Mental health competencies are stronger determinants of well-being than mental disorder symptoms in both psychiatric and non-clinical samples.

The present study aimed to investigate whether the strength of mental health competencies and the severity of mental disorder symptoms, and their interaction, differ in the strength of their associations with several dimensions of well-being in Hungarian adult psychiatric and non-clinical samples. All respondent in the psychiatric sample (129 patients (44 male, 85 female)) and in the non-clinical community sample (253 adults (43 male, 210 female)) completed the Mental Health Test, six measures of well-being and mental health, and the Symptom Checklist-90-Revised. Including both mental health competencies and mental disorder symptoms in a regression model in both samples can predict patients' well-being even more accurately. Mental health competencies were positively related; mental disorder symptoms were negatively related to subjective well-being. In all models and in both samples, mental health competencies were found to be stronger determinants of well-being than mental disorder symptoms. The interaction of mental health competencies and mental disorder symptoms is no more predictive of well-being in either psychiatric or non-clinical samples than when the effects of each are considered separately. The assessment of mental health competencies has an important predictive value for well-being in the presence of psychopathological symptoms and/or mental disorders.

Assessment of vitamin B12 levels and cardiovascular risk factors in metformin- and non-metformin-treated type 2 diabetic patients.

Oxidative stress enhances cardiovascular risk. Metformin decreases intestinal absorption of vitamin B12. Our objective was the evaluation of type 2 diabetics focusing on differences due to their treatment. A prospective study on 224 type 2 diabetics was realized between 2015-2018 in Targu Mures, Romania, divided into 2 subgroups (metformin vs. other therapy - 2nd/3rd generation sulfonylureas, insulin, dietary regimen -, followed for at least one year) and non-diabetic controls (n=25) for oxidative stress level comparison. Serum homocysteine (HC), vitamin B12 were determined by chemiluminescence (Immulite One). Lipid peroxidation was assessed by serum malondialdehyde (MDA) measurement (HPLC). Biochemical tests, minerals, cystatin C, high-sensitivity C reactive protein (hs-CRP) were measured on Konelab20Xti, glycated hemoglobin on Nycocard Reader. GraphPad InStat-3 was used for statistics. Negative correlation occured between serum vitamin B12 and HC, this vitamin's level was significantly lower and serum zinc was significantly higher in patients on metformin. Hyperhomocysteinemia was present in 87% of the subjects, 46% had zinc deficiency and 41% elevated hs-CRP. Serum cystatin C showed positive correlation with creatinine. Serum MDA was significantly higher in diabetics compared to control patients. Elevated hs-CRP and homocysteine represent raised cardiovascular risk. Intense oxidative stress, vitamin, mineral deficiencies are frequent in diabetic subjects.

The Management of COVID-19-Related Coagulopathy: A Focus on the Challenges of Metabolic and Vascular Diseases.

The course of COVID-19 is highly dependent on the associated cardiometabolic comorbidities of the patient, which worsen the prognosis of coronavirus infection, mainly due to systemic inflammation, endothelium dysfunction, and thrombosis. A search on the recent medical literature was performed in five languages, using the PubMed, Embase, Cochrane, and Google Scholar databases, for the review of data regarding the management of patients with a high risk for severe COVID-19, focusing on the associated coagulopathy. Special features of COVID-19 management are presented, based on the underlying conditions (obesity, diabetes mellitus, and cardiovascular diseases), emphasizing the necessity of a modern, holistic approach to thromboembolic states. The latest findings regarding the most efficient therapeutic approaches are included in the article, offering guidance for medical professionals in severe, complicated cases of SARS-CoV-2 infection. We can conclude that severe COVID-19 is closely related to vascular inflammation and intense cytokine release leading to hemostasis disorders. Overweight, hyperglycemia, cardiovascular diseases, and old age are important risk factors for severe outcomes of coronavirus infection, involving a hypercoagulable state. Early diagnosis and proper therapy in complicated SARS-CoV-2-infected cases could reduce mortality and the need for intensive care during hospitalization in patients with cardiometabolic comorbidities.

