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Same-day discharge (SDD) following left atrial appendage closure (LAAC) is increasingly common but predictors of successful SDD and 1-year clinical outcomes have not been described.The purpose of this study was to explore predictors of successful SDD and report 1-year outcomes in patients undergoing LAAC with SDD.A prospective analysis was performed over a 20-month period of 225 consecutive patients that underwent LAAC in a large, academic hospital. All patients included in the study underwent a SDD protocol. Baseline characteristics and 1-year outcomes of patients discharged same day of the procedure versus those that required at least one overnight stay were compared. Adverse events, procedural success, and procedure times were evaluated.One hundred and sixty-one patients (72%) of patients were discharged the same day and 64 patients (28%) required at least an overnight stay (non-SDD: NSDD). NSDD patients were older and more often female. Procedure time was also longer in the NSDD group than in the SDD (63.4 vs. 55.1 min; p = 0.01). While overall procedural success rates were similar between the SDD and NSDD groups (99.4% vs. 98.4%; p = 0.39), NSDD patients had more complications (9.4% vs. 0%; p = 0.01) and higher number of devices per procedure (1.2 vs. 1.0; p = 0.01) as compared to SDD. At 1 year, there were no significant difference between the SDD and NSDD groups in stroke (1.1% vs. 0%; log-rank p = 0.44) and all-cause mortality (3.9% vs. 4.7%; log-rank p = 0.70).In this single-center LAAC experience, female sex, older age, and longer procedure duration were associated with higher likelihood for need of overnight stay. At 1-year follow-up, there were no significant differences in stroke events and death rates between SDD and NSDD groups.

The epidural space is commonly accessed via an interlaminar or transforaminal approach to administer corticosteroids for radicular pain. An alternative is a transarticular approach, which may be considered when conventional access to the epidural space is either not desired or contraindicated. This approach has been described in the cervical spine using computed tomography guidance but not fluoroscopic guidance. We describe a cervical transarticular approach to the epidural space under fluoroscopy and review the computed tomography-guided literature. The risks of transarticular epidural injections are likely low given that when performed prudently, they avoid direct contact with the vertebral artery, spinal medullary arteries, venous plexus, spinal cord, and nerve roots.

Clinically used inhibitors of mammalian target of rapamycin (mTOR) negatively impacts endothelial-dependent vasodilatation (EDD) through unidentified mechanisms. Here we show that either the endothelium-specific deletion of Mtor to inhibit both mTOR complexes, or depletion of Raptor or Rictor to disrupt mTORC1 or mTORC2, causes impaired EDD, accompanied by reduced NO in the serum of mice. Consistently, inhibition of mTOR decreases NO production by human and mouse EC. Specifically, inhibition of mTORC1 suppresses eNOS gene expression, due to impairment in p70S6K-mediated posttranscriptional regulation of the transcription factor KLF2 expression. In contrast to mTORC1 inhibition, a positive-feedback between MAPK (p38 and JNK) activation and Nox2 upregulation contributes to the excessive generation of reactive oxygen species (ROS), which causes eNOS uncoupling and decreased NO bioavailability in mTORC2-inhibited EC. Adeno-associated virus-mediated EC-specific overexpression of KLF2 or suppression of Nox2 restores EDD function in endothelial mTORC1- or mTORC2-inhibited mice.

Recognition of integrins by CD62P has not been reported and this motivated a docking simulation using integrin αvβ3 as a target. We predicted that the C-type lectin domain of CD62P functions as a potential integrin ligand and observed that it specifically bound to soluble β3 and β1 integrins. Known inhibitors of the interaction between CD62P–PSGL-1 did not suppress the binding, whereas the disintegrin domain of ADAM-15, a known integrin ligand, suppressed recognition by the lectin domain. Furthermore, an R16E/K17E mutation in the predicted integrin-binding interface located outside of the glycan-binding site within the lectin domain, strongly inhibited CD62P binding to integrins. In contrast, the E88D mutation that strongly disrupts glycan binding only slightly affected CD62P-integrin recognition, indicating that the glycan and integrin-binding sites are distinct. Notably, the lectin domain allosterically activated integrins by binding to the allosteric site 2. We conclude that CD62P-integrin binding may function to promote a diverse set of cell–cell adhesive interactions given that β3 and β1 integrins are more widely expressed than PSGL-1 that is limited to leukocytes.

Radiculopathy is diagnosed using a combination of history, physical examination, and imaging. Unfortunately, well-established dermatomal and myotomal maps are an oversimplification of the convoluted nature of spinal sensory and motor innervation. When clinical presentation and imaging seemingly contradict one another, it is important to consider variant innervation patterns. This article presents three patients with objective dermatomal and/or myotomal deficits due to disc herniations whose clinical presentations are "textbook" for nerve root pathology that is adjacent to the nerve root that is actually compromised. In addition, the literature is reviewed to discuss the history of dermatomal and myotomal maps, the effectiveness of a clinician's ability to determine the precise pathologic disc and nerve root level in patients presenting with radiculopathy, and anatomical explanations as to why inconsistencies such as those seen in the patients in these cases exist.

Biochemical recurrence develops in almost one-third of men with prostate cancer after treatment with local therapy. There are numerous options for management, including surveillance, salvage radiation, androgen deprivation therapy (ADT), and clinical trials. This article reviews the current approaches to radiation therapy, ADT, and molecular imaging in men with biochemically recurrent prostate cancer. First, radiation therapy, including selection of field, dose, and use of concurrent antiandrogen therapy, is reviewed. Next, molecular imaging is addressed, including prostate-specific membrane antigen PET imaging and its increased sensitivity in identifying sites of disease. Finally, the factors associated with starting ADT are explored, and the data supporting intermittent over continuous ADT are reviewed. Lastly, the use of prostate-specific membrane antigen PET imaging and its potential role influencing therapy are discussed.

Intermediate monocytes (iMo; CD14+CD16+) increase in number in the circulation of patients with unstable coronary artery disease (CAD), and their recruitment to inflamed arteries is implicated in events leading to mortality following MI. Monocyte recruitment to inflamed coronary arteries is initiated by high affinity β2-integrin (CD11c/CD18) that activates β1-integrin (VLA-4) to bind endothelial VCAM-1. How integrin binding under shear stress mechanosignals a functional shift in iMo toward an inflammatory phenotype associated with CAD progression is unknown. Whole blood samples from patients treated for symptomatic CAD including non-ST elevation MI, along with healthy age-matched subjects, were collected to assess chemokine and integrin receptor levels on monocytes. Recruitment on inflamed human aortic endothelium or rVCAM-1 under fluid shear stress was assessed using a microfluidic-based artery on a chip (A-Chip). Membrane upregulation of high affinity CD11c correlated with concomitant activation of VLA-4 within focal adhesive contacts was required for arrest and diapedesis across inflamed arterial endothelium to a greater extent in non-ST elevation MI compared with stable CAD patients. The subsequent conversion of CD11c from a high to low affinity state under fluid shear activated phospho-Syk– and ADAM17-mediated proteolytic cleavage of CD16. This marked the conversion of iMo to an inflammatory phenotype associated with nuclear translocation of NF-κB and production of IL-1β+. We conclude that CD11c functions as a mechanoregulator that activates an inflammatory state preferentially in a majority of iMo from cardiac patients but not healthy patients.

