The MIDA-Q Mortality Risk Score: A Quantitative Prognostic Tool for the Mitral Valve Prolapse Spectrum.

BACKGROUND: Mitral valve prolapse (MVP) is responsible for a considerable disease burden but is widely heterogeneous. The lack of a comprehensive prognostic instrument covering the entire MVP spectrum, encompassing the quantified consequent degenerative mitral regurgitation (DMR), hinders clinical management and therapeutic trials. METHODS: The new Mitral Regurgitation International Database Quantitative (MIDA-Q) registry enrolled 8187 consecutive patients (ages 63±16 years, 47% women, follow-up 5.5±3.3 years) first diagnosed with isolated MVP, without or with DMR quantified prospectively (measuring effective regurgitant orifice [ERO] and regurgitant volume) in routine practice of 5 tertiary care centers from North America, Europe, and the Middle East. The MIDA-Q score ranges from 0 to 15 by accumulating guideline-based risk factors and DMR severity. Long-term survival under medical management was the primary outcome end point. RESULTS: MVP was associated with DMR absent/mild (ERO <20 mm2) in 50%, moderate (ERO 20-40 mm2) in 25%, and severe or higher (ERO ≥40 mm2) in 25%, with mean ERO 24±24 mm2, regurgitant volume 37±35 mL. Median MIDA-Q score was 4 with a wide distribution (10%-90% range, 0-9). MIDA-Q score was higher in patients with EuroScore II ≥1% versus <1% (median, 7 versus 3; P < 0.0001) but with wide overlap (10%-90% range, 4-11 versus 0-7) and mediocre correlation (R2 0.18). Five-year survival under medical management was strongly associated with MIDA-Q score, 97±1% with score 0, 95±1% with score 1 to 2, 82±1% with score 3 to 4, 67±1% with score 5 to 6, 60±1% with score 7 to 8, 44±1% with score 9 to 10, 35±1% with score 11 to 12, and 5±4% with MIDA-Q score ≥13, with hazard ratio 1.31 [1.29-1.33] per 1-point increment. Excess mortality with higher MIDA-Q scores persisted after adjustment for age, sex, and EuroScore II (adjusted hazard ratio, 1.13 [1.11-1.15] per 1-point increment). Subgroup analysis showed persistent association of MIDA-Q score with mortality in all possible subsets, in particular, with EuroScore II<1% (hazard ratio, 1.08 [1.02-1.14]) or ≥1% (hazard ratio, 1.11 [1.08-1.13]) and with no/mild DMR (hazard ratio, 1.14 [1.10-1.19]) or moderate/severe DMR (hazard ratio, 1.13 [1.10-1.16], all per 1-point increment with P<0.0001). Nested-model and bootstrapping analyses demonstrated incremental prognostic power of MIDA-Q score (all P<0.0001). CONCLUSIONS: This large, international cohort of isolated MVP, with prospective DMR quantification in routine practice, demonstrates the wide range of risk factor accumulation and considerable heterogeneity of outcomes after MVP diagnosis. The MIDA-Q score is strongly, independently, and incrementally associated with long-term survival after MVP diagnosis, irrespective of presentation, and is therefore a crucial prognostic instrument for risk stratification, clinical trials, and management of patients diagnosed with all forms of MVP.

Factors influencing post-surgical survival in degenerative mitral regurgitation.

AIMS: Indications for surgery in patients with degenerative mitral regurgitation (DMR) are increasingly liberal in all clinical guidelines but the role of secondary outcome determinants (left atrial volume index ≥60 mL/m2, atrial fibrillation, pulmonary artery systolic pressure ≥50 mmHg and moderate to severe tricuspid regurgitation) and their impact on post-operative outcome remain disputed. Whether these secondary outcome markers are just reflective of the DMR severity or intrinsically affect survival after DMR surgery is uncertain and may have critical importance in the management of patients with DMR. To address these gaps of knowledge the present study gathered a large cohort of patients with quantified DMR, accounted for the number of secondary outcome markers and examined their independent impact on survival after surgical correction of the DMR. METHODS AND RESULTS: The Mitral Regurgitation International DAtabase-Quantitative registry includes patients with isolated DMR from centres across North America, Europe, and the Middle East. Patient enrolment extended from January 2003 to January 2020. All patients undergoing mitral valve surgery within 1 year of registry enrolment were selected. A total of 2276 patients [65 (55-73) years, 32% male] across five centres met study eligibility criteria. Over a median follow-up of 5.6 (3.6 to 8.7) years, 278 patients (12.2%) died. In a comprehensive multivariable Cox regression model adjusted for age, EuroSCORE II, symptoms, left ventricular ejection fraction (LVEF), left ventricular end-systolic diameter (LV ESD) and DMR severity, the number of secondary outcome determinants was independently associated with post-operative all-cause mortality, with adjusted hazard ratios of 1.56 [95% confidence interval (CI): 1.11-2.20, P = 0.011], 1.78 (95% CI: 1.23-2.58, P = 0.002) and 2.58 (95% CI: 1.73-3.83, P < 0.0001) for patients with one, two, and three or four secondary outcome determinants, respectively. A model incorporating the number of secondary outcome determinants demonstrated a higher C-index and was significantly more concordant with post-operative mortality than models incorporating traditional Class I indications alone [the presence of symptoms (P = 0.0003), or LVEF ≤60% (P = 0.006), or LV ESD ≥40 mm (P = 0.014)], while there was no significant difference in concordance observed compared with a model that incorporated the number of Class I indications for surgery combined (P = 0.71). CONCLUSION: In this large cohort of patients treated surgically for DMR, the presence and number of secondary outcome determinants was independently associated with post-surgical survival and demonstrated better outcome discrimination than traditional Class I indications for surgery. Randomised controlled trials are needed to determine if patients with severe DMR who demonstrate a cardiac phenotype with an increasing number of secondary outcome determinants would benefit from earlier surgery.

