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Incident cardiovascular disease (CVD) increases with increasing low-density lipoprotein cholesterol (LDL-C) concentration and exposure duration. Area under the LDL-C versus age curve is a possible risk parameter. Data-based demonstration of this metric is unavailable and whether the time course of area accumulation modulates risk is unknown.Using CARDIA (Coronary Artery Risk Development in Young Adults) study data, we assessed the relationship of area under LDL-C versus age curve to incident CVD event risk and modulation of risk by time course of area accumulation-whether risk increase for the same area increment is different at different ages.This prospective study included 4,958 asymptomatic adults age 18 to 30 years enrolled from 1985 to 1986. The outcome was a composite of nonfatal coronary heart disease, stroke, transient ischemic attack, heart failure hospitalization, cardiac revascularization, peripheral arterial disease intervention, or cardiovascular death.During a median 16-year follow-up after age 40 years, 275 participants had an incident CVD event. After adjustment for sex, race, and traditional risk factors, both area under LDL-C versus age curve and time course of area accumulation (slope of LDL-C curve) were significantly associated with CVD event risk (hazard ratio: 1.053; p 0.0001 per 100 mg/dl × years; hazard ratio: 0.797 per mg/dl/year; p = 0.045, respectively).Incident CVD event risk depends on cumulative prior exposure to LDL-C and, independently, time course of area accumulation. The same area accumulated at a younger age, compared with older age, resulted in a greater risk increase, emphasizing the importance of optimal LDL-C control starting early in life.

Background The health status of newborns is a major concern for parents and medical personnel. Recent studies have provided increasing evidence that factors from the foetal and perinatal periods of life influence health later in life. The “Follow‐up of the Survey of Neonates in Pomerania” (SNiP‐I‐Follow‐up) is the first follow‐up of the population‐based birth cohort study, SNiP‐I, established in north‐east Germany. Objectives The primary aim of SNiP‐I‐Follow‐up study was the collection of longitudinal data on children and adolescents. The associations will be analysed between risk factors in pregnancy and the perinatal period and health status in infancy and later childhood. Population The population‐based cohort study SNiP‐I was conducted in Pomerania in north‐east Germany between February 2002 and November 2008. All mothers from the SNiP‐I birth cohort were recontacted when their children were from 9 to 15 years of age. Design The SNiP‐I‐Follow‐up study was carried out between December 2016 and August 2017 and is a questionnaire‐based survey. Methods Physical development, health status, and social behaviour (school and leisure behaviour) of children were analysed using a questionnaire comprising medical, epidemiological, and socio‐economic data, associated health care risk factors, and life circumstances of newborns, children, and their parents. Preliminary results Out of 5725 children invited to participate in the SNiP‐I‐Follow‐up study between December 2016 and August 2017, 29% (n = 1665) children participated in the SNiP‐I‐Follow‐up study, providing data on 1665 mothers‐child dyads. Responders had higher socio‐economic status, especially in relation to maternal education status. Conclusion As a longitudinal birth cohort from rural Germany, the SNiP cohort will be a resource to address urgent research needs and contribute to overall population health.

Cellular and circuit hyperexcitability are core features of fragile X syndrome and related autism spectrum disorder models. However, the cellular and synaptic bases of this hyperexcitability have proved elusive. We report in a mouse model of fragile X syndrome, glutamate uncaging onto individual dendritic spines yields stronger single-spine excitation than wild-type, with more silent spines. Furthermore, fewer spines are required to trigger an action potential with near-simultaneous uncaging at multiple spines. This is, in part, from increased dendritic gain due to increased intrinsic excitability, resulting from reduced hyperpolarization-activated currents, and increased NMDA receptor signaling. Using super-resolution microscopy we detect no change in dendritic spine morphology, indicating no structure-function relationship at this age. However, ultrastructural analysis shows a 3-fold increase in multiply-innervated spines, accounting for the increased single-spine glutamate currents. Thus, loss of FMRP causes abnormal synaptogenesis, leading to large numbers of poly-synaptic spines despite normal spine morphology, thus explaining the synaptic perturbations underlying circuit hyperexcitability., Fragile X syndrome and autism spectrum disorders are associated with circuit hyperexcitability, however, its cellular and synaptic bases are not well understood. Here, the authors report abnormal synaptogenesis with an increased prevalence of polysynaptic spines with normal morphology in a mouse model of fragile X.

Sensory hypersensitivity is a common and debilitating feature of neurodevelopmental disorders such as Fragile X Syndrome (FXS). How developmental changes in neuronal function culminate in network dysfunction that underlies sensory hypersensitivities is unknown. By systematically studying cellular and synaptic properties of layer 4 neurons combined with cellular and network simulations, we explored how the array of phenotypes in Fmr1-knockout (KO) mice produce circuit pathology during development. We show that many of the cellular and synaptic pathologies in Fmr1-KO mice are antagonistic, mitigating circuit dysfunction, and hence may be compensatory to the primary pathology. Overall, the layer 4 network in the Fmr1-KO exhibits significant alterations in spike output in response to thalamocortical input and distorted sensory encoding. This developmental loss of layer 4 sensory encoding precision would contribute to subsequent developmental alterations in layer 4-to-layer 2/3 connectivity and plasticity observed in Fmr1-KO mice, and circuit dysfunction underlying sensory hypersensitivity., Somatosensory hypersensitivity in Fmr-1 knockout mice is thought to arise from an increase in cortical circuit excitability. Here, the authors report that the loss of precision of sensory encoding in the Layer 4 of barrel cortex is the primary developmental circuit alteration that drives the other compensatory circuit dysfunction.

Novel psychoactive substances have emerged as drugs of abuse. 2-Fluorodeschloroketamine (2-FDCK) is a ketamine derivative that can be purchased online for as little as $12 per gram. We report the case of a patient with a history of polysubstance use presenting after insufflation of 2-FDCK, with subsequent confirmation of metabolites in the patient's urine. A 28-year-old man presented to the Emergency Department in a dissociated state. He recovered well with supportive care, and described during interview his experience of substance use including the novel psychoactive substance 2-FDCK. A urine sample was sent for analysis and 2-FDCK metabolites were isolated. This case is concerning because 2-FDCK is a relatively new agent that has not yet been reported in the United States. It is easy to obtain over the internet and has significant abuse potential.

Introduction: The majority of venomous snake exposures in the United States are due to snakes from the subfamily Crotalinae (pit vipers). There are three types of US pit vipers: rattlesnakes (Crota...

Background: The prevalence of obstructive sleep apnea (OSA) is very high in stroke patients, whereas the acceptance of positive airway pressure (PAP) therapy is low. Although telemedicine offers new options to increase acceptance, effective concepts and patient groups are not yet known. Objective: The aim of this study was to investigate the effect of a telemedicine concept consisting of telemonitoring and support when usage time drops. Methods: PAP naive stroke patients with apnea-hypopnea index (AHI) >15 were randomized in a prospective parallel design comparing home therapy with standard care (SC) as opposed to telemedicine care (TC) over a period of 6 months. The TC group received a standardized phone call to offer help and advice if the average weekly usage of PAP fell below 4 h/night. Results: Eighty patients were included, 5 were lost to follow-up, 75 (20 females, age: 57.0 ± 9.9, body mass index: 30.9 ± 6.0 kg/m2, AHI: 39.4 ± 18.6) were evaluated. While inpatient usage was similar in both groups, a significant difference was identified after 6 months of receiving home therapy (TC: 4.4 ± 2.5 h, SC: 2.1 ± 2.2 h; p < 0.000063). On average, 4.7 ± 3.1 interventional phone calls were needed (173 calls in total, ranging from 0 to 10 calls per patient), primarily for the purpose of motivation (61.3%), mask problems (16.2%), nasopharyngeal complaints or humidification issues (11.2%), and technical questions (10.6%). Sleepiness (Epworth Sleepiness Scale [ESS]) differed significantly (TC: 3.7 + 3.2, SC: 6.1 + 4.1; p = 0.008), as well as systolic blood pressure, which was available in a subgroup of 55 patients (TC: 129.5 + 15.2 mm Hg, SC: 138.8 + 16.1 mm Hg; p = 0.034). Conclusion: A concept of telemonitoring and short telephone calls from the sleep lab raised PAP therapy adherence significantly in a group of stroke patients with moderate to severe OSA.