Background Inadvertent intravascular injection has been suggested as the most probable mechanism behind serious neurological complications during transforaminal epidural steroid injections. Authors believe a smaller gauge needle may lead to less intravascular uptake and less pain. Theoretically, there is less chance for a smaller gauge needle to encounter a blood vessel during an injection compared to a larger gauge needle. Studies have also shown smaller gauge needle to cause less pain. The aim of the study was to quantify the difference between a 22-gauge needle and 25-gauge needle during lumbosacral transforaminal epidural steroid injection in regards to intravascular uptake and pain perception. Methods This was a prospective single blind randomized clinical trial performed at outpatient spine practice locations of two academic institutions. One hundred sixty-two consecutive patients undergoing lumbosacral transforaminal epidural injections from February 2018 to June 2019 were recruited and randomized to each arm of the study – 84 patients were randomized to the 22-gauge needle arm and 78 patients to 25-gauge arm. Each transforaminal injection level was considered a separate incidence, hence total number of incidence was 249 (136 in 22-gauge arm and 113 in 25-gauge arm). The primary outcome measure was intravascular uptake during live fluoroscopy and/or blood aspiration. The secondary outcome measure was patient reported pain during the procedure on the numerical rating scale. Results Fisher exact test was used to detect differences between 2 groups in regards to intravascular uptake and paired t-tests were used to detect differences in pain scores. The incidence of intravascular uptake for a 22-gauge needle was 5.9% (95% confidence interval: 1.9 to 9.8%) and for a 25-gauge needle, 7.1% (95% confidence interval: 2.4 to 11.8%) [p = 0.701]. Average numerical rating scale scores during the initial needle entry for 22-gauge and 25-gauge needle was 3.46 (95% confidence interval: 2.94 to 3.98) and 3.13 (95% confidence interval: 2.57 to 3.69) respectively [p = 0.375]. Conclusions The study showed no statistically significant difference in intravascular uptake or pain perception between a 22-gauge needle and 25-gauge needle during lumbosacral transforaminal epidural steroid injections. Trial registration ClinicalTrials.gov NCT04350307. Registered 4/17/2020. (Retrospectively registered).

Objectives The aim of this study was to develop and validate a risk prediction model for high-grade atrioventricular block requiring cardiac implantable electronic device (CIED) implantation after transcatheter aortic valve replacement (TAVR). Background High-grade atrioventricular block requiring CIED remains a significant sequelae following TAVR. Although several pre-operative characteristics have been associated with the risk of post-operative CIED implantation, an accurate and validated risk prediction model is not established yet. Methods This was a single center, retrospective study of consecutive patients who underwent TAVR from March 10, 2011, to October 8, 2018. This cohort sample was randomly divided into a derivation cohort (group A) and a validation cohort (group B). A scoring system for risk prediction of post-TAVR CIED implantation was devised using logistic regression estimates in group A and the calibration and validation were done in group B. Results A total of 1,071 patients underwent TAVR during the study period. After excluding pre-existing CIED, a total of 888 cases were analyzed (group A: 507 and group B: 381). Independent predictive variables were as follows: self-expanding valve (1 point), hypertension (1 point), pre-existing first-degree atrioventricular block (1 point), and right bundle branch block (2 points). The resulting score was calculated from the total points. The internal validation in group B showed an ideal linear relationship in calibration plot (R2 = 0.933) and a good predictive accuracy (area under the curve: 0.693; 95% confidence interval: 0.627 to 0.759). Conclusions This prediction model accurately predicts post-operative risk of CIED implantation with simple pre-operative parameters.

Aims Mammalian target of rapamycin (mTOR) inhibitors used in drug-eluting stents (DES) to control restenosis have been found to delay endothelialization and increase incidence of late-stent thrombosis through mechanisms not completely understood. We revealed that mTOR inhibition (mTORi) upregulated the expression of cell growth suppressor IRF-1 in primary human arterial endothelial cells (HAEC). This study aimed to examine how mTOR-regulated IRF-1 expression contributes to the suppressive effect of mTORi on arterial endothelial proliferation. Methods and results Western blotting, quantitative PCR, and a dual-luciferase reporter assay indicated that mTOR inhibitors rapamycin and torin 1 upregulated IRF-1 expression and increased its transcriptional activity. IRF-1 in turn contributed to the suppressive effect of mTORi by mediating HAEC apoptosis and cell cycle arrest in part through upregulation of caspase 1 and downregulation of cyclin D3, as revealed by CCK-8 assay, Annexin V binding assay, measurement of activated caspase 3, BrdU incorporation assay, and matrigel tube formation assay. In a mouse model of femoral artery wire injury, administration of rapamycin inhibited EC recovery, an effect alleviated by EC deficiency of IRF-1. Chromatin immunoprecipitation assay with HAEC and rescue expression of wild type or dominant-negative IRF-1 in EC isolated from Irf1−/− mice confirmed transcriptional regulation of IRF-1 on the expression of CASP1 and CCND3. Furthermore, mTORi activated multiple PKC members, among which PKCζ was responsible for the growth-inhibitory effect on HAEC. Activated PKCζ increased IRF1 transcription through JAK/STAT-1 and NF-κB signaling. Finally, overexpression of wild type or mutant raptor incapable of binding mTOR indicated that mTOR-free raptor contributed to PKCζ activation in mTOR-inhibited HAEC. Conclusions The study reveals an IRF-1-mediated mechanism that contributes to the suppressive effects of mTORi on HAEC proliferation. Further study may facilitate the development of effective strategies to reduce the side effects of DES used in coronary interventions.

Objective: A Mediterranean diet supplemented with olive oil and nuts prevents cardiovascular disease in clinical studies, but the underlying mechanisms are incompletely understood. We investigated whether the preventive effect of the diet could be due to inhibition of atherosclerosis and foamy monocyte formation in Ldlr –/– mice fed with a diet in which milkfat in a Western diet (WD) was replaced with extra-virgin olive oil and nuts (EVOND). Approach and Results: Ldlr –/– mice were fed EVOND or a Western diet for 3 (or 6) months. Compared with the Western diet, EVOND decreased triglyceride and cholesterol levels but increased unsaturated fatty acid concentrations in plasma. EVOND also lowered intracellular lipid accumulation in circulating monocytes, indicating less formation of foamy monocytes, compared with the Western diet. In addition, compared with the Western diet, EVOND reduced monocyte expression of inflammatory cytokines, CD36, and CD11c, with decreased monocyte uptake of oxLDL (oxidized LDL [low-density lipoprotein]) ex vivo and reduced CD11c + foamy monocyte firm arrest on vascular cell adhesion molecule-1 and E-selectin–coated slides in an ex vivo shear flow assay. Along with these changes, EVOND compared with the Western diet reduced the number of CD11c + macrophages in atherosclerotic lesions and lowered atherosclerotic lesion area of the whole aorta and aortic sinus. Conclusions: A diet enriched in extra-virgin olive oil and nuts, compared with a Western diet high in saturated fat, lowered plasma cholesterol and triglyceride levels, inhibited foamy monocyte formation, inflammation, and adhesion, and reduced atherosclerosis in Ldlr –/– mice.

Percutaneous left atrial appendage occlusion (LAAO) with the Watchman device is FDA approved for stroke prevention in patients with nonvalvular atrial fibrillation who have an appropriate indication. During the COVID-19 pandemic, a same-day discharge protocol (SDDP) was employed to improve resource utilization, relieve hospital occupation, and reduce the possible risk of in-hospital virus transmission.We sought to analyze the safety, feasibility, and cost effectiveness for SDDP in patients receiving LAAO.A prospective analysis of 142 consecutive patients, 119 treated prior to SDDP and 23 who underwent SDDP following LAAO with cardiac computed tomography angiography (CTA)-guided pre-procedural planning and intracardiac echocardiogram (ICE). Procedures were performed in a single, large academic hospital in the United States. In-hospital and 45-day procedural success, adverse events, length of procedure, and length-of-stay were evaluated.Baseline patient characteristics including mean CHA2DS2VASc scores and mean HAS-BLED scores were similar in both groups. All procedures were successful. There was no significant difference in rates of procedural complications or in-hospital adverse events. The mean procedure time in the SDDP group was 11 minutes longer than in the conventional group (62.1 ± 5.9 vs 51.1 ± 21; P=.01). Outcomes at 45-day follow-up were similar. SDDP was associated with a reduced length of stay compared with conventional strategy and a 15% reduction in total costs.Same-day discharge strategy for LAAO appears safe, feasible and could become the new standard approach for LAAO. A protocol including CTA pre-procedural planning, ICE-guided deployment and conscious sedation reduces hospital occupation and lowers costs.

