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Although percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) has been increasing in recent years, CTO PCI is still one of the most challenging procedures with relatively higher rates of procedural complications and adverse clinical events after PCI. Due to the innate limitations of invasive coronary angiography, intravascular imaging (IVI) has been used as an adjunctive tool to complement PCI, especially in complex coronary artery disease. Considering the complexity of CTO lesions, the role of IVI is particularly important in CTO intervention. IVI has been a useful adjunctive tool in every step of CTO PCI including assisted wire crossing, confirmation of wire location within CTO segment, and stent optimization. The meticulous use of IVI has been one of the greatest contributors to recent progress of CTO PCI. Nevertheless, studies evaluating the role of IVI during CTO PCI are limited. The current review provides a comprehensive overview of the mechanistic advantages of IVI in CTO PCI, summarizes previous studies and trials, and presents future perspective of IVI in CTO PCI.

Abstract Cancer cells with BRCA1/2 deficiencies are sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. We evaluated the efficacy of talazoparib in DNA-Damage Repair (DDR)-altered patients. In this phase II trial, patients were enrolled onto one of four cohorts based on molecular alterations: (1) somatic BRCA1/2, (2) other homologous recombination repair pathway, (3) PTEN and (4) germline BRCA1/2. The primary endpoint was a clinical benefit rate (CBR): complete response, partial response or stable disease ≥24 weeks. 79 patients with a median of 4 lines of therapy were enrolled. CBR for cohorts 1–4 were: 32.5%, 19.7%, 9.4% and 30.6%, respectively. PTEN mutations correlated with reduced survival and a trend towards shorter time to progression.Talazoparib demonstrated clinical benefit in selected DDR-altered patients. PTEN mutations/loss patients derived limited clinical benefit. Further study is needed to determine whether PTEN is prognostic or predictive of response to PARP inhibitors.

Abstract Prognostic effect of discontinuing renin–angiotensin–aldosterone-system-inhibitor (RAASi) for patients with heart failure (HF) after acute myocardial infarction (AMI) whose left ventricular (LV) systolic function was restored during follow-up is unknown. To investigate the outcome after discontinuing RAASi in post-AMI HF patients with restored LV ejection fraction (EF). Of 13,104 consecutive patients from the nationwide, multicenter, and prospective Korea Acute Myocardial Infarction-National Institutes of Health (KAMIR-NIH) registry, HF patients with baseline LVEF

Background Recently, diastolic stress testing and invasive hemodynamic measurements have been emphasized for diagnosis of heart failure with preserved ejection fraction (HFpEF) because when determined using noninvasive parameters it can fall into a nondiagnostic intermediate range. The current study evaluated the discriminative and prognostic roles of invasive measured left ventricular end‐diastolic pressure in the population with suspected HFpEF, particularly for patients with intermediate Heart Failure Association Pre‐test Assessment, Echocardiography & Natriuretic Peptide, Functional Testing, Final Etiology (HFA‐PEFF) score. Methods and Results A total of 404 patients with symptoms or signs of HF and preserved left ventricular systolic function were enrolled. All subjects underwent left heart catheterization with left ventricular end‐diastolic pressure measurement for confirmation of HFpEF (≥16 mm Hg). The primary outcome was all‐cause death or readmission due to HF within 10 years. Among the study population, 324 patients (80.2%) were diagnosed as invasively confirmed HFpEF, and 80 patients (19.8%) were as noncardiac dyspnea. The patients with HFpEF showed a significantly higher HFA‐PEFF score than the patients with noncardiac dyspnea (3.8±1.8 versus 2.6±1.5, P

Abstract Cyclin E is frequently encoded by CCNE1 gene amplification in various malignancies. We reviewed the medical records of patients with solid tumors displaying CCNE1 amplification to determine the effect of this amplification for future therapeutic development. We reviewed the medical records of patients with advanced solid tumors harboring CCNE1 amplification who were seen at the phase I clinic between September 1, 2012, and December 31, 2019. Among 79 patients with solid tumors harboring CCNE1 amplification, 56 (71%) received phase 1 clinical trial therapy, 39 (49%) had 3 or more concurrent genomic aberrances, and 52 (66%) had a concurrent TP53 mutation. The median overall survival (OS) after patients’ initial phase I visit was 8.9 months and after their initial metastasis diagnosis was 41.4 months. We identified four factors associated with poor risk: age upper limit of normal. In patients treated with gene aberration-related therapy, anti-angiogenic therapy led to significantly longer OS after their initial phase I trial therapy than those who did not: 26 months versus 7.4 months, respectively (P = 0.04). This study provided preliminary evidence that CCNE1 amplification was associated with frequent TP53 mutation and aggressive clinical outcomes. Survival benefit was observed in patients who received antiangiogenic therapy and gene aberration-related treatment, supporting the future development of a personalized approach to combine gene aberration-related therapy with antiangiogenesis for the treatment of advanced malignancies harboring CCNE1 amplification.

