Modelling atopic dermatitis in healthy human skin for the characterization of topical compounds.

Suitable human models for the development and characterization of topical compounds for inflammatory skin diseases such as atopic dermatitis are not readily available to date. We describe here the development of a translational model involving healthy human skin mimicking major aspects of AD and its application for the characterization of topical Janus kinase inhibitors. Full thickness human abdominal skin obtained from plastic surgery stimulated in vitro with IL4 and IL13 shows molecular features of AD. This is evidenced by STAT6 phosphorylation assessed by immunohistochemistry and analysis of skin lysates. Broad transcriptome changes assessed by AmpliSeq followed by gene set variation analysis showed a consistent upregulation of gene signatures characterizing AD in this model. Topical application of experimental formulations of compounds targeting the JAK pathway to full thickness skin normalizes the molecular features of AD induced by IL4 and IL13 stimulation. The inhibitory effects of topical JAK inhibitors on molecular features of AD are supported by pharmacokinetic analysis. The model described here is suited for the characterization of topical compounds for AD and has the potential to be extended to other inflammatory skin diseases and pathophysiological pathways.

Quality of life, effectiveness, and safety of aflibercept plus FOLFIRI in older patients with metastatic colorectal cancer: An analysis of the prospective QoLiTrap study.

INTRODUCTION: Colorectal cancer (CRC) mainly affects older patients. The pivotal VELOUR phase III trial of aflibercept plus FOLFIRI in metastatic CRC (mCRC) included only 5.9% of patients aged ≥75 years. Herein, we report a preplanned analysis from QoLiTrap, a large prospective observational study evaluating the impact of age on quality of life (QoL), effectiveness, and safety of aflibercept plus FOLFIRI in daily clinical practice in Europe. MATERIALS AND METHODS: Enrolled patients had progressive mCRC, had failed a prior oxaliplatin-based regimen, and had received aflibercept (4 mg/kg) plus FOLFIRI every two weeks until disease progression, death, unacceptable toxicity, or physician/patient decision. Analyses were performed by age classes (<60, 60-64, 65-69, 70-74, and ≥ 75 years). The primary endpoint was the percentage of patients whose global health status (GHS) of the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) was maintained (i.e., no worsening from baseline by at least 5% over a 12-week treatment). Secondary endpoints included tumor objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Overall, 1277 patients (<60 years, n = 327; 60-64 years, n = 231; 65-69 years, n = 227; 70-74 years, n = 259; and ≥ 75 years, n = 233) were treated, of whom 872 were evaluable for QoL. GHS was maintained in 36.5%, 41.6%, 38.9%, 41.8%, and 44.8% of patients aged <60, 60-64, 65-69, 70-74, and ≥ 75 years, respectively. Age did not influence PFS (median 7.8 months), OS (median 14.4 months), or ORR (20.8%). Number of cycles, dose delays for any cause, and dose reductions for adverse events (AEs) were comparable between age classes. Grade ≥ 3 AEs occurred in 47.7%, 51.9%, 51.5%, 55.2%, and 55.8% of patients aged <60, 60-64, 65-69, 70-74, and ≥ 75 years, respectively. The main grade ≥ 3 AEs were hypertension (11.2%) and diarrhea (9%) in patients aged ≥75 years. DISCUSSION: The results suggest that aflibercept plus FOLFIRI maintains QoL and retains its activity, including a high objective tumor response, regardless of age and treatment line. In fit older patients, the safety profile seems manageable, with no new safety signals.

Adriforant is a functional antagonist of histamine receptor 4 and attenuates itch and skin inflammation in mice.

BACKGROUND: Histamine has been postulated to play a role in atopic dermatitis via histamine receptor 4, mediating pruritic and inflammatory effects. The H4R antagonist adriforant (PF-3893787 or ZPL389) indicated clinical efficacy in a Ph2a study in atopic dermatitis. Preclinical investigations of adriforant had been scarce as experiments in transfectants with H4R from several species suggested partial agonism, not seen in human cells. OBJECTIVE: During the Ph2b trial in AD, we performed experiments to understand the pharmacology of adriforant in primary murine cells and in vivo models. We assessed its effects on ERK phosphorylation and transcriptional changes in bone marrow-derived mast cells, histamine-dependent Ca2+ flux in neurons and histamine-induced itch response. In addition, its impact on MC903-induced skin inflammation was evaluated. RESULTS: We show that, contrary to transfectants, adriforant is a competitive antagonist of the murine histamine receptor 4, antagonizes histamine-induced ERK phosphorylation, normalizes histamine-induced transcriptional changes in mast cells and reduces histamine-dependent Ca2+ flux in neurons. Administration to mice reduces acute histamine-induced itch response. In addition, adriforant ameliorates inflammation in the mouse MC903 model. CONCLUSIONS: Our results suggest that functional inhibition of histamine receptor 4 by adriforant reduces itch and inflammation in vivo. The effects observed in mice, however, did not translate to clinical efficacy in patients as the Ph2b clinical trial with adriforant did not meet pre-specified efficacy endpoints. Given the complex pathogenesis of AD, antagonism of histamine receptor 4 alone appears insufficient to reduce disease severity in AD patients, despite the effects seen in mouse models.

