Quantitative assay to analyze neutralization and inhibition of authentic Middle East respiratory syndrome coronavirus.

To date, there is no licensed vaccine for Middle East respiratory syndrome coronavirus (MERS-CoV). Therefore, MERS-CoV is one of the diseases targeted by the Coalition for Epidemic Preparedness Innovations (CEPI) vaccine development programs and has been classified as a priority disease by the World Health Organization (WHO). An important measure of vaccine immunogenicity and antibody functionality is the detection of virus-neutralizing antibodies. We have developed and optimized a microneutralization assay (MNA) using authentic MERS-CoV and standardized automatic counting of virus foci. Compared to our standard virus neutralization assay, the MNA showed improved sensitivity when analyzing 30 human sera with good correlation of results (Spearman's correlation coefficient r = 0.8917, p value < 0.0001). It is important to use standardized materials, such as the WHO international standard (IS) for anti-MERS-CoV immunoglobulin G, to compare the results from clinical trials worldwide. Therefore, in addition to the neutralizing titers (NT50 = 1384, NT80 = 384), we determined the IC50 and IC80 of WHO IS in our MNA to be 0.67 IU/ml and 2.6 IU/ml, respectively. Overall, the established MNA is well suited to reliably quantify vaccine-induced neutralizing antibodies with high sensitivity.

Full-body blue light irradiation as treatment for atopic dermatitis: a randomized sham-controlled clinical trial (AD-Blue).

BACKGROUND: Visible blue light (wavelength 400-495 nm) is a promising new treatment option for both psoriasis and atopic dermatitis (AD). Whilst previous clinical trials featured various devices and blue light at a variety of wavelengths, none of these interventions were challenged in objective clinical criteria. PATIENTS AND METHODS: Eighty-seven patients diagnosed with AD were enrolled in AD-Blue, an international, prospective, double-blinded, three-armed (415 nm vs. 450 nm vs. sham control), randomized trial designed to investigate the safety and efficacy of prototype full-body blue light devices. RESULTS: Full-body irradiation with 450 nm blue light but not 415 nm had a significant impact on itch (Itch-VAS, -1.6 ± 2.3; p  =  0.023 vs. sham irradiation). PO-SCORAD values also decreased significantly in response to irradiation at 415 nm (-11.5 ± 18.4; p = 0.028 vs. sham irradiation). None of the other outcome measures (EASI, SCORAD, IGA, DLQI) changed significantly. No safety signals were observed. Evaluation of skin transcriptomes, cytokine levels in serum, and ELISpots from peripheral blood mononuclear cells isolated from a subset of patients revealed moderate decreases in IL-31 in response to irradiation with blue light. CONCLUSIONS: Despite its favorable safety profile and moderate reductions in itch and IL-31 levels, full-body blue light irradiation did not lead to an amelioration of any of the objective measures of AD.

Cost-Effectiveness of Inter-Professional Collaboration to Reduce Hospitalisations in Nursing Home Residents: Results from the German Interprof ACT Trial.

Background: The German multi-centre cluster-randomised controlled trial interprof ACT investigated interventions to increase inter-professional collaboration between nursing home (NH) staff and local general practitioners to reduce hospitalisations and improve nursing homes residents' (NHRs) quality of life. The trial was funded by the German Health Care Innovation Fund. Methods: Cost-effectiveness of interprof ACT interventions was evaluated and compared to current standard of care (SOC) over 12 months, including 622 NHRs in 34 NHs in Germany. Multiplying resource use of healthcare services with German-specific unit costs generated costs. Health outcome was measured in quality-adjusted life-years QALYs), utility by multiplying EQ-5D-5L values with German-specific utility weights. Incremental cost-effectiveness analysis used an intention-to-treat approach and scenario analyses (SAs). Net-benefit-regression and cost-effectiveness acceptability curves addressed uncertainty. A German healthcare insurance perspective was assumed. Results: Base case results showed non-significant cost savings of 851.88€ and non-significant QALY loss of -0,056. Discussion: Dependency levels at baseline were non-significantly higher in IG compared to control group (CG). Lack of baseline costing data eliminated possibility to evaluate changes in costs due to the interprof ACT measures for both groups. Conclusion: Interprof ACT interventions are not cost-effective compared to current SOC.

