Pediatric multi-drug-resistant tuberculosis in Germany - diagnostic and therapeutic challenges of an "orphan disease".

Unlabelled: Delay in diagnosing multidrug-resistant tuberculosis (MDR-pTB) in children prolongs time to effective treatment. Data on risk factors for pediatric MDR from low-incidence countries are scarce. Retrospective nationwide case-control study to analyze MDR-pTB cases in Germany between 2010 and 2020 in comparison to a drug-susceptible (DS)-pTB group.

Diagnosis, therapeutic advances, and key recommendations for the management of factor X deficiency.

Factor X deficiency is a rare coagulation disorder that can be hereditary or acquired. The typology and severity of the associated bleeding symptoms are highly heterogeneous, adding to the difficulties of diagnosis and management. Evidence-based guidelines and reviews on factor X deficiency are generally limited to publications covering a range of rare bleeding disorders.

Practical considerations for nonfactor-replacement therapies in the treatment of haemophilia with inhibitors.

New therapeutic agents for haemophilia with inhibitors that are in development or already licensed are expected to provide transformative treatment options. Many of these new therapies are not based on simply replacing the missing factor; new strategies include bispecific antibody technology that mimics factor VIII coagulation function (emicizumab), and inhibition of anticoagulant proteins such as tissue factor pathway inhibitor (eg PF-06741086) and antithrombin (eg fitusiran). These agents are administered subcutaneously and should significantly reduce treatment burden and increase the ability to deliver prophylaxis for patients.

Primary mismatch repair deficient IDH-mutant astrocytoma (PMMRDIA) is a distinct type with a poor prognosis.

Diffuse IDH-mutant astrocytoma mostly occurs in adults and carries a favorable prognosis compared to IDH-wildtype malignant gliomas. Acquired mismatch repair deficiency is known to occur in recurrent IDH-mutant gliomas as resistance mechanism towards alkylating chemotherapy. In this multi-institutional study, we report a novel epigenetic group of 32 IDH-mutant gliomas with proven or suspected hereditary mismatch repair deficiency.

Optimizing the management of patients with haemophilia A and inhibitors in the era of emicizumab: Recommendations from a German expert panel.

Standard treatment of haemophilia A is based on replacing the missing coagulation factor VIII (FVIII) to treat and prevent bleeding episodes. The most challenging complication of FVIII therapy is the development of neutralizing antibodies (inhibitors) that can render treatment ineffective. Eradication of the inhibitor through immune tolerance induction (ITI) remains the most effective strategy for managing these patients.

Prognostic impact of distinct genetic entities in pediatric diffuse glioma WHO-grade II-Report from the German/Swiss SIOP-LGG 2004 cohort.

Reports on pediatric low-grade diffuse glioma WHO-grade II (DG2) suggest an impaired survival rate, but lack conclusive results for genetically defined DG2-entities. We analyzed the natural history, treatment and prognosis of DG2 and investigated which genetically defined sub-entities proved unfavorable for survival. Within the prospectively registered, population-based German/Swiss SIOP-LGG 2004 cohort 100 patients (age 0.

Intravenous dosing of tocilizumab in patients younger than two years of age with systemic juvenile idiopathic arthritis: results from an open-label phase 1 clinical trial.

Background: The anti-interleukin-6 receptor-alpha antibody tocilizumab was approved for intravenous (IV) injection in the treatment of patients with systemic juvenile idiopathic arthritis (sJIA) aged 2 to 17 years based on results of a randomized controlled phase 3 trial. Tocilizumab treatment in systemic juvenile idiopathic arthritis (sJIA) patients younger than 2 was investigated in this open-label phase 1 trial and compared with data from the previous trial in patients aged 2 to 17 years.

Methods: Patients younger than 2 received open-label tocilizumab 12 mg/kg IV every 2 weeks (Q2W) during a 12-week main evaluation period and an optional extension period.

Inhibitors in haemophilia A and B: Management of bleeds, inhibitor eradication and strategies for difficult-to-treat patients.

The standard therapy for patients with haemophilia is prophylactic treatment with replacement factor VIII (FVIII) or factor IX (FIX). Patients who develop inhibitors against FVIII/FIX face an increased risk of bleeding, and the likelihood of early development of progressive arthropathy, alongside higher treatment-related costs. Bypassing agents can be used to prevent and control bleeding, as well as the recently licensed prophylaxis, emicizumab, but their efficacy is less predictable than that of factor replacement therapy.

Diagnosis and care of patients with mild haemophilia: practical recommendations for clinical management.

Mild haemophilia is defined by factor levels between 0.05 and 0.40 IU/mL and is characterised by traumatic bleeds.

