Synthesis, characterization, and antibacterial activity studies of two Co(II) complexes with 2-[(E)-(3-acetyl-4-hydroxyphenyl)diazenyl]-4-(2-hydroxyphenyl)thiophene-3-carboxylic acid as a ligand.

Two new Cobalt(II) complexes 12 and 13 have been synthesized from 2-[(E)-(3-acetyl-4-hydroxyphenyl)diazenyl]-4-(2-hydroxyphenyl)thiophene-3-carboxylic acid (11) as a novel ligand. These three new compounds were characterized on the basis of their powder X-Ray Diffraction, UV-Vis, IR, NMR, elemental analysis and MS spectral data. DFT/B3LYP mode of calculations were carried out to determine some theorical parameters of the molecular structure of the ligand. The purity of the azoic ligand and the metal complexes were ascertained by TLC and melting points. The analysis of the IR spectra of the polyfunctionalized azo compound 11 and its metal complexes 12 and 13, reveals that the coordination patterns of the ligand are hexadentate and tetradentate respectively. Based on the UV-Vis electronic spectral data and relevant literature reports, the ligand and derived complexes were assigned the E (trans) isomer form. Likewise, octahedral and square-planar geometries were respectively assigned to the cobalt(II) complexes. The broth microdilution method was used for antibacterial assays through the determination of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). The ligand 11 displayed moderate antibacterial activity (MIC = 32-128 µg/mL) against Staphylococcus aureus ATCC25923, Escherichia coli ATCC25922, Pseudomonas aeruginosa and Klebsiella pneumoniae 22. The octahedral cobalt(II) complex 12 showed moderate activity against Pseudomonas aeruginosa (MIC = 128 µg/mL) and Klebsiella pneumoniae 22 (MIC = 64 µg/mL) and none against Staphylococcus aureus ATCC25923 and Escherichia coli ATCC25922, whereas the square-planar complex 13 displayed moderate activity only on Klebsiella pneumoniae 22 (MIC = 64 µg/mL).

Coupling of a Major Allergen to the Surface of Immune Cells for Use in Prophylactic Cell Therapy for the Prevention of IgE-Mediated Allergy.

Up to a third of the world's population suffers from allergies, yet the effectiveness of available preventative measures remains, at large, poor. Consequently, the development of successful prophylactic strategies for the induction of tolerance against allergens is crucial. In proof-of-concept studies, our laboratory has previously shown that the transfer of autologous hematopoietic stem cells (HSC) or autologous B cells expressing a major grass pollen allergen, Phl p 5, induces robust tolerance in mice. However, eventual clinical translation would require safe allergen expression without the need for retroviral transduction. Therefore, we aimed to chemically couple Phl p 5 to the surface of leukocytes and tested their ability to induce tolerance. Phl p 5 was coupled by two separate techniques, either by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) or by linkage via a lipophilic anchor, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol)-maleimide (DSPE-PEG-Mal). The effectiveness was assessed in fresh and cultured Phl p 5-coupled cells by flow cytometry, image cytometry, and immunofluorescence microscopy. Chemical coupling of Phl p 5 using EDC was robust but was followed by rapid apoptosis. DSPE-PEG-Mal-mediated linkage was also strong, but antigen levels declined due to antigen internalization. Cells coupled with Phl p 5 by either method were transferred into autologous mice. While administration of EDC-coupled splenocytes together with short course immunosuppression initially reduced Phl p 5-specific antibody levels to a moderate degree, both methods did not induce sustained tolerance towards Phl p 5 upon several subcutaneous immunizations with the allergen. Overall, our results demonstrate the successful chemical linkage of an allergen to leukocytes using two separate techniques, eliminating the risks of genetic modifications. More durable surface expression still needs to be achieved for use in prophylactic cell therapy protocols.

10 Years of SYNTAX: Closing an Era of Clinical Research After Identifying New Outcome Determinants.

The SYNTAX trial randomized patients equally eligible for coronary artery bypass grafting or percutaneous coronary intervention using the Heart Team approach. The SYNTAXES study achieved a follow-up rate of 93.8% and reported the 10-year vital status. Factors associated with increased mortality at 10 years were pharmacologically treated diabetes mellitus, increased waist circumference, reduced left ventricular function, prior cerebrovascular and peripheral vascular disease, western Europe and North American descent, current smoking, chronic obstructive pulmonary disease, elevated C-reactive protein, anemia, and an increase in HbA1c. Procedural factors associated with higher 10 years mortality include periprocedural myocardial infarction, extensive stenting, small stents, ≥1 heavily calcified lesion, ≥1 bifurcation lesion, residual SYNTAX score >8, and staged percutaneous coronary intervention. Optimal medical therapy at 5 years, use of statins, on-pump coronary artery bypass grafting, multiple arterial grafts, and higher physical component score and mental component score were associated with lower mortality at 10 years. Numerous scores and prediction models were developed to help individualize risk assessment. Machine learning has emerged as a novel approach for developing risk models.