Cluster randomised trial of a complex interprofessional intervention (interprof ACT) to reduce hospital admission of nursing home residents.

BACKGROUND: Some hospital admissions of nursing home residents (NHRs) might be attributed to inadequate interprofessional collaboration. To improve general practitioner-nurse collaboration in nursing homes (NHs), we developed an intervention package (interprof ACT) in a previous study. OBJECTIVE: To assess the impact of interprof ACT on the proportion of hospitalisation and other clinical parameters within 12 months from randomisation among NHRs. METHODS: Multicentre, cluster randomised controlled trial in 34 German NHs. NHRs of the control group received usual care, whereas NHRs in the intervention group received interprof ACT. Eligible NHs had at least 40 long-term care residents. NHs were randomised 1:1 pairwise. Blinded assessors collected primary outcome data. RESULTS: Seventeen NHs (320 NHRs) were assigned to interprof ACT and 17 NHs (323 NHRs) to usual care. In the intervention group, 136 (42.5%) NHRs were hospitalised at least once within 12 months from randomisation and 151 (46.7%) in the control group (odds ratio (OR): 0.82, 95% confidence interval (CI): [0.55; 1.22], P = 0.33). No differences were found for the average number of hospitalisations: 0.8 hospitalisations per NHR (rate ratio (RR) 0.90, 95% CI: [0.66, 1.25], P = 0.54). Average length of stay was 5.7 days for NHRs in the intervention group and 6.5 days in the control group (RR: 0.70, 95% CI: [0.45, 1.11], P = 0.13). Falls were the most common adverse event, but none was related to the study intervention. CONCLUSIONS: The implementation of interprof ACT did not show a statistically significant and clinically relevant effect on hospital admission of NHRs.

Incidence and risk factors for macular oedema after primary rhegmatogenous retinal detachment surgery: a prospective single-centre study.

PURPOSE: To assess the incidence of cystoid macular oedema (CME) diagnosed by spectral domain optical coherence tomography (SD-OCT) after primary rhegmatogenous retinal detachment (RRD) surgery. METHODS: From April 2016 to October 2017, 150 eyes of 150 patients presenting with primary RRD were included consecutively in this prospective single-centre study. Patients with the following characteristics were excluded: previous vitreoretinal surgery, combined cataract surgery, preoperatively presentation with any intraocular or systemic inflammatory condition, visible macular oedema or epiretinal membrane (ERM) on funduscopy. SD-OCT (Spectralis, Heidelberg Engineering) was conducted 3 and 6 weeks after surgery. RESULTS: One hundred and twenty-eight of the 150 patients completed the study, of whom 107 (age: 61.7 ± 11.5 years, mean ± SD) showed successful retinal attachment during follow-up visits. The most frequent operation method was scleral buckling (54.2%), followed by vitrectomy (25.2%) and the combination of both techniques (20.6%). Postoperative SD-OCT revealed CME, neurosensory detachment and ERM in 18.7, 31.8 and 32.7% of all cases, respectively. The risk of postoperative CME was significantly elevated in patients with ERM (42.9 versus 6.9%, p < 0.001). In addition, patients with initial detachment of the macula had more postoperative CME (26.5 versus 11.1%, p = 0.044). BCVA improvement was significantly lower in patients with CME compared to patients without 6 weeks after surgery for macula-on RRD. CONCLUSIONS: This prospective study confirmed that postoperative CME is a frequent complication after RRD surgery; we identified ERM and macula-off RRD as potential risk factors. As CME potentially delays visual recovery, postoperative follow-ups should include SD-OCT.

Ebola Virus Activates IRE1α-Dependent XBP1u Splicing.

