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Ischemic stroke accounts for 80% of overall stroke, and is one of the leading causes of death, disability and dementia in worldwide. Management of patients with acute ischemic stroke dramatically improved over time with the implementation of intensive care stroke units, the development of acute recanalization strategies, the optimization of the management of post-stroke complications, and the prevention of early stroke recurrence. The objective of this article is to provide a general overview of the current management of patients with acute ischemic stroke aiming at improving post-stroke outcome.

OBJECTIVE: Research has identified several potential mechanisms of behavior change (MOBCs) in cognitive–behavioral therapy for alcohol use disorder, including alcohol abstinence self-efficacy (AASE), negative affect (NA), and positive affect (PA). However, little is known about when MOBCs affect clinical outcomes during alcohol use disorder treatment. Such information could advance MOBC research by identifying relationships between specific treatment content and variations in MOBCs. This study examined three MOBCs simultaneously to determine their timing and relative influence on percent days abstinent (PDA) and drinks per day (DPD). METHOD: Data were derived from a parent study assessing pretreatment change in drinking. Participants (n = 205) received 12 sessions of cognitive–behavioral therapy for alcohol use disorder. AASE, NA, and PA were measured at each treatment session, and time-varying effect models (TVEM) were used to examine their association with PDA and DPD. RESULTS: All three MOBCs were associated with PDA and DPD but varied with regard to time course, strength, and direction. For PDA, AASE was positively associated throughout treatment, NA was negatively associated from Sessions 1 to 10, and PA was positively associated from Sessions 1 to 3 and 11 to 12. For DPD, AASE was positively associated from Session 5 to the end of treatment, NA was positively associated throughout treatment although the strength of the association varied and was strongest at the beginning of treatment, and PA was positively associated from Sessions 5 to 12. CONCLUSIONS: Results show that MOBCs exert their effects at different times during treatment. In addition to replicating these results, future research should attempt to manipulate MOBCs directly and examine their influence on alcohol outcomes.

Anterior cruciate ligament ruptures are commonly associated with ramp lesions of the medial meniscus. These posterior longitudinal peripheral tears induce medial meniscus instability and increase the anteroposterior and rotational knee laxity. We divided ramp lesions in 3 types: meniscocapsular ligament tears, meniscotibial ligament tears, and a combination of both lesions. The conventional surgical technique for treating meniscal ramp lesions is to use a suture hook device through a posteromedial approach, which is a complex process requiring a learning curve and extensive surgical time. An anterior approach often is criticized as underestimating the true incidence of ramp lesion and to offer insufficient operating space. The purpose of this technical note is to describe our arthroscopic repair technique in cases of isolated meniscotibial ligament tears. The suture is performed by an under-meniscus anterior approach with a percutaneous medial collateral ligament release to create an additional opening of the medial compartment. This simple procedure allows for accurate diagnoses of the meniscotibial lesions and enables repair of the lesions with an all-inside suture device without the usual drawbacks of a posteromedial approach., Technique Video Video 1 Description of our arthroscopic diagnosis and repair technique in cases of isolated meniscotibial ligament tears. The video shows a procedure in a right knee. The suture is performed with an under-meniscus anteromedial approach with a percutaneous medial collateral ligament release to increase medial compartment opening. This simple procedure provides an accurate diagnosis of the meniscotibial lesions and allows for repair with an all-inside suture device without the drawbacks of a posteromedial approach.

Extracellular adenosine in tumors can suppress immune responses and promote tumor growth. Adenosine deaminase 2 (ADA2) converts adenosine into inosine. The role of ADA2 in cancer and whether it can target adenosine for cancer therapy has not been investigated. Here we show that increased ADA2 expression is associated with increased patient survival and enrichment of adaptive immune response pathways in several solid tumor types. Several ADA2 variants were created to improve catalytic efficiency, and PEGylation was used to prolong systemic exposure. In mice, PEGylated ADA2 (PEGADA2) inhibited tumor growth by targeting adenosine in an enzyme activity–dependent manner and thereby modulating immune responses. These findings introduce endogenous ADA2 expression as a prognostic factor and PEGADA2 as a novel immunotherapy for cancer. Significance: This study identifies ADA2 as a prognostic factor associated with prolonged cancer patient survival and introduces the potential of enzymatic removal of adenosine with engineered ADA2 for cancer immunotherapy.