Incorporation and Deposition of Spin Crossover Materials into and onto Electrospun Nanofibers.

We synthesized iron(II)-triazole spin crossover compounds of the type [Fe(atrz)3]X2 and incorporated and deposited them on electrospun polymer nanofibers. For this, we used two separate electrospinning methods with the goal of obtaining polymer complex composites with intact switching properties. In view of possible applications, we chose iron(II)-triazole-complexes that are known to exhibit spin crossover close to ambient temperature. Therefore, we used the complexes [Fe(atrz)3]Cl2 and [Fe(atrz)3](2ns)2 (2ns = 2-Naphthalenesulfonate) and deposited those on fibers of polymethylmethacrylate (PMMA) and incorporated them into core-shell-like PMMA fiber structures. These core-shell structures showed to be inert to outer environmental influences, such as droplets of water, which we purposely cast on the fiber structure, and it did not rinse away the used complex. We analyzed both the complexes and the composites with IR-, UV/Vis, Mössbauer spectroscopy, SQUID magnetometry, as well as SEM and EDX imaging. The analysis via UV/Vis spectroscopy, Mössbauer spectroscopy, and temperature-dependent magnetic measurements with the SQUID magnetometer showed that the spin crossover properties were maintained and were not changed after the electrospinning processes.

Clinical Practice Experiences Using a Professional Diabetes Management Ecosystem During COVID.

BACKGROUND: Challenges of patient care in diabetes were exacerbated by COVID, undermining the ability of patients to engage in-person with health care professionals (HCPs). To combat this, there has been accelerated adoption of telemedicine to support patient and provider connectivity. METHODS: We collated survey information regarding telemedicine from 21 European clinical institutions. Health care professionals joined virtual meetings focusing on the OneTouch Reveal (OTR) ecosystem and its utility for conducting telemedicine. Selected HCPs provided clinical case studies to explain how the OTR ecosystem supported patient care. RESULTS: Remote consultations increased by nearly 50% in 21 European clinics during the pandemic (Belgium [24%], Iberia [65%], Germany [34%], Italy [54%]). In all, 52% of people with diabetes using OTR app to connect remotely with HCPs had type 1 diabetes and 48% had type 2 diabetes. Remote connection methods included telephone (60%), email (19%), video chat (10%), text only (3%), or a mix of these methods (8%). Health care professionals usually reviewed patient data during consultations (45%) rather than before consultations (25%). Fifty-five percent of HCPs indicated digital ecosystems like OTR ecosystem would become their standard of care for diabetes management. In-depth conversations with HCPs provided a deeper understanding of how a digital ecosystem integrated into clinical practice and population management. In addition, five patient case studies using OTR ecosystem were provided by a selection of our HCPs. CONCLUSION: Diabetes management solutions, such as OTR ecosystem, supported telemedicine during the pandemic and will continue to play a valuable role in patient care beyond the pandemic.

10-Year All-Cause Mortality Following Percutaneous or Surgical Revascularization in Patients With Heavy Calcification.

