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  • 1
    Language: German
    In: Medizinische Genetik, 2019-11-04, Vol.31 (3), p.335-343
    Description: Zusammenfassung In der genetischen Diagnostik geht der Weg von Einzelgenanalysen hin zu Genpanelanalysen, insbesondere bei seltenen genetischen Erkrankungen. Im Juli 2016 wurde mit einer Änderung des EBM (Einheitlicher Bewertungsmaßstab) die Möglichkeit geschaffen, bei Patienten mit seltenen Erkrankungen im Rahmen der gesetzlichen Krankenversicherung genetische Analysen mittels „next generation sequencing“ (NGS) zu erbringen. Allerdings wurde die Mutationssuche in mehr als 25 Kilobasen (kb) kodierender Sequenz unter einen Genehmigungsvorbehalt durch die Krankenkassen gestellt und im zeitlichen Verlauf durch einen Abrechnungsausschluss zur Analyse einzelner oder weniger Gene mit einem Analyseumfang von weniger als 25 kb weiter eingeschränkt. Aus Diagnostiklaboren des bayerischen Landesverbandes des BVDH (Berufsverband Deutscher Humangenetiker e. V.) berichten wir über die Erfahrungen, die mit Antragstellung, Widerspruchsverfahren, Genehmigungsquote, Ablehnungsgründen und diagnostischem Outcome bei der Analyse großer Genpanels im Rahmen seltener Erkrankungen gewonnen wurden. Im Erhebungszeitraum von 7 Quartalen wurden in vier Laboren insgesamt 314 Gutachten zur Begründung eines Antrags nach GOP 11514 erstellt, die alle durch den MDK begutachtet wurden. 71 % der Anträge wurden abgelehnt. Insgesamt 95 Anträge (29 %) wurden genehmigt, teilweise allerdings erst nach bis zu 5 Widersprüchen. Die Ablehnungen wurden sowohl mit sozialmedizinischen als auch mit formalen Argumenten begründet, wobei in den meisten Fällen eine als fehlend angesehene therapeutische Relevanz als sozialmedizinisches Argument aufgeführt wurde. Durch die genehmigten umfassenden NGS-Analysen konnte bei über 30 % der untersuchten Patienten eine genetische Diagnose gestellt werden, die in zwei Drittel der Fälle behandlungsrelevant war. Zusammenfassend stehen der Genehmigungsvorbehalt einer NGS-Analyse nach GOP 11514 und die damit aufgebauten Widerstände einer medizinisch notwendigen und sinnvollen Diagnostik in der Versorgung von Patienten mit seltenen Erkrankungen im Wege.
    Subject(s): Antragsverfahren „großes Panel ; Application procedure “large panel” ; Einheitlicher Bewertungsmaßstab ; Gene panel ; Gene Therapy ; general ; Genpanel ; GOP 11514 ; Gynecology ; Human Genetics ; Medicine ; Medicine & Public Health ; Next-generation sequencing ; Oncology ; Panel diagnostics ; Panel-Diagnostik ; Reproductive Medicine ; Scale of charges position 11514 ; Uniform assessment benchmark ; Zur Diskussion
    ISSN: 0936-5931
    E-ISSN: 1863-5490
    Source: Alma/SFX Local Collection
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  • 2
    Language: German
    In: Medizinische Genetik, 2019-11-01, Vol.31 (3), p.335-343
    Description: In genetic diagnostics, the path goes from single-gene testing to gene-panel analyses, especially for rare genetic diseases. In July 2016, an amendment to the EBM (Einheitlicher Bewertungsma ss stab, Regulations on Fees for Statutory Health Insurance) introduced the possibility of performing genetic analyses using next-generation sequencing (NGS) on patients with rare diseases. However, the mutation search in a sequence encoding more than 25 kilobases (kb) was subject to approval by the health insurance funds and was further restricted over time by a billing exclusion for a previous analysis of individual genes of less than 25kb. We report from the diagnostic laboratories of the Bavarian State Association of the BVDH (Berufsverband Deutscher Humangenetiker e.V.) on the experiences we have gained with the application procedures, the objections, the approval rate, the reasons for rejection and the diagnostic outcome in the analysis of large gene panels for various rare disorders. In the survey period of seven quarters, a total of 314 applications were prepared in four diagnostic laboratories to justify an application according to GOP (Gebuhrenordnungsposition, fee schedule position) 11514, all of which were reviewed by the MDK (Medizinischer Dienst der Krankenkassen; Medical Service to Health Insurance Funds). 71% of the applications were rejected. A total of 95 applications (29%) were approved, but in some cases only after up to five objections. The rejections were based on both socio-medical and formal criteria, whereby in most cases a therapeutic relevance considered to be lacking was used as a socio-medical argument. The approved comprehensive NGS analyses made it possible to make a genetic diagnosis in more than 30% of the patients examined, which was relevant to treatment in two thirds of the cases. In summary, the conditional approval of an NGS analysis according to GOP 11514 and the resulting obstacles hinder the medically necessary and useful diagnostics in the care of patients with rare diseases.