Die Transplantation mesenchymaler pluripotenter Zellen zur Regeneration von Knorpelschaden wurde aufgrund gesetzlicher Reglementierungen bisher hauptsachlich in ausereuropaischen Landern durchgefuhrt. Adipogene Stammzellen konnen in der stromal-vaskularen Fraktion (SVF) gefunden werden und haben vergleichbare immunmodulatorische und antiinflammatorische Eigenschaften zu Stammzellen, welche im Knochenmark vorkommen. Der unkomplizierte Zugang und die geringe Entnahmemorbiditat machen die Therapie mit SVF zur einer besonders interessanten Therapieoption fur die Behandlung der Arthrose. Die Studie untersucht, ob die Infiltration des Hoffa-Fettkorpers mit SVF bei Patienten mit Gonarthrose eine effektive und sichere Therapieoption darstellt. Des Weiteren werden die Anzahl und Vitalitat der injizierten Zellen sowie die klinische Wirksamkeit evaluiert. Es handelt sich um eine prospektive Fallserie, in der13 Patienten im Alter von 55–88 Jahren mit einem Kellgren-Lawrence-Score bis 3 eine Infiltration mit SVF in den Hoffa’schen Fettkorper erhalten. Die Anzahl und Vitalitat der Zellen werden mit einem Zellzahler gemessen. Das klinische Ergebnis wird mit der visuellen Analogskala (VAS) fur Schmerzempfindung und dem Knee Injury and Osteoarthritis Outcome Score (KOOS) mit einer geplanten Follow-up-Periode von 2 Jahren uberpruft. Auswertbare, vollstandige Verlaufe uber 6 Monate liegen bei 13 Patienten vor. Es wurden 3,21 E + 07 ± 2,45 E + 07 Zellen injiziert. Der durchschnittliche Anteil an vitalen Zellen betrug 78 ± 9 %. Nach 6 Monaten konnte eine signifikante Verbesserung der VAS und der jeweiligen Subskalen des KOOS im Vergleich zum Basiswert beobachtet werden. Es traten keine Komplikationen oder Nebenwirkungen auf. Diese ersten Ergebnisse zeigen, dass die Behandlung mit SVF eine sichere Therapieoption darstellt, welche das Potenzial hat, die durch Kniegelenksarthrose entstehenden/entstandenen Schmerzen zu lindern und die Funktion signifikant zur verbessern. Die Zellzahl und Vitalitat der Zellen liegen im erwarteten und bisher publizierten Bereich.

Stage 4S neuroblastoma (4SNB) is associated with spontaneous tumor regression and an excellent prognosis. However, a small group of the patients have a poor prognosis. One hundred eighty-five stage 4SNB cases filed at the Children's Oncology Group Neuroblastoma Pathology Reference Laboratory were studied. MYCN oncogene status [non-amplified (NA) vs. Amplified (A)] determined by fluorescence in situ hybridization, MYC-family (MYCN/MYC) protein expression [no-overexpression(-)/(+/-) vs. overexpression(+)] by immunohistochemistry and histopathology by International Neuroblastoma Pathology Classification [Favorable Histology (FH) vs. Unfavorable Histology (UH)] with particular attention to nucleolar hypertrophy [NH(-) vs. (+)] were assessed with patient survival. One hundred forty-seven (79.5%) tumors were MYCN-NA, FH, MYC-family protein(-)/(+/-), and NH(-) with a good prognosis [88.5±3.1% 3-y event-free survival (EFS); 94.1±2.3% 3-y overall survival (OS)]. Among MYCN-NA tumors, 11 demonstrated MYCN protein(+) with a moderate and uniform (M/U) staining pattern: they were FH(10/11), NH(-), 1 showed MYC protein(+) simultaneously, and all patients are alive. Also found were 5 MYC protein(+) and MYCN(-)/(+/-) tumors; they were FH without NH (4/5), and all patients are alive. Among MYCN-A tumors, 18 had MYCN protein(+) with a strong and heterogeneous (S/H) staining pattern, 9 had UH (44.4±23.4% EFS/OS) and 9 had FH (68.6±19.2% EFS/OS), and 15 showed NH(+). Two tumors had MYCN protein(-)/(+/-) despite MYCN-A; both were FH and NH(-), and 1 patient died. S/H staining pattern of MYCN protein overexpression by immunohistochemistry was associated with MYCN amplification, NH(+) and a poor prognosis. In contrast, the M/U staining pattern was associated with MYCN nonamplification and NH(-), and had no adverse prognostic effects for the stage 4SNB patients.

Aim: To classify the association between the maternal lipidome and DNA methylation in cord blood leukocytes. Materials & methods: Untargeted lipidomics was performed on first trimester maternal plasma (M1) and delivery maternal plasma (M3) in 100 mothers from the Michigan Mother-Infant Pairs cohort. Cord blood leukocyte DNA methylation was profiled using the Infinium EPIC bead array and empirical Bayes modeling identified differential DNA methylation related to maternal lipid groups. Results: M3-saturated lysophosphatidylcholine was associated with 45 differentially methylated loci and M3-saturated lysophosphatidylethanolamine was associated with 18 differentially methylated loci. Biological pathways enriched among differentially methylated loci by M3 saturated lysophosphatidylcholines were related to cell proliferation and growth. Conclusion: The maternal lipidome may be influential in establishing the infant epigenome.

Endoscopic necrosectomy has emerged as the preferred treatment modality for walled-off pancreatic necrosis. This study was designed to evaluate the safety and efficacy of direct endoscopic necrosectomy with and without hydrogen peroxide (H2O2) lavage.Retrospective chart reviews were performed for all patients undergoing endoscopic transmural management of walled-off pancreatic necrosis at 9 major medical centers from November 2011 to August 2018. Clinical success was defined as the resolution of the collection by imaging within 6 months, without requiring non-endoscopic procedures or surgery.Of 293 patients, 204 met the inclusion criteria. Technical and clinical success rates were 100% (204/204) and 81% (166/189), respectively. For patients, 122 (59.8%) patients had at least one H2O2 necrosectomy (H2O2 group) and 82 (40.2%) patients had standard endoscopic necrosectomy. Clinical success was higher in the H2O2 group: 106/113 (93.8%) vs 60/76 (78.9%), P = 0.002. On a multivariate analysis, the use of H2O2 was associated with higher clinical success rate (odds ratio 3.30, P = 0.033) and earlier resolution (odds ratio 2.27, P0.001). During a mean follow-up of 274 days, 27 complications occurred. Comparing procedures performed with and without H2O2 (n = 250 vs 183), there was no difference in post-procedure bleeding (7 vs 9, P = 0.25), perforation (2 vs 3, P = 0.66), infection (1 vs 2, P = 0.58), or overall complication rate (n = 13 [5.2%] vs 14 [7.7%], P = 0.30).H2O2-assisted endoscopic necrosectomy had a higher clinical success rate and a shorter time to resolution with equivalent complication rates relative to standard necrosectomy.See the visual abstract at http://links.lww.com/AJG/B714.(Equation is included in full-text article.).

