Structural insight into selectivity of amylin and calcitonin receptor agonists.

Amylin receptors (AMYRs), heterodimers of the calcitonin receptor (CTR) and one of three receptor activity-modifying proteins, are promising obesity targets. A hallmark of AMYR activation by Amy is the formation of a 'bypass' secondary structural motif (residues S19-P25). This study explored potential tuning of peptide selectivity through modification to residues 19-22, resulting in a selective AMYR agonist, San385, as well as nonselective dual amylin and calcitonin receptor agonists (DACRAs), with San45 being an exemplar. We determined the structure and dynamics of San385-bound AMY3R, and San45 bound to AMY3R or CTR. San45, via its conjugated lipid at position 21, was anchored at the edge of the receptor bundle, enabling a stable, alternative binding mode when bound to the CTR, in addition to the bypass mode of binding to AMY3R. Targeted lipid modification may provide a single intervention strategy for design of long-acting, nonselective, Amy-based DACRAs with potential anti-obesity effects.

Real-world insights and outcomes related to ciclosporin A 0.1% cationic emulsion for the long-term treatment of dry eye disease in Germany: Country-level sub-analysis of the PERSPECTIVE study.

PURPOSE: The PERSPECTIVE study was a real-world European, non-interventional, multicenter, observational study that evaluated the effectiveness, tolerability, and safety of ciclosporin A (CsA) 0.1% cationic emulsion (CE) in routine clinical practice as a treatment for adults with severe keratitis and dry eye disease (DED) that remained insufficiently controlled with artificial tears. This sub-analysis examined data from ophthalmology clinics in Germany to provide more precise insights into treatment patterns, outcomes, and clinical decision-making related to CsA 0.1% CE. METHODS: Study data were collected from adults starting CsA 0.1% CE (one drop in both eyes at bedtime) and followed up at Week 4, 12, and 24, and Month 12. The primary endpoint was mean change from baseline in corneal fluorescein staining (CFS) score (Oxford Grade Scale) at Month 12. Secondary endpoints examined the severity of ocular signs and symptoms, and adverse events (AEs). RESULTS: A total of 236 patients from 20 ophthalmology clinics in Germany participated in the PERSPECTIVE study (69.9% female; mean age 60.8 years). Following treatment with CsA 0.1% CE, patients experienced significant reductions in CFS score from Week 4, which were maintained through to Month 12 (P < 0.0001). From baseline, 81.6% of patients experienced an improvement in CFS score at Month 12. CsA 0.1% CE provided significant reductions in the severity of eyelid and conjunctival erythema at Month 12 compared with baseline (P < 0.001), as well as significant reductions in the severity of subjective ocular symptoms (all P ≤ 0.015). Safety data were consistent with the known safety profile of CsA 0.1% CE. Tolerability was rated as "satisfactory," "good," or "very good" by 97.2% of physicians and 95.7% of patients. CONCLUSION: Outcomes in Germany were similar to those reported for the overall European study population and are indicative of the treatment results that ophthalmologists may expect to see with CsA 0.1% CE treatment in real-life clinical practice. Treatment with CsA 0.1% CE provided long-term improvements over 12 months and was generally well tolerated.

Long-term changes in the subgingival microbiota in patients with stage III-IV periodontitis treated by mechanical therapy and adjunctive systemic antibiotics: A secondary analysis of a randomized controlled trial.

AIM: To explore whether adjunctive antibiotics can relevantly influence long-term microbiota changes in stage III-IV periodontitis patients. MATERIALS AND METHODS: This is a secondary analysis of a randomized clinical trial on periodontal therapy with adjunctive 500 mg amoxicillin and 400 mg metronidazole or placebo thrice daily for 7 days. Subgingival plaque samples were taken before and 2, 8, 14 and 26 months after mechanical therapy. The V4-hypervariable region of the 16S rRNA gene was sequenced with Illumina MiSeq 250 base pair paired-end reads. Changes at the ribosomal sequence variant (RSV) level, diversity and subgingival-microbial dysbiosis index (SMDI) were explored with a negative binomial regression model and non-parametric tests. RESULTS: Overall, 50.2% of all raw reads summed up to 72 RSVs (3.0%) that were generated from 163 stage III-IV periodontitis patients. Of those, 16 RSVs, including Porphyromonas gingivalis, Tannerella forsythia and Aggregatibacter actinomycetemcomitans, changed significantly over 26 months because of adjunctive systemic antibiotics. SMDI decreased significantly more in the antibiotic group at all timepoints, whereas the 2-month differences in alpha and beta diversity between groups were not significant at 8 and 14 months, respectively. CONCLUSIONS: Mechanical periodontal therapy with adjunctive antibiotics induced a relevant and long-term sustainable change towards an oral microbiome more associated with oral health.