OBJECTIVES: The aim of this study was to assess 10-year all-cause mortality in patients with heavily calcified lesions (HCLs) undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). BACKGROUND: Limited data are available on very long term outcomes in patients with HCLs according to the mode of revascularization. METHODS: This substudy of the SYNTAXES (Synergy Between PCI With Taxus and Cardiac Surgery Extended Survival) study assessed 10-year all-cause mortality according to the presence of HCLs within lesions with >50% diameter stenosis and identified during the calculation of the anatomical SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) score among 1,800 patients with the 3-vessel disease and/or left main disease randomized to PCI or CABG in the SYNTAX trial. Patients with HCLs were further stratified according to disease type (3-vessel disease or left main disease) and assigned treatment (PCI or CABG). RESULTS: The 532 patients with ≥1 HCL had a higher crude mortality rate at 10 years than those without (36.4% vs 22.3%; HR: 1.79; 95% CI: 1.49-2.16; P < 0.001). After adjustment, an HCL remained an independent predictor of 10-year mortality (HR: 1.36; 95% CI: 1.09-1.69; P = 0.006). There was a significant interaction in mortality between treatment effect (PCI and CABG) and the presence or absence of HCLs (Pinteraction = 0.005). In patients without HCLs, mortality was significantly higher after PCI than after CABG (26.0% vs 18.8%; HR: 1.44; 95% CI: 0.97-1.41; P = 0.003), whereas in those with HCLs, there was no significant difference (34.0% vs 39.0%; HR: 0.85; 95% CI: 0.64-1.13; P = 0.264). CONCLUSIONS: At 10 years, the presence of an HCL was an independent predictor of mortality, with a similar prognosis following PCI or CABG. Whether HCLs require special consideration when deciding the mode of revascularization beyond their current contribution to the anatomical SYNTAX score deserves further evaluation. (Synergy Between PCI With TAXUS and Cardiac Surgery: SYNTAX Extended Survival [SYNTAXES], NCT03417050; SYNTAX Study: TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries [SYNTAX], NCT00114972).

Hematopoietic cell transplantation in severe combined immunodeficiency: The SCETIDE 2006-2014 European cohort.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) represents a curative treatment for patients with severe combined immunodeficiency (SCID), a group of monogenic immune disorders with an otherwise fatal outcome. OBJECTIVE: We performed a comprehensive multicenter analysis of genotype-specific HSCT outcome, including detailed analysis of immune reconstitution (IR) and the predictive value for clinical outcome. METHODS: HSCT outcome was studied in 338 patients with genetically confirmed SCID who underwent transplantation in 2006-2014 and who were registered in the SCETIDE registry. In a representative subgroup of 152 patients, data on IR and long-term clinical outcome were analyzed. RESULTS: Two-year OS was similar with matched family and unrelated donors and better than mismatched donor HSCT (P < .001). The 2-year event-free survival (EFS) was similar in matched and mismatched unrelated donor and less favorable in mismatched related donor (MMRD) HSCT (P < .001). Genetic subgroups did not differ in 2-year OS (P = .1) and EFS (P = .073). In multivariate analysis, pretransplantation infections and use of MMRDs were associated with less favorable OS and EFS. With a median follow-up of 6.2 years (range, 2.0-11.8 years), 73 of 152 patients in the IR cohort were alive and well without Ig dependency. IL-2 receptor gamma chain/Janus kinase 3/IL-7 receptor-deficient SCID, myeloablative conditioning, matched donor HSCT, and naive CD4 T lymphocytes >0.5 × 10e3/µL at +1 year were identified as independent predictors of favorable clinical and immunologic outcome. CONCLUSION: Recent advances in HSCT in SCID patients have resulted in improved OS and EFS in all genotypes and donor types. To achieve a favorable long-term outcome, treatment strategies should aim for optimal naive CD4 T lymphocyte regeneration.

Long-term survival after coronary bypass surgery with multiple versus single arterial grafts.

OBJECTIVES: This study sought to evaluate the long-term differences in survival between multiple arterial grafts (MAG) and single arterial grafts (SAG) in patients who underwent coronary artery bypass grafting (CABG) in the SYNTAX study. METHODS: The present analysis included the randomized and registry-treated CABG patients (n = 1509) from the SYNTAX Extended Survival study (SYNTAXES). Patients with only venous (n = 42) or synthetic grafts (n = 1) were excluded. The primary end point was all-cause death at the longest follow-up. Multivariable Cox regression was used to adjust for differences in baseline characteristics. Sensitivity analysis using propensity matching with inverse probability for treatment weights was performed. RESULTS: Of the 1466 included patients, 465 (31.7%) received MAG and 1001 (68.3%) SAG. Patients receiving MAG were younger and at lower risk. At the longest follow-up of 12.6 years, all-cause death occurred in 23.6% of MAG and 40.0% of SAG patients [adjusted hazard ratio (HR) 0.74, 95% confidence interval (CI) (0.55-0.98); P = 0.038], which was confirmed by sensitivity analysis. MAG in patients with the three-vessel disease was associated with significant lower unadjusted and adjusted all-cause death at 12.6 years [adjusted HR 0.65, 95% CI (0.44-0.97); P = 0.033]. In contrast, no significance was observed after risk adjustment in patients with the left main disease, with and without diabetes, or among SYNTAX score tertiles. CONCLUSIONS: In the present post hoc analysis of all-comers patients from the SYNTAX trial, MAG resulted in markedly lower all-cause death at 12.6-year follow-up compared to a SAG strategy. Hence, this striking long-term survival benefit of MAG over SAG encourages more extensive use of multiple arterial grafting in selected patients with reasonable life expectancy. TRIAL REGISTRATION: SYNTAXES ClinicalTrials.gov reference: NCT03417050; SYNTAX ClinicalTrials.gov reference: NCT00114972.

