Single points of access to fill the "GAP" for unattached patients in primary care: what makes paediatric users more likely to require a medical appointment?

Unattachment to a regular primary care professional can affect children's and adolescents' well-being, considering their unique health needs. Having no alternative, many turn to emergency departments for non-urgent conditions. To help unattached patients access healthcare services while on waitlists, Quebec's government implemented single access points in each administrative region across the province. Our study aimed to describe the paediatric population using single access points and identify associations between their characteristics and need for a medical appointment. Clinical-administrative data of 1,323 paediatric access point users in the Montérégie region from November 2022 to March 2023 were utilized to conduct bivariate and multivariable regression analyses. Our study showed that young age, assessment trajectory, and specific reasons for calling were more likely to necessitate a medical appointment. While access points improve accessibility to doctors, questions remain regarding the relevance of medical consultations, inequities, and possible security issues resulting from the overall process.

Significant mitral regurgitation in patients undergoing TAVR: Mechanisms and imaging variables associated with improvement.

BACKGROUND: Significant mitral regurgitation (MR) is associated with poorer outcomes in patients undergoing transcatheter aortic valve replacement (TAVR). Factors associated with MR improvement have not been studied thoroughly. METHODS: Retrospective analysis of consecutive patients treated with TAVR with more than mild MR at baseline. MR evolution was assessed at 1-3 and 6-12 months after intervention. MR severity and mechanisms were assessed by echocardiography. Mitral annulus calcification (MAC) was quantified using preoperative cardiac CT. RESULTS: From 674 consecutive TAVR recipients, 78 with more than mild MR had a 6-12 months follow-up. Following TAVR, MR improved in 34 patients (43%), remained stable in 38 (49%) and worsened in 6 (8%). Patients with MR improvement had greater tenting area (141 ± 56 vs. 99 ± 40 mm2 , P < 0.01), tenting height (7.2 ± 1.9 vs. 5.6 ± 1.9 mm, P < 0.01) and lower ejection fraction (43 ± 16 vs. 52 ± 14%, P = 0.01). MAC was frequent (87.7% of patients) and a trend in greater MAC was observed in patients without MR improvement (3560 ± 5587 vs. 2053 ± 2800, P = 0.16). In multivariable analysis, tenting area (OR per 10 mm2 increase: 1.012, 95% CI, 1.001-1.024 P = 0.039) and annulus calcifications associated with leaflet restriction (OR = 0.108, 95% CI, 0.012-0.956, P = 0.045) were independently associated with MR outcome after TAVR. CONCLUSION: Larger mitral valve tenting area was associated with more improvement of MR after TAVR whereas extensive MAC associated with leaflet restriction was associated with less improvement. This may help in the clinical decision-making process of TAVR candidates with concomitant MR.

Renal injury in pediatric anorexia nervosa: a retrospective study.

PURPOSE: Although primarily a mental health disorder, anorexia nervosa (AN) has many physical consequences. Among them, the consequences on kidney function are often underestimated. We evaluated renal function in adolescent AN inpatients and investigated the correlation between the GFR and intrinsic patient characteristics. METHODS: A single-center retrospective study was conducted on 51 patients hospitalized for the restrictive type of AN in 2013. Data were divided into: (1) medical history of AN; (2) growth parameters and vital signs upon admission; and (3) blood tests. The glomerular filtration rate (GFR) was calculated using the Cockroft-Gault, MAYO Clinical Quadratic (MCQ), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), the Modification of Diet in Renal Disease (MDRD), and Schwartz equations. RESULTS: The calculated percentages of patients with a GFR below 90 mL/min/1.73 m2 according to the different equations were as follows: Cockroft-Gault, 45%; MDRD, 28%; CKD-EPI, 14%; MCQ, 12%, and Schwartz, 4%. There was a strong association between the body mass index (BMI) and the GFR according to all equations (p < 0.0001). The lowest heart rate was significantly associated with a reduced GFR according to the Cockroft-Gault equation (p = 0.03). The GFR values did not differ significantly after rehydration. CONCLUSION: Clinicians should evaluate AN patients for renal complications, especially when the BMI and heart rate are very low. Dehydration was not solely responsible for renal impairment. LEVEL OF EVIDENCE: Level III, single-center retrospective cohort study.