Ebola (EBOV) and Marburg virus (MARV) are highly pathogenic filoviruses that influence cellular signaling according to their own needs. MARV has been shown to regulate the IRE1α-dependent unfolded protein response (UPR) to ensure optimal virus replication. It was not known whether EBOV affects this signaling cascade, which can be beneficial or detrimental for viruses. Activation of IRE1α leads to the expression of the transcription factor XBP1s, which binds to cis-acting UPR elements (UPRE), resulting in the expression of genes aimed at restoring homeostasis in the endoplasmic reticulum. We observed that EBOV infection, in contrast to MARV infection, led to UPR activation by IRE1α-dependent but not ATF6-dependent signaling. We showed an activation of IRE1α, XBP1s and UPRE target genes upon EBOV infection. ATF6, another UPRE transcription factor, was not activated. UPRE activation was mainly attributed to the EBOV nucleoprotein NP and the soluble glycoprotein sGP. Finally, activation of UPR by thapsigargin, a potent ER-stress inducer, in parallel to infection as well as knock-out of XBP1 had no effect on EBOV growth, while MARV proliferation was affected by thapsigargin-dependent UPR activation. Taken together EBOV and MARV differ in their strategy of balancing IRE1α-dependent signaling for their own needs.

Predicting the individual probability of macular hole closure following intravitreal ocriplasmin injections for vitreomacular traction release using baseline characteristics.

The primary objective was to create and establish a new formula that predicts the individual probability of macular hole closure for eyes with full thickness macular holes (FTMH) accompanied by vitreomacular traction (VMT) which received enzymatic vitreolysis using intravitreally administered ocriplasmin. The secondary objective was to evaluate the forecast reliability of a previously published formula for VMT resolution in VMT-only eyes (OddsIVO-Success = eIntercept × ORyears × ORln(µm); ProbabilityIVO-Success = OddsIVO-Success/(OddsIVO-Success + 1)) on VMT resolution using the current dataset of eyes with FTMH accompanied by VMT. Retrospective analysis of the OASIS, ORBIT, and INJECT-studies. Patients with FTMH and VMT with complete information (n = 213) were included. The effect of gender, age, FTMH diameter, lens status and the presence of epiretinal membranes (ERM) on FTMH closure was assessed using separate univariate logistic regression analyses. With regard to VMT release separate univariate regression analyses were carried out and results were compared with formerly published data of VMT resolution in eyes with VMT only. Overall, 126 eyes (63%) experienced VMT resolution within 28 days. Younger age (p < 0.0001) and VMT diameter (p = 0.041) had a significant impact on VMT release. Overall, 81 eyes (38%) treated with ocriplasmin showed FTMH closure within 28 days. Univariate analysis of the different predictors analyzed revealed that FTMH diameter < 250 µm had a significant impact on treatment success (p = 0.0495). It was not possible to calculate and establish a new multivariate formula that can predict the individual FTMH closure probability for eyes with FTMHs and VMT. However, the results of VMT release prediction in eyes with FTMHs accompanied by VMT matched the prediction of VMT release in eyes with VMT only when using the previously published formula. All in all, predictors for calculating the individual probability of VMT resolution on the one hand and FTMH closure on the other hand are different suggesting diverse pathophysiological mechanisms.

Herbal treatment with uva ursi extract versus fosfomycin in women with uncomplicated urinary tract infection in primary care: a randomized controlled trial.

OBJECTIVE: We explored whether initial treatment with the herbal drug uva ursi (UU) reduces antibiotic use in women with uncomplicated urinary tract infection (UTI) without increasing symptom burden and complication frequency compared with antibiotic treatment. METHODS: A double-blind randomized controlled trial was conducted in 42 family practices in Germany. The participants were adult women with suspected uncomplicated UTIs receiving either UU 105 mg 3 × 2 tablets for 5 days (intervention) or fosfomycin a 3-g single dose (control), and their respective placebos. Participants and investigators were blinded. The primary outcome included (1) antibiotic courses day 0-28 as superiority, and (2) symptom burden (sum of daily symptom scores) day 0-7, as non-inferiority outcome (margin 125%). Clinicaltrials.gov: NCT03151603. RESULTS: Overall, 398 patients were randomly allocated to groups receiving UU (n = 207) and fosfomycin (n = 191). The number of antibiotic courses was 63.6% lower (95% CI 53.6%-71.4%; p < 0.0001) in the UU group than in the fosfomycin group. The ratio of total symptom burden in the UU group compared with control was 136.5% (95% CI 122.7-151.9; p 0.95), failing non-inferiority. Eight women developed pyelonephritis in the UU group compared with two in the fosfomycin group (mean difference 2.8; 95% CI 0.2-5.9; p 0.067). Adverse events were similar between the groups. DISCUSSION: In women with uncomplicated UTIs, initial treatment with UU reduced antibiotic use but led to a higher symptom burden and more safety concerns than fosfomycin.

