Increasing sample diversity in psychiatric genetics - Introducing a new cohort of patients with schizophrenia and controls from Vietnam - Results from a pilot study.

OBJECTIVES: Genome-Wide Association Studies (GWAS) of Schizophrenia (SCZ) have provided new biological insights; however, most cohorts are of European ancestry. As a result, derived polygenic risk scores (PRS) show decreased predictive power when applied to populations of different ancestries. We aimed to assess the feasibility of a large-scale data collection in Hanoi, Vietnam, contribute to international efforts to diversify ancestry in SCZ genetic research and examine the transferability of SCZ-PRS to individuals of Vietnamese Kinh ancestry. METHODS: In a pilot study, 368 individuals (including 190 SCZ cases) were recruited at the Hanoi Medical University's associated psychiatric hospitals and outpatient facilities. Data collection included sociodemographic data, baseline clinical data, clinical interviews assessing symptom severity and genome-wide SNP genotyping. SCZ-PRS were generated using different training data sets: (i) European, (ii) East-Asian and (iii) trans-ancestry GWAS summary statistics from the latest SCZ GWAS meta-analysis. RESULTS: SCZ-PRS significantly predicted case status in Vietnamese individuals using mixed-ancestry (R2 liability = 4.9%, p = 6.83 × 10-8), East-Asian (R2 liability = 4.5%, p = 2.73 × 10-7) and European (R2 liability = 3.8%, p = 1.79 × 10-6) discovery samples. DISCUSSION: Our results corroborate previous findings of reduced PRS predictive power across populations, highlighting the importance of ancestral diversity in GWA studies.

Recommendations for rosacea diagnosis, classification and management: update from the global ROSacea COnsensus 2019 panel.

BACKGROUND: A transition from a subtyping to a phenotyping approach in rosacea is underway, allowing individual patient management according to presenting features instead of categorization by predefined subtypes. The ROSacea COnsensus (ROSCO) 2017 recommendations further support this transition and align with guidance from other working groups. OBJECTIVES: To update and extend previous global ROSCO recommendations in line with the latest research and continue supporting uptake of the phenotype approach in rosacea through clinical tool development. METHODS: Nineteen dermatologists and two ophthalmologists used a modified Delphi approach to reach consensus on statements pertaining to critical aspects of rosacea diagnosis, classification and management. Voting was electronic and blinded. RESULTS: Delphi statements on which the panel achieved consensus of ≥ 75% voting 'Agree' or 'Strongly agree' are presented. The panel recommends discussing disease burden with patients during consultations, using four questions to assist conversations. The primary treatment objective should be achievement of complete clearance, owing to previously established clinical benefits for patients. Cutaneous and ocular features are defined. Treatments have been reassessed in line with recent evidence and the prior treatment algorithm updated. Combination therapy is recommended to benefit patients with multiple features. Ongoing monitoring and dialogue should take place between physician and patients, covering defined factors to maximize outcomes. A prototype clinical tool (Rosacea Tracker) and patient case studies have been developed from consensus statements. CONCLUSIONS: The current survey updates previous recommendations as a basis for local guideline development and provides clinical tools to facilitate a phenotype approach in practice and improve rosacea patient management. What's already known about this topic? A transition to a phenotype approach in rosacea is underway and is being recommended by multiple working groups. New research has become available since the previous ROSCO consensus, necessitating an update and extension of recommendations. What does this study add? We offer updated global recommendations for clinical practice that account for recent research, to continue supporting the transition to a phenotype approach in rosacea. We present prototype clinical tools to facilitate use of the phenotype approach in practice and improve management of patients with rosacea.

Update of the evidence based, interdisciplinary guideline for anti-inflammatory treatment of uveitis associated with juvenile idiopathic arthritis.

