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Introduction: The Oncotype DX Breast RS test has been adopted in Scotland and has been the subject of a large population-based study by a Scottish Consensus Group to assess the uptake of the recurrence score (RS), evaluate co-variates associated with the RS and to analyse the effect it may have had on clinical practice.Materials & Methods: Pan-Scotland study between August 2018–August 2021 evaluating 833 patients who had a RS test performed as part of their diagnostic pathway. Data was extracted retrospectively from electronic records and analysis conducted to describe change in chemotherapy administration (by direct comparison with conventional risk assessment tools), and univariate/multivariate analysis to assess relationship between covariates and the RS. Results: Chemotherapy treatment was strongly influenced by the RS (p

Objective: Acute myocardial infarction (AMI) is one of the leading causes of death; however, updated data regarding clinical presentation and current management are missing in Greece. This study aimed to prospectively record the demographic and clinical characteristics of a representative sample of patients suffering from AMI, their management, and short-term outcomes. Methods: ILIAKTIS is a national, prospective, multicenter, noninterventional study conducted under the auspices of Hellenic Society of Cardiology (HCS) and the European Initiative Stent - Save a Life. From 1st April 2020 to 30th June 2020, consecutive adult patients with STEMI or NSTEMI were enrolled in the 50 participating hospitals, appropriately selected to match the geographical and population distribution in the Greek territory. Results: In total, 1862 patients (mean age: 64.2 ± 13.2 yrs.; 77.2% males) with AMI were enrolled. More patients presented with NSTEMI (56.8%) than with STEMI (43.2%). Primary PCI (pPCI) was the preferable treatment option for STEMI patients in PCI-hospitals (76.9% vs. 39.9% for non-PCI, p

The impact of the ionization source in the ITER far SOL associated with main chamber deuterium puffing on the overall SOL performance is studied numerically using SOLPS-ITER modeling. It is found out that this source can have significant influence on the retention of the seeded impurity radiator (Ne) in the divertor and on plasma temperature in far SOL. The former is responsible for typical separatrix concentration of seeded impurity compatible with the required power handling limits on the divertor targets, while the latter is responsible for sputtering of divertor material. Both factors indicate the beneficial effect of high fuel throughput on separatrix and pedestal plasma composition.

Purpose: Quality assessment of the treatment plans in the Danish Breast Cancer Group (DBCG) HYPO trial was carried out based on prospectively reported dosimetric parameters and evidence-based dose constraints for whole breast radiation therapy were derived. Materials and methods: From 2009 to 2014, 1882 patients (pts) were randomised between 50 Gy/25fractions (fr) versus 40 Gy/15fr. Doses to CTVp_breast (V95%, V107%-V110%, Dmax, and in addition for 40 Gy plans V105%-V107%), ipsilateral lung (V20Gy/V17Gy), heart (V20Gy/V17Gy, V40Gy/V35Gy), and left anterior descending coronary artery (LADCA) (Dmax) and use of respiratory gated technique were prospectively reported to the DBCG database. After end of accrual, these dosimetric parameters from all plans in the trial were compared to the pre-specified treatment constraints. Results: In total, 1854 pts from eight radiation therapy (RT) centres in three countries were treated. No statistically significant differences were found between the results for 40 Gy and 50 Gy plans, except for CTVp_breast hot-spot volume (V107%-V110%). Of the 40 Gy pts, 90% with CTVp_breast > 600 mL and 95% with CTVp_breast ≤ 600 mL had a CTVp_breast hot-spot volume (V105%-V107%) 600 mL, respectively. Compliance was >99% for both heart and lung constraints. Largest deviation from protocol constraints was found for the volume of CTVp_breast covered with 95% of the prescription dose or more (V95%). The CTV dose coverage (V95%) was >94.3% in 95% of the right-sided pts, whereas the figures for 95% of the left-sided pts treated with and without respiratory gating were 93.2% and 88.8%, respectively. Conclusion: A high degree of compliance with protocol dose constraints was found for treatment plans in the DBCG HYPO trial. New constraints for dose to organs at risk and high-dose volumes in the breast are suggested for breast-only RT planning.

Several genome-wide association studies (GWAS), GWAS meta-analyses, and mouse studies have demonstrated that wingless-related integration site 16 (WNT16) gene is associated with bone mineral density (BMD), cortical bone thickness, bone strength and fracture risk. Practically no data exist regarding the significance of WNT16 in childhood-onset osteoporosis and related fractures. We hypothesized that pathogenic variants and genetic variations in WNT16 could explain skeletal fragility in affected children. We screened the WNT16 gene by Sanger sequencing in three pediatric cohorts: 35 with primary osteoporosis, 59 with multiple fractures, and in 95 healthy controls. Altogether, we identified 12 variants in WNT16. Of them one was a rare 5′UTR variant rs1386898215 in genome aggregate and medical trans-omic databases (GnomAD, TOPMED; minor allele frequency (MAF) 0.00 and 0.000008, respectively). One variant rs1554366753, overrepresented in children with osteoporosis (MAF = 0.06 vs healthy controls MAF = 0.01), was significantly associated with lower BMD. This variant was found associated with increased WNT16 gene expression at mRNA level in fibroblast cultures. None of the other identified variants were rare (MAF

Suggestions that Lyme disease exists in Greece remain controversial and no study to date has definitively identified the presence of a Borrelia species that infects humans. We examined patients throughout Greece suspected for Lyme disease by enzyme-linked immunosorbent assay (ELISA) and by western blotting for Borrelia burgdorferi sensu lato species. We found one patient positive for Borrelia burgdorferi and two patients positive for Borrelia afzelii specific IgG antibodies. Both B. afzelii patients were suffering by neurological manifestations and had never traveled abroad. We provide serological evidence of two autochthonous Lyme disease cases in Greece, possibly caused by B. afzelii.

Modern neurosurgical equipment and techniques, neuroendoscopy in particular, allow performing complex operations even in the deep and narrow anatomical structures of the brain without injuring vessels or soft tissue and consequently lowers risk of postoperative complications. The surgical treatment includes classical open microsurgical and mini-invasive neuroendoscopic cystoventriculostomy or cystocysternostomy depending on the cyst localization. In this work, we present a case of surgical treatment of a pineal cyst of a 1 year 6 months old boy with a semi-rigid neuroendoscope under neuronavigation and ultrasound guidance and provide the advantages of this technique. The good clinical and radiological improvement observed in our patient is the result of the use of triple intraoperative monitoring including a semi-rigid needle neuroendoscope, neuronavigation, ultrasound and, thus, the neurosurgeon has the entire picture of the delicate structures that allows carry our surgical intervention (endoscopic cyst fenestration) with the greatest precision and safety.