Clinical benefits of systemic amoxicillin/metronidazole may depend on periodontitis stage and grade: An exploratory sub-analysis of the ABPARO trial.

AIM: Assessment of treatment response after systemic amoxicillin/metronidazole adjunctive to subgingival instrumentation (SI) according to stages and grades of the 2018 classification of periodontal diseases. MATERIALS AND METHODS: We carried out exploratory re-analysis of the placebo-controlled, multi-centre ABPARO trial (52; 45/60 years of age; 205 males, 114 active smokers). Patients were randomized to SI with systemic amoxicillin 500 mg/metronidazole 400 mg (three times a day for 7 days, n = 205; ANTI) or placebo (n = 200; PLAC) and maintenance therapy every 3 months. Patients were reclassified according to the 2018 classification (stage/extent/grade). Treatment effect was the percentage of sites per patient with new attachment loss ≥1.3 mm (PSAL ≥ 1.3 mm) at 27.5 months post-baseline/randomization. RESULTS: All patients were assigned according to the stage (n = 49 localized stage III, n = 206 generalized stage III, n = 150 stage IV). Because of missing radiographs, only 222 patients were assigned to grades (n = 73 B, n = 149 C). Treatment (PLAC/ANTI) resulted in PSAL ≥ 1.3 mm (median; lower/upper quartile) in localized stage III (PLAC: 5.7; 3.3/8.4% vs. ANTI: 4.9; 3.0/8.3%; p = .749), generalized stage III (8.0; 4.5/14.3% vs. 4.7; 2.4/9.0%; p < .001), stage IV (8.5; 5.1/14.4% vs. 5.7; 3.3/10.6%; p = .008), grade B (4.4; 2.4/6.7% vs. 3.6; 1.9/4.7%; p = .151) and grade C (9.4; 5.3/14.3% vs. 4.8; 2.5/9.4%; p < .001). CONCLUSIONS: In generalized periodontitis stage III/grade C, a clinically relevant lower percentage of disease progression after adjunctive systemic amoxicillin/metronidazole was observed compared to placebo (PLAC: 9.7; 5.8/14.3% vs. ANTI: 4.7; 2.4/9.0%; p < .001).

Psychopathologies and socioeconomic status as risk indicators for periodontitis: a survey-based investigation in German dental practices.

OBJECTIVES: Periodontitis is a highly prevalent multifactorial disease associated with various mental disorders. However, study results about this association are still contradictory. One methodological reason could be the neglect of potential confounders, such as socioeconomic factors or mental comorbidity. Our study examined a wide range of potential psychosocial risk indicators to identify those with relevant associations to periodontitis. MATERIALS AND METHODS: In a cross-sectional study, 111 patients with periodontitis (PERIO) (> 30% teeth with approximal attachment loss ≥ 5 mm) and 110 patients without periodontitis (NON-PERIO) were recruited in four dental practices in Germany. Clinical attachment loss, pocket depth, plaque, bleeding on probing, and DMFT were measured. Psychopathologic symptoms and socioeconomic status were recorded using self-report questionnaires (DAS, PHQ-8, GAD-7, CTS, SCOFF, AUDIT, FTND, SSS-8, SES). RESULTS: The PERIO group reported significantly lower socioeconomic status (Cohen's d = 0.49) and higher psychopathological symptom burden than the NON-PERIO regarding dental anxiety (d = 0.86) and avoidance behavior, nicotine dependency (d = 0.84), depressiveness (d = 0.46), general anxiety (d = 0.45), somatic symptoms (d = 0.42), and childhood traumatization (d = 0.34). No significant group differences existed for alcohol abuse and eating disorders. Dental anxiety was the strongest predictor of periodontitis and showed significant correlations with other psychopathologies and social status. CONCLUSIONS: Out of all psychosocial factors, socioeconomic status and dental anxiety showed the greatest association with periodontitis. CLINICAL RELEVANCE: Dentists should encourage socially disadvantaged and dentally anxious patients in the utilization of prevention and dental care. Furthermore, physicians and psychotherapists can contribute to the early detection of dental anxiety, oral diseases, and avoidance behavior.

The Role of Polymorphisms at the Interleukin-1, Interleukin-4, GATA-3 and Cyclooxygenase-2 Genes in Non-Surgical Periodontal Therapy.