Unidirectional left-to-right interatrial shunting for treatment of patients with heart failure with reduced ejection fraction: a safety and proof-of-principle cohort study.

BACKGROUND: In patients with heart failure, interventions to reduce elevated left atrial pressure improve symptoms and reduce the risk of hospital admission. We aimed to assess the safety and potential efficacy of therapeutic left-to-right interatrial shunting in patients with heart failure with reduced ejection fraction. METHODS: We did this proof-of-principle cohort study at one centre in Canada. Patients (aged ≥18 years) with New York Heart Association (NYHA) class III chronic heart failure with reduced ejection fraction were enrolled under the Canadian special access programme. Shunt implants were done after transseptal catheterisation with transoesophageal echocardiographic guidance under general anaesthesia. Patients had clinical and echocardiography evaluations at baseline and months 1 and 3 after shunt implantation. FINDINGS: Between Oct 10, 2013, and March 27, 2015, we enrolled ten patients. The device was successfully implanted in all patients; no device-related or procedural adverse events occurred during follow-up. Transoesophageal echocardiography at 1 month showed that all shunts were patent, with no thrombosis or migration. From baseline to 3 month follow-up, we recorded improvements in NYHA classification (from class III to class II in seven [78%] of nine patients, from class III to class I in one [11%] patient, and no change in one [11%] patient; p=0·0004); quality of life, as assessed by the Duke Activity Status Index (from a mean score of 13 [SD 6·2] to 24·8 [12·9]; p=0·016) and the Kansas City Cardiomyopathy Questionnaire (from a mean score of 44·3 [SD 9·8] to 79·1 [13·0]; p=0·0001); and 6 min walk test distance (from a mean of 244 m [SD 112] to 318 m [134]; p=0·016). Pulmonary capillary wedge pressure was reduced from a mean of 23 mm Hg (SD 5) at baseline to 17 mm Hg (8) at 3 months (p=0·035), with no changes in right atrial pressure, pulmonary arterial pressure, or pulmonary resistance. No patient was admitted to hospital for worsening heart failure. One (10%) patient was admitted to hospital with gastrointestinal bleeding at month 1; one (10%) patient died after incessant ventricular tachycardia storm, which led to terminal heart failure 2 months post-procedure. INTERPRETATION: This first-in-man experience with an implanted left-to-right interatrial shunt demonstrates initial safety and early beneficial clinical and haemodynamic outcomes in patients with heart failure with reduced ejection fraction. Further large-scale randomised studies are warranted. FUNDING: V-Wave.

Serial analysis of 38 proteins during the progression of human breast tumor in mice using an antibody colocalization microarray.

Proteins in serum or plasma hold great potential for use in disease diagnosis and monitoring. However, the correlation between tumor burden and protein biomarker concentration has not been established. Here, using an antibody colocalization microarray, the protein concentration in serum was measured and compared with the size of mammary xenograft tumors in 11 individual mice from the time of injection; seven blood samples were collected from each tumor-bearing mouse as well as control mice on a weekly basis. The profiles of 38 proteins detected in sera from these animals were analyzed by clustering, and we identified 10 proteins with the greatest relative increase in serum concentration that correlated with growth of the primary mammary tumor. To evaluate the diagnosis of cancer based on these proteins using either an absolute threshold (i.e. a concentration cutoff) or self-referenced differential threshold based on the increase in concentration before cell injection, receiver operating characteristic curves were produced for 10 proteins with increased concentration, and the area under curve was calculated for each time point based on a single protein or on a panel of proteins, in each case showing a rapid increase of the area under curve. Next, the sensitivity and specificity of individual and optimal protein panels were calculated, showing high accuracy as early as week 2. These results provide a foundation for studies of tumor growth through measuring serial changes of protein concentration in animal models.

Clinical Presentation and Value of Echocardiography in the Diagnosis of Freestyle Aortic Bioprosthesis Leaflet Tears: A Retrospective Study.