    Subject(s): Genetics & Heredity ; Life Sciences & Biomedicine ; Science & Technology
    ISSN: 0936-5931
    E-ISSN: 1863-5490
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
    Source: Alma/SFX Local Collection
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  • 3
    Language: English
    In: NAR Genomics and Bioinformatics, 2021-06-23, Vol.3 (3), p.lqab078-lqab078
    Description: Abstract Many rare syndromes can be well described and delineated from other disorders by a combination of characteristic symptoms. These phenotypic features are best documented with terms of the Human Phenotype Ontology (HPO), which are increasingly used in electronic health records (EHRs), too. Many algorithms that perform HPO-based gene prioritization have also been developed; however, the performance of many such tools suffers from an over-representation of atypical cases in the medical literature. This is certainly the case if the algorithm cannot handle features that occur with reduced frequency in a disorder. With Cada, we built a knowledge graph based on both case annotations and disorder annotations. Using network representation learning, we achieve gene prioritization by link prediction. Our results suggest that Cada exhibits superior performance particularly for patients that present with the pathognomonic findings of a disease. Additionally, information about the frequency of occurrence of a feature can readily be incorporated, when available. Crucial in the design of our approach is the use of the growing amount of phenotype–genotype information that diagnostic labs deposit in databases such as ClinVar. By this means, Cada is an ideal reference tool for differential diagnostics in rare disorders that can also be updated regularly.
    ISSN: 2631-9268
    E-ISSN: 2631-9268
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: PubMed Central
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  • 4
    Language: German
    Description: Provider: Deutsche Digitale Bibliothek - Institution: Deutsche Nationalbibliothek - Data provided by Europeana Collections- München, Technische Universität München, Diss., 2016- All metadata published by Europeana are available free of restriction under the Creative Commons CC0 1.0 Universal Public Domain Dedication. However, Europeana requests that you actively acknowledge and give attribution to all metadata sources including Europeana
    Subject(s): MED Medizin ; Medizin, Gesundheit
    Source: Europeana Collections
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  • 5
    Language: English
    In: NeuroImage (Orlando, Fla.), 2017-04-15, Vol.150, p.112-118
    Description: The role of the cerebellum in pathologies of the trigeminal nervous system is still unknown although recently gathered evidence point to a modulatory rather than a passive role. Here we provide evidence for the activation of specific cerebellar areas during nociceptive trigeminal input in the left nostril in a large number of volunteers (54 subjects) and an additional independent group (18 subjects) as measured by functional magnetic resonance imaging (fMRI). Peak voxel activity ipsilateral to the stimulated side can be seen in cerebellar lobules VI, VIIIa and Crus I, and vermal lobule VIIIa, although some activations are also seen in the contralateral side. The individuals’ intensity and unpleasantness ratings are mostly processed in the hemispheric lobules VI stretching to V, representing the face areas of the cerebellar's fractured homunculus. We found a robust functional connectivity during nociception between the cerebellum and the rostral part of the pons as well as the periaqueductal grey and the thalamus, involving the descending antinociceptive network as well as areas known to form close loops with the cerebellum in the motor domain. Cerebellar connectivity with higher cortical areas include most of the known hubs in pain processing which are the insular cortex, operculum and putamen, and the face areas in the precentral gyrus. The current data provide a solid basis for further research of the cerebellar's activity and connectivity in primary headache and facial pain syndromes. •The cerebellum is highly active during nociceptive, trigeminal processing.•The cerebellar's activity is modulated by perceived intensity of pain.•Its functional connectivity to brainstem and cortex is altered by nociception.