Clinical Presentation Is Dependent on Age and Calendar Year of Diagnosis in Celiac Disease: A Hungarian Cross-Sectional Study.

International trends indicate that celiac disease (CeD) is becoming more common, while the clinical presentation of CeD tends to change. We aimed to investigate factors associated with the clinical presentation of CeD. We reviewed all CeD cases diagnosed at our tertiary center, University of Pécs (Hungary), between 1992 and 2019. We collected data of verified CeD patients on clinical presentations (classified by the Oslo Classification), the age at and calendar year of diagnosis, and sex, serology and histology at diagnosis. To assess the associations of baseline variables with clinical presentations, we applied univariate and multivariate (binary logistic regression) statistics. A total of 738 CeD patients were eligible for inclusion. In the univariate analysis, patients with classical CeD were more common in the latest calendar period (p < 0.001) and tended to be older (p = 0.056), but we failed to observe a significant association between the clinical presentation and sex, serology or histology at diagnosis. In the multivariate analysis, only age at diagnosis and calendar year were independently associated with clinical presentations (OR = 1.02, CI: 1.01-1.04 and OR = 0.93, CI: 0.89-0.98, respectively). Our findings confirmed that classical CeD is independently associated with age at diagnosis and calendar year of diagnosis of CeD, whereas other parameters were not significantly associated with clinical presentations.

Pathways of Coagulopathy and Inflammatory Response in SARS-CoV-2 Infection among Type 2 Diabetic Patients.

Chronic inflammation and endothelium dysfunction are present in diabetic patients. COVID-19 has a high mortality rate in association with diabetes, partially due to the development of thromboembolic events in the context of coronavirus infection. The purpose of this review is to present the most important underlying pathomechanisms in the development of COVID-19-related coagulopathy in diabetic patients. The methodology consisted of data collection and synthesis from the recent scientific literature by accessing different databases (Cochrane, PubMed, Embase). The main results are the comprehensive and detailed presentation of the very complex interrelations between different factors and pathways involved in the development of arteriopathy and thrombosis in COVID-19-infected diabetic patients. Several genetic and metabolic factors influence the course of COVID-19 within the background of diabetes mellitus. Extensive knowledge of the underlying pathomechanisms of SARS-CoV-2-related vasculopathy and coagulopathy in diabetic subjects contributes to a better understanding of the manifestations in this highly vulnerable group of patients; thus, they can benefit from a modern, more efficient approach regarding diagnostic and therapeutic management.

Relationship between Nutrition, Lifestyle Habits and Laboratory Parameters in Hypertensive Patients with/without Cognitive Dysfunction.

(1) Background: Cognitive dysfunction is a major concern in hypertensive patients. Lifestyle habits and nutrition influence laboratory parameters, with an impact on clinical course. The objective of the study was to evaluate nutrition and lifestyle habits in hypertensive patients with/without cognitive dysfunction and establish correlations to laboratory parameters. MATERIAL AND METHODS: 50 patients admitted to the Cardiovascular Rehabilitation Clinic in Târgu Mureș were enrolled in this study between March-June 2021. We evaluated their cognitive function, and they filled in a questionnaire about lifestyle and nutrition. Biochemical blood tests were performed using a Konelab Prime 60i analyzer. IBM-SPSS22 and GraphPad InStat3 were used for statistics. RESULTS: Mean age of hypertensive patients (n = 50) was 70.42 ± 4.82 (SD) years, half of them had cognitive dysfunction. Zinc deficiency was present in 74% of the subjects. The subgroup with cognitive dysfunction had significantly higher BMI (p = 0.009) and microalbuminuria (p = 0.0479), as well as significantly lower magnesium intake (p = 0.032) and cholesterol intake (p = 0.022), compared to those with normal cognitive status. CONCLUSIONS: Nutrition is in a close relationship with laboratory parameters; significant differences (microalbuminuria, cholesterol intake, BMI, etc.) are present between hypertensive patients with/without cognitive dysfunction. A healthy diet is important for the maintenance of metabolic balance, the achievement of optimal body weight, and the prevention of complications.

Digital Biomarkers for Supporting Transitional Care Decisions: Protocol for a Transnational Feasibility Study.