With the passage of the Affordable Care Act, states were given the option to expand their Medicaid programs. Since then, thirty-eight states and Washington, D.C., have done so. Previous work has identified the widespread effects of expansion on enrollment and the financial implications for individuals, hospitals, and the federal government, yet administrative expenditures have not been considered. Using data from all fifty states for the period 2007-17, our study estimated the effects of Medicaid expansion overall, as well as differing effects by the size and nature of the expansions. Using a quasi-experimental approach, we found no overall effect of expansion on administrative spending. However, the size of the expansion may have produced differing effects. States with small expansions experienced some increases in administrative spending, whereas states with large expansions experienced some decreases in administrative spending, including a $77 reduction in per enrollee administrative spending compared with nonexpansion states. As more states consider expanding their Medicaid programs, our findings provide evidence of potential effects.

Prevention of cardiovascular disease is currently guided by probabilistic risk scores that may misclassify individual risk and commit many middle-aged patients to prolonged pharmacotherapy. The coronary artery calcium (CAC) score, although endorsed for intermediate-risk patients, is not widely adopted because of barriers in reimbursement. The impact of removing cost barrier on cardiovascular outcomes in real-world settings is not known. Within the University Hospitals Health System (Cleveland, Ohio), CAC was offered to patients with at least 1 cardiovascular risk factor at low charge between 2014 and 2017 ($99) and no charge from January 1, 2018 onward. CAC use and access, patient characteristics, reclassification of risk compared with the pooled cohort equations (PCEs) for atherosclerotic vascular disease, statin use, changes in parameters of cardiometabolic health, downstream cardiovascular testing, downstream coronary revascularization, and cardiovascular outcomes were evaluated. A total of 52,151 patients underwent CAC testing over the study period. Median 10-year PCE for atherosclerotic vascular disease, in the entire cohort was 8.3% (4.0% to 15.9%). Among patients with PCE20%, 21% had CAC100, whereas 37% of those with PCE7.5% had CAC ≥100. Among patients who were not on statin before CAC testing, 1-year statin prescription was 24% and was significantly associated with higher CAC scores. Total cholesterol, low-density lipoprotein cholesterol, and triglycerides all decreased significantly 1-year after CAC, and the degree of decrease was strongly linked with CAC scores. One year after CAC, 14% underwent noninvasive ischemic evaluation, 1.4% underwent invasive coronary angiography, and 0.9% underwent revascularization. The majority (74%) of revascularization procedures occurred in patients with CAC400. In conclusion, reducing or removing the cost burden of CAC leads to significant test uptake by patients, which is followed by reclassification of statin eligibility, increases in the use of preventive medications, and improvement in risk factors, with very low rates of invasive downstream testing.

The American Society of Regional Anesthesia currently recommends ceasing antithrombotic medications for all spinal epidural steroid injections, however there is a paucity of data on the true risk of spinal epidurals via various approaches versus the risk of cessation of an agent as it relates to the underlying medical condition.This study evaluated the complication rate of caudal epidural steroid injections in patients who remain on antithrombotic medications.Retrospective chart review.Physiatric Spine Clinic in Orthopedic Specialty Office and Surgical Center.A retrospective chart review was performed identifying patients (n = 335) who received a caudal epidural steroid injection (n = 673) from June 2015 through April 2020. Patients were included if they had received the injection while taking an antithrombotic medication. Patients were excluded if they were not taking an antithrombotic. The patient's age, indication for the injection including magnetic resonance imaging or computed tomography findings, antithrombotic medication, the medical condition requiring an antithrombotic, and any complications following the injection were collected via chart review.Of the 443 injections included in the study, 51 encounters were lost to follow-up. Of the other 392 injections, there were no reported complications, regardless of the patient's imaging findings, age, the antithrombotic medication used, or the underlying medical condition for which an antithrombotic medication was indicated.This is a retrospective study. Therefore, a prospective study may have yielded fewer encounters lost to follow-up. Patients were not contacted directly after the procedure and chart reviews were utilized to evaluate for complications, which was limited to a patient's reporting of perceived complications without any imaging.We conclude that caudal epidural steroid injections can be performed safely in patients while taking antithrombotic medications. Catastrophic events have been observed in patients who have discontinued antithrombotic agents preceding procedures. Thus, discontinuing antithrombotic medications may pose a greater risk than benefit for patients on an antithrombotic medication who have painful lumbar radiculopathy.

OBJECTIVE This research aims to elucidate drivers of blood use in an older population, with a focus on unplanned transfusions following ED presentation. METHODS In a retrospective cohort study we examined 2015 data for ED presentations and blood use in two hospitals serving a population containing a high proportion (21%) of adults aged ≥65 years. Unplanned blood use was defined as any transfusion ≤24 h of presentation. Data were analysed by age, sex, Major Diagnostic Category, triage category and time to transfusion. RESULTS A total of 5294 blood components were transfused, comprising red cells (n = 3784), fresh frozen plasma (n = 657), platelets (n = 563) and cryoprecipitate (n = 290). Men aged ≥65 years were the highest users (40%, 2107 components). Unplanned transfusions accounted for 28% (n = 1057) of annual red cell use. Of 85 014 ED presentations, 494 (0.6%) were associated with unplanned red cell transfusion. Four Major Diagnostic Categories accounted for 81% (n = 853) of unplanned red cell use: gastrointestinal (n = 375), haematology (n = 267), trauma (n = 144) and cardiovascular (n = 67). Over one-fifth of unplanned transfusions (21%, n = 222 of 1057) were associated with ICD-10 codes for anaemia as a reason for presentation within the Haematology Major Diagnostic Category. Adults aged ≥65 years accounted for 62% of overall red cell use and 61% of transfusions ≤24 h of presentation. Odds of unplanned red cell transfusion increased with age, peaking at odds ratio 28.5 (95% confidence interval 14.2-57.4) in those aged 85 years and above. CONCLUSIONS Unplanned blood use accounted for 28% of annual hospital blood consumption. Blood component use increased with age and was greatest in older men. A significant burden of anaemia treatment was identified by the ED.

COVID-19 vaccination campaigns continue in the United States, with the expectation that vaccines will slow transmission of the virus, save lives, and enable a return to normal life in due course. However, the extent to which faster vaccine administration has affected COVID-19-related deaths is unknown. We assessed the association between US state-level vaccination rates and COVID-19 deaths during the first five months of vaccine availability. We estimated that by May 9, 2021, the US vaccination campaign was associated with a reduction of 139,393 COVID-19 deaths. The association varied in different states. In New York, for example, vaccinations led to an estimated 11.7 fewer COVID-19 deaths per 10,000, whereas Hawaii observed the smallest reduction, with an estimated 1.1 fewer deaths per 10,000. Overall, our analysis suggests that the early COVID-19 vaccination campaign was associated with reductions in COVID-19 deaths. As of May 9, 2021, reductions in COVID-19 deaths associated with vaccines had translated to value of statistical life benefit ranging between $625 billion and $1.4 trillion.

Re-admission is an important source of patient dissatisfaction and increased hospital costs. A simple calculator to determine the probability of re-admission may help guide patient dismissal planning.Using the national readmissions database (NRD), we identified admissions for isolated primary coronary artery bypass (CABG) and stratified them according to 30-day readmission. Including pre, intra and postoperative variables, we prepared a logistic regression model to determine the probability for re-admission. The model was tested for reliability with boot-strapping and 10-fold cross-validation.From 135,699 procedures, 19,355 were readmitted at least once within 30days of dismissal. Patients who were readmitted were older (67±10 vs 65 ± 10 years, p0.01), females (32% vs 24%; p0.01) and had a higher Elixhauser comorbidity score (1.5±1.4 vs 1.1±1.2; p0.01). Our final model (c- statistic=0.65) consisted of 16 pre and three postoperative factors. End-stage renal disease (OR 1.79 [1.57-2.04]) and length of stay9days (OR 1.60 [1.52-1.68]) were most prominent indicators for readmission. Compared to Medicaid beneficiaries, those with private insurance (OR 0.62 [0.57-0.68]) and Medicare (OR 0.85 [0.79-0.92]) coverage were less likely to be readmitted.Our simple 30-days CABG readmission calculator can be used as a strategic tool to help reduce readmissions after coronary artery bypass surgery.