A foil of a metastable β Titanium alloy Ti-15V-3Cr-3Sn-3Al was irradiated at the J-PARC neutrino experimental facility with 1.4 × 1020 30 GeV protons at low temperature (100–130 °C at most), and microstructural characterization and hardness testing were conducted as an initial study on the radiation damage effects of Titanium alloy by the high energy proton beam exposure. Expected radiation damage at the beam center is about 0.06–0.12 displacement per atom. A high density (> 1023 m−3) of a nanometer-sized precipitate was observed by TEM studies, which would be identified as martensite α-phase and athermal ω-phase formed during the solution-treatment process to fabricate metastable β alloy. They did not appear to change substantially after irradiation with protons. In the irradiated specimen, we could not identify an obvious signature of radiation damage distributed along the proton beam profile. Very small, nanometer-scale black dots were present at a low density in the most highly irradiated region, and may be small dislocation loops formed during irradiation. The micro-indentation test indicated that the radiation exposure led to tiny increase in Vickers micro-hardness of ΔHV = 20 at beam center. Atom probe tomography reveals compositional fluctuations that reach a maximum amplitude of 10 at% Ti within a space of

In the present study, grape pomace (GP) was used as feed additive in the diet of weaned piglets in order to develop innovative feedstuffs and to investigate their potential beneficial effects on welfare, productivity and meat quality. For examining the antioxidant capacity of the experimental feeds, 24 piglets of 20 days old were assigned to two experimental groups receiving standard or experimental diet for 30 days. Blood and tissues collections were performed at four different time-points, 2, 20, 35 and 50 days post birth. The collected tissues were brain, heart, kidney, liver, lung, quadriceps muscle, pancreas, spleen and stomach. The following oxidative stress markers were assessed: reduced glutathione (GSH), catalase activity, total antioxidant capacity (TAC), thiobarbituric acid reactive substances (TBARS), protein carbonyls (CARB) and H2O2 decomposition activity. The effect on bacterial growth was assessed by examining microbial populations in piglets’ fecal microbiota. Furthermore, the average daily gain (ADG) was calculated and the fatty acid profile of quadriceps muscle was assessed. The results showed that piglets fed with the diet supplemented with GP, had significantly increased antioxidants mechanisms in almost all the tissues as shown by increases in GSH, H2O2 decomposition activity and TAC compared with control group. Piglets fed with the experimental diet exhibited decreased oxidative stress-induced damage to lipids and proteins as shown by decreases in TBARS and CARB in GP group compared with control. In addition, the experimental diet increased significantly ADG (by 23.65%) (P

Introduction: Eosinopenia as a criterion of sepsis has been the subject of debate for decades. Different authors have proposed different cut-off values. Methods: A prospective study was conducted from February to August 2016. Hospitalized adults suffering from a bacterial infection with eosinopenia, defined as an eosinophil count

Background: Mismatch negativity (MMN) is a measure of pre-attentive auditory information processing related to change detection. Traditional scalp-level EEG methods consistently find attenuated MMN in patients with chronic but not first-episode schizophrenia. In the current paper, we use a source-resolved method to assess MMN and hypothesize that more subtle changes can be identified with this analysis method. Method: Fifty-six first-episode antipsychotic-naïve schizophrenia (FEANS) patients (31 males, 25 females, mean age 24.6) and 64 matched controls (37 males, 27 females, mean age 24.8) were assessed for duration-, frequency- and combined-type MMN and P3a as well as 4 clinical, 3 cognitive and 3 psychopathological measures. To evaluate and correlate MMN at source-level, independent component analysis (ICA) was applied to the continuous EEG data to derive equivalent current dipoles which were clustered into 19 clusters based on cortical location. Results: No scalp channel group MMN or P3a amplitude differences were found. Of the localized clusters, several were in or near brain areas previously suggested to be involved in the MMN response, including frontal and anterior cingulate cortices and superior temporal and inferior frontal gyri. For duration deviants, MMN was attenuated at the right superior temporal gyrus in patients compared to healthy controls (p = 0.01), as was P3a at the superior frontal cortex (p = 0.01). No individual patient correlations with clinical, cognitive, or psychopathological measures survived correction for multiple comparisons. Conclusion: Attenuated source-localized MMN and P3a peak contributions can be identified in FEANS patients using a method based on independent component analysis (ICA). This indicates that deficits in pre-attentive auditory information processing are present at this early stage of schizophrenia and are not the result of disease chronicity or medication. This is to our knowledge the first study on FEANS patients using this more detailed method. Keywords: Mismatch negativity, Schizophrenia, First episode, EEG, ICA

Purpose: The optimal delivery schedule for stereotactic body radiation therapy (SBRT) in treating stage I non-small cell lung cancer (NSCLC) is unknown. This study used the National Cancer Database to examine daily versus every other day (QOD) SBRT scheduling, including trends over time and association with survival. Methods and Materials: The National Cancer Database was used to retrospectively identify patients with stage I NSCLC treated with 3-, 4-, or 5-fraction of SBRT between 2004 and 2016. Survival analysis was performed using the Kaplan-Meier method and Cox regression modeling. Results: Of 15,269 patients, 3927 (25.7%) received SBRT daily, and 11,342 (74.3%) received treatment QOD. The use of QOD treatment increased from 63.2% in 2007 to 78.3% in 2016, and 5-fraction SBRT increased from 3.7% in 2004 to 51.4% in 2016 (both P < .0001). QOD 5-fraction became the most prevalent scheduling from 2012 to 2016 (28.5% in 2012 to 41.6% in 2016). Factors significantly associated with daily SBRT scheduling included number of fractions, race, lower income, lower comorbidities, and treatment at academic/research programs (all P ≤ .01).Median survival for daily SBRT was 37.9 months versus 38.4 months for QOD (P = .4). On multivariable analysis, no difference was found in overall survival between daily versus QOD scheduling (adjusted hazard ratio [aHR], 0.99; 95% confidence interval [CI], 0.94-1.04; P = .55). Five-fraction SBRT was associated with worse survival versus 3 fractions (aHR, 1.09; 95% CI, 1.03-1.15; P = .002). With 3-fraction SBRT, QOD treatment was associated with improved survival versus daily treatment (aHR, 0.91; 95% CI, 0.84-0.98; P = .02). With 5-fraction SBRT, QOD treatment was associated with worse survival versus daily treatment (aHR, 1.11; 95% CI, 1.02-1.22; P = .02). Conclusions: QOD SBRT schedules were more frequently used to treat stage I NSCLC than daily regimens by a factor of 3:1, and QOD 5-fraction SBRT became the most common dose schedule after 2012. Three-fraction QOD SBRT was associated with improved survival versus daily, whereas 5-fraction QOD SBRT was associated with worse survival versus daily.