Major alterations in metabolism occur during pregnancy enabling the mother to provide adequate nutrients to support infant development, affecting birth weight (BW) and potentially long-term risk of obesity and cardiometabolic disease. We classified dynamic changes in the maternal lipidome during pregnancy and identified lipids associated with Fenton BW z-score and the umbilical cord blood (CB) lipidome. Lipidomics was performed on first trimester maternal plasma (M1), delivery maternal plasma (M3), and CB plasma in 106 mother-infant dyads. Shifts in the maternal and CB lipidome were consistent with the selective transport of long-chain polyunsaturated fatty acids (PUFA) as well as lysophosphatidylcholine (LysoPC) and lysophosphatidylethanolamine (LysoPE) species into CB. Partial correlation networks demonstrated fluctuations in correlations between lipid groups at M1, M3, and CB, signifying differences in lipid metabolism. Using linear models, LysoPC and LysoPE groups in CB were positively associated with BW. M1 PUFA containing triglycerides (TG) and phospholipids were correlated with CB LysoPC and LysoPE species and total CB polyunsaturated TGs. These results indicate that early gestational maternal lipid levels influence the CB lipidome and its relationship with BW, suggesting an opportunity to modulate maternal diet and improve long-term offspring cardiometabolic health.

Background and Purpose: Because of several methodological limitations, previous studies focusing on the prevalence of large vessel occlusion in ischemic stroke (IS) patients provided conflicting results. We evaluated the incidence of IS with a visible arterial occlusion using a comprehensive population-based registry. Methods: Patients with acute IS were prospectively identified among residents of Dijon, France, using a population-based registry (2013–2017). All arterial imaging exams were reviewed to assess arterial occlusion. Annual incidence rates of IS (first-ever and recurrent events) and IS with a visible occlusion were calculated. Results: One thousand sixty cases of IS were recorded (mean age: 76.0±15.8 years, 53.9% women). Information about arterial imaging was available in 971 (91.6%) of them, and only preexisting dementia was independently associated with having missing information (odds ratio=0.34 [95% CI, 0.18–0.65], P =0.001). Among these patients, 284 (29.2%) had a visible arterial occlusion. Occlusion site was the anterior circulation in 226 patients (23.3% of overall patients with available data) and the posterior circulation in 58 patients (6.0%). A proximal occlusion of the anterior circulation was observed in 167 patients (17.2%). The crude annual incidence rate of total IS per 100 000 was 138 (95% CI, 129–146). Corresponding standardized rates were 66 (95% CI, 50–82) to the World Health Organization and 141 (95% CI, 118–164) to the 2013 European populations. The crude annual incidence rate of IS with a visible arterial occlusion per 100 000 was 37 (95% CI, 33–41) and that of IS with a proximal occlusion of the anterior circulation was 22 (95% CI, 18–25). Corresponding standardized rates were 18 (95% CI, 10–26) and 10 (95% CI, 8–13) to the World Health Organization population, and 38 (95% CI, 26–50) and 23 (95% CI, 19–26) to the 2013 European population, respectively. Conclusions: These results will be helpful to plan the need for thrombectomy-capable stroke center resources.

Psychosocial stress in early childhood is associated with adult obesity and cardiometabolic disease. The association of psychosocial stress with the metabolome in childhood is unknown.Low-income children (n = 28, mean age 1.8 years), recruited from the community, participated. Psychosocial stress was measured by diurnal salivary cortisol (cortisol intercept and slope) and by mother-reported chaos in the home using the Confusion, Hubbub, and Order Scale (CHAOS). At mean age 6.1 years, anthropometry was collected and fasting metabolites measured using an untargeted metabolomics and shotgun lipidomics platform.Cortisol slope was inversely associated with fatty acid (FA) 20:3, FA 20:4 and polyunsaturated fatty acids (PUFA) metabolites. A higher CHAOS score was associated with lower very long-chain PUFA metabolites and a trend towards lower long-chain PUFA containing triglycerides.Psychosocial stress in early childhood, measured with both biological markers and parent report, was associated with lower PUFAs later in childhood. Future work should examine potential mechanisms of association, including dietary intake or direct effects on polyunsaturated fatty acid levels or metabolism.In this longitudinal study, the key message is that diurnal cortisol patterns and greater parent-reported psychosocial stress exposure in early childhood are associated with lower plasma polyunsaturated fatty acid containing lipids 5 years later, potentially indicating altered dietary intake or metabolism associated with psychosocial stress. Untargeted metabolomics and lipidomics can be used to assess changes in metabolism response to psychosocial stress. Stress exposure in early childhood may be associated with the future metabolome. Future work should examine potential pathways of association, including dietary intake and direct effects on metabolism.