It remains uncertain how advances in revascularization techniques, availability of new evidence, and updated guidelines have influenced the annual rates of coronary revascularization in the United States.We used the Nationwide Inpatient Sample data from 2005 to 2014 with appropriate weighting to determine national procedural volumes. To present accurately overall percutaneous coronary intervention (PCI) rates, PCI with same-day discharge numbers per year were estimated from the available literature and added to annual PCI procedures performed.Annual PCI rate declined from 353 per 100,000 adults in 2005 to 277 per 100,000 adults in 2009 (P.001) but remained stable thereafter (P = .50). Annual coronary artery bypass grafting (CABG) rate declined steadily, at a shallower slope than PCI, from 120 per 100,000 in 2005 to 93 per 100,000 in 2009 (P = .02) but remained stable thereafter (P = .60). Similar trends were seen in men and women. Both PCI and CABG rates were lower in women than men over the study period (PCI, 482 to 324/100,000 in men vs 232 to 153/100,000 in women; CABG, 172 to 118/100,000 in men vs 64 to 38/100,000 in women). Annual PCI rates were higher than CABG rates in patients of all age groups including in younger patients (age50) and octogenarians. The proportion of coronary revascularization procedures performed per insurance type remained relatively similar across the study period.Annual rates of coronary revascularization have changed significantly over time, potentially because of advances in revascularization techniques, availability of new evidence, and updated guidelines. Rates of PCI declined more steeply than CABG before plateauing but remained higher than rates of CABG across the study period.

Background: The Patient-Reported Outcomes Measurement Information System Upper Extremity (PROMIS UE) computer adaptive test was developed to improve precision and reduce question burden. We hypothesized that in patients with carpal tunnel syndrome (CTS): (1) PROMIS UE would correlate with established patient-reported outcome measures (PROs); (2) the time and number of questions required would be lower than current metrics; (3) there would be no floor or ceiling effects; and (4) PROMIS UE would not correlate with disease severity. Methods: Patients undergoing electrodiagnostic evaluation found to have a primary diagnosis of unilateral CTS prospectively completed PROMIS UE, Quick Disabilities of the Arm, Shoulder and Hand (qDASH), and Boston Carpal Tunnel Syndrome Questionnaire (BCTQ). Electrophysiologic and clinical severity was recorded. The relationships among PROs were described with Spearman coefficients. A floor or ceiling effect was confirmed if >15% of patients achieved the lowest or highest possible score, respectively. Results: Fifty-one patients (average, 53.9 years) were enrolled. An excellent correlation was identified between PROMIS UE and qDASH ( R = −0.76, P < .001). There was a good correlation between PROMIS UE and BCTQ ( R = −0.58, P < 0.001). The PROMIS UE required less time and fewer questions than qDASH and BCTQ ( P = .02 and P < .001). There were no floor or ceiling effects. Neither neurophysiologic nor clinical severity correlated with PROMIS UE ( R = 0.24, P > .05 and R = −0.18, P > .05). Conclusions: The PROMIS UE has an excellent correlation with qDASH and a good correlation with BCTQ in patients with CTS. Furthermore, PROMIS UE required less time and fewer questions than established PROs. Used as a single PRO, PROMIS UE represents a practical alternative to current metrics in patients with CTS.

Leukocyte integrin-dependent downregulation of the transcription factor FOXP1 is required for monocyte differentiation and macrophage functions, but the precise gene regulatory mechanism is unknown. Here, we identify multi-promoter structure (P1, P2, and P3) of the human FOXP1 gene. Clustering of the β(2)-leukocyte integrin Mac-1 downregulated transcription from these promoters. We extend our prior observation that IL-1 receptor-associated kinase 1 (IRAK1) is physically associated with Mac-1 and provide evidence that IRAK1 is a potent suppressor of human FOXP1 promoter. IRAK1 reduced phosphorylation of histone deacetylase 4 (HDAC4) via inhibiting phosphorylation of calcium/calmodulin dependent protein kinase II delta (CaMKIIδ), thereby promoting recruitment of HDAC4 to P1 chromatin. A novel human FOXP1 intronic transcript 1 (FOXP1-IT1) long non-coding RNA (lncRNA), whose gene is embedded within that of FOXP1, has been cloned and found to bind directly to HDAC4 and regulate FOXP1 in cis manner. Overexpression of FOXP1-IT1 counteracted Mac-1 clustering-dependent downregulation of FOXP1, reduced IRAK1 downregulation of HDAC4 phosphorylation, and attenuated differentiation of THP-1 monocytic cells. In contrast, Mac-1 clustering inhibited FOXP1-IT1 expression with reduced binding to HDAC4 as well as phosphorylation of CaMKIIδ to activate the IRAK1 signaling pathway. Importantly, both IRAK1 and HDAC4 inhibitors significantly reduced integrin clustering-triggered downregulation of FOXP1 expression in purified human blood monocytes. Identification of this Mac-1/IRAK-1/FOXP1-IT1/HDAC4 signaling network featuring crosstalk between lncRNA and epigenetic factor for the regulation of FOXP1 expression provides new targets for anti-inflammatory therapeutics.

A 53-year-old woman with no significant medical history presented with 10/10 right buttock pain that radiated to the right groin. With no reported recent injury, the absence of fever, and no identifiable risk factors, an infectious etiology, including septic sacroiliitis (SSI), is at the end spectrum of the differential. SSI is a rare condition with nonspecific findings that can lead to major complications, including death. To our knowledge, there are only 4 recent major literature reviews on SSI, with most cases reported to have at least 1 risk factor or clinical sign indicating the possibility of an infectious etiology. The patient reported in this case had no identifiable risk factors; therefore, high clinical suspicion is needed to prevent debilitating consequences from prolonged infection. LEVEL OF EVIDENCE: V.

Registries show international variations in the characteristics and outcome of patients with heart failure (HF), but national samples are rarely large, and case selection may be biased owing to enrolment in academic centers. National administrative datasets provide large samples with a low risk of bias. In this study, we compared the characteristics, health care resource use (HRU) and outcomes of patients with primary HF hospitalizations (HFH) using electronic health records (EHR) from 4 high-income countries (United States, UK, Taiwan, Japan) on 3 continents.We used electronic health record to identify unplanned HFH between 2012 and 2014. We identified 231,512, 10,991, 36,900, and 133,982 patients with a primary HFH from the United States, the UK, Taiwan, and Japan, respectively. HFH per 100,000 population was highest in the United States and lowest in Taiwan. Fewer patients in Taiwan and Japan were obese or had chronic kidney disease. The length of hospital stay was shortest in the United States (median 4 days) and longer in the UK, Taiwan, and Japan (medians of 7, 9, and 17 days, respectively). HRU during hospitalization was highest in Japan and lowest in UK. Crude and direct standardized in-hospital mortality was lowest in the United States (direct standardized rates 1.8, 95% confidence interval 1.7%-1.9%) and progressively higher in Taiwan (direct standardized rates 3.9, 95% CI 3.8%-4.1%), the UK (direct standardized rates 6.4, 95% CI 6.1%-6.7%), and Japan (direct standardized rates 6.7, 95% CI 6.6%-6.8%). The 30-day all-cause (25.8%) and HF (7.2%) readmissions were highest in the United States and lowest in Japan (11.9% and 5.1%, respectively).Marked international variations in patient characteristics, HRU, and clinical outcomes exist; understanding them might inform health care policy and international trial design.

