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Abstract Williams Beuren syndrome (WBS) is a multiple malformations/intellectual disability (ID) syndrome caused by 7q11.23 microdeletion and clinically characterized by a typical neurocognitive profile including excessive talkativeness and social disinhibition, often defined as “overfriendliness” and “hyersociability”. WBS is generally considered as the polar opposite phenotype to Autism Spectrum Disorder (ASD). Surprisingly, the prevalence of ASD has been reported to be significantly higher in WBS (12%) than in general population (1%). Our study aims to investigate the molecular basis of the peculiar association of ASD and WBS. We performed chromosomal microarray analysis and whole exome sequencing in six patients presenting with WBS and ASD, in order to evaluate the possible presence of chromosomal or gene variants considered as pathogenic. Our study shows that the presence of ASD in the recruited WBS patients is due to i) neither atypically large deletions; ii) nor the presence of pathogenic variants in genes localized in the non-deleted 7q11.23 allele which would unmask recessive conditions; iii) moreover, we did not identify a second, indisputable independent genetic diagnosis, related to pathogenic Copy Number Variations or rare pathogenic exonic variants in known ID/ASD causing genes, although several variants of unknown significance were found. Finally, imprinting effect does not appear to be the only cause of autism in WBS patients, since the deletions occurred in alleles of both maternal and paternal origin. The social disinhibition observed in WBS does not follow common social norms and symptoms overlapping with ASD, such as restricted interests and repetitive behavior, can be observed in “typical” WBS patients: therefore, the terms “overfriendliness” and “hypersociability” appear to be a misleading oversimplification. The etiology of ASD in WBS is likely to be heterogeneous. Further studies on large series of patients are needed to clarify the observed variability in WBS social communication, ranging from excessive talkativeness and social disinhibition to absence of verbal language and social deficit.

Cheyne–Stokes respiration (CSR) may trigger ventricular arrhythmia in patients with heart failure with reduced ejection fraction (HFrEF) and central sleep apnoea (CSA). This study determined the prevalence and predictors of a high nocturnal ventricular arrhythmia burden in patients with HFrEF and CSA (with and without CSR) and to evaluate the temporal association between CSR and the ventricular arrhythmia burden. This cross-sectional ancillary analysis included 239 participants from the SERVE-HF major sub-study who had HFrEF and CSA, and nocturnal ECG from polysomnography. CSR was stratified in ≥20% and 30 premature ventricular complexes (PVCs) per hour of TRT. A sub-analysis was performed to evaluate the temporal association between CSR and ventricular arrhythmias in sleep stage N2. High ventricular arrhythmia burden was observed in 44% of patients. In multivariate logistic regression analysis, male sex, lower systolic blood pressure, non-use of antiarrhythmic medication and CSR ≥20% were significantly associated with PVCs >30·h−1 (OR 5.49, 95% CI 1.51–19.91, p=0.010; OR 0.98, 95% CI 0.97–1.00, p=0.017; OR 5.02, 95% CI 1.51–19.91, p=0.001; and OR 2.22, 95% CI 1.22–4.05, p=0.009; respectively). PVCs occurred more frequently during sleep phases with versus without CSR (median (interquartile range): 64.6 (24.8–145.7) versus 34.6 (4.8–75.2)·h−1 N2 sleep; p=0.006). Further mechanistic studies and arrhythmia analysis of major randomised trials evaluating the effect of treating CSR on ventricular arrhythmia burden and arrhythmia-related outcomes are warranted to understand how these data match with the results of the parent SERVE-HF study.

Background: The effectiveness of positive airway pressure therapies (PAP) is contingent on treatment adherence. We hypothesized that forgoing healthcare may be a determinant of adherence to PAP therapy.Research Question: The objectives were: (i) to assess the impact of forgoing healthcare on adherence to PAP in patients with Chronic Respiratory Failure (CRF) and patients with Obstructive Sleep Apnea Syndrome (OSAS); (ii) to compare forgoing healthcare patterns in these two chronic conditions.Study design and methods: Prospective cohort of patients with OSAS or CRF, treated with PAP therapies at home for at least 12 months. At inclusion, patients were asked to fill-in questionnaires investigating (i) healthcare forgone, (ii) deprivation (EPICES score), (iii) socio-professional and familial status. Characteristics at inclusion were extracted from medical records. PAP adherence was collected from the device's built-in time counters. Multivariable logistic regression models were used to assess the associations between healthcare forgone and the risk of being non-adherent to CPAP treatment.Results: Among 298 patients included (294 analyzed); 33.7% reported forgoing healthcare. Deprivation (EPICES score > 30) was independently associated with the risk of non-adherence (OR = 3.57, 95%CI [1.12; 11.37]). Forgoing healthcare had an additional effect on the risk of non-adherence among deprived patients (OR = 7.74, 95%CI [2.59; 23.12]). OSAS patients mainly forwent healthcare for financial reasons (49% vs. 12.5% in CRF group), whereas CRF patients forwent healthcare due to lack of mobility (25%, vs. 5.9 % in OSAS group).Interpretation: Forgoing healthcare contributes to the risk of PAP non-adherence particularly among deprived patients. Measures tailored to tackle forgoing healthcare may improve the overall quality of care in PAP therapies.Clinical Trial Registration: The study protocol was registered in ClinicalTrials.gov, identifier: NCT03591250.

BackgroundNasal high flow (NHF) is a non-invasive breathing therapy that is based on the delivery via a large-caliber nasal cannula of heated and humidified air at flow rates that exceed peak inspiratory flow. It is thought that positive airway pressure generated by NHF can help reduce gas trapping and improve regional lung ventilation. There are no data to confirm this hypothesis at flow rates applicable in stable chronic obstructive pulmonary disease (COPD) patients.MethodsIn this study, we used non-rigid registration of computed tomography (CT) images acquired at maximal expiration and inspiration to compute regional lung attenuation changes (ΔHU), and lung displacement (LD), indices of regional lung ventilation. Parametric response maps (Galban et al., 2012) were also computed in each experimental condition. Eight COPD patients were assessed at baseline (BL) and after 5 min of NHF and expiratory resistive loading (ERL).ResultsΔHU was: BL (median, IQR): 85 (67.2, 102.8); NHF: 90.7 (57.4, 97.6); ERL: 74.6 (46.4, 89.6) HU (p = 0.531); and LD: 27.8 (22.3, 39.3); 17.6 (15.4, 27.9); and 20.4 (16.6, 23.6) mm (p = 0.120) in the 3 conditions, respectively. No significant difference in trapping was observed. Respiratory rate significantly decreased with both treatments [BL: 17.3 (16.4, 18.9); NHF: 13.7; ERL: 11.4 (9.6, 13.2) bpm; and p < 0.001].ConclusionNeither NHF at 25 L/min nor ERL significantly improved the regional lung ventilation of stable COPD patients with gas trapping, based on functional lung CT imaging. Further study including more subjects is needed to assess the potential effect of NHF on regional lung function at higher flow rates.Clinical Trial Registrationwww.clinicaltrials.gov/under, identifier NCT03821311.

The surface morphology of faults controls the spatial anisotropy of their frictional properties and hence their mechanical stability. Such anisotropy is only rarely studied in seismology models of fault slip, although it might be paramount to understand the seismic rupture in particular areas, notably where slip occurs in a direction different from that of the main striations of the fault. To quantify how the anisotropy of fault surfaces affects the friction coefficient during sliding, we sheared synthetic fault planes made of plaster of Paris. These fault planes were produced by 3D-printing real striated fault surfaces whose 3D roughness was measured in the field at spatial scales from millimeters to meters. Here, we show how the 3D-printing technology can help for the study of frictional slip. The results show that fault anisotropy controls the coefficient of static friction, with μS//, the friction coefficient along the striations being three to four times smaller than μS⊥, the friction coefficient along the orientation perpendicular to the striations. This is true both at the meter and the millimeter scales. The anisotropy in friction and the average coefficient of static friction are also shown to decrease with the normal stress applied to the faults, as a result of the increased surface wear under increased loading.