BACKGROUND: Uveitis in juvenile idiopathic arthritis (JIAU) is frequently associated with the development of complications and visual loss. Topical corticosteroids are the first line therapy, and disease modifying anti-rheumatic drugs (DMARDs) are commonly used. However, treatment has not been standardized. METHODS: Interdisciplinary guideline were developed with representatives from the German Ophthalmological Society, Society for Paediatric Rheumatology, Professional Association of Ophthalmologists, German Society for Rheumatology, parents' group, moderated by the Association of the Scientific Medical Societies in Germany. A systematic literature analysis in MEDLINE was performed, evidence and recommendations were graded, an algorithm for anti-inflammatory treatment and final statements were discussed in a consensus meeting (Nominal Group Technique), a preliminary draft was fine-tuned and discussed thereafter by all participants (Delphi procedure). RESULTS: Consensus was reached on recommendations, including a standardized treatment strategy according to uveitis severity in the individual patient. Thus, methotrexate shall be introduced for uveitis not responding to low-dose (≤ 2 applications/day) topical corticosteroids, and a TNFalpha antibody (preferably adalimumab) used, if uveitis inactivity is not achieved. In very severe active uveitis with uveitis-related deterioration of vision, systemic corticosteroids should be considered for bridging until DMARDs take effect. If TNFalpha antibodies fail to take effect or lose effect, another biological should be selected (tocilizumab, abatacept or rituximab). De-escalation of DMARDs should be preceded by a period of  ≥ 2 years of uveitis inactivity. CONCLUSIONS: An interdisciplinary, evidence-based treatment guideline for JIAU is presented.

Systemic therapy of ocular and cutaneous rosacea in children.

BACKGROUND: In paediatric rosacea, ocular symptoms are often predominant. Literature about systemic therapy of paediatric ocular rosacea is sparse, though. OBJECTIVE: Analysis of children with ocular rosacea treated systemically, particularly addressing remission and recurrence rates. METHODS: Retrospective study reviewing the medical records of children with ocular rosacea treated with systemic antibiotic therapy. Nine of 19 patients were chosen for detailed analysis. To our knowledge, this is the first study in paediatric ocular rosacea requiring systemic therapy with a larger patient group and a longer follow-up (mean follow-up = 30.2 months). RESULTS: 17 patients (89.5%) suffered from blepharitis, 15 patients (78.9%) from conjunctivitis, twelve patients (63.2%) from chalazia/styes and nine female patients (47.4%) from corneal involvement. We used erythromycin (n = 9) or roxithromycin (n = 1) in patients younger than 8 years and doxycycline (n = 8) or minocycline (n = 1) in patients older than 8 years. Seven of nine patients treated with erythromycin, one of eight patients treated with doxycycline and the patient treated with minocycline achieved a complete remission of ocular and cutaneous symptoms. Two of nine patients treated with erythromycin, seven of eight patients treated with doxycycline and the patient treated with roxithromycin achieved a partial remission. Relapses occurred in the patient treated with minocycline (cutaneous), two of eight patients treated with doxycycline (ocular and cutaneous) and one of nine patients treated with erythromycin (cutaneous). CONCLUSION: To achieve a complete remission of cutaneous and ocular rosacea, a long-term anti-inflammatory treatment of at least 6 months is necessary. The relapse rates seem to be lower than in adults especially in the patients treated with erythromycin.

[Two children with intermediate uveitis and granuloma annulare from the same neighbourhood]. / Zwei Kinder mit intermediärer Uveitis und Granuloma anulare in derselben Nachbarschaft.

Two children from the same neighbourhood presented with concomitant granuloma annulare (GA) and intermediate uveitis (IU) at an interval of 2 weeks. A coincidence seemed unlikely, as IU is very rare in children and even more so in connection with GA. Thorough diagnosis was performed to exclude other associated diseases. No systemic disease, no special features of vaccination or medication, no history of infection, and no toxic cause could be found. An association between GA and IU based on other, as yet undiagnosed factors, is still possible. Therefore, when evaluating patients with newly diagnosed IU, clinical work-up should also include medical history and examination to rule out GA.

Clinical Trial Simulations From a Model-Based Meta-Analysis of Studies in Patients With Advanced Hepatocellular Carcinoma Receiving Antiangiogenic Therapy.

A mixed effect model describing median overall survival (mOS) in patients with advanced hepatocellular carcinoma (aHCC) treated with antiangiogenic therapy (AAT) was developed from literature data. Data were extracted from 59 studies, representing 4,813 patients. The final model included estimates of mOS after AAT (8.5 months) or placebo (7.1 months) administration. The mOS increased 21% when the AAT was sorafenib (SOR) or 42% when locoregional therapy was coadministered. The mOS decreased when patients received prior systemic therapy (↓7%) or concomitant chemotherapy (↓4%) or the percentage of patients with hepatitis B increased (↓∼0.4%/%). Clinical trial simulations of a phase II comparative trial predicted an mOS ratio (placebo:AAT) of 0.687 or 0.831, with a 65% or 22% probability of demonstrating superiority, for SOR or other AATs, respectively. Additionally, the 95% confidence interval (CI) of the simulated median mOS ratio for non-SOR AATs was similar to the 95% CI of the hazard ratio (HR) observed in the trial.