Single or multiple arterial bypass graft surgery vs. percutaneous coronary intervention in patients with three-vessel or left main coronary artery disease.

AIM: The aim of this study was to compare long-term all-cause mortality between patients receiving percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) using multiple (MAG) or single arterial grafting (SAG). METHODS AND RESULTS: The current study is a post hoc analysis of the SYNTAX Extended Survival Study, which compared PCI with CABG in patients with three-vessel (3VD) and/or left main coronary artery disease (LMCAD) and evaluated survival with ≥10 years of follow-up. The primary endpoint was all-cause mortality at maximum follow-up (median 11.9 years) assessed in the as-treated population. Of the 1743 patients, 901 (51.7%) underwent PCI, 532 (30.5%) received SAG, and 310 (17.8%) had MAG. At maximum follow-up, all-cause death occurred in 305 (33.9%), 175 (32.9%), and 70 (22.6%) patients in the PCI, SAG, and MAG groups, respectively (P < 0.001). Multiple arterial grafting [adjusted hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.49-0.89], but not SAG (adjusted HR 0.83, 95% CI 0.67-1.03), was associated with significantly lower all-cause mortality compared with PCI. In patients with 3VD, both MAG (adjusted HR 0.55, 95% CI 0.37-0.81) and SAG (adjusted HR 0.68, 95% CI 0.50-0.91) were associated with significantly lower mortality than PCI, whereas in LMCAD patients, no significant differences between PCI and MAG (adjusted HR 0.90, 95% CI 0.56-1.46) or SAG (adjusted HR 1.11, 95% CI 0.81-1.53) were observed. In patients with revascularization of all three major myocardial territories, a positive correlation was observed between the number of myocardial territories receiving arterial grafts and survival (Ptrend = 0.003). CONCLUSION: Our findings suggest that MAG might be the more desirable configuration for CABG to achieve lower long-term all-cause mortality than PCI in patients with 3VD and/or LMCAD. TRIAL REGISTRATION: Registered on clinicaltrial.gov. SYNTAXES: NCT03417050 (https://clinicaltrials.gov/ct2/show/NCT03417050); SYNTAX: NCT00114972 (https://www.clinicaltrials.gov/ct2/show/NCT00114972).

Ten-year all-cause mortality according to smoking status in patients with severe coronary artery disease undergoing surgical or percutaneous revascularization.

AIMS: To evaluate the impact of various smoking status on 10-year all-cause mortality and to examine a relative treatment benefit of coronary artery bypass grafting (CABG) vs. percutaneous coronary intervention (PCI) according to smoking habits. METHODS AND RESULTS: The SYNTAX Extended Survival study evaluated vital status up to 10 years in 1800 patients with de novo three-vessel disease and/or left main coronary artery disease randomized to CABG or PCI in the SYNTAX trial. In the present analysis, patients were divided into three groups (current, former, or never smokers), and the primary endpoint of 10-year all-cause mortality was assessed according to smoking status. Smoking status was available in 1793 (99.6%) patients at the time of randomization, of whom 363 were current smokers, 798 were former smokers, and 632 were never smokers. The crude rates of 10-year all-cause mortality were 29.7% in current smokers, 25.3% in former smokers, and 25.9% in never smokers (Log-rank P = 0.343). After adjustment for imbalances in baseline characteristics, current smokers had a significantly higher risk of 10-year all-cause mortality than never smokers [adjusted hazard ratio (aHR): 2.29; 95% confidence interval (CI): 1.60-3.27; P < 0.001], whereas former smokers did not. PCI was associated with a higher risk of all-cause mortality than CABG among current smokers (HR: 1.60; 95% CI: 1.09-2.35; P = 0.017), but it failed to show a significant interaction between revascularization strategies and smoking status (Pinteraction = 0.910). CONCLUSION: Current smokers had a higher adjusted risk of 10-year all-cause mortality, whereas former smokers did not. The treatment effect of CABG vs. PCI did not differ significantly according to smoking status. CLINICAL TRIAL REGISTRATION: SYNTAX: ClinicalTrials.gov reference: NCT00114972; SYNTAX Extended Survival. ClinicalTrials.gov reference: NCT03417050.