BACKGROUND: Virtual Health and Wellbeing Living Lab Infrastructure is a Horizon 2020 project that aims to harmonize Living Lab procedures and facilitate access to European health and well-being research infrastructures. In this context, this study presents a joint research activity that will be conducted within Virtual Health and Wellbeing Living Lab Infrastructure in the transitional care domain to test and validate the harmonized Living Lab procedures and infrastructures. The collection of data from various sources (information and communications technology and clinical and patient-reported outcome measures) demonstrated the capacity to assess risk and support decisions during care transitions, but there is no harmonized way of combining this information. OBJECTIVE: This study primarily aims to evaluate the feasibility and benefit of collecting multichannel data across Living Labs on the topic of transitional care and to harmonize data processes and collection. In addition, the authors aim to investigate the collection and use of digital biomarkers and explore initial patterns in the data that demonstrate the potential to predict transition outcomes, such as readmissions and adverse events. METHODS: The current research protocol presents a multicenter, prospective, observational cohort study that will consist of three phases, running consecutively in multiple sites: a cocreation phase, a testing and simulation phase, and a transnational pilot phase. The cocreation phase aims to build a common understanding among different sites, investigate the differences in hospitalization discharge management among countries, and the willingness of different stakeholders to use technological solutions in the transitional care process. The testing and simulation phase aims to explore ways of integrating observation of a patient's clinical condition, patient involvement, and discharge education in transitional care. The objective of the simulation phase is to evaluate the feasibility and the barriers faced by health care professionals in assessing transition readiness. RESULTS: The cocreation phase will be completed by April 2022. The testing and simulation phase will begin in September 2022 and will partially overlap with the deployment of the transnational pilot phase that will start in the same month. The data collection of the transnational pilots will be finalized by the end of June 2023. Data processing is expected to be completed by March 2024. The results will consist of guidelines and implementation pathways for large-scale studies and an analysis for identifying initial patterns in the acquired data. CONCLUSIONS: The knowledge acquired through this research will lead to harmonized procedures and data collection for Living Labs that support transitions in care. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/34573.

Cocreating a Harmonized Living Lab for Big Data-Driven Hybrid Persona Development: Protocol for Cocreating, Testing, and Seeking Consensus.

BACKGROUND: Living Labs are user-centered, open innovation ecosystems based on a systematic user cocreation approach, which integrates research and innovation processes in real-life communities and settings. The Horizon 2020 Project VITALISE (Virtual Health and Wellbeing Living Lab Infrastructure) unites 19 partners across 11 countries. The project aims to harmonize Living Lab procedures and enable effective and convenient transnational and virtual access to key European health and well-being research infrastructures, which are governed by Living Labs. The VITALISE consortium will conduct joint research activities in the fields included in the care pathway of patients: rehabilitation, transitional care, and everyday living environments for older adults. This protocol focuses on health and well-being research in everyday living environments. OBJECTIVE: The main aim of this study is to cocreate and test a harmonized research protocol for developing big data-driven hybrid persona, which are hypothetical user archetypes created to represent a user community. In addition, the use and applicability of innovative technologies will be investigated in the context of various everyday living and Living Lab environments. METHODS: In phase 1, surveys and structured interviews will be used to identify the most suitable Living Lab methods, tools, and instruments for health-related research among VITALISE project Living Labs (N=10). A series of web-based cocreation workshops and iterative cowriting processes will be applied to define the initial protocols. In phase 2, five small-scale case studies will be conducted to test the cocreated research protocols in various real-life everyday living settings and Living Lab infrastructures. In phase 3, a cross-case analysis grounded on semistructured interviews will be conducted to identify the challenges and benefits of using the proposed research protocols. Furthermore, a series of cocreation workshops and the consensus seeking Delphi study process will be conducted in parallel to cocreate and validate the acceptance of the defined harmonized research protocols among wider Living Lab communities. RESULTS: As of September 30, 2021, project deliverables Ethics and safety manual and Living lab standard version 1 have been submitted to the European Commission review process. The study will be finished by March 2024. CONCLUSIONS: The outcome of this research will lead to harmonized procedures and protocols in the context of big data-driven hybrid persona development among health and well-being Living Labs in Europe and beyond. Harmonized protocols enable Living Labs to exploit similar research protocols, devices, hardware, and software for interventions and complex data collection purposes. Economies of scale and improved use of resources will speed up and improve research quality and offer novel possibilities for open data sharing, multidisciplinary research, and comparative studies beyond current practices. Case studies will also provide novel insights for implementing innovative technologies in the context of everyday Living Lab research. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/34567.