Comparative effectiveness of three versions of a stepped care model for insomnia differing in the amount of therapist support in internet-delivered treatment: study protocol for a pragmatic cluster randomised controlled trial (GET Sleep).

INTRODUCTION: It is unclear how internet-delivered cognitive-behavioural therapy for insomnia (CBT-I) can be integrated into healthcare systems, and little is known about the optimal level of therapist guidance. The aim of this study is to investigate three different versions of a stepped care model for insomnia (IG1, IG2, IG3) versus treatment as usual (TAU). IG1, IG2 and IG3 rely on treatment by general practitioners (GPs) in the entry level and differ in the amount of guidance by e-coaches in internet-delivered CBT-I. METHODS AND ANALYSIS: In this randomised controlled trial, 4268 patients meeting International Classification of Diseases, Tenth Revision (ICD-10) criteria for insomnia will be recruited. The study will use cluster randomisation of GPs with an allocation ratio of 3:3:3:1 (IG1, IG2, IG3, TAU). In step 1 of the stepped care model, GPs will deliver psychoeducational treatment; in step 2, an internet-delivered CBT-I programme will be used; in step 3, GPs will refer patients to specialised treatment. Outcomes will be collected at baseline, and 4 weeks, 12 weeks and 6 months after baseline assessment. The primary outcome is insomnia severity at 6 months. An economic evaluation will be conducted and qualitative interviews will be used to explore barriers and facilitators of the stepped care model. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of the Medical Centre-University of Freiburg. The results of the study will be published irrespective of the outcome. TRIAL REGISTRATION NUMBER: DRKS00021503.

Advanced Glycation End Product (AGE) and Soluble Receptor of AGE (sRAGE) Levels in Relation to Periodontitis Severity and as Putative 3-Year Outcome Predictors in Patients Undergoing Coronary Artery Bypass Grafting (CABG).

Tissue concentrations of advanced glycation end product (AGE) and peripheral soluble receptor of AGE (sRAGE) levels may be associated with periodontitis severity. Both parameters and periodontitis might serve as outcome predictors for patients undergoing coronary artery bypass grafting (CABG). This study aimed to investigate possible associations between periodontitis and AGE/sRAGE. Ultimately, we wanted to examine whether AGE, sRAGE, and severe periodontitis are associated with the incidence of new cardiovascular events within 3 years of follow-up after CABG. Ninety-five patients with coronary vascular disease (CVD) (age 69 years, 88.3% males) needing CABG surgery were included. Periodontal diagnosis was made according to the guidelines of the "Centers for Disease Control and Prevention (CDC)" (2007) and staged according to the new classification of periodontal diseases (2018). AGE tissue concentrations were assessed as skin autofluorescence (sAF). sRAGE levels were determined by using a commercially available enzyme-linked immunoabsorbance assay (ELISA) kit. Univariate and multivariate baseline and survival analyses were carried out with Mann-Whitney U test, Chi² test, Kaplan-Meier curves with Log-Rank test, and logistic and Cox regression. sAF was identified as an independent risk indicator for severe periodontitis with respect to the cofactors age, gender, plaque index, and diabetes (adjusted odds ratio [OR] = 2.9, p = 0.028). The degree of subgingival inflammation assessed as a percentage of sites with bleeding on probing (BOP) was inversely correlated with sRAGE concentration (r = -0.189, p = 0.034). Both sAF (Hazard Ratio [HR] = 2.4, p = 0.004) and sRAGE (HR = 1.9, p = 0.031) increased the crude risk for new adverse events after CABG. The occurrence of severe periodontitis trends towards a higher risk for new cardiovascular events (HR = 1.8, p = 0.115). Applying multivariate Cox regression, only peripheral arterial disease (adjusted HR = 2.7, p = 0.006) and history of myocardial infarction (adjusted HR = 2.8, p = 0.010) proved to be independent risk factors for cardiovascular outcome. We conclude that sAF may represent a new, independent risk indicator for severe periodontitis. In contrast, sAF, sRAGE, and severe periodontitis were not independent prognostic factors for postoperative outcome in patients undergoing CABG.