Risk Factors for Severe Bleeding Complications in Vitreoretinal Surgery and the Role of Antiplatelet or Anticoagulant Agents.

PURPOSE: To evaluate the influences and risk factors for severe bleeding complications during vitreoretinal surgery and to investigate the role of antiplatelet and anticoagulant agents. DESIGN: Prospective trial. PARTICIPANTS: Patients undergoing vitreoretinal surgery. METHODS: The procedures included were pars plana vitrectomy and scleral buckling. We developed a uniform classification to grade the bleeding severity. Bleeding was graded on an ordinal scale ranging from 0 to 5. Immediately after surgery and 1 day later, the incidence and the severity of bleeding events was documented on a standardized form. A grade of 3 or more was defined as severe bleeding. Furthermore, the influence of known systemic disorders before surgery, the type of anesthesia, type of surgical procedure, intraoperative blood pressure, and the use or change of antiplatelet or anticoagulant agents on intraoperative bleeding was analyzed. MAIN OUTCOME MEASURES: Incidence and risk factors for severe intraoperative bleeding events. RESULTS: Data from 374 eyes undergoing vitreoretinal procedures were included in our study (mean age, 67.6 ± 12.9 years). A severe intraoperative bleeding event was observed in 15 eyes (4%). We found that concomitant diseases such as diabetes mellitus and carotid artery stenosis, the presence of diabetic retinopathy, younger age, and scleral buckling combined with a transscleral puncture were associated significantly with severe bleeding events. By contrast, use of antiplatelet or anticoagulant agents, or both, had no significant influence on severe intraoperative bleeding events. CONCLUSIONS: Although external manipulations during buckling surgery (e.g., drainage of subretinal fluid) and concomitant diseases such as diabetes mellitus and carotid artery stenosis influences the risk of severe intraoperative bleeding events, we did not detect an increased risk related to coexisting antiplatelet or anticoagulant medication use, or both.

Influence of pars plana vitrectomy for macular surgery on the medium term intraocular pressure.

PURPOSE: To evaluate the long-term effect of 20 and 23 gauge pars plana vitrectomy (PPV) on intraocular pressure (IOP). METHODS: Study type: Monocentric retrospective cohort study. 249 eyes of 249 patients undergoing PPV due to epiretinal membrane (EM), idiopathic macular hole (IMH) or vitreoretinal traction (VT) were included. The fellow eye served as control. Exclusion criteria were factors known to influence the IOP, such as cataract surgery during follow-up, extended use of steroids, cryotherapy and silicone oil endotamponade. The relative change of IOP (operated vs. fellow eye) at 6-12 months after surgery was defined as primary endpoint. Secondary endpoints were the relative change of IOP at 3-6 and 12-24 months. Possible influencing cofactors were analysed using ANCOVA. RESULTS: The primary endpoint did not show a significant IOP reduction of the operated eye relative to the fellow eye (P = 0.089, n = 84). However, the IOP of the operated eye alone was significantly reduced at 6-12 and 12-24 months after surgery (-0.75 ± 2.80 and -1.22 ± 3.29 mmHg, P = 0.008 and 0.007, respectively). The IOP of the fellow eye was also significantly reduced at the 12-24 months period (-0.75 ± 2.73 mmHg, P = 0.008). In the subgroup analysis, sclerotomy size was a significant influencing cofactor, leading to lower IOP after 20G compared to 23G vitrectomy (P = 0.04). CONCLUSION: Pars plana vitrectomy did not induce a significant long-term IOP reduction relative to the contralateral eye. However, we observed a IOP lowering potential in 20G vitrectomy.