Background: Conflicting data exist regarding the benefit of urgent coronary angiogram and percutaneous coronary intervention (PCI) after sudden cardiac arrest, particularly in the absence of ST-segment elevation. We hypothesized that the type of lesions treated (stable versus unstable) influences the benefit derived from PCI. Methods: Data were taken between May 2011 and 2014 from a prospective registry enrolling all sudden cardiac arrest in Paris and suburbs (6.7 million inhabitants). Patients undergoing emergent coronary angiogram were included. Decision to perform PCI was left to the discretion of local teams. We assessed the impact of emergent PCI on survival at discharge according to whether the treated lesion was angiographically unstable or stable, and we investigated the predictive factors for unstable coronary lesions. Results: Among 9265 sudden cardiac arrests occurring during the study period, 1078 underwent emergent coronary angiogram (median age: 59.6 years, 78.3% males): 463 (42.9%) had an unstable lesion, 253 (23.5%) only stable lesions, and 362 (33.6%) no significant lesions. Emergent PCI was performed in 478 patients (91.4% of unstable and 21.7% of stable lesions). At discharge, PCI of unstable lesions was associated with twice-higher survival rate compared with untreated unstable lesions (47.9% versus 25.6%, P =0.013), while stable lesions PCI did not improve survival (25.5% versus 26.3%, P =1.00). After adjustment, PCI of unstable coronary lesions was independently associated with improved survival (odds ratio, 2.09 [95% CI, 1.42–3.09], P P =0.824). Angina, initial shockable rhythm, ST-segment elevation, and absence of known coronary artery disease were independent predictors of unstable lesions. Conclusions: Emergent PCI of unstable lesions is associated with improved survival after sudden cardiac arrest, contrary to PCI of stable lesions. Accordingly, early PCI should only be performed in patients with unstable lesions. Four factors (chest pain, ST-elevation, absence of coronary artery disease history, and shockable initial rhythm) could help identify patients with unstable lesions who would, therefore, benefit from emergent coronary angiogram.

Treatment of advanced pulmonary emphysema with endobronchial coils can improve clinical outcomes like quality of life (QOL). Yet, patients with chronic obstructive pulmonary disease (COPD) are also known to suffer from reduced sleep quality. The effect of coil therapy on sleep has not yet been investigated. The primary aim of this study was to investigate sleep efficiency before and after coil treatment. Secondly, we investigated the effects on nocturnal breathing pattern, QOL, and physical activity. Polysomnography (PSG) testing was performed before (T0), 6 month after (T3), and 12 months after (T4) treatment with endobronchial coils. Further examinations included QOL by St George’s Respiratory Questionnaire (SGRQ) and COPD assessment test (CAT), and physical activity using an accelerometer for 1 week after each visit. Of 21 patients, 14 completed the study: 6 women; mean age 58.0 ± 4.9 years; BMI 22.6 ± 4.6 kg/m2; FEV1 28.6 ± 7.1% predicted; residual volume (RV) 278.2 ± 49.4% predicted. Sleep efficiency did not vary between baseline and follow-up examinations (T0 69.0 ± 15.8%; T3 70.9 ± 16.0%; T4 66.8 ± 18.9%). Non-REM respiratory rate decreased compared to baseline (T0 19.4 ± 3.9/min; T3 17.8 ± 3.5/min; T4 17.1 ± 3.1/min (p = 0.041; p = 0.030) and QOL improved meeting the minimal clinically important difference (MCID) (SGRQ, T3 −12.8 units; T4 −7.1 units; CAT: T3 −5.6 units; T4 −3.4 units). No increase in physical activity was recorded (light activity T0 31.9 ± 9.9; T3 30.8 ± 16.9; T4 26.3 ± 10.6 h/week). Treatment with endobronchial coils did not influence objectively measured sleep quality or physical activity, but reduced nocturnal breathing frequency and improved QOL in severe emphysema patients. ClinicalTrials.gov Identifier: NCT02399514, First Posted: March 26, 2015

The local anesthetic lidocaine, which has been used extensively during liposuction, has been reported to have cytotoxic effects and therefore would be unsuitable for use in autologous lipotransfer. We evaluated the effect of lidocaine on the distribution, number, and viability of adipose-derived stem cells (ASCs), preadipocytes, mature adipocytes, and leukocytes in the fatty and fluid portion of the lipoaspirate using antibody staining and flow cytometry analyses. Adipose tissue was harvested from 11 female patients who underwent liposuction. Abdominal subcutaneous fat tissue was infiltrated with tumescent local anesthesia, containing lidocaine on the left and lacking lidocaine on the right side of the abdomen, and harvested subsequently. Lidocaine had no influence on the relative distribution, cell number, or viability of ASCs, preadipocytes, mature adipocytes, or leukocytes in the stromal-vascular fraction. Assessing the fatty and fluid portions of the lipoaspirate, the fatty portions contained significantly more ASCs (p &lt, 0.05), stem cells expressing the preadipocyte marker Pref-1 (p &lt, 0.01 w/lidocaine, p &lt, 0.05 w/o lidocaine), and mature adipocytes (p &lt, 0.05 w/lidocaine, p &lt, 0.01 w/o lidocaine) than the fluid portions. Only the fatty portion should be used for transplantation. This study found no evidence that would contraindicate the use of lidocaine in lipotransfer. Limitations of the study include the small sample size and the inclusion of only female patients.

Case details A 51-year-old man presented with rapid onset encephalopathy and respiratory failure after a suspected intravascular envenomation from a North American pit viper. The patient received antivenom and was transferred to a tertiary care facility where he had cardiovascular collapse and persistent coagulopathy requiring 28 vials of Crotalidae polyvalent immune Fab antivenom for initial control and six vials for maintenance. The patient's coagulopathy was monitored using “traditional” measures (platelets, fibrinogen, and prothrombin time/international normalized ratio) and rotational thromboelastometry (ROTEM®). The patient also subsequently developed intestinal necrosis requiring exploratory laparotomy with ileum and colonic resections, and anuric renal failure requiring continuous renal replacement therapy. After coordinated multidisciplinary management, he was discharged to an acute inpatient rehabilitation on hospital day 25 and has since made a full recovery. Discussion In the setting of a severe intravascular pit viper envenomation, thromboelastometry correlated well with “traditional” measures. During recovery, ROTEM® demonstrated measurable improvements in the extrinsic coagulation pathway while the INR remained between 1.5 and 1.6. Patient's intestinal necrosis may have resulted from microvascular thrombosis due to Crotalinae venom. The patient's ultimate recovery necessitated a coordinated multidisciplinary effort. ROTEM® abnormalities after North American pit viper envenomation may be more sensitive than “traditional” measures and may have prognostic value to determine the severity of envenomation, but further research to define its utility is required.

Aim To describe our initial experience with the Occlutech Duct Occluder (ODO) for percutaneous closure of patent ductus arteriosus (PDA). Methods Retrospective review of patients undergoing transcatheter PDA closure with the ODO in 2 academic centers. Results From April 2013 to September 2017, 42 patients underwent PDA closure. Median age at implantation was 34 months (range 4 months–68 years) and median weight was 12 kg (range 4.1–57 kg). Ducts were Krichenko type A duct ( n = 34), type E ( n = 6), and type C ( n = 2). The mean duct diameter was 3.76 mm (range 1.69 to 9.95 mm, median 3.1 mm). Implantation succeeded in all. There was neither device embolization nor hemolysis. At device release, immediate angiogram showed a small residual shunt in 54.7%. During follow-up, Doppler echocardiography demonstrated 71% of full occlusion at day one, rising to 95% at one month and 100% at one year and half after implantation. The mean maximal systolic pressure gradient in left pulmonary artery was 4.2 ± 4.3 mm and across the distal aortic arch 5.4 ± 4.7 mm Hg. No patient had any significant stenosis with clinical relevance. Conclusions ODO is safe and effective in transcatheter closure of PDA including relatively large sized ducts. The results are satisfactory with a high level of full occlusion and a low rate of complications. Further evaluation with larger studies and longer follow-up will be required to confirm these preliminary good results.

Objectives Published reports have suggested that the concurrent use of alcohol or drugs occurs among some snakebite victims, but no national assessment of such data exists. Methods We used data from US poison control centers collected during telephone calls in calendar years 2000-2013 to compare snake envenomations with concomitant use of drugs, alcohol, or both to snakebites lacking such use. Results A total of 608 snakebites with 659 instances of concomitant alcohol/drug use were reported, which represent approximately 1% of 92,751 snakebites reported to US poison control centers. An annual mean of 48 snakebites with concomitant use of alcohol/drugs was reported, compared with a mean of 6625 snakebites per year with no concomitant use of alcohol/drugs. Most cases involved men, peaked during the summer months, and involved copperheads or rattlesnakes, which mirrored overall trends. Snakebite victims who also used alcohol/drugs were more likely than victims with only a snakebite reported to be bitten by rattlesnakes, to be admitted to the hospital, and die. Alcohol was the most common reported concomitant substance, but other substances were reported. Conclusions Snakebites with concomitant use of alcohol/drugs are uncommon, accounting for approximately 1% of the snakebite envenomations reported annually to US poison control centers; however, snakebite victims also reporting alcohol/drug use are more likely to be bitten by rattlesnakes, be admitted to a healthcare facility, and die.

