Treatment as required versus regular monthly treatment in the management of neovascular age-related macular degeneration: a systematic review and meta-analysis

Background: To investigate whether treatment as required ‘pro re nata’ (PRN) versus regular monthly treatment regimens lead to differences in outcomes in neovascular age-related macular degeneration (nAMD). Regular monthly administration of vascular endothelial growth factor (VEGF) inhibitors is an established gold standard treatment, but this approach is costly. Replacement of monthly by PRN treatment can only be justified if there is no difference in patient relevant outcomes. Methods: Systematic review and meta-analysis. The intervention was PRN treatment and the comparator was monthly treatment with VEGF-inhibitors. Four bibliographic databases were searched for randomised controlled trials comparing both treatment regimens directly (head-to-head studies). The last literature search was conducted in December 2014. Risk of bias assessment was performed after the Cochrane Handbook for Systematic Reviews of Interventions. Findings: We included 3 head-to-head studies (6 reports) involving more than 2000 patients. After 2 years, the weighted mean difference in best corrected visual acuity (BCVA) was 1.9 (95% CI 0.5 to 3.3) ETDRS letters in favour of monthly treatment. Systemic adverse events were higher in PRN treated patients, but these differences were not statistically significant. After 2 years, the total number of intravitreal injections required by the patients in the PRN arms were 8.4 (95% CI 7.9 to 8.9) fewer than those having monthly treatment. The studies were considered to have a moderate risk of bias. Conclusions: PRN treatment resulted in minor but statistically significant decrease in mean BCVA which may not be clinically meaningful. There is a small increase in risk of systemic adverse events for PRN treated patients. Overall, the results indicate that an individualized treatment approach with anti-VEGF using visual acuity and OCT-guided re-treatment criteria may be appropriate for most patients with nAMD

Patients' perspective on emergency treatment of ophthalmologic diseases during the first phase of SARS-CoV2 pandemic in a tertiary referral center in Germany - the COVID-DETOUR questionnaire study

Background During the first wave of the COVID-19 pandemic, the need of treatment of urgent ophthalmological diseases and the possible risk of a SARS-CoV-2 infection had to be weighed against each other. In this questionnaire study, we aimed to analyze potential barriers and patients' health beliefs during and after the lockdown early 2020 in a tertiary referral center in Kiel, Germany. Results Ninety-three patients were included, 43 in subgroup A (before April 20th) and 50 in subgroup B (April 20th or later). Retinal disorders were the most common causes for admission (approximately 60%).. Only 8 patients (8.6%) experienced a delay between their decision to visit a doctor until the actual examination. Every fourth patient was afraid of a COVID-19 infection, and expected a higher likelihood for an infection at the hospital. Patients with comorbidities tended to be more likely to be afraid of an infection (correlation coefficient 0.183, p = 0.0785) and were significantly more likely to be concerned about problems with organizing follow-up care (corr. Coefficient 0.222, p = 0.0328). Higher age was negatively correlated with fear of infection (corr. Coefficient - 0.218, p-value 0.034). Conclusion In this questionnaire study, only a minority of patients indicated a delay in treatment, regardless of whether symptoms occurred before or after the lockdown before April 20th, 2020. While patients with comorbidities were more concerned about infection and problems during follow-up care, patients of higher age - who have a higher mortality - were less afraid. Protection of high-risk groups should be prioritized during the SARS-CoV-2 pandemic. Trial registration The study was registered as DRKS00021630 at the DRKS (Deutsches Register Klinischer Studien) before the conduction of the study on May 5th, 2020

Hepatocyte IKK2 Protects Mdr2−/− Mice from Chronic Liver Failure

Mice lacking the Abc4 protein encoded by the multidrug resistance-2 gene (Mdr2−/−) develop chronic periductular inflammation and cholestatic liver disease resulting in the development of hepatocellular carcinoma (HCC). Inhibition of NF-κB by expression of an IκBα super-repressor (IκBαSR) transgene in hepatocytes was shown to prevent HCC development in Mdr2−/− mice, suggesting that NF-κB acts as a tumour promoter in this model of inflammation-associated carcinogenesis. On the other hand, inhibition of NF-κB by hepatocyte specific ablation of IKK2 resulted in increased liver tumour development induced by the chemical carcinogen DEN. To address the role of IKK2-mediated NF-κB activation in hepatocytes in the pathogenesis of liver disease and HCC in Mdr2−/− mice, we generated Mdr2-deficient animals lacking IKK2 specifically in hepatocytes using the Cre-loxP system. Mdr2−/− mice lacking IKK2 in hepatocytes developed spontaneously a severe liver disease characterized by cholestasis, major hyperbilirubinemia and severe to end-stage fibrosis, which caused muscle wasting, loss of body weight, lethargy and early spontaneous death. Cell culture experiments showed that primary hepatocytes lacking IKK2 were more sensitive to bile acid induced death, suggesting that hepatocyte-specific IKK2 deficiency sensitized hepatocytes to the toxicity of bile acids under conditions of cholestasis resulting in greatly exacerbated liver damage. Mdr2−/−IKK2Hep-KO mice remarkably recapitulate chronic liver failure in humans and might be of special importance for the study of the mechanisms contributing to the pathogenesis of end-stage chronic liver disease or its implications on other organs. Conclusion: IKK2-mediated signaling in hepatocytes protects the liver from damage under conditions of chronic inflammatory cholestasis and prevents the development of severe fibrosis and liver failure