Introduction: Systemic treatment with chemotherapy is warranted for patients with extensive-stage SCLC (ES-SCLC). The objective of this study was to determine whether racial and other healthcare disparities exist in receipt of chemotherapy for ES-SCLC. Methods: Utilizing the National Cancer Database, 148,961 patients diagnosed to have stage IV SCLC from 2004 to 2016 were identified. Adjusted ORs with 95% confidence intervals (95% CIs) were computed for receipt of chemotherapy using multivariate logistic regression modeling. Cox regression modeling was used to perform overall survival analysis, and adjusted hazard ratios were calculated. Results: A total of 82,592 patients were included, among which chemotherapy was not administered to 6557 (7.9%). Higher education, recent year of diagnosis, and treatment at more than one facility were associated with increased odds of receiving chemotherapy. Factors associated with a decreased likelihood of receiving chemotherapy were increasing age, race, nonprivate insurance, and comorbidities. On multivariate analysis, black patients had lower odds of receiving chemotherapy compared with white patients (adjusted OR, 0.85; 95% CI: 0.77–0.93, p = 0.0004). Furthermore, black patients had better survival compared with white patients (adjusted hazard ratio, 0.91; 95% CI: 0.89–0.94, p = 0.91). The 1-year survival (median survival) for black and white patients was 31.7% (8.3 mo) and 28.6% (8 mo), respectively. Conclusions: Black patients with ES-SCLC were less likely to receive chemotherapy, as were elderly, uninsured, and those with nonprivate insurance. Further studies are required to address underlying reasons for lack of chemotherapy receipt in black patients with ES-SCLC and guide appropriate interventions to mitigate disparities.

Background: A recent study showed that the accuracy of heart failure (HF) cardiologists and family doctors to predict mortality in outpatients with HF proved suboptimal, performing less well than models., Objectives: The authors sought to evaluate patient and physician factors associated with physician accuracy., Methods: The authors included outpatients with HF from 11 HF clinics. Family doctors and HF cardiologists estimated patient 1-year mortality. They calculated predicted mortality using the Seattle HF Model and followed patients for 1 year to record mortality (or urgent heart transplant or ventricular assist device implant as mortality-equivalent events). Using multivariable logistic regression, the authors evaluated associations among physician experience and confidence in estimates, duration of patient-physician relationship, patient-physician sex concordance, patient race, and predicted risk, with concordant results between physician and model predictions., Results: Among 1,643 patients, 1-year event rate was 10% (95% CI: 8%-12%). One-half of the estimates showed discrepant results between model and physician predictions, mainly owing to physician risk overestimation. Discrepancies were more frequent with increasing patient risk from 38% in low-risk to ∼75% in high-risk patients. When making predictions on male patients, female HF cardiologists were 26% more likely to have discrepant predictions (OR: 0.74; 95% CI: 0.58-0.94). HF cardiologist estimates in Black patients were 33% more likely to be discrepant (OR: 0.67; 95% CI: 0.45-0.99). Low confidence in predictions was associated with discrepancy. Analyses restricted to high-confidence estimates showed inferior calibration to the model, with risk overestimation across risk groups., Conclusions: Discrepant physician and model predictions were more frequent in cases with perceived increased risk. Model predictions outperform physicians even when they are confident in their predictions. (Predicted Prognosis in Heart Failure [INTUITION]; NCT04009798)., Competing Interests: Funding Support and Author Disclosures This study received funding from a Grant-in-Aid offered by the Heart and Stroke Foundation of Canada. Dr Alba has received funding by the Heart and Stroke Foundation of Canada Clinician-Scientist Program. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Cardiovascular conditions are among the most frequent causes of impairment to drive, because they might induce unpredictable mental state alterations via diverse mechanisms like myocardial ischemia, cardiac arrhythmias, and vascular dysfunction. Accordingly, health professionals are often asked to assess patients' fitness to drive (FTD). The Canadian Cardiovascular Society previously published FTD guidelines in 2003-2004; herein, we present updated FTD guidelines. Because there are no randomized trials on FTD, observational studies were used to estimate the risk of driving impairment in each situation, and recommendations made on the basis of Canadian Cardiovascular Society Risk of Harm formula. More restrictive recommendations were made for commercial drivers, who spend longer average times behind the wheel, use larger vehicles, and might transport a larger number of passengers. We provide guidance for individuals with: (1) active coronary artery disease; (2) various forms of valvular heart disease; (3) heart failure, heart transplant, and left ventricular assist device situations; (4) arrhythmia syndromes; (5) implantable devices; (6) syncope history; and (7) congenital heart disease. We suggest appropriate waiting times after cardiac interventions or acute illnesses before driving resumption. When short-term driving cessation is recommended, recommendations are on the basis of expert consensus rather than the Risk of Harm formula because risk elevation is expected to be transient. These recommendations, although not a substitute for clinical judgement or governmental regulations, provide specialists, primary care providers, and allied health professionals with a comprehensive list of a wide range of cardiac conditions, with guidance provided on the basis of the level of risk of impairment, along with recommendations about ability to drive and the suggested duration of restrictions., (Copyright © 2023 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Left ventricular assist devices (LVADs) are increasingly used in patients with end-stage heart failure (HF). There is a significant risk of HF admissions and hemocompatibility-related adverse events that can be minimized by optimizing the LVAD support. Invasive hemodynamic assessment, which is currently underutilized, allows personalization of care for patients with LVAD, and may decrease the need for recurrent hospitalizations. It also aids in triaging patients with persistent low-flow alarms, evaluating reversal of pulmonary vasculature remodeling, and assessing right ventricular function. In addition, it can assist in determining the precipitant for residual HF symptoms and physical limitation during exercise and is the cornerstone of the assessment of myocardial recovery. This review provides a comprehensive approach to the use of invasive hemodynamic assessments in patients supported with LVADs., Competing Interests: Funding Support and Author Disclosures Dr Brahmbhatt has received salary support from TRANSFORM-HF and conference travel support from Abbott Laboratories. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. All rights reserved.)

Background: Early right heart failure (RHF) remains a major source of morbidity and mortality after left ventricular assist device (LVAD) implantation, yet efforts to predict early RHF have proven only modestly successful. Pharmacologic unloading of the left ventricle may be a risk stratification approach allowing for assessment of right ventricular and hemodynamic reserve., Methods: We performed a multicenter, retrospective analysis of patients who had undergone continuous-flow LVAD implantation from October 2011 to April 2020. Only those who underwent vasodilator testing with nitroprusside during their preimplant right heart catheterization were included (n = 70). Multivariable logistic regression was used to determine independent predictors of early RHF as defined by Mechanical Circulatory Support-Academic Research Consortium., Results: Twenty-seven patients experienced post-LVAD early RHF (39%). Baseline clinical characteristics were similar between patients with and without RHF. Patients without RHF, however, achieved higher peak stroke volume index (SVI) (30.1 ± 8.8 vs 21.7 ± 7.4 mL/m 2 ; p < 0.001; AUC: 0.78; optimal cut-point: 22.1 mL/m 2 ) during nitroprusside administration. Multivariable analysis revealed that peak SVI was significantly associated with early RHF, demonstrating a 16% increase in risk of early RHF per 1 ml/m 2 decrease in SVI. A follow up cohort of 10 consecutive patients from July 2020 to October 2021 resulted in all patients being categorized appropriately in regards to early RHF versus no RHF according to peak SVI., Conclusion: Peak SVI with nitroprusside administration was independently associated with post-LVAD early RHF while resting hemodynamics were not. Vasodilator testing may prove to be a strong risk stratification tool when assessing LVAD candidacy though additional prospective validation is needed., Competing Interests: Financial disclosures No grants, contracts, or other financial support was received for this manuscript., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Objective: Health policy and system leaders need to know whether long travel time to a delivery facility adversely affects birth outcomes. In this study, we estimated associations between travel time to delivery and outcomes in low-risk pregnancies., Methods: This population-based cohort included all singleton births without obstetric comorbidities or intrapartum facility transfers in British Columbia, Canada, from 2012 to 2019. Travel time was measured from maternal residential postal code to delivery facility using road network analysis. We estimated associations between travel time and severe maternal morbidity, stillbirth, pre-term birth, and small-for-gestational age (SGA) and large-for-gestational age (LGA) status using logistic regression, adjusted for confounders (adjusted odds ratios [aORs]). To examine variations in associations between travel time and outcomes by antenatal care utilization, we stratified models by antenatal care categories., Results: Of 232 698 births, 3.8% occurred at a facility ≥60 minutes from the maternal residence. Obesity, adolescent age, substance use, inadequate prenatal care, and low socioeconomic status were more frequent among those traveling farther for delivery. Travel time ≥120 minutes was associated with increased risk of stillbirth (aOR 1.8; 95% CI 1.2-2.8), pre-term birth (aOR 2.3; 95% CI 2.1-2.5), LGA (aOR 1.5; 95% CI 1.4-1.6), and severe maternal morbidity (aOR 1.5; 95% CI 1.2-1.8), but not SGA (aOR 1.0; 95% CI 0.8-1.1), when compared with a travel time of 1-29 minutes. Risk of stillbirth was greatest with inadequate and intensive (adequate plus) antenatal care but persisted for severe maternal morbidity, pre-term birth, and LGA across categories., Conclusion: Longer travel time to delivery was associated with increased risk of adverse outcomes in low-risk pregnancies after adjusting for confounding factors. Associations were stronger among those with inadequate antenatal care., (Copyright © 2022 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. All rights reserved.)

