Publications by authors named "Andreas Hahn"

351 Publications

Reliability of task-specific neuronal activation assessed with functional PET, ASL and BOLD imaging.

J Cereb Blood Flow Metab 2021 Jun 2:271678X211020589. Epub 2021 Jun 2.

Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.

Mapping the neuronal response during cognitive processing is of crucial importance to gain new insights into human brain function. BOLD imaging and ASL are established MRI methods in this endeavor. Recently, the novel approach of functional PET (fPET) was introduced, enabling absolute quantification of glucose metabolism at rest and during task execution in a single measurement. Here, we report test-retest reliability of fPET in direct comparison to BOLD imaging and ASL. Twenty healthy subjects underwent two PET/MRI measurements, providing estimates of glucose metabolism, cerebral blood flow (CBF) and blood oxygenation. A cognitive task was employed with different levels of difficulty requiring visual-motor coordination. Task-specific neuronal activation was robustly detected with all three imaging approaches. The highest reliability was obtained for glucose metabolism at rest. Although this dropped during task performance it was still comparable to that of CBF. In contrast, BOLD imaging yielded high performance only for qualitative spatial overlap of task effects but not for quantitative comparison. Hence, the combined assessment of fPET and ASL offers reliable and simultaneous absolute quantification of glucose metabolism and CBF at rest and task.
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http://dx.doi.org/10.1177/0271678X211020589DOI Listing
June 2021

Comparative Assessment of In-House Real-Time PCRs Targeting Enteric Disease-Associated Microsporidia in Human Stool Samples.

Pathogens 2021 May 26;10(6). Epub 2021 May 26.

Department of Hospital Hygiene & Infectious Diseases, University Medicine Göttingen, 37075 Göttingen, Germany.

Microsporidiosis is an infection predominantly occurring in immunosuppressed patients and infrequently also in travelers. This study was performed to comparatively evaluate the diagnostic accuracy of real-time PCR assays targeting microsporidia with etiological relevance in the stool of human patients in a latent class analysis-based test comparison without a reference standard with perfect accuracy. Thereby, two one-tube real-time PCR assays and two two-tube real-time PCR assays targeting and spp. were included in the assessment with reference stool material (20), stool samples from Ghanaian HIV-positive patients (903), and from travelers, migrants and Colombian indigenous people (416). Sensitivity of the assays ranged from 60.4% to 97.4% and specificity from 99.1% to 100% with substantial agreement according to Cohen's kappa of 79.6%. Microsporidia DNA was detected in the reference material and the stool of the HIV patients but not in the stool of the travelers, migrants, and the Colombian indigenous people. Accuracy-adjusted prevalence was 5.8% ( = 78) for the study population as a whole. In conclusion, reliable detection of enteric disease-associated microsporidia in stool samples by real-time PCR could be demonstrated, but sensitivity between the compared microsporidia-specific real-time PCR assays varied.
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http://dx.doi.org/10.3390/pathogens10060656DOI Listing
May 2021

Diagnosing SARS-CoV-2 with Antigen Testing, Transcription-Mediated Amplification and Real-Time PCR.

J Clin Med 2021 May 29;10(11). Epub 2021 May 29.

Institute for Medical Microbiology, University Medical Center Göttingen, 37075 Göttingen, Germany.

This study was performed as a head-to-head comparison of the performance characteristics of (1) two SARS-CoV-2-specific rapid antigen assays with real-time PCR as gold standard as well as (2) a fully automated high-throughput transcription-mediated amplification (TMA) assay and real-time PCR in a latent class analysis-based test comparison without a gold standard with several hundred samples in a low prevalence "real world" setting. Recorded sensitivity and specificity of the NADAL and the LumiraDx antigen assays and the Hologic Aptima SARS-CoV-2 TMA assay were 0.1429 (0.0194, 0.5835), 0.7644 (0.7016, 0.8174), and 0.7157 (0, 1) as well as 0.4545 (0.2022, 0.7326), 0.9954 (0.9817, 0.9988), and 0.9997 (not estimable), respectively. Agreement kappa between the positive results of the two antigen-based assays was 0.060 (0.002, 0.167) and 0.659 (0.492, 0.825) for TMA and real-time PCR. Samples with low viral load as indicated by cycle threshold (Ct) values > 30 were generally missed by both antigen assays, while 1:10 pooling suggested higher sensitivity of TMA compared to real-time PCR. In conclusion, both sensitivity and specificity speak in favor of the use of the LumiraDx rather than the NADAL antigen assay, while TMA results are comparably as accurate as PCR, when applied in a low prevalence setting.
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http://dx.doi.org/10.3390/jcm10112404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199284PMC
May 2021

Functional dynamics of dopamine synthesis during monetary reward and punishment processing.