BACKGROUND: The unique design of the Freestyle stentless aortic bioprosthesis has led to different mechanisms of failure, particularly leaflet tearing. The aim of this retrospective study was to review the clinical presentation and echocardiographic data of symptomatic patients with leaflet tears and significant aortic regurgitation (AR) following implantation of the Freestyle bioprosthesis. METHODS: Between January 1993 and May 2011, a total of 430 consecutive patients was identified at the authors' institution who had undergone primary aortic valve replacement with a Freestyle stentless aortic bioprosthesis. Clinical and echocardiographic data were collected prospectively for all patients. Structural valve deterioration was the major cause of bioprosthetic valve failure. RESULTS: Twenty symptomatic patients presented with significant AR due to leaflet tears in the absence of more than mild valvular calcification. At presentation, all patients complained of dyspnea. Some 50% of patients (n = 10) presented with acute pulmonary edema, and 10% (n = 2) with cardiogenic shock. A leaflet tear was initially diagnosed using transthoracic echocardiography in five cases (25%), using transesophageal echocardiography (TEE) in eight cases (40%), or at surgery in seven cases (35%). An appropriate diagnosis of leaflet tearing was recognized at surgery in more than one-third of patients. Consequently, clinicians must be aware of the variety of clinical presentations and should have a high degree of suspicion regarding leaflet tears in patients who have received a Freestyle stentless aortic bioprosthesis and present with moderate to severe AR. CONCLUSIONS: For the optimal management of patients with Freestyle stentless aortic bioprosthesis and new moderate to severe AR, TEE should be considered in all patients.

High-performance low-cost antibody microarrays using enzyme-mediated silver amplification.

Antibody microarrays can detect multiple proteins simultaneously, but the need for bulky and expensive fluorescence scanners limits their adaptation in clinical settings. Here we introduce a 15-plex enzyme-mediated silver enhanced sandwich immunoassay (SENSIA) on a microarray as an economic alternative to conventional fluorescence microarray assays. We compared several gold and silver amplification schemes, optimized HRP-mediated silver amplification, and evaluated the use of flatbed scanners for microarray quantification. Using the optimized assay condition, we established binding curves for 15 proteins using both SENSIA and conventional fluorescence microarray assays and compared their limits of detection (LODs) and dynamic ranges (DRs). We found that the LODs for all proteins are in the pg/mL range, with LODs for 12 proteins below 10 pg/mL. All but two proteins (ENDO and IL4) have similar LODs (less than 10-fold difference) and all but two proteins (IL1b and MCP1) are similar in DR (less than 1.5-log difference). Furthermore, we spiked six proteins in diluted serum and measured them by both silver enhancement and fluorescence detection and found a good agreement (R(2) > 0.9) between the two methods, suggesting that a complex matrix such as serum has a minimal effect on the measurement. By combining enzyme-mediated silver enhancement and consumer electronics for optical detection, SENSIA presents a new opportunity for low-cost high-sensitivity multiplex immunoassays for clinical applications.

Evaluating mixtures of 14 hygroscopic additives to improve antibody microarray performance.

Microarrays allow the miniaturization and multiplexing of biological assays while only requiring minute amounts of samples. As a consequence of the small volumes used for spotting and the assays, evaporation often deteriorates the quality, reproducibility of spots, and the overall assay performance. Glycerol is commonly added to antibody microarray printing buffers to decrease evaporation; however, it often decreases the binding of antibodies to the surface, thereby negatively affecting assay sensitivity. Here, combinations of 14 hygroscopic chemicals were used as additives to printing buffers for contact-printed antibody microarrays on four different surface chemistries. The ability of the additives to suppress evaporation was quantified by measuring the residual buffer volume in open quill pins over time. The seven best additives were then printed either individually or as a 1:1 mixture of two additives, and the homogeneity, intensity, and reproducibility of both the spotted protein and of a fluorescently labeled analyte in an assay were quantified. Among the 28 combinations on the four slides, many were found to outperform glycerol, and the best additive mixtures were further evaluated by changing the ratio of the two additives. We observed that the optimal additive mixture was dependent on the slide chemistry, and that it was possible to increase the binding of antibodies to the surface threefold compared to 50 % glycerol, while decreasing whole-slide coefficient of variation to 5.9 %. For the two best slides, improvements were made for both the limit of detection (1.6× and 5.9×, respectively) and the quantification range (1.2× and 2.1×, respectively). The additive mixtures identified here thus help improve assay reproducibility and performance, and might be beneficial to all types of microarrays that suffer from evaporation of the printing buffers.