Deprescribing of medications such as benzodiazepines and benzodiazepine receptor agonists (z-drugs) can be a complex process that varies across practices, specialties, and health care systems. Care coordination among healthcare providers, patients, families, and other healthcare system components is critical to achieving high levels of deprescribing and person-centered care. We present a framework for promoting care coordination in the context of benzodiazepine/z-drug deprescribing. Future efforts are needed to study the impact of better care coordination on benzodiazepines/z-drug discontinuation and other outcomes that are important to stakeholders., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: Gene fusion variants in ALK-rearranged NSCLC may predict patient outcomes, but previous results have been inconclusive. Fusion isoforms coexisting in the same tumor may affect the efficacy of targeted therapy, but they have not been investigated., Methods: Patients with ALK-rearranged NSCLC who received crizotinib treatments were recruited. Precrizotinib tumor tissues were analyzed by the anchored multiplex polymerase chain reaction for targeted RNA sequencing. Kaplan-Meier and Cox regression were used to compare overall and progression-free survivals., Results: Of the 51 studied subjects, EML4-ALK variant types v1, v2, v3, and others were detected in 23 (45.1%), five (9.8%), 19 (37.3%), and four patients (7.8%), respectively. Multiple EML4-ALK RNA isoforms were detected in 24 tumors (47.1%), and single isoform in 27 (52.9%). Most of the v3 tumors (16 of 19) harbored both v3a and v3b RNA isoforms. Multiple isoforms were also detected in eight non-v3 tumors (33.3% of all 24 multiple isoforms; five v1, two v5', and one v2). Compared with patients with single isoform, those with multiple isoforms had worse progression-free (hazard ratio and 95% confidence interval: 2.45 [1.06-5.69]) and overall (hazard ratio [95% confidence interval]: 3.74 [1.26-11.13]) survivals after adjusting for potential confounders including variant type. Using the patient-derived H2228 cells known to express v3a and v3b, our single-cell polymerase chain reaction detected either v3a or v3b in most single cells. Treatment of H2228 cells by three ALK inhibitors revealed increased ratios of v3a-to-v3b expression over time., Conclusions: Intratumoral EML4-ALK isoforms may predict the efficacy of targeted therapy in ALK-rearranged NSCLC. Temporal changes of intratumoral fusion isoforms may result from differential selection pressures that a drug might have on one isoform over another. Larger studies on fusion heterogeneity using RNA sequencing are warranted., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

In heart failure with reduced ejection fraction (HFrEF), diminished tonic and reflex vagal heart rate modulation and exaggerated sympathetic outflow and neural norepinephrine release are evident from disease inception. Each of these disturbances of autonomic regulation has been independently associated with shortened survival, and β-adrenoceptor antagonism and therapeutic autonomic modulation by other means have been demonstrated, in clinical trials, to lessen symptoms and prolong survival. In contrast, data concerning the autonomic status of patients with heart failure with preserved ejection fraction (HFpEF) are comparatively sparse. Little is known concerning the prognostic consequences of autonomic dysregulation in such individuals, and therapies applied with success in HFrEF have in most trials failed to improve symptoms or survival of those with HFpEF. A recent HFpEF Expert Scientific Panel report emphasised that without a deeper understanding of the pathophysiology of HFpEF, establishing effective treatment will be challenging. One aspect of such pathology may be cardiovascular autonomic disequilibrium, often worsened by acute exercise or routine daily activity. This review aims to summarise existing knowledge concerning parasympathetic and sympathetic function of patients with HFpEF, consider potential mechanisms and specific consequences of autonomic disturbances that have been identified, and propose hypotheses for future investigation., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Acetylcholine (ACh) regulates inflammation via α 7 nicotinic acetylcholine receptor ( α 7 nAChR). Acetylcholinesterase (AChE), an enzyme hydrolyzing ACh, is expressed in immune cells suggesting non-classical function in inflammatory responses. Here, the expression of PRiMA-linked G4 AChE was identified on the surface of macrophages. In lipopolysaccharide-induced inflammatory processes, AChE was upregulated by the binding of NF- κ B onto the ACHE promotor. Conversely, the overexpression of G4 AChE inhibited ACh-suppressed cytokine release and cell migration, which was in contrast to that of applied AChE inhibitors. AChEmt, a DNA construct without enzymatic activity, was adopted to identify the protein role of AChE in immune system. Overexpression of G4 AChEmt induced cell migration and inhibited ACh-suppressed cell migration. The co-localization of α 7 nAChR and AChE was found in macrophages, suggesting the potential interaction of α 7 nAChR and AChE. Besides, immunoprecipitation showed a close association of α 7 nAChR and AChE protein in cell membrane. Hence, the novel function of AChE in macrophage by interacting with α 7 nAChR was determined. Together with hydrolysis of ACh, AChE plays a direct role in the regulation of inflammatory response. As such, AChE could serve as a novel target to treat age-related diseases by anti-inflammatory responses., (© 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Background: Food- and water-borne pathogens exhibit spatial heterogeneity, but attribution to specific environmental processes is lacking while anthropogenic climate change alters these processes. The goal of this study was to investigate ecology, land-use and health associations of these pathogens and to make future disease projections., Methods: The rates of five acute gastrointestinal illnesses (AGIs) (campylobacteriosis, Verotoxin- producing Escherichia coli, salmonellosis, giardiasis and cryptosporidiosis) from 2000 to 2013 in British Columbia, Canada, were calculated across three environmental variables: ecological zone, land use, and aquifer type. A correlation analysis investigated relationships between 19 climatic factors and AGI. Mean annual temperature at the ecological zone scale was used in a univariate regression model to calculate annual relative AGI risk per 1 °C increase. Future cases attributable to climate change were estimated into the 2080s., Findings: Each of the bacterial AGI rates was correlated with several annual temperature-related factors while the protozoan AGIs were not. In the regression model, combined relative risk for the three bacterial AGIs was 1.1 [95% CI: 1.02-1.21] for every 1 °C in mean annual temperature. Campylobacteriosis, salmonellosis and giardiasis rates were significantly higher (p < 0.05) in the urban land use class than in the rural one. In rural areas, bacteria and protozoan AGIs had significantly higher rates in the unconsolidated aquifers. Verotoxin-producing Escherichia coli rates were significantly higher in watersheds with more agricultural land, while rates of campylobacteriosis, salmonellosis and giardiasis were significantly lower in agricultural watersheds. Ecological zones with higher bacterial AGI rates were generally projected to expand in range by the 2080s., Interpretation: These findings suggest that risk of AGI can vary across ecosystem, land use and aquifer type, and that warming temperatures may be associated with an increased risk of food-borne AGI. In addition, spatial patterns of these diseases are projected to shift under climate change., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