Importance Modern data regarding incidence and modes of death of patients with aortic stenosis (AS) are restricted to tertiary centers or studies of aortic valve replacement (AVR). Objective To provide new insights into the natural history of outpatients with native AS based on a large regionwide population study with inclusion by all cardiologists regardless of their mode of practice. Design, Setting, and Participants Between May 2016 and December 2017, consecutive outpatients with mild (peak aortic velocity, 2.5-2.9 m/s), moderate (peak aortic velocity, 3-3.9 m/s), and severe (peak aortic velocity, ≥4 m/s) native AS graded by echocardiography were included by 117 cardiologists from the Nord-Pas-de-Calais region in France. Analysis took place between August and November 2020. Main Outcomes and Measures Natural history, need for AVR, and survival of patients with AS were followed up. Indications for AVR were based on current guideline recommendations. Results Among 2703 patients (mean [SD] age, 76.0 [10.8] years; 1260 [46.6%] women), 233 (8.6%) were recruited in a university public hospital, 757 (28%) in nonuniversity public hospitals, and 1713 (63.4%) by cardiologists working in private practice. A total of 1154 patients (42.7%) had mild, 1122 (41.5%) had moderate, and 427 (15.8%) had severe AS. During a median (interquartile range) of 2.1 (1.4-2.7) years, 634 patients underwent AVR and 448 died prior to AVR. Most deaths were cardiovascular (200 [44.7%]), mainly associated with congestive heart failure (101 [22.6%]) or sudden death (60 [13.4%]). Deaths were noncardiovascular in 186 patients (41.5%) and from unknown causes in 62 patients (13.8%). Compared with patients with mild AS, there was increased cardiovascular mortality in those with moderate (hazard ratio, 1.47 [95% CI, 1.07-2.02]) and severe (hazard ratio, 3.66 [95% CI, 2.52-5.31]) AS. The differences remained significant when adjusted for baseline characteristics or in time-dependent analyses considering AS progression. In asymptomatic patients, moderate and mild AS were associated with similar cardiovascular mortality (hazard ratio, 0.99 [95% CI, 0.44-2.21]). Conclusions and Relevance While patients in this study with moderate AS had a slightly higher risk of cardiovascular death than patients with mild AS, this risk was much lower than that observed in patients with severe AS. Moreover, in asymptomatic patients, moderate and mild AS were associated with similar cardiovascular mortality.

Associations of early creatine phosphokinase-MB (CK-MB) elevation and new Q waves and their association with cardiovascular death (CVD) after coronary artery bypass grafting (CABG) have been reported, but this association has not been studied in a large population of patients with diabetes mellitus. In this study, we examine the association of periprocedural CK-MB elevations and new Q waves with CVD in the Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease trial. Cox proportional hazards regression was used to assess the relation of CK-MB elevations and new Q waves in the first 24 hours after procedure and their relation to CVD; logistic regression was used to assess odds ratios of these variables. Hazard ratios, 95% confidence intervals, and p values associated with Wald chi-square test are reported. CK-MB elevation in first 24 hours after procedure was independently associated with CVD. CVD hazard increased by 6% (p0.001) with each multiple of CK-MB above the upper reference limit (URL); odds of new post-CABG Q waves increased by a factor of 1.08 (p0.001); at 7× CK-MB URL, HR was2. CK-MB URL multiples of 7, 12, and 15 were associated with new Q-wave odds ratios of 9, 16, and 27 times, respectively (p ≤0.001, C-statistic0.70). New Q waves were independently associated with survival in the multivariate model only when CK-MB was excluded (p = 0.01). In conclusion, independent associations included (1) CVD and early post-CABG CK-MB elevation; (2) new Q waves with early post-CABG CK-MB elevation; (3) CVD with new Q waves only when CK-MB elevation is excluded from analysis.

Karl-Josef Franke,1,2 Ulrike Domanski,1 Maik Schroeder,1 Volker Jansen,3 Frank Artmann,4 Uwe Weber,5 Rainer Ettler,6 Georg Nilius1,2 1Department of Pneumology and Critical Care Medicine, HeliosKlinik Ambrock, Hagen, 2Witten/Herdecke University, Witten, 3Lung Practice Jansen, Menden, 4Aeroprax Wuppertal,Wuppertal, 5Lung PracticeWitten, Witten, 6Lung Practice Ettler, Hagen, Germany Background: Regular physical activity is associated with reduced mortality in patients with chronic obstructive pulmonary disease (COPD). Interventions to reduce time spent in sedentary behavior could improve outcomes. The primary purpose was to investigate the impact of telemonitoring with supportive phone calls on daily exercise times with newly established home exercise bicycle training. The secondary aim was to examine the potential improvement in health-related quality of life and physical activity compared to baseline. Methods: This prospective crossover-randomized study was performed over 6 months in stable COPD patients. The intervention phase (domiciliary training with supporting telephone calls) and the control phase (training without phone calls) were randomly assigned to the first or the last 3 months. In the intervention phase, patients were called once a week if they did not achieve areal-time monitored daily cycle time of 20 minutes. Secondary aims were evaluated at baseline and after 3 and 6 months. Health-related quality of life was measured by the COPD Assessment Test (CAT), physical activity by the Godin Leisure Time Exercise Questionnaire (GLTEQ). Results: Of the 53 included patients, 44 patients completed the study (forced expiratory volume in 1 second 47.5%±15.8% predicted). In the intervention phase, daily exercise time was significantly higher compared to the control phase (24.2±9.4 versus 19.6±10.3 minutes). Compared to baseline (17.6±6.1), the CAT-score improved in the intervention phase to 15.3±7.6 and in the control phase to 15.7±7.3units. The GLTEQ-score increased from 12.2±12.1 points to 36.3±16.3 and 33.7±17.3. Conclusion: Telemonitoring is a simple method to enhance home exercise training and physical activity, improving health-related quality of life. Keywords: telehealthcare, physical activity, COPD assessment test, telephone support

The FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) trial demonstrated that for patients with diabetes mellitus (DM) and multivessel coronary disease (MVD), coronary artery bypass grafting (CABG) is superior to percutaneous coronary intervention with drug-eluting stents (PCI-DES) in reducing the rate of major adverse cardiovascular and cerebrovascular events after a median follow-up of 3.8 years. It is not known, however, whether CABG confers a survival benefit after an extended follow-up period.The purpose of this study was to evaluate the long-term survival of DM patients with MVD undergoing coronary revascularization in the FREEDOM trial.The FREEDOM trial randomized 1,900 patients with DM and MVD to undergo either PCI with sirolimus-eluting or paclitaxel-eluting stents or CABG on a background of optimal medical therapy. After completion of the trial, enrolling centers and patients were invited to participate in the FREEDOM Follow-On study. Survival was evaluated using Kaplan-Meier analysis, and Cox proportional hazards models were used for subgroup and multivariate analyses.A total of 25 centers (of 140 original centers) agreed to participate in the FREEDOM Follow-On study and contributed a total of 943 patients (49.6% of the original cohort) with a median follow-up of 7.5 years (range 0 to 13.2 years). Of the 1,900 patients, there were 314 deaths during the entire follow-up period (204 deaths in the original trial and 110 deaths in the FREEDOM Follow-On). The all-cause mortality rate was significantly higher in the PCI-DES group than in the CABG group (24.3% [159 deaths] vs. 18.3% [112 deaths]; hazard ratio: 1.36; 95% confidence interval: 1.07 to 1.74; p = 0.01). Of the 943 patients with extended follow-up, the all-cause mortality rate was 23.7% (99 deaths) in the PCI-DES group and 18.7% (72 deaths) in the CABG group (hazard ratio: 1.32; 95% confidence interval: 0.97 to 1.78; p = 0.076).In patients with DM and MVD, coronary revascularization with CABG leads to lower all-cause mortality than with PCI-DES in long-term follow-up. (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes [FREEDOM]; NCT00086450).