Bioprosthetic Total Artificial Heart in Autoregulated Mode Is Biologically Hemocompatible: Insights for Multimers of von Willebrand Factor.

BACKGROUND: Carmat bioprosthetic total artificial heart (Aeson; A-TAH) is a pulsatile and autoregulated device. The aim of this study is to evaluate level of hemolysis potential acquired von Willebrand syndrome after A-TAH implantation. METHODS: We examined the presence of hemolysis and acquired von Willebrand syndrome in adult patients receiving A-TAH support (n=10) during their whole clinical follow-up in comparison with control subjects and adult patients receiving Heartmate II or Heartmate III support. We also performed a fluid structure interaction model coupled with computational fluid dynamics simulation to evaluate the A-TAH resulting shear stress and its distribution in the blood volume. RESULTS: The cumulative duration of A-TAH support was 2087 days. A-TAH implantation did not affect plasma free hemoglobin over time, and there was no association between plasma free hemoglobin and cardiac output or beat rate. For VWF (von Willebrand factor) evaluation, A-TAH implantation did not modify multimers profile of VWF in contrast to Heartmate II and Heartmate III. Furthermore, fluid structure interaction coupled with computational fluid dynamics showed a gradually increase of blood damage according to increase of cardiac output (P<0.01), however, the blood volume fraction that endured significant shear stresses was always inferior to 0.03% of the volume for both ventricles in all regimens tested. An inverse association between cardiac output, beat rate, and high-molecular weight multimers ratio was found. CONCLUSIONS: We demonstrated that A-TAH does not cause hemolysis or AWVS. However, relationship between HMWM and cardiac output depending flow confirms relevance of VWF as a biological sensor of blood flow, even in normal range.

Comparison of Short and Midterm Aortic Reinterventions in Acute Type A Aortic Dissection Treated by Frozen Elephant Trunk or Conventional Arch Repair.

BACKGROUND: Long-term outcomes after acute type A aortic dissection (ATAAD) are related to remodelling of the descending thoracic aorta and aortic reinterventions. We compared the impact of an extensive repair at the index procedure using the Frozen Elephant Trunk (FET) technique, versus a conventional arch repair, on long-term remodelling of the descending thoracic and reintervention related to the aorta. METHODS: Consecutive patients who underwent conventional arch repair (conventional group) or FET repair (FET group) for an ATAAD from September 2018 to November 2021 were included. Patients who died before discharge or were lost to follow-up prior to the first appointment were excluded from the analysis. Preoperative and postoperative computed tomography angiography was reconstructed and diameter of the true/false lumen of the remaining aorta was compared up to 1 year. Negative (increased total diameter ≥ 5 mm) aortic remodelling was collected for each computed tomography angiography, as well as aortic reinterventions. Comparison of demographic, anatomical, and perioperative complications data were performed using Wilcoxon test for continuous variables or Chi-square test for categorical covariates. The Kaplan-Meier method estimator was used to assess survival rates. The Log rank test was used to compare survival curves between the 2 groups. RESULTS: Thirty nine patients were included, 22 in the conventional group and 17 in the FET group (82% males, mean age 60 ± 12 years). In the FET group, distal anastomosis was performed in zone 0 or 1 for 82% of patients using the simplified delivery technique. Median maximum preoperative descending aortic diameter was larger in the FET group (33 mm [30; 37] vs. 30 mm [28; 32] [P = 0.0172]). At 30 days, the rate of negative remodelling on the descending thoracic aorta was significantly higher in the conventional group (50%) than in the FET group (8%, P = 0.02). At 1 year, Kaplan-Meier analysis shown a freedom from descending aortic negative remodeling of 35.1% (95% confidence interval (CI) 18.7-66.1%) in conventional group and 44.9% (CI 95% 26.1-77.2%) in FET group with no significant difference. However, early negative remodelling was observed for the conventional group. Within a year, freedom from reintervention was observed for 74.4% (95% CI 57.1-97%) of patients in the conventional group and 75.5 (95% CI 57.1-99.7%) of patients in the FET group with no significant difference. CONCLUSIONS: Negative evolution of descending aorta remains a challenge after ATAAD. An extensive repair using the FET technique during the index procedure seems to be associated with satisfying short-term remodelling of descending aorta.