Background: The objectives of this study were to describe right ventricular-pulmonary arterial elastance coupling hemodynamic phenotypes and their frequency in patients with advanced heart failure and to evaluate the association of elastance-based indices with all-cause mortality, cardiac transplantation, and left ventricular assist device therapy., Methods: This study included 175 patients with heart failure undergoing right heart catheterization to evaluate candidacy for advanced therapies and 21 healthy controls. We modified a single-beat approach to elastance to account for the magnitude of pulmonary arterial pressure and estimated right ventricular end-systolic elastance (E es ), pulmonary arterial elastance (E a ), and the E es :E a ratio. We defined elevated pulmonary arterial load as an E a > 0.5 mm Hg/ml, and ventriculo-arterial uncoupling as an E es :E a < 0.8. We evaluated associations between E es , E a , and E es :E a with all-cause mortality and composite event-free survival using multivariable Cox proportional-hazard models, adjusted for age and sex., Results: All 21 controls had E a ≤ 0.5 mm Hg/ml and E es :E a ≥ 0.8. Of 175 patients with heart failure, 63% had E a > 0.5 mm Hg/ml. E es :E a was lower in patients than in controls (p < 0.001), and 47% of the patients demonstrated E es :E a < 0.8, including 8% with normal E a . In median follow-up of 2.2 (0.8-4.6) years, 53 died, 37 received cardiac transplantation, and 33 received a left ventricular assist device. By multivariable analysis, E a (hazard ratios [HR]: 2.01, 95% CI 1.18-3.41) and E es :E a (HR: 0.46, 95% CI: 0.26-0.82) were independently associated with mortality, whereas E es was not., Conclusions: Right ventricular-pulmonary vascular coupling is frequently impaired in heart failure and associated with greater mortality. Elevated pulmonary arterial elastance is associated with greater mortality even when coupling is preserved., (Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Overactivation of N-methyl-D-aspartate (NMDA) receptors has been associated with neurodegenerative disorders such as Alzheimer's disease (AD), cerebral vascular disorders and amyotrophic lateral sclerosis (ALS). We have previously designed and synthesized a series of memantine nitrate and some of them have shown vessel dilatory effects and neuroprotective effects; however, the detailed mechanisms have not been elucidated. In this study, we further demonstrated that memantine nitrate-06 (MN-06), one of the novel compounds derived from memantine, possessed significant neuroprotective effects against glutamate-induced excitotoxicity in rat primary cerebellar granule neurons (CGNs). Pretreatment of MN-06 reversed the activation of GSK3b and the suppression of phosphorylated Akt induced by glutamate. In addition, the neuroprotective effects of MN-06 could be abolished by LY294002, the specific phosphatidylinositol 3-kinase (PI3-K) inhibitor. Ca 2+ imaging shown that pretreatment of MN-06 prevented Ca 2+ influx induced by glutamate. Moreover, MN-06 might inhibit the NMDA-mediated current by antagonizing NDMA receptors, which was further confirmed by molecular docking simulation. Taken together, MN-06 protected against glutamate-induced excitotoxicity by blocking calcium influx and attenuating PI3-K/Akt/GSK-3b pathway, indicating that MN-06 might be a potential drug for treating neurodegenerative disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Aims: Potassium-wasting (loop diuretics [LD]) and potassium-sparing (spironolactone) medications used for heart failure (HF) may alter renal potassium handling and confound the use of twenty-four-hour (24-h) urine collections as a surrogate marker for potassium intake, an effect that has been observed with dietary sodium assessment. The objective was to determine the strength of association between 24-h urine collections and weighed food records in assessing potassium intake in HF patients stratified by LD usage and spironolactone usage., Methods and Results: Stable outpatients with HF simultaneously completed two 24-h urine collections and two weighed food records on consecutive days. Analyses compared patients stratified by LD and/or spironolactone use. Pearson's correlation and the Bland-Altman method of agreement assessed the relationship between the techniques. Overall, 109 patients (61 ± 11 yrs, 74% male) were included. The mean difference in dietary potassium estimated between 24-h urine collections and food records was -353 ± 1043 mg (p < 0.01) for all patients, with no differences between measures among subgroups. The association between the two methods was r = 0.551 (95% CI, 0.373 to 0.852, p < 0.001) for LD users; r = 0.287 (95% CI, 0.01 to 0.570, p = 0.050) for LD non-users; r = 0.321 (95% CI, 0.13 to 0.798, p = 0.043) for spironolactone users, and; r = 0.534 (95% CI, 0.331 to 0.747, p < 0.001) for spironolactone non-users. There were no significant mean biases identified as part of the Bland-Altman analysis., Conclusion: Among HF patients, potassium-wasting and potassium-sparing medications do not influence the agreement between the two methods in the assessment of potassium intake., Competing Interests: Declaration of Competing Interest All the authors confirmed that they have no conflicts of interest., (Copyright © 2020 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Geographic factors may influence cardiovascular disease outcomes in Canada. Circulatory diseases are a major reason for higher population mortality rates in Northern Ontario, but it is unknown if hospitalized patients with cardiovascular disease experience differential outcomes compared with those in the South., Methods: We examined 30-day and 1-year mortality and readmissions for patients hospitalized with acute myocardial infarction (AMI), heart failure (HF), atrial fibrillation (AF), or stroke in Northern compared with Southern Ontario, using the Canadian Institute for Health Information Discharge Abstract Database (2005-2016). Northern patients were defined as those residing and hospitalized in the Northwest or Northeast Local Health Integration Network regions. We used multiple Cox proportional hazards regression analysis for time-to-first event and Prentice-Williams-Peterson method to evaluate repeat and multiply admitted patients., Results: A total of 47,745 Northern and 465,353 Southern patients hospitalized with AMI (n = 182,158), HF (n = 130,770), AF (n = 72,326), or stroke (n = 127,844) were studied. Rates of first readmission were higher among Northern patients for AMI (adjusted hazard ratio [HR], 1.32), HF (HR, 1.16), AF (HR, 1.21), and stroke (HR, 1.27) compared with Southern patients (all P < 0.001). Repeat readmission rates among Northern patients for AMI (HR, 1.23), HF (HR, 1.13), AF (HR, 1.18), and stroke (HR, 1.22) were also increased (all P < 0.001 vs Southern). Thirty-day mortality did not differ significantly between Northern and Southern patients., Conclusions: Readmissions were increased in those residing and hospitalized in the North. To reduce readmissions in the North, the quality of postacute transitional care should be examined further., (Copyright © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: We previously showed in heart failure (HF) patients that obstructive respiratory events during sleep and generation of negative intrathoracic pressure during Mueller manoeuvres, mimicking obstructive apneas, acutely reduced stroke volume (SV). We also showed that treating obstructive sleep apnea (OSA) with continuous positive airway pressure (CPAP) increased left ventricular ejection fraction over a 1-month period. We therefore hypothesized that, in HF patients, those with OSA would have greater overnight declines in SV and cardiac output (CO) than in those without sleep apnea, and that therapy of OSA using CPAP would prevent these declines., Methods: We examined overnight percent change in SV and CO in 32 HF patients with and 28 without OSA using digital photoplethysmography. Among patients with OSA, we also examined changes in SV and CO during a CPAP titration study., Results: During the baseline polysomnogram SV and CO decreased more overnight in those with OSA than in those without sleep apnea (-12.6 ± 7.7% vs -3.2 ± 6.8%; P < 0.001 and -16.2 ± 9.9% vs -3.7 ± 8.3%; P < 0.001, respectively). Overnight changes in SV and CO correlated inversely with total apnea-hypopnea index (r = -0.551; P < 0.001 and r = -0.522; P < 0.001, respectively). In 21 patients with OSA, CPAP reduced the total apnea-hypopnea index from 37.7 ± 21.4 to 15.0 ± 16.0 (P < 0.001) in association with attenuation of the overnight reduction of SV (from -14.0 ± 7.9% to -3.4 ± 9.8%; P = 0.002) and CO (from -17.2 ± 9.0% to -9.7 ± 10.7%; P = 0.042)., Conclusions: In patients with HF, coexisting OSA causes overnight declines in SV and CO that are prevented through reversal of OSA by CPAP., (Copyright © 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: The outcome of patients with chronic thromboembolic pulmonary hypertension (CTEPH) undergoing pulmonary endarterectomy (PEA) after urgent hospitalization for decompensated right heart failure (DRHF) remains unclear., Methods: Among 120 consecutive patients undergoing PEA, 16 (13%) presented with a history of urgent hospitalization for DRHF (severe RHF group). This group was compared with the remaining 104 patients presenting with total peripheral vascular resistance (TPR) < 1,200 dynes · sec · cm(-5) (n = 78, control group) and >1,200 dynes · sec · cm(-5) (n = 26, high TPR group)., Results: DRHF occurred predominantly in patients with TPR > 1,200 dynes · sec · cm(-5) (prevalence of 32% vs 5% in patients with TPR < 1,200 dynes · sec · cm(-5), p < 0.0001). The overall in-hospital mortality after PEA was 4% (n = 5). All deaths occurred in patients with TPR > 1,200 dynes · sec · cm(-5) and DRHF. The proportion of patients with residual PH immediately after surgery was higher in the high TPR group (50%) and severe RHF group (56%) compared with the control group (29%; p = 0.04). In multivariate analysis, risk factors for residual PH after surgery were TPR > 1,200 dynes · sec · cm(-5), Jamieson disease Type III-IV, and female gender. A history of DRHF by itself was not a risk factor for residual PH after PEA. The overall 5-year survival was 87%. After a median follow-up of 20 months, the proportion of patients receiving medical therapy for residual PH was higher in patients with post-operative mean pulmonary artery pressure ≥35 mm Hg (61% vs 9%, p = 0.0007)., Conclusions: DRHF occurs more frequently in patients with TPR > 1,200 dynes · sec · cm(-5), increasing the operative risk in these patients. The outcome of patients with high TPR in the absence of DRHF is excellent. However, patients with residual mean pulmonary artery pressure ≥35 mm Hg frequently receive pulmonary hypertension therapy after PEA., (Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Bis(12)-hupyridone (B12H), derived from the Chinese medicinal component huperzine A, was originally designed as a novel acetylcholinesterase (AChE) inhibitor. In this paper, we report that B12H (24-h pretreatment) effectively blocked glutamate-induced neuronal excitotoxicity in cerebellar granule neurons (CGNs). However, the huge discrepancy between the EC50 value and IC50 value of B12H, to protect against neuronal toxicity (0.09 μM) and to block the NMDA receptor (21.8 μM) respectively, suggests that the neuroprotection of B12H might be not primarily due to the blockade of the NMDA receptor. Pretreatment by specific antagonists of alpha7-nicotinic acetylcholine receptor (α7nAChR), but not muscarinic acetylcholine receptor (mAChR) or α4β2nAChR, decreased the neuroprotection of B12H. The neuroprotection of B12H could also be abolished by the pretreatment of specific PI3-K inhibitors. Furthermore, B12H restored the suppressed activation of the Akt pathway caused by glutamate as evidenced by the decreased expressions of pSer473-Akt and pSer9-GSK3β. All these results suggest that B12H substantially protected CGNs against glutamate-induced neuronal excitotoxicity via activating α7nAChR/PI3-K/Akt cascade., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Heart failure (HF) clinics have been shown to reduce hospital readmissions and generally have favourable effects on quality of life, survival, and care costs. This study investigated the rates of referral and use of HF clinics and examined factors related to program use., Methods: This study represents a secondary analysis of a larger prospective cohort study conducted in Ontario. In hospital, 474 HF inpatients from 11 hospitals across Ontario completed a survey that examined predisposing, enabling, and need factors affecting HF clinic use. Then 1 year later, 271 HF patients completed a mailed survey that assessed referral to and use of HF clinics., Results: Forty-one patients (15.2%) self-reported referral, and 35 (13%) self-reported attending an HF clinic. Generalized estimating equations showed that factors related to greater program use were having an HF clinic at the site of hospital recruitment (odds ratio [OR] = 8.40; P = 0.04), referral to other disease management programs (OR = 4.87; P = 0.04), higher education (OR = 4.61; P = 0.02), lower stress (OR = 0.93; P = 0.03), and lower functional status (OR = 0.97; P = 0.03)., Conclusion: Similar to previous research, only one-seventh of HF patients were referred to and used an HF clinic. Both patient-level and health-system factors were related to HF clinic use. Given the benefits of HF clinics, more research examining how equitable access can be increased is needed. Also, the appropriateness and cost repercussions of use of multiple disease management programs should be investigated., (Copyright © 2012 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary endarterectomy (PEA) is the treatment of choice for patients with chronic thromboembolic pulmonary hypertension (PH). However, this surgery remains performed in few experienced centres only. The goal of the study is to review our overall experience since the implementation of our program in August 2005., Methods: Review all patients referred to our program between August 2005 and July 2011., Results: Among 84 consecutive patients referred to our program, 52 patients underwent elective PEA and 6 emergency PEA. After PEA, 74% patients were extubated within 2 days, 71% were discharged from the intensive care unit within 4 days and 64% were discharged from hospital within 15 days. One patient undergoing elective surgery and 2 patients undergoing emergency surgery died within 30 days of surgery for an operative mortality of 1.9% after elective pulmonary endarterectomy and an overall operative mortality of 5.2%, when the 6 emergency operative cases were included. The total pulmonary vascular resistance decreased from 965±445 to 383±162 dynes per second per cm(-5) and was associated with significant improvement in World Health Organization/New York Heart Association (WHO/NYHA) functional class, 6 minutes walk distance, echocardiographic findings, and brain natriuretic peptide level at 6 months after PEA. After a median follow-up of 23 months (1-65 months), 3 patients had to be started on targeted PH therapy for deterioration of their (WHO/NYHA) functional class., Conclusions: Elective PEA can be performed with limited risk, and results in excellent early and long-term outcome. All patients diagnosed with chronic thromboembolic PH should be referred for consideration of PEA in a specialized centre., (Copyright © 2011 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Despite a major reduction in pulmonary vascular resistance (PVR), patients with chronic thromboembolic pulmonary hypertension (CTEPH) do not always return to functional New York Heart Association (NYHA) class I after pulmonary endarterectomy (PEA). We hypothesized that residual abnormal compliance (Cp) after PEA is associated with incomplete functional recovery despite major improvement in PVR., Methods: The Cp of 34 consecutive patients with CTEPH was assessed before and after PEA. Cp was defined as stroke volume over pulse pressure and was divided into three groups: < 2.0 mL/mm Hg, 2.0 to 3.9 mL/mm Hg, and ≥ 4 mL/mm Hg. To establish predicted Cp after PEA, we collected an age- and gender-matched control group., Results: Before PEA, Cp was < 2.0 mL/mm Hg in 82% (n = 28) of the patients. After PEA, Cp improved to 2.0 to 3.9 mL/mm Hg in 11 patients and to ≥ 4.0 mL/mm Hg in 14 patients. Residual Cp < 2.0 mL/mm Hg was associated with delayed extubation and prolonged hospital stay. At 3 months' follow-up, 13 patients (93%) with postoperative Cp ≥ 4.0 mL/mm Hg returned to NYHA class I, whereas 45% with Cp of 2.0 to 3.9 mL/mm Hg and 25% with Cp < 2.0 mL/mm Hg returned to NYHA class I. In multivariate analysis, postoperative Cp ≥ 4.0 mL/mm Hg was the only predictor of functional recovery to NYHA class I. The group of patients with postoperative Cp ≥ 4.0 mL/mm Hg was also the only group to achieve hemodynamic parameters similar to those of their matched control subjects., Conclusions: Postoperative Cp is an important predictor of recovery after PEA. Residual vascular stiffness after PEA can be associated with persistent functional limitation and lack of complete remodeling of the right ventricle.