To ventilate or not to ventilate during bystander CPR - A EuReCa TWO analysis.

BACKGROUND: Survival after out-of-hospital cardiac arrest (OHCA) is still low. For every minute without resuscitation the likelihood of survival decreases. One critical step is initiation of immediate, high quality cardiopulmonary resuscitation (CPR). The aim of this subgroup analysis of data collected for the European Registry of Cardiac Arrest Study number 2 (EuReCa TWO) was to investigate the association between OHCA survival and two types of bystander CPR namely: chest compression only CPR (CConly) and CPR with chest compressions and ventilations (FullCPR). METHOD: In this subgroup analysis of EuReCa TWO, all patients who received bystander CPR were included. Outcomes were return of spontaneous circulation and survival to 30-days or hospital discharge. A multilevel binary logistic regression analysis with survival as the dependent variable was performed. RESULTS: A total of 5884 patients were included in the analysis, varying between countries from 21 to 1444. Survival was 320 (8%) in the CConly group and 174 (13%) in the FullCPR group. After adjustment for age, sex, location, rhythm, cause, time to scene, witnessed collapse and country, patients who received FullCPR had a significantly higher survival rate when compared to those who received CConly (adjusted odds ration 1.46, 95% confidence interval 1.17-1.83). CONCLUSION: In this analysis, FullCPR was associated with higher survival compared to CConly. Guidelines should continue to emphasise the importance of compressions and ventilations during resuscitation for patients who suffer OHCA and CPR courses should continue to teach both.

Long-term safety and effectiveness of berotralstat for hereditary angioedema: The open-label APeX-S study.

BACKGROUND: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein recently approved for prevention of angioedema attacks in adults and adolescents with hereditary angioedema (HAE). The objective of this report is to summarize results from an interim analysis of an ongoing long-term safety study of berotralstat in patients with HAE. METHODS: APeX-S is an ongoing, phase 2, open-label study conducted in 22 countries (ClinicalTrials.gov, NCT03472040). Eligible patients with a clinical diagnosis of HAE due to C1 inhibitor deficiency (HAE-C1-INH) were centrally allocated to receive berotralstat 150 or 110 mg once daily. The primary objective was to determine long-term safety and the secondary objective was to evaluate effectiveness. RESULTS: Enrolled patients (N = 227) received berotralstat 150 mg (n = 127) or 110 mg (n = 100) once daily. The median (range) duration of exposure was 342 (11-540) and 307 (14-429) days for the 150-mg and 110-mg groups, respectively. Treatment-emergent adverse events (TEAEs) occurred in 91% (n = 206) of patients. The most common TEAEs across treatment groups were upper respiratory tract infection (n = 91, 40%), abdominal pain (n = 57, 25%), headache (n = 40, 18%), and diarrhea (n = 31, 14%) and were mostly mild to moderate. Fifty percent (n = 113) of patients had at least one drug-related adverse event (AE; 150 mg, n = 57 [45%]; 110 mg, n = 56 [56%]), and discontinuations due to AEs occurred in 19 (8%) patients (150 mg, n = 13 [10%]; 110 mg, n = 6 [6%]). Three (1.3%) patients experienced a drug-related serious TEAE. Among patients who received berotralstat through 48 weeks (150 mg, n = 73; 110 mg, n = 30), median HAE attack rates were low in month 1 (150 mg, 1.0 attacks/month; 110 mg, 0.5 attacks/month) and remained low through 12 months (0 attacks/month in both dose groups). Mean HAE attack rates followed a similar trend, and no evidence for patient tolerance to berotralstat emerged. In both dose groups, angioedema quality of life scores showed clinically meaningful changes from baseline. CONCLUSIONS: In this analysis, both berotralstat doses, 150  and 110 mg once daily, were generally well tolerated. Effectiveness results support the durability and robustness of berotralstat as prophylactic therapy in patients with HAE. TRIAL REGISTRATION: The study is registered with ClinicalTrials.gov (NCT03472040).