Renal complications in anorexia nervosa.

PURPOSE: Anorexia nervosa is a malady with possible long-lasting physiological consequences. Among these, little is known about the renal effects, which remain rarely investigated. METHODS: A literature review was conducted using electronic databases and manual search of relevant articles, discussing the renal impacts of anorexia nervosa. RESULTS: Renal failure has been described in malnourished patients, but the optimal non-invasive tool to assess the glomerular function rate in this population needs to be further evaluated. Significant disruptions in osmolar regulation, even in the absence of potomania, arise from multiple factors: hypothalamic dysfunction, intrinsic renal insufficiency, and use of psychotropic medications. Urinary urgency and nocturnal enuresis are frequent symptoms, rarely reported by patients. Among hydroelectrolytic disorders, hypokalemia is the most frequent, especially in settings of vomiting or medication misuse. Hyponatremia, hypomagnesemia, and hypophosphatemia may also be encountered. Urinary lithiases are relatively frequent as a consequence of dehydration, laxative use, or both. CONCLUSION: Investigation and follow-up of the renal function are essential in patients with an eating disorder, especially when the illness has been present for a long time.

The SHP-1 protein tyrosine phosphatase negatively modulates glucose homeostasis.

The protein tyrosine phosphatase SHP-1 is a well-known inhibitor of activation-promoting signaling cascades in hematopoietic cells but its potential role in insulin target tissues is unknown. Here we show that Ptpn6(me-v/me-v) (also known as viable motheaten) mice bearing a functionally deficient SHP-1 protein are markedly glucose tolerant and insulin sensitive as compared to wild-type littermates, as a result of enhanced insulin receptor signaling to IRS-PI3K-Akt in liver and muscle. Downregulation of SHP-1 activity in liver of normal mice by adenoviral expression of a catalytically inert mutant of SHP-1, or after small hairpin RNA-mediated SHP-1 silencing, further confirmed this phenotype. Tyrosine phosphorylation of CEACAM1, a modulator of hepatic insulin clearance, and clearance of serum [125I]-insulin were markedly increased in SHP-1-deficient mice or SHP-1-deficient hepatic cells in vitro. These findings show a novel role for SHP-1 in the regulation of glucose homeostasis through modulation of insulin signaling in liver and muscle as well as hepatic insulin clearance.

Microarray-to-microarray transfer of reagents by snapping of two chips for cross-reactivity-free multiplex immunoassays.

Whereas microarray and microfluidic technologies have progressed on many fronts, servicing microchips with minute amounts of reagents still constitutes an important challenge for many applications. Recently, chip-to-chip reagent transfer methods were introduced that simplify the delivery of reagents but required manual, visual alignment, custom-built microwells, and only showed the reaction of a single sample with multiple chemicals. Here, we present the snap chip, which uses common glass slides for transfer, back-side alignment for achieving precise alignment in spite of mirroring, and a snap-apparatus for facile transfer of arrays of chemicals at once by snapping the two slides together. We recently established that cross-reactivity was a significant problem in multiplex assays both theoretically and experimentally and found that it can be eliminated by avoiding mixing, but which necessitates delivering each detection antibody to a single spot with the cognate capture antibody. Using the snap chip, multiplexed sandwich immunoassays without mixing were performed: a slide with multiple arrays of 10 different capture antibodies was incubated with a sample, and then all detection antibodies transferred at once by snapping, each to the single cognate spot. All binding curves were established and limits of detection in the pg/mL range were obtained. Snap chips were stored up to 3 months prior to usage. The snap chip, by dissociating microarray production, which requires expensive equipment, from assay execution, which can be achieved using a hand-held alignment apparatus, will allow for multiplex reactions to be performed using a user-friendly kit. This new liquid handling format can be easily adapted to other applications that require transfer of minute amounts of different reagents in parallel.

Heavy Burden of Toxic Dilated Cardiomyopathy Among Young Adults: A Retrospective Study and Review of the Literature.