Background: Twenty-four-hour urine collections are considered the optimal method for sodium intake assessment. Whether a diagnosis of heart failure (HF) or the use of loop diuretic (LD) therapy for HF compromises the validity of 24-h urine collections as a surrogate marker for sodium intake is unknown., Objective: The objective was to determine the strength of association between 24-h urine collections and food records for sodium intake assessment in non-HF cardiac patients and in HF patients stratified by LD usage., Design: Food records and 24-h urine collections were simultaneously completed for 2 consecutive days. Correlation coefficients and the Bland-Altman method of agreement described the relation between the techniques., Results: Non-HF cardiac patients (n = 96; mean ± SD age: 65 ± 11 y), HF patients who were not taking an LD (n = 47; 62 ± 11 y), and HF patients who were taking an LD (n = 62; age: 60 ± 12 y) were included. Correlation coefficients for sodium intake between food records and urine collections were r = 0.624 (P < 0.001) for non-HF cardiac patients and r = 0.678 (P < 0.001) for HF patients who were not taking an LD. However, no significant association (r = 0.132, P = 0.312) was observed for HF patients who were taking LDs. The 95% limits of agreement between the non-HF cardiac patients and the HF patients who were not taking LDs were similar but were ≈50% wider for HF patients who were taking LDs., Conclusions: For the assessment of sodium intake, food records agree well with 24-h urine collections in non-HF patients with cardiovascular disease and in HF patients who are not receiving LD but not for HF patients who are taking LDs. Therefore, food records may provide a better estimate of sodium intake in HF patients who are receiving LD therapy.