This non-interventional post-authorisation safety study (PASS) assessed the long-term safety of everolimus in patients with tuberous sclerosis complex (TSC) who participated in the TuberOus SClerosis registry to increase disease Awareness (TOSCA) clinical study and received everolimus for the licensed indications in the European Union. The rate of adverse events (AEs), AEs that led to dose adjustments or treatment discontinuation, AEs of potential clinical interest, treatment-related AEs (TRAEs), serious AEs (SAEs), and deaths were documented. One hundred seventy-nine patients were included in the first 5 years of observation; 118 of 179 patients had an AE of any grade, with the most common AEs being stomatitis (7.8%) and headache (7.3%). AEs caused dose adjustments in 56 patients (31.3%) and treatment discontinuation in nine patients (5%). AEs appeared to be more frequent and severe in children. On Tanner staging, all patients displayed signs of age-appropriate sexual maturation. Twenty-two of 106 female (20.8%) patients had menstrual cycle disorders. The most frequent TRAEs were stomatitis (6.7%) and aphthous mouth ulcer (5.6%). SAEs were reported in 54 patients (30.2%); the most frequent SAE was pneumonia (>3% patients; grade 2, 1.1%, and grade 3, 2.8%). Three deaths were reported, all in patients who had discontinued everolimus for more than 28 days, and none were thought to be related to everolimus according to the treating physicians. The PASS sub-study reflects the safety and tolerability of everolimus in the management of TSC in real-world routine clinical practice.

Objective The earliest possible detection of individuals with COVID-19 has been essential to curb the spread of infection. Existing digital tools have been scaled up to address this issue. Every night telemonitoring data on continuous positive airway pressure (CPAP) device use, the first-line therapy for obstructive sleep apnoea (OSA), is collected worldwide. We asked whether the changes in CPAP adherence patterns of might constitute an alert for COVID-19. Methods We analysed preliminary results of telemonitoring data, recorded between February 1 and April 30, 2020, on OSA patients followed by our sleep clinics and diagnosed with COVID-19. Results CPAP telemonitoring data from the first 19 patients diagnosed with COVID-19 showed a clear decrease or halt in adherence in the 20 days immediately preceding COVID-19 diagnosis compared to an earlier period (p

The Botryosphaeriaceae is a fungal family that includes many destructive vascular pathogens of woody plants (e.g., Botryosphaeria dieback of grape, Panicle blight of pistachio). Species in the genera Botryosphaeria, Diplodia, Dothiorella, Lasiodiplodia, Neofusicoccum, and Neoscytalidium attack a range of horticultural crops, but they vary in virulence and their abilities to infect their hosts via different infection courts (flowers, green shoots, woody twigs). Isolates of seventeen species, originating from symptomatic apricot, grape, pistachio, and walnut were tested for pathogenicity on grapevine wood after 4 months of incubation in potted plants in the greenhouse. Results revealed significant variation in virulence in terms of the length of the internal wood lesions caused by these seventeen species. Phylogenomic comparisons of the seventeen species of wood-colonizing fungi revealed clade-specific expansion of gene families representing putative virulence factors involved in toxin production and mobilization, wood degradation, and nutrient uptake. Statistical analyses of the evolution of the size of gene families revealed expansions of secondary metabolism and transporter gene families in Lasiodiplodia and of secreted cell wall degrading enzymes (CAZymes) in Botryosphaeria and Neofusicoccum genomes. In contrast, Diplodia, Dothiorella, and Neoscytalidium generally showed a contraction in the number of members of these gene families. Overall, species with expansions of gene families, such as secreted CAZymes, secondary metabolism, and transporters, were the most virulent (i.e., were associated with the largest lesions), based on our pathogenicity tests and published reports. This study represents the first comparative phylogenomic investigation into the evolution of possible virulence factors from diverse, cosmopolitan members of the Botryosphaeriaceae.

In California vineyards, spore dispersal of fungi that cause grapevine trunk diseases Botryosphaeria dieback and Eutypa dieback occurs with winter rains. Spores infect through pruning wounds made to the woody structure of the vine in winter. Better timing of preventative practices that minimize infection may benefit from routine spore-trapping, which could pinpoint site-specific time frames of spore dispersal. To speed pathogen detection from environmental spore samples, we identified species-specific PCR primers and protocols. Then we compared the traditional culture-based method versus our new DNA-based method. • PCR primers for Botryosphaeria-dieback pathogen Neofusicoccum parvum and Eutypa-dieback pathogen Eutypa lata were confirmed species-specific, through extensive testing of related species (in families Botryosphaeriaceae and Diatrypaceae, respectively), other trunk-disease pathogens, and saprophytic fungi that sporulate in vineyards. • Consistent detection of N. parvum was achieved from spore suspensions used fresh or stored at -20°C, whereas consistent detection of E. lata was achieved only with a new spore-lysis method, using zirconia/silica beads in a FastPrep homogenizer (MP Biomedicals; Solon, Ohio, USA), and only from spore suspensions used fresh. Freezing E. lata spores at -20°C made detection inconsistent. • From environmental samples, spores of E. lata were detected only via PCR, whereas spores of N. parvum were detected both via PCR and in culture.

BackgroundThe symptomatic response to continuous positive airway pressure (CPAP) therapy in COPD-obstructive sleep apnea overlap syndrome (OVS) compared to OSA syndrome (OSA) alone has not been well studied so far. The aim of this study is to explore main differences in the clinical response to CPAP treatment in OVS compared to OSA alone.Study design and methodsUsing prospective data from the French National Sleep Apnea Registry, we conducted an observational study among 6320 patients with moderate-to-severe OSA, available spirometry, and at least one follow-up visit under CPAP therapy.ResultsCPAP efficacy measured on the residual apnea-hypopnea index and median adherence were similar between OVS and OSA patients. In both groups, the overall burden of symptoms related to sleep apnea improved with CPAP treatment. In a multivariable model adjusted for age, gender, body mass index, adherence to treatment and residual apnea-hypopnea index, OVS was associated with higher odds for persistent morning headaches (OR: 1.37 [95% CI; 1.04; 1.79]; P = 0.02), morning tiredness (OR: 1.33 [95% CI: 1.12; 1.59]; PInterpretationCPAP therapy was effective in normalizing the apnea-hypopnea index and significantly improved OSA-related symptoms, regardless of COPD status. CPAP should be offered to patients with OVS on a trial basis as a significant improvement in OSA-related symptoms can be expected, although the range of response may be less dramatic than in OSA alone.

Background Total liquid ventilation (TLV) has been shown to prevent neurological damage though ultrafast cooling in animal models of cardiac arrest. We investigated whether its neuroprotective effect could be explained by mitigation of early inflammatory events. Methods and Results Rabbits were submitted to 10 minutes of ventricular fibrillation. After resuscitation, they underwent normothermic follow‐up (control) or ultrafast cooling by TLV and hypothermia maintenance for 3 hours (TLV). Immune response, survival, and neurological dysfunction were assessed for 3 days. TLV improved neurological recovery and reduced cerebral lesions and leukocyte infiltration as compared with control (eg, neurological dysfunction score=34±6 versus 66±6% at day 1, respectively). TLV also significantly reduced interleukin‐6 blood levels during the hypothermic episode (298±303 versus 991±471 pg/mL in TLV versus control at 3 hours after resuscitation, respectively), but not after rewarming (752±563 versus 741±219 pg/mL in TLV versus control at 6 hours after resuscitation, respectively). In vitro assays confirmed the high temperature sensitivity of interleukin‐6 secretion. Conversely, TLV did not modify circulating high‐mobility group box 1 levels or immune cell recruitment into the peripheral circulation. The link between interleukin‐6 early transcripts (8 hours). Conclusions The neuroprotective effect of hypothermic TLV was associated with a mitigation of humoral interleukin‐6 response. A temperature‐dependent attenuation of immune cell reactivity during the early phase of the post–cardiac arrest syndrome could explain the potent effect of rapid hypothermia. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00999583.