Intracranial haemorrhage in children and adolescents with severe haemophilia A or B - the impact of prophylactic treatment.

The discussion of prophylactic therapy in haemophilia is largely focused on joint outcomes. The impact of prophylactic therapy on intracranial haemorrhage (ICH) is less known. This study aimed to analyse ICH in children with haemophilia, with a focus on different prophylaxis regimens and sequelae of ICH.

Outcome measures for adult and pediatric hemophilia patients with inhibitors.

Recent advancements in almost all aspects of hemophilia treatment have vastly improved patient care and management, and new and emerging treatments hold the promise of further progress. However, there remains a scarcity of data on long-term outcomes in hemophilia, particularly among those patients with inhibitors, for whom no validated outcome assessment tools are currently available. At the 15 Zürich Haemophilia Forum, an expert panel reviewed the most important outcome measures in inhibitor patients and considered the challenges associated with assessing outcomes in this population.

Pain and pain management in haemophilia.

Joint pain is common in haemophilia and may be acute or chronic. Effective pain management in haemophilia is essential to reduce the burden that pain imposes on patients. However, the choice of appropriate pain-relieving measures is challenging, as there is a complex interplay of factors affecting pain perception.

Beyond stopping the bleed: short-term episodic prophylaxis with recombinant activated factor FVII in haemophilia patients with inhibitors.

Preventing haemarthroses and arthropathy is a major challenge in patients with haemophilia and inhibitors, as treatment options are limited. One potential strategy is short-term episodic prophylaxis, which extends bypassing agent therapy beyond the resolution of bleeding to include the post-bleed inflammatory phase. At the 13 Zürich Haemophilia Forum, an expert panel reviewed the rationale behind this strategy, explored its current use with recombinant activated factor VII (rFVIIa) and considered treatment monitoring and optimisation.

Long-term safety of etanercept and adalimumab compared to methotrexate in patients with juvenile idiopathic arthritis (JIA).

Importance: Published evidence on the long-term safety of etanercept (ETA) and adalimumab (ADA) in patients with polyarticular juvenile idiopathic arthritis (pJIA) is still limited.

Objectives: To investigate the rates of serious adverse events (SAE) and of events of special interest (ESI) under ETA and ADA treatment.

Design, Setting And Participants: Patients with pJIA were prospectively observed in the national JIA biological register, Biologika in der Kinderrheumatologie, and its follow-up register, Juvenile arthritis Methotrexate/Biologics long-term Observation.

Rationale for individualizing haemophilia care.

Owing to the heterogeneity in the clinical phenotype of haemophilia A and B, it is now recognized that disease severity (based on factor VIII/IX activity) may no longer be the most appropriate guide for treatment and that a 'one-size-fits-all' approach is unlikely to achieve optimal therapy. Based on the present literature and consensus views of a group of experts in the field, this article highlights key gaps in the understanding of the diverse relationships between bleeding phenotype and factors such as joint health, genetic susceptibility, laboratory parameters, quality of life and management of pain. Early prophylaxis is a potential 'gold standard' therapy and issues surrounding inhibitor development, variations in its clinical use and long-term outcomes are discussed.

Joint disease, the hallmark of haemophilia: what issues and challenges remain despite the development of effective therapies?

Although effective therapies for haemophilia have been available for decades, the prevention and treatment of joint disease remain major clinical concerns for all haemophilia patients. Early identification of joint disease is vital to initiate or modify treatment, and prevent arthropathy. However, there remains a need for more sensitive and accurate methods, which may also detect improvement in patient outcome with new therapies or different prophylaxis regimens.

Beyond patient benefit: clinical development in hemophilia.

Historically in hemophilia, outcome measures have not been collected systematically. Hence, there are insufficient clearly defined, evidence-based measures that can be applied consistently across hemophilia trials. This review focuses on some key challenges to evaluating patient outcomes and performing trials identified by experts at the Fourth and Fifth Zurich Haemophilia Forums.

Prophylaxis in rare coagulation disorders -- factor X deficiency.

Factor X (FX) is a vitamin K-dependent protease that plays a central role in the blood coagulation cascade. Deficiency of FX is one of the rarest congenital coagulation disorders, resulting in a variable clinical phenotype. The molecular basis for FX deficiency is characterised by a large number of gene mutations and polymorphisms.

Cloning of the gene encoding the decorin-binding protein B (DbpB) in Borrelia burgdorferi sensu lato and characterisation of the antibody responses to DbpB in Lyme borreliosis.

A genome walking technique was applied to borrelial DNA to clone the gene encoding decorin-binding protein B (DbpB) in Borrelia garinii and B. afzelii. Sequence analysis showed 62-67% identity of the predicted amino acid sequences of DbpB between the B.