomes and indicate a need to enhance the value of subspecialty certification.

Predicting detection limits of enzyme-linked immunosorbent assay (ELISA) and bioanalytical techniques in general.

The detection limit is one of the most important performance parameters for bioanalytical techniques. Here we present a generic method to estimate the detection limit of biomolecular assays based on a step-by-step analysis of the assay procedure. Enzyme-linked immunosorbent assay (ELISA) is used here as an example; however, much of the information presented in this article may be applied to other types of biomolecular assays and analytical techniques. A clear understanding of what affects the detection limit can help researchers to evaluate different bio-analytical techniques properly, and to design better strategies to optimize and achieve the best analytical performance.

Reporting of PPI and the MCID in phase III/IV randomised controlled trials-a systematic review.

BACKGROUND: Patient and public involvement (PPI) in clinical trial design contributes to ensuring the research objectives and outcome measures are relevant to patients. The minimal clinically important difference (MCID) in the primary outcome influences trial design and feasibility and should be predicated on PPI. We aimed to determine current practice of reporting PPI and the MCID in phase III/IV randomised controlled trials (RCTs). METHODS: Following a search of Medline, Embase, and the Cochrane Central Register of Controlled Trials, we included primary publications of phase III/IV RCTs, in English, inclusive of any medical specialty or type of intervention, that reported a health-related outcome. We excluded protocols and secondary publications of RCTs. We extracted RCT characteristics, the use of PPI, and use of the MCID. RESULTS: Between 1 July 2019 and 13 January 2020, 123 phase III/IV RCTs matched our eligibility criteria. Ninety percent evaluated a medical rather than surgical intervention. Oncology accounted for 21% of all included RCTs. Only 2.4% (n = 3) and 1.6% (n = 2) RCTs described PPI and the MCID respectively. CONCLUSIONS: PPI and the MCID are poorly reported, so it is uncertain how these contributed to trial design. Improvement in the reporting of these items would increase confidence that results are relevant and clinically significant to patients, contributing to improving the overall trial design. TRIAL REGISTRATION: Not registered.

Starvation decreases immunity and immune regulatory factor NF-κB in the starlet sea anemone Nematostella vectensis.

Lack of proper nutrition has important consequences for the physiology of all organisms, and nutritional status can affect immunity, based on many studies in terrestrial animals. Here we show a positive correlation between nutrition and immunity in the sea anemone Nematostella vectensis. Gene expression profiling of adult anemones shows downregulation of genes involved in nutrient metabolism, cellular respiration, and immunity in starved animals. Starved adult anemones also have reduced protein levels and activity of immunity transcription factor NF-κB. Starved juvenile anemones have increased sensitivity to bacterial infection and also have lower NF-κB protein levels, as compared to fed controls. Weighted Gene Correlation Network Analysis (WGCNA) is used to identify significantly correlated gene networks that were downregulated with starvation. These experiments demonstrate a correlation between nutrition and immunity in an early diverged marine metazoan, and the results have implications for the survival of marine organisms as they encounter changing environments.

Studies with neutralizing antibodies suggest CXCL8-mediated neutrophil activation is independent of C-C motif chemokine receptor-like 2 (CCRL2) ligand binding function.

C-C motif chemokine receptor-like 2 (CCRL2) is a non-signaling 7 transmembrane receptor that binds chemotactic ligands to shape leukocyte recruitment to sites of inflammation. However, there is a lack of consensus on the ligands that directly bind CCRL2 or their functional impact. Studies with CCRL2 knockout mice have demonstrated that neutrophils have impaired degranulation and migration in response to CXCL8, where the underlying molecular mechanism is proposed to be due to the formation of CCRL2 heterodimers with the chemokine receptor CXCR2. Herein, we characterized the ligands that bind directly to CCRL2 and interrogated the impact of CCRL2 neutralization on CXCL8 signaling in neutrophils using pharmacological antibody tools. Using flow cytometry and Surface Plasmon Resonance microscopy (SPRm) cell binding experiments, we confirmed that chemerin, but not previously reported C-C chemokines, binds CCRL2. Furthermore, we identified human and mouse CCRL2 antibodies that neutralized chemerin binding to CCRL2. Unexpectedly, we found that neutralization of CCRL2 with these antibodies did not attenuate CXCL8-induced human neutrophil degranulation nor CXCL8-induced murine neutrophil recruitment to the peritoneum. Based on the observed differences in modulating CCRL2 function with neutralizing antibodies compared to the reported CCRL2 deficient murine models, we hypothesize that the ligand binding function of CCRL2 is dispensable for CXCL8 signaling in neutrophils. Finally, extensive profiling of CCRL2 expression on peripheral blood leukocytes revealed monocytes, dendritic cells (DC), and subpopulations of natural killer T (NKT) cells as additional targets, highlighting potential roles for CCRL2 in human cell types beyond neutrophils that warrants future investigation.