PKCα-mediated phosphorylation of the diacylglycerol kinase ζ MARCKS domain switches cell migration modes by regulating interactions with Rac1 and RhoA.

Cells can switch between Rac1 (lamellipodia-based) and RhoA (blebbing-based) migration modes, but the molecular mechanisms regulating this shift are not fully understood. Diacylglycerol kinase ζ (DGKζ), which phosphorylates diacylglycerol to yield phosphatidic acid, forms independent complexes with Rac1 and RhoA, selectively dissociating each from their common inhibitor RhoGDI. DGKζ catalytic activity is required for Rac1 dissociation but is dispensable for RhoA dissociation; instead, DGKζ stimulates RhoA release via a kinase-independent scaffolding mechanism. The molecular determinants that mediate the selective targeting of DGKζ to Rac1 or RhoA signaling complexes are unknown. Here, we show that protein kinase Cα (PKCα)-mediated phosphorylation of the DGKζ MARCKS domain increased DGKζ association with RhoA and decreased its interaction with Rac1. The same modification also enhanced DGKζ interaction with the scaffold protein syntrophin. Expression of a phosphomimetic DGKζ mutant stimulated membrane blebbing in mouse embryonic fibroblasts and C2C12 myoblasts, which was augmented by inhibition of endogenous Rac1. DGKζ expression in differentiated C2 myotubes, which have low endogenous Rac1 levels, also induced substantial membrane blebbing via the RhoA-ROCK pathway. These events were independent of DGKζ catalytic activity, but dependent upon a functional C-terminal PDZ-binding motif. Rescue of RhoA activity in DGKζ-null cells also required the PDZ-binding motif, suggesting that syntrophin interaction is necessary for optimal RhoA activation. Collectively, our results define a switch-like mechanism whereby DGKζ phosphorylation by PKCα plays a role in the interconversion between Rac1 and RhoA signaling pathways that underlie different cellular migration modes.

Replacement Myocardial Fibrosis in Patients With Mitral Valve Prolapse: Relation to Mitral Regurgitation, Ventricular Remodeling, and Arrhythmia.

BACKGROUND: Mitral valve prolapse (MVP) is a frequent disease that can be complicated by mitral regurgitation (MR), heart failure, arterial embolism, rhythm disorders, and death. Left ventricular (LV) replacement myocardial fibrosis, a marker of maladaptive remodeling, has been described in patients with MVP, but the implications of this finding remain scarcely explored. We aimed at assessing the prevalence, pathophysiological and prognostic significance of LV replacement myocardial fibrosis through late gadolinium enhancement (LGE) by cardiac magnetic resonance in patients with MVP. METHODS: Four hundred patients (53±15 years of age, 55% male) with MVP (trace to severe MR by echocardiography) from 2 centers, who underwent a comprehensive echocardiography and LGE cardiac magnetic resonance, were included. Correlates of replacement myocardial fibrosis (LGE+), influence of MR degree, and ventricular arrhythmia were assessed. The primary outcome was a composite of cardiovascular events (cardiac death, heart failure, new-onset atrial fibrillation, arterial embolism, and life-threatening ventricular arrhythmia). RESULTS: Replacement myocardial fibrosis (LGE+) was observed in 110 patients (28%; 91 with myocardial wall including 71 with basal inferolateral wall, 29 with papillary muscle). LGE+ prevalence was 13% in trace-mild MR, 28% in moderate MR, and 37% in severe MR, and was associated with specific features of mitral valve apparatus, more dilated LV and more frequent ventricular arrhythmias (45% versus 26%, P<0.0001). In trace-mild MR, despite the absence of significant volume overload, abnormal LV dilatation was observed in 16% of patients and ventricular arrhythmia in 25%. Correlates of LGE+ in multivariable analysis were LV mass (odds ratio, 1.01 [95% CI, 1.002-1.017], P=0.009) and moderate-severe MR (odds ratio, 2.28 [95% CI, 1.21-4.31], P=0.011). LGE+ was associated with worse 4-year cardiovascular event-free survival (49.6±11.7 in LGE+ versus 73.3±6.5% in LGE-, P<0.0001). In a stepwise multivariable Cox model, MR volume and LGE+ (hazard ratio, 2.6 [1.4-4.9], P=0.002) were associated with poor outcome. CONCLUSIONS: LV replacement myocardial fibrosis is frequent in patients with MVP; is associated with mitral valve apparatus alteration, more dilated LV, MR grade, and ventricular arrhythmia; and is independently associated with cardiovascular events. These findings suggest an MVP-related myocardial disease. Last, cardiac magnetic resonance provides additional information to echocardiography in MVP.

