Chalfont St Giles, United Kingdom

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.

Digital Implementation of the German S3 Clinical Practice Guideline for Multimorbidity

The web application gp-multitool.de study is a digital tool for implementing the German S3 clinical practice guideline for multimorbidity of the German Society of General Practitioners and Family Physicians in primary care. The tool enhances evidence-based and patient-centered care for patients with multimorbidity by assessing and providing information relevant for the primary care of this patient group. The study intervention is based on this digital tool and aims to reduce the probability of hospital admissions (primary outcome) and their outpatient health care use, and to improve process quality of care, patients' health-related quality of life, and patient satisfaction (secondary outcomes). This cluster-randomized clinical evaluation study examines the effectiveness of the gp-multitool.de intervention in GP practices. GPs in the intervention group implement the intervention in consultations with participating patients for 12 months. Intervention GPs gain access to the digital tool, and get a brief introduction to its functionalities, a video tutorial, a written manual, and contact data of telephone support, which can be called in case of any technical or organizational problems in relation to the digital tool. In addition, they receive a short training in the intervention and a checklist of requirements defined in the study protocol. Moreover, each intervention practice will be provided with a mobile device, facilitating inclusion of patients without access to the internet. GPs in the control group receive no intervention and provide care as usual. Patients will be recruited from GP practices in urban and rural administrative districts in Germany. The evaluation study is based on telephone interviews of patients and their GPs. Practices will be randomized after the baseline assessment by an independent statistician who does not have access to the assessed patient and practice data. The primary outcome will be analyzed using a multilevel mixed-effects logistic regression model, and secondary outcomes will be analyzed by multilevel mixed-effects linear and negative-binomial regression models. The project staff conducting patient interviews will be blinded regarding allocation of the patient's practices.

European Registry of Next Generation Imaging in Advanced Prostate Cancer

This registry is intended to collect real-world data on patient demographics, medical history, clinical endpoints, histological tumour characteristics and imaging explorations of the patients with prostate cancer at high risk for harbouring metastatic deposits at the hormone-sensitive stage, who require imaging exploration (conventional, NGI, or their combination) either at the diagnostic workup of a "naïve" patient or at biochemical relapse/progression after local treatment. Stage 1: cross-sectional observation 1. To identify the proportion of patients for whom an imaging work-up with NGI at baseline may result beneficial, according to physician criteria. 2. Assess management prompted by NGI vs. conventional imaging in usual clinical practice. 3. To identify the proportion of patients for whom conventional imaging is considered informative enough for making a clinical decision, according to physician criteria. 4. Stratification of metastatic prostate cancer patients by the number, volume, and location of deposits, according to the different imaging tools employed. 5. Reclassification of HSPC (M0 vs low vs. high volume) based on NGI respect to CI when both imaging modalities are used. Stage 2: longitudinal observation 1. Evaluation of survival outcomes and their relationship with the imaging pathway undertaken (overall and per subgroup of imaging modality). 2. Identification of prognostic factors related to treatment response and disease progression.

Continuous Finger-cuff Arterial Pressure Monitoring and Intraoperative Hypotension During Non-cardiac Surgery: the Randomized DETECT II Trial

not provided

Urethral PeRfusion Index-Guided Hemodynamic ManagemenT in Patients Having Major Abdominal Surgery: the UPRIGHT Randomized Feasibility Trial

Bifocal Transcranial Alternating Current Stimulation Targeting the Frontoparietal Network in Stroke Patients

Hand and arm function is often significantly impaired in stroke patients, making recovery of these functions a primary goal in stroke rehabilitation. Despite advances in acute stroke thera-pies, more than 50% of stroke survivors continue to experience motor deficits, particularly in hand and arm function, which negatively impacts their quality of life. The integrity of neural networks, especially the frontoparietal network, plays a central role in motor control, and has been shown to be altered after stroke. Transcranial alternating current stimulation (tACS) offers a promis-ing approach to modulate these brain network connections, potentially influencing motor func-tion in stroke patients. In a randomized, controlled, triple-blind, crossover design, this study investigates the effects of 24Hz bifocal tACS on functional connectivity between the ipsilesional anterior intraparietal sulcus (aIPS) and ventral premotor cortex (PMv) in stroke patients during the subacute to chronic recovery phase. Each patient will receive three types of stimulation-(i) in-phase tACS, (ii) out-of-phase tACS, and (iii) sham stimulation-in a randomized order, with a one-week washout pe-riod between sessions to avoid carryover effects. During in-phase tACS, 24Hz stimulation over aIPS and PMv will be in phase; during out-of-phase stimulation, the phase across sights will vary by 180 degrees. Bifocal tACS will be delivered using two four-electrode montages centered over the aIPS and PMv of the lesioned hemisphere for approximately 21 minutes per session. During each session, patients will perform a Reach-to-Grasp (RTG) task three times: before stimulation, during stimu-lation, and after stimulation. Patients will perform both a pinch grip and a whole-hand grasp during the RTG task. EEG data will be collected pre- and post-stimulation, while kinematic meas-urements will also be recorded during the stimulation task. To minimize skin sensations under the electrodes and improve blinding, a local anesthetic consisting of lidocaine and prilocaine will be applied prior to electrode placement. Clinical assessments as well as structural and func-tional imaging will be obtained to characterize each patient. The investigators hypothesize that 24Hz bifocal tACS on the frontoparietal network alters its connectivity compared to sham stimulation. This study seeks to enhance the understanding of functional coupling within the frontoparietal network, aiming to establish bifocal tACS as a targeted and innovative therapy to improve motor function in stroke patients.

Assessment of Transcatheter Edge-to-Edge Repair in Atrial Functional Mitral Regurgitation (ATRIAL-MR)

REACH: RWE Retrospective Study to Evaluate Cenobamate Impact on Health Care Resource Utilization

Treating Intraoperative Bradycardia in Non-cardiac Surgery Patients With Atropine at Heart Rates Below 60 Versus 30 Beats Per Minute and Norepinephrine Requirements

Assessment of Infection Activity in Travelers and Migrants Diagnosed With Chronic Schistosomiasis