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Tiotropium as an add-on treatment option for severe uncontrolled asthma in preschool patients
(2021)
Background: Toddlers with asthma suffer disproportionally more than school-aged children from exacerbations with emergency visits and hospital admissions despite inhaled corticosteroid (ICS) treatment. A recent trial for children ≤ 5 years showed tolerability of tiotropium and potential to reduce asthma-related events.
Methods: We conducted a retrospective analysis of electronic outpatient records (2017‒2019) of children < 6 years treated with ICS plus long-acting β2-agonists (LABAs) plus tiotropium as an add-on for uncontrolled severe asthma. The primary endpoint was a comparison of systemic corticosteroid (SCS) prescriptions 6 months before and after ICS/LABA/tiotropium start. Secondary endpoints included physician visits, hospitalisations and antibiotic prescriptions. We compared outcomes with children without asthma matched for age, sex, season and screening date.
Results: Compared with a mean 2.42 (95% CI: 1.75, 3.36) SCS courses per patient within 6 months prior to ICS/LABA/tiotropium, 0.74 (95% CI: 0.25, 1.08) SCS courses per patient were prescribed within 6 months after starting ICS/LABA/tiotropium (P< 0.001). Physician visits dropped from 9.23 (95% CI: 7.15, 12.72) to 5.76 (95% CI: 3.10, 7.70) per patient (P< 0.01). Nineteen hospitalisations were recorded 6 months before ICS/LABA/tiotropium compared with one hospitalisation after (P< 0.01). A mean 1.79 antibiotic courses (95% CI: 1.22, 2.23) per patient were prescribed before ICS/LABA/tiotropium compared with 0.74 (95% CI: 0.22, 1.00) after ICS/LABA/tiotropium (P< 0.001). Hospitalisation rates for patients at observation end were not statistically different from healthy controls before/after matching.
Interpretation: Our retrospective study showed that adding tiotropium to ICS/LABA is a new treatment option for patients with severe preschool asthma; however, larger confirmatory studies are needed.
Artificial Intelligence (AI) has the potential to greatly improve the delivery of healthcare and other services that advance population health and wellbeing. However, the use of AI in healthcare also brings potential risks that may cause unintended harm. To guide future developments in AI, the High-Level Expert Group on AI set up by the European Commission (EC), recently published ethics guidelines for what it terms “trustworthy” AI. These guidelines are aimed at a variety of stakeholders, especially guiding practitioners toward more ethical and more robust applications of AI. In line with efforts of the EC, AI ethics scholarship focuses increasingly on converting abstract principles into actionable recommendations. However, the interpretation, relevance, and implementation of trustworthy AI depend on the domain and the context in which the AI system is used. The main contribution of this paper is to demonstrate how to use the general AI HLEG trustworthy AI guidelines in practice in the healthcare domain. To this end, we present a best practice of assessing the use of machine learning as a supportive tool to recognize cardiac arrest in emergency calls. The AI system under assessment is currently in use in the city of Copenhagen in Denmark. The assessment is accomplished by an independent team composed of philosophers, policy makers, social scientists, technical, legal, and medical experts. By leveraging an interdisciplinary team, we aim to expose the complex trade-offs and the necessity for such thorough human review when tackling socio-technical applications of AI in healthcare. For the assessment, we use a process to assess trustworthy AI, called 1Z-Inspection® to identify specific challenges and potential ethical trade-offs when we consider AI in practice.
Immune profile and radiological characteristics of progressive multifocal leukoencephalopathy
(2021)
Background and purpose: Progressive multifocal leukoencephalopathy (PML) constitutes a severe disease with increasing incidence, mostly in the context of immunosuppressive therapies. A detailed understanding of immune response in PML appears critical for the treatment strategy. The aim was a comprehensive immunoprofiling and radiological characterization of magnetic resonance imaging (MRI) defined PML variants.
Methods: All biopsy-confirmed PML patients (n = 15) treated in our department between January 2004 and July 2019 were retrospectively analysed. Data from MRI, histology as well as detailed clinical and outcome data were collected. The MRI-defined variants of classical (cPML) and inflammatory (iPML) PML were discriminated based on the intensity of gadolinium enhancement. In these PML variants, intensity and localization (perivascular vs. parenchymal) of inflammation in MRI and histology as well as the cellular composition by immunohistochemistry were assessed. The size of the demyelinating lesions was correlated with immune cell infiltration.