Building a home ventilation programme: population, equipment, delivery and cost.

Home mechanical ventilation (HMV) improves quality of life and survival in patients with neuromuscular disorders (NMD). Developing countries may benefit from published evidence regarding the prevalence, cost of equipment, technical issues and organisation of HMV in NMD, facilitating the development of local turn-key HMV programmes. Unfortunately, such evidence is scattered in the existing literature. We searched Medline for publications in English and French from 2005 to 2020. This narrative review analyses 24 international programmes of HMV. The estimated prevalence (min-max) of HMV is ±7.3/100 000 population (1.2-47), all disorders combined. The prevalence of HMV is associated with the gross domestic product per capita in these 24 countries. The prevalence of NMD is about 30/100 000 population, of which ±10% would use HMV. Nocturnal (8/24 hour), discontinuous (8-16/24 hours) and continuous (>16/24 hours) ventilation is likely to concern about 60%, 20% and 20% of NMD patients using HMV. A minimal budget of about 168€/patient/year (504€/100 000 population), including the cost of equipment solely, should address the cost of HMV equipment in low-income countries. When services and maintenance are included, the budget can drastically increase up to between 3232 and 5760€/patient/year. Emerging programmes of HMV in developing countries reveal the positive impact of international cooperation. Today, at least 12 new middle, and low-income countries are developing HMV programmes. This review with updated data on prevalence, technical issues, cost of equipment and services for HMV should trigger objective dialogues between the stakeholders (patient associations, healthcare professionals and politicians); potentially leading to the production of workable strategies for the development of HMV in patients with NMD living in developing countries.

Did COVID-19 impact Positive Airway Pressure adherence in 2020? A cross-sectional study of 8477 patients with sleep apnea.

BACKGROUND: Whether the COVID-19 pandemic impacts Positive Airway Pressure (PAP) adherence over the long-term is unknown and only preliminary short-term data have been reported. METHODS: With the aim of describing the impact of the first and second waves of COVID-19 on PAP adherence during 2020 in France, we designed a cross-sectional study of Sleep-Apnea (SA)-patients under PAP telemonitoring. To examine PAP adherence in adult SA patients, we assessed de-identified data from a non-profit healthcare provider database during the period January 1, 2019 to December 31, 2020. Included patients met the following criteria: (i) PAP-treated for at least 4 months before January 1, 2019 and with continuous PAP during both 2019 and 2020; (ii) ≥ 360 daily PAP telemonitored data per year. For PAP adherence, data were collected using the PAP-software. RESULTS: 8477/10482 patients were finally included in the analysis [72.4% male, median age 70 years (IQ25-75: 61-77], 25.6% < 62 years old, initial Apnea-Hypopnea Index (AHI) of 41 (31-59)/h. Median PAP adherence was 7.21 (6.12-8.10) h/day in 2020 versus 7.12 (6.05-8.02) h/day in 2019, p < 0.001. The median difference in PAP adherence between the first 2020 lockdown and the corresponding 2019 weeks was 9.75 (CI95% 8.75-10.75) min/day, p < 0.001. The median difference in PAP adherence between the second 2020 lockdown and the corresponding 2019 weeks was 5.00 (CI95% 4.00-6.00) min/day, p < 0.001. If we consider the minimal clinically important difference of 30 min for PAP adherence, 30.4% and 26% of the patients increased their PAP adherence by at least 30 min during the first and second lockdowns respectively; 17.6% and 19.3% of the patients lowered their PAP adherence by at least 30 min in the first and second lockdowns, respectively. CONCLUSION: During the first and second lockdowns, the COVID-19 pandemic had a clinically irrelevant effect on PAP adherence for the study population. Future studies are needed to describe COVID-19 pandemic impact on PAP adherence not only for long-term PAP-treated SA patients but also for incident cases. Trial registration The COVADENE study was registered on March 1st, 2021 on ClinicalTrials.gov (Identifier: NCT04775966).

