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A Multicentric Cohort and Biomarker Study for Improved Care of Patients with Extrapulmonary Tuberculosis

Background: According to the World Health Organization (WHO), 10 million people fell ill with tuberculosis (TB) in 2019, and 1.4 million people died from this disease. Among infectious agents, Mycobacterium tuberculosis (Mtb) remains the major cause of mortality and morbidity worldwide. Control of the disease is increasingly complicated due to growing numbers of infections with multi-drug resistant strains. In Germany, we witnessed a sharp increase of new cases (7.3 cases per 100,000) in 2015. From 2016 to 2017 the incidence decreased, while the numbers in 2018 (5,429 reported TB cases; 6.5 cases per 100,000) kept almost unchanged. Migrants from high incidence areas account for the majority of all TB patients (67,1% in 2019). While pulmonary TB (PTB) is the most common manifestation, any other organ can be involved. Extrapulmonary TB (EPTB) constitutes for 27,8% (1,321) of all cases in Germany. While the overall incidence of TB is decreasing in industrialized countries, the proportion of EPTB has been constantly increasing in Germany and other European countries. The reasons for this are not fully understood. An extensive retrospective study performed in China showed a significantly higher proportion of multi-drug resistant TB among patients with EPTB than among patients with PTB. This clearly highlights the need for improved EPTB control measures in order to avoid the development of drug resistance and to achieve the goal of TB eradication on a national and international level (e.g. WHO End-TB-strategy) which is further challenged by the SARS-CoV-2 pandemic. The mEX-TB project focuses on EPTB with the main goal of optimizing clinical management of EPTB patients. A prospective clinical cohort of EPTB will be established, involving multiple researchers and clinical sites (Frankfurt, Heidelberg, Borstel, Hamburg, Bonn, Cologne), which will enable us to conduct detailed clinical and translational studies addressing this disease entity. Description: Study population, research design and research methods Adult patients newly diagnosed with EPTB (N=150) will prospectively be enrolled into the study. PTB patients (N=30) will also be included and serve as a control group to test the technical feasibility. In addition, a healthy control group (N=30) will be added, mainly to address aim 1. Clinical data will be collected using standardized questionnaires over the whole treatment period for each individual. Additionally, body fluids (blood, urine) will be collected and stored in a central biobank (Cologne). However, not all contributing centers will be able to provide high quality peripheral blood mononuclear cells (PBMCs) for storage. In order not to lose patients with incomplete sample collections, the cohort study will have several strata: 1. EPTB patients (N=100) with clinical data (e.g. weight gain, imaging results etc.) and a full collection of bio samples (routine laboratory parameters, peripheral blood mononuclear cells (PBMCs), PAXgene RNA/DNA tubes for gene signatures, absolute and relative CD4/CD8 cell count, Vitamin D (25(OH)D), urine, plasma) 2. EPTB patients (N=50) with clinical data (e.g. weight gain, imaging results, microbiology results etc.) plus/minus a partial collection of bio samples (e.g. routine laboratory results, Vitamin D (25(OH)D), PAXgene, plasma) 3. Healthy controls (N=30) and a full collection of bio samples as described for stratum 1 at one timepoint. Data collection Pseudonymized clinical and laboratory data will be recorded at the following time points: diagnosis/ treatment initiation (day 0 / +/- 7 days); 4 weeks post treatment initiation (+/- 7 days); 3 months post treatment initiation (+/- 7 days); 6 months post treatment initiation (+/- 7 days); 3 months post end of treatment (+/- 7 days). In patients requiring treatment of more than 6 months (i.e. multi-drug resistant TB, disseminated TB etc.) data will be collected regularly until end of treatment. Pseudonymization of patient data and acquisition of biomaterial is performed through a patient ID-generator. A paper case report form (CRF) will be used to collect patient data. The CRF data will be then transferred to an electronic database. Outcome: Laboratory based biomarkers for assessing treatment responses similar to sputum conversion used for PTB are not available in most cases of EPTB. Unspecific inflammation markers such as C-reactive protein (CRP) can be utilized to assess early treatment response. We will systematically and longitudinally assess radiologic parameters (lesion size in CT, ultrasonography or MRI), laboratory findings and clinical signs (e.g. weight gain, less pain, absence of fever etc.). We will then exploit response algorithms specifically evaluated for EPTB patients initiating anti-TB treatment. A combination of three clinical parameters will be used 1) improvement in reported symptoms 2) weight gain (any weight gain or ≥ 5% weight gain) 3) regression of lymph node swelling, pleural or peritoneal effusion or other local findings, during and after treatment. A combination of these parameters predicts favorable or unfavorable outcome early during the treatment process. Aims: Our aim is to assess the treatment response using these parameters, supported by two independent clinicians and experts in the field (blind review). Data will be correlated with blood based biomarker findings described below. The main objectives of this study are the development of EPTB specific biomarkers for improved EPTB diagnostics and assessment of treatment responses by correlating immunological and blood based parameters and signatures with clinical features at baseline and longitudinally. For this purpose, our biomarker study will focus on two major aims: Study aim I: Evaluation of blood biomarkers as diagnostic tools for EPTB Sputum or lung fluid based laboratory diagnostics as performed with PTB is not possible in most cases of EPTB. Blood based biomarkers are required. - We will focus on two approaches: 1) blood derived gene expression signatures associated with tuberculosis; 2) T-cell based assays (e.g. TAM-TB assay). - For this aim, we will first investigate markers that have already been analyzed in PTB patients. We will also be able to investigate EPTB specific markers in an unbiased fashion if necessary. Study aim II: Evaluation of blood biomarkers predicting treatment response or failure and cure in EPTB - Predicting cure or the risk of treatment failure is crucial for the management of EPTB. Various outcome definitions for PTB are based on culture and smear results which is not applicable in EPTB. Our aim is to correlate blood based biomarkers with the treatment response which we will assess with well-defined clinical parameters. - For this aim we will continue with our evaluation of plasma IP-10 as a simple and cost-effective treatment response marker. Additional plasma-based markers have been described in our proposal. More complex markers/signatures (gene expression via RNA-seq and T-cell response based) will be applied using technical approaches similar to the ones exploited in Aim 1. We will primarily focus on signatures that have already been evaluated for PTB. The overarching goal of this unique multicenter cohort of patients with EPTB is the development.