Campylobacter Species of the Oral Microbiota as Prognostic Factor for Cardiovascular Outcome after Coronary Artery Bypass Grafting Surgery.

BACKGROUND: The oral microbiota has been implicated in a variety of systemic diseases, including cardiovascular (CV) disease. The main objective of this study (DRKS-ID: DRKS00015776) was to evaluate the prognostic importance of the oral microbiota for further CV events in patients undergoing coronary artery bypass grafting surgery (3-year follow-up). METHODS: In this longitudinal cohort study, 102 CV patients were enrolled, of whom 95 completed the 3-year follow-up. The CV outcome was assessed using the major adverse cardiac and cerebrovascular events criteria. To evaluate subgingival colonization, 16S rRNA genes were amplified, targeting the V3/V4 region (Illumina MiSeq). RESULTS: Regarding the specific number of operational taxonomic units (OTUs), no significant differences in CV outcome were determined (alpha diversity, Shannon index). In linear discriminant analyses and t-tests, the disease-specific differences in the beta diversity of the microbiota composition were evaluated. It was evident that bacteria species of the genus Campylobacter were significantly more prevalent in patients with a secondary CV event (p = 0.015). This hierarchical order also includes Campylobacter rectus, which is considered to be of comprehensive importance in both periodontal and CV diseases. CONCLUSIONS: Here, we proved that subgingival occurrence of Campylobacter species has prognostic relevance for cardiovascular outcomes in CV patients undergoing coronary artery bypass grafting.

Relation Between Gender and Concomitant Medications With Erythropoietin-Treatment on Wound Healing in Burn Patients. Post Hoc Subgroup-Analysis of the Randomized, Placebo-Controlled Clinical Trial "EPO in Burns".

Burns are leading causes of mortality and morbidity, including prolonged hospitalization, disfigurement, and disability. Erythropoietin (EPO) is a well-known hormone causing erythropoiesis. However, EPO may play a role in healing acute and chronic wounds due to its anti-inflammatory and pro-regenerative effects. Therefore, the large, prospective, placebo-controlled, randomized, double-blind, multi-center clinical trial "EPO in Burns" was initiated to investigate the effects of EPO versus placebo treatment in severely burned patients. The primary endpoint of "EPO in Burns" was defined as the time elapsed until complete re-epithelialization of a defined split skin graft donor site. Additional analyses of post hoc defined subgroups were performed in view of the primary endpoint. The verum (n 45) and control (n 39) groups were compared with regard to the time it took for study wounds (a predefined split skin graft donor site) to reach the three stages of wound healing (re-epithelialization levels). In addition, the effects of gender (females n 18) and concomitant medications insulin (n 36), non-steroidal anti-inflammatory drugs (NSAIDs) (n 41), and vasopressor agents (n 43) were tested. Life tables were used to compare study groups (EPO vs. placebo) within subgroups. The Cox regression model was applied to evaluate interactions between the study drug (EPO) and concomitant medications for each re-epithelialization level. Using our post hoc defined subgroups, we observed a lower chance of wound healing for women compared to men (in terms of hazard ratio: hr100%: 5.984 [95%-CI: (0.805-44.490), p = 0.080]) in our study population, regardless of the study medication. In addition, results indicated an earlier onset of re-epithelialization in the first days of EPO treatment (EPO: 10% vs. Placebo: 3%). Moreover, the interpretation of the hazard ratio suggested EPO might have a positive, synergistic effect on early stages of re-epithelialization when combined with insulin [hr50%: 1.307 (p = 0.568); hr75%: 1,199 (p = 0.715)], as well as a stabilizing effect on critically ill patients [reduced need for vasopressors in the EPO group (EPO: 44% vs. Placebo 59%)]. However, additional high-quality data from clinical trials designed to address these endpoints are required to gain further insight into these effects.

Regional Disparities in Caries Experience and Associating Factors of Ghanaian Children Aged 3 to 13 Years in Urban Accra and Rural Kpando.