J Cereb Blood Flow Metab 2021 May 30:271678X211019827. Epub 2021 May 30.

Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.

The assessment of dopamine release with the PET competition model is thoroughly validated but entails disadvantages for the investigation of cognitive processes. We introduce a novel approach incorporating 6-[F]FDOPA uptake as index of the dynamic regulation of dopamine synthesis enzymes by neuronal firing. The feasibility of this approach is demonstrated by assessing widely described sex differences in dopamine neurotransmission. Reward processing was behaviorally investigated in 36 healthy participants, of whom 16 completed fPET and fMRI during the monetary incentive delay task. A single 50 min fPET acquisition with 6-[F]FDOPA served to quantify task-specific changes in dopamine synthesis. In men monetary gain induced stronger increases in ventral striatum dopamine synthesis than loss. Interestingly, the opposite effect was discovered in women. These changes were further associated with reward (men) and punishment sensitivity (women). As expected, fMRI showed robust task-specific neuronal activation but no sex difference. Our findings provide a neurobiological basis for known behavioral sex differences in reward and punishment processing, with important implications in psychiatric disorders showing sex-specific prevalence, altered reward processing and dopamine signaling. The high temporal resolution and magnitude of task-specific changes make fPET a promising tool to investigate functional neurotransmitter dynamics during cognitive processing and in brain disorders.
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http://dx.doi.org/10.1177/0271678X211019827DOI Listing
May 2021

Mutations in HID1 Cause Syndromic Infantile Encephalopathy and Hypopituitarism.

Ann Neurol 2021 May 17. Epub 2021 May 17.

Department of Child Neurology, Justus-Liebig-University, Giessen, Germany.

Objective: Precursors of peptide hormones undergo posttranslational modifications within the trans-Golgi network (TGN). Dysfunction of proteins involved at different steps of this process cause several complex syndromes affecting the central nervous system (CNS). We aimed to clarify the genetic cause in a group of patients characterized by hypopituitarism in combination with brain atrophy, thin corpus callosum, severe developmental delay, visual impairment, and epilepsy.

Methods: Whole exome sequencing was performed in seven individuals of six unrelated families with these features. Postmortem histopathological and HID1 expression analysis of brain tissue and pituitary gland were conducted in one patient. Functional consequences of the homozygous HID1 variant p.R433W were investigated by Seahorse XF Assay in fibroblasts of two patients.

Results: Bi-allelic variants in the gene HID1 domain-containing protein 1 (HID1) were identified in all patients. Postmortem examination confirmed cerebral atrophy with enlarged lateral ventricles. Markedly reduced expression of pituitary hormones was found in pituitary gland tissue. Colocalization of HID1 protein with the TGN was not altered in fibroblasts of patients compared to controls, while the extracellular acidification rate upon stimulation with potassium chloride was significantly reduced in patient fibroblasts compared to controls.

Interpretation: Our findings indicate that mutations in HID1 cause an early infantile encephalopathy with hypopituitarism as the leading presentation, and expand the list of syndromic CNS diseases caused by interference of TGN function. ANN NEUROL 2021.
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http://dx.doi.org/10.1002/ana.26127DOI Listing
May 2021

Abdominal Obesity-Related Disturbance of Insulin Sensitivity Is Associated with CD8 EMRA Cells in the Elderly.

Cells 2021 Apr 23;10(5). Epub 2021 Apr 23.

Department of Exercise Physiology and Sports Therapy, Institute of Sports Science, Justus-Liebig-University Giessen, Kugelberg 62, 35394 Giessen, Germany.