Management and outcomes of ventricular septal defects after acute myocardial infarction: A multicenter retrospective study.

BACKGROUND AND AIM: The mortality rate of patients with post-myocardial infarction (MI) ventricular septal defects (VSDs) is high, and the benefit of surgery is unclear. We aimed to investigate the management and outcomes of post-MI VSD over a 10-year period in a large cohort. METHODS: Data of patients with post-MI VSD admitted in three French university hospitals from 2008 to 2019 were examined. The characteristics of those who underwent surgery were compared with those who received medical treatment. Mortality risk factors, survival curves, and outcomes at 30 days and 1 year after treatment were determined. RESULTS: Of the 92 patients whose data were examined, 50 underwent surgery and 42 received exclusive medical treatment. All patients were critically ill. Overall, 76.1% of patients received inotropic support, and 63% received mechanical ventilation. Circulatory assistance, mainly via intra-aortic balloon pump and extra-corporeal membrane oxygenation, was provided to 46.7% patients, with 14.1% requiring a second assistance. The median time to surgery was 4 days. At 1 year, mortality was 46% in those who underwent surgery and 83.3% in those treated medically (p < .001). Survival curves at 1 and 3 months showed major differences, and the survival rate showed little change 30 days after treatment. Cardiogenic shock and cardiac arrest emerged as risk factors for mortality. CONCLUSIONS: In our retrospective, multicenter study, the mortality resulting from post-MI VSD did not seem to improve over the last decade. Although surgery carried considerable risks, it improved survival.

The effect of tongue elevation muscle training in patients with obstructive sleep apnea: A randomised controlled trial.

BACKGROUND: Oropharyngeal myofunctional therapy is a multi-component therapy effective to reduce the severity of obstructive sleep apnoea (OSA). However, existing protocols are difficult to replicate in the clinical setting. There is a need to isolate the specific effectiveness of each component of the therapy. OBJECTIVE: To assess the effects of a 6 weeks tongue elevation training programme in patients with OSA. METHODS: We conducted a multicentre randomised controlled trial. Eligible participants were adults diagnosed with moderate OSA who presented low adherence to continuous positive airway pressure therapy (mean use <4 h per night). The intervention group completed a 6 weeks tongue elevation training protocol that consisted in anterior tongue elevation strength and endurance tasks with the Iowa Oral Performance Instrument. The control group completed a 6 weeks sham training protocol that involved expiratory muscle training at very low intensity. Polygraphy data, tongue force and endurance, and OSA symptoms were evaluated pre- and post-intervention. The primary outcome was apneoa-hypopnea index (AHI). RESULTS: Twenty-seven patients (55 ± 11 years) were recruited. According to modified intention-to-treat analysis (n = 25), changes in AHI and c did not significantly differ between groups. Daytime sleepiness (Epworth Sleepiness Scale) and tongue endurance significantly improved in the intervention group compared to the control group (p = .015 and .022, respectively). In the intervention group, 75% of participants had a decrease in daytime sleepiness that exceeded the minimal clinically important difference. CONCLUSION: Six weeks of tongue elevation muscle training had no effect on OSA severity.

Substrate Tumbling in a Chemisorbed Diastereomeric α-Ketoester/1-(1-Naphthyl)ethylamine Complex.

Scanning tunneling microscopy (STM) data for α-ketoester/1-(1-naphthyl)ethylamine complexes on Pt(111) reveal a tumbling motion that couples two neighboring binding states. The interconversion, resulting in prochiral inversion of the α-ketoester, occurs in single complexes without breaking them apart. This is a surprising observation because the overall motion requires rotation of the α-ketoester away from the surface without branching exclusively into diffusion away from the complex or desorption. The multi-step interconversion is rationalized in terms of sequences of bound states that combine transient H-bond interactions with the chiral molecule and weakened adsorption interactions with the metal. The observation of tumbling in single long-lived complexes is of relevance to self-assembly and directed molecular motion on surfaces, to ligand-controlled surface reactions, and most directly to stereocontrol in asymmetric heterogeneous catalysis.

Nasal versus oronasal masks for home non-invasive ventilation in patients with chronic hypercapnia: a systematic review and individual participant data meta-analysis.