Abstract Background Gel staining is a crucial step that allows the visualisation of proteins separated through SDS-PAGE. Colloidal Coomassie Brilliant Blue-G (CBB-G) staining is among the commonly used visualisation methods due to several factors such as compatibility with mass spectrometry (MS) analysis, sensitivity, reproducibility, and simplicity of the staining process. However, the standard colloidal CBB-G staining has a drawback: the resolution of protein bands is compromised because of diffusion of proteins during the washing step. Results A modification to an established colloidal CBB-G staining method, which greatly increases the resolution of protein bands, is described. The addition of a fixation step, which prevents the diffusion of proteins during the washing step, is shown to increase protein band resolution. Conclusion The fixation step is fast, flexible, and also retains all the advantages of the standard colloidal CBB-G staining methods. As there are no drawbacks, incorporating this fixation step into the standard colloidal CBB-G staining is an easy way to improve protein visualisation in SDS-PAGE. Graphical Abstract

This paper proposes HYPER, a method for screening more people using fewer tests by testing pools formed via hypergraph factorization. HYPER is not only efficient but is also simple to implement, flexible, and has maximally balanced pools.

Background Coronary microvascular dysfunction (CMD) has been considered as a possible cause of cardiac diastolic dysfunction. The current study evaluated the association between cardiac diastolic dysfunction and CMD, and their prognostic implications in patients without significant left ventricular systolic dysfunction and epicardial coronary stenosis. Methods and Results A total of 330 patients without left ventricular systolic dysfunction (ejection fraction ≥50%) and significant epicardial coronary stenosis (fractional flow reserve >0.80) were analyzed. Cardiac diastolic dysfunction was defined by echocardiographic parameters (early diastolic transmitral flow velocity/early diastolic mitral annular velocity, e' velocity, tricuspid regurgitation velocity, and left atrial volume index). Overt CMD was defined as coronary flow reserve

BackgroundThe prognostic role of myocardial ischemia in patients with heart failure with preserved ejection fraction (HFpEF) has not been fully elucidated. Therefore, we investigated the change in echocardiographic parameters and clinical outcomes based on the presence of epicardial coronary artery disease (CAD) and positive stress tests in HFpEF patients.MethodsSymptomatic patients with left ventricular end diastolic pressure ≥15 mmHg who underwent coronary angiography were analyzed between January 2000 and August 2019 after exclusion of patients with acute coronary syndrome.ResultsA total of 555 HFpEF patients were invasively confirmed, 285 (51%) had angiographically-proven CAD. HFpEF patients with CAD displayed greater deterioration in left ventricular ejection fraction (p = 0.002) over time but this was not observed in those without CAD (p = 0.99) on follow-up echocardiography; however, the mitral annulus early diastolic velocity (e') was significantly decreased in both groups (p < 0.001 and p = 0.003, respectively). Among 274 patients that received stress tests, those with positive stress tests showed a decline in e' (p 0.001), but this was not found in subjects with negative stress tests (p = 0.44). There was no significant difference in all-cause mortality between patients with CAD and without CAD (p = 0.26) with a median follow-up of 10.6 years.ConclusionIn HFpEF patients, CAD was associated with greater deterioration in the left ventricular systolic function but not with mortality during the follow-up. In addition, myocardial ischemia with a positive stress test may contribute to greater deterioration of diastolic dysfunction.

Background Intracoronary physiologic indexes such as coronary flow reserve (CFR) and left ventricular ejection fraction (LVEF) have been regarded as prognostic indicators in patients with coronary artery disease. The current study evaluated the association between intracoronary physiologic indexes and LVEF and their differential prognostic implications in patients with coronary artery disease. Methods and Results A total of 1889 patients with 2492 vessels with available CFR and LVEF were selected from an international multicenter prospective registry. Baseline physiologic indexes were measured by thermodilution or Doppler methods and LVEF was recorded at the index procedure. The primary outcome was target vessel failure, which was a composite of cardiac death, target vessel myocardial infarction, or clinically driven target vessel revascularization over 5 years of follow‐up. Patients with reduced LVEF