Pleural effusion (PE), excess fluid in the pleural space, is often observed in lung cancer patients and also forms due to many benign ailments. Classifying it quickly is critical, but this remains an analytical challenge often lengthening the diagnosis process or exposing patients to unnecessary risky invasive procedures. We tested the analysis of PE using a multiplexed cytokeratin (CK) panel with targeted mass spectrometry-based quantitation for its rapid classification. CK markers are often assessed in pathological examinations for cancer diagnosis and guiding treatment course. We developed methods to simultaneously quantify 33 CKs in PE using peptide standards for increased analytical specificity and a simple CK enrichment method to detect their low amounts. Analyzing 121 PEs associated with a variety of lung cancers and noncancerous causes, we show that abundance levels of 10 CKs can be related to PE etiology. CK-6, CK-7, CK-8, CK-18, and CK-19 were found at significantly higher levels in cancer-related PEs. Additionally, elevated levels of vimentin and actin differentiated PEs associated with bacterial infections. A classifier algorithm effectively grouped PEs into cancer-related or benign PEs with 81% sensitivity and 79% specificity. A set of undiagnosed PEs showed that our method has potential to shorten PE diagnosis time. For the first time, we show that a cancer-relevant panel of simple-epithelial CK markers currently used in clinical assessment can also be quantitated in PEs. Additionally, while requiring less invasive sampling, our methodology demonstrated a significant ability to identify cancer-related PEs in clinical samples and thus could improve patient care in the future.

Porous alloplastic materials such as titanium mesh and porous polyethylene allow for the ingrowth of fibrovascular tissues into the implant; stabilizing the implant and reducing the risk of extrusion and extrusion-related complications (such as hematoma formation). The literature contains 2 specific reports of delayed atraumatic orbital hematomas occurring 8 months and 3 years after orbital floor reconstruction with porous polyethylene implants. In this study, an atraumatic orbital hematoma occurring 16 years after orbital floor reconstruction with a porous polyethylene implant was presented. The hematoma was evacuated and the implant was removed without replacement of a secondary implant. The remaining fibrovascular tissue on the underside of the implant provided enough support of the orbital soft tissues to achieve excellent anatomic and physiologic outcomes.

In adults, membranous nephropathy is the second most common cause of nephrotic syndrome. In contrast, minimal change disease and focal segmental glomerulosclerosis constitute the most common forms of nephrotic syndrome in children, while membranous nephropathy accounts for 5% of cases. In adults, causes of membranous nephropathy include autoantibodies directed against phospholipase A

Increasingly frequent, it is clinically indicated to obtain tissue from a peripheral lung lesion (PLL) to yield a pathological diagnosis. The aim of the present study was to evaluate the diagnostic sensitivity of transbronchial needle aspiration (TBNA) and transbronchial catheter aspiration (TBCA) in addition to transbronchial forceps biopsy (TBB) at conventional bronchoscopy. Eligible patients showing a PLL on computed tomography scans were included in the study. In all patients, following TBB, TBNA and TBCA were employed in randomised order under fluoroscopy. Fourty-eight patients were enrolled, of whom 46 patients with 46 PLLs were included in the analysis. The mean ± SD diameter of the PLL was 27.0 ± 13.3 mm. The overall sensitivity for all modalities was 69.6 %; PLL ≤20 or >20 and ≤30 mm in diameter showed a sensitivity of 60.0 and 72.2 %, respectively. For malignant PLL (n = 33), the combined sensitivity of TBNA + TBCA versus TBB was significantly higher (63.6 vs. 33.3 %, p ≤ 0.05), and could not further be improved by TBB. For benign PLL, TBB was superior to TBNA + TBCA (76.9 vs. 38.5 %). TBB, TBNA and TBCA are complementary to one another. Combining the three techniques, even allows transbronchial specimen collection of PLL

Heart failure patients supported with left ventricular assist devices (LVAD) enjoy improvements in functional capacity and quality of life. We reasoned that such improvements in exercise capacity should be reflected in an objective increase in peak oxygen consumption as measured by cardiopulmonary exercise testing (CPET). We performed a retrospective review of all recipients of a HeartMate II LVAD at our center from June 2009 to June 2012 who completed CPET. Thirty-seven patients completed CPET an average of 6 months after implantation. Of these, 10 patients had CPET performed before LVAD implantation. Overall, 91.4% of patients improved by at least two New York Heart Association classes, with 34.3% improving by three classes. Postimplant VO2 max was significantly less than predicted (14.7 ± 3.1 vs. 29.8 ± 6.6 ml/kg/min, p < 0.001; percent-predicted 51% ± 12%). For 10 patients with pre- and post-implant studies, VO2 max increased significantly from 11.6 ± 5.0 to 15.4 ± 3.9 ml/kg/min (p = 0.009). VO2 max improves significantly with LVAD support but fails to normalize to predicted values, in spite of improvements in functional class. The severity of preimplantation heart failure does not associate with the degree of VO2 max improvement.

Post-transplant diabetes mellitus (PTDM) is a metabolic disorder occurring after solid organ transplantation during the therapy with calcineurin inhibitors. ATP-sensitive potassium channels KCNJ11 and KCNQ1 play an important role in the regulation of insulin secretion by β cells and development of diabetes mellitus. Numerous studies have confirmed the association between KCNJ11 and KCNQ1 gene polymorphisms and type 2 diabetes. The aim of this study was to examine the association between KCNJ11 and KCNQ1 gene polymorphisms and posttransplant diabetes mellitus in kidney allograft recipients treated with tacrolimus. The study included 201 patients who received kidney transplants. The patients were subdivided into two subgroups: patients with PTDM (N = 35) and patients without PTDM (N = 166). The association between KCNJ11 and KCNQ1 gene polymorphisms and post-transplant diabetes was studied in three models of univariate Cox regression analysis, i.e., additive, dominant and recessive. In these three models there were no statistically significant associations between KCNJ11 and KCNQ1 gene polymorphisms and PTDM. The results of this study suggest lack of association between KCNJ11 and KCNQ1 gene polymorphisms and post-transplant diabetes mellitus in kidney allograft recipients treated with tacrolimus in the Polish population.

Georg Nilius,1,2 Nato Katamadze,1,2 Ulrike Domanski,1 Maik Schroeder,1 Karl-Josef Franke1,2 1HELIOS Klinik Hagen-Ambrock, 2Internal Medicine I, Witten/Herdecke University, Witten, Germany Background: COPD patients who develop chronic hypercapnic respiratory failure have a poor prognosis. Treatment of choice, especially the best form of ventilation, is not well known. Objectives: This study compared the effects of pressure-controlled (spontaneous timed [ST]) non-invasive ventilation (NIV) and NIV with intelligent volume-assured pressure support (IVAPS) in chronic hypercapnic COPD patients regarding the effects on alveolar ventilation, adverse patient/ventilator interactions and sleep quality. Methods: This prospective, single-center, crossover study randomized patients to one night of NIV using ST then one night with the IVAPS function activated, or vice versa. Patients were monitored using polysomnography (PSG) and transcutaneous carbon dioxide pressure (PtcCO2) measurement. Patients rated their subjective experience (total score, 0–45; lower scores indicate better acceptability). Results: Fourteen patients were included (4 females, age 59.4±8.9 years). The total number of respiratory events was low, and similar under pressure-controlled (5.4±6.7) and IVAPS (8.3±10.2) conditions (P=0.064). There were also no clinically relevant differences in PtcCO2 between pressure-controlled and IVAPS NIV (52.9±6.2 versus 49.1±6.4 mmHg). Respiratory rate was lower under IVAPS overall; between-group differences reached statistical significance during wakefulness and non-rapid eye movement sleep. Ventilation pressures were 2.6 cmH2O higher under IVAPS versus pressure-controlled ventilation, resulting in a 20.1 mL increase in breathing volume. Sleep efficiency was slightly higher under pressure-controlled ventilation versus IVAPS. Respiratory arousals were uncommon (24.4/h [pressure-controlled] versus 25.4/h [IVAPS]). Overall patient assessment scores were similar, although there was a trend toward less discomfort during IVAPS. Conclusion: Our results show that IVAPS NIV allows application of higher nocturnal ventilation pressures versus ST without affecting sleep quality or inducing ventilation-associated events. Keywords: NIV, IVAPS, COPD, hypercapnia

Background: Angiosarcomas may develop as primary tumours of unknown cause or as secondary tumours, most commonly following radiotherapy to the involved field. The different causative agents may be linked to alternate tumorigenesis, which led us to investigate the genetic profiles of morphologically indistinguishable primary and secondary angiosarcomas.Methods: Whole-genome (18k) c-DNA-mediated annealing, selection, extension and ligation analysis was used to genetically profile 26 primary and 29 secondary angiosarcomas. Key findings were thereafter validated using RT-qPCR, immunohistochemistry and validation of the gene signature to an external data set.Results: In total, 103 genes were significantly deregulated between primary and secondary angiosarcomas. Secondary angiosarcomas showed upregulation of MYC, KIT and RET and downregulation of CDKN2C. Functional annotation analysis identified multiple target genes in the receptor protein tyrosine kinase pathway. The results were validated using RT-qPCR and immunohistochemistry. Further, the gene signature was applied to an external data set and, herein, distinguished primary from secondary angiosarcomas.Conclusions: Upregulation of MYC, KIT and RET and downregulation of CDKN2C characterise secondary angiosarcoma, which implies possibilities for diagnostic application and a mechanistic basis for therapeutic evaluation of RET-kinase-inhibitors in these highly aggressive tumours.