BACKGROUND: Dilated cardiomyopathy (DCM) is a well described entity for heart failure (HF) with reduced left ventricular ejection fraction (LVEF). Recently, drugs and other substance of abuse have been recognised as potential triggers for DCM. The aim of this study was to assess the survival in patients ≤ 65 years of age with toxic cardiomyopathy (TCM). Left ventricular remodelling and the potential usefulness of left ventricular assist devices (LVADs) was also assessed. METHODS: This was a single-centre retrospective study from January 2003 to August 2019 of 553 patients ≤ 65 years old with LVEF < 40% at a tertiary-care cardiology centre. RESULTS: A total of 201 patients (36%) had a diagnosis of idiopathic DCM. Further analysis identified 38 patients (19%) for which a TCM was the most likely etiology (amphetamine [50%], cocaine [37%], anabolic steroids [8%], and energy drinks [5%]). Despite a mean LVEF of 17 ± 8% at presentation, most patients (n = 27; 71%) had event-free survival with guideline-directed medical therapy, and 61% (n = 23) recovered an LVEF ≥ 40% after a median follow-up of 21 ± 23 months. Seven patients (18%) required an LVAD and 1 patient (3%) a transplantation. All LVADs were explanted or decommissioned after partial or complete LVEF recovery after a median support time of 11 ± 4 months. CONCLUSIONS: TCM induced by substance abuse is a frequent cause of HF, accounting for almost 20% of patients ≤ 65 years of age with DCM of unknown etiology. Treatment must be tailored on an individual basis. Mechanical circulatory support demonstrated its usefulness in carefully selected patients.

Usefulness of exercise-stress echocardiography for risk stratification of true asymptomatic patients with aortic valve stenosis.

Aims Abnormal exercise test defined as the occurrence of exercise limiting symptoms, fall in blood pressure below baseline, or complex ventricular arrhythmias is useful to predict clinical events in asymptomatic patients with aortic stenosis (AS). The purpose of this study was to determine whether exercise-stress echocardiography (ESE) adds any incremental prognostic value to resting echocardiography in patients with AS having a normal exercise response. Methods and results One hundred and eighty-six asymptomatic patients with at least moderate AS and preserved LV ejection fraction (>/=50%) were assessed by Doppler-echocardiography at rest and during a maximum ramp semi-supine bicycle exercise test. Fifty-one (27%) patients had an abnormal exercise test and were excluded from the present analysis. Among the 135 patients with normal exercise test, 67 had an event (aortic valve replacement motivated by symptoms or cardiovascular death) at a mean follow-up of 20 +/- 14 months. The variables independently associated with events were: age >/=65 years [hazard ratio (HR) = 1.96; 95% confidence interval (CI): 1.15-3.47; P = 0.01], diabetes, (HR = 3.20; 95% CI: 1.33-6.87; P = 0.01), LV hypertrophy (HR = 1.96; 95% CI: 1.17-3.27; P = 0.01), resting mean gradient >35 mmHg (HR = 3.60; 95% CI: 2.11-6.37; P < 0.0001), and exercise-induced increase in mean gradient >20 mmHg (HR = 3.83; 95% CI: 2.16-6.67; P < 0.0001). Conclusion The exercise-induced increase in transvalvular gradient may be helpful to improve risk stratification in asymptomatic AS patients with normal exercise response. These results thus suggest that ESE may provide additional prognostic information over that obtained from standard exercise testing and resting echocardiography.

Precise Chip-to-Chip Reagent Transfer for Cross-Reactivity-Free Multiplex Sandwich Immunoassays.

Common multiplex sandwich immunoassays suffer from cross-reactivity due to the mixing of detection antibodies and the combinatorial, undesired interaction between all reagents and analytes. Here we present the snap chip to perform antibody colocalization microarrays that eliminates undesirable interactions by running an array of singleplex assays realized by sequestering detection antibodies in individual nanodroplets. When detecting proteins in biological fluids, the absence of cross-reactivity allows a higher level of multiplexing, reduced background, increased sensitivity, and ensures accurate and specific results. The use of the snap chip is illustrated by measuring highly related analytes such as proteins isoforms and phospho-proteins, both particularly prone to cross-reactivity, in a single experiment. The main steps of the protocol are preparation of sample, incubation on an assay slide harboring the microarrayed capture antibodies, transfer of the microarrayed detection antibodies on their cognate spots, and measurement of the assay results by fluorescence.