Neutrophils are essential to protect the host against invading pathogens but can promote disease progression in sickle cell disease (SCD) by becoming adherent to inflamed microvascular networks in peripheral tissue throughout the body. During the inflammatory response, leukocytes extravasate from the bloodstream using selectin adhesion molecules and migrate to sites of tissue insult through activation of integrins that are essential for combating pathogens. However, during vaso-occlusion associated with SCD, neutrophils are activated during tethering and rolling on selectins upregulated on activated endothelium that line blood vessels. Recently, we reported that recognition of sLex on L-selectin by E-selectin during neutrophil rolling initiates shear force resistant catch-bonds that facilitate tethering to endothelium and activation of integrin bond clusters that anchor cells to the vessel wall. Evidence indicates that blocking this important signaling cascade prevents the congestion and ischemia in microvasculature that occurs from neutrophil capture of sickled red blood cells, which are normally deformable ellipses that flow easily through small blood vessels. Two recently completed clinical trials of therapies targeting selectins and their effect on neutrophil activation in small blood vessels reveal the importance of mechanoregulation that in health is an immune adaption facilitating rapid and proportional leukocyte adhesion, while sustaining tissue perfusion. We provide a timely perspective on the mechanism underlying vaso-occlusive crisis (VOC) with a focus on new drugs that target selectin mediated integrin adhesive bond formation.

Background: Low- and-middle-income-countries (LMICs) currently bear 80% of the world’s cardiovascular disease (CVD) mortality burden. The same countries are underequipped to handle the disease burden due to critical shortage of resources. Functional cardiac catheterization laboratories (cath labs) are central in the diagnosis and management of CVDs. Yet, most LMICs, including Uganda, fall remarkably below the minimum recommended standards of cath lab:population ratio due to a host of factors including the start-up and recurring costs. Objectives: To review the performance, challenges and solutions employed, lessons learned, and projections for the future for a single cath lab that has been serving the Ugandan population of 40 million people in the past eight years. Methods: A retrospective review of the Uganda Heart Institute cath lab clinical database from 15 February 2012 to 31 December 2019 was performed. Results: In the initial two years, this cath lab was dependent on skills transfer camps by visiting expert teams, but currently, Ugandan resident specialists independently operate this lab. 3,542 adult and pediatric procedures were conducted in 8 years, including coronary angiograms and percutaneous coronary interventions, device implantations, valvuloplasties, and cardiac defect closures, among others. There was a consistent expansion of the spectrum of procedures conducted in this cath lab each year. The initial lack of technical expertise and sourcing for equipment, as well as the continual need for sundries present(ed) major roadblocks. Government support and leveraging existing multi-level collaborations has provided a platform for several solutions. Sustainability of cath lab services remains a significant challenge especially in relation to the high cost of sundries and other consumables amidst a limited budget. Conclusion: A practical example of how centers in LMIC can set up and sustain a public cardiac catheterization laboratory is presented. Government support, research, and training collaborations, if present, become invaluable leverage opportunities.

The Institutions for Mental Diseases (IMD) exclusion prohibits use of federal Medicaid funds to treat enrollees ages 21-64 in psychiatric residential treatment facilities that have more than sixteen beds. In 2015 the federal government created a streamlined application pathway for state waivers of this rule to allow Medicaid coverage for substance use disorder (SUD) treatment in residential facilities. Nine states received IMD waivers during the period 2015-18. Using data from the 2010-18 National Survey of Substance Abuse Treatment Services, we examined changes in residential and outpatient SUD treatment facilities' acceptance of Medicaid and other types of health coverage, as well as self-pay arrangements and provision of charity care, after states' adoption of IMD waivers. Acceptance of Medicaid increased 34 percent at residential treatment facilities and 9 percent at intensive outpatient facilities two years after waiver implementation. Delivery of medications for opioid use disorder did not increase in residential facilities post waiver but did increase to some extent in outpatient facilities. Our findings suggest that IMD waivers may be an important tool for advancing access to a full continuum of SUD treatment for Medicaid enrollees.

OBJECTIVES To compare clinical outcomes in high bleeding risk (HBR) patients with and without complex percutaneous coronary intervention (PCI) treated with Resolute Onyx zotarolimus-eluting stents (ZES) after 1-month dual antiplatelet therapy (DAPT). BACKGROUND PCI with 1-month DAPT has been demonstrated to be safe in HBR patients treated with Resolute Onyx ZES. Whether these outcomes are consistent in patients with complex lesions is uncertain. METHODS Among HBR patients who were event-free 1��month after PCI with ZES and treated thereafter with single antiplatelet therapy (SAPT), the clinical outcomes between 1 month and 1 year were compared after complex PCI (3 vessels treated, ��� 3 lesions treated, total stent length > 60���mm, bifurcation with ��� 2 stents implanted, atherectomy, or left main, surgical bypass graft or chronic total occlusion PCI) versus noncomplex PCI. Propensity score adjustment was performed to adjust for baseline differences among complex and noncomplex patients. RESULTS Complex patients (N��=��401, 26.6% of total) had a higher prevalence of hyperlipidemia, diabetes mellitus and previous myocardial infarction (MI). Between 1 month and 1 year, rates of MI (7.1% vs. 4.0%, p��=��0.02) and cardiac death/MI (9.3% vs. 6.1%, p��=��0.04) were higher among complex versus noncomplex patients, although stent thrombosis rates were similar. After adjustment for baseline characteristics, differences in outcomes were no longer significant between groups. CONCLUSIONS Higher rates of ischemic outcomes in complex PCI patients were largely explained by baseline clinical differences, rather than lesion complexity, among HBR patients treated with 1-month DAPT following PCI with Resolute Onyx ZES.

Changes in the microbiota composition are associated with many human diseases, but factors that govern strain abundance remain poorly defined. We show that a commensal Escherichia coli strain and a pathogenic Salmonella enterica serovar Typhimurium isolate both utilize nitrate for intestinal growth, but each accesses this resource in a distinct biogeographical niche. Commensal E.coli utilizes epithelial-derived nitrate, whereas nitrate in the niche occupied by S. Typhimurium is derived from phagocytic infiltrates. Surprisingly, avirulent S. Typhimurium was shown to be unable to utilize epithelial-derived nitrate because its chemotaxis receptors McpB and McpC exclude the pathogen from the niche occupied by E.coli. In contrast, E.coli invades the niche constructed by S. Typhimurium virulence factors and confers colonization resistance by competing for nitrate. Thus, nutrient niches are not defined solely by critical resources, but they can be further subdivided biogeographically within the host into distinct microhabitats, thereby generating new niche opportunities for distinct bacterial species.

Superparamagnetic iron oxide nanoparticles (SPION) are employed as diagnostics and therapeutics following intravenous delivery for the treatment of iron deficiency anemia (IDA) in adult patients with chronic kidney failure. Neutrophils are the first defense against blood borne foreign insult and recruit to vascular sites of inflammation via a sequential process that is characterized by adhesive capture, rolling, and shear resistant arrest. A primary chemotactic agonist presented on the glycocalyx of inflamed endothelium is IL-8, which upon binding to its cognate membrane receptor (CXCR1/2) activates a suite of responses in neutrophils. An early response is degranulation with accompanying upregulation of β2-integrin (CD11/CD18) and shedding of L-selectin (CD62L) receptors, which exert differential effects on the efficiency of endothelial recruitment. Feraheme is an FDA approved SPION treatment for IDA, but its effect on the innate immune response of neutrophils during inflammation has not been reported. Here, we studied the immunomodulatory effects of Feraheme on neutrophils freshly isolated from healthy human subjects and stimulated in suspension or on inflammatory mimetic substrates with IL-8. Cells treated with Feraheme exhibited reduced sensitivity to stimulation with IL-8, indicated by reduced upregulation of membrane CD11b/CD18 receptors, high affinity (HA) CD18, and shedding of CD62L. Feraheme also inhibited N-formyl-Met-Leu-Phe (fMLP) induced reactive oxygen species production. Neutrophil rolling, arrest, and migration was assessed in vascular mimetic microfluidic channels coated with E-selectin and ICAM-1 to simulate inflamed endothelium. Neutrophils exposed to Feraheme rolled faster on E-selectin and arrested less frequently on ICAM-1, in a manner dependent upon SPION concentration. Subsequent neutrophil shape change, and migration were also significantly inhibited in the presence of Feraheme. Lastly, Feraheme accelerated clearance of cytosolic calcium flux following IL-8 stimulation. We conclude that uptake of Feraheme by neutrophils inhibits chemotactic activation and downregulates normal rolling to arrest under shear flow. The mechanism involves increased calcium clearance following chemotactic activation, which may diminish the efficiency of recruitment from the circulation at vascular sites of inflammation.