(1) The objective of this socio-epidemiologic cross-sectional study was to investigate caries burdens in Ghanaian children aged 3 to 13 years. The main focus was the analysis of urban-rural disparities and associating socio-demographic and behavioural factors. (2) Standardized caries examination with documentation of decayed, missing, filled deciduous (dmft) and permanent teeth (DMFT) was conducted in 11 school facilities according to WHO guidelines. A parental questionnaire gathered data considering associating factors. Descriptive statistics were used to evaluate their influence on caries prevalence and experience using mean dmft+DMFT, Significant Caries Index (SiC), and Specific Affected Caries Index (SaC). (3) In total, 313 study participants were included (mean age 7.7 ± 3.8 years; 156 urban, 157 rural). The urban region showed slightly higher caries prevalence (40.4% vs. 38.9%). The rural region had higher caries experience in mean dmft+DMFT (1.22 ± 2.26 vs. 0.96 ± 1.58), SiC (3.52 ± 2.73 vs. 2.65 ± 1.71), and SaC (3.15 ± 2.68 vs. 2.37 ± 1.68). Lower education and occupation level of parents and rural residence were associated to higher caries values. Sugary diet showed an inverse relation with caries prevalence and oral hygiene practices supported the generally known etiologic correlation. (4) This study highlights the importance of targeting children vulnerable to caries due to social inequality with adequate preventive means. The implementation of regular dental screening and education, e.g. in schools, may be helpful.

Nonsurgical Periodontal Treatment Options and Their Impact on Subgingival Microbiota.

BACKGROUND: Different periodontal treatment methods (quadrant-wise debridement, scaling and root planing (Q-SRP), full-mouth scaling (FMS), full-mouth disinfection (FMD), and FMD with adjuvant erythritol air-polishing (FMDAP)) were applied in periodontitis patients (stage III/IV). The study objective (substudy of ClinicalTrials.gov Identifier: NCT03509233) was to compare the impact of treatments on subgingival colonization. METHODS: Forty patients were randomized to the treatment groups. Periodontal parameters and subgingival colonization were evaluated at baseline and 3 and 6 months after treatment. RESULTS: Positive changes in clinical parameters were recorded in every treatment group during the 3-month follow-up period, but did not always continue. In three groups, specific bacteria decreased after 3 months; however, this was associated with a renewed increase after 6 months (FMS: Porphyromonas gingivalis; FMD: Eubacterium nodatum, Prevotella dentalis; and FMDAP: uncultured Prevotella sp.). CONCLUSIONS: The benefit of all clinical treatments measured after 3 months was associated with a decrease in pathogenic bacteria in the FMS, FMD, and FMDAP groups. However, after 6 months, we observed further improvement or some stagnation in clinical outcomes accompanied by deterioration of the microbiological profile. Investigating the subgingival microbiota might help appraise successful periodontal treatment and implement individualized therapy.

Pathobiology of Second-Generation Antihistamines Related to Sleep in Urticaria Patients.

Background: Standard treatment options for urticaria are second-generation antihistamines; however, their effect on sleep is uncertain. This study measures the influence of different antihistamines on the biologic sleep pattern of urticaria patients and the relevance of sleep in urticaria patients. Methods: Ten patients with chronic spontaneous urticaria (CSU) and uncontrolled symptoms under a single dose of second-generation antihistamines were included. Two nights were monitored: the first night after 5 days on single dosage and the second night after 5 days on fourfold dosage. Patient-rated questionnaires were used and sleep was monitored using polygraphy. Results: The patients' rated daytime sleepiness decreased (p = 0.0319), as did their insomnia severity (p = 0.0349). The urticaria control (UCT) improved (p = 0.0007), as did the quality of life (p < 0.0001). There was no significant change of nightly pruritus (p = 0.1173), but there was an improvement of daytime pruritus (p = 0.0120). A significant increase in rapid eye movement (REM) sleep was seen (p = 0.0002) (from a mean of 3.9% to 14.3%). The deep sleep state (N3) also improved (8.7% to 12.3%) (p = 0.1172). Conclusion: This study has demonstrated an improvement of the sleep pattern in CSU patients under up-dosed second-generation antihistamines, without increased daytime sleepiness, alongside an improvement of urticaria symptoms and quality of life.

Polymorphism of CD14 Gene Is Associated with Adverse Outcome among Patients Suffering from Cardiovascular Disease.