Aging and overweight increase the risk of developing type 2 diabetes mellitus. In this cross-sectional study, we aimed to investigate the potential mediating role of T-EMRA cells and inflammatory markers in the development of a decreased insulin sensitivity. A total of 134 healthy older volunteers were recruited (age 59.2 ( 5.6) years). T cell subpopulations were analyzed by flow cytometry. Furthermore, body composition, HOMA-IR, plasma tryptophan (Trp) metabolites, as well as cytokines and adipokines were determined. Using subgroup and covariance analyses, the influence of BMI on the parameters was evaluated. Moreover, correlation, multiple regression, and mediation analyses were performed. In the subgroup of participants with obesity, an increased proportion of CD8+EMRA cells and elevated concentrations of plasma kynurenine (KYN) were found compared to the lower-weight subgroups. Linear regression analysis revealed that an elevated HOMA-IR could be predicted by a higher proportion of CD8+EMRA cells and KYN levels. A mediation analysis showed a robust indirect effect of the Waist-to-hip ratio on HOMA-IR mediated by CD8+EMRA cells. Thus, the deleterious effects of abdominal obesity on glucose metabolism might be mediated by CD8+EMRA cells in the elderly. Longitudinal studies should validate this assumption and analyze the suitability of CD8+EMRA cells as early predictors of incipient prediabetes.
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http://dx.doi.org/10.3390/cells10050998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146929PMC
April 2021

[Home infusion therapy for Pompe disease: Recommendations for German-speaking countries].

Fortschr Neurol Psychiatr 2021 Apr 27. Epub 2021 Apr 27.

Friedrich-Baur- Institut der Neurologischen Klinik , Klinikum der Universität München, Deutschland.

Background: Pompe disease is a lysosomal multisystem disorder with predominant proximal myopathy. Treatment with enzyme replacement therapy (ERT) is available requiring life-long biweekly infusions of recombinant α-glucosidase. To minimize the burden of ERT patients ask for home infusion therapy.

Aims And Methods: Pompe disease experts from Germany, Austria, and Switzerland discussed in two consensus meetings in 2019 and 2020 requirements for home infusion therapy, adequate execution of treatment, and the legal situation for delegating physicians.

Results And Discussion: Home infusion therapy is principally feasible for patients with Pompe disease if certain preconditions are fulfilled, but the decision to implement has to be made on an individual basis. The treating physician delegates the execution of ERT to nursing staff but retains full legal responsibility. Home infusion therapy has to be carried out by specially trained and qualified staff. Infusion-related risks comprise mainly allergic reactions, and adequate medical treatment must be warranted. In German-speaking countries, clear rules for conducting home infusion therapy are needed to reduce psychosocial stress for patients with Pompe disease, and providing legal certainty for delegating physicians.
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http://dx.doi.org/10.1055/a-1482-6041DOI Listing
April 2021

Gastrointestinal Symptoms in Children With Life-Limiting Conditions Receiving Palliative Home Care.

Front Pediatr 2021 31;9:654531. Epub 2021 Mar 31.

Internal Medicine IV/V, University Hospital, Justus Liebig University Giessen, Giessen, Germany.

Children with life-limiting diseases suffer from gastrointestinal (GI) symptoms. Since the introduction of specialized palliative home care (SPHC) in Germany, it is possible to care for these children at home. In phase 1 of care the aim is to stabilize the patient. In phase 2, terminal support is provided. Analysis were performed of the differences between these phases. The causes and modalities/outcome of treatment were evaluated. A retrospective study was performed from 2014 to 2020. All home visits were analyzed with regard to the abovementioned symptoms, their causes, treatment and results. In total, 149 children were included (45.9% female, mean age 8.17 ± 7.67 years), and 126 patients were evaluated. GI symptoms were common in both phases. Vomiting was more common in phase 2 (59.3 vs. 27.1%; < 0.001). After therapy, the proportion of asymptomatic children in phase 1 increased from 40.1 to 75.7%; ( < ). Constipation was present in 52.3% (phase 1) and 54.1% (phase 2). After treatment, the proportion of asymptomatic patients increased from 47.3 to 75.7% in phase 1 ( < 0.001), and grade 3 constipation was reduced from 33.9 to 15% in phase 2 ( < 0.05). Painful GI symptoms occur in both palliative care phases but are more common in phase 2. The severity and frequency can usually be controlled at home. The study limitations were the retrospective design and small number of patients, but the study had a representative population, good data quality and a unique perspective on the reality of outpatient pediatric palliative care in Germany.
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http://dx.doi.org/10.3389/fped.2021.654531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044350PMC
March 2021

A form of muscular dystrophy associated with pathogenic variants in JAG2.