International audience; Aims: The aim was to assess the effect of a telemonitoring programme vs. standard care (SC) in preventing all‐cause deaths or unplanned hospitalisations in heart failure (HF) at 18 months.Methods and results: OSICAT was a randomised, multicentre, open‐label French study in 937 patients hospitalised for acute HF ≤12 months before inclusion. Patients were randomised to telemonitoring (daily body weight measurement, daily recording of HF symptoms, and personalised education) (n = 482) or to SC (n = 455). Mean ± standard deviation number of events for the primary outcome was 1.30 ± 1.85 for telemonitoring and 1.46 ± 1.98 for SC [rate ratio 0.97, 95% confidence interval (CI) 0.77–1.23; P = 0.80]. In New York Heart Association (NYHA) class III or IV HF, median time to all‐cause death or first unplanned hospitalisation was 82 days in the telemonitoring group and 67 days in the SC group (P = 0.03). After adjustment for known predictive factors, telemonitoring was associated with a 21% relative risk reduction in first unplanned hospitalisation for HF [hazard ratio (HR) 0.79, 95% CI 0.62–0.99; P = 0.044); the relative risk reduction was 29% in patients with NYHA class III or IV HF (HR 0.71, 95% CI 0.53–0.95; P = 0.02), 38% in socially isolated patients (HR 0.62, 95% CI 0.39–0.98; P = 0.043), and 37% in patients who were ≥70% adherent to body weight measurement (HR 0.63, 95% CI 0.45–0.88; P = 0.006).Conclusion: Telemonitoring did not result in a significantly lower rate of all‐cause deaths or unplanned hospitalisations in HF patients. The pre‐specified subgroup results suggest the telemonitoring approach improves clinical outcomes in selected populations but need further confirmation.

Context A person’s intrinsic metabolism, reflected in the metabolome, may describe the relationship between nutrient intake and metabolic health. Objectives Untargeted metabolomics was used to identify metabolites associated with metabolic health. Path analysis classified how habitual dietary intake influences body mass index z-score (BMIz) and insulin resistance (IR) through changes in the metabolome. Design Data on anthropometry, fasting metabolites, C-peptide, and dietary intake were collected from 108 girls and 98 boys aged 8 to 14 years. Sex-stratified linear regression identified metabolites associated with BMIz and homeostatic model assessment of IR using C-peptide (HOMA-CP), accounting for puberty, age, and muscle and fat area. Path analysis identified clusters of metabolites that underlie the relationship between energy-adjusted macronutrient intake with BMIz and HOMA-CP. Results Metabolites associated with BMIz include positive associations with diglycerides among girls and positive associations with branched chain and aromatic amino acids in boys. Intermediates in fatty acid metabolism, including medium-chain acylcarnitines (AC), were inversely associated with HOMA-CP. Carbohydrate intake is positively associated with HOMA-CP through decreases in levels of AC, products of β-oxidation. Approaching significance, fat intake is positively associated with HOMA-CP through increases in levels of dicarboxylic fatty acids, products of omega-oxidation. Conclusions This cross-sectional analysis suggests that IR in children is associated with reduced fatty acid oxidation capacity. When consuming more grams of fat, there is evidence for increased extramitochondrial fatty acid metabolism, while higher carbohydrate intake appears to lead to decreases in intermediates of β-oxidation. Thus, biomarkers of IR and mitochondrial oxidative capacity may depend on macronutrient intake.

BRCA1 and BRCA2 gene pathogenic variants account for most hereditary breast cancer and are increasingly used to determine eligibility for PARP inhibitor (PARPi) therapy of BRCA-related cancer. Because issues of BRCA testing in clinical practice now overlap with both preventive and therapeutic management, updated and comprehensive practice guidelines for BRCA genotyping are needed. The integrative recommendations for BRCA testing presented here aim to (1) identify individuals who may benefit from genetic counselling and risk-reducing strategies; (2) update germline and tumour-testing indications for PARPi-approved therapies; (3) provide testing recommendations for personalised management of early and metastatic breast cancer; and (4) address the issues of rapid process and tumour analysis. An international group of experts, including geneticists, medical and surgical oncologists, pathologists, ethicists and patient representatives, was commissioned by the French Society of Predictive and Personalised Medicine (SFMPP). The group followed a methodology based on specific formal guidelines development, including (1) evaluating the likelihood of BRCAm from a combined systematic review of the literature, risk assessment models and expert quotations, and (2) therapeutic values of BRCAm status for PARPi therapy in BRCA-related cancer and for management of early and advanced breast cancer. These international guidelines may help clinicians comprehensively update and standardise BRCA testing practices. ispartof: EUROPEAN JOURNAL OF CANCER vol:146 pages:30-47 ispartof: location:England status: published

As the incidence of obesity and type 2 diabetes (T2D) is occurring at a younger age, studying adolescent nutrient metabolism can provide insights on the development of T2D. Metabolic challenges, including an oral glucose tolerance test (OGTT) can assess the effects of perturbations in nutrient metabolism. Here, we present alterations in the global metabolome in response to an OGTT, classifying the influence of obesity and insulin resistance (IR) in adolescents that arrived at the clinic fasted and in a random-fed state. Participants were recruited as lean (n = 55, aged 8–17 years, BMI percentile 5–85%) and overweight and obese (OVOB, n = 228, aged 8–17 years, BMI percentile ≥ 85%). Untargeted metabolomics profiled 246 annotated metabolites in plasma at t0 and t60 min during the OGTT. Our results suggest that obesity and IR influence the switch from fatty acid (FA) to glucose oxidation in response to the OGTT. Obesity was associated with a blunted decline of acylcarnitines and fatty acid oxidation intermediates. In females, metabolites from the Fasted and Random-Fed OGTT were associated with HOMA-IR, including diacylglycerols, leucine/isoleucine, acylcarnitines, and phosphocholines. Our results indicate that at an early age, obesity and IR may influence the metabolome dynamics in response to a glucose challenge.