Oxidative stress and peripartum outcomes (Review).

Pregnancy, labor and childbirth are accompanied by excessive oxidative aggression. The excessive formation of free radicals [reactive oxygen species (ROS), reactive nitrogen species (RNS), chlorine reactive species (CRS)] causes cellular oxidative damage, which can be scavenged by enzymatic or non-enzymatic antioxidants in normal healthy pregnancy, physiological labor and delivery without any complications. An imbalance between the pro-oxidant and antioxidant factors may lead to oxidative stress, which contributes to the development of many diseases. This oxidative aggression can be a precursor for pathologies in the pregnant woman including eclampsia, miscarriage, preterm labor, and intrauterine growth retardation; in the offspring it may lead to bronchopulmonary dysplasia/chronic lung disease, necrotizing enterocolitis, retinopathy of prematurity, and periventricular leukomalacia. This review summarizes the studies conducted to identify the mechanisms of oxidative stress and the effect of cell membrane oxidation, the mechanisms that are behind oxidative stress-related diseases, and also those studies which have demonstrated the effect of antioxidants in preventing diseases or diminishing the effects of oxidative stress in the body, in obstetrics and neonatology.

Randomized Trial of the Efficacy and Safety of Berotralstat (BCX7353) as an Oral Prophylactic Therapy for Hereditary Angioedema: Results of APeX-2 Through 48 Weeks (Part 2).

BACKGROUND: Berotralstat (BCX7353) is a recently approved, oral, once-daily kallikrein inhibitor for hereditary angioedema (HAE) prophylaxis. In the APeX-2 trial, berotralstat reduced HAE attack rates over 24 weeks, with a favorable safety and tolerability profile. OBJECTIVE: Evaluate berotralstat safety, tolerability, and effectiveness over 48 weeks. METHODS: APeX-2 is a phase 3, parallel-group, multicenter trial (NCT03485911) in patients with HAE due to C1 esterase inhibitor deficiency. Part 1 was double-blind and placebo-controlled, with patients randomized to 24 weeks of berotralstat 150 mg, 110 mg, or placebo. In part 2, patients continued berotralstat the same dose or, if initially randomized to placebo, were rerandomized to berotralstat 150 mg or 110 mg through weeks 24 to 48. The primary end point was safety and tolerability. RESULTS: One hundred eight patients received 1 or more doses of berotralstat in part 2. Treatment-emergent adverse events (TEAEs) occurred in 30 of 39 patients (77%) in the placebo group during part 1, and 25 of 34 patients (74%) re-randomized from placebo to berotralstat 110 mg or 150 mg in part 2, with drug-related TEAEs in 13 of 39 (33%), and 11 of 34 (32%) in the same groups. Most TEAEs were mild or moderate, with no serious drug-related TEAEs. The most common TEAEs were upper respiratory tract infections, abdominal pain, diarrhea, and vomiting. Mean (±standard error of the mean) monthly attack rates at baseline and week 48 were 3.06 (±0.25) and 1.06 (±0.25) in the berotralstat 150mg 48-week group and 2.97 (±0.21) and 1.35 (±0.33) in the berotralstat 110mg 48-week group. CONCLUSIONS: The safety, tolerability, and effectiveness of berotralstat were maintained over 48 weeks of treatment.

Oral berotralstat for the prophylaxis of hereditary angioedema attacks in patients in Japan: A phase 3 randomized trial.