Am J Hum Genet 2021 May 15;108(5):840-856. Epub 2021 Apr 15.

Centre de Référence Neuromusculaire and Paediatric Neurology Department, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, 1020 Brussels, Belgium.

JAG2 encodes the Notch ligand Jagged2. The conserved Notch signaling pathway contributes to the development and homeostasis of multiple tissues, including skeletal muscle. We studied an international cohort of 23 individuals with genetically unsolved muscular dystrophy from 13 unrelated families. Whole-exome sequencing identified rare homozygous or compound heterozygous JAG2 variants in all 13 families. The identified bi-allelic variants include 10 missense variants that disrupt highly conserved amino acids, a nonsense variant, two frameshift variants, an in-frame deletion, and a microdeletion encompassing JAG2. Onset of muscle weakness occurred from infancy to young adulthood. Serum creatine kinase (CK) levels were normal or mildly elevated. Muscle histology was primarily dystrophic. MRI of the lower extremities revealed a distinct, slightly asymmetric pattern of muscle involvement with cores of preserved and affected muscles in quadriceps and tibialis anterior, in some cases resembling patterns seen in POGLUT1-associated muscular dystrophy. Transcriptome analysis of muscle tissue from two participants suggested misregulation of genes involved in myogenesis, including PAX7. In complementary studies, Jag2 downregulation in murine myoblasts led to downregulation of multiple components of the Notch pathway, including Megf10. Investigations in Drosophila suggested an interaction between Serrate and Drpr, the fly orthologs of JAG1/JAG2 and MEGF10, respectively. In silico analysis predicted that many Jagged2 missense variants are associated with structural changes and protein misfolding. In summary, we describe a muscular dystrophy associated with pathogenic variants in JAG2 and evidence suggests a disease mechanism related to Notch pathway dysfunction.
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http://dx.doi.org/10.1016/j.ajhg.2021.03.020DOI Listing
May 2021

Comparison of five commercial real-time PCRs for in-vitro diagnosis of Entamoeba histolytica, Giardia duodenalis, Cryptosporidium spp., Cyclospora cayetanensis, and Dientamoeba fragilis in human stool samples.

Travel Med Infect Dis 2021 May-Jun;41:102042. Epub 2021 Mar 31.

Bernhard Nocht Institute for Tropical Medicine Hamburg, Hamburg, Germany; National Reference Centre for Tropical Pathogens, Hamburg, Germany.

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http://dx.doi.org/10.1016/j.tmaid.2021.102042DOI Listing
March 2021

Comparative Assessment of Sera from Individuals after S-Gene RNA-Based SARS-CoV-2 Vaccination with Spike-Protein-Based and Nucleocapsid-Based Serological Assays.

Diagnostics (Basel) 2021 Mar 3;11(3). Epub 2021 Mar 3.

Institute for Medical Microbiology, University Medical Center Göttingen, 37075 Göttingen, Germany.

Due to the beginning of vaccination against COVID-19, serological discrimination between vaccine-associated humoral response and serology-based surveillance of natural SARS-CoV-2 infections as well as breakthrough infections becomes an issue of relevance. Here, we assessed the differentiated effects of the application of an RNA vaccine using SARS-CoV-2 spike protein epitopes on the results of both anti-spike protein-based serology (EUROIMMUN) and anti-nucleocapsid-based serology (VIROTECH). A total of 80 serum samples from vaccinees acquired at different time points after vaccination was assessed. While positive or borderline serological response in the anti-spike protein assay was observed for all samples (90% both IgG and IgA, 6.3% IgA only, 3.8% borderline IgG only), only a single case of a falsely positive IgM was observed for the anti-nucleocapsid assay as expected due to this assay's specificity. Positive anti-spike protein antibodies were already detectable in the second week after the first dose of vaccination, with higher titers after the second dose of the vaccine. In conclusion, the combined application of anti-spike protein-based serology and anti-nucleocapsid-based serology will provide a useful option for the discrimination of vaccination response and natural infection.
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http://dx.doi.org/10.3390/diagnostics11030426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998789PMC
March 2021

Prescription patterns of antiseizure drugs in tuberous sclerosis complex (TSC)-associated epilepsy: a multicenter cohort study from Germany and review of the literature.