Stress Doppler echocardiography for early detection of systemic sclerosis-associated pulmonary arterial hypertension

Introduction: In patients with systemic sclerosis (SSc), associated pulmonary arterial hypertension (SSc-APAH) is the leading cause of death. The objective of this prospective screening study was to analyse sensitivity and specificity of stress Doppler echocardiography (SDE) in detecting pulmonary hypertension (PH). Methods: Pulmonary artery pressures and further parameters of PH were assessed by echocardiography and right heart catheterisation (RHC) at rest and during exercise in patients with SSc. Investigators of RHC were blinded to the results of non-invasive measurements. Results: Of 76 patients with SSc (64 were female and mean age was 58±14 years), 22 (29 %) had manifest PH confirmed by RHC: four had concomitant left heart diseases, three had lung diseases, and 15 had SSc-APAH. Echocardiography at rest missed PH diagnosis in five of 22 patients with PH when a cutoff value for systolic pulmonary arterial pressure (PASP) was more than 40 mm Hg at rest. The sensitivity of echocardiography at rest was 72.7 % (95 % confidence interval (CI) 0.52–0.88), and specificity was 88.2 % (95 % CI 0.78–0.95). When a cutoff value for PASP was more than 45 mm Hg during low-dose exercise, SDE missed PH diagnosis in one of the 22 patients with PH and improved sensitivity to 95.2 % (95 % CI 0.81–1.0) but reduced specificity to 84.9 % (95 % CI 0.74–0.93). Reduction of specificity was partly due to concomitant left heart disease. Conclusions: The results of this prospective cross-sectional study using RHC as gold standard in all patients showed that SDE markedly improved sensitivity in detecting manifest PH to 95.2 % compared with 72.7 % using echocardiography at rest only. Thus, for PH screening in patients with SSc, echocardiography should be performed at rest and during exercise. Trial registration: ClinicalTrials.gov NCT01387035 . Registered 29 June 2011

Change of right heart size and function by long-term therapy with riociguat in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension

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Sensitive Commercial NASBA Assay for the Detection of Respiratory Syncytial Virus in Clinical Specimen

The aim of the study was to evaluate the usability of three diagnostic procedures for the detection of respiratory syncytial virus in clinical samples. Therefore, the FDA cleared CE marked NOW® RSV ELISA, the NucliSENS® EasyQ RSV A+B NASBA, and a literature based inhouse RT-PCR protocol were compared for their relative sensitivities. Thereby, NASBA turned out to be the most sensitive method with a total number of 80 RSV positive samples out of a cohort of 251 nasopharyngeal washings from patients suffering from clinical symptoms, followed by the inhouse RT-PCR (62/251) and ELISA (52/251). Thus, NASBA may serve as a rapid and highly sensitive alternative for RSV diagnostics

Hemodynamic and genetic analysis in children with idiopathic, heritable, and congenital heart disease associated pulmonary arterial hypertension

Background: Aim of this prospective study was to compare clinical and genetic findings in children with idiopathic or heritable pulmonary arterial hypertension (I/HPAH) with children affected with congenital heart defects associated PAH (CHD-APAH). Methods: Prospectively included were 40 consecutive children with invasively diagnosed I/HPAH or CHD-APAH and 117 relatives. Assessment of family members, pedigree analysis and systematic screening for mutations in TGFß genes were performed. Results: Five mutations in the bone morphogenetic protein type II receptor (BMPR2) gene, 2 Activin A receptor type II-like kinase-1 (ACVRL1) mutations and one Endoglin (ENG) mutation were found in the 29 I/HPAH children. Two mutations in BMPR2 and one mutation in ACVRL1 and ENG, respectively, are described for the first time. In the 11 children with CHD-APAH one BMPR2 gene mutation and one Endoglin gene mutation were found. Clinical assessment of relatives revealed familial aggregation of the disease in 6 children with PAH (HPAH) and one CHD-APAH patient. Patients with mutations had a significantly lower PVR. Conclusion: Mutations in different TGFß genes occurred in 8/29 (27.6%) I/HPAH patients and in 2/11 (18.2%) CHD-APAH patients and may influence the clinical status of the disease. Therefore, genetic analysis in children with PAH, especially in those with I/HPAH, may be of clinical relevance and shows the complexity of the genetic background