Risk of perioperative bleeding complications in rhegmatogenous retinal detachment surgery: a retrospective single-center study.

PURPOSE: The goal of this study was to analyze the incidence of perioperative bleeding complications in rhegmatogenous retinal detachment. The handling of perioperative anticoagulation during vitreoretinal surgery remains controversial, since the risk of bleeding complications by its continuation has to be balanced against the risk of progression of retinal detachment and the risk of thromboembolic events when anticoagulation is interrupted. Nevertheless, only few studies have investigated the risk of perioperative bleeding complications in an emergency such as retinal detachment surgery. METHODS: We therefore examined the rate of all perioperative hemorrhages and separately the rate of only severe bleedings during vitrectomy, scleral buckling with or without drainage of subretinal fluid (SRD), or combined procedures due to retinal detachment in patients undergoing different types of perioperative anticoagulation including acetylsalicylic acetate (ASA), clopidogrel, heparin, low molecular weight heparin, and phenprocoumon. RESULTS: This retrospective single-center study included 893 patients with primary rhegmatogenous retinal detachment, n = 192 on anticoagulation and n = 701 serving as control without anticoagulation. Our analysis revealed no significantly increased rate of perioperative hemorrhages under anticoagulation with ASA 100 mg (all, 11.4%; severe, 5.0%) or phenprocoumon (all, 11.6%; severe, 2.3%) compared with controls (all, 13.0%; severe, 5.4%). However, frequencies of bleeding complications varied markedly regarding the type of surgical procedure: Scleral buckling plus SRD showed the highest rates of hemorrhages (all, 18.9%; severe, 9.1%) with significant difference (P < 0.001) compared with scleral buckling without SRD (all, 3.8%; severe, 0.6%) and vitrectomy (all, 9.2%; severe, 1.5%), respectively. Furthermore, subretinal bleeding was the most common type of perioperative hemorrhage. CONCLUSIONS: The data suggest not to stop ASA therapy prior to vitreoretinal surgery. Furthermore, we found no evidence of an increased risk for perioperative bleedings in patients under anticoagulation with vitamin-k antagonists with an INR within the sub-therapeutic range. SRD during scleral buckling procedure should be avoided as possible and regardless of any type of anticoagulation.

[Complications in sutured scleral fixation of artificial lens implantation]. / Komplikationen bei skleranahtfixierter Kunstlinsenimplantation.

BACKGROUND: Sutured scleral fixation of an artificial posterior chamber lens is a frequently used method for the treatment of eyes with poor or absent capsular support; however, the complication profile is often considered unfavorable. OBJECTIVE: To analyze the postoperative complication profile. METHODS: In this monocentric and retrospective analysis of a consecutive case series of patients with standardized sutured scleral fixation of a posterior chamber lens between 2007 and 2017, the documented complications were categorized as a permanent threat to visual acuity, such as endophthalmitis, choroidal hemorrhage, retinal detachment and clinically relevant but without a permanent threat to visual acuity, such as hemorrhage and hypotension. Additionally, the time point when complications first occurred was categorized into the 3 periods 0-3, 4-30 and ≥31 days. RESULTS: This is the largest patient collective of a study with scleral fixation of a posterior chamber lens published so far. A total of 338 eyes from 338 patients were included in the study (women 47%) and the median postoperative follow-up period was 60 days (range 1-5833 days). In 68% of the patients at least 1 complication was documented. Complications with a permanent threat to visual acuity occurred in 3% (n = 10) of the patients. The most frequent clinically relevant complications were intraocular hypotension ≤10 mm Hg (35%; n = 119), pupil decentration (28%; n = 93), hyphema, iris or vitreous hemorrhage (10%; n = 34), secondary glaucoma (9%; n = 32) and iris capture (5%; n = 17). Of the complications 41% occurred within the first 3 days and 70% within the first 30 days. Revision surgery was carried out in 4.5% (n = 15) of the patients. CONCLUSION: Although complications occurred in two thirds of the interventions, the number of permanent complications with a permanent threat to visual acuity was low. Scleral fixation of an artificial posterior chamber lens is still a justifiable intervention.