BACKGROUND: The optimal interface for the delivery of home non-invasive ventilation (NIV) to treat chronic respiratory failure has not yet been determined. The aim of this individual participant data (IPD) meta-analysis was to compare the effect of nasal and oronasal masks on treatment efficacy and adherence in patients with COPD and obesity hypoventilation syndrome (OHS). METHODS: We searched Medline and Cochrane Central Register of Controlled Trials for prospective randomised controlled trials (RCTs) of at least 1 month's duration, published between January 1994 and April 2019, that assessed NIV efficacy in patients with OHS and COPD. The main outcomes were diurnal PaCO2, PaO2 and NIV adherence (PROSPERO CRD42019132398). FINDINGS: Of 1576 articles identified, 34 RCTs met the inclusion criteria and IPD were obtained for 18. Ten RCTs were excluded because only one type of mask was used, or mask data were missing. Data from 8 RCTs, including 290 IPD, underwent meta-analysis. Oronasal masks were used in 86% of cases. There were no differences between oronasal and nasal masks for PaCO2 (0.61 mm Hg (95% CI -2.15 to 3.38); p=0.68), PaO2 (-0.00 mm Hg (95% CI -4.59 to 4.58); p=1) or NIV adherence (0·29 hour/day (95% CI -0.74 to 1.32); p=0.58). There was no interaction between the underlying pathology and the effect of mask type on any outcome. INTERPRETATION: Oronasal masks are the most used interface for the delivery of home NIV in patients with OHS and COPD; however, there is no difference in the efficacy or tolerance of oronasal or nasal masks.

Mask side-effects in long-term CPAP-patients impact adherence and sleepiness: the InterfaceVent real-life study.

BACKGROUND: For some patients, Continuous Positive Airway Pressure (CPAP) remains an uncomfortable therapy despite the constant development of technological innovations. To date, no real life study has investigated the relationship between mask related side-effects (MRSEs) and CPAP-non-adherence (defined as < 4 h/day) or residual-excessive-sleepiness (RES, Epworth-Sleepiness-Scale (ESS) score ≥ 11) in the long-term. METHODS: The InterfaceVent-CPAP study is a prospective real-life cross-sectional study conducted in an apneic adult cohort undergoing at least 3 months of CPAP with unrestricted mask-access (34 different masks). MRSEs were evaluated using visual-analogue-scales, CPAP-data using CPAP-software, sleepiness using ESS. RESULTS: 1484 patients were included in the analysis (72.2% male, median age 67 years (IQ25-75: 60-74), initial Apnea-Hypopnea-Index (AHI) of 39 (31-56)/h, residual AHIflow was 1.9 (0.9-4) events/h), CPAP-treatment lasted 4.4 (2.0-9.7) years, CPAP-usage was 6.8 (5.5-7.8) h/day, the prevalence of CPAP-non-adherence was 8.6%, and the prevalence of RES was 16.17%. Leak-related side-effects were the most prevalent side-effects (patient-reported leaks concerned 75.4% of responders and had no correlation with CPAP-reported-leaks). Multivariable logistic regression analyses evaluating explanatory-variable (demographic data, device/mask data and MRSEs) effects on variables-of-interest (CPAP-non-adherence and RES), indicated for patient-MRSEs significant associations between: (i) CPAP-non-adherence and dry-mouth (p = 0.004); (ii) RES and patient-reported leaks (p = 0.007), noisy mask (p < 0.001), dry nose (p < 0.001) and harness pain (p = 0.043). CONCLUSION: In long-term CPAP-treated patients, leak-related side-effects remain the most prevalent side-effects, but patient-reported leaks cannot be predicted by CPAP-reported-leaks. Patient-MRSEs can be independently associated with CPAP-non-adherence and RES, thus implying a complementary role for MRSE questionnaires alongside CPAP-device-reported-data for patient monitoring. Trial registration InterfaceVent is registered with ClinicalTrials.gov (NCT03013283).

Pancreatic Cancer Progression in a Patient With Lynch Syndrome Receiving Immunotherapy: A Cautionary Tale.

Pancreatic ductal adenocarcinomas (PDACs) with DNA mismatch repair deficiency (MMRd) respond preferentially to immune checkpoint inhibitors (ICIs). However, a subset of MMRd PDACs does not respond to these agents. This report describes a patient with PDAC who experienced rapid disease progression suggestive of hyperprogressive disease. The case involved a 63-year-old man carrying a pathogenic germline PMS2 mutation who developed metastatic PDAC. His tumor showed isolated loss of PMS2 expression by immunohistochemistry (IHC). He was treated with pembrolizumab, but his disease rapidly progressed. Whole-genome and transcriptome sequencing of a liver metastasis biopsy, acquired at disease progression, showed a retained wild-type PMS2 allele and hallmarks of microsatellite stability, including low tumor mutational burden and low MSIsensor score. PCR-based microsatellite instability (MSI) testing of the treatment-naïve tumor showed microsatellite stability. The ICI-treated tumor had a lower density of CD8+ T-cell infiltration than the treatment-naïve tumor, which is contrary to the expected evolution with ICI responsiveness. Through this case and a review of the literature, we highlight the low penetrance of PMS2 germline mutations in PDAC and discuss pitfalls in ascertaining MMRd and MSI based on IHC testing alone. An orthogonal confirmatory assay is warranted in the presence of uncommon immunophenotypes, such as isolated PMS2 loss, to optimize selection of patients with PDAC for immunotherapy.