Periodontitis is a multifactorial disease. The aim of this explorative study was to investigate the role of Interleukin-(IL)-1, IL-4, GATA-3 and Cyclooxygenase-(COX)-2 polymorphisms after non-surgical periodontal therapy with adjunctive systemic antibiotics (amoxicillin/metronidazole) and subsequent maintenance in a Caucasian population. Analyses were performed using blood samples from periodontitis patients of a multi-center trial (ClinicalTrials.gov NCT00707369=ABPARO-study). Polymorphisms were analyzed using quantitative real-time PCR. Clinical attachment levels (CAL), percentage of sites showing further attachment loss (PSAL) ≥1.3 mm, bleeding on probing (BOP) and plaque score were assessed. Exploratory statistical analysis was performed. A total of 209 samples were genotyped. Patients carrying heterozygous genotypes and single-nucleotide-polymorphisms (SNP) on the GATA-3-IVS4 +1468 gene locus showed less CAL loss than patients carrying wild type. Heterozygous genotypes and SNPs on the IL-1A-889, IL-1B +3954, IL-4-34, IL-4-590, GATA-3-IVS4 +1468 and COX-2-1195 gene loci did not influence CAL. In multivariate analysis, CAL was lower in patients carrying GATA-3 heterozygous genotypes and SNPs than those carrying wild-types. For the first time, effects of different genotypes were analyzed in periodontitis progression after periodontal therapy and during supportive treatment using systemic antibiotics demonstrating a slight association of GATA-3 gene locus with CAL. This result suggests that GATA-3 genotypes are a contributory but non-essential risk factor for periodontal disease progression.

Short- and long-term agreement and reproducibility of 48-hours intraocular pressure measurements in glaucoma patients.

BACKGROUND: Glaucomatous eyes often show strong intraocular pressure (IOP) fluctuations and individual measurements at different time points are necessary for personalized therapy. To survey IOP variations 48-hours diurnal and nocturnal IOP measurements were performed on two consecutive days. Aims of this study were to investigate the short-term repeatability of 48-hours measurements within one patient's IOP profile and long-term repeatability between two separate IOP profiles of the same patient. METHODS: A retrospective cohort study was performed evaluating data of 90 glaucoma patients in a German university medical center between 2006 and 2013. All patients underwent two separate diurnal IOP profiles of 48 h. IOP was measured at 8 am, 2 pm, 6 pm, 9 pm using Goldmann applanation tonometry and at 12 midnight using Perkins tonometry in supine position on two consecutive days. Intraclass correlation coefficients (ICC) were calculated to evaluate agreement for the same time points (each time point agreement) and for consecutive measurements within the IOP profiles (between time point agreement). ICC ≤ 0.4 was defined as poor agreement, 0.4-0.75 as moderate and ≥ 0.75 as excellent. Differences between time points were investigated by Bland Altman plots. RESULTS: Each time point measurements of profile 1 showed moderate to excellent agreement (ICCs 0.62-0.93). There was a moderate to excellent agreement for measurements between time points of profile 1 (ICCs day one 0.57-0.86, day two 0.71-0.90). Profile 2 was performed at a median interval of 12.0 months (quartiles 11.0 to 21.0). Each time point agreements within profile 2 showed ICCs from 0.23 to 0.81. It showed moderate to excellent agreement for changes between time points (ICCs 0.53-0.94). Day two demonstrated ICCs from 0.74 to 0.88. Long term IOP repeatability (over both pressure profiles) showed moderate to good agreement (ICCs 0.39-0.67). CONCLUSIONS: Short and long-term agreement of IOP measurements evaluated by diurnal IOP profiles is moderate to good. Due to mostly moderate agreements, which we believe represent IOP fluctuations, we conclude that it is necessary to perform 48-hours IOP profiles to gain a better overview of the individual IOP fluctuations.

Impact of 0.1% octenidine mouthwash on plaque re-growth in healthy adults: a multi-center phase 3 randomized clinical trial.