Objectives:. To construct a highly detailed yet practical, attainable roadmap for enhancing the likelihood of neurologically intact survival following sudden cardiac arrest. Design, Setting, and Patients:. Population-based outcomes following out-of-hospital cardiac arrest were collated for 10 U.S. counties in Alaska, California, Florida, Ohio, Minnesota, Utah, and Washington. The 10 identified emergency medical services systems were those that had recently reported significant improvements in neurologically intact survival after introducing a more comprehensive approach involving citizens, hospitals, and evolving strategies for incorporating technology-based, highly choreographed care and training. Detailed inventories of in-common elements were collated from the ten 9-1-1 agencies and assimilated. For reference, combined averaged outcomes for out-of-hospital cardiac arrest occurring January 1, 2017, to February 28, 2018, were compared with concurrent U.S. outcomes reported by the well-established Cardiac Arrest Registry to Enhance Survival. Interventions:. Most commonly, interventions and components from the ten 9-1-1 systems consistently included extensive public cardiopulmonary resuscitation training, 9-1-1 system-connected smart phone applications, expedited dispatcher procedures, cardiopulmonary resuscitation quality monitoring, mechanical cardiopulmonary resuscitation, devices for enhancing negative intrathoracic pressure regulation, extracorporeal membrane oxygenation protocols, body temperature management procedures, rapid cardiac angiography, and intensive involvement of medical directors, operational and quality assurance officers, and training staff. Measurements and Main Results:. Compared with Cardiac Arrest Registry to Enhance Survival (n = 78,704), the cohorts from the 10 emergency medical services agencies examined (n = 2,911) demonstrated significantly increased likelihoods of return of spontaneous circulation (mean 37.4% vs 31.5%; p < 0.001) and neurologically favorable hospital discharge, particularly after witnessed collapses involving bystander cardiopulmonary resuscitation and shockable cardiac rhythms (mean 10.7% vs 8.4%; p < 0.001; and 41.6% vs 29.2%; p < 0.001, respectively). Conclusions:. The likelihood of neurologically favorable survival following out-of-hospital cardiac arrest can improve substantially in communities that conscientiously and meticulously introduce a well-sequenced, highly choreographed, system-wide portfolio of both traditional and nonconventional approaches to training, technologies, and physiologic management. The commonalities found in the analyzed systems create a compelling case that other communities can also improve out-of-hospital cardiac arrest outcomes significantly by conscientiously exploring and adopting similar bundles of system organization and care.

Fractures play an important role as flow paths in porous media. When an undersaturated reactive fluid is flowing in a fracture, the dissolution process will alter the flow paths locally. Dissolution patterns grow slowly, but they may lead to a dramatic reorganization of the flow. Here, we study dissolution in a radial geometry, which is relevant for a number of practical applications, e.g., the acidization of oil reservoirs. Different dissolution patterns are presented in a phase diagram with the Péclet and Damköhler numbers as parameters. We also analyze quantitatively the density of wormholes and the relation between the aperture roughness and the ramified patterns.

Renal angiomyolipomas are one of the most common renal manifestations in patients with tuberous sclerosis complex (TSC), with potentially life-threatening complications and a poor prognosis. Despite the considerable progress in understanding TSC-associated renal angiomyolipomas, there are no large scale real-world data. The aim of our present study was to describe in detail the prevalence and outcome of renal angiomyolipomas in patients with TSC, enrolled into the TuberOus SClerosis registry to increase disease Awareness (TOSCA) from 170 sites across 31 countries worldwide. We also sought to evaluate the relationship of TSC-associated renal angiomyolipomas with age, gender and genotype. The potential risk factors for renal angiomyolipoma-related bleeding and chronic kidney disease (CKD) were studied in patients who participated in the TOSCA renal angiomyolipoma substudy. Of the 2,211 eligible patients, 1,062 (48%) reported a history of renal angiomyolipomas. The median age of TSC diagnosis for the all subjects (n = 2,211) was 1 year. The median age of diagnosis of renal angiomyolipoma in the 1,062 patients was 13 years. Renal angiomyolipomas were significantly more prevalent in female patients (p < 0.0001). Rates of angiomyolipomas >3 cm (p = 0.0119), growing lesions (p = 0.0439), and interventions for angiomyolipomas (p = 0.0058) were also higher in females than males. Pre-emptive intervention for renal angiomyolipomas with embolisation, surgery, or mammalian target of rapamycin (mTOR) inhibitor may have abolished the gender difference in impaired renal function, hypertension, and other complications. The rate of interventions for angiomyolipomas was less common in children than in adults, but interventions were reported in all age groups. In the substudy of 76 patients the complication rate was too low to be useful in predicting risk for more severe CKD. In addition, in this substudy no patient had a renal hemorrhage after commencing on an mTOR inhibitor. Our findings confirmed that renal angiomyolipomas in subjects with TSC1 mutations develop on average at the later age, are relatively smaller in size and less likely to be growing; however, by age 40 years, no difference was observed in the percentage of patients with TSC1 and TSC2 mutations needing intervention. The peak of appearance of new renal angiomyolipomas was observed in patients aged between 18 and 40 years, but, given that angiomyolipomas can occur later, lifelong surveillance is necessary. We found that pre-emptive intervention was dramatically successful in altering the outcome compared to historical controls; with high pre-emptive intervention rates but low rates of bleeding and other complications. This validates the policy of surveillance and pre-emptive intervention recommended by clinical guidelines.

Research on tuberous sclerosis complex (TSC) to date has focused mainly on the physical manifestations of the disease. In contrast, the psychosocial impact of TSC has received far less attention. The aim of this study was therefore to examine the impact of TSC on health, quality of life (QoL), and psychosocial well-being of individuals with TSC and their families. Questionnaires with disease-specific questions on burden of illness (BOI) and validated QoL questionnaires were used. After completion of additional informed consent, we included 143 individuals who participated in the TOSCA (TuberOus SClerosis registry to increase disease Awareness) study. Our results highlighted the substantial burden of TSC on the personal lives of individuals with TSC and their families. Nearly half of the patients experienced negative progress in their education or career due to TSC (42.1%), as well as many of their caregivers (17.6% employed; 58.8% unemployed). Most caregivers (76.5%) indicated that TSC affected family life, and social and working relationships. Further, well-coordinated care was lacking: a smooth transition from pediatric to adult care was mentioned by only 36.8% of adult patients, and financial, social, and psychological support in 21.1, 0, and 7.9%, respectively. In addition, the moderate rates of pain/discomfort (35%) and anxiety/depression (43.4%) reported across all ages and levels of disease demonstrate the high BOI and low QoL in this vulnerable population.