Expert Rev Clin Pharmacol 2021 Jun 31;14(6):749-760. Epub 2021 May 31.

Department of Neuropediatrics and Social Pediatrics, St. Josef-Hospital, University Hospital of Pediatrics and Adolescent Medicine, Ruhr-University Bochum, Bochum, Germany.

Objective: Seizures are a primary and early disease manifestation of Tuberous Sclerosis Complex (TSC). We aimed to describe the age-stratified patterns of antiseizure drug (ASD) treatments among children, adolescents, and adults with TSC in Germany. Additionally, we reviewed real-world and clinical study evidence regarding ASD utilization in patients with TSC.

Methods: We evaluated the pattern of routine ASD use and everolimus prescriptions based on a 2019 multicenter survey of 268 individuals with TSC-associated epilepsy. We contextualized the results with a structured review of real-world and clinical study evidence.

Results: TSC-associated epilepsy treatment comprises a wide variety of ASDs. In this German sample, the majority of patients were treated with polytherapy, and lamotrigine (34.7%), valproate (32.8%), oxcarbazepine (28.7%), vigabatrin (19.0%), and levetiracetam (17.9%) were identified as the most-commonly used ASDs. In addition, everolimus was used by 32.5% of patients. In adherence to current TSC guidelines, the disease-modifying ASD vigabatrin was widely used in children (58% below the age of 5 years), whereas treatment in adults did not necessarily reflect guideline preference for (partial) GABAergic ASDs.

Conclusions: The selection of ASDs for patients with TSC-associated epilepsy follows well-evaluated recommendations, including the guidelines regarding vigabatrin use in children. Several characteristics, such as the comparatively high frequency of valproate use and polytherapy, reflect the severity of TSC-associated epilepsy.
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http://dx.doi.org/10.1080/17512433.2021.1911643DOI Listing
June 2021

Evaluation of a duplex real-time PCR in human serum for simultaneous detection and differentiation of Schistosoma mansoni and Schistosoma haematobium infections - cross-sectional study.

Travel Med Infect Dis 2021 May-Jun;41:102035. Epub 2021 Mar 26.

Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany; National Reference Centre for Tropical Pathogens, Hamburg, Germany.

Background: We evaluated a one-tube multiplex real-time PCR targeting DNA of Schistosoma haematobium complex and S. mansoni complex in serum samples obtained at different German diagnostic centers.

Methods: Simplex real-time PCR protocols for the detection of the multi-copy DNA-repeats Dra1 of S. haematobium complex and Sm1-7 of S. mansoni complex in serum were combined to a new one-tube multiplex format. The new PCR was subjected to full validation including evaluation in a diagnostic real-life setting with travelers and migrants. PCR results were compared with those of stool and urine microscopy, serology, and circulating cathodic antigen (CCA) rapid diagnostic tests in urine. Sensitivity and specificity of the diagnostic approaches were analyzed using latent class analysis (LCA).

Results: LCA assessment indicated sensitivity and specificity of 94.9% and 98.4%, respectively, for serum PCR if serology was included in the calculation, and 100% and 95.6%, respectively, if serology was not included as a parameter not necessarily associated with active infection. Agreement between the compared diagnostic procedures at genus level was fair (kappa 0.273) if serology was included and moderate (kappa 0.420) if serology was not included.

Discussion: The PCR assay proved to be highly reliable for the diagnosis of schistosomiasis in travelers and migrants.
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http://dx.doi.org/10.1016/j.tmaid.2021.102035DOI Listing
March 2021

Challenges in Transition From Childhood to Adulthood Care in Rare Metabolic Diseases: Results From the First Multi-Center European Survey.

Front Med (Lausanne) 2021 25;8:652358. Epub 2021 Feb 25.

MetabERN, Regional Coordinating Center for Rare Diseases, Udine University Hospital, Udine, Italy.