Impact of Optimal Medical Therapy on 10-Year Mortality After Coronary Revascularization.

BACKGROUND: The benefit of optimal medical therapy (OMT) on 5-year outcomes in patients with 3-vessel disease and/or left main disease after percutaneous coronary intervention or coronary artery bypass grafting (CABG) was demonstrated in the randomized SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) trial. OBJECTIVES: The objective of this analysis is to assess the impact of the status of OMT at 5 years on 10-year mortality after percutaneous coronary intervention or CABG. METHODS: This is a subanalysis of the SYNTAXES (Synergy Between PCI With Taxus and Cardiac Surgery Extended Survival) study, which evaluated for up to 10 years the vital status of patients who were originally enrolled in the SYNTAX trial. OMT was defined as the combination of 4 types of medications: at least 1 antiplatelet drug, statin, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, and beta-blocker. After stratifying participants by the number of individual OMT agents at 5 years and randomized treatment, a landmark analysis was conducted to assess the association between treatment response and 10-year mortality. RESULTS: In 1,472 patients, patients on OMT at 5 years had a significantly lower mortality at 10 years compared with those on ≤2 types of medications (13.1% vs 19.9%; adjusted HR: 0.470; 95% CI: 0.292-0.757; P = 0.002) but had a mortality similar to those on 3 types of medications. Furthermore, patients undergoing CABG with the individual OMT agents, antiplatelet drug and statin, at 5 years had lower 10-year mortality than those without. CONCLUSIONS: In patients with 3-vessel and/or left main disease undergoing percutaneous coronary intervention or CABG, medication status at 5 years had a significant impact on 10-year mortality. Patients on OMT with guideline-recommended pharmacologic therapy at 5 years had a survival benefit. (Synergy Between PCI With Taxus and Cardiac Surgery: SYNTAX Extended Survival [SYNTAXES]; NCT03417050; Taxus Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries [SYNTAX]; NCT00114972).

From the (skin) doctor's office to the lecture hall: An innovative, practice-oriented, media-supported teaching project with supra-regional interdisciplinary usage options.

BACKGROUND: The transfer of practical knowledge and skills is the focus of modern medical teaching (master plan medical studies 2020). The aim of the teaching project is to provide medical students with important dermatological learning goals and contents by using innovative methods. METHODS: As part of a teaching project funded by the Federal Ministry of Education and Research (BMBF) at the Department of Dermatology, University Hospital Schleswig-Holstein in Kiel, various new, partly media-supported teaching modules were developed in addition to curricular teaching and optimized by regular acceptance evaluations during the development process. RESULTS: (1.) Professionally created instructional movies present essential techniques for diagnosis and therapy: standardized dermatological whole-body examination, wound smear sampling, performing of biopsies, curettages and excisions as well as skin suturing techniques on exercise material and on patients. (2.) Tutor-based courses offer students the ability to practice these techniques independently. (3.) Seminar lectures show different clinical pictures in university medicine and doctor's offices as well as the important interaction between clinic and doctor's practice in patient care. (4.) One-day internships in a teaching practice convey the activity in this setting. (5.) Seminars on psychodermatology provide insight into the stress caused by the skin disease using the "bio-psychosocial disease model". So far, 282 students have participated in the modules. In 88-100 % of the evaluations, there was a desire for further expansion of the new courses and integration into curricular teaching. CONCLUSIONS: Our innovative teaching modules resulted in great acceptance by the students. The freely available instructional films were successfully used by other university locations due to networking in the Academic Teaching Forum. One perspective is the supra-regional and sustainable use of our teaching modules and the transfer of the concept to other departments and faculties.

Ten-Year All-Cause Death According to Completeness of Revascularization in Patients With Three-Vessel Disease or Left Main Coronary Artery Disease: Insights From the SYNTAX Extended Survival Study.