Purpose FACE is a prospective cohort study designed to assess the effect of adding adaptive servoventilation (ASV) to standard care on morbidity and mortality in patients with chronic heart failure (HF) with preserved (HFpEF), mid-range (HFmrEF) or reduced ejection fraction (HFrEF) who have sleep-disordered breathing (SDB) with an indication for ASV. We describe the study design, ongoing data collection and baseline participant characteristics.Participants Consecutive patients with HFpEF, HFmrEF or HFrEF plus SDB with central sleep apnoea (CSA) and indication for ASV were enrolled in the study cohort between November 2009 and December 2018; the ASV group includes those treated with ASV and the control group consists of patients who refused ASV or stopped treatment early. Follow-up is based on standard clinical practice, with visits at inclusion, after 3, 12 and 24 months of follow-up. Primary endpoint is the time to first event: all-cause death or unplanned hospitalisation (or unplanned prolongation of a planned hospitalisation) for worsening of HF, cardiovascular death or unplanned hospitalisation for worsening of HF, and all-cause death or all-cause unplanned hospitalisation.Findings to date 503 patients have been enrolled, mean age of 72 years, 88% male, 31% with HFrEF. HF was commonly of ischaemic origin, and the number of comorbidities was high. SDB was severe (median Apnoea–Hypopnoea Index 42/hour), and CSA was the main indication for ASV (69%). HF was highly symptomatic; most patients were in NYHA class II (38%) or III (29%).Future plans Patient follow-up is ongoing. Given the heterogeneous nature of the enrolled population, a decision was made to use latent class analysis to define homogeneous patient subgroups, and then evaluate outcomes by cluster, and in the ASV and control groups (overall and within patient clusters). First analysis will be performed after 3 months, a second analysis at the 2-year follow-up.Trial registration number NCT01831128; Pre-results.

Background: Knowledge is increasing about TSC-Associated Neuropsychiatric Disorders (TAND), but little is known about the potentially confounding effects of intellectual ability (IA) on the rates of TAND across age, sex, and genotype. We evaluated TAND in (a) children vs. adults, (b) males vs. females, and (c) TSC1 vs. TSC2 mutations, after stratification for levels of IA, in a large, international cohort.Methods: Individuals of any age with a documented visit for TSC in the 12 months prior to enrolment were included. Frequency and percentages of baseline TAND manifestations were presented by categories of IA (no intellectual disability [ID, intelligence quotient (IQ)>70]; mild ID [IQ 50–70]; moderate-to-profound ID [IQ

Background: Growth hormone (GH) stimulates the production of insulin-like growth factor 1 (IGF-1) in most tissues and together GH and IGF-1 profoundly impact adipose tissue deposition, glucose metabolism and cardiovascular function. A low serum IGF-I level has been reported as being associated with obstructive sleep apnea (OSA) and might be one of the mechanisms underlying cardio-metabolic risk in OSA patients.Methods: In a multicenter national study, 817 patients consulting for suspicion of OSA (OSA confirmed for 567 patients) underwent serum IGF-1 measurements. We analyzed the association between an IGF-1 level below the median value of the population and variables related to cardio-metabolic risk: body mass index (BMI) and waist circumference, apnea hypopnea index (AHI), cholesterol and triglycerides (expressed as median and divided into quartiles for continuous variables).Results: After adjustment for age and gender, low IGF-1 levels were associated with increased BMI and AHI (Odds ratios (OR) = 2.83; p < 0.0001 and OR = 3.03, p < 0.0001 for Quartile 4 vs. Quartile1, respectively), with elevated cholesterol levels (OR = 1.36, p = 0.0444), and elevated triglyceride levels (OR = 1.36; p = 0.0008).Conclusions: Both adiposity and sleep apnea synergistically predict low levels of IGF-1 and thus could together contribute toward cardio-metabolic risk. Further work are needed to confirm whether IGF-1 levels allow grading severity and predicting response to treatments to aim at a personalized medicine for patients suffering from OSA.

The progression of chronic obstructive pulmonary disease (COPD) is characterized by episodes of acute exacerbation (AECOPD) of symptoms, decline in respiratory function, and reduction in quality-of-life increasing morbi-mortality and often requiring hospitalization. Exacerbations can be triggered by environmental exposures, changes in lifestyle, and/or physiological and psychological factors to greater or lesser extents depending on the individual’s COPD phenotype. The prediction and early detection of an exacerbation might allow patients and physicians to better manage the acute phase. We summarize the recent scientific data on remote telemonitoring (TM) for the prediction and management of acute exacerbations in COPD patients. We discuss the components of remote monitoring platforms, including the integration of environmental monitoring data; patient reported outcomes collected via interactive Smartphone apps, with data from wearable devices that monitor physical activity, heart rate, etc.; and data from medical devices such as connected non-invasive ventilators. We consider how telemonitoring and the deluge of data it potentially generates could be combined with electronic health records to provide personalized care and multi-disease management for COPD patients.

Abstract Cytospora species are destructive canker and dieback pathogens of woody hosts in natural and agroecosystems around the world. In this genus, molecular identification has been limited due to the paucity of multi-locus sequence typing studies and the lack of sequence data from type specimens in public repositories, stalling robust phylogenetic reconstructions. In most cases a morphological species concept could not be applied due to the plasticity of characters and significant overlap of morphological features such as spore dimensions and fruiting body characters. In this study, we employed a molecular phylogenetic framework with the inclusion of four nuclear loci (ITS, translation elongation factor 1-alpha, actin, and beta-tubulin) to unveil the biodiversity and taxonomy of this understudied important genus of plant pathogens. Phylogenetic inferences based on 150 Californian isolates revealed 15 Cytospora species associated with branch and twig cankers and dieback of almond, apricot, cherry, cottonwood, olive, peach, pistachio, plum, pomegranate, and walnut trees in California. Of the 15 species recovered in this study, 10 are newly described and typified, in addition to one new combination. The pathogenic status of the newly described Cytospora species requires further investigation as most species were associated with severe dieback and decline of diverse and economically important fruit and nut crops in California.

Abstract Allergic rhinitis (AR) is impacted by allergens and air pollution but interactions between air pollution, sleep and allergic diseases are insufficiently understood. POLLAR (Impact of air POLLution on sleep, Asthma and Rhinitis) is a project of the European Institute of Innovation and Technology (EIT Health). It will use a freely-existing application for AR monitoring that has been tested in 23 countries (the Allergy Diary, iOS and Android, 17,000 users, TLR8). The Allergy Diary will be combined with a new tool allowing queries on allergen, pollen (TLR2), sleep quality and disorders (TRL2) as well as existing longitudinal and geolocalized pollution data. Machine learning will be used to assess the relationship between air pollution, sleep and AR comparing polluted and non-polluted areas in 6 EU countries. Data generated in 2018 will be confirmed in 2019 and extended by the individual prospective assessment of pollution (portable sensor, TLR7) in AR. Sleep apnea patients will be used as a demonstrator of sleep disorder that can be modulated in terms of symptoms and severity by air pollution and AR. The geographic information system GIS will map the results. Consequences on quality of life (EQ-5D), asthma, school, work and sleep will be monitored and disseminated towards the population. The impacts of POLLAR will be (1) to propose novel care pathways integrating pollution, sleep and patients’ literacy, (2) to study sleep consequences of pollution and its impact on frequent chronic diseases, (3) to improve work productivity, (4) to propose the basis for a sentinel network at the EU level for pollution and allergy, (5) to assess the societal implications of the interaction. MASK paper N°32.