Ignorance is not bliss: Statistical power is not probability of trial success.

The purpose of this commentary is to place probability of trial success, or assurance, in the context of decision making in drug development, and to illustrate its properties in an intuitive manner for the readers of Clinical Pharmacology and Therapeutics. The hope is that this will stimulate a dialog on how assurance should be incorporated into a quantitative decision approach for clinical development and trial design that uses all available information.

[Diagnostics and treatment of choroidal lymphoma]. / Diagnostik und Therapie der choroidalen Lymphome.

Choroidal lymphoma is a rare disease and can be classified into primary and secondary choroidal lymphomas. Primary choroidal lymphoma is a low-grade extranodal marginal zone B-cell lymphoma and secondary choroidal lymphomas present ocular manifestations of disseminated systemic lymphomas. Typical clinical features of choroidal lymphoma are multifocal, yellow-whitish choroidal infiltrates. The vitreous body is usually clear and cell-free. Choroidal lymphoma has a tendency to extend through the sclera. In contrast to primary choroidal lymphoma, which is more often unilateral, does not show signs of anterior segment involvement and has a slow progression, secondary choroidal lymphoma is more often bilateral, has a rapidly progressive course with anterior segment and vitreous involvement and belongs to the high-grade lymphomas. The definitive diagnosis of choroidal lymphoma can only be confirmed by histopathological examination of biopsy tissue. The choroidal biopsy is the gold standard in the diagnostics of choroidal lymphoma. To date, no standardized treatment for choroidal lymphoma has been established. The treatment modalities include external beam radiotherapy, immunotherapy with rituximab and chemotherapy. The prognosis for survival of primary choroidal lymphoma is usually good. The prognosis of secondary choroidal lymphoma depends on the malignancy grade of systemic lymphoma.

[Therapy of intermediate uveitis]. / Therapie der intermediären Uveitis.

Intermediate uveitis is a form of intraocular inflammation in which the vitreous body is the major site of inflammation. Intermediate uveitis is primarily treated medicinally and systemic corticosteroids are the mainstay of therapy. When recurrence of uveitis or side effects occur during corticosteroid therapy an immunosuppressive treatment is required. Cyclosporine A is the only immunosuppressive agent that is approved for therapy of uveitis in Germany; however, other immunosuppressive drugs have also been shown to be effective and well-tolerated in patients with intermediate uveitis. In severe therapy-refractory cases when conventional immunosuppressive therapy has failed, biologics can be used. In patients with unilateral uveitis or when the systemic therapy is contraindicated because of side effects, an intravitreal steroid treatment can be carried out. In certain cases a vitrectomy may be used.

[Atopic keratoconjunctivitis]. / Atopische Keratokonjunktivitis.

It is useful to define atopic keratoconjunctivitis (AKC) as a non-infectious inflammatory condition of the ocular surface, which is associated with atopy. The pathogenesis of the disorder is not completely understood. The diagnosis is based on the patient's history and the clinical manifestations. Successful management of AKC, which can become a serious condition, requires a multidisciplinary approach that involves prevention, dermatological care and an adequate ophthalmological treatment algorithm.

Long-term oral therapy with valganciclovir in patients with Posner-Schlossman syndrome.

BACKGROUND: To assess the short-term and long-term efficacy of oral therapy with valganciclovir in patients with Posner-Schlossman Syndrome (PSS). METHODS: This is a retrospective observational study on 11 patients with PSS treated with valganciclovir. The PSS was diagnosed clinically on the basis of recurrent episodes of anterior uveitis associated with attacks of elevated intraocular pressure (IOP). All patients who did not respond to aciclovir, or whose cytomegalovirus (CMV) DNA polymerase chain reaction (PCR) analysis of the aqueous humour was positive, were treated with valganciclovir (Valcyte®). Initially, the drug was given 900 mg twice daily for 3 weeks, followed by 450 mg twice daily for a mean period of 20 months (range 10-46 months). RESULTS: Eleven patients with mean age of 44 years were included in this study. Four of 11 patients were working in a sanitary profession. Before initiation of valgancicloivir therapy, the highest IOP was 68 mmHg (mean 45 mmHg ±9 mmHg). In the first week of treatment, the IOP decreased significantly (mean 16 mmHg ±10 mmHg) and maintained stability during the entire treatment period. In seven of 11 (63.6 %) patients, valganciclovir led to resolution of inflammatory activity and stable IOP. In six patients, the therapy could be discontinued after a mean of 14 months. However, two patients had a recurrence after discontinuation of valganciclovir treatment. No side effects of therapy were observed. CONCLUSIONS: Long-term oral therapy with valganciclovir seems to lower the recurrence rate in patients with clinically diagnosed PSS.