BACKGROUND: Ten-year all-cause death according to incomplete (IR) versus complete revascularization (CR) has not been fully investigated in patients with 3-vessel disease and left main coronary artery disease undergoing percutaneous coronary intervention (PCI) versus coronary artery bypass grafting (CABG). METHODS: The SYNTAX Extended Survival study (Synergy Between PCI With TAXUS and Cardiac Surgery: SYNTAX Extended Survival [SYNTAXES]) evaluated vital status up to 10 years in patients who were originally enrolled in the SYNTAX trial. In the present substudy, outcomes of the CABG CR group were compared with the CABG IR, PCI CR, and PCI IR groups. In addition, in the PCI cohort, the residual SYNTAX score (rSS) was used to quantify the extent of IR and to assess its association with fatal late outcome. The rSS of 0 suggests CR, whereas a rSS>0 identifies the degree of IR. RESULTS: IR was more frequently observed in patients with PCI versus CABG (56.6% versus 36.8%) and more common in those with 3-vessel disease than left main coronary artery disease in both the PCI arm (58.5% versus 53.8%) and the CABG arm (42.8% versus 27.5%). Patients undergoing PCI with CR had no significant difference in 10-year all-cause death compared with those undergoing CABG (22.2% for PCI with CR versus 24.3% for CABG with IR versus 23.8% for CABG with CR). In contrast, those with PCI and IR had a significantly higher risk of all-cause death at 10 years compared with CABG and CR (33.5% versus 23.7%; adjusted hazard ratio, 1.48 [95% CI, 1.15-1.91]). When patients with PCI were stratified according to the rSS, those with a rSS≤8 had no significant difference in all-cause death at 10 years as the other terciles (22.2% for rSS=0 versus 23.9% for rSS>0-4 versus 28.9% for rSS>4-8), whereas a rSS>8 had a significantly higher risk of 10-year all-cause death than those undergoing PCI with CR (50.1% versus 22.2%; adjusted hazard ratio, 3.40 [95% CI, 2.13-5.43]). CONCLUSIONS: IR is common after PCI, and the degree of incompleteness was associated with 10-year mortality. If it is unlikely that complete (or nearly complete; rSS<8) revascularization can be achieved with PCI in patients with 3-vessel disease, CABG should be considered. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00114972. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03417050.

Hydrocortisone dosing in children with classic congenital adrenal hyperplasia: results of the German/Austrian registry.

OBJECTIVE: Treatment of classic congenital adrenal hyperplasia (CAH) is necessary to compensate for glucocorticoid/mineralocorticoid deficiencies and to suppress androgen excess. Hydrocortisone (HC) is preferred in growing children with classic CAH but recommendations regarding dosage/administration are inconsistent. The aim of this study was to evaluate HC dosing in children with CAH in relation to chronological age, sex, and phenotype based on a multicenter CAH registry. DESIGN: The CAH registry was initiated in 1997 by the AQUAPE in Germany. On December 31st 2018, data from 1571 patients were included. METHODS: A custom-made electronic health record software is used at the participating centers. Pseudonymized data are transferred for central analysis. Parameters were selected based on current guidelines. Descriptive analyses and linear regression models were implemented with SAS 9.4. RESULTS: We identified 1288 patients on exclusive treatment with hydrocortisone three times daily (604 boys; median age 7.2 years; 817 salt-wasting phenotype, 471 simple-virilizing phenotype). The mean (lower-upper quartiles) daily HC dose (mg/m² body surface area) was 19.4 (18.9-19.8) for patients <3 months (n = 329), 15.0 (14.6-15.3) for age ≥3-12 months (n = 463), 14.0 (13.7-14.3) for age 1-5.9 years (n = 745), 14.2 (14.0-14.5) for age 6 years to puberty entry (n = 669), and 14.9 (14.6-15.2) during puberty to 18 years (n = 801). Fludrocortisone was administered in 74.1% of patients with a median daily dosage of 88.8 µg. CONCLUSION: Our analyses showed that still a high proportion of children are treated with HC doses higher than recommended. This evaluation provides comprehensive information on nationwide hydrocortisone substitution dosages in children with CAH underlining the benefit of systematic data within a registry to assess daily practice.

Mortality 10 Years After Percutaneous or Surgical Revascularization in Patients With Total Coronary Artery Occlusions.