Abstract Background Most evidence for TSC-associated neuropsychiatric disorders (TAND) to date have come from small studies and case reports, and very little is known about TAND in adults. We explored baseline TAND data from the large-scale international TOSCA natural history study to compare childhood and adult patterns, describe age-based patterns, and explore genotype-TAND correlations. Results The study enrolled 2216 eligible participants with TSC from 170 sites across 31 countries at the data cut-off for the third interim analysis (data cut-off date: September 30, 2015). The most common behavioural problems (reported in > 10% of participants) were overactivity, sleep difficulties, impulsivity, anxiety, mood swings, severe aggression, depressed mood, self-injury, and obsessions. Psychiatric disorders included autism spectrum disorder (ASD, 21.1%), attention deficit hyperactivity disorder (ADHD, 19.1%), anxiety disorder (9.7%), and depressive disorder (6.1%). Intelligence quotient (IQ) scores were available for 885 participants. Of these, 44.4% had normal IQ, while mild, moderate, severe, and profound degrees of intellectual disability (ID) were observed in 28.1, 15.1, 9.3, and 3.1%, respectively. Academic difficulties were identified in 58.6% of participants, and neuropsychological deficits (performance

Abstract Background Ultrafast cooling by total liquid ventilation (TLV) provides potent cardio- and neuroprotection after experimental cardiac arrest. However, this was evaluated in animals with no initial lung injury, whereas out-of-hospital cardiac arrest is frequently associated with early-onset pneumonia, which may lead to acute respiratory distress syndrome (ARDS). Here, our objective was to determine whether hypothermic TLV could be safe or even beneficial in an aspiration-associated ARDS animal model. Methods ARDS was induced in anesthetized rabbits through a two-hits model including the intra-tracheal administration of a pH = 1 solution mimicking gastric content and subsequent gaseous non-protective ventilation during 90 min (tidal volume [Vt] = 10 ml/kg with positive end-expiration pressure [PEEP] = 0 cmH2O). After this initial period, animals either received lung protective gas ventilation (LPV; Vt = 8 ml/kg and PEEP = 5 cmH2O) under normothermic conditions, or hypothermic TLV (TLV; Vt = 8 ml/kg and end-expiratory volume = 15 ml/kg). Both strategies were applied for 120 min with a continuous monitoring of respiratory and cardiovascular parameters. Animals were then euthanized for pulmonary histological analyses. Results Eight rabbits were included in each group. Before randomization, all animals elicited ARDS with arterial oxygen partial pressure over inhaled oxygen fraction ratios (PaO2/FiO2) below 100 mmHg, as well as decreased lung compliance. After randomization, body temperature rapidly decreased in TLV versus LPV group (32.6 ± 0.6 vs. 38.2 ± 0.4 °C after 15 min). Static lung compliance and gas exchanges were not significantly different in the TLV versus LPV group (PaO2/FiO2 = 62 ± 4 vs. 52 ± 8 mmHg at the end of the procedure, respectively). Mean arterial pressure and arterial bicarbonates levels were significantly higher in TLV versus LPV. Histological analysis also showed significantly lower inflammation in TLV versus LPV group (median histological score = 3 vs. 4.5/5, respectively; p = 0.03). Conclusion Hypothermic TLV can be safely induced in rabbits during aspiration-associated ARDS. It modified neither gas exchanges nor respiratory mechanics but reduced lung inflammation and hemodynamic failure in comparison with LPV. Since hypothermic TLV was previously shown to provide neuro- and cardio protective effects after cardiac arrest, these findings suggest a possible use of TLV in the settings of cardiac arrest-associated ARDS.

Much research in France or abroad has highlighted the medical practice variation (MPV) phenomenon. There is no consensus on the origin of MPV between preference-centered approaches versus opportunities and constraints approaches. This study's main purpose is to assess the relevance of hypotheses which assume that physicians adopt a uniform practice style for their patients for each similar clinical decision in a context of medical decision with low uncertainty and professional practice with weak regulation. Multilevel models are evaluated: first to measure variability of antibiotics prescription by French general practitioners (GPs) for acute rhinopharyngitis regarding clinical guidelines, and to test its significance in order to determine to what extent prescription differences are due to between or within GPs discrepancies; second, to prioritize its determinants, especially those relating to a GP or his/her practice setting environment, while controlling visit or patient confounders. The study was based on 2001 activity data, along with an ad hoc questionnaire, of a sample of 778 GP taken from a panel of 1006 computerized French GPs. We observed that a large part of the total variation was due to intra-physician variability (70%). It is patient characteristics that largely explain the prescription, even if GP or practice setting characteristics (location, level of activity, network participation, continuing medical education) and environmental factors (visit from pharmaceutical sales representatives) also exert considerable influence. This suggests that MPV are partly caused by differences in the type of dissemination of medical information and this may help policy makers to identify and develop facilitators for promoting better use of antibiotics in France and, more generally, for influencing GP practices when it is of interest. [ABSTRACT FROM AUTHOR]

Background: Total liquid ventilation (TLV) of the lungs could provide radically new benefits in critically ill patients requiring lung lavage or ultra-fast cooling after cardiac arrest. It consists in an initial filling of the lungs with perfluorocarbons and subsequent tidal ventilation using a dedicated liquid ventilator. Here, we propose a new paradigm for a lung-conservative TLV using pulmonary volumes of perfluorocarbons below functional residual capacity (FRC). Methods and findings: Using a dedicated technology, we showed that perfluorocarbon end-expiratory volumes could be maintained below expected FRC and lead to better respiratory recovery, preserved lung structure and accelerated evaporation of liquid residues as compared to complete lung filling in piglets. Such TLV below FRC prevented volutrauma through preservation of alveolar recruitment reserve. When used with temperature-controlled perfluorocarbons, this lung-conservative approach provided neuroprotective ultra-fast cooling in a model of hypoxic-ischemic encephalopathy. The scale-up and automating of the technology confirmed that incomplete initial lung filling during TLV was beneficial in human adult-sized pigs, despite larger size and maturity of the lungs. Our results were confirmed in aged non-human primates, confirming the safety of this lung-conservative approach. Interpretation: This study demonstrated that TLV with an accurate control of perfluorocarbon volume below FRC could provide the full potential of TLV in an innovative and safe manner. This constitutes a new paradigm through the tidal liquid ventilation of incompletely filled lungs, which strongly differs from the previously known TLV approach, opening promising perspectives for a safer clinical translation. Fund: ANR (COOLIVENT), FRM (DBS20140930781), SATT IdfInnov (project 273). Keywords: Liquid ventilation, Critical care, Therapeutic hypothermia, Biomedical engineering

BackgroundObstructive sleep apnea (OSA) is associated with cardiovascular co-morbidities and mortality. Arterial stiffness is an independent predictor of cardiovascular risk and mortality, and is influenced by the presence of OSA and related comorbidities. There is a paucity of data regarding long-term evolution of arterial stiffness in CPAP-treated OSA patients. We aimed to prospectively study long term PWV variations and determinants of PWV deterioration.MethodsIn a prospective obese OSA cohort, at time of diagnosis and after several years of follow-up we collected arterial stiffness measured by carotid-femoral pulse wave velocity (PWV), clinical and metabolic parameters, and CPAP adherence. Univariate and multivariate analyses were performed in order to determine contributing factors.ResultsSeventy two OSA patients (men: 52.8%, median age: 55.8 years and median BMI of 38.5 kg/m2) with a prevalence of hypertension: 58.3%, type 2 diabetes: 20.8%, hypercholesterolemia: 33.3%, current or past smoking: 59.7%, were evaluated after a median follow-up of 7.4 [5.8; 8.3] years. Over the period of follow-up, the median increase in PWV was 1.34 [0.10; 2.37] m/s. In multivariate analysis, the increase in PWV was associated with older age (10 extra years was associated with a 5.24 [1.35; 9.12] % increase in PWV) and hypertension (a significant increase in PWV of 8.24 [1.02; 15.57] %). No impact of CPAP adherence on PWV evolution was found.ConclusionPWV progression in CPAP-treated OSA patients is mainly related to pre-existing cardio-metabolic comorbidities and not influenced by CPAP adherence. In this high cardiovascular risk population, it is crucial to associated weight management and exercise with CPAP treatment.