BACKGROUND: With no approved treatments in Japan for the prevention of hereditary angioedema (HAE) attacks, there is a significant unmet need for long-term prophylactic therapies for Japanese patients with HAE. Berotralstat (BCX7353) is an oral, once-daily, highly selective inhibitor of plasma kallikrein in development for prophylaxis of angioedema attacks in HAE patients. METHODS: APeX-J is a phase 3, randomized, double-blind, placebo-controlled, parallel-group, 3-part trial conducted in Japan (University Hospital Medical Information Network identifier, UMIN000034869; ClinicalTrials.gov identifier, NCT03873116). Patients with a clinical diagnosis of type 1 or 2 HAE underwent a prospective run-in period of 56 days to determine eligibility, allowing enrollment of those with ≥2 expert-confirmed angioedema attacks. Patients were randomly assigned (1:1:1) and stratified by baseline attack rate (≥2 vs. <2 expert-confirmed attacks/month between screening and randomization) to receive once-daily berotralstat 110 mg, berotralstat 150 mg, or placebo. The primary endpoint was the rate of expert-confirmed angioedema attacks during dosing in the 24-week treatment period. RESULTS: Nineteen patients were randomized to receive once-daily berotralstat 110 mg (n = 6), berotralstat 150 mg (n = 7), or placebo (n = 6). Treatment with berotralstat 150 mg significantly reduced HAE attacks relative to placebo (1.11 vs. 2.18 attacks/month, p = .003). The most frequently reported treatment-emergent adverse events (TEAEs) in berotralstat-treated patients (n = 13) were nasopharyngitis (n = 4, 31%), abdominal pain, cough, diarrhea, and pyrexia (n = 2 each, 15%). CONCLUSIONS: Orally administered, once-daily berotralstat 150 mg significantly reduced the frequency of HAE attacks and was safe and well tolerated, supporting its use as a prophylactic therapy in patients with type 1 or 2 HAE in Japan.

Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: A randomized, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein in development for the prophylaxis of hereditary angioedema (HAE) attacks. OBJECTIVE: Our aim was to determine the efficacy, safety, and tolerability of berotralstat in patients with HAE over a 24-week treatment period (the phase 3 APeX-2 trial). METHODS: APeX-2 was a double-blind, parallel-group study that randomized patients at 40 sites in 11 countries 1:1:1 to receive once-daily berotralstat in a dose of 110 mg or 150 mg or placebo (Clinicaltrials.gov identifier NCT03485911). Patients aged 12 years or older with HAE due to C1 inhibitor deficiency and at least 2 investigator-confirmed HAE attacks in the first 56 days of a prospective run-in period were eligible. The primary efficacy end point was the rate of investigator-confirmed HAE attacks during the 24-week treatment period. RESULTS: A total of 121 patients were randomized; 120 of them received at least 1 dose of the study drug (n = 41, 40, and 39 in the 110-mg dose of berotralstat, 150-mg of dose berotralstat, and placebo groups, respectively). Berotralstat demonstrated a significant reduction in attack rate at both 110 mg (1.65 attacks per month; P = .024) and 150 mg (1.31 attacks per month; P < .001) relative to placebo (2.35 attacks per month). The most frequent treatment-emergent adverse events that occurred more with berotralstat than with placebo were abdominal pain, vomiting, diarrhea, and back pain. No drug-related serious treatment-emergent adverse events occurred. CONCLUSION: Both the 110-mg and 150-mg doses of berotralstat reduced HAE attack rates compared with placebo and were safe and generally well tolerated. The most favorable benefit-to-risk profile was observed at a dose of 150 mg per day.

Experimental assessment of three electrosurgical tissue-sealing devices in a porcine model.

Three electrosurgical tissue-sealing devices (EnSeal ETSDRC-01, LigaSure LS1500 and Thunderbeat TB-0535PC) were compared regarding sealing time (ST), maximum working temperature (WTmax) and the total (MTZtotal) as well as the collateral microscopic thermal injury zone (MTZcollat) using laparoscopic handpieces 5 mm in diameter on four types of tissue (liver, mesentery, cross striated muscle and spleen) in an in vivo porcine model. LigaSure had the lowest mean ST in spleen, mesentery, muscle and liver, followed by Thunderbeat and EnSeal with significant differences between all types of tissues and devices. The significantly lowest mean WTmax was obtained for EnSeal in mesentery, muscle and liver. LigaSure and EnSeal operated at the lowest temperature in spleen without a significant difference between them. Thunderbeat produced significantly higher temperature peaks in all cases. The lowest mean MTZtotal was caused by LigaSure and EnSeal in spleen, mesentery and muscle without significant differences between them, followed by the significantly higher values of Thunderbeat. Nevertheless, Thunderbeat produced the significantly lowest mean MTZtotal in the liver. EnSeal produced the lowest mean MTZcollat in the liver, followed by LigaSure and Thunderbeat showing significant differences. EnSeal and LigaSure produced the lowest mean MTZcollat in the spleen, mesentery and muscle without significant differences between them, followed by the significantly higher values of Thunderbeat. Based on the results of this study, Thunderbeat seems to be more invasive to tissue integrity (even without the activation of the ultrasonic scissor function) than EnSeal or LigaSure, that operate at lower temperatures and were found to cause negligible collateral thermal damage.