Extremity reconstruction surgery is increasingly performed rather than amputation for patients with large-segment pathologic bone loss. Debate persists as to the optimal void filler for this “limb salvage” surgery, whether metal or allograft bone. Clinicians focus on optimizing important functional gains for patients, and the risk of devastating implant infection has been thought to be similar regardless of implant material. Recent insights into infection pathophysiology are challenging this equipoise, however, with both basic science data suggesting a novel mechanism of infection of Staphylococcus aureus (the most common infecting agent) into the host lacunar–canaliculi network, and also clinical data revealing a higher rate of infection of allograft over metal. The current translational study was therefore developed to bridge the gap between these insights in a longitudinal murine model of infection of allograft bone and metal. Real-time Staphylococci infection characteristics were quantified in cortical bone vs metal, and both microarchitecture of host implant and presence of host immune response were assessed. An orders-of-magnitude higher bacterial burden was established in cortical allograft bone over both metal and cancellous bone. The establishment of immune-evading microabscesses was confirmed in both cortical allograft haversian canal and the submicron canaliculi network in an additional model of mouse femur bone infection. These study results reveal a mechanism by which Staphylococci evasion of host immunity is possible, contributing to elevated risks of infection in cortical bone. The presence of this local infection reservoir imparts massive clinical implications that may alter the current paradigm of osteomyelitis and bulk allograft infection treatment.

Supplemental Digital Content is available in the text., Background: Despite treatment guidance endorsing shortened dual antiplatelet therapy (DAPT) duration in high bleeding risk (HBR) patients after drug-eluting stents, limited evidence exists to support these recommendations. The present study was designed to examine the safety and effectiveness of 1-month DAPT duration following percutaneous coronary intervention with zotarolimus-eluting stents in HBR patients. Methods: Onyx ONE Clear was a prospective, multicenter, nonrandomized study evaluating the safety and effectiveness of 1-month DAPT followed by single antiplatelet therapy in HBR patients undergoing percutaneous coronary intervention with Resolute Onyx drug-eluting stents. The primary analysis of cardiac death or myocardial infarction between 1 month and 1 year was performed in the prespecified one-month clear population of patients pooled from the Onyx ONE US/Japan study and Onyx ONE randomized controlled trial. One-month clear was defined as DAPT adherence and without major adverse events during the first month following percutaneous coronary intervention. Results: Among patients enrolled in Onyx ONE US/Japan (n=752) and Onyx ONE randomized controlled trial (n=1018), 1506 patients fulfilled one-month clear criteria. Mean HBR characteristics per patient was 1.6 with 44.7% having multiple risks. By 2 months and 1 year, respectively, 96.9% and 89.3% of patients were taking single antiplatelet therapy. Between 1 month and 1 year, the rate of the primary end point was 7.0%. The 1-sided upper 97.5% CI was 8.4%, less than the performance goal of 9.7% (P

We share our center's experience with the use of transcatheter valvular therapies in the setting of failed bioprostheses.As medicine continues to advance, the lifespan of individuals continues to increase, and current surgical valvular therapies begin to degrade prior to a person's end of life. It is important to evaluate the efficacy and durability of transcatheter valves within failed surgical bioprostheses.Baseline characteristics, periprocedural complications, and long-term outcomes were collected and assessed in patients who received transcatheter valves for failing surgical aortic valve bioprostheses and mitral valve and ring bioprostheses from March 2011 to July 2018.From our cohort of 1048 patients, we identified 45 individuals (4.3%) who underwent transcatheter replacement of a failed bioprosthetic valve or ring. Mean age at presentation was 80.8 ± 10.7 years and 75.5 ± 9.3 years, mean STS score was 9.3 ± 5.1 and 13.3 ± 8.7, and mean time to failure was 12.0 ± 5.2 years and 7.3 ± 4.5 years for aortic and mitral positions, respectively. At 1 year, time to event analysis suggested a 16.4% mortality rate for aortic replacement and 12.8% mortality rate for mitral replacement.We demonstrate outcomes from one of the largest single-center United States based cohorts of transcatheter replacements of failed surgical bioprostheses. Our center has demonstrated that it is feasible to pursue the replacement of failed surgical bioprostheses in the aortic and mitral positions with transcatheter valves given appropriate patient selection.

A growing body of literature examining the effects of the Affordable Care Act (ACA) on nonelderly adults provides promising evidence of improvements in health outcomes through insurance expansions. Our review of forty-three studies that employed a quasi-experimental research design found encouraging evidence of improvements in health status, chronic disease, maternal and neonatal health, and mortality, with some findings corroborated by multiple studies. Some studies further suggested that the beneficial effects have grown over time and thus may continue to grow if the ACA insurance expansions remain in force. However, not all studies reported a significant positive relationship between ACA provisions that expanded insurance coverage and health status. We highlight the challenges facing researchers, including the importance of nonmedical factors in determining individual health and the use of outcome data predominantly drawn from self-reports. In closing, we identify opportunities to enhance researchers' understanding of the relationship between the ACA insurance expansions and health outcomes using new data sources, including electronic health records.

Recruitment of leukocytes to sites of acute inflammation is guided by spatial and temporal cues that ensure appropriate cell numbers infiltrate the tissue at precise locations to protect it from infection and initiate repair. On inflamed endothelium, neutrophil rolling via selectins elicits cytosolic calcium release from endoplasmic reticulum (ER)-stores that are synergistic with chemokine signaling to activate formation of high affinity (HA) LFA-1 bonds to ICAM-1, which is necessary to anchor cells against the drag force of blood flow. Bond tension on LFA-1 within the area of adhesive contact with endothelium elicits calcium entry through calcium release-activated calcium channel protein 1 (Orai-1) membrane channels that in turn activate neutrophil shape change and migration. We hypothesized that mechanotransduction via LFA-1 is mediated by assembly of a cytosolic molecular complex consisting of Kindlin-3, receptor for activated C kinase 1 (RACK1), and Orai1. Initiation of Ca2+ flux at sites of adhesive contact required a threshold level of shear stress and increased with the magnitude of bond tension transduced across as few as 200 HA LFA-1. A sequential mechanism triggered by force acting on LFA-1/Kindlin-3 precipitated dissociation of RACK1, which formed a concentration gradient above LFA-1 bond clusters. This directed translocation of ER proximal to Orai1, where binding of inositol 1,4,5-triphosphate receptor type 1 and activation via stromal interaction molecule 1 elicited Ca flux and subsequent neutrophil shape change and motility. We conclude that neutrophils sense adhesive traction on LFA-1 bonds on a submicron scale to direct calcium influx, thereby ensuring sufficient shear stress of blood flow is present to trigger cell arrest and initiate transmigration at precise regions of vascular inflammation.