Health disturbances and exposure to radiofrequency electromagnetic fields from mobile-phone base stations in French urban areas.

The effects of radiofrequency exposure on the health of people living near mobile-phone base stations (MPBSs) have been the subject of several studies since the mid-2000s, with contradictory results. We aimed to investigate the association between measured exposure to radiofrequency electromagnetic fields (RF-EMF) from MPBSs and the presence of self-reported non-specific and insomnia-like symptoms. A cross-sectional survey conducted between 2015 and 2017 in five large cities in France involved 354 people living in buildings located at a distance of 250 m or less from an MPBS and in the main transmit beam of the antennas. Information on environmental concerns, anxiety, and non-specific and insomnia-like symptoms was collected with a questionnaire administrated by telephone. A complete broadband field-meter measurement [100 kHz - 6 GHz] was then made at five points of each dwelling, followed by a spectral analysis at the point of highest exposure, detailing the contribution of each service, including MPBS. The median exposure from MPBS was 0.27 V/m (0.44 V/m for global field), ranging from 0.03 V/m to 3.58 V/m, MPBSs being the main source of exposure for 64% of the dwellings. In this study population, the measured exposure from MPBSs was not associated with self-reported non-specific or insomnia-like symptoms. However, for insomnia-like symptoms, a significant interaction was found between RF-EMF exposure from MPBSs and environmental concerns. These findings do not support the hypothesis of an effect of RF-EMF from MPBSs on non-specific or insomnia-like symptoms in the overall population. Studies are needed to further investigate the positive association observed between exposure from MPBSs and insomnia-like symptoms among people reporting environmental concerns.

Radiofrequency exposure of people living near mobile-phone base stations in France.

In response to the demand from a growing number of people concerned about the possible impact of RF-EMF on health, the French National Frequency Agency (ANFR) has published a standardized protocol for in-situ measurements of radiofrequency electromagnetic fields (RF-EMF). This protocol was based on the search for the point of highest field strength and the use of spot measurement. In the framework of an epidemiological study, such spot measurements were implemented in the homes of 354 participants located in urban areas within 250 m of a mobile-phone base station (MPBS) and in the main beam direction of the antenna. Among the participants, more than half accepted to be enrolled in a longer-term study, among whom 152 were equipped with a personal exposure meter (PEM) for 48 h and 40 for seven continuous days. Both spot and PEM measurements quantified downlink field strengths, i.e. FM, TV3-4-5, TETRA I-II-III, 2 GHz-5GHz Wi-Fi, WiMax, GSM900, GSM1800, UMTS900, UMTS 2100, LTE800, LTE1800, and LTE2600. Spot measurements showed a mean/median field strength of 0.58/0.44 V/m for total RF-EMF and 0.43/0.27 V/m from the MPBS. RF-EMF from the MPBS was the dominant source of exposure in 64% of households. Exposure to RF-EMF was influenced by the position of the windows with respect to the MPBS, in particular line-of-site visibility, the distance of the antenna and the floor of the apartment. The PEM surveys showed the measured exposure to be higher during outings than at home and during the day than at night, but there was no difference between the weekends and working days. There was a strong correlation between exposure quantified by both spot and PEM measurements, although spot measures were approximately three times higher than those by PEMs. This study is the first to assess exposure to RF-EMF of people living near a MPBS in urban areas in France. These preliminary results suggest the value of using spot measurements to estimate the impact of the evolution of the mobile-phone network and technology on the exposure of populations to RF-EMF. The low levels of RF-RMF expressed as mean values do not necessarily rule out possible health effects of this exposure.

Heparin Anti-Xa Activity, a Readily Available Unique Test to Quantify Apixaban, Rivaroxaban, Fondaparinux, and Danaparoid Levels.