BACKGROUND: The long-term clinical benefit after percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) in patients with total occlusions (TOs) and complex coronary artery disease has not yet been clarified. OBJECTIVES: The objective of this analysis was to assess 10-year all-cause mortality in patients with TOs undergoing PCI or CABG. METHODS: This is a subanalysis of patients with at least 1 TO in the SYNTAXES (Synergy Between PCI With Taxus and Cardiac Surgery Extended Survival) study, which investigated 10-year all-cause mortality in the SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) trial, beyond its original 5-year follow-up. Patients with TOs were further stratified according to the status of TO recanalization or revascularization. RESULTS: Of 1,800 randomized patients to the PCI or CABG arm, 460 patients had at least 1 lesion of TO. In patients with TOs, the status of TO recanalization or revascularization was not associated with 10-year all-cause mortality, irrespective of the assigned treatment (PCI arm: 29.9% vs. 29.4%; adjusted hazard ratio [HR]: 0.992; 95% confidence interval [CI]: 0.474 to 2.075; p = 0.982; and CABG arm: 28.0% vs. 21.4%; adjusted HR: 0.656; 95% CI: 0.281 to 1.533; p = 0.330). When TOs existed in left main and/or left anterior descending artery, the status of TO recanalization or revascularization did not have an impact on the mortality (34.5% vs. 26.9%; adjusted HR: 0.896; 95% CI: 0.314 to 2.555; p = 0.837). CONCLUSIONS: At 10-year follow-up, the status of TO recanalization or revascularization did not affect mortality, irrespective of the assigned treatment and location of TOs. The present study might support contemporary practice among high-volume chronic TO-PCI centers where recanalization is primarily offered to patients for the management of angina refractory to medical therapy when myocardial viability is confirmed. (Synergy Between PCI With TAXUS and Cardiac Surgery: SYNTAX Extended Survival [SYNTAXES]; NCT03417050; SYNTAX Study: TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries [SYNTAX]; NCT00114972).

Ten-year all-cause death following percutaneous or surgical revascularization in patients with prior cerebrovascular disease: insights from the SYNTAX Extended Survival study.

BACKGROUND: Coronary bypass artery grafting (CABG) has a higher procedural risk of stroke than percutaneous coronary intervention (PCI), but may offer better long-term survival. The optimal revascularization strategy for patients with prior cerebrovascular disease (CEVD) remains unclear. METHODS AND RESULTS: The SYNTAXES study assessed the vital status out to 10 year of patients with three-vessel disease and/or left main coronary artery disease enrolled in the SYNTAX trial. The relative efficacy of PCI vs. CABG in terms of 10 year all-cause death was assessed according to prior CEVD. The primary endpoint was 10 year all-cause death. The status of prior CEVD was available in 1791 (99.5%) patients, of whom 253 patients had prior CEVD. Patients with prior CEVD were older and had more comorbidities (medically treated diabetes, insulin-dependent diabetes, metabolic syndrome, peripheral vascular disease, chronic obstructive pulmonary disease, impaired renal function, and congestive heart failure), compared with those without prior CEVD. Prior CEVD was an independent predictor of 10 year all-cause death (adjusted HR: 1.35; 95% CI: 1.04-1.73; p = 0.021). Patients with prior CEVD had a significantly higher risk of 10 year all-cause death (41.1 vs. 24.1%; HR: 1.92; 95% CI: 1.54-2.40; p < 0.001). The risk of 10 year all-cause death was similar between patients receiving PCI or CABG irrespective of the presence of prior CEVD (p-interaction = 0.624). CONCLUSION: Prior CEVD was associated with a significantly increased risk of 10 year all-cause death which was similar in patients treated with PCI or CABG. These results do not support preferential referral for PCI rather than CABG in patients with prior CEVD. TRIAL REGISTRATION: SYNTAX: ClinicalTrials.gov reference: NCT00114972. SYNTAX Extended Survival: ClinicalTrials.gov reference: NCT03417050.

Extended stereotactic brain biopsy in suspected primary central nervous system angiitis: good diagnostic accuracy and high safety.

OBJECTIVE: To evaluate the diagnostic accuracy and safety of extended stereotactic brain biopsy (ESBB) in a single center cohort with suspected primary angiitis of the central nervous system (PACNS). METHODS: A standardized stereotactic biopsy targeting MRI-positive lesions and collecting samples from the meninges and the cortex as well as from the white matter was performed in 23 patients with clinically suspected PACNS between 2010 and 2017. The relationship between biopsy yield and clinical characteristics, cerebrospinal fluid parameters, MR-imaging, time point of biopsy and exact localization of biopsy as well as number of tissue samples were examined. RESULTS: PACNS was confirmed in 7 of 23 patients (30.4%). Alternative diagnoses were identified in 7 patients (30%). A shorter time period between the onset or worsening of symptoms (p = 0.018) and ESBB significantly increased the diagnostic yield. We observed only minor and transient postoperative complications in 3 patients (13.0%). ESBB led to a direct change of the therapeutic regime in 13 of 23 patients (56.5%). Careful neuropathological analysis furthermore revealed that cortical samples were crucial in obtaining a diagnosis. CONCLUSION: ESBB is a safe approach with good feasibility, even in critically ill patients, and high diagnostic accuracy in patients with suspected PACNS changing future therapies in 13 of 23 patients (56.5%). Early biopsy after symptom onset/worsening is crucial and (sub)acute MRI-lesions should be targeted with a particular need for biopsy samples from the cortical layer.