Screening for asymptomatic diabetes and metabolic comorbidities in pediatric patients during therapy for acute lymphoblastic leukemia.

OBJECTIVES: Chronic metabolic disturbances related to cancer treatment are well reported among survivors of pediatric acute lymphoblastic leukemia (ALL). However, few studies have investigated the incidence of these complications during the phase of chemotherapy. We evaluated the incidence of acute metabolic complications occurring during therapy in our cohort of patients diagnosed with ALL. METHODS: A prospective study involving 50 ALL pediatric patients diagnosed and treated between 2012 and 2016 in our oncology unit. We collected weight, blood pressure, fasting plasma glucose and hemoglobin A1C (HBA1c) levels during the two years of therapy. RESULTS: Obesity and overweight occurred in 43 and 25%, respectively among patients and have been reached at 12 months of chemotherapy. About 26% of the patients developed high blood pressure and 14% experienced hyperglycemias without meeting diabetes criteria. There was a significant decrease of HBA1c levels between the beginning and the end of therapy (p<0.0001). CONCLUSIONS: Increase of body mass index in our ALL pediatric patients occurred during the first months of therapy and plateaued after a year of treatment. We should target this population for early obesity prevention. HbA1c levels measured during therapy did not reveal diabetes criteria. Hence, fasting blood glucose levels are sufficient to monitor ALL pediatric patients' glycemia.

The serine protease inhibitor serpinE2 is a novel target of ERK signaling involved in human colorectal tumorigenesis.

BACKGROUND: Among the most harmful of all genetic abnormalities that appear in colorectal cancer (CRC) development are mutations of KRAS and its downstream effector BRAF as they result in abnormal extracellular signal-related kinase (ERK) signaling. In a previous report, we had shown that expression of a constitutive active mutant of MEK1 (caMEK) in normal rat intestinal epithelial cells (IECs) induced morphological transformation associated with epithelial to mesenchymal transition, growth in soft agar, invasion and metastases in nude mice. Results from microarrays comparing control to caMEK-expressing IECs identified the gene encoding for serpinE2, a serine protease inhibitor, as a potential target of activated MEK1. RESULTS: 1- RT-PCR and western blot analyses confirmed the strong up-regulation of serpinE2 expression and secretion by IECs expressing oncogenic MEK, Ras or BRAF. 2- Interestingly, serpinE2 mRNA and protein were also markedly enhanced in human CRC cells exhibiting mutation in KRAS and BRAF. 3- RNAi directed against serpinE2 in caMEK-transformed rat IECs or in human CRC cell lines HCT116 and LoVo markedly decreased foci formation, anchorage-independent growth in soft agarose, cell migration and tumor formation in nude mice. 4- Treatment of CRC cell lines with U0126 markedly reduced serpinE2 mRNA levels, indicating that expression of serpinE2 is likely dependent of ERK activity. 5- Finally, Q-PCR analyses demonstrated that mRNA levels of serpinE2 were markedly increased in human adenomas in comparison to healthy adjacent tissues and in colorectal tumors, regardless of tumor stage and grade. CONCLUSIONS: Our data indicate that serpinE2 is up-regulated by oncogenic activation of Ras, BRAF and MEK1 and contributes to pro-neoplastic actions of ERK signaling in intestinal epithelial cells. Hence, serpinE2 may be a potential therapeutic target for colorectal cancer treatment.

Usefulness of an accelerated transoesophageal stress echocardiography in the preoperative evaluation of high risk severely obese subjects awaiting bariatric surgery.