OBJECTIVES: To investigate plaque inhibition of 0.1% octenidine mouthwash (OCT) vs. placebo over 5 days in the absence of mechanical plaque control. MATERIALS AND METHODS: For this randomized, placebo-controlled, double-blind, parallel group, multi-center phase 3 study, 201 healthy adults were recruited. After baseline recording of plaque index (PI) and gingival index (GI), collection of salivary samples, and dental prophylaxis, subjects were randomly assigned to OCT or placebo mouthwash in a 3:1 ratio. Rinsing was performed twice daily for 30 s. Colony forming units in saliva were determined before and after the first rinse. At day 5, PI, GI, and tooth discoloration index (DI) were assessed. Non-parametric van Elteren tests were applied with a significance level of p < 0.05. RESULTS: Treatment with OCT inhibited plaque formation more than treatment with placebo (PI: 0.36 vs. 1.29; p < 0.0001). OCT reduced GI (0.04 vs. placebo 0.00; p = 0.003) and salivary bacterial counts (2.73 vs. placebo 0.24 lgCFU/ml; p < 0.0001). Tooth discoloration was slightly higher under OCT (DI: 0.25 vs. placebo 0.00; p = 0.0011). Mild tongue staining and dysgeusia occurred. CONCLUSIONS: OCT 0.1% mouthwash inhibits plaque formation over 5 days. It therefore can be recommended when regular oral hygiene is temporarily compromised. CLINICAL RELEVANCE: When individual plaque control is compromised, rinsing with octenidine mouthwash is recommended to maintain healthy oral conditions while side effects are limited.

Incretin combination therapy for the treatment of non-alcoholic steatohepatitis.

AIMS: To test specific mono-agonists to the glucagon-like peptide-1 receptor (GLP-1R), glucagon receptor (GCGR) and glucose-dependent insulinotropic peptide receptor (GIPR), individually and in combination, in a mouse model of diet-induced non-alcoholic steatohepatitis (NASH) and fibrosis in order to decipher the contribution of their activities and potential additive effects to improving systemic and hepatic metabolism. MATERIALS AND METHODS: We induced NASH by pre-feeding C57BL/6J mice a diet rich in fat, fructose and cholesterol for 36 weeks. This was followed by 8 weeks of treatment with the receptor-specific agonists 1-GCG (20 µg/kg twice daily), 2-GLP1 (3 µg/kg twice daily) or 3-GIP (30 µg/kg twice daily), or the dual (1 + 2) or triple (1 + 2 + 3) combinations thereof. A dual GLP-1R/GCGR agonistic peptide, 4-dual-GLP1/GCGR (30 µg/kg twice daily), and liraglutide (100 µg/kg twice daily) were included as references. RESULTS: Whereas low-dose 1-GCG or 3-GIP alone did not influence body weight, liver lipids and histology, their combination with 2-GLP1 provided additional weight loss, reduction in liver triglycerides and improvement in histological disease activity score. Notably, 4-dual-GLP-1R/GCGR and the triple combination of selective mono-agonists led to a significantly stronger reduction in the histological non-alcoholic fatty liver disease activity score compared to high-dose liraglutide, at the same extent of body weight loss. CONCLUSIONS: GCGR and GIPR agonism provide additional, body weight-independent improvements on top of GLP-1R agonism in a murine model of manifest NASH with fibrosis.

Effect of periodontal therapy on adipokine biomarkers in overweight.

AIM: The aim of this study was to evaluate the effect of non-surgical periodontal therapy on circulating levels of the systemic inflammation-associated biomarkers orosomucoid (ORM), high-sensitivity C-reactive protein (hsCRP), chemerin, and retinol-binding protein 4 (RBP4) in overweight or normal-weight patients with periodontitis at 27.5 months after therapy. MATERIALS AND METHODS: This exploratory subanalysis includes patients from the ABPARO-trial (ClinicalTrials.gov NCT00707369). The per-protocol collective provided untreated periodontitis patients with high (≥28 kg/m2 ) or moderate (21-24 kg/m2 ) BMI. Out of the per-protocol collective, 80 patients were randomly selected and stratified for BMI group, sex, and treatment group (antibiotics/placebo), resulting in 40 overweight and normal-weight patients. Patients received non-surgical periodontal therapy and maintenance at 3-month intervals. Plasma samples from baseline and 27.5 months following initial treatment were used to measure the concentrations of ORM, hsCRP, chemerin, and RBP4. RESULTS: At the 27.5-month examination, ORM and hsCRP decreased noticeably in the overweight group (ORM: p = .001, hsCRP: p = .004) and normal-weight patients (ORM: p = .007, hsCRP: p < .001). Chemerin decreased in the overweight group (p = .048), and RBP4 concentrations remained stable. CONCLUSION: Non-surgical periodontal therapy reduced systemically elevated inflammation-associated biomarkers in periodontitis patients. These improvements were more pronounced in overweight patients than in normal-weight patients.

Ionising radiation and lens opacities in interventional physicians: results of a German pilot study.