Background Improving access to thrombolytic therapy for patients with ischemic stroke is challenging. We assessed a prehospital process based on firemen rescuers under strict medical direction, aimed at facilitating thrombolysis of eligible patients. Methods This was a prospective observational study conducted over 4 months in Paris, France. Prehospital patients with suspected stroke were included after telephone consultation with a physician. If the time since the onset of symptoms was less than 6 hours, patients were transported directly to a neurovascular unit (NVU); if symptom onset was more than 6 hours ago, they were transported to an emergency department (ED). Confirmation of stroke diagnosis, the rate of thrombolysis, and the time intervals between the call and hospital arrival and imaging were assessed. Comparison used Fisher exact test. Results Of the 271 patients transported to an NVU, 218 were diagnosed with a stroke (166 with ischemic stroke), 69 received thrombolytic therapy, and the mean stroke-thrombolysis interval was 150 minutes. Of 64 patients admitted to the ED, 36 patients had a stroke (ischemic, 24). None were thrombolysed. Globally, 36% of ischemic strokes were thrombolysed (27% of all strokes diagnosed). The mean interval call-hospital was 65 minutes (ED vs NVU, P = .61). The interval call-imaging was 202 minutes (interquartile range, 105.5-254.5) for ED and 92 minutes (interquartile range, 77-116) for NVU ( P Conclusions The prehospital management of stroke by rescuers, under strict medical direction, seemed to be feasible and effective for selection of patients with stroke in an urban environment and may improve the access to thrombolysis.

To compare and evaluate the performance of the HEART, Global Registry of Acute Coronary Events (GRACE), and Thrombolysis in Myocardial Infarction (TIMI) scores to predict major adverse cardiac event (MACE) rates after index placement in an emergency department observation unit (EDOU) and to determine the need for observation unit initiation of emergent cardiac imaging tests, that is, noninvasive cardiac stress tests and invasive coronary angiography.A prospective observational single center study was conducted from January 2014 through June 2015. EDOU chest pain patients were included. HEART, GRACE, and TIMI scores were categorized as low (HEART ≤ 3, GRACE ≤ 108, and TIMI ≤1) versus elevated based on thresholds suggested in prior studies. Patients were followed for 6 months postdischarge. The results of emergent cardiac imaging tests, EDOU length of stay (LOS), and MACE occurrences were compared. Student t test was used to compare groups with continuous data, and χ testing was used for categorical data analysis.Of 986 patients, emergent cardiac imaging tests were performed on 62%. A majority of patients were scored as low risk by all tools (85% by HEART, 81% by GRACE, and 80% by TIMI, P0.05). The low-risk patients had few abnormal cardiac imaging test results as compared with patients scored as intermediate to high risk (1% vs. 11% in HEART, 1% vs. 9% in TIMI, and 2% vs. 4% in GRACE, P0.05). The average LOS was 33 hours for patients with emergent cardiac imaging tests performed and 25 hours for patients without (P0.05). MACE occurrence rate demonstrated no significant difference regardless of whether tests were performed emergently (0.31% vs. 0.97% in HEART, 0.27% vs. 0.95% in TIMI, and 0% vs. 0.81% in GRACE, P0.05).Chest pain risk stratification via clinical decision tool scores can minimize the need for emergent cardiac imaging tests with less than 1% MACE occurrence, especially when the HEART score is used.

There exists a growing demand in the proteomics community to standardize experimental methods and liquid chromatography–mass spectrometry (LC/MS) platforms in order to enable the acquisition of more precise and accurate quantitative data. This necessity is heightened by the evolving trend of verifying and validating candidate disease biomarkers in complex biofluids, such as blood plasma, through targeted multiple reaction monitoring (MRM)-based approaches with stable isotope-labeled standards (SIS). Considering the lack of performance standards for quantitative plasma proteomics, we previously developed two reference kits to evaluate the MRM with SIS peptide approach using undepleted and non-enriched human plasma. The first kit tests the effectiveness of the LC/MRM-MS platform (kit #1), while the second evaluates the performance of an entire analytical workflow (kit #2). Here, these kits have been refined for practical use and then evaluated through intra- and inter-laboratory testing on 6 common LC/MS platforms. For an identical panel of 22 plasma proteins, similar concentrations were determined, regardless of the kit, instrument platform, and laboratory of analysis. These results demonstrate the value of the kit and reinforce the utility of standardized methods and protocols. Biological significance The proteomics community needs standardized experimental protocols and quality control methods in order to improve the reproducibility of MS-based quantitative data. This need is heightened by the evolving trend for MRM-based validation of proposed disease biomarkers in complex biofluids such as blood plasma. We have developed two kits to assist in the inter- and intra-laboratory quality control of MRM experiments: the first kit tests the effectiveness of the LC/MRM-MS platform (kit #1), while the second evaluates the performance of an entire analytical workflow (kit #2). In this paper, we report the use of these kits in intra- and inter-laboratory testing on 6 common LC/MS platforms. This article is part of a Special Issue entitled: Standardization and Quality Control in Proteomics.

Soft tissue tumors in children under one year of age (infants) are rare. The etiology is usually unknown, with external factors or congenital birth defects and hereditary syndromes being recognized in only a small proportion of the cases. We ascertained the cytogenetic findings in 16 infants from whom tumor tissue had been obtained during a 25-year period. In eight of them, single nucleotide polymorphism (SNP) array analyses could also be performed. No constitutional chromosome aberrations were detected, and assessment of clinical files did not reveal any congenital or later anatomical defects. Three tumors--one infantile fibrosarcoma, one embryonal rhabdomyosarcoma, and one angiomatoid fibrous histiocytoma (AFH)--had abnormal karyotypes. As the AFH had an exchange between chromosome arms 12p and 15q, additional fluorescence in situ hybridization and reverse transcription-polymerase chain reaction analyses were performed, unexpectedly revealing an ETV6/NTRK3 fusion. Three of the eight tumors, including the AFH with an abnormal karyotype, analyzed by SNP array showed aberrations (loss of heterozygosity or imbalances). The present series suggests that the addition of array-based technologies is valuable for detecting underlying pathogenetic mechanisms.

ObjectivesThis study evaluated data from 3 federally funded trials that focused on optimal medical therapy to determine if formalized attempts at risk factor control within clinical trials are effective in achieving guideline-driven treatment goals for diabetic patients with coronary artery disease (CAD).BackgroundDespite clear evidence of benefit for CAD secondary prevention, the level of risk factor control in clinical practice has been disappointing.MethodsWe obtained data from the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) diabetes subgroup, (n = 766 of 2,287), the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial (n = 2,368), and the FREEDOM (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes) trial (n = 1,900) to evaluate the proportion of patients achieving guideline-based, protocol-driven treatment targets for systolic blood pressure, low-density lipoprotein cholesterol, smoking cessation, and hemoglobin A1c. The primary outcome measure was the proportion of diabetic CAD patients meeting all 4 pre-specified targets at 1 year after enrollment.ResultsThe pooled data include 5,034 diabetic patients. The percentages of patients achieving the 1-year low-density lipoprotein cholesterol targets compared with baseline increased from 55% to 77% in COURAGE, from 59% to 75% in BARI 2D, and from 34% to 42% in FREEDOM. Although similar improved trends were seen for systolic blood pressure, glycemic control, and smoking cessation, only 18% of the COURAGE diabetes subgroup, 23% of BARI 2D patients, and 8% of FREEDOM patients met all 4 pre-specified treatment targets at 1 year of follow-up.ConclusionsA significant proportion of diabetic CAD patients fail to achieve pre-specified targets for 4 major modifiable cardiovascular risk factors in clinical trials. We conclude that fundamentally new thinking is needed to explore approaches to achieve optimal secondary prevention treatment goals. (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation; NCT00007657) (Bypass Angioplasty Revascularization Investigation 2 Diabetes [BARI 2D]; NCT00006305) (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes [FREEDOM]; NCT00086450)