Inherited Metabolic Diseases (IMDs) are rare diseases caused by genetic defects in biochemical pathways. Earlier diagnosis and advances in treatment have improved the life expectancy of IMD patients over the last decades, with the majority of patients now surviving beyond the age of 20. This has created a new challenge: as they grow up, the care of IMD patients' needs to be transferred from metabolic pediatricians to metabolic physicians specialized in treating adults, through a process called "transition." The purpose of this study was to assess how this transition is managed in Europe: a survey was sent to all 77 centers of the European Reference Network for Hereditary Metabolic Disorders (MetabERN) to collect information and to identify unmet needs regarding the transition process. Data was collected from 63/77 (81%) healthcare providers (HCPs) from 20 EU countries. Responders were mostly metabolic pediatricians; of these, only ~40% have received appropriate training in health issues of adolescent metabolic patients. In most centers (~67%) there is no designated transition coordinator. About 50% of centers provide a written individualized transition protocol, which is standardized in just ~20% of cases. In 77% of centers, pediatricians share a medical summary, transition letter and emergency plan with the adult team and the patient. According to our responders, 11% of patients remain under pediatric care throughout their life. The main challenges identified by HCPs in managing transition are lack of time and shortage of adult metabolic physician positions, while the implementations that are most required for a successful transition include: medical staff dedicated to transition, a transition coordinator, and specific metabolic training for adult physicians. Our study shows that the transition process of IMD patients in Europe is far from standardized and in most cases is inadequate or non-existent. A transition coordinator to facilitate collaboration between the pediatric and adult healthcare teams should be central to any transition program. Standardized operating procedures, together with adequate financial resources and specific training for adult physicians focused on IMDs are the key aspects that must be improved in the rare metabolic field to establish successful transition processes in Europe.
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http://dx.doi.org/10.3389/fmed.2021.652358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962750PMC
February 2021

The p.Ala2430Val mutation in filamin C causes a "hypertrophic myofibrillar cardiomyopathy".

J Muscle Res Cell Motil 2021 Mar 12. Epub 2021 Mar 12.

Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, Bonn, Germany.

Hypertrophic cardiomyopathy (HCM) often leads to heart failure. Mutations in sarcomeric proteins are most frequently the cause of HCM but in many patients the gene defect is not known. Here we report on a young man who was diagnosed with HCM shortly after birth. Whole exome sequencing revealed a mutation in the FLNC gene (c.7289C > T; p.Ala2430Val) that was previously shown to cause aggregation of the mutant protein in transfected cells. Myocardial tissue from patients with this mutation has not been analyzed before and thus, the underlying etiology is not well understood. Myocardial tissue of our patient obtained during myectomy at the age of 23 years was analyzed in detail by histochemistry, immunofluorescence staining, electron microscopy and western blot analysis. Cardiac histology showed a pathology typical for myofibrillar myopathy with myofibril disarray and abnormal protein aggregates containing BAG3, desmin, HSPB5 and filamin C. Analysis of sarcomeric and intercalated disc proteins showed focally reduced expression of the gap junction protein connexin43 and Xin-positive sarcomeric lesions in the cardiomyocytes of our patient. In addition, autophagy pathways were altered with upregulation of LC3-II, WIPI1 and HSPB5, 6, 7 and 8. We conclude that the p.Ala2430Val mutation in FLNC most probably is associated with HCM characterized by abnormal intercalated discs, disarray of myofibrils and aggregates containing Z-disc proteins similar to myofibrillar myopathy, which supports the pathological effect of the mutation.
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http://dx.doi.org/10.1007/s10974-021-09601-1DOI Listing
March 2021

Binary surrogate endpoints in clinical trials from the perspective of case definitions.

Eur J Microbiol Immunol (Bp) 2021 Mar 4. Epub 2021 Mar 4.

1Institute for Medical Microbiology, Virology and Hygiene, University Medicine Rostock, Rostock, Germany.

Introduction: Surrogate endpoints are widely used in clinical trials, especially in situations where the endpoint of interest is not directly observable or to avoid long trial periods. A typical example for this case is frequently found in clinical trials in oncology, where overall survival (OS) as endpoint of interest and progression free survival (PFS) as surrogate endpoint are discriminated.

Methods: Based on the perspective of case definitions on surrogate endpoints, we provide a formal definition of such endpoints followed by a description of the structure of surrogate endpoints.

Results: Surrogate endpoints can be considered as case definitions for the endpoint of interest. Therefore, the performance of surrogate endpoints can be described using the classical terminology of diagnostic tests including sensitivity and specificity. Since such endpoints always focus on sensitivity with necessarily reduced specificity, efficacy estimates based on such endpoints are in general biased.