We assessed the feasibility of an epidemiological study on the risk of radiation-related lens opacities among interventional physicians in Germany. In a regional multi-centre pilot study associated with a European project, we tested the recruitment strategy, a European questionnaire on work history for the latter dosimetry calculation and the endpoint assessment. 263 interventional physicians and 129 non-exposed colleagues were invited. Questionnaires assessed eligibility criteria, risk factors for cataract, and work history relating to occupational exposure to ionising radiation, including details on type and amount of procedures performed, radiation sources, and use of protective equipment. Eye examinations included regular inspection by an ophthalmologist, digital slit lamp images graded according to the lens opacities classification system, and Scheimpflug camera measurements. 46 interventional (17.5%) and 30 non-exposed physicians (23.3%) agreed to participate, of which 42 and 19, respectively, met the inclusion criteria. Table shields and ceiling suspended shields were used as protective equipment by 85% and 78% of the interventional cardiologists, respectively. However, 68% of them never used lead glasses. More, although minor, opacifications were diagnosed among the 17 interventional cardiologists participating in the eye examinations than among the 18 non-exposed (59% versus 28%), mainly nuclear cataracts in interventional cardiologists and cortical cataracts in the non-exposed. Opacification scores calculated from Scheimpflug measurements were higher among the interventional cardiologists, especially in the left eye (56% versus 28%). Challenges of the approach studied include the dissuading time investment related to pupil dilatation for the eye examinations, the reliance on a retrospective work history questionnaire to gather exposure-relevant information for dose reconstructions and its length, resulting in a low participation rate. Dosimetry data are bound to get better when the prospective lens dose monitoring as foreseen by 2013 European Directives is implemented and doses are recorded.

Effect of toothpaste containing amine fluoride and stannous chloride on the reduction of dental plaque and gingival inflammation. A randomized controlled 12-week home-use study.

OBJECTIVES: This single-centre, controlled, randomized, double-blinded clinical study in parallel groups was performed to assess the efficacy of an experimental toothpaste on plaque and gingivitis. METHODS: In adult subjects with gingivitis, amine fluoride/stannous chloride toothpaste (test) and monofluorophosphate toothpaste (control) were applied twice daily by regular toothbrushing at home. Evaluations of plaque index (PI), gingival index (GI), modified sulcus bleeding index (mSBI) and safety took place at baseline and after 3 and 12 weeks of study product use. After study completion, all subjects received a dental prophylaxis. A descriptive statistical analysis included means and standard deviations. Unpaired t tests compared index reductions between groups at a significance level of 0.05. RESULTS: Intention-to-treat analysis included 240 out of 241 subjects. Baseline mean PI was reduced by 0.87 ± 0.35 in the test group and by 0.65 ± 0.41 in the control group. Within-group differences and between-group differences in index reduction were statistically significant (P < 0.001). Mean GI and mSBI were reduced significantly over time (P < 0.001) with no clinically meaningful differences between groups. CONCLUSIONS: Both toothpastes reduced plaque and gingivitis statistically significant and clinically meaningful over 12 weeks. Compared to the control toothpaste, application of the amine fluoride/stannous chloride toothpaste led to a clinically meaningful and more pronounced plaque reduction.

Design and Baseline Characteristics of the HELP Study: An Extended and Long-Term Observation of Pathological Myopia in Caucasians.

PURPOSE: To assess the natural disease progression of high myopia in Caucasians considered at risk for the development of myopic choroidal neovascularization (mCNV). METHODS: Subjects were recruited in 25 clinical sites between June 2014 and June 2016. Main inclusion criteria included axial length of ≥26 mm, best-corrected visual acuity ≥0.05 decimal equivalent and presence of at least one out of five predefined morphological disease risk criteria. These were (1) subfoveal choroidal thinning < 50 µm, (2) enhanced choroidal curvature length > 6,300 µm, (3) lacquer cracks, (4) patchy atrophy > 5 mm2 and (5) preexisting mCNV in the fellow eye (German Clinical Trial Register DRKS00007761). RESULTS: A total of 150 participants (66% females) with a mean age of 57.2 (±12.7) years (range 21.9-86.2 years) were included. The disease criteria most frequently encountered were choroidal thinning (33.3%) and lacquer cracks (32.7%). Enhanced choroidal curvature length was detected in only 8 subjects and always occurred in combination with other disease criteria. Presence of patchy atrophy was found to be more common in older subjects (p = 0.0012) and also associated with a more severe disease manifestation. CONCLUSION: The baseline data of this study indicate that enhanced choroidal curvature might be less common in Caucasians than in Asian populations. Further, disease severity in patients with high myopia is relatively high in the presence of patchy atrophy.

Impact of different concentrations of an octenidine dihydrochloride mouthwash on salivary bacterial counts: a randomized, placebo-controlled cross-over trial.