Background: A low-sodium diet is an accepted treatment of patients with heart failure (HF), although minimal evidence exists on the appropriate amount of sodium intake for this population. Certain HF guidelines have liberalized dietary sodium recommendations, which actually exceed guidelines for healthy adults., Objectives: We tested the hypothesis that high sodium intake is related to acute decompensated HF (ADHF) in ambulatory HF patients. Secondary outcomes included all-cause hospitalization and mortality., Design: We prospectively enrolled medically stable, ambulatory patients with systolic HF (n = 123; mean ± SD age: 60 ± 13 y) from 2 outpatient HF clinics from 2003 to 2007. Baseline estimates of dietary sodium and other nutrient intakes were obtained from two 3-d food records., Results: The median follow-up time was 3.0 y. Mean (±SD) sodium intakes were 1.4 ± 0.3, 2.4 ± 0.3, and 3.8 ± 0.8 g Na/d in the lower, middle, and upper tertiles, respectively. Cumulative ADHF event rates at 3 y were 12 ± 6%, 15 ± 7%, and 46 ± 11% in the low, middle, and upper tertiles, respectively (log-rank P = 0.001). For ADHF, the upper tertile was associated with an adjusted hazard ratio of 2.55 (95% CI: 1.61, 4.04; P < 0.001). Time-to-event probabilities were significant for mortality (log-rank P = 0.022) but not for all-cause hospitalization (log-rank P = 0.224). The high-sodium tertile was associated with an adjusted hazard ratio of 1.39 (95% CI: 1.06, 1.83; P = 0.018) for all-cause hospitalization and 3.54 (95% CI: 1.46, 8.62; P = 0.005) for mortality., Conclusions: To our knowledge, this study provides the first prospective evidence that ambulatory HF patients who consume higher amounts of sodium are at greater risk of an ADHF event. These data provide support for more stringent sodium intake guidelines than those currently recommended for HF patients.