BACKGROUND: Severe obesity is associated with an increased risk of coronary artery disease (CAD). Bariatric surgery is an effective procedure for long term weight management as well as reduction of comorbidities. Preoperative evaluation of cardiac operative risk may often be necessary but unfortunately standard imaging techniques are often suboptimal in these subjects. The purpose of this study was to demonstrate the feasibility, safety and utility of transesophageal dobutamine stress echocardiography (TE-DSE) using an adapted accelerated dobutamine infusion protocol in severely obese subjects with comorbidities being evaluated for bariatric surgery for assessing the presence of myocardial ischemia. METHODS: Subjects with severe obesity [body mass index (BMI) >40 kg/m2] with known or suspected CAD and being evaluated for bariatric surgery were recruited. RESULTS: Twenty subjects (9M/11F), aged 50 +/- 8 years (mean +/- SD), weighing 141 +/- 21 kg and with a BMI of 50 +/- 5 kg/m2 were enrolled in the study and underwent a TE-DSE. The accelerated dobutamine infusion protocol used was well tolerated. Eighteen (90%) subjects reached their target heart rate with a mean intubation time of 13 +/- 4 minutes. Mean dobutamine dose was 31.5 +/- 9.9 ug/kg/min while mean atropine dose was 0.5 +/- 0.3 mg. TE-DSE was well tolerated by all subjects without complications including no significant arrhythmia, hypotension or reduction in blood arterial saturation. Two subjects had abnormal TE-DSE suggestive of myocardial ischemia. All patients underwent bariatric surgery with no documented cardiovascular complications. CONCLUSIONS: TE-DSE using an accelerated infusion protocol is a safe and well tolerated imaging technique for the evaluation of suspected myocardial ischemia and cardiac operative risk in severely obese patients awaiting bariatric surgery. Moreover, the absence of myocardial ischemia on TE-DSE correlates well with a low operative risk of cardiac event.

Canadian Real-World Experience of Using Sacubitril/Valsartan in Patients With Heart Failure With Reduced Ejection Fraction: Insight From the PARASAIL Study.

BACKGROUND: To determine the effectiveness of sacubitril/valsartan 97/103 mg twice daily (b.i.d.) on tolerability, safety, and quality of life (QoL) in Canadian patients with heart failure with reduced ejection fraction in a real-life setting. METHODS: In Prospective, Multicenter, Open Label, Post-Approval Study Aimed at Characterizing the Use of LCZ696 at 97 mg Sacubitril/103 mg Valsartan bid in Patients With HFrEF (PARASAIL), an open-label, prospective, phase IV, multicentre study, outpatients with heart failure with reduced ejection fraction and New York Heart Association functional class II-III were followed up for 12 months. The suggested starting dose of sacubitril/valsartan was 24/26 mg b.i.d. replacing angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, with an uptitration to 97/103 mg b.i.d. or as per clinical judgement. The primary endpoint was the proportion of patients achieving the target dose of sacubitril/valsartan 97/103 mg b.i.d. after 6 months of treatment. RESULTS: For the 302 patients included, the mean age was 64.47 years, and a majority of patients (82.8%) belonged to New York Heart Association class II. Overall, 195 (64.6%) patients were on maximum dose of sacubitril/valsartan 97/103 mg b.i.d. after 6 months and 62.3% remained on this dose at month 12. Using patient global assessment, patients experienced an improvement in QoL. For Minnesota Living with Heart Failure Questionnaire scores, a significant decrease from the baseline was observed at weeks 4, 12, and 24 (P < 0.0001 for all), which indicated an improvement in QoL. The patient global assessment and Minnesota Living with Heart Failure Questionnaire results correlate with moderate but significant changes in Euro quality of life-5D visual analogue scale scores. CONCLUSIONS: Results of the PARASAIL study in a real-life setting have shown that most patients were on sacubitril/valsartan 97/103 mg b.i.d. and the treatment was well tolerated. The patient-reported outcomes showed an overall improvement in patients' QoL.