OBJECTIVES: This bi-centric, placebo-controlled, randomized, evaluator-blinded, incomplete cross-over clinical phase II trial was initialized to identify the most appropriate concentration of octenidine dihydrochloride (OCT) in mouth rinses. MATERIALS AND METHODS: Rinses of 0.10, 0.15, and 0.20% OCT were compared to a saline placebo rinse regarding the reduction of salivary bacterial counts (SBCs) in 90 gingivitis patients over 4 days. Changes in plaque (PI) and gingival index (GI), taste perception, and safety issues were evaluated. RESULTS: At baseline, the first OCT (0.10, 0.15, 0.20%) rinse resulted in a decrease of SBC (reduction by 3.63-5.44 log10 colony forming units [CFU]) compared to placebo (p < 0.001). Differences between OCT concentrations were not verified. After 4 days, the last OCT rinse again resulted in a significant SBC decrease (3.69-4.22 log10 CFU) compared to placebo (p < 0.001). Overall, SBC reduction between baseline and day 4 was significantly higher in OCT 0.15 and 0.20% groups compared to OCT 0.10% and placebo. Mean GI/PIs were significantly lower in OCT groups than in the placebo group (p < 0.001). Differences in GI/PI between OCT groups were not verified. Adverse effects increased with increasing OCT concentrations. CONCLUSIONS: Considering antibacterial efficacy, frequency of adverse events, and user acceptance, 0.10% OCT was identified as the preferred concentration to be used in future clinical trials. CLINICAL RELEVANCE: Due to its low toxicity and pronounced antibacterial properties, octenidine dihydrochloride (OCT) is a promising candidate for the use in antiseptic mouth rinses. OCT concentrations of 0.10% are recommended for future clinical trials evaluating the plaque-reducing properties of OCT mouth rinses. ( www.clinicaltrials.gov , NCT022138552).

Course of serum autoantibodies in patients after acute angle-closure glaucoma attack.

BACKGROUND: The aim of our investigation was to analyze the autoantibody -reactivities of patients after acute angle-closure glaucoma (AACG) by means of a protein microarray approach to identify intraocular pressure(IOP)-dependent antibodies. METHODS: Collected sera from different study time points (AACG n = 6, 0, 2, 4 and 12 weeks) and control group (CTRL n = 11, 0 and 12 weeks) were analyzed. Protein-microarrays were incubated with sera, and occurring immunoreactivities were visualized with fluorescence labeled secondary antibodies. To detect changes, spot intensities were digitized and compared with statistical techniques. RESULTS: Three autoantibodies with significant level-alteration in the time course of the survey could be identified. Immunoreactivities to heat shock 27-kDa protein (HSP27), tubulin-tyrosine ligase-like protein 12 (TTLL12), and neuron-specific enolase (NSE) show an increasing linear trend from week 0 up to week 12 with a positive correlation coefficient (P ≤ 0.05, r ≥ 0.4). In the CTRL- group, no significant alterations could be detected in corresponding autoantibody-level. Analysis of variance revealed significant changes of antibody-level between certain time points (anti-HSP27 antibody [week 0 vs. 2], anti-TTLL12 antibody [week 0 vs. 12], and anti-NSE antibody [week 4 vs. 12] [P ≤ 0.05, respectively]) in AACG group. CONCLUSIONS: With this autoantibodies profiling approach, we were able to detect autoimmune reactivities in sera of patients without former indication for glaucomatous damage after rise of IOP due to AACG attack. After further validation in subsequent studies, this autoantibodies could give further insights into the pathogenesis of glaucoma and could possibly help to understand the effect of IOP on glaucomatous optic neuropathy.

A Randomized Trial of a Schlemm's Canal Microstent with Phacoemulsification for Reducing Intraocular Pressure in Open-Angle Glaucoma.