Abstract Background More than two-thirds of youth experience trauma during childhood, and up to 1 in 5 of these youth develops posttraumatic stress symptoms that significantly impair their functioning. Although trauma-focused cognitive behavior therapy (TF-CBT) has a strong evidence base, it is rarely adopted, delivered with adequate fidelity, or evaluated in the most common setting where youth access mental health services—schools. Given that individual behavior change is ultimately required for successful implementation, even when organizational factors are firmly in place, focusing on individual-level processes represents a potentially parsimonious approach. Beliefs and Attitudes for Successful Implementation in Schools (BASIS) is a pragmatic, motivationally focused multifaceted strategy that augments training and consultation and is designed to target precise mechanisms of behavior change to produce enhanced implementation and youth clinical outcomes. This study protocol describes a hybrid type 2 effectiveness-implementation trial designed to concurrently evaluate the main effects, mediators, and moderators of both the BASIS implementation strategy on implementation outcomes and TF-CBT on youth mental health outcomes. Methods Using a cluster randomized controlled design, this trial will assign school-based mental health (SMH) clinicians and schools to one of three study arms: (a) enhanced treatment-as-usual (TAU), (b) attention control plus TF-CBT, or (c) BASIS+TF-CBT. With a proposed sample of 120 SMH clinicians who will each recruit 4–6 youth with a history of trauma (480 children), this project will gather data across 12 different time points to address two project aims. Aim 1 will evaluate, relative to an enhanced TAU condition, the effects of TF-CBT on identified mechanisms of change, youth mental health outcomes, and intervention costs and cost-effectiveness. Aim 2 will compare the effects of BASIS against an attention control plus TF-CBT condition on theoretical mechanisms of clinician behavior change and implementation outcomes, as well as examine costs and cost-effectiveness. Discussion This study will generate critical knowledge about the effectiveness and cost-effectiveness of BASIS—a pragmatic, theory-driven, and generalizable implementation strategy designed to enhance motivation—to increase the yield of evidence-based practice training and consultation, as well as the effectiveness of TF-CBT in a novel service setting. Trial registration ClinicalTrials.gov registration number NCT04451161 . Registered on June 30, 2020.

Background In the absence of obstructive coronary stenoses, abnormality of noninvasive stress tests (NIT) in patients with chronic coronary syndromes may indicate myocardial ischemia of nonobstructive coronary arteries (INOCA). The differential prognosis of INOCA according to the presence of coronary microvascular dysfunction (CMD) and incremental prognostic value of CMD with intracoronary physiologic assessment on top of NIT information remains unknown. Methods and Results From the international multicenter registry of intracoronary physiologic assessment (ILIAS [Inclusive Invasive Physiological Assessment in Angina Syndromes] registry, N=2322), stable patients with NIT and nonobstructive coronary stenoses with fractional flow reserve >0.80 were selected. INOCA was diagnosed when patients showed positive NIT results. CMD was defined as coronary flow reserve ≤2.5. According to the presence of INOCA and CMD, patients were classified into 4 groups: group 1 (no INOCA nor CMD, n=116); group 2 (only CMD, n=90); group 3 (only INOCA, n=41); and group 4 (both INOCA and CMD, n=40). The primary outcome was major adverse cardiovascular events, a composite of all‐cause death, target vessel myocardial infarction, or clinically driven target vessel revascularization at 5 years. Among 287 patients with nonobstructive coronary stenoses (fractional flow reserve=0.91±0.06), 81 patients (38.2%) were diagnosed with INOCA based on positive NIT. By intracoronary physiologic assessment, 130 patients (45.3%) had CMD. Regardless of the presence of INOCA, patients with CMD showed a significantly lower coronary flow reserve and higher hyperemic microvascular resistance compared with patients without CMD (P

ObjectivesWhile coronary computed tomography angiography (CCTA) enables the evaluation of anatomic and hemodynamic plaque characteristics of coronary artery disease (CAD), the clinical roles of these characteristics are not clear. We sought to evaluate the prognostic implications of CCTA-derived anatomic and hemodynamic plaque characteristics in the prediction of subsequent coronary events.MethodsThe study cohort consisted of 158 patients who underwent CCTA with suspected CAD within 6–36 months before percutaneous coronary intervention (PCI) for acute myocardial infarction (MI) or unstable angina and age-/sex-matched 62 patients without PCI as the control group. Preexisting high-risk plaque characteristics (HRPCs: low attenuation plaque, positive remodeling, napkin-ring sign, spotty calcification, minimal luminal area 0.80), adding HRPCs into clinical risk factors significantly increased discriminant and reclassification abilities for subsequent coronary events (c-index 0.687 vs. 0.576, P = 0.005; NRI 0.412, P = 0.002; IDI 0.064, P = 0.001) but not for vessels with positive FFRCT (≤0.80).ConclusionIn predicting subsequent coronary events, both HRPCs and hemodynamic parameters by CCTA allow better prediction of subsequent coronary events than clinical risk factors. HRPCs provide more incremental predictability than clinical risk factors alone among vessels with negative FFRCT but not among vessels with positive FFRCT.Clinical Trial RegistrationPreDiction and Validation of Clinical CoursE of Coronary Artery DiSease With CT-Derived Non-INvasive HemodYnamic Phenotyping and Plaque Characterization (DESTINY Study), NCT04794868.