BackgroundMore advanced knowledge is needed on how COPD alters the clinical presentation of obstructive sleep apnea (OSA) and how the association of both diseases, known as 'overlap syndrome' (OVS), impacts on cardiovascular health.ObjectiveTo investigate differences between patients with OVS and those with moderate-to-severe OSA alone.MethodsA cross-sectional study conducted in the French National Sleep Apnea Registry between January 1997 and January 2017. Univariable and multivariable logistic regression models were used to compare OVS versus OSA alone on symptoms and cardiovascular health.Results46,786 patients had moderate-to-severe OSA. Valid spirometry was available for 16,466 patients: 14,368 (87%) had moderate-to-severe OSA alone and 2098 (13%) had OVS. A lower proportion of OVS patients complained of snoring, morning headaches and excessive daytime sleepiness compared to OSA alone (median Epworth Sleepiness Scale score: 9 [interquartile range (IQR) 6-13] versus 10 (IQR 6-13), respectively; P ConclusionsIn adults with moderate-to-severe OSA, OVS was minimally symptomatic, but exhibited higher odds for prevalent coronary heart disease, heart failure and peripheral arteriopathy.

INTRODUCTION:Sleepiness is the main clinical expression of obstructive sleep apnea (OSA) syndrome resulting from upper airway collapse. Recent studies have discussed the fact that the presence of T. gondii cysts in the brain and the resulting biochemical and immunological mechanisms could be linked to neurobehavioral disorders. The aim of the present study was to explore the potential impact of chronic toxoplasmosis on sleepiness and on obstructive sleep apnea (OSA) severity in OSA obese patients. MATERIALS AND METHODS:A case control study on obese patients screened for OSA was performed. According to the sleep disorder and matched based on gender, age and body mass index (BMI), two groups of obese patients were selected from our sample collection database. All patients were tested for toxoplasmosis serological status measuring anti-Toxoplasma IgG and IgM levels. Univariable and multivariable logistic regression models were performed to assess the impact of chronic toxoplasmosis on sleepiness and OSA severity. RESULTS:107 obese patients suffering from OSA were included in the study (median age: 53.3 years Interquartile range (IQR): [41.9-59.9]; median BMI: 39.4 kg/m2 IQR: [35.5-44.1], apnea-hypopnea index = 27.5 events/h [10.7-49.9]). Chronic toxoplasmosis was present in 63.4% and 70.7% of patients with or without sleepiness (p = 0.48), respectively and was not associated either to sleepiness (OR: 0.76, 95% CI: [0.52; 2.33], p = 0.64) or OSA severity (OR = 1.75, 95% CI: [0.51; 5.98] p = 0.37). CONCLUSION:Although chronic Toxoplasma infection in immunocompetent humans has been associated to several behavioral disorders or pathologies in recent literature, we demonstrate here that chronic toxoplasmosis is not associated to sleepiness and to sleep apnea syndrome severity in obese patients suspected of sleep apnea syndrome.

The intermittent dynamics of slow drainage flows in a porous medium is studied experimentally. This kind of two-phase flow is characterized by a rich burst activity and our setup allows us to characterize those bursts directly via images of the flow and pressure measurements. Two different boundary conditions were analyzed: controlled withdrawal rate (CWR) and controlled imposed pressure (CIP). We have characterized geometrical and statistical properties of the bursts from images and pressure measurements. We have shown that in spite of leading to similar final invasion patterns, some dynamical features of the invasion differ considerably between the CWR and CIP boundary conditions. In particular, their pressure signatures are very distinct, which then translates into very distinct features on the power spectrum density of the pressure signals. A fully integrable analytical framework is presented which successfully describes the scaling features of the power spectrum for the CIP case.

At the time of energy transition, it is important to be able to predict the effects of fluid overpressures in different geological scenarios as these can lead to the development of hydrofractures and dilating high-porosity zones. In order to develop an understanding of the complexity of the resulting effective stress fields, fracture and failure patterns, and potential fluid drainage, we study the process with a dynamic hydromechanical numerical model. The model simulates the evolution of fluid pressure buildup, fracturing, and the dynamic interaction between solid and fluid. Three different scenarios are explored: fluid pressure buildup in a sedimentary basin, in a vertical zone, and in a horizontal layer that may be partly offset by a fault. Our results show that the geometry of the area where fluid pressure is successively increased has a first-order control on the developing pattern of porosity changes, on fracturing, and on the absolute fluid pressures that sustained without failure. If the fluid overpressure develops in the whole model, the effective differential and mean stress approach zero and the vertical and horizontal effective principal stresses flip in orientation. The resulting fractures develop under high lithostatic fluid overpressure and are aligned semihorizontally, and consequently, a hydraulic breccia forms. If the area of high fluid pressure buildup is confined in a vertical zone, the effective mean stress decreases while the differential stress remains almost constant and failure takes place in extensional and shear modes at a much lower fluid overpressure. A horizontal fluid pressurized layer that is offset shows a complex system of effective stress evolution with the layer fracturing initially at the location of the offset followed by hydraulic breccia development within the layer. All simulations show a phase transition in the porosity where an initially random porosity reduces its symmetry and forms a static porosity wave with an internal dilating zone and the presence of dynamic porosity channels within this zone. Our results show that patterns of fractures, hence fluid release, that form due to high fluid overpressures can only be successfully predicted if the geometry of the geological system is known, including the fluid overpressure source and the position of seals and faults that offset source layers and seals.

Introduction: The TuberOus SClerosis registry to increase disease Awareness (TOSCA) is an international disease registry designed to provide insights into the clinical characteristics of patients with Tuberous Sclerosis Complex (TSC). The aims of this study were to identify issues that arose during the design, execution, and publication phases of TOSCA, and to reflect on lessons learnt that may guide future registries in rare and complex diseases.Methods: A questionnaire was designed to identify the strengths, weaknesses, and issues that arose at any stage of development and implementation of the TOSCA registry. The questionnaire contained 225 questions distributed in 7 sections (identification of issues during registry planning, during the operation of the registry, during data analysis, during the publication of the results, other issues, assessment of lessons learnt, and additional comments), and was sent by e-mail to 511 people involved in the registry, including 28 members of the Scientific Advisory Board (SAB), 162 principal investigators (PIs), and 321 employees of the sponsor belonging to the medical department or that were clinical research associate (CRA). Questionnaires received within the 2 months from the initial mailing were included in the analysis.Results: A total of 53 (10.4%) questionnaires were received (64.3% for SAB members, 12.3% for PIs and 4.7% for employees of the sponsor), and the overall completeness rate for closed questions was 87.6%. The most common issues identified were the limited duration of the registry (38%) and issues related to handling of missing data (32%). In addition, 25% of the respondents commented that biases might have compromised the validity of the results. More than 80% of the respondents reported that the registry improved the knowledge on the natural history and manifestations of TSC, increased disease awareness and helped to identify relevant information for clinical research in TSC.Conclusions: This analysis shows the importance of registries as a powerful tool to increase disease awareness, to produce real-world evidence, and to generate questions for future research. However, there is a need to implement strategies to ensure patient retention and long-term sustainability of patient registries, to improve data quality, and to reduce biases.