Survival after out-of-hospital cardiac arrest in Europe - Results of the EuReCa TWO study.

BACKGROUND: The epidemiology and outcome after out-of-hospital cardiac arrest (OHCA) varies across Europe. Following on from EuReCa ONE, the aim of this study was to further explore the incidence of and outcomes from OHCA in Europe and to improve understanding of the role of the bystander. METHODS: This prospective, multicentre study involved the collection of registry-based data over a three-month period (1st October 2017 to 31st December 2017). The core study dataset complied with the Utstein-style. Primary outcomes were return of spontaneous circulation (ROSC) and survival to hospital admission. Secondary outcome was survival to hospital discharge. RESULTS: All 28 countries provided data, covering a total population of 178,879,118. A total of 37,054 OHCA were confirmed, with CPR being started in 25,171 cases. The bystander cardiopulmonary resuscitation (CPR) rate ranged from 13% to 82% between countries (average: 58%). In one third of cases (33%) ROSC was achieved and 8% of patients were discharged from hospital alive. Survival to hospital discharge was higher in patients when a bystander performed CPR with ventilations, compared to compression-only CPR (14% vs. 8% respectively). CONCLUSION: In addition to increasing our understanding of the role of bystander CPR within Europe, EuReCa TWO has confirmed large variation in OHCA incidence, characteristics and outcome, and highlighted the extent to which OHCA is a public health burden across Europe. Unexplained variation remains and the EuReCa network has a continuing role to play in improving the quality management of resuscitation.

Palladium nanoparticles on a pyridinium supported ionic liquid phase: a recyclable and low-leaching palladium catalyst for aminocarbonylation reactions.

A new SILP (Supported Ionic Liquid Phase) palladium catalyst was prepared and characterized by 13C and 29Si CP MAS NMR, DTG, FTIR and TEM. The presence of the grafted pyridinium cations on the surface of the support was found to result in the formation of highly dispersed Pd nanoparticles with their diameter in the range of 1-2 nm. The catalyst was proved to be active not only in the aminocarbonylation of some model compounds but also in the synthesis of active pharmaceutical ingredients. Catalyst recycling and palladium leaching studies were carried out for the first time in aminocarbonylations leading to CX-546(1-(1,4-benzodioxan-6-ylcarbonyl)piperidine), Moclobemide, Nikethamide and a precursor of Finasteride. The latter reaction proves that not only aryl iodides but also an iodoalkene can be converted into the products with the help of the heterogeneous catalyst. The results show that the conditions should be always fine-tuned in the reactions of different substrates to achieve optimal results. Palladium loss was also observed to depend considerably on the nature of the reaction partners.

Regulated complex assembly safeguards the fidelity of Sleeping Beauty transposition.

The functional relevance of the inverted repeat structure (IR/DR) in a subgroup of the Tc1/mariner superfamily of transposons has been enigmatic. In contrast to mariner transposition, where a topological filter suppresses single-ended reactions, the IR/DR orchestrates a regulatory mechanism to enforce synapsis of the transposon ends before cleavage by the transposase occurs. This ordered assembly process shepherds primary transposase binding to the inner 12DRs (where cleavage does not occur), followed by capture of the 12DR of the other transposon end. This extra layer of regulation suppresses aberrant, potentially genotoxic recombination activities, and the mobilization of internally deleted copies in the IR/DR subgroup, including Sleeping Beauty (SB). In contrast, internally deleted sequences (MITEs) are preferred substrates of mariner transposition, and this process is associated with the emergence of Hsmar1-derived miRNA genes in the human genome. Translating IR/DR regulation to in vitro evolution yielded an SB transposon version with optimized substrate recognition (pT4). The ends of SB transposons excised by a K248A excision+/integration- transposase variant are processed by hairpin resolution, representing a link between phylogenetically, and mechanistically different recombination reactions, such as V(D)J recombination and transposition. Such variants generated by random mutation might stabilize transposon-host interactions or prepare the transposon for a horizontal transfer.