CONTEXTE: L'objectif était de déterminer, en contexte réel, l'efficacité de l'association sacubitril à 97 mg/valsartan à 103 mg, deux fois par jour, sous l'angle de la tolérabilité, de l'innocuité et de la qualité de vie (QV) chez des patients canadiens atteints d'insuffisance cardiaque avec fraction d'éjection réduite. MÉTHODOLOGIE: Au cours de l'étude multicentrique et prospective sans insu de phase IV PARASAIL ( P rospective, Multicenter, Open L a bel, Post-App r ov a l S tudy Ai med at Characterizing the Use of L CZ696 at 97 mg Sacubitril/103 mg Valsartan bid in Patients With HFrEF), des patients externes atteints d'insuffisance cardiaque de classe fonctionnelle II ou III selon la NYHA (New York Heart Association) avec fraction d'éjection réduite ont été suivis durant 12 mois. La dose initiale recommandée était de 24 mg de sacubitril/26 mg de valsartan, deux fois par jour, à la place d'un inhibiteur de l'enzyme de conversion de l'angiotensine ou d'un antagoniste des récepteurs de l'angiotensine; la dose devait être augmentée à 97 mg de sacubitril/103 mg de valsartan, deux fois par jour, ou selon le jugement du clinicien. Le critère d'évaluation principal était la proportion de patients chez qui la dose cible de 97 mg de sacubitril/103 mg de valsartan, deux fois par jour, se trouvait atteinte après six mois de traitement. RÉSULTATS: L'âge moyen des 302 patients admis était de 64,47 ans. La majorité de ces patients (82,8 %) présentaient une insuffisance cardiaque de classe II selon la NYHA. Globalement, 195 (64,6 %) patients prenaient la dose maximale de 97 mg de sacubitril/103 mg de valsartan, deux fois par jour, après six mois de traitement; 62,3 % continuaient de prendre cette dose à 12 mois de traitement. L'évaluation globale des patients indique une amélioration de leur QV. Les scores au Minnesota Living With Heart Failure Questionnaire avaient significativement diminué par rapport aux scores de départ aux semaines 4, 12 et 24 (p < 0,0001 à tous les temps d'évaluation), ce qui indique une amélioration de la QV. L'évaluation globale des patients et les scores au Minnesota Living With Heart Failure Questionnaire sont corrélés avec des variations modérées, mais significatives des scores de QV à l'échelle visuelle analogique du questionnaire EQ-5D. CONCLUSIONS: Les résultats obtenus en contexte réel au cours de l'étude PARASAIL montrent que la plupart des patients prenaient la dose de 97 mg de sacubitril/103 mg de valsartan, deux fois par jour, et que le traitement était bien toléré. Les résultats rapportés par les patients témoignent d'une amélioration globale de la QV de ces derniers.

Interatrial Shunting for Treating Acute and Chronic Left Heart Failure.

The creation of an interatrial shunt has emerged as a new therapy to decompress the left atrium in patients with acute and chronic left heart failure (HF). Current data support the safety of this therapy, and promising preliminary efficacy results have been reported in patients who are refractory to optimal medical/device therapy. This article aims to provide an updated overview and clinical perspective on interatrial shunting for treating different HF conditions, and highlights the potential challenges and future directions of this therapy.

The role of protein tyrosine phosphatases in the regulation of allergic asthma: implication of TC-PTP and PTP-1B in the modulation of disease development.

Protein tyrosine phosphorylation is an important early event in the signal transduction of numerous cell receptors involved in the immune response. The implication of protein tyrosine kinases in allergic asthma is well recognized, but the role of protein tyrosine phosphatases (PTPs) remains poorly understood. However, we recently reported that global inhibition of PTPs during either the allergen-sensitization phase or the allergen-challenge phase reduced the development of asthma and that this correlated with an increased T helper 1 (Th1) response in both lung and spleen tissues. Therefore, in this study we investigated individual roles of PTPs involved in regulating the immune response. We observed that genetic deficiency for PTP-1B resulted in increased recruitment of lung inflammatory cells, while protein tyrosine phosphatase-phosphatase and tensin homologue deleted (PTP-PEST)-deficient mice exhibited a phenotype similar to that of wild-type mice. Importantly, we found that a heterozygous mutation of T cell PTP (TC-PTP) dramatically abrogates immunoglobulin E production and reduces the recruitment of inflammatory cells to the lung, conferring an important role for TC-PTP in the development of allergic asthma. As opposed to other studies on Src homology phosphatase-1 (SHP-1) deficiency, specific acute SHP-1 inhibition during allergen challenge did not affect disease outcome. Collectively, our results underscore the importance of PTPs in the development of allergic asthma.