Tuberous Sclerosis Complex (TSC) is a rare autosomal-dominant disorder caused by mutations in the TSC1 or TSC2 genes. Patients with TSC may suffer from a wide range of clinical manifestations; however, the burden of TSC and its impact on healthcare resources needed for its management remain unknown. Besides, the use of resources might vary across countries depending on the country-specific clinical practice. The aim of this paper is to describe the use of TSC-related resources and treatment patterns within the TOSCA registry. A total of 2,214 patients with TSC from 31 countries were enrolled and had a follow-up of up to 5 years. A search was conducted to identify the variables containing both medical and non-medical resource use information within TOSCA. This search was performed both at the level of the core project as well as at the level of the research projects on epilepsy, subependymal giant cell astrocytoma (SEGA), lymphangioleiomyomatosis (LAM), and renal angiomyolipoma (rAML) taking into account the timepoints of the study, age groups, and countries. Data from the quality of life (QoL) research project were analyzed by type of visit and age at enrollment. Treatments varied greatly depending on the clinical manifestation, timepoint in the study, and age groups. GAB Aergics were the most prescribed drugs for epilepsy, and mTOR inhibitors are dramatically replacing surgery in patients with SEGA, despite current recommendations proposing both treatment options. mTOR inhibitors are also becoming common treatments in rAML and LAM patients. Forty-two out of the 143 patients (29.4%) who participated in the QoL research project reported inpatient stays over the last year. Data from non-medical resource use showed the critical impact of TSC on job status and capacity. Disability allowances were more common in children than adults (51.1% vs 38.2%). Psychological counseling, social services and social worker services were needed by

The onset and growth of subependymal giant cell astrocytoma (SEGA) in tuberous sclerosis complex (TSC) typically occurs in childhood. There is minimal information on SEGA evolution in adults with TSC. Of 2,211 patients enrolled in TOSCA, 220 of the 803 adults (27.4%) ever had a SEGA. Of 186 patients with SEGA still ongoing in adulthood, 153 (82.3%) remained asymptomatic, and 33 (17.7%) were reported to ever have developed symptoms related to SEGA growth. SEGA growth since the previous scan was reported in 39 of the 186 adults (21%) with ongoing SEGA. All but one patient with growing SEGA had mutations in TSC2. Fourteen adults (2.4%) were newly diagnosed with SEGA during follow-up, and majority had mutations in TSC2. Our findings suggest that surveillance for new or growing SEGA is warranted also in adulthood, particularly in patients with mutations in TSC2.

Reaction-infiltration instability refers to the morphological instability of a reactive fluid front flowing in a soluble porous medium. This process is important for many naturally occurring phenomena, such as the weathering and diagenesis of rocks, dissolution in salt deposits and melt extraction from the mantle. This paper is focused on experiments on dissolution finger growth in radial geometries in an analog fracture. In the experiments, pure water dissolves a plaster sample forming one of the fracture walls in a Hele-Shaw cell with controlled injection rate and aperture. The flow is directed inwards to the center, and we observe the reaction-infiltration instability developing along the relatively long perimeter of the plaster. Our experimental results show a number of features consistent with the theoretical and numerical predictions on the finger growth dynamics such as screening and selection between the fingers. Statistical properties of the dissolved part evolution with time are also investigated.

Background: This study evaluated the characteristics of subependymal giant cell astrocytoma (SEGA) in patients with tuberous sclerosis complex (TSC) entered into the TuberOus SClerosis registry to increase disease Awareness (TOSCA).Methods: The study was conducted at 170 sites across 31 countries. Data from patients of any age with a documented clinical visit for TSC in the 12 months preceding enrollment or those newly diagnosed with TSC were entered.Results: SEGA were reported in 554 of 2,216 patients (25%). Median age at diagnosis of SEGA was 8 years (range, 18 years. SEGA were symptomatic in 42.1% of patients. Symptoms included increased seizure frequency (15.8%), behavioural disturbance (11.9%), and regression/loss of cognitive skills (9.9%), in addition to those typically associated with increased intracranial pressure. SEGA were significantly more frequent in patients with TSC2 compared to TSC1 variants (33.7 vs. 13.2 %, p < 0.0001). Main treatment modalities included surgery (59.6%) and mammalian target of rapamycin (mTOR) inhibitors (49%).Conclusions: Although SEGA diagnosis and growth typically occurs during childhood, SEGA can occur and grow in both infants and adults.

Obstructive sleep apnoea (OSA) is a major health concern worldwide and adversely affects multiple organs and systems. OSA is associated with obesity in >60% of cases and is independently linked with the development of numerous comorbidities including hypertension, arrhythmia, stroke, coronary heart disease and metabolic dysfunction. The complex interaction between these conditions has a significant impact on patient care and mortality. The pathophysiology of cardiometabolic complications in OSA is still incompletely understood; however, the particular form of intermittent hypoxia (IH) observed in OSA, with repetitive short cycles of desaturation and re-oxygenation, probably plays a pivotal role. There is fast growing evidence that IH mediates some of its detrimental effects through adipose tissue inflammation and dysfunction. This article aims to summarise the effects of IH on adipose tissue in experimental models in a comprehensive way. Data from well-designed controlled trials are also reported with the final goal of proposing new avenues for improving phenotyping and personalised care in OSA.

Despite the high likelihood of infection and substantial yield losses from trunk diseases, many California practitioners wait to adopt field-tested, preventative practices (delayed pruning, double pruning, and application of pruning-wound protectants) until after disease symptoms appear in the vineyard at around 10 years old. We evaluate net benefits from adoption of these practices before symptoms appear in young Cabernet Sauvignon vineyards and after they become apparent in mature vineyards to identify economic hurdles to early adoption. We simulate winegrape production in select counties of California and find widespread benefits from early adoption, increasing vineyard profitable lifespans, in some cases, by close to 50%. However, hurdles may result from uncertainty about the cost and returns from adoption, labor constraints, long time lags in benefits from early adoption, growers’ perceived probabilities of infection, and their discount rate. Development of extension resources communicating benefits and potential hurdles to growers likely reduces uncertainty, increasing early adoption. Improvements in efficacy of preventative practices, perhaps by detecting when pathogen spores are released into the vineyard, will increase early adoption. Lastly, practice cost reductions will increase early adoption too, especially when the time it takes for adoption to payoff and infection uncertainty are influential in adoption decisions.

Mechanical algesia is an important process for the preservation of living organisms, allowing potentially life-saving reflexes or decisions when given body parts are stressed. Yet, its various underlying mechanisms remain to be fully unraveled. Here, we quantitatively discuss how the detection of painful mechanical stimuli by the human central nervous system may, partly, rely on thermal measurements. Indeed, most fractures in a body, including microscopic ones, release some heat, which diffuses in the surrounding tissues. Through this physical process, the thermo-sensitive TRP proteins, that translate abnormal temperatures into action potentials, shall be sensitive to damaging mechanical inputs. The implication of these polymodal receptors in mechanical algesia has been regularly reported, and we here provide a physical explanation for the coupling between thermal and mechanical pain. In particular, in the human skin, we show how the neighboring neurites of a broken collagen fiber can undergo a sudden thermal elevation that ranges from a fraction to tens of degrees. As this theoretical temperature anomaly lies in the sensibility range of the TRPV3 and TRPV1 cation channels, known to trigger action potentials in the neural system, a degree of mechanical pain can hence be generated.

It is commonly assumed that asexual lineages are short-lived evolutionarily, yet many asexual organisms can generate genetic and phenotypic variation, providing an avenue for further evolution. Previous work on the asexual plant pathogen Phytophthora ramorum NA1 revealed considerable genetic variation in the form of Structural Variants (SVs). To better understand how SVs arise and their significance to the California NA1 population, we studied the evolutionary histories of SVs and the forest conditions associated with their emergence. Ancestral state reconstruction suggests that SVs arose by somatic mutations among multiple independent lineages, rather than by recombination. We asked if this unusual phenomenon of parallel evolution between isolated populations is transmitted to extant lineages and found that SVs persist longer in a population if their genetic background had a lower mutation load. Genetic parallelism was also found in geographically distant demes where forest conditions such as host density, solar radiation, and temperature, were similar. Parallel SVs overlap with genes involved in pathogenicity such as RXLRs and have the potential to change the course of an epidemic. By combining genomics and environmental data, we identified an unexpected pattern of repeated evolution in an asexual population and identified environmental factors potentially driving this phenomenon.