The optimal revascularization strategy for diabetic patients with multivessel coronary artery disease (MVD) remains uncertain for lack of an adequately powered, randomized trial. The FREEDOM trial was designed to compare contemporary coronary artery bypass grafting (CABG) to percutaneous coronary intervention (PCI) with drug-eluting stents in diabetic patients with MVD against a background of optimal medical therapy.A total of 1,900 diabetic participants with MVD were randomized to PCI or CABG worldwide from April 2005 to March 2010. FREEDOM is a superiority trial with a mean follow-up of 4.37 years (minimum 2 years) and 80% power to detect a 27.0% relative reduction. We present the baseline characteristics of patients screened and randomized, and provide a comparison with other MVD trials involving diabetic patients.The randomized cohort was 63.1 ± 9.1 years old and 29% female, with a median diabetes duration of 10.2 ± 8.9 years. Most (83%) had 3-vessel disease and on average took 5.5 ± 1.7 vascular medications, with 32% on insulin therapy. Nearly all had hypertension and/or dyslipidemia, and 26% had a prior myocardial infarction. Mean hemoglobin A1c was 7.8 ± 1.7 mg/dL, 29% had low-density lipoprotein70 mg/dL, and mean systolic blood pressure was 134 ± 20 mm Hg. The mean SYNTAX score was 26.2 with a symmetric distribution. FREEDOM trial participants have baseline characteristics similar to those of contemporary multivessel and diabetes trial cohorts.The FREEDOM trial has successfully recruited a high-risk diabetic MVD cohort. Follow-up efforts include aggressive monitoring to optimize background risk factor control. FREEDOM will contribute significantly to the PCI versus CABG debate in diabetic patients with MVD.

Novel substances often referred to as "designer drugs" have emerged as drugs of abuse, and recognition of these is difficult as routine blood and urine screening tests do not detect these agents. U-47700 is a synthetic selective μ-opioid agonist that can be bought online for as little as $40 per gram. We report two patients presenting after insufflation of U-47700, with subsequent confirmation of this substance in urine samples.A 26-year-old man and 24-year-old woman insufflated a substance they believed to be "synthetic cocaine." The man was found down with cyanosis and agonal respirations. He was intubated and taken to hospital where he recovered well with supportive care. The woman presented with anxiety, tremors and drowsiness and was admitted for observation. Urine samples from both patients were analyzed using GC/MS/MS and LC/QToF, and U-47700 was isolated in both cases. No other opioids were detected.These cases are concerning because U-47700 is a relatively new agent that is easy to obtain over the internet and has the potential to cause significant morbidity and mortality.

Clearance of expired air in upper airways by nasal high flow (NHF) can be extended below the soft palate and de facto causes a reduction of dead space. Using scintigraphy, the authors found a relationship between NHF, time, and clearance. Direct measurement of CO2 and O2 in the trachea confirmed a reduction of rebreathing, providing the actual data on inspired gases, and this can be used for the assessment of other forms of respiratory support., Recent studies show that nasal high flow (NHF) therapy can support ventilation in patients with acute or chronic respiratory disorders. Clearance of dead space has been suggested as being the key mechanism of respiratory support with NHF therapy. The hypothesis of this study was that NHF in a dose-dependent manner can clear dead space of the upper airways from expired air and decrease rebreathing. The randomized crossover study involved 10 volunteers using scintigraphy with 81mKrypton (81mKr) gas during a breath-holding maneuver with closed mouth and in 3 nasally breathing tracheotomized patients by volumetric capnography and oximetry through sampling CO2 and O2 in the trachea and measuring the inspired volume with inductance plethysmography following NHF rates of 15, 30, and 45 l/min. The scintigraphy revealed a decrease in 81mKr gas clearance half-time with an increase of NHF in the nasal cavities [Pearson’s correlation coefficient cc = −0.55, P < 0.01], the pharynx (cc = −0.41, P < 0.01), and the trachea (cc = −0.51, P < 0.01). Clearance rates in nasal cavities derived from time constants and MRI-measured volumes were 40.6 ± 12.3 (SD), 52.5 ± 17.7, and 72.9 ± 21.3 ml/s during NHF (15, 30, and 45 l/min, respectively). Measurement of inspired gases in the trachea showed an NHF-dependent decrease of inspired CO2 that correlated with an increase of inspired O2 (cc = −0.77, P < 0.05). NHF clears the upper airways of expired air, which reduces dead space by a decrease of rebreathing making ventilation more efficient. The dead space clearance is flow and time dependent, and it may extend below the soft palate. NEW & NOTEWORTHY Clearance of expired air in upper airways by nasal high flow (NHF) can be extended below the soft palate and de facto causes a reduction of dead space. Using scintigraphy, the authors found a relationship between NHF, time, and clearance. Direct measurement of CO2 and O2 in the trachea confirmed a reduction of rebreathing, providing the actual data on inspired gases, and this can be used for the assessment of other forms of respiratory support.

Objective assessment of maximal aerobic capacity using peak oxygen consumption (peak VO2) can be helpful in the management of patients with asymptomatic aortic stenosis (AS). The relationship between peak VO2 and AS severity criteria derived from rest and supine exercise echocardiography (SEE) has never been explored.We aimed to determine whether low peak VO2 (85% of predicted value) is associated with severity parameters in SEE, and poor clinical outcome.Fifty one asymptomatic patients (mean age of 54±21years) with moderate to severe aortic stenosis (Vmax3m/s) and left ventricle ejection fraction50% prospectively underwent resting and SEE and cardiopulmonary exercise testing (CPX).Peak VO2 was lower than expected (21.9±7.4mL/kg/min), i.e.85% of predicted value in 57% patients, secondary to cardiac limitation in most of them (69%). In multiple regression analysis, age, BMI and female gender were the only independent determinants of peak VO2. Interestingly no parameter derived from SEE was associated with peak VO2. After 21±7month follow-up, no patient died, 20 underwent cardiac surgery. Peak VO285% of predicted value was associated with lower event free survival compared to normal peak VO2 (57%±11% vs 93±6%, p=0.036) whereas no exercise echocardiographic parameter could predict such events. Peak VO2≥85% had a negative predictive value of 97%.CPX detects a high proportion of false asymptomatic AS patients with poorer outcome that cannot be predicted by SEE markers of AS severity. Assessment of aerobic capacity should be part of current approach within a "watchful waiting" strategy.

Back ground Regular exercise at a safe level, i.e. 3–5 metabolic equivalents, is recommended to improve blood pressure control and quality of life even after aortic dissection, although aerobic exercise capacities in these patients are unexplored yet. Methods We prospectively collected data from 105 patients with a history of post aortic dissection referred for a cardiopulmonary exercise testing (CPX) aiming to guide exercise rehabilitation. Results The population was composed of 76% of male, with a mean age of 57.9±12.4years. There were an equal distribution between the two type of dissection (47% of type A and 53% of type B aortic dissection). No cardiac event occurred during or after CPX. One third of patients have normal aerobic exercise capacity defined as peak oxygen uptake upper than 85% of their predicted capacity. Mean oxygen uptake peak was quite low 19.2±5.2ml/kg/min (5.5±1.5 metabolic equivalents). Aerobic capacity was limited by cardiac chronotropic incompetence in 42% or peripheral deconditioning in 45%. Blood pressure remained in an acceptable range during the exercise. Systolic and diastolic blood pressures were respectively 151±20 and 77±13mmHg at first ventilatory threshold. Conclusions CPX is a safe exploration in patients with post aortic dissection syndrome. Given the fact that most of these patients are faced with significant alteration of aerobic capacities, the recommended daily practice of moderate exercise at 3–5 METS should be adapted and personalized to each patient thanks to CPX.

Ossifying fibromyxoid tumor (OFMT) is a soft tissue tumor of unknown lineage. Although most cases are histologically and clinically benign, some show malignant morphological features and local recurrences are not uncommon; a few may even metastasize. In the present study, cytogenetic analysis identified different structural rearrangements of chromosome band 6p21 in tumor cells from three cases of OFMT, including one with typical, one with atypical, and one with malignant morphological features. Mapping of the 6p21 breakpoint by fluorescence in situ hybridization (FISH) indicated that the PHF1 gene was rearranged in all three cases. Further FISH, 5'-rapid amplification of cDNA ends, and RT-PCR analyses disclosed an EP400/PHF1 fusion transcript in one of the cases. Interphase FISH on tumor sections from 13 additional cases of OFMT showed rearrangement of the PHF1 locus in four of four typical, two of three atypical, and one of six malignant lesions. Thus, the PHF1 gene, previously shown to be the 3'-partner of fusion genes in endometrial stromal tumors, is also recurrently involved in the pathogenesis of OFMTs, irrespective of whether they are diagnosed as typical, atypical, or malignant lesions. The PHF1 protein interacts with the polycomb-repressive complex 2 (PRC2), which, in turn, regulates the expression of a variety of developmental genes. Thus, the results indicate that deregulation of PRC2 target genes is crucial for OFMT development.