A Study of Obexelimab in Patients With Systemic Lupus Erythematosus

This study consists of a 24-week treatment period followed by a 12-week follow-up period. Patients must have a clinical diagnosis of SLE at least 24 weeks prior to screening and meet the 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) Classification Criteria. To enter the Screening Period (Day -28 to Day -1) patients will have active SLE as defined by having: a) hybrid Systemic Lupus Erythematosus Disease Activity Index (hSLEDAI) ≥ 6 and clinical hSLEDAI ≥ 4, and b) British Isles Lupus Assessment Group (BILAG)-2004 Grade A or B in ≥ 1 organ system. Patients must be treated with one or more of the following background nonbiologic lupus standard of care therapies: oral corticosteroid, antimalarial, and/or immunosuppressant. On Day 1, patients will be randomized 1:1 to obexelimab or placebo subcutaneous (SC) injection once per week (QW) for 24 weeks. All patients will return to the study site for scheduled visits at Week 2, Week 4, and then every 4 weeks thereafter until study completion. During the study, patients will undergo assessments for efficacy, safety, PK, PD, and immunogenicity. Including screening and follow-up, the maximum duration of participation in this study for an individual patient is approximately 40 weeks (i.e., up to a 28-day Screening Period, 24-week Treatment Period, and a 12-week follow-up).