PURPOSE: To assess the safety and effectiveness of the Hydrus Microstent (Ivantis, Inc, Irvine, CA) with concurrent cataract surgery (CS) for reducing intraocular pressure (IOP) in open-angle glaucoma (OAG). DESIGN: Prospective, multicenter, randomized, single-masked, controlled clinical trial. PARTICIPANTS: One hundred eyes from 100 patients 21 to 80 years of age with OAG and cataract with IOP of 24 mmHg or less with 4 or fewer hypotensive medications and a washed-out diurnal IOP (DIOP) of 21 to 36 mmHg. METHODS: On the day of surgery, patients were randomized 1:1 to undergo CS with the microstent or CS alone. Postoperative follow-up was at 1 day, 1 week, and 1, 3, 6, 12, 18, and 24 months. Washout of hypotensive medications was repeated at 12 and 24 months. MAIN OUTCOME MEASURES: Response to treatment was defined as a 20% or more decrease in washed out DIOP at 12 and 24 months of follow-up compared with baseline. Mean DIOP at 12 and 24 months, the proportion of subjects requiring medications at follow-up, and the mean number of medications were analyzed. Safety measures included change in visual acuity, slit-lamp observations, and adverse events. RESULTS: The proportion of patients with a 20% reduction in washed out DIOP was significantly higher in the Hydrus plus CS group at 24 months compared with the CS group (80% vs. 46%; P = 0.0008). Washed out mean DIOP in the Hydrus plus CS group was significantly lower at 24 months compared with the CS group (16.9±3.3 mmHg vs. 19.2±4.7 mmHg; P = 0.0093), and the proportion of patients using no hypotensive medications was significantly higher at 24 months in the Hydrus plus CS group (73% vs. 38%; P = 0.0008). There were no differences in follow-up visual acuity between groups. The only notable device-related adverse event was focal peripheral anterior synechiae (1-2 mm in length). Otherwise, adverse event frequency was similar in the 2 groups. CONCLUSIONS: Intraocular pressure was clinically and statistically significantly lower at 2 years in the Hydrus plus CS group compared with the CS alone group, with no differences in safety.

Tooth staining potential of experimental amine fluoride/stannous fluoride mouth rinse formulations-a randomized crossover forced staining study.

OBJECTIVES: It was the aim to investigate experimental mouth rinses concerning their tooth and tongue staining potential using the standardized short-term forced staining model. MATERIALS AND METHODS: A single centre, clinically controlled, randomized, investigator-blinded study was conducted in a crossover design. In healthy dental students, three experimental AmF/SnF2 (A, B, C) mouth rinses and a phenolic/essential oil rinse (D) were compared to a water control (E). Four treatment days consisted of eight hourly rinses with mouth rinse and black tea. Mechanical oral hygiene was ceased. At the fifth day, tooth and tongue staining indices were recorded. Between treatment periods, a 10-day washout phase was performed. RESULTS: Twenty-eight participants entered and completed the study. All mouth rinses including the water control led to tooth and tongue staining. Most tooth staining occurred after rinsing with test rinse A, followed by B, D, C and E. Statistically significant differences existed between products A and C, D, and E. Most tongue staining happened in group B, followed by A, D, C and E (not statistically significant). CONCLUSION: Within the limitations of the model, mouth rinse C has a promising potential of causing less tooth discoloration than other AmF/SnF2 rinses. C is highly recommended to be investigated in further long-term clinical studies on its in vivo staining potential and antiplaque efficacy. CLINICAL RELEVANCE: This forced staining study has proven that one of the experimental AmF/SnF2 rinses leads to less staining than the other experimental AmF/SnF2 rinses. These experimental results have to be confirmed by further clinical investigations.

Intravitreal Aflibercept Injection for Macular Edema Resulting from Central Retinal Vein Occlusion: One-Year Results of the Phase 3 GALILEO Study.

PURPOSE: To evaluate the efficacy and safety of intravitreal aflibercept injections for treatment of macular edema secondary to central retinal vein occlusion (CRVO). DESIGN: A randomized, multicenter, double-masked phase 3 study. PARTICIPANTS: A total of 177 treatment-naive patients with macular edema secondary to CRVO were randomized in a 3:2 ratio. METHODS: Patients received either 2-mg intravitreal aflibercept or sham injections every 4 weeks for 20 weeks. From week 24 to 48, the aflibercept group received aflibercept as needed (pro re nata [PRN]), and the sham group continued receiving sham injections. MAIN OUTCOME MEASURES: The primary efficacy end point was the proportion of patients who gained 15 letters or more in best-corrected visual acuity (BCVA) at week 24. This study reports week 52 results including the proportion of patients who gained 15 letters or more in BCVA and the mean change from baseline BCVA and central retinal thickness. Efficacy end points at week 52 were all exploratory. RESULTS: At week 52, the mean percentage of patients gaining 15 letters or more was 60.2% in the aflibercept group and 32.4% in the sham group (P = 0.0004). Aflibercept patients, compared with sham patients, had a significantly higher mean improvement in BCVA (+16.9 letters vs. +3.8 letters, respectively) and reduction in central retinal thickness (-423.5 µm vs. -219.3 µm, respectively) at week 52 (P < 0.0001 for both). Aflibercept patients received a mean of 2.5 injections (standard deviation, 1.7 injections) during PRN dosing. The most common ocular adverse events in the aflibercept group were related to the injection procedure or the underlying disease, and included macular edema (33.7%), increased intraocular pressure (17.3%), and eye pain (14.4%). CONCLUSIONS: Treatment with intravitreal aflibercept provided significant functional and anatomic benefits after 52 weeks as compared with sham. The improvements achieved after 6 monthly doses at week 24 largely were maintained until week 52 with as-needed dosing. Intravitreal aflibercept generally was well tolerated.