Conclusion: The abovementioned has to be taken into account while interpreting the results of clinical trials and should not be ignored while planning or conducting a study.
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http://dx.doi.org/10.1556/1886.2020.00031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042653PMC
March 2021

Differing Effects of Standard and Harsh Nucleic Acid Extraction Procedures on Diagnostic Helminth Real-Time PCRs Applied to Human Stool Samples.

Pathogens 2021 Feb 9;10(2). Epub 2021 Feb 9.

Department of Hospital Hygiene & Infectious Diseases, University Medicine Göttingen, 37075 Göttingen, Germany.

This study aimed to assess standard and harsher nucleic acid extraction schemes for diagnostic helminth real-time PCR approaches from stool samples. A standard procedure for nucleic acid extraction from stool and a procedure including bead-beating as well as proteinase K digestion were compared with group-, genus-, and species-specific real-time PCR assays targeting helminths and nonhelminth pathogens in human stool samples. From 25 different in-house and commercial helminth real-time PCR assays applied to 77 stool samples comprising 67 historic samples and 10 external quality assessment scheme samples positively tested for helminths, higher numbers of positive test results were observed after bead-beating-based nucleic acid extraction for 5/25 (20%) real-time PCR assays irrespective of specificity issues. Lower cycle threshold values were observed for one real-time PCR assay after the standard extraction scheme, and for four assays after the bead-beating-based scheme. Agreement between real-time PCR results after both nucleic acid extraction strategies according to Cohen's kappa ranged from poor to almost perfect for the different assays. Varying agreement was observed in eight nonhelminth real-time PCR assays applied to 67 historic stool samples. The study indicates highly variable effects of harsh nucleic acid extraction approaches depending on the real-time PCR assay used.
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http://dx.doi.org/10.3390/pathogens10020188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916106PMC
February 2021

[Home infusion therapy for Pompe disease: Recommendations for German-speaking countries].

Fortschr Neurol Psychiatr 2021 Feb 9. Epub 2021 Feb 9.

Friedrich-Baur- Institut der Neurologischen Klinik , Klinikum der Universität München, Deutschland.

Background: Pompe disease is a lysosomal multisystem disorder with predominant proximal myopathy. Treatment with enzyme replacement therapy (ERT) is available requiring life-long biweekly infusions of recombinant α-glucosidase. To minimize the burden of ERT patients ask for home infusion therapy.

Aims And Methods: Pompe disease experts from Germany, Austria, and Switzerland discussed in two consensus meetings in 2019 and 2020 requirements for home infusion therapy, adequate execution of treatment, and the legal situation for delegating physicians.

Results And Discussion: Home infusion therapy is principally feasible for patients with Pompe disease if certain preconditions are fulfilled, but the decision to implement has to be made on an individual basis. The treating physician delegates the execution of ERT to nursing staff but retains full legal responsibility. Home infusion therapy has to be carried out by specially trained and qualified staff. Infusion-related risks comprise mainly allergic reactions, and adequate medical treatment must be warranted. In German-speaking countries, clear rules for conducting home infusion therapy are needed to reduce psychosocial stress for patients with Pompe disease, and providing legal certainty for delegating physicians.
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http://dx.doi.org/10.1055/a-1365-8977DOI Listing
February 2021

Comparison of Five Serological Assays for the Detection of SARS-CoV-2 Antibodies.

Diagnostics (Basel) 2021 Jan 6;11(1). Epub 2021 Jan 6.

Institute for Medical Microbiology, University Medical Center Göttingen, 37075 Göttingen, Germany.

Serological assays can contribute to the estimation of population proportions with previous immunologically relevant contact with the Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) virus. In this study, we compared five commercially available diagnostic assays for the diagnostic identification of SARS-CoV-2-specific antibodies. Depending on the assessed immunoglobulin subclass, recorded sensitivity ranged from 17.0% to 81.9% with best results for immunoglobulin G. Specificity with blood donor sera ranged from 90.2% to 100%, with sera from EBV patients it ranged from 84.3% to 100%. Agreement from fair to nearly perfect was recorded depending on the immunoglobulin class between the assays, the with best results being found for immunoglobulin G. Only for this immunoglobulin class was the association between later sample acquisition times (about three weeks after first positive PCR results) and positive serological results in COVID-19 patients confirmed. In conclusion, acceptable and comparable reliability for the assessed immunoglobulin G-specific assays could be shown, while there is still room for improvement regarding the reliability of the assays targeting the other immunoglobulin classes.
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http://dx.doi.org/10.3390/diagnostics11010078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825051PMC
January 2021

New Therapeutics Options for Pediatric Neuromuscular Disorders.