Cellularity and structure of fresh human coronary thrombectomy specimens; presence of cells with markers of progenitor cells.

Acute coronary syndromes and acute myocardial infarctions are often related to plaque rupture and the formation of thrombi at the site of the rupture. We examined fresh coronary thrombectomy specimens from patients with acute coronary syndromes and assessed their structure and cellularity. The thrombectomy specimens consisted of platelets, erythrocytes and inflammatory cells. Several specimens contained multiple cholesterol crystals. Culture of thrombectomy specimens yielded cells growing in various patterns depending on the culture medium used. Culture in serum-free stem cell enrichment medium yielded cells with features of endothelial progenitor cells which survived in culture for a year. Immunohistochemical analysis of the thrombi revealed cells positive for CD34, cells positive for CD15 and cells positive for desmin in situ, whereas cultured cell from thrombi was desmin positive but pancytokeratin negative. Cells cultured in endothelial cell medium were von Willebrand factor positive. The content of coronary thrombectomy specimens is heterogeneous and consists of blood cells but also possibly cells from the vascular wall and cholesterol crystals. The culture of cells contained in the specimens yielded multiplying cells, some of which demonstrated features of haematopoietic progenitor cells and which differentiated into various cell-types.

"Almost Looks Illegal": Family Dick's Daddy's Little Boy Gay Pornography Series and Its Too-Young Look.

Family Dick is a commercial gay pornography website that has courted controversy for both its stepfather-son theme and for the youthful stylings of its Daddy's Little Boy series. This article reads viewer commentary (selected from more than 700 comments) of scenes within the series posted to its Pornhub channel. Textual analysis is employed to read the series itself and its distinctive esthetic, which logically leads to discussion of views on the too-young "look" of the series and the use of certain "legislative language" by those who deem the content to be potentially unlawful. The article also considers the implications resultant from the range of views presented in the discourse and a tendency for the series to inspire viewers to reflect on personal experiences and desires. As the first study of its kind, it ends by nominating a range of future research directions.

Prevalence of Noncardiac Multimorbidity in Patients Admitted to Two Cardiac Intensive Care Units and Their Association with Mortality.

BACKGROUND: Current cardiac intensive care unit (CICU) practice has seen an increase in patient complexity, including an increase in noncardiac organ failure, critical care therapies, and comorbidities. We sought to describe the changing epidemiology of noncardiac multimorbidity in the CICU population. METHODS: We analyzed consecutive unique patient admissions to 2 geographically distant tertiary care CICUs (n = 16,390). We assessed for the prevalence of 0, 1, 2, and ≥3 noncardiac comorbidities (diabetes, chronic lung, liver, and kidney disease, cancer, and stroke/transient ischemic attack) and their associations with hospital and postdischarge 1-year mortality using multivariable logistic regression. RESULTS: The prevalence of 0, 1, 2, and ≥3 noncardiac comorbidities was 37.7%, 31.4%, 19.9%, and 11.0%, respectively. Increasing noncardiac comorbidities were associated with a stepwise increase in mortality, length of stay, noncardiac indications for ICU admission, and increased utilization of critical care therapies. After multivariable adjustment, compared with those without noncardiac comorbidities, there was an increased hospital mortality for patients with 1 (odds ratio [OR] 1.30; 95% confidence interval [CI], 1.10-1.54, P = .002), 2 (OR 1.47; 95% CI, 1.22-1.77, P < .001), and ≥3 (OR 1.79; 95% CI, 1.44-2.22, P < .001) noncardiac comorbidities. Similar trends for each additional noncardiac comorbidity were seen for postdischarge 1-year mortality (P < .001, all). CONCLUSIONS: In 2 large contemporary CICU populations, we found that noncardiac multimorbidity was highly prevalent and a strong predictor of short- and long-term adverse clinical outcomes. Further study is needed to define the best care pathways for CICU patients with acute cardiac illness complicated by noncardiac multimorbidity.

Transition From an Open to Closed Staffing Model in the Cardiac Intensive Care Unit Improves Clinical Outcomes.