Treatment of Atopic Dermatitis Using a Full-Body Blue Light Device (AD-Blue): Protocol of a Randomized Controlled Trial.

BACKGROUND: Irradiation with visible blue light (wavelength 400-495 nm) is a promising, effective, and safe new treatment option for chronic inflammatory skin diseases such as psoriasis and atopic dermatitis. OBJECTIVE: We will perform a multicenter, placebo-controlled, double-blinded, 3-armed, prospective, randomized controlled trial to investigate the efficacy and safety of full-body blue light devices (wavelengths: 415 nm and 450 nm) compared with that of placebo irradiation for the treatment of atopic dermatitis. METHODS: We are planning to enroll a total of 150 patients at the University hospitals in Göttingen (Germany), Marburg (Germany), and Geneva (Switzerland). RESULTS: The trial was approved by the lead ethics committee of the medical faculty of the University of Göttingen (21/11/16). Further approvals were obtained from local and federal authorities (ethics committee Marburg, Cantonal Commission for Research Ethics Geneva, Suisse Medic, and Bundesinstitut für Arzneimittel und Medizinprodukte). CONCLUSIONS: We will disseminate the results in a peer-reviewed journal. TRIAL REGISTRATION: ClinicalTrials.gov NCT03085303; https://clinicaltrials.gov/ct2/show/NCT03085303 (Archived by WebCite at http://www.webcitation.org/73ucqkkA1). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/11911.

Analysis of the multifunctionality of Marburg virus VP40.

The Marburg virus (MARV) matrix protein, VP40, is a multifunctional protein that is essential for the assembly and release of viral particles, inhibition of the interferon response and viral transcription/replication. VP40 is assumed to be present as soluble monomers and membrane-bound higher-order oligomers. To investigate the functional relevance of oligomerization and lipid binding of VP40 we constructed mutants with impaired VP40-VP40 or VP40-lipid interactions and tested their capacity to bind the plasma membrane, to form virus-like particles (VLPs) and to inhibit viral RNA synthesis. All of the analysed VP40 mutants formed perinuclear aggregates and were defective in their delivery to the plasma membrane and in VLP production. The VP40 mutants that were competent for oligomerization but lacked VP40-lipid interactions formed fibril-like structures, influenced MARV inclusion body formation and inhibited viral transcription/replication more strongly than the VP40 wild-type. Altogether, mutations that interfere with VP40's transition from monomer to higher-order oligomers and/or lipid interactions destroy the protein's multifunctionality.

Atrial fibrillation in retinal vascular occlusion disease and non-arteritic anterior ischemic optic neuropathy.

BACKGROUND: Patients with retinal vascular occlusion disease have an increased risk for ischemic stroke and share some risk factors with cerebrovascular disease. The purpose of this study was to analyze the prevalence of atrial fibrillation (AF) in subjects with retinal vascular occlusive disease and anterior ischemic optic neuropathy and to compare these data to an ischemic stroke group. METHODS: Prospective, observational single-center trial. Subjects with retinal artery occlusion (RAO), retinal vein occlusion (RVO) and anterior ischemic optic neuropathy (AION) were included. Patients with ischemic stroke (IS) from a previous observational trial were used as control. Investigation included 7-day Holter ECG, echocardiography, duplex ultrasonography of the carotid arteries, and 24-hour blood pressure monitoring. Further vascular risk factors were documented. RESULTS: During the 1-year study period, 101 patients were recruited. The control group with ischemic stroke consisted of 272 subjects. At inclusion, the prevalence of AF was 12% (RAO), 10.2% (RVO), 11.1% (NAION) and 15.8% (IS). The final prevalence after Holter ECG rose to 16% (RAO), 18.4% (RVO), 14.8% (NAION) and 26.5% (IS). No significant difference was measured between groups. CONCLUSIONS: We detected a similar prevalence of AF in all groups. RVO patients tended to exhibit a higher AF detection rate and lower number needed to screen than RAO and NAION. The detection of AF rose considerably via Holter ECG. As a consequence, we recommend prolonged ECG monitoring in patients with acute ophthalmic vascular diseases.