    Subject(s): Adult ; Brain ; Brain Mapping ; Brainstem ; Cerebellum ; Cerebellum - physiology ; Cerebral Cortex - physiology ; Female ; Functional connectivity ; Humans ; Image Interpretation, Computer-Assisted ; Magnetic Resonance Imaging ; Male ; Migraine ; Modulation of pain intensity ; Neural Pathways - physiology ; Neurosciences ; Nociception - physiology ; Pain ; Trigeminal Nerve - physiology ; Trigeminal nociception
    ISSN: 1053-8119
    E-ISSN: 1095-9572
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 6
    Language: English
    In: Annals of neurology, 2020-04, Vol.87 (4), p.646-651
    Description: Objective Although migraine is defined by the headache and headache‐associated symptoms, the true beginning of a migraine attack lies in the premonitory phase. To understand the generation of attacks, one needs to investigate the phase before headache starts. The premonitory phase of migraine is characterized by a well‐described complex of symptoms. Its duration, however, is not clearly defined, and there are no biomarkers to help define when this phase starts. Methods Here, we used functional magnetic resonance imaging (MRI) to elucidate the duration of the premonitory phase in spontaneous human migraine attacks. Because migraine attacks are hardly predictable and thereby the premonitory phase is difficult to catch, we scanned 9 patients daily over a minimum period of 30 days using a well‐established paradigm for functional MRI of trigeminal nociception. Results Seven patients were included in the analysis, thus providing cumulative data of 27 spontaneous human migraine attacks including scans before, during, and after migraine pain as well as interictal scans. As a response to painful trigeminal stimulation, activation of the hypothalamus was present within the last 48 hours before headache onset but not earlier. Interpretation Using hypothalamic activation as a potential marker for the premonitory phase of migraine in this unique dataset, our data corroborated a duration of 48 hours for the premonitory phase of migraine. We suggest applying this time criterion in future studies when focusing on this phase of the migraine cycle. ANN NEUROL 2020;87:646–651
    ISSN: 0364-5134
    E-ISSN: 1531-8249
    Source: Hellenic Academic Libraries Link
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  • 7
    Language: English
    In: Brain (London, England : 1878), 2020-12-05, Vol.143 (11), p.e93-e93
    Subject(s): Abridged Index Medicus ; Brain ; Cerebral Cortex ; Gray Matter - diagnostic imaging ; Humans ; Migraine Disorders
    E-ISSN: 1460-2156
    Source: Get It Now
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  • 8
    Language: English
    In: Nature (London), 2018-11, Vol.563 (7732), p.569-573
    Description: Autophagy captures intracellular components and delivers them to lysosomes, where they are degraded and recycled to sustain metabolism and to enable survival during starvation . Acute, whole-body deletion of the essential autophagy gene Atg7 in adult mice causes a systemic metabolic defect that manifests as starvation intolerance and gradual loss of white adipose tissue, liver glycogen and muscle mass . Cancer cells also benefit from autophagy. Deletion of essential autophagy genes impairs the metabolism, proliferation, survival and malignancy of spontaneous tumours in models of autochthonous cancer . Acute, systemic deletion of Atg7 or acute, systemic expression of a dominant-negative ATG4b in mice induces greater regression of KRAS-driven cancers than does tumour-specific autophagy deletion, which suggests that host autophagy promotes tumour growth . Here we show that host-specific deletion of Atg7 impairs the growth of multiple allografted tumours, although not all tumour lines were sensitive to host autophagy status. Loss of autophagy in the host was associated with a reduction in circulating arginine, and the sensitive tumour cell lines were arginine auxotrophs owing to the lack of expression of the enzyme argininosuccinate synthase 1. Serum proteomic analysis identified the arginine-degrading enzyme arginase I (ARG1) in the circulation of Atg7-deficient hosts, and in vivo arginine metabolic tracing demonstrated that serum arginine was degraded to ornithine. ARG1 is predominantly expressed in the liver and can be released from hepatocytes into the circulation. Liver-specific deletion of Atg7 produced circulating ARG1, and reduced both serum arginine and tumour growth. Deletion of Atg5 in the host similarly regulated [corrected] circulating arginine and suppressed tumorigenesis, which demonstrates that this phenotype is specific to autophagy function rather than to deletion of Atg7. Dietary supplementation of Atg7-deficient hosts with arginine partially restored levels of circulating arginine and tumour growth. Thus, defective autophagy in the host leads to the release of ARG1 from the liver and the degradation of circulating arginine, which is essential for tumour growth; this identifies a metabolic vulnerability of cancer.