BACKGROUND: The biological link between severe periodontitis and cardiovascular disease is well established. Both complex inflammatory diseases are influenced by genetic background. Therefore, the impact of genetic variations of receptors of the innate immune system-(Toll-like receptors (TLRs)) TLR2, TLR4, cluster of differentiation 14 (CD14), and the transcription factor nuclear factor-κΒ (NF-κB)-was investigated. MATERIALS AND METHODS: In this study (ClinicalTrials.gov identifier: NCT01045070), 1002 cardiovascular (CV) patients were included. In a 3-year follow-up period, new vascular events were assessed. SNPs in CD14 (rs2569190), NF-κΒ (rs28362491), TLR2 (rs5743708), and TLR4 (rs4986790) were genotyped. The impact of these genetic variants on severe periodontitis as well as on CV outcome was assessed. RESULTS: All investigated genetic variants were not associated with preexisting CV events or severe periodontitis in CV patients. In Kaplan-Meier survival analyses, the CT genotype of CD14 single-nucleotide polymorphism (SNP) rs2569190 was shown to be an independent predictor for combined CV endpoint (log rank: p = 0.035; cox regression; hazard ratio: 1.572; p = 0.044) as well as cardiovascular death (log rank: p = 0.019; cox regression; hazard ratio: 1.585; p = 0.040) after three years of follow-up. CONCLUSIONS: SNPs in CD14, NF-κΒ, TLR2, and TLR4 are no risk modulators for preexisting CV events or severe periodontitis in CV patients. The CT genotype of CD14 SNP rs2569190 provides prognostic value for further CV events within 3 years of follow-up.

Preparation of Neutral trans - cis [Ru(O2CR)2P2(NN)], Cationic [Ru(O2CR)P2(NN)](O2CR) and Pincer [Ru(O2CR)(CNN)P2] (P = PPh3, P2 = diphosphine) Carboxylate Complexes and their Application in the Catalytic Carbonyl Compounds Reduction.

The diacetate complexes trans-[Ru(κ1-OAc)2(PPh3)2(NN)] (NN = ethylenediamine (en) (1), 2-(aminomethyl)pyridine (ampy) (2), 2-(aminomethyl)pyrimidine (ampyrim) (3)) have been isolated in 76-88% yield by reaction of [Ru(κ2-OAc)2(PPh3)2] with the corresponding nitrogen ligands. The ampy-type derivatives 2 and 3 undergo isomerization to the thermodynamically most stable cationic complexes [Ru(κ1-OAc)(PPh3)2(NN)]OAc (2a and 3a) and cis-[Ru(κ1-OAc)2(PPh3)2(NN)] (2b and 3b) in methanol at RT. The trans-[Ru(κ1-OAc)2(P2)2] (P2 = dppm (4), dppe (5)) compounds have been synthesized from [Ru(κ2-OAc)2(PPh3)2] by reaction with the suitable diphosphine in toluene at 95 °C. The complex cis-[Ru(κ1-OAc)2(dppm)(ampy)](6) has been obtained from [Ru(κ2-OAc)2(PPh3)2] and dppm in toluene at reflux and reaction with ampy. The derivatives trans-[Ru(κ1-OAc)2P2(NN)] (7-16; NN = en, ampy, ampyrim, 8-aminoquinoline; P2 = dppp, dppb, dppf, (R)-BINAP) can be easily synthesized from [Ru(κ2-OAc)2(PPh3)2] with a diphosphine and treatment with the NN ligands at RT. Alternatively these compounds have been prepared from trans-[Ru(OAc)2(PPh3)2(NN)] by reaction with the diphosphine in MEK at 50 °C. The use of (R)-BINAP affords trans-[Ru(κ1-OAc)2((R)-BINAP)(NN)] (NN = ampy (11), ampyrim (15)) isolated as single stereoisomers. Treatment of the ampy-type complexes 8-15 with methanol at RT leads to isomerization to the cationic derivatives [Ru(κ2-OAc)P2(NN)]OAc (8a-15a; NN = ampy, ampyrim; P2 = dppp, dppb, dppf, (R)-BINAP). Similarly to 2, the dipivalate trans-[Ru(κ1-OPiv)2(PPh3)2(ampy)] (18) is prepared from [Ru(κ2-OPiv)2(PPh3)2] (17) and ampy in CHCl3. The pincer acetate [Ru(κ1-OAc)(CNNOMe)(PPh3)2] (19) has been synthesized from [Ru(κ2-OAc)2(PPh3)2] and HCNNOMe ligand in 2-propanol with NEt3 at reflux. In addition, the dppb pincer complexes [Ru(κ1-OAc)(CNN)(dppb)] (CNN = AMTP (20), AMBQPh (21)) have been obtained from [Ru(κ2-OAc)2(PPh3)2], dppb, and HAMTP or HAMBQPh with NEt3, respectively. The acetate NN and pincer complexes are active in transfer hydrogenation with 2-propanol and hydrogenation with H2 of carbonyl compounds at S/C values of up to 10000 and with TOF values of up to 160000 h-1.