Severe diseases such as the ongoing COVID-19 pandemic, as well as the previous SARS and MERS outbreaks, are the result of coronavirus infections and have demonstrated the urgent need for antiviral drugs to combat these deadly viruses. Due to its essential role in viral replication and function, 3CLpro> has been identified as a promising target for the development of antiviral drugs. Previously reported SARS-CoV 3CLpro non-covalent inhibitors were used as a starting point for the development of covalent inhibitors of SARS-CoV-2 3CLpro. We report herein our efforts in design and synthesis which led to submicromolar covalent inhibitors when the enzymatic activity of the viral protease was used as a screening platform.

We have previously described several different chemical series of bicyclic prolyl oligopeptidase (POP) inhibitors as probes for neurodegenerative diseases that demonstrated nanomolar activity in vitro and submicromolar activity in cellulo. The more recent implication of POP in cancer, together with homologous fibroblast activation protein α (FAP), implicated in tumor growth, led us to consider developing POP/FAP dual inhibitors as a promising strategy for the development of cancer therapeutics. We report herein docking-guided design of a new bicyclic scaffold and synthesis of both covalent and non-covalent bicyclic inhibitors. Biological evaluation of first-of-their-kind [4.3.0] bicyclic compounds confirmed that reactive groups, or covalent warheads, are required for inhibitor activity. This work ultimately led to a dual inhibitor equipotent to the only anti-POP/FAP drug that ever-reached clinical trials.

OBJECTIVES: To reveal alterations in metabolic pathways in response to an oral glucose tolerance test (OGTT) underlying the development of insulin resistance during the pubertal transition. METHODS: Participants were recruited as healthy controls (HC, n = 55, aged 8.3–18.0 years, BMI percentile 5–85%) and overweight and obese individuals (OVOB, n = 228, aged 8.1–17.9 years, BMI percentile ≥ 85%). Participants were grouped based on their peak insulin response to the OGTT, stratified by peak at t30 (Group 1, n = 163), t60 (Group 2, n = 75), and t120 minutes (Group 3, n = 44). Untargeted metabolomics profiled 267 annotated metabolites and > 3000 unannotated features in plasma at t0 and t60 minutes. Regression classified changes in metabolites across the time-course, assessing the influence of BMI and insulin response (FDR

Multiple sclerosis (MS) is an autoimmune condition of the central nervous system with a well-characterized genetic background. Prior analyses of MS genetics have identified broad enrichments across peripheral immune cells, yet the driver immune subsets are unclear. We utilized chromatin accessibility data across hematopoietic cells to identify cell type-specific enrichments of MS genetic signals. We found that CD4 T and B cells were independently enriched for MS genetics and further refined the driver subsets to Th17 and memory B cells, respectively. We replicated our findings in data from untreated and treated MS patients and found that immunomodulatory treatments suppress chromatin accessibility at driver cell types. Integration of statistical fine-mapping and chromatin interactions nominated numerous putative causal genes, illustrating complex interplay between shared and cell-specific genes. Our study highlights how careful integration of genetics and epigenetics can provide fine-scale insights into causal cell types and nominate new genes and pathways for disease.

Funding Acknowledgements Type of funding sources: None. Background Heart failure (HF) is associated with a high mortality rate and recurrent hospitalizations. Purpose To present the first data of the patients using Satelia® Cardio solution Method Satelia® Cardio is a HF patient management solution with a remote monitoring system and a therapeutic guidance by a dedicated-nurse phone platform, supported by the ETAPES Program. The system is accessible from any device and requiring no installation. After the inclusion, the patient is contacted by the nurse, he then receives an SMS alerts following cardiologist prescription (on regular basis), with a link leading to a web page on which he will answer 7 questions and enter his current body weight. Satelia® Cardio algorithm is based on these data inputs, their variability, and the weight. In case of worsening of symptoms, the cardiologist will be notified. Since Covid-19 lockdown, more than 1400 patients have been monitored with the solution. Results 165 centers (306 cardiologists) are using Satelia® Cardio with 3540 HF patients monitored in the last 29 months. The patients with a mean age of 72 years (19-100) are predominantly males (67%), and mostly NYHA II/III (69%/31%) with a mean LVEF of 40%. The adherence to the system is very good (91%) with 78% of patients still monitored (n = 2787). The main reasons for stopping are related to the occurrence of death (205/753) or patient/HCP decision (392/753), or other reasons (156/753). Over the period of analysis, the HF patients answered to 163 700 questionnaires, generating 8210 alerts transmitted to the referent cardiologists. Conclusion Patient management solution with a remote monitoring system is key to improving the follow-up of HF patients. The solution Satelia® Cardio is an easy way to use a web application to monitor HF patients, especially on the current period of Covid-19 with a low rate of premature discontinuation. A further step will be to initiate studies to assess the potential benefits for both patients and HCPs of such remote monitoring solution in HF.

Background: Myocardial injury (MI) is common with transcatheter aortic valve implantation (TAVI) and may predict poor outcome. We aim: 1) to evaluate the difference in change of high-sensitivity-Tr...