[Ocular rosacea]. / Ophthalmorosazea.

Half of patients with rosacea develop ocular involvement. The complaints are often nonspecific. The most common ocular manifestation is blepharoconjunctivitis with dry eye, while on rare occasion rosacea keratitis can lead to corneal ulcer, which then requires urgent ophthalmologic consultation. Topical therapy with preservative-free artificial lubricants and lid hygiene is recommended for the primary treatment of ocular rosacea. Secondarily, systemic medications are indicated depending on severity of the ocular and skin findings.

[Treatment of Behçet's disease yesterday and today]. / Therapie des Morbus Behçet gestern und heute.

Uveitis due to Behçet's disease belongs to those types of intraocular inflammation with a poor visual prognosis. Despite early treatment with corticosteroids and immunosuppressants, patients often become blind. With the so-called biologicals, highly effective drugs are now available which very rapidly lead to quiescence of intraocular inflammation and which successfully avoid further uveitis relapse. Recently, an interdisciplinary group of experts on behalf of the EULAR developed nine recommendations for the treatment of Behçet's disease. Two of these address ocular involvement. Compared with TNF alpha antagonists, interferon alpha offers the advantage that even after cessation of treatment a high percentage of patients remain in remission. This article provides an overview on current medical treatment of ocular Behçet's disease.

Evidence-based, interdisciplinary guidelines for anti-inflammatory treatment of uveitis associated with juvenile idiopathic arthritis.

Uveitis in juvenile idiopathic arthritis (JIA) is frequently associated with the development of complications and visual loss. Topical corticosteroids are the first-choice therapy, and immunosuppression is commonly used. However, treatment has not been standardized. Representatives from the German Ophthalmological Society, Society for Childhood and Adolescent Rheumatology, and the German Society for Rheumatology reached consensus on a standardized treatment strategy according to disease severity in the individual patient. The recommendations were based on a systematic literature analysis in MEDLINE and consensus expert meetings. Evidence and recommendations were graded, and an algorithm for anti-inflammatory treatment and final statements confirmed in a Delphi method. An interdisciplinary, evidence-based treatment guideline for JIA uveitis is presented.

[Janus-faced?: Effects and side-effects of interferon therapy in ophthalmology]. / Ein Januskopf?: Wirkungen und Nebenwirkungen der Interferontherapie in der Augenheilkunde.

Interferon alpha (IFN-α) and interferon beta (IFN-ß) are naturally occurring cytokines, which belong to the type I interferons and share the same receptor leading to very similar therapeutic effects. The immunomodulatory effect of type I interferons includes modulation of antibody production, inhibition of lymphocyte proliferation, inhibition of delayed-type hypersensitivity and enhancement of T-cell and NK-cell cytotoxicity. An increasing number of open clinical studies and case reports have demonstrated the efficacy of IFN-α for severe ocular inflammation in patients with Behçet's disease and of interferon-ß, which has been used mainly for the treatment of multiple sclerosis.

[Problems associated with treating ocular disease in underlying inflammatory rheumatic disease]. / Probleme bei der Versorgung von Augenerkrankungen im Rahmen entzündlich rheumatischer Grunderkrankungen.

Ocular findings can be very typical for general disorders associated with rheumatological diseases. Of these ocular diseases, scleritis and uveitis are of particular significance. The present article discusses and attempts to solve the problems which can be seen when ocular inflammation is associated with rheumatological disorders. The identification of "uveitis" should not be sufficient to initiate diagnosis and therapy, but rather its localisation and, where possible, also its etiology should be known. These can usually be found with good clinical investigation and careful patient history. Only rarely are ocular and rheumatological inflammation active at the same time, as will be discussed later using HLA-B27-associated uveitis and juvenile idiopathic arthritis-associated uveitis as examples. It is important in the case of ocular inflammation that the indication for treatment be made by an ophthalmologist. Finally, the role of the rheumatologist in the treatment of this patient group will be described in detail.