Mid-term real world outcomes of the Hydrus® Microstent in open angle glaucoma.

PURPOSE: To evaluate the mid-term clinical results and the safety aspects of the Hydrus® Microstent (Ivantis, Inc, Irvine, CA) in a real-life setting. DESIGN: Retrospective case series. METHODS: Hydrus® Microstent was implanted in phakic eyes (88 eyes, 87.1%) and in pseudophakic eyes (13 eyes, 12.9%), respectively. Mean follow-up time was 16 ± 9 months with 27 eyes having a follow-up time of more than 24 months. MAIN OUTCOME MEASURES: The primary endpoint was reduction in IOP compared to baseline. Target IOP levels were set at ≤20 mmHg, ≤18 mmHg and ≤15 mmHg. Kaplan-Meier survival was defined as a reduction in IOP of ≥20% compared to baseline. Secondary endpoints were reduction in number of glaucoma medications and safety assessments addressing visual acuity, adverse events, re-surgery rate and identification of factors that made the implantation more difficult. RESULT: 101 eyes underwent Hydrus® implantation. The mean preoperative IOP was 21.60 mmHg (SD 6.6) on 2.18 (SD 1.3) medications. After a mean follow up time of 16 months, the mean IOP was reduced to 14.61 ± 3.7 mmHg on 1.12 (SD 1.1) medication classes (p < 0.001). Mean decrease in IOP was 26.7%. Analysis of the target IOP levels showed that in 29%, 34% and 35% of cases an IOP of ≤15 mmHg, ≤18 mmHg and ≤20 mmHg respectively could be achieved. BCVA improved from 0.56 ± 0.3 at baseline to 0.85 ± 0.3 more than 24 months after surgery (p < 0.001). The rate of re-operation was low at <3%. Adverse events occurred in 4 eyes (<4%). CONCLUSION: This study underlines the effectiveness and the safety of the Hydrus® Microstent in an elective setting, but it also demonstrates certain limits and risk factors of this procedure.

Direct cost and predictive factors for treatment in patients with ocular hypertension or early, moderate and advanced primary open-angle glaucoma: the CoGIS study in Germany.

BACKGROUND: The main objectives of this analysis were to assess the treatment costs and to identify major cost drivers and factors predicting direct costs in German patients with ocular hypertension (OHT) or primary open-angle glaucoma (POAG). METHODS: This non-interventional cross-sectional study was conducted in two university hospitals and 13 ophthalmology practices in Germany regions (Bavaria, Rhineland-Palatinate, North Rhine-Westphalia, Hamburg and Mecklenburg-Western Pomerania) between May 2009 and January 2010 to assess resource utilisation in patients with OHT (ICD-10: 40.0) or POAG (ICD-10: 40.1) at early, moderate or advanced stages, according to the European Glaucoma Society classification Guidelines. Treatment patterns and direct costs were evaluated retrospectively for 5 years. Resource utilisation data (medication, hospitalisation, outpatient surgery, visits to ophthalmologists) were abstracted from the charts, and unit costs were applied to estimate direct costs per year (in Euros, 2009), calculated from the perspective of the statutory health insurance in Germany (Gesetzliche Krankenversicherung). Factors predicting costs were assessed in multivariate regression analysis. RESULTS: One hundred and fifty-four patients (17.5% OHT, 27.9% early, 22.7% moderate, and 31.8% advanced POAG), on average 67 years old (SD 11) were included in the study. Average total annual direct costs per patient for OHT were 226 (SD 117), for early POAG 423 (SD 647), moderate 493 (SD 385) and advanced POAG 809 (SD 877). Glaucoma-related medications and hospitalisation represented the two major components of direct costs, increasing with the progression of glaucoma. In addition to treatment switches (p = 0.0001), factors predictive of an increase in total direct costs included the number of hospital interventions (p < 0.0001), disease-state changes since the start of treatment (p = 0.05), and current disease state (p = 0.05). CONCLUSIONS: Direct costs of treatment are higher in glaucoma compared to OHT and further increase in more severe glaucoma states. Additional treatment changes are major contributing factors to the increased treatment costs of glaucoma. If intraocular pressure can be controlled over the long term, progression to moderate and advanced states avoided, and patients remain on initial treatments, treatment costs could decline due to reduced and less expensive healthcare resource utilisation.