Ligelizumab treatment for severe asthma: learnings from the clinical development programme.

OBJECTIVE: Ligelizumab is a humanised IgG1 anti-IgE antibody that binds IgE with higher affinity than omalizumab. Ligelizumab had greater efficacy than omalizumab on inhaled and skin allergen provocation responses in mild allergic asthma. This multi-centre, randomised, double-blind study was designed to test ligelizumab in severe asthma patients not adequately controlled with high-dose inhaled corticoids plus long-acting ß2-agonist. METHODS: Patients received 16 weeks ligelizumab (240 mg q2w), omalizumab or placebo subcutaneously, and ACQ-7 was measured as primary outcome at Week 16. In addition, the study generated dose-ranging data of ligelizumab and safety data. RESULTS: A total of 471 patients, age 47.4 ± 13.36 years, were included in the study. Treatment with ligelizumab did not significantly improve asthma control (ACQ-7) and exacerbation rates compared to omalizumab and placebo. Therefore, primary and secondary objectives of the study were not met. The compound was well tolerated, and the safety profile showed no new safety findings. Pharmacokinetic data demonstrated faster clearance and lower serum concentrations of ligelizumab than historical omalizumab data, and exploratory in vitro data showed differential IgE blocking properties relative to FcεRI and FcεRII/CD23 between the two compounds. CONCLUSION: Ligelizumab failed to demonstrate superiority over placebo or omalizumab. Although ligelizumab is more potent than omalizumab at inhibiting IgE binding to the high-affinity FcεRI, there is differential IgE blocking properties relative to FcεRI and FcεRII/CD23 between the two compounds. Therefore, the data suggest that different anti-IgE antibodies might be selectively efficacious for different IgE-mediated diseases.

Is Periodontitis a Predictor for an Adverse Outcome in Patients Undergoing Coronary Artery Bypass Grafting? A Pilot Study.

Periodontitis is a risk factor for atherosclerosis and coronary vascular disease (CVD). This research evaluated the relationship between periodontal conditions and postoperative outcome in patients who underwent coronary artery bypass grafting (CABG). A total of 101 patients with CVD (age 69 years, 88.1% males) and the necessity of CABG surgery were included. Periodontal diagnosis was made according to the guidelines of the Centers for Disease Control and Prevention (CDC, 2007). Additionally, periodontal epithelial surface area (PESA) and periodontal inflamed surface area (PISA) were determined. Multivariate survival analyses were carried out after a one-year follow-up period with Cox regression. All study subjects suffered from periodontitis (28.7% moderate, 71.3% severe). During the follow-up period, 14 patients (13.9%) experienced a new cardiovascular event (11 with angina pectoris, 2 with cardiac decompensation, and 1 with cardiac death). Severe periodontitis was not significant associated with the incidence of new events (adjusted hazard ratio, HR = 2.6; p = 0.199). Other risk factors for new events were pre-existing peripheral arterial disease (adjusted HR = 4.8, p = 0.030) and a history of myocardial infarction (HR = 6.1, p = 0.002). Periodontitis was not found to be an independent risk factor for the incidence of new cardiovascular events after CABG surgery.

[Opioid Substitution Treatment in Germany: Physicians' View on the Effects of the 3rd Revision of the Narcotic Drugs Prescription Ordinance]. / Die Substitutionstherapie Opioidabhängiger in Deutschland: Auswirkungen der 3. BtMVVÄndV aus der Sicht substituierender Ärztinnen und Ärzte.

STUDY AIM: Opioid substitution treatment (OST) is the most effective drug treatment for opioid dependence worldwide. This form of therapy is also well established in Germany. Nevertheless, there are gaps in the provision of care, especially in rural areas and some states, due to a decreasing number of physicians involved in implementing the substitution programs. The 3rd revision of the Narcotic Drugs Prescription Ordinance (NDPO), which came into force in 2017, transferred medical therapeutic tasks of OST to the policy-making power of the German Medical Association. This comprehensive reform of the general conditions for OST led to greater legal certainty for this form of treatment. The present study aimed to analyze the effects of the 3rd revision of the Narcotic Drugs Prescription Ordinance from the providers' perspective. METHODS: Between August and December 2019, a questionnaire on individual experiences with the changes implemented in 3rd revision of the Narcotic Drugs Prescription Ordinance was sent by the Federal Opium Agency and the Associations of Statutory Health Insurance Physicians of the chosen federal states to 2,503 physicians implementing the substitution program in Germany as well as 563 physicians in Hamburg, Bavaria, North Rhine-Westphalia and Saxony who were not or no longer involved in this field of medical practice.The evaluation distinguished between physicians with and without further training in addiction medicine and between urban and rural districts. RESULTS: The response rate of physicians was 34.1%. The average age was 57.9 (±8.7) years, and 64.5% were male. The most relevant changes of the NDPO revision were found to be no time limit for achieving opioid abstinence (85.3%), new assessment and treatment using additional psychotropic substances (71.0%), extending take-home regulation to a maximum of 30 days (70.0%) and greater legal certainty (66.2%). Widening of consultative care up to 10 patients met with little approval (14.8%); 36.7% did not believe that care of substituted patients was assured either now or in the future. CONCLUSIONS: The NDPO revisions were considered to be relevant in terms of increased legal certainty and treatment liberties. Information was needed in rural areas, among physicians who carried out substitution therapy without advanced training in addiction medicine and physicians no longer involved in substitution therapy.