Background Several studies have shown improved outcomes in closed compared with open medical and surgical intensive care units. However, very little is known about the ideal organizational structure in the modern cardiac intensive care unit (CICU). Methods and Results We retrospectively reviewed consecutive unique admissions (n=3996) to our tertiary care CICU from September 2013 to October 2017. The aim of our study was to assess for differences in clinical outcomes between an open compared with a closed CICU. We used multivariable logistic regression adjusting for demographics, comorbidities, and severity of illness. The primary outcome was in-hospital mortality. We identified 2226 patients in the open unit and 1770 in the closed CICU. The unadjusted in-hospital mortality in the open compared with closed unit was 9.6% and 8.9%, respectively (P=0.42). After multivariable adjustment, admission to the closed unit was associated with a lower in-hospital mortality (odds ratio [OR], 0.69; 95% CI: 0.53-0.90, P=0.007) and CICU mortality (OR, 0.70; 95% CI, 0.52-0.94, P=0.02). In subgroup analysis, admissions for cardiac arrest (OR, 0.42; 95% CI, 0.20-0.88, P=0.02) and respiratory insufficiency (OR, 0.43; 95% CI, 0.22-0.82, P=0.01) were also associated with a lower in-hospital mortality in the closed unit. We did not find a difference in CICU length of stay or total hospital charges (P>0.05). Conclusions We found an association between lower in-hospital and CICU mortality after the transition to a closed CICU. These results may help guide the ongoing redesign in other tertiary care CICUs.

Randomized Evaluation of TriGuard 3 Cerebral Embolic Protection After Transcatheter Aortic Valve Replacement: REFLECT II.

OBJECTIVES: The REFLECT II (Randomized Evaluation of TriGuard 3 Cerebral Embolic Protection After Transcatheter Aortic Valve Implantation) trial was designed to investigate the safety and efficacy of the TriGUARD 3 (TG3) cerebral embolic protection in patients undergoing transcatheter aortic valve replacement. BACKGROUND: Cerebral embolization occurs frequently following transcatheter aortic valve replacement and procedure-related ischemic stroke occurs in 2% to 6% of patients at 30 days. Whether cerebral protection with TriGuard 3 is safe and effective in reducing procedure-related cerebral injury is not known. METHODS: This prospective, multicenter, single-blind, 2:1 randomized (TG3 vs. no TG3) study was designed to enroll up to 345 patients. The primary 30-day safety endpoint (Valve Academic Research Consortium-2 defined) was compared with a performance goal (PG). The primary hierarchical composite efficacy endpoint (including death or stroke at 30 days, National Institutes of Health Stroke Scale score worsening in hospital, and cerebral ischemic lesions on diffusion-weighted magnetic resonance imaging at 2 to 5 days) was compared using the Finkelstein-Schoenfeld method. RESULTS: REFLECT II enrolled 220 of the planned 345 patients (63.8%), including 41 roll-in and 179 randomized patients (121 TG3 and 58 control subjects) at 18 US sites. The sponsor closed the study early after the U.S. Food and Drug Administration recommended enrollment suspension for unblinded safety data review. The trial met its primary safety endpoint compared with the PG (15.9% vs. 34.4% (p < 0.0001). The primary hierarchal efficacy endpoint at 30 days was not met (mean scores [higher is better]: -8.58 TG3 vs. 8.08 control; p = 0.857). A post hoc diffusion-weighted magnetic resonance imaging analysis of per-patient total lesion volume above incremental thresholds showed numeric reductions in total lesion volume >500 mm3 (-9.7%) and >1,000 mm3 (-44.5%) in the TG3 group, which were more pronounced among patients with full TG3 coverage: -51.1% (>500 mm3) and -82.9% (>1,000 mm3). CONCLUSIONS: The REFLECT II trial demonstrated that the TG3 was safe compared with a historical PG but did not meet its pre-specified primary superiority efficacy endpoint.

Gay Porn's Bareback Momentum.

A profound shift has occurred in the last decade in mainstream commercial gay pornography from condoms to "bareback" (condomless) depictions of anal sex between men. This article explores gay porn's "bareback momentum" as demonstrated by the displacement of condoms in the 10 most visited gay porn Web sites (that have operated for 10 years or more). While all 10 began by releasing condom pornography, the study finds all except one (Falcon) have since gone bareback-represented visually as a timeline. The sites analyzed are, in order of popularity: Sean Cody, Helix Studios, Lucas Entertainment, Corbin Fisher, Bel Ami, Next Door Studios, Randy Blue, Falcon Studios, Cocky Boys, and Chaos Men. Textual analysis reads each site's transition individually, yet connections between the sites are the article's central concern, from which an emphasis on couples and break-up narratives is revealed. Falcon's commitment to retain the condom is attributed to its brand identity.

Acute myocardial infarction as the presenting symptom of systemic lupus erythematosus.

We report a case of acute myocardial infarction due to non-antiphospholipid-related coronary artery thrombosis as the presenting manifestation of systemic lupus erythematosus in a young patient. We present the acute workup and the results of successful transcatheter coronary intervention. The causes of acute myocardial infarction and coronary artery thrombosis in pediatric patients are reviewed.