Risk of progression in macula-on rhegmatogenous retinal detachment.

PURPOSE: To identify factors that may lead to a rapid progression in macula-on rhegmatogenous retinal detachment (RRD), in particular, those that may lead to macular involvement. METHODS: Observational, prospective, single-center study. Patients referred for surgery due to primary rhegmatogenous retinal detachment with the macula on between 2009 and 2013 were included. Relevant factors analyzed included age, time delay until surgery, lens status, myopia, the detachment's location and configuration as well as number, size and type of retinal breaks. Eyes underwent optical coherence tomography to detect macular detachment. A multivariate analysis was performed to investigate the effect of several factors in the progression of retinal detachment. RESULTS: A total of 116 eyes of 116 patients were included. Mean time delay between admission and surgery was 1.8 ± 1.4 days. Progression was observed in 19.8% of the eyes. Of those, 47.8% presented macular detachment. Ten of the 11 (90.9%) eyes presenting progression involving the macula also exhibited a bullous configuration, which was the only parameter that correlated significantly with detachment progression in patients with (p = 0.0036) and without (p = 0.0014) macular involvement. CONCLUSIONS: For the first time in a prospective trial, a bullous configuration was found to be a highly significant predictor for progression in macula-on detachments. Our data support prompt surgery in patients diagnosed with bullous macula-on RRD.

Efficacy and safety of a fixed bimonthly ranibizumab treatment regimen in eyes with neovascular age-related macular degeneration: results from the RABIMO trial.

PURPOSE: To evaluate prospectively the efficacy and safety of a fixed bimonthly ranibizumab treatment regimen (RABIMO) in eyes with neovascular age-related macular degeneration (nAMD) and to compare these results with a pro re nata (PRN) treatment scheme. METHODS: This was a 12-month, phase IV, single center, randomised, non-inferiority study. Following three initial monthly injections, patients were randomised to receive either ranibizumab bimonthly (RABIMO group) or ranibizumab PRN (PRN group) (n = 20 each). Main outcome measures were best-corrected visual acuity (BCVA), central retinal thickness (CRT), number of injections, and adverse events (AEs). RESULTS: BCVA [median (interquartile range, IQR)] increased significantly in both groups after 12 months [RABIMO group +8.5 (14); PRN group +6.5 (16) ETDRS letters] when compared to baseline (p < 0.0001; p = 0.0085). At month 12, the RABIMO treatment regimen was non-inferior to the PRN scheme (∆BCVA = 3.5 ETDRS letters; p < 0.0001). CRT was significantly reduced in both groups after the 12-month study period (p < 0.0001 each), with no significant difference between groups (p = 0.6772). Number of overall injections [median (IQR)] was 8 (0) in the RABIMO versus 4 (5) in the PRN group (p = 0.0037). Three patients in the RABIMO group received one additional unscheduled injection. We observed no significant differences between groups in the number of patients with reported SAEs/AEs (RABIMO group n = 6/15; PRN group n = 7/13) (p = 0.7357/p = 0.4902). CONCLUSIONS: We found no evidence of significant functional or anatomical differences between the RABIMO and PRN treatment regimens. However, the RABIMO group's number of injections was twice as high as the PRN group's (protocol-driven). In light of potential side effects, the fixed bimonthly treatment regimen might not be advisable for routine clinical care, but it might be a worthwhile treatment option if monthly monitoring is not possible. Eudra-CT number: 2009-017324-11.

Transcutaneous noninvasive vagus nerve stimulation (tVNS) in the treatment of schizophrenia: a bicentric randomized controlled pilot study.