Results: Patients with MRI-defined iPML showed a stronger intensity of inflammation with an increased lymphocyte infiltration on histological level. Also, iPML was characterized by a predominantly perivascular inflammation. However, cPML patients also demonstrated certain inflammatory tissue alterations. Infiltration of CD163-positive microglia and macrophage (M/M) subtypes correlated with PML lesion size.
Conclusions: The non-invasive MRI-based discrimination of PML variants allows for an estimation of inflammatory tissue alterations, although exhibiting limitations in MRI-defined cPML. The association of a distinct phagocytic M/M subtype with the extent of demyelination might reflect disease progression.
The role and timing of radiotherapy (RT) in prostate cancer (PCa) patients treated with radical prostatectomy (RP) remains controversial. While recent trials support the oncological safety of early salvage RT (SRT) compared to adjuvant RT (ART) in selected patients, previous randomized studies demonstrated that ART might improve recurrence-free survival in patients at high risk for local recurrence based on adverse pathology. Although ART might improve survival, this approach is characterized by a risk of overtreatment in up to 40% of cases. SRT is defined as the administration of RT to the prostatic bed and to the surrounding tissues in the patient with PSA recurrence after surgery but no evidence of distant metastatic disease. The delivery of salvage therapies exclusively in men who experience biochemical recurrence (BCR) has the potential advantage of reducing the risk of side effects without theoretically compromising outcomes. However, how to select patients at risk of progression who are more likely to benefit from a more aggressive treatment after RP, the exact timing of RT after RP, and the use of hormone therapy and its duration at the time of RT are still open issues. Moreover, what the role of novel imaging techniques and genomic classifiers are in identifying the most optimal post-operative management of PCa patients treated with RP is yet to be clarified. This narrative review summarizes most relevant published data to guide a multidisciplinary team in selecting appropriate candidates for post-prostatectomy radiation therapy.
The function of the cerebral cortex essentially depends on the ability to form functional assemblies across different cortical areas serving different functions. Here we investigated how developmental hearing experience affects functional and effective interareal connectivity in the auditory cortex in an animal model with years-long and complete auditory deprivation (deafness) from birth, the congenitally deaf cat (CDC). Using intracortical multielectrode arrays, neuronal activity of adult hearing controls and CDCs was registered in the primary auditory cortex and the secondary posterior auditory field (PAF). Ongoing activity as well as responses to acoustic stimulation (in adult hearing controls) and electric stimulation applied via cochlear implants (in adult hearing controls and CDCs) were analyzed. As functional connectivity measures pairwise phase consistency and Granger causality were used. While the number of coupled sites was nearly identical between controls and CDCs, a reduced coupling strength between the primary and the higher order field was found in CDCs under auditory stimulation. Such stimulus-related decoupling was particularly pronounced in the alpha band and in top–down direction. Ongoing connectivity did not show such a decoupling. These findings suggest that developmental experience is essential for functional interareal interactions during sensory processing. The outcomes demonstrate that corticocortical couplings, particularly top-down connectivity, are compromised following congenital sensory deprivation.
Background: Inflammation is essential for the pathogenesis of multiple sclerosis (MS). While the immune system contribution to the development of neurological symptoms has been intensively studied, inflammatory biomarkers for mental symptoms such as depression are poorly understood in the context of MS. Here, we test if depression correlates with peripheral and central inflammation markers in MS patients as soon as the diagnosis is established. Methods: Forty-four patients were newly diagnosed with relapsing-remitting MS, primary progressive MS or clinically isolated syndrome. Age, gender, EDSS, C-reactive protein (CRP), albumin, white blood cells count in cerebrospinal fluid (CSF WBC), presence of gadolinium enhanced lesions (GE) on T1-weighted images and total number of typical MS lesion locations were included in linear regression models to predict Beck Depression Inventory (BDI) score and the depression dimension of the Symptoms Checklist 90-Revised (SCL90RD). Results: CRP elevation and GE predicted significantly BDI (CRP: p = 0.007; GE: p = 0.019) and SCL90RD (CRP: p = 0.004; GE: p = 0.049). The combination of both factors resulted in more pronounced depressive symptoms (p = 0.04). CSF WBC and EDSS as well as the other variables were not correlated with depressive symptoms. Conclusions: CRP elevation and GE are associated with depressive symptoms in newly diagnosed MS patients. These markers can be used to identify MS patients exhibiting a high risk for the development of depressive symptoms in early phases of the disease.