The role of Saccharibacteria (TM7) in the subginival microbiome as a predictor for secondary cardiovascular events.

BACKGROUND: The composition of the subgingival microbiota is of great importance in both oral and systemic diseases. However, a possible association of the oral microbiome and cardiovascular (CV) outcome has not yet been considered in a complex model. The primary objective of the study (DRKS-ID: DRKS00015776) was to assess differences in complex subgingival bacterial composition, depending on the CV outcome in patients undergoing Coronary Artery Bypass Grafting Surgery (CABG). MATERIAL AND METHODS: We conducted a longitudinal cohort study enrolling 102 CV patients. After a one-year follow-up, the postoperative outcome was evaluated applying MACCE (Major Adverse Cardiac and Cerebrovascular Events) criteria. The complex oral microbiome was evaluated depending on CV outcome. The mathematical data processing included Qiime 2 software workflow and DADA2 pipeline as well as Human Oral Microbiome Database (HOMD) and Greengenes database classification. For identifying biomarkers distinguishing patients suffering from secondary CV events, the Cox Proportional Hazard Model for survival analysis was applied. RESULTS: In total, 19,418 Operational Taxonomic Units (OTU) were mapped according to the HOMD and Greengenes database. No significant differences in alpha and beta diversity were linked to CV outcomes (Shannon index; Principal Coordinates Analysis). No biomarker predicting secondary CV events were identified applying the area under the receiver operating characteristic curve (AUC) model. However, in survival analysis, one biomarker of Saccharibacteria phylum (class: TM7-3, order: CW040, family: F16) was associated with the incidence of a secondary CV event (p = 0.016). CONCLUSIONS: For the first time, a subgingival biomarker has been identified that supports a cardiovascular prognosis in CV patients undergoing coronary artery bypass grafting.

[Positive association between successful rehabilitation and patient hospital ratings: Experience reports of patients in rehabilitation on a hospital rating and review site]. / Klinik-Weiterempfehlung bei Reha-Erfolg: Erfahrungsberichte von Rehabilitanden auf einer Klinik-Bewertungsplattform.

INTRODUCTION: Feedback from patients about aspects of rehabilitation services is increasingly provided online, for example, on specialized hospital comparison websites. Therefore, we examined which kind of online statements from rehabilitation patients published on the leading hospital comparison website "Klinikbewertungen.de" (KB) is associated with a positive recommendation of a rehabilitation clinic and which negative aspects are associated with a non-recommendation. METHODS: For eight indication groups stratified online statements of rehabilitants at KB were evaluated qualitatively using content analysis. The relationship between positive (negative) statements and the (non-) recommendation was examined. RESULTS: Content analysis of 911 experience reports revealed 20 categories. Most often, it was the "rehabilitation success" perceived by rehabilitation patients that was significantly associated with a recommendation or a non-recommendation of a hospital, and in five quality assurance (QA) comparison groups the category "catering" was associated with a positive or negative recommendation. In all QS comparison groups, there was an association with at least one of the following process-oriented rehabilitation categories: "rehabilitation measures", "rehabilitation plan and rehabilitation goals" and / or "diagnosis to discharge". DISCUSSION AND CONCLUSION: Patient experiences with the perceived "rehabilitation success" and with the central processes of rehabilitation are particularly important for the recommendation or non-recommendation of a hospital for patients in all eight indication groups. On the basis of these results, rehabilitation hospitals can specifically identify the aspects of care that are important when patients recommend a hospital for rehabilitation. Online narratives of patients provide additional insights into the reasons for patients' satisfaction or dissatisfaction with their rehabilitation. These narratives are available to potential rehabilitation patients as a low-threshold source of information and decision-making aid.