Background: polymer-free drug-coated stents provide superior clinical outcomes to bare-metal stents in patients at high bleeding risk who undergo percutaneous coronary intervention (PCI) and are treated with 1 month of dual antiplatelet therapy. Data on the use of polymer-based drug-eluting stents, as compared with polymer-free drug-coated stents, in such patients are limited. Methods: in an international, randomized, single-blind trial, we compared polymer-based zotarolimus-eluting stents with polymer-free umirolimus-coated stents in patients at high bleeding risk. After PCI, patients were treated with 1 month of dual antiplatelet therapy, followed by single antiplatelet therapy. The primary outcome was a safety composite of death from cardiac causes, myocardial infarction, or stent thrombosis at 1 year. The principal secondary outcome was target-lesion failure, an effectiveness composite of death from cardiac causes, target-vessel myocardial infarction, or clinically indicated target-lesion revascularization. Both outcomes were powered for noninferiority. Results: a total of 1996 patients at high bleeding risk were randomly assigned in a 1:1 ratio to receive zotarolimus-eluting stents (1003 patients) or polymer-free drug-coated stents (993 patients). At 1 year, the primary outcome was observed in 169 of 988 patients (17.1%) in the zotarolimus-eluting stent group and in 164 of 969 (16.9%) in the polymer-free drug-coated stent group (risk difference, 0.2 percentage points; upper boundary of the one-sided 97.5% confidence interval [CI], 3.5; noninferiority margin, 4.1; P = 0.01 for noninferiority). The principal secondary outcome was observed in 174 patients (17.6%) in the zotarolimus-eluting stent group and in 169 (17.4%) in the polymer-free drug-coated stent group (risk difference, 0.2 percentage points; upper boundary of the one-sided 97.5% CI, 3.5; noninferiority margin, 4.4; P = 0.007 for noninferiority). Conclusions: among patients at high bleeding risk who received 1 month of dual antiplatelet therapy after PCI, use of polymer-based zotarolimus-eluting stents was noninferior to use of polymer-free drug-coated stents with regard to safety and effectiveness composite outcomes. (Funded by Medtronic; ONYX ONE ClinicalTrials.gov number, NCT03344653.).

Atrioventricular conduction disturbances requiring implantation of permanent pacemaker (PPM) are a common complication following transcatheter aortic valve implantation (TAVI). Previous registry data are conflicting but suggestive of an increased risk in heart failure admissions in the post-TAVI PPM cohort. Given the expanding use of TAVI, the present study evaluates the effects of chronic right ventricular pacing (RV pacing) in post-TAVI patients. This is a single-center study of 672 patients who underwent TAVI from 2011 to 2017 of which 146 underwent PPM. Follow-up 1-year post-TAVI outcome data were available for 55 patients and were analyzed retrospectively. Patients who underwent PPM were more likely to have heart failure admissions (17.1% vs 10.1%; hazard ratio [HR] 1.70; 95% confidence interval [CI] 1.10 to 2.64; p 0.019) and a trend toward increased mortality (21.9% vs 15.4%; HR 1.42; 95% CI 0.99 to 2.05; p 0.062). At 1-year follow-up, 30 of 55 (54.5%) patients demonstrated40% RV pacing. Compared with patients who had40% RV pacing, those with40% RV pacing were more likely to have heart failure admissions (8% vs 40%; HR 5.0; 95% CI 1.23 to 20.27; p 0.007) and demonstrated a trend toward increased mortality (12% vs 33.3%; HR 2.78; 95% CI 0.86 to 9.00; p 0.064). This is suggestive that the post-TAVI PPM cohort is particularly sensitive to chronic RV pacing.

Prostate cancer responds to therapies that suppress androgen receptor (AR) activity (androgen deprivation therapy, ADT) but invariably progresses to castration-resistant prostate cancer (CRPC). The Tec family nonreceptor tyrosine kinase BMX is activated downstream of PI3K and has been implicated in regulation of multiple pathways and in the development of cancers including prostate cancer. However, its precise mechanisms of action, and particularly its endogenous substrates, remain to be established. Here, we demonstrate that BMX expression in prostate cancer is suppressed directly by AR via binding to the BMX gene and that BMX expression is subsequently rapidly increased in response to ADT. BMX contributed to CRPC development in cell line and xenograft models by positively regulating the activities of multiple receptor tyrosine kinases through phosphorylation of a phosphotyrosine-tyrosine (pYY) motif in their activation loop, generating pYpY that is required for full kinase activity. To assess BMX activity in vivo, we generated a BMX substrate–specific antibody (anti-pYpY) and found that its reactivity correlated with BMX expression in clinical samples, supporting pYY as an in vivo substrate. Inhibition of BMX with ibrutinib (developed as an inhibitor of the related Tec kinase BTK) or another BMX inhibitor BMX-IN-1 markedly enhanced the response to castration in a prostate cancer xenograft model. These data indicate that increased BMX in response to ADT contributes to enhanced tyrosine kinase signaling and the subsequent emergence of CRPC, and that combination therapies targeting AR and BMX may be effective in a subset of patients. Significance: The tyrosine kinase BMX is negatively regulated by androgen and contributes to castration-resistant prostate cancer by enhancing the phosphorylation and activation of multiple receptor tyrosine kinases following ADT. Cancer Res; 78(18); 5203–15. ©2018 AACR.

Psoriasis patients experience chronic systemic skin inflammation and develop cardiovascular comorbidities that shorten their lifespan. Whether cardiovascular disease is improved by treatment with current biologics that target disease-specific pathways is unclear. KC-Tie2 mice develop psoriasiform skin inflammation with increases in IL-23 and IL-17A and proinflammatory monocytosis and neutrophilia that precedes development of carotid artery thrombus formation. To examine whether targeted blockade of IL-23 or IL-17A in KC-Tie2 pso- riasis mice improves cardiovascular outcomes, mice were treated systemically for 6 weeks with antibodies targeting IL-17A, IL-17RA, IL-12/23p40, or IL-23p19. Skin inflammation; thrombosis clotting times; and percentage of splenic monocytes, neutrophils, and CD4 T cells were examined. Skin inflammation significantly improved in KC-Tie2 mice treated with each of the antibodies targeting IL-23, IL-17A, or IL-17RA, consistent with clinical efficacy observed in psoriasis patients. The time to occlusive thrombus formation lengthened in these mice and correlated with attenuated acanthosis. This decrease in skin inflammation paralleled decreases in splenic neutrophils (CD11b(+)Ly6G(+)) but not monocytes (CD11b(+)Ly6C(high)) or T cells (CD4(+)). Our data show that targeted inhibition of IL-23 or IL-17A improves psoriasis-like skin disease and also improves cardiovascular disease in mice.

Objective The normal process of skin tissue repair following injury invariably results in visual scarring. It is known that topical treatment with hydrophobic cosmetics rich in silicone and mineral oil content can improve the appearance of scars and striae. Given lifestyle preferences of many cosmetic consumers towards so-called natural treatments, the objective of this controlled randomized study was to investigate the efficacy of a plant body oil rich in oleic and linoleic acids (Bio Skin Oil® ) for improving the appearance of scars and striae. Methods A panel of 80 volunteers with non-hypertrophic scars (40) or stretch marks (40) not older than 3 years applied a cosmetic face and body oil for 8 weeks. Compared to an untreated scar/stretch mark region, a blinded investigator as well as volunteer assessments with given observed parameters demonstrated the efficacy of the oil under test. Results On the Observer Scar Assessment Scale (OSAS), the mean score was reduced on the product-treated area by approximately 5% (P = 0.006). The untreated area remained unchanged. Observed effects by volunteers were more pronounced - Patient Scar Assessment Scale (PSAS) giving a reduction of approximately 20% on the treated area, and on the control untreated area a reduction of approximately 6%. The overall product effect of 14% was shown to be clearly significant (P = 0.001). All statements relating to product traits achieved higher frequencies of agreements than of non-agreements and were therefore assessed positively by the volunteers. Highest frequencies of agreements occurred in statements that the test product provides a long-lasting, soft and supple skin feeling (93%); caring effect (87%); and quick absorbance (84%). Agreement was also found for statements that the product improves the skin appearance (61%) and that scars/striae appear less pronounced (51%). Only 17% of volunteers felt the oil had no benefit to the appearance of their scars/striae. Conclusions The oil blend under test is effective in improving the appearance of non-keloid scars and striae. Further work is required to understand the mechanisms of how plant oil fatty acids ameliorate scar and striae appearance.