FMRI-neurofeedback in Parkinson's Disease

Parkinson's disease (PD) is associated with progressive neurodegeneration of dopaminergic neurons of the substantia nigra. It is characterized by both motor and non-motor system manifestations. Dopamine replacement therapy or dopaminergic medication are the key therapeutic strategies, but deep brain stimulation (DBS) is increasingly being used in cases where drug response is/ has become insufficient or hampered by unacceptable side effects. Neurofeedback (NF) entails training of self-regulation of brain regions or networks via mental imagery and real-time feedback of neural signals, for example obtained by functional MRI (fMRI). NF enables patients to develop personal strategies that are most effective in self-regulating brain areas and networks. Thereby, it can provide an individually tailored intervention. NF is a highly sustainable form of non-invasive neuromodulation because, once learnt, the self-regulation strategies can in principle be applied by patients whenever needed to overcome disease symptomology. NF can be used to train patients to change their brain activity in different directions, or to modulate patterns of co-activation between regions. Mental imagery of moving one's own body (also called kinaesthetic imagery) can potentially be used to improve motor functions and neuroplasticity in PD. Kinaesthetic imagery is also a suitable strategy for increasing activation in the brain's motor network, and motor imagery training can be reinforced through combination with NF. A NF paradigm involving upregulation training of motor areas through kinaesthetic imagery thus has good plausibility for PD. The PI's group has shown proof-of-concept of such an fMRI-NF training (targeting the supplementary motor area, SMA) in PD and has recently completed a feasibility study of fMRI-NF targeting the putamen in 12 PD patients (NCT05627895). The aim of the current investigator-initiated study is to investigate the effects of putamen upregulation training on motor function and other outcome parameters in PD.

Analysis of the Epidemiology, Clinical Presentation and Therapy as Well as Therapy-associated Risk of Demyelination Syndrome in Patients With Profound Hyponatremia in the Emergency Department

A Study to Evaluate the Efficacy and Safety of ESK-001 in Patients With Moderate to Severe Plaque Psoriasis

Long-Term Follow-up of Patients Treated With Miltenyi Cell and Gene Therapies

The focus in this trial is on the occurrence of any late adverse reactions (AR), serious adverse events (SAE), serious adverse reactions (SAR) and adverse events of special interest (AESI), i.e. relapse or progression of the underlying disease, life-threatening infections, death due to any case, new and secondary malignancies, lymphocyte counts, detection of the transgene of the CAR T cells, detection of replication-competent lentivirus (RCL), developmental tracking in pediatric patients and furthermore, assessment of the primary status of disease progression and overall survival.

IMPLEMENT - Model Project for Quality-assured Exercise Therapy for Cancer Patients

IMPLEMENT is an exploratory, open-label, non-randomized, mixed-methods study. No additional treatments or therapies that can influence the course of the disease are provided to the participating patients. Rather, various implementation strategies will be developed to bring more patients into the existing quality-assures oncological exercise therapy (qOET), to further develop other exercise and sports offers for qOET or to create completely new offers of qOET. The implementation strategies are examined with regard to their degree of effectiveness. The effectiveness is determined by means of a before-and-after comparison (e.g. number of patients in qOET at baseline) and, if applicable, with comparable studies. IMPLEMENT is evaluated using the RE-AIM framework. The aim of the data collection carried out in IMPLEMENT is to provide the necessary data for the evaluation with RE-AIM on the one hand, and to provide information for the development and adaptation of suitable implementation strategies on the other. Risks to achieving the objectives include the willingness of patients to participate in qOET and the willingness of doctors, therapists and other people working in oncological care to implement the interventions and to expand and adapt their professional activities accordingly. To address these challenges, a mixed-methods approach is used to identify barriers and facilitators. A mixed-methods approach enables a theoretical understanding of the implementation process and provides a more comprehensive picture of the factors relevant to successful implementation than qualitative or exclusively quantitative methods alone.

AltaValve Pivotal Trial

Regulation of Extracellular Sodium in End Stage Renal Disease Upon Volume and Electrolyte Challenges

Prospective Pilot Trial to Address Feasibility and Safety of Oral Zinc in GNAO1 Associated Disorders