Abstract Background Limited data are available on the impact of a specialized extracorporeal membrane oxygenation (ECMO) team on clinical outcomes in patients with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS). This study evaluated whether specialized ECMO team is associated with improved in-hospital mortality in AMI patients undergoing veno-arterial (VA) ECMO. Methods A total of 255 AMI patients who underwent VA-ECMO were included. In January 2014, a multidisciplinary ECMO team was founded at our institution. Eligible patients were classified into a pre-ECMO team group (n = 131) and a post-ECMO team group (n = 124). The primary outcome was in-hospital mortality. Results In-hospital mortality (pre-ECMO team vs. post-ECMO team, 54.2% vs. 33.9%; p = 0.002) and cardiac intensive care unit mortality (pre-ECMO team vs. post-ECMO team, 51.9% vs. 30.6%; p = 0.001) were significantly lower after the implementation of a multidisciplinary ECMO team. On multivariable logistic regression model, implementation of the multidisciplinary ECMO team was associated with reduction of in-hospital mortality [odds ratio: 0.37, 95% confidence interval (CI) 0.20–0.67; p = 0.001]. Incidence of all-cause mortality [58.3% vs. 35.2%; hazard ratio (HR): 0.49, 95% CI 0.34–0.72; p

The prognostic value of atrial thrombi (AT) among elective patients with atrial fibrillation (AF) referred for a rhythm control strategy is unclear. In this study, clinical variables were correlated with the presence of AT and long term survival among 205 patients submitted to transesophageal echocardiography before elective AF cardioversion or ablation. Atrial thrombi were present in 7.8% of cases and were significantly associated with reduced survival. Obesity was the only independent clinical predictor of AT [OR 4.27 (1.15–15.79), p = 0.03]. In patients with AF, AT appear to be associated with adverse outcomes, possibly indicating more advanced atrial cardiomyopathy.

BackgroundInpatient health care facilities restricted inpatient visitation due to the COVID-19 pandemic. There is no existing evidence of how they communicated these policies to the public nor the impact of their communication choices on public perception. ObjectiveThis study aims to describe patterns of inpatient visitation policies during the initial peak of the COVID-19 pandemic in the United States and the communication of these policies to the general public, as well as to identify communication strategies that maximize positive impressions of the facility despite visitation restrictions. MethodsWe conducted a sequential, exploratory, mixed methods study including a qualitative analysis of COVID-19 era visitation policies published on Pennsylvania-based facility websites, as captured between April 30 and May 20, 2020 (ie, during the first peak of the COVID-19 pandemic in the United States). We also conducted a factorial survey-based experiment to test how key elements of hospitals’ visitation policy communication are associated with individuals’ willingness to seek care in October 2020. For analysis of the policies, we included all inpatient facilities in Pennsylvania. For the factorial experiment, US adults were drawn from internet research panels. The factorial survey-based experiment presented composite policies that varied in their justification for restricted visitation, the degree to which the facility expressed ownership of the policy, and the inclusion of family-centered care support plans. Our primary outcome was participants’ willingness to recommend the hypothetical facility using a 5-point Likert scale. ResultsWe identified 104 unique policies on inpatient visitation from 363 facilities’ websites. The mean Flesch-Kincaid Grade Level for the policies was 14.2. Most policies prohibited family presence (99/104, 95.2%). Facilities justified the restricted visitation policies on the basis of community protection (59/104, 56.7%), authorities’ guidance or regulations (34/104, 32.7%), or scientific rationale (23/104, 22.1%). A minority (38/104, 36.5%) addressed how restrictive visitation may impair family-centered care. Most of the policies analyzed used passive voice to communicate restrictions. A total of 1321 participants completed the web-based survey. Visitation policy elements significantly associated with willingness to recommend the facility included justifications based on community protection (OR 1.44, 95% CI 1.24-1.68) or scientific rationale (OR 1.30, 95% CI 1.12-1.51), rather than those based on a governing authority. The facility expressed a high degree of ownership over the decision (OR 1.16, 95% CI 1.04-1.29), rather than a low degree of ownership; and inclusion of family-centered care support plans (OR 2.80, 95% CI 2.51-3.12), rather than no such support. ConclusionsHealth systems can immediately improve public receptiveness of restrictive visitation policies by emphasizing community protection, ownership over the facility’s policy, and promoting family-centered care.