Background: In patients with severe left ventricular (LV) dysfunction, visible pulsus alternans coincides with visible T-wave alternans (TWA), but a similar relationship has not been described for nonvisible microscopic systolic pressure alternans (MSPA) and microvolt TWA (MTWA)., Objective: The purpose of this study was to determine the prevalence of MSPA and its relationship to MTWA in patients with cardiomyopathy., Methods: Using the spectral method, MSPA was measured from finger pressure during incremental atrial pacing and then validated against MSPA measured from the LV pressure in 12 patients. In 23 other patients with cardiomyopathy (LV ejection fraction <40%), noninvasive MSPA and MTWA were measured simultaneously during incremental atrial pacing., Results: MSPA (<1 mm Hg) was detected in 80% of patients with cardiomyopathy and in 43% of controls. The presence of finger MSPA showed 100% positive concordance with LV MSPA; however, finger MSPA was 20% larger due to peripheral augmentation. Finger MSPA was highly concordant (96% positive concordance and 90% negative concordance) with MTWA. The magnitudes of MSPA and MTWA showed a linear correlation (R = 0.66, P <.001), and the k value, a measure of signal-to-noise ratio, was significantly larger for MSPA compared to MTWA (108 ± 88 vs 24 ± 48, P <.001). Premature beats resulted in concordant and coincident changes in MSPA and MTWA. During follow-up (454 ± 274 days), 2 (8.6%) patients experienced ventricular tachycardia, and both manifested MSPA and MTWA during pacing at 600 ms., Conclusion: MSPA can be detected noninvasively in patients with cardiomyopathy and is coupled to MTWA, suggesting a common mechanism. The high signal-to-noise ratio of MSPA may provide a novel robust metric of sudden cardiac death risk in these patients., (Copyright © 2011 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Objective: Atherosclerosis is influenced by the interaction of environmental and genetic susceptibility risk factors. We used global microarray expression profiling to investigate differentially regulated genes in aorta during development of atherosclerosis in a susceptible genetically modified mouse model in response to the interaction between risk factors including hyperlipidemic genotype, shear stress, diet, and age., Methods and Results: In this study we investigated transcriptional changes in lesion-prone and lesion-resistant regions of aortas in genetically modified mice lacking both genes of the LDL receptor and the apolipoprotein B mRNA editing enzyme (LDb; Ldlr(-/-)Apobec1(-/-)). Risk factors including hyperlipidemic genotype (LDb vs. C57BL/6 wildtype), shear stress (lesion-prone vs. lesion resistant aortic regions), diet (chow vs. Western high-fat), and age (2- vs. 8-months) were studied. We hybridized aortic RNA samples with microarray chips containing probes for 45,000 mouse genes and expressed sequence tags (ESTs). Overall, the differentially expressed genes were components of 20 metabolic and physiological pathways. Notably, calcium signaling is the major pathway identified with differential regulation of 30 genes within this pathway. We also found differential expression of calcium-signaling genes in cultured primary endothelial cells from lesion-prone and lesion-resistant arterial regions (LDb mice vs. C57BL/6 controls), providing further support for involvement of calcium signaling in the pathogenesis of atherosclerosis. Moreover, we demonstrated protein expression of genes in the calcium-signaling pathway using Western blot analysis and immunofluorescence., Conclusions: Our results suggest that calcium signaling may play an important role in regulation of genes expressed in aorta during development of atherosclerosis. Calcium signaling may act via mechanistic responses to genetic, mechanical, and environmental insults that trigger an imbalance of intracellular calcium homeostasis, resulting in altered biological processes leading to lesion development., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Better knowledge of the evolution of persistent pulmonary hypertension after acute pulmonary embolism (PE) is required to optimize the indication and timing of pulmonary endarterectomy (PEA)., Methods: We reviewed our experience with 17 consecutive patients demonstrated to have persistent pulmonary hypertension after acute massive (n = 1), submassive (n = 7), or recurrent PE (n = 9)., Results: After a median of 18 weeks of anticoagulation (range, 12 to 30 weeks) since the last PE, 10 patients showed residual pulmonary artery systolic pressure (PAsP) > 50 mm Hg. These patients demonstrated a significant progression in PAsP over the ensuing 6 to 12 months, from 73 +/- 14 to 101 +/- 26 mm Hg (p = 0.005) [mean +/- SD], and eight patients were found to be suitable candidates for PEA. In contrast, among seven patients with residual PAsP from 35 to 40 mm Hg (n = 3) and 41 to 50 mm Hg (n = 4), six patients had evidence of residual perfusion defects on the ventilation/perfusion scan and CT. The PAsP did not change significantly over the ensuing 6 to 12 months, except in two patients who had new episodes of acute PE., Conclusions: Two groups of patients can be identified based on the degree of residual pulmonary hypertension after acute PE. Patients with residual PAsP > 50 mm Hg should be evaluated for PEA since their pulmonary artery pressures will significantly progress over the ensuing 6 to 12 months despite the absence of recurrent PE. In contrast, patients with PAsP from 35 to 50 mm Hg are at risk for severe pulmonary hypertension if new PE occurs, and should therefore be closely monitored.

There is extensive experimental evidence from in vitro and animal experiments that congestive heart failure (CHF) is a state of oxidative stress. Moreover, in animal models, the development of CHF is accompanied by changes in the antioxidant defense mechanisms of the myocardium as well as evidence of oxidative myocardial injury. This has led to the hypothesis that oxidative stress may be a mechanism of disease progression in CHF. Indeed, many patients consume antioxidant supplements making the assumption that no harm will result and, possibly, that this therapy will yield some clinical benefits. The focus of this review is to examine the oxidative stress hypothesis of CHF as it pertains to humans. To date, human studies that have sought evidence for a role of oxidative stress in patients with CHF have fallen short of providing strong support for this hypothesis. Studies that have demonstrated an association between oxidant stress and CHF are small and are hindered by methodologic limitations that diminish the impact of their conclusions. Randomized trials of antioxidant supplementation for CHF are scarce, and to our knowledge no study yet convincingly demonstrates any benefit from consuming antioxidant supplements. Therefore, the available evidence is insufficient to support or negate the oxidative stress hypothesis of CHF and the use of antioxidants cannot be recommended as a specific therapy for this condition.

Study Objectives: To determine the effects of hyperoxia on left ventricular (LV) function in humans with and without congestive heart failure (CHF)., Design: An acute physiologic study of the effect of hyperoxia on right-heart hemodynamics, LV contractility (peak positive rate of rise of LV pressure [+dP/dt]), time constant of isovolumic left ventricular relaxation (tau), and LV filling pressures., Setting: Bayer Cardiovascular Clinical Research Laboratory at the Mount Sinai Hospital, Toronto, Ontario., Patients: Sixteen patients with stable CHF and 12 subjects with normal LV function received the hyperoxia intervention., Interventions: Patients received 21% O(2) by a nonrebreather mask, followed by 100% O(2) for 20 min, and 21% O(2) for a 10-min recovery period., Results: In response to hyperoxia, there was a 22 +/- 6% increase in LV end-diastolic pressure (LVEDP) in the CHF group and a similar 29 +/- 14% increase in LVEDP in the normal LV function group (p < 0.05 for both; mean +/- SEM). Hyperoxia was also associated with a prolongation in tau of 10 +/- 2% in the CHF group (p < 0.05) and 8 +/- 2% in the normal LV function group (p < 0.05). No changes in +dP/dt were observed in either group., Conclusions: Hyperoxia was associated with impairment of cardiac relaxation and increased LV filling pressures in patients with and without CHF. These observations indicate that caution should be used in the administration of high inspired O(2) fractions to normoxic patients, especially in the setting of CHF.