[Glaucoma and retinal surgery]. / Glaukom und Netzhautchirurgie.

In the therapeutic approach to complex glaucomas different initial situations were considered: pre-existing glaucoma, induction of glaucoma after vitreoretinal surgery and antiglaucomatous procedures. In pre-existing glaucoma and after filtering surgery maintenance of the filtering bleb requires a vitreoretinal approach for conjunctiva preservation with techniques such as pneumatic retinopexy or small gauge vitrectomy. After vitreoretinal surgery an increase in intraocular pressure (IOP) is common. Secondary glaucoma may occur after scleral buckling and after vitrectomy with or without gas or silicone oil tamponade as well as after application of steroids. Angle closure glaucoma after scleral buckling develops because of congestion and anterior rotation of the ciliary body. Vitreous tamponades with expansive or saturated gases may cause angle-closure glaucoma with or without pupillary blockage and may critically shorten ocular perfusion. Postoperative checks, immediate action and a ban on boarding aircraft over the period of intraocular gas tamponade prevent permanent damage to the eye. The majority of secondary glaucomas can effectively be controlled by topical medication and adequate postoperative posture of the patient. Besides the temporary use of systemic antiglaucomatous medication or laser therapy, very rarely in cases of massive swelling or overfill, a direct intervention, such as partial gas or silicone oil removal is required. A prophylactic inferior peripheral iridectomy prevents pupillary blockage in aphakic eyes with intraocular tamponade. In cases of heavy silicone oil use, the peripheral iridectomy is placed in the superior position. Nd:YAG laser application will regulate IOP in cases of occlusion. Secondary glaucoma due to silicone oil emulsification overload is treated by trabecular meshwork aspiration and lavage. In refractory glaucoma repetitive cyclophotocoagulation and drainage implants represent an approved method for long-term IOP regulation. The underlying cause of secondary glaucoma after vitreoretinal surgery is often multifactorial in nature and may benefit from an exact analysis for an adequate and successful treatment regimen.

[Glaucoma and corneal transplantation]. / Glaukom und Keratoplastik.

Glaucoma and corneal disorders are often associated and are of diagnostic, therapeutic and prognostic relevance for each other. Glaucoma is already present in approximately 15% of eyes prior to keratoplasty, whereas in addition approximately 15% of cases are diagnosed following corneal transplantation. Corneal opacities, surface irregularities and pachymetric deviations from the norm can have a negative impact on tonometry, perimetry and morphological glaucoma diagnosis. Digital and intracameral tonometry as well as flash VEP to determine the visual potential can be helpful in this setting. Increased intraocular pressure (IOP), long-term application of antiglaucomatous medication or the use of antimetabolites in glaucoma surgery can all induce keratopathy. Therefore, intraocular pressure should be regulated prior to corneal transplantation. Risk factors for the evolution of glaucoma following corneal transplantation are the specific indication and surgical technique (e. g. combined corneal and cataract/vitreoretinal surgery), as well as postoperative steroid application and chamber angle synechiae. Unpreserved glaucoma medication without pro-inflammatory effects should be preferred following keratoplasty. In the long term surgery to control IOP is required in approximately 25% of eyes. The wider use of lamellar techniques for corneal transplantation is likely to reduce the incidence of secondary glaucoma.

[Glaucoma and cataract]. / Glaukom und Katarakt.

The coincidence of cataract and glaucoma is increasing due to population development. Trabeculectomy is still the most commonly used procedure in combined glaucoma-cataract surgery. However, a two-step approach, starting with cataract surgery should be preferred to minimize the risk of secondary filtering bleb scarring. Postoperative fibrin exudation and the complication rate are more pronounced after combined trabeculectomy compared to combined trabeculotomy and non-penetrating glaucoma surgery. Canaloplasty is a new innovative non-penetrating glaucoma procedure. The results after canaloplasty show an even lower intraocular pressure (IOP) after combined procedures compared to canaloplasty alone. Long-term results have to confirm a sustained decrease of IOP. Surgery of the chamber angle combined with cataract surgery has hardly any complications and preserves the conjunctiva. It also allows medication to be saved and more invasive surgery to be postponed.