    Subject(s): Adipose tissues ; Allografts ; Analysis ; Animals ; Arginase - blood ; Arginase - metabolism ; Arginine ; Arginine - administration & dosage ; Arginine - blood ; Arginine - pharmacology ; Autophagy (Cytology) ; Autophagy - genetics ; Autophagy-Related Protein 5 - deficiency ; Autophagy-Related Protein 5 - genetics ; Autophagy-Related Protein 7 - deficiency ; Autophagy-Related Protein 7 - genetics ; Autophagy-Related Protein 7 - metabolism ; Cancer ; Cancer cells ; Carcinogenesis - drug effects ; Carcinogenesis - genetics ; Cell Proliferation - drug effects ; Cell Proliferation - genetics ; Dietary Supplements ; Enzymes ; Glycogen ; Growth ; Health aspects ; Hepatocytes - enzymology ; Hepatocytes - metabolism ; Liver ; Liver - enzymology ; Male ; Mice ; Neoplasm Transplantation ; Neoplasms - blood ; Neoplasms - genetics ; Neoplasms - pathology ; Ornithine - metabolism ; Physiological aspects ; Tumors
    ISSN: 0028-0836
    E-ISSN: 1476-4687
    Source: Get It Now
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  • 9
    Language: English
    In: Clinical cancer research, 2017-09-01, Vol.23 (17), p.4992-5002
    Description: Recent advances in immuno-oncology and regulatory approvals have been rapid and paradigm shifting in many difficult-to-treat malignancies. Despite immune checkpoint inhibitor therapy becoming the standard of care across multiple tumor types, there are many unanswered questions that need to be addressed before this therapeutic modality can be fully harnessed. Areas of limitations include treatment of patients not sufficiently represented in clinical trials, uncertainty of the optimal treatment dosing and duration, and lack of understanding regarding long-term immune related toxicities and atypical tumor responses. Patients such as those with autoimmune disease, chronic viral infections, limited performance status, and brain metastases were often excluded from initial trials due to concerns of safety. However, limited data suggest that some of these patients can benefit from therapy with manageable toxicities; thus, future studies should incorporate these patients to clearly define safety and efficacy. There are still controversies regarding the optimal dosing strategy that can vary from weight-based to flat dosing, with undefined treatment duration. Further elucidation of the optimal dosing approach and evaluation of predictive biomarkers should be incorporated in the design of future trials. Finally, there are long-term immune-mediated toxicities, atypical tumor responses such as pseudoprogression and endpoints unique to immuno-oncology that are not adequately captured by traditional trial designs; thus, novel study designs are needed. In this article, we discuss in detail the above challenges and propose needed areas of research for exploration and incorporation in the next generation of immuno-oncology clinical trials.
    Subject(s): Clinical Trials as Topic ; Humans ; Medical Oncology - trends ; Neoplasms - drug therapy ; Neoplasms - immunology ; Research Design
    ISSN: 1078-0432
    E-ISSN: 1557-3265
    Source: HighWire Press (Free Journals)
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
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  • 10
    Language: English
    In: Head & neck, 2021-04, Vol.43 (4), p.1229-1241
    Description: Background Compared with other malignancies, head and neck cancer (HNC) increases the risk of not returning to work (RTW). Methods Within a cross‐sectional study, patients with HNC filled out the OncoFunction questionnaire, a version of the International Classification of Functioning Core Sets for HNC. In 231 patients below 65 years of age, associations of sociodemographic, clinical, functional, and psychological factors with employment and participation in rehabilitation program were explored. Results Unemployed patients reported more swallowing difficulties and speaking problems. Being unemployed was associated with higher levels of depressive and anxiety symptoms, fatigue, and lower global health. Rehabilitation participation was not significantly associated with any of the assessed factors except for smoking. Conclusions Unemployed patients with HNC are more burdened than employed patients with HNC regarding clinical, psychological, and functional factors. These differences are more evident later in recovery. Rehabilitation participation was not associated with psychological and functional burden which indicates the need for tailored HNC rehabilitation programs.
    Subject(s): Cancer patients ; Care and treatment ; Employment ; functional impairment ; Head and neck cancer ; Medical research ; Medicine, Experimental ; rehabilitation ; return to work ; World health
    ISSN: 1043-3074
    E-ISSN: 1097-0347
    Source: Hellenic Academic Libraries Link
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