Triple‐negative breast cancer (TNBC) liver metastasis is associated with poor prognosis and low patient survival. It occurs when tumor cells disseminate from primary tumors, circulate in blood/lymph [circulating tumor cells (CTCs)], and acquire distinct characteristics during disease progression toward the metastatic phenotype. The purpose of this study was to decipher the genomic/transcriptomic properties of TNBC liver metastasis and its recurrence for potential therapeutic targeting. We employed a negative depletion strategy to isolate and interrogate CTCs from the blood of patients with TNBC, and to establish sequential generations of CTC‐derived xenografts (CDXs) through injection of patient CTCs in immunodeficient mice. The isolation and validation of CDX‐derived cell populations [analyses of CTCs were paired with bone marrow‐resident cells (BMRTCs) and liver tissue cells obtained from the same animal] were performed by multiparametric flow cytometry, immune phenotyping, and genomic sequencing of putative CTCs. Comprehensive characterization of gene expression arrays from sequentially generated CDX‐derived cell populations, online gene expression arrays, and TCGA databases were employed to discover a CTC‐driven, liver metastasis‐associated TNBC signature. We discovered a distinct transcriptomic signature of TNBC patient‐isolated CTCs from primary TNBCs, which was consistent throughout sequential CDX modeling. We established a novel TNBC liver metastasis‐specific CDX model that selectively recapitulates CTC biology for four sequential generations of mice. The evaluation of online databases and CDX‐derived populations revealed 597 genes specific to the TNBC liver metastasis signatures. Further investigation of the TNBC liver metastasis signature predicted 16 hub genes, 6 biomarkers with clinically available drugs, and 22 survival genes. The sequential interrogation of CDX‐CTCs is an innovative liquid biopsy‐based approach for the discovery of organ metastasis‐specific signatures of CTCs. This represents the first step for mechanistic and analytical validation in their application as prognostic indicators and therapeutic targets. Targeting CTC drug candidate biomarkers along with combination therapy can improve the clinical outcome of TNBC patients in general and recurrence of liver metastasis in particular.

Abstract Background The PI3K/AKT pathway is activated through PIK3CA or AKT1 mutations and PTEN loss in breast cancer. We conducted a phase II trial with an allosteric AKT inhibitor MK-2206 in patients with advanced breast cancer who had tumors with PIK3CA/AKT1 mutations and/or PTEN loss/mutation. Methods The primary endpoint was objective response rate (ORR). Secondary endpoints were 6-month progression-free survival (6 m PFS), predictive and pharmacodynamic markers, safety, and tolerability. Patients had pre-treatment and on-treatment biopsies as well as collection of peripheral blood mononuclear cells (PBMC) and platelet-rich plasma (PRP). Next-generation sequencing, immunohistochemistry, and reverse phase protein arrays (RPPA) were performed. Results Twenty-seven patients received MK-2206. Eighteen patients were enrolled into the PIK3CA/AKT1 mutation arm (cohort A): 13 had PIK3CA mutations, four had AKT1 mutations, and one had a PIK3CA mutation as well as PTEN loss. ORR and 6 m PFS were both 5.6% (1/18), with one patient with HR+ breast cancer and a PIK3CA E542K mutation experiencing a partial response (on treatment for 36 weeks). Nine patients were enrolled on the PTEN loss/mutation arm (cohort B). ORR was 0% and 6 m PFS was 11% (1/9), observed in a patient with triple-negative breast cancer and PTEN loss. The study was stopped early due to futility. The most common adverse events were fatigue (48%) and rash (44%). On pre-treatment biopsy, PIK3CA and AKT1 mutation status was concordant with archival tissue testing. However, two patients with PTEN loss based on archival testing had PTEN expression on the pre-treatment biopsy. MK-2206 treatment was associated with a significant decline in pAKT S473 and pAKT T308 and PI3K activation score in PBMC and PRPs, but not in tumor biopsies. By IHC, there was no significant decrease in median pAKT S473 or Ki-67 staining, but a drop was observed in both responders. Conclusions MK-2206 monotherapy had limited clinical activity in advanced breast cancer patients selected for PIK3CA/AKT1 or PTEN mutations or PTEN loss. This may, in part, be due to inadequate target inhibition at tolerable doses in heavily pre-treated patients with pathway activation, as well as tumor heterogeneity and evolution in markers such as PTEN conferring challenges in patient selection. Trial registration ClinicalTrials.gov, NCT01277757. Registered 13 January 2011.