The analytical performance of a standard-flow ultra-high-performance liquid chromatography (UHPLC) and a nano-flow high-performance liquid chromatography (HPLC) system, interfaced to the same state-of-the-art triple-quadrupole mass spectrometer, were compared for the multiple reaction monitoring (MRM)-mass spectrometry (MS)-based quantitation of a panel of 48 high-to-moderate-abundance cardiovascular disease-related plasma proteins. After optimization of the MRM transitions for sensitivity and testing for chemical interference, the optimum sensitivity, loading capacity, gradient, and retention-time reproducibilities were determined. We previously demonstrated the increased robustness of the standard-flow platform, but we expected that the standard-flow platform would have an overall lower sensitivity. This study was designed to determine if this decreased sensitivity could be compensated for by increased sample loading. Significantly fewer interferences with the MRM transitions were found for the standard-flow platform than for the nano-flow platform (2 out of 103 transitions compared with 42 out of 103 transitions, respectively), which demonstrates the importance of interference-testing when nano-flow systems are used. Using only interference-free transitions, 36 replicate LC/MRM-MS analyses resulted in equal signal reproducibilities between the two platforms (9.3 % coefficient of variation (CV) for 88 peptide targets), with superior retention-time precision for the standard-flow platform (0.13 vs. 6.1 % CV). Surprisingly, for 41 of the 81 proteotypic peptides in the final assay, the standard-flow platform was more sensitive while for 9 of 81 the nano-flow platform was more sensitive. For these 81 peptides, there was a good correlation between the two sets of results (R 2 = 0.98, slope = 0.97). Overall, the standard-flow platform had superior performance metrics for most peptides, and is a good choice if sufficient sample is available.

GOALS We aimed to investigate the prevalence of cardiovascular disease in patients with nonalcoholic steatohepatitis (NASH) versus non-NASH fatty liver. BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular disease, which is a leading cause of death in this patient population. NASH is a subset of NAFLD that carries a higher risk of progression to cirrhosis and its associated complications. STUDY We conducted a retrospective chart review of patients with biopsy-confirmed NAFLD, including NASH and non-NASH fatty liver, within the Gastroenterology and Hepatology clinic at Brooke Army Medical Center. Patients with secondary causes of chronic liver disease were excluded. The patients' records were reviewed for the presence of significant cardiovascular disease, which was defined as a history of stroke, unstable angina, myocardial infarction, congestive heart failure, or need for revascularization. RESULTS Nine hundred thirteen patients were identified and 377 patients met inclusion and exclusion criteria and were included in the final analysis. Of these, 219 patients had biopsies showing the presence of at least grade I NASH. The overall prevalence of cardiovascular disease was 6.63%. After controlling for age, sex, body mass index, and the presence of diabetes, there was no significant increase in the prevalence of cardiovascular disease in the NASH cohort over the non-NASH group. CONCLUSIONS Cardiovascular disease is common among patients with NAFLD. However, no increased risk of cardiovascular disease was found among those patients with NASH as compared with those with non-NASH fatty liver.

Background Ezrin is a cytoskeletal protein involved in tumour growth and invasion. Ezrin expression has been suggested to play a role in metastasis in paediatricosteosarcoma and rhabdomyosarcoma. Aim To evaluate the prognostic role of ezrin in a large series of soft tissue sarcoma of the extremities and trunk wall. Methods Ezrin expression was evaluated by immunohistochemistry on tissue microarrays from a mixed series of 256 soft tissue sarcomas. The expression patterns were correlated to local recurrence and metastasis as well as to established prognostic factors in soft tissue sarcoma. Results Increased ezrin expression predicted development of metastasis (HR=1.8, 95% CI 1.1 to 2.8; p=0.007) and local recurrence, also after adjustment for surgical margin (HR=2.4, 95% CI 1.4 to 4.3; p=0.02). Correlations to established prognostic factors showed strong associations between ezrin and necrosis (OR=3.9, p Conclusions Ezrin independently predicts development of local recurrences and metastases in soft tissue sarcomas. The possibility of preoperative evaluation makes ezrin a potential marker for identification of high-risk sarcoma patients who would benefit from neoadjuvant therapy.

We utilized data from patients with stable coronary artery disease (CAD) to assess the risk of new onset diabetes (NOD) with beta-blockers, and to determine whether angiotensin converting enzyme (ACE) inhibition would modify this risk. The Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) trial randomized 8290 patients with stable CAD to trandolapril or placebo. The presence of NOD was assessed at each study visit over a median follow-up time of 4.8 years. We examined the risk of NOD associated with beta-blockers use with Cox regression models, adjusting for 25 baseline covariates, and tested whether this risk was modified by randomization to the ACE inhibitor. Of 6910 patients without diabetes mellitus at enrollment (1179 females/5731 males, mean age 64 ± 8 years), 4147 (60%) were taking beta blockers, and 733 (8.8%) developed NOD. We observed a significant interaction between beta-blocker use and randomization to ACE inhibitor with respect to new onset diabetes (p = 0.028). Participants taking beta-blockers assigned to the placebo group (N=2090) were at increased risk for NOD adjusting for baseline covariates (HR 1.63, 95% confidence interval 1.29, 2.05, p

Purpose: Low-grade fibromyxoid sarcoma (LGFMS) is typically characterized by the specific translocation t(7;16)(q33;p11) and the corresponding fusion gene FUS-CREB3L2. The present study aimed to extract LGFMS-specific, and putatively FUS-CREB3L2–dependent, gene expression patterns to learn more about the pathogenesis of this tumor. Experimental Design: We carried out single nucleotide polymorphism (SNP) and global gene expression array analyses, and/or immunohistochemical (IHC) analyses on 24 LGFMS tumor biopsies. Tumor types that are important differential diagnoses to LGFMS were included as comparison in the gene and protein expression analyses. In addition, cells that stably expressed FUS-CREB3L2 were analyzed with gene expression array and the influence of FUS-CREB3L2 on gene expression was investigated in vitro. Results: The SNP array analysis detected recurrent microdeletions in association with the t(7;16) chromosomal breakpoints and gain of 7q in cases with ring chromosomes. Gene expression analysis clearly distinguished LGFMS from morphologically similar tumors and MUC4 was identified as a potential diagnostic marker for LGFMS by gene expression and IHC analysis. FOXL1 was identified as the top upregulated gene in LGFMS and CD24 was upregulated in both LGFMS tumors and FUS-CREB3L2 expressing cells. FUS-CREB3L2 was capable of activating transcription from CD24 regulatory sequences in luciferase assays, suggesting an important role for the upregulation of this gene in LGFMS. Conclusions: The gene expression profile of LGFMS is distinct from that of soft tissue tumors with similar morphology. The data could be used to identify a potential diagnostic marker for LGFMS and to identify possible FUS-CREB3L2 regulated genes. Clin Cancer Res; 17(9); 2646–56. ©2011 AACR.

With the advance of nanotechnology in biomaterials science and tissue engineering, it is essential that new techniques become available to observe processes that take place at the direct interface between tissue and scaffold materials. Here, Cryo DualBeam focused ion beam-scanning electron microscopy (FIB-SEM) was used as a novel approach to observe the interactions between frozen hydrated cells and nanometric structures in high detail. Through a comparison of images acquired with transmission electron microscopy (TEM), conventional FIB-SEM operated at ambient temperature, and Cryo DualBeam FIB-SEM, the advantages and disadvantages of each technique were evaluated. Ultrastructural details of both (extra)cellular components and cell organelles were best observe with TEM. However, processing artifacts such as shrinkage of cells at the substrate interface were introduced in both TEM and conventional FIB-SEM. In addition, the cellular contrast in conventional FIB-SEM was low; consequently, cells were difficult to distinguish from the adjoining substrate. Cryo DualBeam FIB-SEM did preserve (extra)cellular details like the contour, cell membrane, and mineralized matrix. The three described techniques have proven to be complementary for the evaluation of processes that take place at the interface between tissue and substrate.