ENHANZE® drug delivery technology is based on the proprietary recombinant human hyaluronidase PH20 enzyme (rHuPH20; Halozyme Therapeutics, Inc.) that facilitates the subcutaneous (SC) delivery of co-administered therapeutics. rHuPH20 works by degrading the glycosaminoglycan hyaluronan (HA), which plays a role in resistance to bulk fluid flow in the SC space, limiting large volume SC drug delivery, dispersion, and absorption. Co-administration of rHuPH20 with partner therapies can overcome administration time and volume barriers associated with existing SC therapeutic formulations, and has been shown to reduce the burden on patients and healthcare providers compared with intravenous formulations. rHuPH20 (as HYLENEX® recombinant) is currently FDA-approved for subcutaneous fluid administration for achieving hydration, to increase the dispersion and absorption of other injected drugs, and in subcutaneous urography for improving resorption of radiopaque agents. rHuPH20 is also co-formulated with two anticancer therapies, trastuzumab (i.e. Herceptin® SC) and rituximab (i.e. RITUXAN HYCELA®/RITUXAN® SC/MabThera® SC) and dosed sequentially with human immunoglobin to treat primary immunodeficiency (i.e. HyQvia®/HYQVIA®). This article reviews pharmaceutical properties of rHuPH20, its current applications with approved therapeutics, and the potential for future developments.

Objective: We assessed the association between pre-stroke cognitive status and 90-day case-fatality. Methods: Patients with ischemic stroke (IS) or spontaneous intracerebral hemorrhage (ICH) were prospectively identified among residents of Dijon, France, between 2013 and 2015, using a population-based registry. Association between pre-stroke cognitive status and case-fatality at 90 days was evaluated using Cox regression. Results: Seven hundred sixty-two patients were identified, and information about pre-stroke cognitive status was obtained for 716 (92.6%) of them, including 603 IS (84.2%) and 113 ICH (15.8%). Before stroke, 99 (13.8%) patients had mild cognitive impairment (MCI) and 98 (13.7%) had dementia. Patients with cognitive impairment were older, had a higher prevalence of several risk factors, more severe stroke, more frequent ICH, and less admission to stroke unit. Case-fatality rate at 90 days was 11.7% in patients without cognitive impairment, 32.3% in MCI patients, and 55.1% in patients with dementia. In multivariable analyses, pre-existing MCI (hazard ratio [HR] 2.22, 95% CI 1.21–4.05, p = 0.009) and dementia (HR 4.35, 95% CI 2.49–7.61, p < 0.001) were both associated with 90-day case-fatality. Conclusion: Pre-stroke MCI and dementia were both associated with increased mortality. These associations were not fully explained by baseline characteristics, pre-stroke dependency, stroke severity or patient management, and underlying reasons need to be investigated.

Aim Pneumonia is the leading infectious cause of death among children under five globally. Many pneumonia deaths result from inappropriate treatment due to misdiagnosis of signs and symptoms. This study aims to identify whether health extension workers (HEWs) in Ethiopia, using an automated multimodal device (Masimo Rad‐G), adhere to required guidelines while assessing and classifying under five children with cough or difficulty breathing and to understand device acceptability. Methods A cross‐sectional study was conducted in three districts of Southern Nations, Nationalities, and Peoples' Region, Ethiopia. Between September and December 2018, 133 HEWs were directly observed using Rad‐G while conducting 599 sick child consultations. Usability was measured as adherence to the World Health Organization requirements to assess fast breathing and device manufacturer instructions for use. Acceptability was assessed using semi‐structured interviews with HEWs, first‐level health facility workers and caregivers. Results Adherence using the Rad‐G routinely for 2 months was 85.3% (95% CI 80.2, 89.3). Health workers and caregivers stated a preference for Rad‐G. Users highlighted a number of device design issues. Conclusion While demonstrating high levels of acceptability and usability, the device modifications to consider include better probe fit, improved user interface with exclusive age categories and simplified classification outcomes.

The human microbiota is believed to influence health. Microbiome dysbiosis may be linked to neurological conditions like Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD). We report the ability of a probiotic bacterial strain in reversing neurodegeneration phenotypes. We show that Lacticaseibacillus rhamnosus HA-114 is neuroprotective in C. elegans models of ALS and HD. Our results show that neuroprotection from L. rhamnosus HA-114 is unique from other L. rhamnosus strains, and resides in its fatty acid content. Neuroprotection by L. rhamnosus HA-114 requires acdh-1/ACADSB, kat-1/ACAT1 and elo-6/ELOVL3/6, which are key fatty acid metabolism and mitochondrial β-oxidation genes. Moreover, L. rhamnosus HA-114 delayed disease onset and suppressed motor neuron degeneration in an aggressive mouse model of ALS. Our data suggest that disrupted lipid metabolism contributes to neurodegeneration and that dietary intervention with L. rhamnosus HA-114 restores lipid homeostasis and energy balance through mitochondrial β-oxidation. L. rhamnosus HA-114 is suitable for human consumption opening the possibility of modifying disease progression by dietary intervention.