Purpose The receptor tyrosine kinase rearranged during transfection (RET) can be oncogenically activated by gene fusions or point mutations. Multikinase inhibitors such as cabozantinib, lenvatinib and vandetanib have demonstrated activity in RET-dependent malignancies, and selective RET inhibitors (Selpercatinib and Pralsetinib) are in clinical trials. However, the responsiveness of RET-dependent malignancies to immune checkpoint inhibitors (ICIs) is unknown. We compared the time to treatment discontinuation (TTD) for ICI versus non-ICI therapy in patients with malignancies harbouring activating RET mutations or fusions (RET+).Methods A retrospective review of all RET+ patients who were referred to the phase I clinical trials programme at the University of Texas MD Anderson Cancer Center was conducted. TTD was estimated using Kaplan-Meier analysis. Multivariate analysis using the Cox proportional hazard model was performed to identify independent risk factors of treatment discontinuation.Results Of 70 patients who received systemic therapy for RET+ malignancies, 20 (28.6%) received ICI and 50 (71.4%) received non-ICI therapy. Non-ICI therapy was associated with decreased risk for treatment discontinuation compared with ICI in the overall population (HR=0.31; 95% CI 0.16–0.62; p=0.000834) and in patients with RET point mutations (HR=0.13; 95% CI 0.04–0.45; p=0.00134). In patients with RET fusions, non-ICI therapy was associated with a non-statistically significant decreased risk of treatment discontinuation (HR=0.59; 95% CI 0.25–1.4; p=0.24). ICI therapy and a diagnosis other than medullary thyroid cancer (MTC) were independent risk factors for treatment discontinuation.Conclusion Our study supports the prioritisation of non-ICI over ICI therapy in patients with RET+ tumours.

Background: A recent systematic review alludes to the effectiveness of social media in facilitating smoking cessation. However, most interventions center on mobile applications in engaging smokers. A novel portable exhaled-carbon-monoxide self-monitoring device, the Smoke-analyzer to Track and Expedite Actions and Decisions to Eliminate Smoking (STEADES) linked to a specially-designed mobile phone application has been developed, which relays exhaled carbon monoxide-related data from the smokers to their selected quit supporters via social media. Aim: The study aimed to determine the precision and feasibility of using the STEADES device among smokers in primary care. Method: This pilot study recruited 15 Asian adult smokers from a primary care polyclinic in Singapore. Their exhaled carbon monoxide measurements were measured serially using STEADES, compared to a commercial smokerlyzer as reference. The subjects could use the device to transmit their exhaled carbon monoxide measurements via mobile application and social media to their acquaintances in the next two weeks. Data on the subjects’ demographic and clinical characteristics, their views on STEADES (from a questionnaire), and its utility (from the application) were collated on enrolment and at the end of study. Results: Measurements using STEADES were significantly correlated with those from a commercial smokerlyzer (Pearson correlation=0.882, p

Tachyzoite to bradyzoite development in Toxoplasma is marked by major changes in gene expression resulting in a parasite that expresses a new repertoire of surface antigens hidden inside a modified parasitophorous vacuole called the tissue cyst. The factors that control this important life cycle transition are not well understood. Here we describe an important transcriptional repressor mechanism controlling bradyzoite differentiation that operates in the tachyzoite stage. The ApiAP2 factor, AP2IV-4, is a nuclear factor dynamically expressed in late S phase through mitosis/cytokinesis of the tachyzoite cell cycle. Remarkably, deletion of the AP2IV-4 locus resulted in the expression of a subset of bradyzoite-specific proteins in replicating tachyzoites that included tissue cyst wall components BPK1, MCP4, CST1 and the surface antigen SRS9. In the murine animal model, the mis-timing of bradyzoite antigens in tachyzoites lacking AP2IV-4 caused a potent inflammatory monocyte immune response that effectively eliminated this parasite and prevented tissue cyst formation in mouse brain tissue. Altogether, these results indicate that suppression of bradyzoite antigens by AP2IV-4 during acute infection is required for Toxoplasma to successfully establish a chronic infection in the immune-competent host.