Background: Decedents who are repatriated to Germany from abroad are not systematically registered nationwide. In Hamburg, in addition to an epidemic hygienic examination, registration and examination of the content of the documents accompanying the corpses of German citizens has been carried out since 2007. In this way, unclear and non-natural deaths in particular are to be followed up as necessary.
Material and methods: Protocols of external and internal autopsies of German nationals who died abroad and were repatriated to Hamburg via the port or airport between 2007 and 2018 were retrospectively evaluated with respect to numbers, completeness of the autopsy abroad and correctness of manner and cause of death.
Results: Between 2007 and 2018 a total of 703 corpses were repatriated via the port or airport of Hamburg and examined by the Port Medical Service for epidemic hygiene and for anything conspicuous in the documents accompanying the corpse. Of them, 307 corpses were examined at the Institute of Legal Medicine at the University Medical Center Hamburg-Eppendorf. In total, 82.4% of the examined cases had an incorrect, unspecific or incomplete foreign death certificate. Of the deceased, 238 were subjected to a second external autopsy by a forensic pathologist and 69 deceased were autopsied again or for the first time in Hamburg. It was found that 84% of the autopsies performed abroad were not performed according to German and European standards. The most common discrepancy was incomplete preparation of the organs. In almost one quarter of the autopsies performed in Hamburg a different cause of death than abroad was determined at autopsy.
Conclusion: Since the quality of autopsies performed abroad sometimes does not meet the standards in Germany and Europe and many papers accompanying corpses are incomplete or incorrectly filled out, a systematic review procedure in the home country is recommended. Through the system established in Hamburg in 2007, at least a re-evaluation of the cases takes place.
Tuberöse Sklerose („tuberous sclerosis complex“ [TSC]) ist eine seltene genetische Erkrankung, die neben kutanen und viszeralen Organmanifestationen typischerweise bereits in einem sehr frühen Erkrankungsstadium mit einer schweren, meist therapierefraktären Epilepsie einhergeht. Aufgrund seiner direkten Wirkung am durch TSC dysregulierten mTOR-Signalweg sowie der synergistischen Effekte auf andere Organmanifestationen kommt das Rapamycin-Derivat Everolimus (EVE) zunehmend zur Anwendung. Ziel dieses systematischen Reviews ist, die Wirksamkeit, Sicherheit und Verträglichkeit von EVE bei Patienten mit TSC-assoziierter, therapierefraktärer Epilepsie aufzuarbeiten.
The conventional approach of looking down a microscope to perform microsurgical procedures is associated with occupational injuries, anti-ergonomic postures, and increased tremor and fatigue, all of which predispose microsurgeons to early retirement. Recently, three-dimensional (3D) visualization of real-time microscope magnification has been developed as an alternative. Despite its commercial availability, no supermicrosurgical procedures have been reported using this technology to date. Lymphovenous anastomoses (LVAs) often require suturing vessels with diameters of 0.2–0.8 mm, thus representing the ultimate microsurgical challenge. After performing the first documented LVA procedure using 3D-augmented visualization in our unit and gaining experience with this technique, we conducted an anonymized in-house survey among microsurgeons who had used this approach. The participants considered that 3D visualization for supermicrosurgery was equivalent in terms of handling, optical detail, depth resolution, and safety to conventional binocular magnification. This survey revealed that team communication, resident education, and ergonomics were superior using 3D digital hybrid visualization. Postoperative muscle fatigue, tremor, and pain were also reduced. The major drawbacks of the 3D visualization microscopic systems are the associated costs, required space, and difficulty of visualizing the lymphatic contrast used.
Cutaneous T cell lymphomas (CTCLs) represent a heterogeneous group of T cell lymphomas that primarily affect the skin. The most frequent forms of CTCL are mycosis fungoides and Sézary syndrome. Both are characterized by frequent recurrence, developing chronic conditions and high mortality with a lack of a curative treatment. In this study, we evaluated the effect of short-chain, cell-permeable C6 Ceramide (C6Cer) on CTCL cell lines and keratinocytes. C6Cer significantly reduced cell viability of CTCL cell lines and induced cell death via apoptosis and necrosis. In contrast, primary human keratinocytes and HaCaT keratinocytes were less affected by C6Cer. Both keratinocyte cell lines showed higher expressions of ceramide catabolizing enzymes and HaCaT keratinocytes were able to metabolize C6Cer faster and more efficiently than CTCL cell lines, which might explain the observed protective effects. Along with other existing skin-directed therapies, C6Cer could be a novel well-tolerated drug for the topical treatment of CTCL.