Background The induction of general anesthesia is preceded by face mask preoxygenation and oxygen delivery during intubation (peroxygenation). High-flow nasal oxygen (HFNO) may be an effective alternative. Methods In this multicenter randomized controlled study, adults undergoing general anesthesia with oral intubation were included, provided written consent, and were assigned to the control group (face mask) or experimental group (HFNO). The primary objective was to validate HFNO as a safe and efficient technique for preoxygenation and peroxygenation. The main outcome was the risk of oxygen desaturation (SpO 2 ≤92%). Analysis was performed with the intention-to-treat principle. Results Among 68 eligible patients, 61 completed the study (31 in the face mask group and 30 in the HFNO group). The patient characteristics were comparable between groups. A decrease in SpO 2 was observed in the HFNO group (P=0.491). Oesophageal intubation at the first attempt occurred twice in the HFNO group, with no oxygen desaturation, and never occurred in the face mask group (P=0.238). There was no difference in airway management or hemodynamic recordings between the groups. The end-tidal CO 2 levels at intubation were similar between the groups: 5.1 (4.7-5.7) kPa in the face mask group vs. 5.2 (4.8-6.0) kPa in the HFNO group (P=0.292). HFNO was preferred by the investigators (P=0.003) and patients, with improved comfort (P=0.018), less submandibular pain (P=0.003), and a similar severity of hoarseness (P=0.686). Conclusions HFNO provides a hands-free induction of general anesthesia and yields adequate preoxygenation and peroxygenation, with a significant improvement in the quality of care.

Background Acute respiratory infections (ARIs), primarily pneumonia, are the leading infectious cause of under-5 mortality worldwide. Manually counting respiratory rate (RR) for 60 seconds using an ARI timer is commonly practiced by community health workers to detect fast breathing, an important sign of pneumonia. However, correctly counting breaths manually and classifying the RR is challenging, often leading to inappropriate treatment. A potential solution is to introduce RR counters, which count and classify RR automatically. Objective This study aims to determine how the RR count of an Automated Respiratory Infection Diagnostic Aid (ARIDA) agrees with the count of an expert panel of pediatricians counting RR by reviewing a video of the child’s chest for 60 seconds (reference standard), for children aged younger than 5 years with cough and/or difficult breathing. Methods A cross-sectional study aiming to enroll 290 children aged 0 to 59 months presenting to pediatric in- and outpatient departments at a teaching hospital in Addis Ababa, Ethiopia, was conducted. Enrollment occurred between April and May 2017. Once enrolled, children participated in at least one of three types of RR evaluations: (1) agreement—measure the RR count of an ARIDA in comparison with the reference standard, (2) consistency—measure the agreement between two ARIDA devices strapped to one child, and (3) RR fluctuation—measure RR count variability over time after ARIDA attachment as measured by a manual count. The agreement and consistency of expert clinicians (ECs) counting RR for the same child with the Mark 2 ARI timer for 60 seconds was also measured in comparison with the reference standard. Results Primary outcomes were (1) mean difference between the ARIDA and reference standard RR count (agreement) and (2) mean difference between RR counts obtained by two ARIDA devices started simultaneously (consistency). Conclusions Study strengths included the design allowing for comparison between both ARIDA and the EC with the reference standard RR count. A limitation is that exactly the same set of breaths were not compared between ARIDA and the reference standard since ARIDA can take longer than 60 seconds to count RR. Also, manual RR counting, even when aided by a video of the child’s chest movements, is subject to human error and can result in low interrater reliability. Further work is needed to reach global consensus on the most appropriate reference standard and an acceptable level of agreement to provide ministries of health with evidence to make an informed decision on whether to scale up new automated RR counters. Trial Registration ClinicalTrials.gov NCT03067558; https://clinicaltrials.gov/ct2/show/NCT03067558 International Registered Report Identifier (IRRID) RR1-10.2196/16531

Myo-inositol hexakisphosphate (IP6) is a natural product known to inhibit vascular calcification (VC), but with limited potency and low plasma exposure following bolus administration. Here we report the design of a series of inositol phosphate analogs as crystallization inhibitors, among which 4,6-di-O-(methoxy-diethyleneglycol)-myo-inositol-1,2,3,5-tetrakis(phosphate), (OEG2)2-IP4, displays increased in vitro activity, as well as more favorable pharmacokinetic and safety profiles than IP6 after subcutaneous injection. (OEG2)2-IP4 potently stabilizes calciprotein particle (CPP) growth, consistently demonstrates low micromolar activity in different in vitro models of VC (i.e., human serum, primary cell cultures, and tissue explants), and largely abolishes the development of VC in rodent models, while not causing toxicity related to serum calcium chelation. The data suggest a mechanism of action independent of the etiology of VC, whereby (OEG2)2-IP4 disrupts the nucleation and growth of pathological calcification., Cardiovascular calcification is a serious pathology for which effective pharmacological treatments are lacking. Here the authors show that an optimized oligo(ethylene glycol) derivative of inositol phosphate interferes with calcium phosphate crystallization and inhibits soft tissue calcification in vivo following subcutaneous injection.

Islet autotransplantation (IAT) is increasingly being performed to mitigate against the diabetic complications of pancreatic resection in patients with benign inflammatory pancreatic disorders; however, the glycemic benefit of IAT in patients undergoing partial pancreatic resection is not known. We aimed to determine whether IAT improved glycemic outcomes in patients undergoing distal pancreatectomy for benign inflammatory disease. We performed a multicenter, retrospective case-control study of patients who underwent distal pancreatic resection with IAT at two U S tertiary care centers. The primary outcome was the mean change in pre- vs post-operative HgA1c following transplant as well as the development of new post-operative diabetes. Nine patients requiring distal pancreatectomy for benign disease underwent IAT and were compared to 13 historical controls without IAT. Baseline characteristics were similar between groups. With a median follow-up of 22 months, those who received an IAT had a smaller increase in their pre- vs post-operative HgA1c (0.42 vs 2.83, P = .004), and one case patient (14.3%) vs three control patients (23.1%) developed new post-operative diabetes (P = .581). We conclude that patients undergoing distal pancreatic resection for benign inflammatory disease should be considered for IAT, as long-term glycemic outcomes appear to be improved in those undergoing transplant.