Shiftwork and Alcohol Consumption: A Systematic Review of the Literature.

INTRODUCTION: Shiftwork can be a risk factor for a number of different somatic and psychological health conditions, especially sleep disorders. Shiftworkers sleep less than dayworkers, and 20-40% of them suffer from difficulties initiating and maintaining sleep, which result in reduced capacity for work and social life. A common coping strategy might be the use of alcohol, which presents a health and safety hazard as it further impairs sleep quality and exacerbates sleepiness in the workplace. This review aimed to assess the extent of such possible connections. METHODS: We performed a systematic search of the scientific literature on shiftwork and alcohol consumption in PubMed, PsycInfo, and Cochrane Library. Only original studies comparing shiftworkers with non-shiftworkers were included. The recommendations of the Preferred Reporting Items of Systematic Reviews and Meta-Analyses were followed. RESULTS: Fourteen articles are included in this review. Six studies report some kind of connection between shift- or nightwork and alcohol consumption, especially as a sleep aid. Conflicting or negative results are reported by 3 studies. DISCUSSION: Shiftwork, especially working at night and in rotation shifts, is associated with binge drinking disorder in different professions. The reasons for pathological consumption of alcohol can be self-medication of sleep problems or coping with stress and psychosocial problems typical for shiftwork. Nurses aged over 50 years represent one important risk group. These results can be important for preventive programs against sleep disorders, including measures other than drinking alcohol as a sleep aid in the workplace of shiftworkers.

rs2476601 in PTPN22 gene in rheumatoid arthritis and periodontitis-a possible interface?

BACKGROUND: Rheumatoid arthritis (RA) and periodontitis (PD) are proven to share common risk markers, including genetic factors. In the present study we focused on genetic variants in PTPN22 (rs2476601), PADI4 (rs2240340), CTLA4 genes (rs3087243) and its impact on RA and PD. MATERIALS AND METHODS: In the study 111 RA patients and 256 systemically healthy controls were involved. A subdivision of patients and controls was carried out according the severity of periodontitis (no/level 1 PD vs. level 2 PD). RESULTS: I. Evaluating the genetic impact on the occurrence of RA the T allele of rs2476601 (PTPN22) (bivariate: p < 0.001; multivariate: p = 0.018) and T allele of rs2240340 (PADI4) (bivariate: p = 0.006; multivariate: p = 0.070) were associated with an increased vulnerability to RA. II. Investigating the genetic influence on level 2 PD the T allele of rs2476601 (PTPN22) was shown to be associated with a higher susceptibility to PD within the RA group (bivariate: p = 0.043; multivariate: p = 0.024). III. The T allele of rs2476601 (PTPN22) was proven to be a significant marker of RA and level 2 PD comorbidity (bivariate: p < 0.001; multivariate: p = 0.028). CONCLUSIONS: These results support the thesis that genetic variations may represent a possible link between PD and RA. The study increases knowledge about disease-specific and cross-disease genetic pattern.

Osteoidosis leads to altered differentiation and function of osteoclasts.

In patients with osteomalacia, a defect in bone mineralization leads to changed characteristics of the bone surface. Considering that the properties of the surrounding matrix influence function and differentiation of cells, we aimed to investigate the effect of osteoidosis on differentiation and function of osteoclasts. Based on osteomalacic bone biopsies, a model for osteoidosis in vitro (OIV) was established. Peripheral blood mononuclear cells were differentiated to osteoclasts on mineralized surfaces (MS) as internal control and on OIV. We observed a significantly reduced number of osteoclasts and surface resorption on OIV. Atomic force microscopy revealed a significant effect of the altered degree of mineralization on surface mechanics and an unmasking of collagen fibres on the surface. Indeed, coating of MS with RGD peptides mimicked the resorption phenotype observed in OIV, suggesting that the altered differentiation of osteoclasts on OIV might be associated with an interaction of the cells with amino acid sequences of unmasked extracellular matrix proteins containing RGD sequences. Transcriptome analysis uncovered a strong significant up-regulation of transmembrane glycoprotein TROP2 in osteoclastic cultures on OIV. TROP2 expression on OIV was also confirmed on the protein level and found on the bone surface of patients with osteomalacia. Taken together, our results show a direct influence of the mineralization state of the extracellular matrix surface on differentiation and function of osteoclasts on this surface which may be important for the pathophysiology of osteomalacia and other bone disorders with changed ratio of osteoid to bone.