In vivo transduction of primitive mobilized hematopoietic stem cells after intravenous injection of integrating adenovirus vectors.

Current protocols for hematopoietic stem/progenitor cell (HSPC) gene therapy, involving the transplantation of ex vivo genetically modified HSPCs are complex and not without risk for the patient. We developed a new approach for in vivo HSPC transduction that does not require myeloablation and transplantation. It involves subcutaneous injections of granulocyte-colony-stimulating factor/AMD3100 to mobilize HSPCs from the bone marrow (BM) into the peripheral blood stream and the IV injection of an integrating, helper-dependent adenovirus (HD-Ad5/35++) vector system. These vectors target CD46, a receptor that is uniformly expressed on HSPCs. We demonstrated in human CD46 transgenic mice and immunodeficient mice with engrafted human CD34+ cells that HSPCs transduced in the periphery home back to the BM where they stably express the transgene. In hCD46 transgenic mice, we showed that our in vivo HSPC transduction approach allows for the stable transduction of primitive HSPCs. Twenty weeks after in vivo transduction, green fluorescent protein (GFP) marking in BM HSPCs (Lin-Sca1+Kit- cells) in most of the mice was in the range of 5% to 10%. The percentage of GFP-expressing primitive HSPCs capable of forming multilineage progenitor colonies (colony-forming units [CFUs]) increased from 4% of all CFUs at week 4 to 16% at week 12, indicating transduction and expansion of long-term surviving HSPCs. Our approach was well tolerated, did not result in significant transduction of nonhematopoietic tissues, and was not associated with genotoxicty. The ability to stably genetically modify HSPCs without the need of myeloablative conditioning is relevant for a broader clinical application of gene therapy.

Reproduction and Growth in a Murine Model of Early Life-Onset Inflammatory Bowel Disease.

Studies in transgenic murine models have provided insight into the complexity underlying inflammatory bowel disease (IBD), a disease hypothesized to result from an injurious immune response against intestinal microbiota. We recently developed a mouse model of IBD that phenotypically and histologically resembles human childhood-onset ulcerative colitis (UC), using mice that are genetically modified to be deficient in the cytokines TNF and IL-10 ("T/I" mice). Here we report the effects of early life onset of colon inflammation on growth and reproductive performance of T/I mice. T/I dams with colitis often failed to get pregnant or had small litters with pups that failed to thrive. Production was optimized by breeding double homozygous mutant T/I males to females homozygous mutant for TNF deficiency and heterozygous for deficiency of IL-10 ("T/I-het" dams) that were not susceptible to spontaneous colon inflammation. When born to healthy (T/I-het) dams, T/I pups initially gained weight similarly to wild type (WT) pups and to their non-colitis-susceptible T/I-het littermates. However, their growth curves diverged between 8 and 13 weeks, when most T/I mice had developed moderate to severe colitis. The observed growth failure in T/I mice occurred despite a significant increase in their food consumption and in the absence of protein loss in the stool. This was not due to TNF-induced anorexia or altered food consumption due to elevated leptin levels. Metabolic studies demonstrated increased consumption of oxygen and water and increased production of heat and CO2 in T/I mice compared to their T/I-het littermates, without differences in motor activity. Based on the clinical similarities of this early life onset model of IBD in T/I mice to human IBD, these results suggest that mechanisms previously hypothesized to explain growth failure in children with IBD require re-evaluation. The T/I mouse model may be useful for further investigation of such mechanisms and for development of therapies to prevent reproductive complications and/or growth failure in humans with IBD.