Auto-CPAP may cause sleep fragmentation due to variations in pressure and unintentional leaks. The aim of this study was to compare air leak between fixed-CPAP and auto-CPAP after 4 months of CPAP treatment. This study is an ancillary analysis of a randomized, double-blind, parallel, controlled trial over 4 months, comparing fixed- and auto-CPAP in newly diagnosed patients with OSA. The following data were extracted from the CPAP devices: mean and 90th percentile pressure, residual apnea-hypopnea index, mean CPAP use, and amount of leak. Within each arm, patients were also randomly allocated to use of one of the three different brands of devices. Since the leak was reported differently for each device, median leak value was determined for each brand and leaks were classified as “above the median” or “below the median”. Data from 269 patients were analyzed. The univariate analysis showed that tobacco consumption, CPAP level, and oronasal masks were associated with leaks above the median value but not the type of CPAP. The multivariate analysis showed that only CPAP level and oronasal masks were associated with leaks below the median. There were no differences in the types of mask used between fixed- and auto-CPAP. There was no impact of the type of CPAP on leaks or the type of interface used. We used a method based on the median leak value to standardize comparisons across devices which report leaks with different definitions.

Total liquid ventilation (TLV) using perfluorocarbons has shown promising results for the management of neonatal respiratory distress. However, one important safety consideration for TLV is a better understanding of the early events during the transition to TLV, especially regarding the fate of residual air in the non-dependent-lung regions. Our objective was to assess perflubron distribution during transition to TLV using electrical impedance tomography, complemented by fluoroscopy, in a neonatal lamb model of induced surfactant deficiency. Eight lambs were anesthetized and ventilated in supine position. Surfactant deficit was induced by saline lung lavage. After deflation, lungs were filled with 25 ml/kg perflubron over 18 s, and TLV was initiated. Electrical impedance tomography data was recorded from electrodes placed around the chest, during the first 10 and at 120 min of TLV. Lung perfusion was also assessed using hypertonic saline injection during apnea. In addition, fluoroscopic sequences were recorded during initial lung filling with perfluorocarbons, then at 10 and 60 min of TLV. Twelve lambs were used as controls for histological comparisons. Transition to TLV involved a short period of increased total lung volume (p = 0.01) secondary to recruitment of the dependent lung regions. Histological analysis shows that TLV was protective of these same regions when compared to gas-ventilated lambs (p = 0.03). The non-dependent lung regions filled with perflubron over at least 10 min, without showing signs of overdistention. Tidal volume distribution was more homogenous in TLV than during the preceding gas ventilation. Perflubron filling was associated with a non-significant increase in the anterior distribution of the blood perfusion signal, from 46 ± 17% to 53 ± 6% (p = 0.4). However, combined to the effects on ventilation, TLV had an instantaneous effect on ventilation-perfusion relationship (p = 0.03), suggesting better coupling. Conclusion: transition to TLV requires at least 10 min, and involves air evacuation or dissolution in perflubron, dependent lung recruitment and rapid ventilation-perfusion coupling modifications. During that time interval, the total lung volume transiently increases. Considering the potential deleterious effect of high lung volumes, one must manage this transition phase with care and, we suggest using a real-time monitoring system such as electrical impedance tomography.

The Ascomycete fungus Phaeoacremonium minimum is one of the primary causal agents of Esca, a widespread and damaging grapevine trunk disease. Variation in virulence among Pm. minimum isolates has been reported, but the underlying genetic basis of the phenotypic variability remains unknown. The goal of this study was to characterize intraspecific genetic diversity and explore its potential impact on virulence functions associated with secondary metabolism, cellular transport, and cell wall decomposition. We generated a chromosome-scale genome assembly, using single molecule real-time sequencing, and resequenced the genomes and transcriptomes of multiple isolates to identify sequence and structural polymorphisms. Numerous insertion and deletion events were found for a total of about 1 Mbp in each isolate. Structural variation in this extremely gene dense genome frequently caused presence/absence polymorphisms of multiple adjacent genes, mostly belonging to biosynthetic clusters associated with secondary metabolism. Because of the observed intraspecific diversity in gene content due to structural variation we concluded that a transcriptome reference developed from a single isolate is insufficient to represent the virulence factor repertoire of the species. We therefore compiled a pan-transcriptome reference of Pm. minimum comprising a non-redundant set of 15,245 protein-coding sequences. Using naturally infected field samples expressing Esca symptoms, we demonstrated that mapping of meta-transcriptomics data on a multi-species reference that included the Pm. minimum pan-transcriptome allows the profiling of an expanded set of virulence factors, including variable genes associated with secondary metabolism and cellular transport.

ObjectiveMost patients with resistant hypertension (RH) have obstructive sleep apnea (OSA). We aimed to determine the impact of OSA and continuous positive airway pressure (CPAP) treatment on the leptin profile and blood pressure (BP) in patients with RH.MethodsAfter an initial case-control study (RH with and without OSA), we performed a randomized, single blind study in OSA + RH patients receiving either sham CPAP (3 months) followed by active CPAP (6 months) or 6 months of active CPAP. The primary outcome was the comparison of leptin levels between groups of RH patients with or without OSA. Secondary outcomes were the comparison of metabolic parameters, biomarkers of sympathetic activity, and BP indices between the two groups of RH patients with or without OSA. The same outcomes were then evaluated and compared before and after sham and effective CPAP intervention.ResultsSixty-two patients (60 ± 10 years; 77% men) with RH (24-h daytime systolic BP (SBP)/diastolic BP: 145 ± 13/85 ± 10 mmHg, 3.7 antihypertensive drugs) were included. The 37 RH patients exhibiting OSA (60%) were predominantly men (87 vs 64% for non-OSA patients), with a greater prevalence of metabolic syndrome and higher creatininemia. Their leptin concentrations were significantly lower than in non-OSA patients [9 (6; 15) vs 17 (6; 29) ng/mL] but increased after 6 months of CPAP. Three months of effective CPAP significantly decreased night-time SBP by 6.4 mmHg and heart rate (HR) by 6.0 bpm, compared to sham CPAP.ConclusionThe association between OSA and RH corresponds to a specific, predominately male phenotype with a higher burden of metabolic syndrome and higher creatininemia but there was no significant difference between OSA and non-OSA patients regarding BP indices, and the number of antihypertensive drugs used. Active CPAP could be efficient at decreasing night-time BP and HR, but there was no difference between CPAP and sham CPAP groups for all metabolic and SNS markers (NCT00746902 RHOOSAS).

The injection of a reactive fluid into an open fracture may modify the fracture surface locally and create a ramified structure around the injection point. This structure will have a significant impact on the dispersion of the injected fluid due to increased permeability, which will introduce large velocity fluctuations into the fluid. Here, we have injected a fluorescent tracer fluid into a transparent artificial fracture with such a ramified structure. The transparency of the model makes it possible to follow the detailed dispersion of the tracer concentration. The experiments have been compared to two dimensional (2D) computer simulations which include both convective motion and molecular diffusion. A comparison was also performed between the dispersion from an initially ramified dissolution structure and the dispersion from an initially circular region. A significant difference was seen both at small and large length scales. At large length scales, the persistence of the anisotropy of the concentration distribution far from the ramified structure is discussed with reference to some theoretical considerations and comparison with simulations.

A systematic review of English and French articles using Pubmed/Medline and Embase included studies assessing objective physical activity levels of obstructive sleep apnea (OSA) patients and exploring the effects of exercise training on OSA severity, body mass index (BMI), sleepiness, and cardiorespiratory fitness [peak oxygen consumption (VO2peak)]. Two independent reviewers analyzed the studies, extracted the data, and assessed the quality of evidence. For objective physical activity levels, eight studies were included. The mean number of steps per day across studies was 5,388 (95% CI: 3,831–6,945; p