Radiation therapy (RT) is an effective strategy for the treatment of localized prostate cancer (PCa) as well as local invasion. However, some locally advanced cancers develop radiation resistance and recur after therapy; therefore, the development of radiation-sensitizing compounds is essential for treatment of these tumors. DOC-2/DAB2 interactive protein (DAB2IP), which is a novel member of the Ras-GTPase activating protein family and a regulator of phosphatidylinositol 3-kinase-Akt activity, is often downregulated in aggressive PCa. Our previous studies have shown that loss of DAB2IP results in radioresistance in PCa cells primarily because of accelerated DNA double-strand break (DSB) repair kinetics, robust G2/M checkpoint control, and evasion of apoptosis. A novel DNA-PKcs inhibitor NU7441 can significantly enhance the effect of radiation in DAB2IP-deficient PCa cells. This enhanced radiation sensitivity after NU7441 treatment is primarily due to delayed DNA DSB repair. More significantly, we found that DAB2IP-deficient PCa cells show dramatic induction of autophagy after treatment with radiation and NU7441. However, restoring DAB2IP expression in PCa cells resulted in decreased autophagy-associated proteins, such as LC3B and Beclin 1, as well as decreased phosphorylation of S6K and mammalian target of rapamycin (mTOR). Furthermore, the presence of DAB2IP in PCa cells can lead to more apoptosis in response to combined treatment of NU7441 and ionizing radiation. Taken together, NU7441 is a potent radiosensitizer in aggressive PCa cells and DAB2IP plays a critical role in enhancing PCa cell death after combined treatment with NU7441 and radiation.

Richard B Rhiew, Sunil Manjila, Andrew M Lozen, David Hong, Murali Guthikonda, S S RengacharyDepartment of Neurosurgery, Wayne State University, Detroit, MI, USAAbstract: Transforaminal lumbar interbody fusion (TLIF) is a widely used method of surgical treatment for a variety of lumbar spinal disorders. Bilateral transpedicular instrumentation is routinely used in conjunction with an interbody graft to provide additional stability. In this technical note, we describe our fusion construct using ipsilateral pedicle screw placement on the side of TLIF and contralateral facet screw placement. We performed this construct at six levels in four patients. Suggested advantages include: low morbidity, small incision and lower cost. Outcomes parameters included radiographic evidence of solid union at four months and improvement in Oswestry Disability Index. A mean improvement from a preoperative score of 73 to 26 after surgery was observed at one-year follow-up. There were no instrument-related complications. In conclusion, this hybrid screw system minimizes contralateral dissection and is an attractive alternative to standard bilateral pedicle screw fixation.Keywords: TLIF, facet screw, pedicle screw, lumbar spine fusion

Cholangiocarcinoma (CCA) is clinically heterogeneous; intra and extrahepatic CCA have diverse clinical presentations. Next generation sequencing (NGS) technology may identify the genetic differences between these entities and identify molecular subgroups for targeted therapeutics.We describe successful NGS-based testing of 75 CCA patients along with the prognostic and therapeutic implications of findings. Mutation profiling was performed using either a) NGS panel of hotspot regions in 46 cancer-related genes using a 318-chip on Ion PGM Sequencer or b) Illumina HiSeq 2000 sequencing platform for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes to an average depth of 1000X. Clinical data was abstracted and correlated with clinical outcome. Patients with targetable mutations were referred to appropriate clinical trials.There were significant differences between intrahepatic (n = 55) and extrahepatic CCA (n = 20) in regard to the nature and frequency of the genetic aberrations (GAs). IDH1 and DNA repair gene alterations occurred more frequently in intrahepatic CCA, while ERBB2 GAs occurred in the extrahepatic group. Commonly occurring GAs in intrahepatic CCA were TP53 (35%), KRAS (24%), ARID1A (20%), IDH1 (18%), MCL1 (16%) and PBRM1 (11%). Most frequent GAs in extrahepatic CCA (n = 20) were TP53 (45%), KRAS (40%), ERBB2 (25%), SMAD4 (25%), FBXW7 (15%) and CDKN2A (15%). In intrahepatic CCA, KRAS, TP53 or MAPK/mTOR GAs were significantly associated with a worse prognosis while FGFR GAs correlated with a relatively indolent disease course. IDH1 GAs did not have any prognostic significance. GAs in the chromatin modulating genes, BAP1 and PBRM1 were associated with bone metastases and worse survival in extrahepatic CCA. Radiologic responses and clinical benefit was noted with EGFR, FGFR, C-met, B-RAF and MEK inhibitors.There are significant genetic differences between intra and extrahepatic CCA. NGS can potentially identify disease subsets with distinct prognostic and therapeutic implications.