Despite many pharmacological and psychosocial treatment options, schizophrenia remains a debilitating disorder. Thus, new treatment strategies rooted in the pathophysiology of the disorder are needed. Recently, vagus nerve stimulation (VNS) has been proposed as a potential treatment option for various neuropsychiatric disorders including schizophrenia. The objective of this study was to investigate for the first time the feasibility, safety and efficacy of transcutaneous VNS in stable schizophrenia. A bicentric randomized, sham-controlled, double-blind trial was conducted from 2010 to 2012. Twenty schizophrenia patients were randomly assigned to one of two treatment groups. The first group (active tVNS) received daily active stimulation of the left auricle for 26 weeks. The second group (sham tVNS) received daily sham stimulation for 12 weeks followed by 14 weeks of active stimulation. Primary outcome was defined as change in the Positive and Negative Symptom Scale total score between baseline and week 12. Various other secondary measures were assessed to investigate safety and efficacy. The intervention was well tolerated with no relevant adverse effects. We could not observe a statistically significant difference in the improvement of schizophrenia psychopathology during the observation period. Neither psychopathological and neurocognitive measures nor safety measures showed significant differences between study groups. Application of tVNS was well tolerated, but did not improve schizophrenia symptoms in our 26-week trial. While unsatisfactory compliance questions the feasibility of patient-controlled neurostimulation in schizophrenia, the overall pattern of symptom change might warrant further investigations in this population.

Rituximab after lymphoma-directed conditioning and allogeneic stem-cell transplantation for relapsed and refractory aggressive non-Hodgkin lymphoma (DSHNHL R3): an open-label, randomised, phase 2 trial.

BACKGROUND: Allogeneic stem-cell transplantation has had limited success for patients with refractory and relapsed aggressive B-cell or T-cell lymphoma. We investigated the effect of adding rituximab to standard prophylaxis for graft-versus-host disease after transplantation and estimated overall survival when using a lymphoma-directed myeloablative conditioning regimen. METHODS: We did this randomised, open-label, phase 2 study at seven German transplantation centres. We enrolled patients with aggressive B-cell or T-cell lymphoma and primary refractory disease, early relapse (<12 months after first-line treatment), or relapse after autologous transplantation. Conditioning with fludarabine (125 mg/m(2)), busulfan (12 mg/kg oral or 9·6 mg/kg intravenous), and cyclophosphamide (120 mg/kg) was followed by allogeneic stem-cell transplantation. Patients were randomly assigned (1:1) to receive rituximab (375 mg/m(2) on days 21, 28, 35, 42, 175, 182, 189, and 196) or not. Allocation was done with a centralised computer-generated procedure; patients were stratified by histological subtype (B-cell vs T-cell lymphoma) and donor match (HLA-identical vs non-identical). Neither investigators nor patients were masked to allocation. The primary endpoints were the incidence of acute graft-versus-host disease grade 2-4 in each treatment group and overall survival at 1 year in both groups combined. All analyses were done for the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT00785330. FINDINGS: Between June 16, 2004, and March 24, 2009, we screened 86 patients and enrolled 84; 42 were randomly assigned to each group. The cumulative incidence of grade 2-4 acute graft-versus-host disease was 46% (95% CI 32-62) in the rituximab group and 42% (95% CI 29-59) in the no rituximab group (hazard ratio [HR] 0·91, 95% CI 0·52-1·60; p=0·74). Overall survival at 1 year for the whole study population was 52% (95% CI 41-62). Grade 4 haematological toxic effects and grade 3 alopecia occurred in all patients. The most common non-haematological grade 5 toxic effects were pneumonia (nine in the no rituximab group vs ten in the rituximab group) and other infections (seven vs four). INTERPRETATION: The lymphoma-directed myeloablative conditioning regimen developed here is promising for patients with refractory and relapsed aggressive B-cell and T-cell lymphomas. However, the addition of rituximab did not affect the incidence of graft-versus-host disease or overall survival. FUNDING: Hoffmann-La Roche, Amgen, Astellas Pharma.