Ready-to-eat (RTE) meat and poultry product samples collected between 2005 and 2017 from RTE-producing establishments for the U.S. Department of Agriculture, Food Safety and Inspection Service (FSIS) ALLRTE/RTEPROD_RAND (random) and RTE001/RTEPROD_RISK (risk-based) sampling projects were tested for Listeria monocytogenes (Lm). Data for 45,897 ALLRTE/RTEPROD_RAND samples collected from 3,607 distinct establishments and 112,347 RTE001/RTEPROD_RISK samples collected from 3,283 distinct establishments were analyzed for the presence of Lm. These data were also analyzed based upon the percentages of establishments with positive samples, annual production volume, sanitation control alternatives, geographic location, and season or month of sample collection. Results revealed low occurrence of Lm-positive samples from the random and risk-based sampling projects, with 152 (0.33%) positive samples for ALLRTE/RTEPROD_RAND and 403 (0.36%) positive samples for RTE001/RTEPROD_RISK. The percentage of positive samples significantly decreased over time, from about 0.7% in 2005 and 2006 to about 0.2% in 2017 (P < 0.05). From 2005 to 2017, 3.9% of establishments sampled under the ALLRTE/RTEPROD_RAND sampling project had at least one Lm-positive sample. Similarly, 10.0% of establishments sampled under the RTE001/RTEPROD_RISK sampling project had at least one positive sample. Samples positive for Lm were found in all geographic regions in all months. Thus, in 13 years of RTE product sampling in FSIS-regulated establishments (2005 through 2017)

Aim Pneumonia is the leading cause of child death after the neonatal period, resulting from late care seeking and inappropriate treatment. Diagnosis involves counting respiratory rate (RR); however, RR counting remains challenging for health workers and miscounting, and misclassification of RR is common. We evaluated the usability of a new automated RR counter, the Philips Children's Respiratory Monitor (ChARM), to Female Community Health Volunteers (FCHVs), and its acceptability to FCHVs and caregivers in Nepal. Methods A cross‐sectional study was conducted in Jumla district, Nepal. About 133 FCHVs were observed between September and December 2018 when using ChARM during 517 sick child consultations, 264 after training and 253 after 2 months of routine use of ChARM. Acceptability of the ChARM was explored using semi‐structured interviews. Results FCHV adherence to guidelines after 2 months of using ChARM routinely was 52.8% (95% CI 46.6‐58.9). The qualitative findings suggest that ChARM is acceptable to FCHVs and caregivers; however, capacity constraints such as older age and low literacy and impacted device usability were mentioned. Conclusion Further research on the performance, cost‐effectiveness and implementation feasibility of this device is recommended, especially among low‐literate CHWs.

Hyaluronan (or hyaluronic acid, HA) is a nonsulfated, negatively charged, single-chain megadalton glycosaminoglycan distributed through the body, especially in soft connective tissue. In many solid tumors, HA accumulates in the extracellular matrix, can impede access of anticancer agents, and is associated with an aggressive tumor phenotype. Recombinant human hyaluronidase PH20 (rHuPH20) enzymatically degrades hyaluronan and has been approved by the US Food and Drug Administration to enhance dispersion and absorption of subcutaneously delivered therapies. A PEGylated version of rHuPH20, pegvorhyaluronidase alfa (PEGPH20), has been developed to enable prolonged systemic exposure to rHuPH20 and to investigate the potential therapeutic effects of hyaluronan degradation. In animal models, intravenous pegvorhyaluronidase alfa enzymatically degrades tumor hyaluronan, reduces tumor interstitial pressure, and improves vascular perfusion, resulting in increased intratumoral access of anticancer agents and increased tumor immune cell density. Consistent with these effects, pegvorhyaluronidase alfa has demonstrated antitumor efficacy when used alone or in combination with other anticancer therapies in nonclinical models. In the Phase II HALO 109-202 trial, pegvorhyaluronidase alfa plus nab-paclitaxel and gemcitabine demonstrated favorable activity in patients with pancreatic cancer. A global, multicenter, Phase III trial (HALO 109-301) of pegvorhyaluronidase alfa in patients with pancreatic cancer is ongoing, with completion expected in 2020.

International audience; Aims: Transition care programmes are designed to improve coordination of care between hospital and home. For heart failure patients, meta-analyses show a high efficacy but with moderate evidence level. Moreover, difficulties for implementation of such programmes limit their extrapolation.Methods and results: We designed a mixed-method study to assess the implementation of the PRADO-IC, a nationwide transition programme that aims to be offered to every patient with heart failure in France. This programme consists essentially in an administrative assistance to schedule follow-up visits and in a nurse follow-up during 2 to 6 months and aims to reduce the annual heart failure readmission rate by 30%. This study assessed three quantitative aims: the cost to avoid a readmission for heart failure within 1 year (primary aim, intended sample size 404 patients), clinical care pathways, and system economic outcomes; and two qualitative aims: perceived problems and benefits of the PRADO-IC. All analyses will be gathered at the end of study for a joint interpretation. Strengths of this study design are the randomized controlled design, the population included in six centres with low motivation bias, the primary efficiency analysis, the secondary efficacy analyses on care pathway and clinical outcomes, and the joint qualitative analysis. Limits are the heterogeneity of centres and of intervention in a control group and parallel development of other new therapeutic interventions in this field.Conclusions: The results of this study may help decision-makers to support an administratively managed transition programme.