Oncogenic BRAF mutations have been found in diverse malignancies and activate RAF/MEK/ERK signaling, a critical pathway of tumorigenesis. We examined the clinical characteristics and outcomes of patients with mutant (mut) BRAF advanced cancer referred to phase 1 clinic.We reviewed the records of 80 consecutive patients with mutBRAF advanced malignancies and 149 with wild-type (wt) BRAF (matched by tumor type) referred to the Clinical Center for Targeted Therapy and analyzed their outcome.Of 80 patients with mutBRAF advanced cancer, 56 had melanoma, 10 colorectal, 11 papillary thyroid, 2 ovarian and 1 esophageal cancer. Mutations in codon 600 were found in 77 patients (62, V600E; 13, V600K; 1, V600R; 1, unreported). Multivariate analysis showed less soft tissue (Odds ratio (OR) = 0.39, 95%CI: 0.20-0.77, P = 0.007), lung (OR = 0.38, 95%CI: 0.19-0.73, p = 0.004) and retroperitoneal metastases (OR = 0.34, 95%CI: 0.13-0.86, p = 0.024) and more brain metastases (OR = 2.05, 95%CI: 1.02-4.11, P = 0.043) in patients with mutBRAF versus wtBRAF. Comparing to the corresponding wtBRAF, mutBRAF melanoma patients had insignificant trend to longer median survival from diagnosis (131 vs. 78 months, p = 0.14), while mutBRAF colorectal cancer patients had an insignificant trend to shorter median survival from diagnosis (48 vs. 53 months, p = 0.22). In melanoma, V600K mutations in comparison to other BRAF mutations were associated with more frequent brain (75% vs. 36.3%, p = 0.02) and lung metastases (91.6% vs. 47.7%, p = 0.007), and shorter time from diagnosis to metastasis and to death (19 vs. 53 months, p = 0.046 and 78 vs. 322 months, p = 0.024 respectively). Treatment with RAF/MEK targeting agents (Hazard ratio (HR) = 0.16, 95%CI: 0.03-0.89, p = 0.037) and any decrease in tumor size after referral (HR = 0.07, 95%CI: 0.015-0.35, p = 0.001) correlated with longer survival in mutBRAF patients.BRAF appears to be a druggable mutation that also defines subgroups of patients with phenotypic overlap, albeit with differences that correlate with histology or site of mutation.

BACKGROUND: The Murray law--based quantitative flow ratio (μFR) is an emerging technique that requires only 1 projection of coronary angiography with similar accuracy to quantitative flow ratio (QFR). However, it has not been validated for the evaluation of noninfarct-related artery (non-IRA) in acute myocardial infarction (AMI) settings. Therefore, our study aimed to evaluate the diagnostic accuracy of μFR and the safety of deferring non-IRA lesions with μFR >0.80 in the setting of AMI. METHODS: μFR and QFR were analyzed for non-IRA lesions of patients with AMI enrolled in the FRAME-AMI trial (Fractional Flow Reserve Versus Angiography-Guided Strategy for Management of Non-Infarction Related Artery Stenosis in Patients With Acute Myocardial Infarction), consisting of fractional flow reserve (FFR)--guided percutaneous coronary intervention and angiography-guided percutaneous coronary intervention groups. The diagnostic accuracy of μFR was compared with QFR and FFR. Patients were classified by the non-IRA μFR value of 0.80 as a cutoff value. The primary outcome was a vessel-oriented composite outcome, a composite of cardiac death, non-IRA--related myocardial infarction, and non-IRA--related repeat revascularization. RESULTS: μFR and QFR analyses were feasible in 443 patients (552 lesions). μFR showed acceptable correlation with FFR (R=0.777; P<0.001), comparable C-index with QFR to predict FFR ≤0.80 (μFR versus QFR: 0.926 versus 0.961, P=0.070), and shorter total analysis time (mean, 32.7 versus 186.9 s; P<0.001). Non-IRA with μFR >0.80 and deferred percutaneous coronary intervention had a significantly lower risk of vessel-oriented composite outcome than non-IRA with performed percutaneous coronary intervention (3.4% versus 10.5%; hazard ratio, 0.37 [95% CI, 0.14-0.99]; P=0.048). CONCLUSIONS: In patients with multivessel AMI, μFR of non-IRA showed acceptable diagnostic accuracy comparable to that of QFR to predict FFR ≤0.80. Deferred non-IRA with μFR >0.80 showed a lower risk of vessel-oriented composite outcome than revascularized non-IRA. [ABSTRACT FROM AUTHOR]