BACKGROUND:: In soft tissue sarcoma, better distinction of high-risk and low-risk patients is needed to individualize treatment and improve survival. Prognostic systems used in clinical practice identify high-risk patients based on various factors, including age, tumor size and depth, histological type, necrosis, and grade. METHODS:: Whole-tumor sections from 239 soft tissue sarcomas of the extremities were reviewed for the following prognostic factors: size, vascular invasion, necrosis, and growth pattern. A new prognostic model, referred to as SING (Size, Invasion, Necrosis, Growth), was established and compared with other clinically applied systems. RESULTS:: Size, vascular invasion, necrosis, and peripheral tumor growth pattern provided independent prognostic information with hazard ratios of 2.2-2.6 for development of metastases in multivariate analysis. When these factors were combined into the prognostic model SING, high risk of metastasis was predicted with a sensitivity of 74% and a specificity of 85%. Moreover, the prognostic performance of SING compared favorably with other widely used systems. CONCLUSIONS:: SING represents a promising prognostic model, and vascular invasion and tumor growth pattern should be considered in soft tissue sarcoma prognostication. Cancer 2010. © 2010 American Cancer Society. (Less)

To determine the effect of a controlled heated breathing tube humidifier (cHH) on the quality of life (QOL), compliance and nasopharyngeal side effects during continuous positive airway pressure (CPAP) therapy in patients with obstructive sleep apnea syndrome (OSAS) in comparison with conventional CPAP. In this prospective randomised cross-over study, 44 patients with OSAS were investigated. During the first two consecutive treatment nights monitored by polysomnography, patients were randomly assigned to receive CPAP with or without cHH. Patients were then randomised to receive one of the treatment modalities at home for 4 weeks. Compliance was recorded and questionnaires assessing side effects and QOL were administered. Sleep parameters measured during the nights in the sleep laboratory did not change. The same result applied to QOL and compliance measured after 4 weeks. During the first two nights we found significant differences between CPAP with and without cHH for dryness of mouth (2.0 ± 1.4 vs. 1.4 ± 1.6) in favour of cHH (p

Contains fulltext : 87804.pdf (Publisher’s version ) (Closed access) Osteoblasts respond to mechanical stimulation by changing morphology, gene expression and matrix mineralization. Introducing surface topography on biomaterials, independently of mechanical loading, has been reported to give similar effects. In the current study, using a nanotextured surface, and mechanical loading, we aimed to develop a multi-factorial model in which both parameters interact. Mechanical stimulation to osteoblast-like cells was applied by longitudinal stretch in parallel direction to the nanotexture (300 nm wide and 60 nm deep grooves), with frequency of 1 Hz and stretch magnitude varying from 1% to 8%. Scanning electron microscopy showed that osteoblast-like cells subjected to mechanical loading oriented perpendicularly to the stretch direction. When cultured on nanotextured surfaces, cells aligned parallel to the texture. However, the parallel cell direction to the nanotextured surface was lost and turned to perpendicular when parallel stretch to the nanotexture, greater than 3% was applied to the cells. This phenomenon could not be achieved when a texture with micro-sized dimensions was used. Moreover, a significant synergistic effect on upregulation of fibronectin and Cfba was observed when dual stimulation was used. These findings can lead to a development of new biomimetic materials that can guide morphogenesis in tissue repair and bone remodeling. 01 oktober 2010

Deep-seated lipomas are often atypical histologically and are considered by some to have a high risk of recurrence after excision. We reviewed 215 deep-seated lipomas of the extremities and trunk wall with reference to histology, cytogenetics, clinical features and local recurrence. We classified tumours with atypical features and/or ring chromosomes as atypical lipomas. These were more common in men, larger than ordinary lipomas and more often located in the upper leg. The annual incidence was estimated as ten per million inhabitants and the ratio of atypical to ordinary lipomas was 1:3. In total, six tumours (3%), recurred locally after a median of eight years (1 to 16); of these, four were classified as atypical. The low recurrence rate of deep-seated lipomas of the extremity or trunk wall, irrespective of histological subtype, implies that if surgery is indicated, the tumour may be shelled out, that atypical lipomas in these locations do not deserve the designation well-differentiated liposarcoma, and that routine review after surgery is not required.

Lipoblastoma is a rare benign tumor that arises from embryonic adipose tissue and usually occurs in young children. Here, we present a review of available cytogenetic data and the karyotypes of 10 new cases of lipoblastoma, of which 7 could be studied further by fluorescence in situ hybridization (FISH) with regard to the involvement of the PLAG1 gene. All seven tumors with clonal aberrations harbored breakpoints in 8q11 approximately q13, in agreement with literature data. Including previously published cases, 33/40 (82%) lipoblastomas had rearrangement of the 8q11 approximately q13 region. These rearrangements target the PLAG1 gene, which becomes upregulated through promoter swapping. FISH revealed that five of seven cases in our series had a rearrangement of the PLAG1 gene. Occasionally, there can be difficulties in distinguishing a lipoblastoma from a conventional lipoma or a myxoid liposarcoma. As 8q11 approximately q13 rearrangements have been reported in only 3% of conventional lipomas and never in myxoid liposarcoma, cytogenetic analysis or FISH for the PLAG1 gene can provide useful differential diagnostic information.

Objective To characterize the cytomorphologic features of pilomatrixoma. Study design Aspirate findings in nine cases of PMX were correlated with clinical data and subsequent histology. This relatively large volume of case material afforded an opportunity to test the cytologic criteria that have been proposed as diagnostic of pilomatrixoma in the case reports published previously. Results Ghost cells, basaloid cells and calcium deposits were the features found to be most characteristic of PMX and were observed in all four cases in which a correct diagnosis was made originally. Conclusion The presence of ghost cells seems to be the key to recognizing PMX. These cells are visible in the majority of air-dried smears but seldom in alcohol-fixed smears. Adequate cytologic sampling and the routine use of both wet-fixed and air-dried smears should preclude an incorrect diagnosis.

Background— Patients with chronic kidney disease are at increased risk for cardiovascular morbidity and mortality. We assessed the association between albuminuria and the risks for death and cardiovascular events among patients with stable coronary disease. Methods and Results— We studied patients enrolled in the Prevention of Events with an ACE inhibitor (PEACE) trial, in which patients with chronic stable coronary disease and preserved systolic function were randomized to trandolapril or placebo and followed up for a median of 4.8 years. The urinary albumin to creatinine ratio (ACR) assessed in a core laboratory in 2977 patients at baseline and in 1339 patients at follow-up (mean 34 months) was related to estimated glomerular filtration rate and outcomes. The majority of patients (73%) had a baseline ACR within the normal range (P P =0.01). The effect of trandolapril therapy on outcomes was not modified significantly by the level of albuminuria. Nevertheless, trandolapril therapy was associated with a significantly lower mean follow-up ACR (12.5 versus 14.6 μg/mg, P =0.0002), after adjustment for baseline ACR, time between collections, and other covariates. An increase in ACR over time was associated with increased risk of cardiovascular death (hazard ratio per log ACR 1.74, 95% CI 1.08 to 2.82). Conclusions— Albuminuria, even in low levels within the normal range, is an independent predictor of cardiovascular and all-cause mortality.

Objective— To determine the prognostic utility of lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) for specific adverse cardiovascular outcomes in patients with stable coronary artery disease (CAD), independent of traditional risk factors and high-sensitivity C-reactive protein (hs-CRP). Methods and Results— We measured Lp-PLA 2 in 3766 patients with stable CAD from the PEACE trial. Patients were followed for a median of 4.8 years for adverse cardiovascular events including death, myocardial infarction (MI), coronary revascularization, hospitalization for unstable angina (UA), and stroke. Multivariable Cox regression was used to adjust for traditional cardiovascular risk factors and to conduct multimarker analyses that included hs-CRP. After adjustment for baseline characteristics, patients in higher quartiles of Lp-PLA 2 remained at significantly greater risk for the composite of cardiovascular death, MI, coronary revascularization, UA, or stroke ( P 2 were highly significant predictors of acute coronary syndromes (cardiovascular death, MI, or UA) ( P for trend 2 ), whereas only Lp-PLA 2 was a significant predictor of coronary revascularization ( P =0.01 for trend). Conclusions— In stable CAD, an elevated level of Lp-PLA 2 was a significant predictor of nonfatal adverse cardiovascular outcomes independent of traditional clinical risk factors and hs-CRP. Further investigation will be needed to establish whether therapies that lower Lp-PLA 2 reduce cardiovascular risk.