The effect of polyethylenglycol gel on the delivery and osteogenic differentiation of homologous tooth germ-derived stem cells in a porcine model.

OBJECTIVES: The aim of this study was to investigate if bone regeneration can be promoted by homologous transplantation of STRO-1 sorted (STRO-1+) porcine tooth germ mesenchymal stem cells (TGSCs) with the combination of polyethylenglycol (PEG)-based hydrogel and biphasic calcium phosphate (BCP) scaffolds. MATERIAL AND METHODS: TGSCs were isolated from impacted third molars of domestic pigs. Nine critical-sized defects were created as (1) untreated defect; filled with (2) autogenous bone; (3) BCP + PEG; (4) BCP + PEG + unsorted TGSCs; (5) BCP + unsorted TGSCs; (6) BCP + PEG + STRO-1-sorted TGSCs; (7) BCP + STRO-1-sorted TGSCs; (8) BCP + PEG + osteogenic induced unsorted TGSCs; and (9) BCP + PEG + osteogenic induced STRO-1-sorted TGSCs in 20 domestic pigs. CM-DiI labelling was used to track cells in vivo. Histomorphometric assessment of new bone formation was achieved by toluidine blue O staining and microradiography after 1, 2, 4 and 12 weeks posttransplantation. RESULTS: Complete healing was achieved in all defects although defects with PEG hydrogel presented better bone formation while STRO-1+ and unsorted TGSCs showed similar ability to form new bone after 12 weeks. Transplanted cells were seen in defects where PEG hydrogel was used as carriers in contrast to defects treated with cells and only bone grafts. CONCLUSIONS: PEG hydrogel is an efficient carrier for homologous stem cell transplantation. TGSCs are capable of promoting bone healing in critical-sized defects in combination with bone graft and PEG hydrogel. CLINICAL RELEVANCE: This study provides information about the importance of the delivery vehicle for future translational stem cell delivery approaches.

MicroRNA-93 acts as an "anti-inflammatory tumor suppressor" in glioblastoma.

BACKGROUND: Inflammation is an important driver of malignant glioma disease. Inflammatory mediators are not only produced by immune cells in the tumor microenvironment, but also by glioblastoma (GBM) cells themselves creating a mutually reinforcing loop. We here aimed at identifying an "anti-inflammatory switch" that allows to dampen inflammation in GBM. METHODS: We used human GBM specimens, primary cultures, and cell lines. The response of GBM cells toward inflammatory stimuli was tested by incubation with supernatant of stimulated human immune cells. Expression levels were measured by whole transcriptome microarrays and qRT-PCR, and protein was quantified by LUMINEX and SDS-PAGE. MicroRNA binding to 3'UTRs was analyzed by luciferase assays. Proliferation rates were determined by flow cytometry, and invasion and angiogenesis were studied using migration and endothelial tube formation assays. RESULTS: We demonstrated GBM cells to secrete high amounts of proinflammatory mediators in an inflammatory microenvironment. We found miR-93 as a potential "anti-inflammatory tumor suppressor" dramatically downregulated in GBM. Concordantly, cytokine secretion dropped after miR-93 re-expression. Transfection of miR-93 in GBM cells led to down-regulation of hubs of the inflammatory networks, namely, HIF-1α and MAP3K2 as well as IL-6, G-CSF, IL-8, LIF, IL-1ß, COX2, and CXCL5. We showed only COX2 and CXCL5 to be indirectly regulated by miR-93 while all other genes are true targets. Phenotypically, re-expression of miR-93 in GBM cells substantially suppressed proliferation, migration, and angiogenesis. CONCLUSIONS: Alleviating GBM-derived inflammation by re-expression of miR-93 may be a powerful tool to mitigate these tumors' aggressiveness and holds promise for new clinical approaches.