BACKGROUND: Despite their usefulness in perioperative and acute care settings, factor-Xa inhibitor-specific assays are scarcely available, contrary to heparin anti-Xa assay. We assessed whether the heparin anti-Xa assay can (1) be used as a screening test to rule out apixaban, rivaroxaban, fondaparinux, and danaparoid levels that contraindicate invasive procedures according to current guidelines (>30 ng·mL-1, >30 ng·mL-1, >0.1 µg·mL-1, and >0.1 IU·mL-1, respectively), (2) quantify the anticoagulant level if found significant, that is, if it exceeded the abovementioned threshold. METHODS: In the derivation cohort then in the validation cohort, via receiver operating characteristics (ROC) curve analysis, we evaluated the ability of heparin anti-Xa assay to detect levels of factor-Xa inhibitors above or below the abovementioned safety thresholds recommended for an invasive procedure (screening test). Among samples with relevant levels of factor-Xa inhibitor, we determined the conversion factor linking the measured level and heparin anti-Xa activity in a derivation cohort. In a validation cohort, the estimated level of each factor-Xa inhibitor was thus inferred from heparin anti-Xa activity. The agreement between measured and estimated levels of factor-Xa inhibitors was assessed. RESULTS: Among 989 (355 patients) and 756 blood samples (420 patients) in the derivation and validation cohort, there was a strong linear relationship between heparin anti-Xa activities and factor-Xa inhibitors measured level (r = 0.99 [95% confidence interval {CI}, 0.99-0.99]). In the derivation cohort, heparin anti-Xa activity ≤0.2, ≤0.3, <0.1, <0.1 IU·mL-1 reliably ruled out a relevant level of apixaban, rivaroxaban, fondaparinux, and danaparoid, respectively (area under the ROC curve ≥0.99). In the validation cohort, these cutoffs yielded excellent classification accuracy (≥96%). If this screening test indicated relevant level of factor-Xa inhibitor, estimated and measured levels closely agreed (Lin's correlation coefficient close to its maximal value: 95% CI, 0.99-0.99). More than 96% of the estimated levels fell into the predefined range of acceptability (ie, 80%-120% of the measured level). CONCLUSIONS: A unique simple test already widely used to assay heparin was also useful for quantifying these 4 other anticoagulants. Both clinical and economic impacts of these findings should be assessed in a specific study.

A simplified delivery frozen elephant trunk technique to reduce circulatory arrest time in hybrid aortic arch surgery.

A simplified delivery technique for the frozen elephant trunk procedure allows the distal suture to be performed on a perfused and loaded aorta in moderate hypothermia-or even normothermia-reducing circulatory arrest time to just a few minutes. Two surgical sealing tourniquets are placed around the aortic arch, usually between the brachiocephalic trunk (BCT) and the left common carotid artery and the aorta is cross-clamped and cardioplegia started. Once in mild hypothermia, the BCT is disconnected and circulatory arrest is initiated while cerebral perfusion is maintained. This modified technique can be used in all pathologies, including dissections.

Celsior® crystalloid cardioplegia versus standard hyperkalemic normothermic blood cardioplegia: Analysis of myocardial protection in elective mitral valve repair.

INTRODUCTION: With the increase and refinement of video assisted mitral valve surgery, cristalloïd cardioplegia started regaining popularity. The aim of our study was to evaluate the effectiveness of Celsior®, a crystalloid cardioplegic solution, on myocardial protection in elective surgical mitral valve repair in comparison to blood based hyperkalemic cardioplegia. METHODS: In this observational retrospective study, all consecutive elective isolated surgical mitral valve repair where Celsior® or normothermic hyperkalemic blood cardioplegia were used were included. Primary endpoint was any sign of myocardial protection failure (troponin levels, need for inotropic or mechanical support, rhythm disturbances, mortality). Secondary endpoint was Celsior® safety (allergic reactions, bleeding, organ toxicities). RESULTS: From January 2009 to August 2016, 382 patients underwent elective isolated mitral valve repair in whom normothermic hyperkalemic blood cardioplegia (n = 181) or Celsior® (n = 201) were used. There were no statistically significant differences in baseline characteristics including Euroscore 2. Peak troponin (pg/ml) release and 30-days mortality were not statistically different. Need for cardioversion was significantly more frequent in the Celsior® group (47% vs 13%, p < 0.001). There was no statistical difference in post-operative atrial fibrillation, permanent pacemaker implantation, reoperation for bleeding, transfusion, acute kidney injury, haemoglobin at discharge or length of stay. No allergic reaction to Celsior® occurred. CONCLUSION: Effective myocardial protection was achieved with the Celsior® cardioplegic solution with no unexpected toxicity. Celsior® may be an efficacious and safe cardioprotective strategy in mitral valve repair.

Energy conservation technique improves dyspnoea when patients with severe COPD climb stairs: a randomised crossover study.

In this randomised, crossover trial, 22 patients with severe chronic obstructive pulmonary disease climbed six flights of stairs (108 steps) twice, under two test conditions: (1) energy conservation technique (ECT): participants were asked to rest for at least 5 seconds every three steps and (2) control condition: participants climbed the stairs at their own pace. Significant lower dyspnoea (primary outcome), leg discomfort, minute ventilation and capillary blood lactate under the ECT condition were found, with no change in total task time. CLINICAL TRIAL REGISTRATION: NCT03564028.