Background The alarmin family member myeloid-related protein (MRP)-14 (S100A9), which has been identified by platelet transcriptional profiling as an acute myocardial infarction gene, regulates vascular inflammation and thrombosis. Elevated plasma levels of MRP-8/14 (S100A8/A9) heterodimer predict first and recurrent cardiovascular events. The aim of this study was to elucidate pathophysiological roles of MRP-8/14 in acute coronary syndrome (ACS). Methods and results In 38 consecutive ACS patients, the MRP-8/14 level in coronary artery blood obtained at thrombus aspiration was higher in 23 patients, in whom aspirated thrombus was confirmed, compared to the 15 patients, in whom it was absent [4.86 (1.95, 8.29) vs 2.94 (1.31, 4.44), P =0.017]. The MRP-8/14 level was correlated with myeloperoxidase (MPO) level (R 2 =0.52), but not with soluble P-selectin level (R 2 =0.0002) in the coronary artery blood. Immunohistochemistry of the aspirated thrombus exhibited that expression of MRP8/14 was co-localized with leukocytes positive for activated Mac-1. Finally, in cultured human umbilical vein endothelial cells, MRP-8/14 increased tissue factor expression. Conclusions Our findings indicate that MRP-8/14 concentration increases in coronary artery blood in association with thrombus formation in ACS, co-localizes with leukocytes, and is associated with leukocyte activation. MRP-8/14 is positioned as a unique biomarker at the interface of inflammation and thrombosis in ACS.

Objective Determine the feasibility and predictors of early discharge after minimalist transcatheter aortic valve replacement (TAVR). Background Duration of hospitalization has a direct impact on overall cost of care, but the clinical impact of length of stay (LOS) in patients undergoing minimalist TAVR remains unclear. Methods We studied 268 patients who underwent minimalist TAVR. Short LOS (sLOS) was defined as post-procedural LOS ≤ 3 days and observed in 163 patients. Prolonged LOS (pLOS) was observed in 105 patients. Propensity score matching based on 39 variables yielded 54 pairs of patients in each group. We analyzed 30-day mortality, 30-day re-hospitalization and long-term survival data. Multivariate regression models were used to define predictors of sLOS. Results Thirty-day mortality was 0% versus 5.5% in the sLOS and pLOS groups, respectively (P = 0.08). Incidence of re-hospitalization was higher in pLOS (13% vs. 3.7%). sLOS was associated with lower odds ratio of minor vascular complication (OR 0.1 [95% CI: 0.01, 0.75], P = 0.05), any bleeding (OR 0.35 [95% CI: 0.14, 0.87], P = 0.02), blood transfusion (OR 0.27 [95% CI: 0.08, 0.81], P = 0.02), and new pacemaker implantation (OR 0.23 [95% CI: 0.1, 0.53], P

Background More than 20% of Medicare beneficiaries receiving cardiac resynchronization therapy defibrillators (CRT-D) have a very wide (≥180 ms) QRS complex duration (QRSD). Outcomes of CRT-D in these patients are not well-established because they have been underrepresented in clinical trials. Objectives This study examined outcomes in patients with CRT-D in a very wide QRSD with left bundle branch block (LBBB) versus those without LBBB. Methods Medicare patients from the Implantable Cardioverter Defibrillator Registry (January 1, 2005, through April 30, 2006) with a CRT-D and confirmed Class I or IIa indications for CRT-D were matched to implantable cardioverter-defibrillator (ICD) patients without CRT despite having Class I or IIa indications for CRT. Mortality and heart failure hospitalizations over 4 years with CRT-D versus standard ICDs based on QRSD and morphology were analyzed. Results We analyzed 24,960 patients. Among those with LBBB, patients with a QRSD ≥180 ms had a greater adjusted survival benefit with CRT-D versus standard ICD (hazard ration [HR] for death: 0.65; 95% confidence interval [CI]: 0.59 to 0.72) compared with those having a QRSD 120 to 149 ms (HR: 0.85; 95% CI: 0.80 to 0.92) and 150 to 179 ms (HR: 0.87; 95% CI: 0.81 to 0.93). CRT-D versus ICD was associated with an improvement in survival in those with non-LBBB and a QRSD ≥180 ms (adjusted HR for death: 0.78; 95% CI: 0.68 to 0.91), but not in those with non-LBBB and a QRSD 150 to 179 ms (adjusted HR for death: 1.06; 95% CI: 0.95 to 1.19). Conclusions Improvements in both survival and heart failure hospitalizations with CRT-D were greatest in patients with a QRSD ≥180 ms with or without LBBB, whereas patients with a QRSD 150 to 179 ms without LBBB had no improvement in survival with CRT-D, and those with a QRSD 150 to 179 ms and LBBB had only a modest improvement.

Mesenchymal stem cell therapies promote wound healing by manipulating the local environment to enhance the function of host cells. Aggregation of mesenchymal stem cells (MSCs) into three-dimensional spheroids increases cell survival and augments their anti-inflammatory and proangiogenic potential, yet there is no consensus on the preferred conditions for maximizing spheroid function in this application. The objective of this study was to optimize conditions for forming MSC spheroids that simultaneously enhance their anti-inflammatory and proangiogenic nature. We applied a design of experiments (DOE) approach to determine the interaction between three input variables (number of cells per spheroid, oxygen tension, and inflammatory stimulus) on MSC spheroids by quantifying secretion of prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF), two potent molecules in the MSC secretome. DOE results revealed that MSC spheroids formed with 40,000 cells per spheroid in 1% oxygen with an inflammatory stimulus (Spheroid 1) would exhibit enhanced PGE2 and VEGF production versus those formed with 10,000 cells per spheroid in 21% oxygen with no inflammatory stimulus (Spheroid 2). Compared to Spheroid 2, Spheroid 1 produced fivefold more PGE2 and fourfold more VEGF, providing the opportunity to simultaneously upregulate the secretion of these factors from the same spheroid. The spheroids induced macrophage polarization, sprout formation with endothelial cells, and keratinocyte migration in a human skin equivalent model—demonstrating efficacy on three key cell types that are dysfunctional in chronic non-healing wounds. We conclude that DOE-based analysis effectively identifies optimal culture conditions to enhance the anti-inflammatory and proangiogenic potential of MSC spheroids.

Aims Most reports estimating national incidence rates of coronary (CAD) and peripheral arterial disease (PAD) have focused on stable outpatients or acute or elective hospital admissions, but not on the overall burden of disease. In this study, we report the changing trends in the population-level incidence of CAD and PAD, respectively from 2006 to 2015, statin utilization for secondary prevention and survival outcomes using multiple nationally representative data sources from the UK (primary care encounters, hospital admissions, and procedure-level data). Methods and results A nationally representative study of linked primary and secondary care electronic health records of 4.6 million individuals from the UK. We calculated crude and standardized annual incidence rates separately for CAD and PAD. Statin use for secondary prevention, trends in annual major vascular event rates, and mortality between 2006 and 2015, were estimated for CAD and PAD, respectively. We identified 160 376 and 70 753 patients with incident CAD and PAD, respectively. The age- and sex-standardized incidence of CAD was similar in 2006 (443 per 100 000 person-years) and 2015 [436 per 100 000 person-years; adjusted incidence rate ratio (IRR) 0.98, 95% confidence interval (CI) 0.96–1.00]. In contrast, there was a 15% decline in the standardized incidence of PAD (236 per 100 000 person-years in 2006 to 202 per 100 000 person-years in 2015; adjusted IRR 0.85, 95% CI 0.82–0.88). The proportion of incident CAD and PAD patients prescribed long-term statins, was only 66% and 55%, respectively and was less common amongst women, patients aged >70 years, with heart failure, chronic lung disease, or depression. Cardiovascular mortality declined by 43% for incident CAD (adjusted IRR 0.57, 95% CI 0.50–0.64) between 2006 and 2015 but did not decline for incident PAD (adjusted IRR 0.84, 95% CI 0.70–1.00). Conclusion and relevance In the UK, the standardized incidence of CAD appears stable but mortality rates are falling, whereas the standardized incidence of PAD is falling but mortality rates are not.