Front Pediatr 2020 23;8:583877. Epub 2020 Nov 23.

Department of Child Neurology, University of Giessen, Giessen, Germany.

Neuromuscular disorders (NMDs) of Childhood onset are a genetically heterogeneous group of diseases affecting the anterior horn cell, the peripheral nerve, the neuromuscular junction, or the muscle. For many decades, treatment of NMDs has been exclusively symptomatic. But this has changed fundamentally in recent years due to the development of new drugs attempting either to ameliorate secondary pathophysiologic consequences or to modify the underlying genetic defect itself. While the effects on the course of disease are still modest in some NMDs (e.g., Duchenne muscular dystrophy), new therapies have substantially prolonged life expectancy and improved motor function in others (e.g., spinal muscular atrophy and infantile onset Pompe disease). This review summarizes recently approved medicaments and provides an outlook for new therapies that are on the horizon in this field.
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http://dx.doi.org/10.3389/fped.2020.583877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719776PMC
November 2020

Comparison of two commercial and one in-house real-time PCR assays for the diagnosis of bacterial gastroenteritis.

Eur J Microbiol Immunol (Bp) 2020 Dec 5. Epub 2020 Dec 5.

1Department of Microbiology and Hospital Hygiene, Bundeswehr Hospital Hamburg, Hamburg, Germany.

Introduction: The aim of the study was a comparative evaluation of in-house real-time PCR and commercial real-time PCR (Fast Track Diagnostics (FTD), ampliCube/Mikrogen) targeting enteropathogenic bacteria from stool in preparation of Regulation (EU) 2017/746 on in vitro diagnostic medical devices.

Methods: Both 241 stool samples from patients and 100 samples from German laboratory control schemes ("Ringversuche") were used to comparatively assess in-house real-time PCR, the FTD bacterial gastroenteritis kit, and the ampliCube gastrointestinal bacterial panels 1&2 either with the in-house PCRs as gold standard and as a test comparison without gold standard applying latent class analysis. Sensitivity, specificity, intra- and inter-assay variation and Cohen's kappa were assessed.

Results: In comparison with the gold standard, sensitivity was 75-100% for strongly positive samples, 20-100% for weakly positive samples, and specificity ranged from 96 to 100%. Latent class analysis suggested that sensitivity ranges from 81.2 to 100% and specificity from 58.5 to 100%. Cohen's kappa varied between moderate and nearly perfect agreement, intra- and inter-assay variation was 1-3 to 1-4 Ct values.

Conclusion: Acceptable agreement and performance characteristics suggested replaceability of the in-house PCR assays by the commercial approaches.
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http://dx.doi.org/10.1556/1886.2020.00030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753976PMC
December 2020

Aetiology and 30-Year Long-Term Outcome of Children with Cardiomyopathy Necessitating Heart Transplantation.

J Pers Med 2020 Nov 27;10(4). Epub 2020 Nov 27.

Pediatric Heart Center, Department of Pediatric Cardiology and Congenital Heart Disease, University Hospital Giessen, Justus Liebig Universität Giessen, 35390 Giessen, Germany.

Studies assessing the long-term outcome after heart transplantation HTX in patients with cardiomyopathy (CM) in the paediatric age range are rare. The aim of this study was to determine the survival rate of children with CM undergoing HTX and to analyse how aetiology of cardiomyopathy influenced morbidity and mortality. We retrospectively analysed the medical records of children; who were transplanted in our centre between June 1988 and October 2019. 236 heart transplantations were performed since 1988 (9 re-transplants). 98 of 227 patients (43.2%) were transplanted because of CM. Survival rates were 93% after 1; 84% after 10 and 75% after 30 years. Overall; the aetiology of CM could be clearly identified in 37 subjects (37.7%). This rate increased up to 66.6% (12/19) by applying a comprehensive diagnostic workup since 2016. The survival rate was lower ( < 0.05) and neurocognitive deficits were more frequent ( = 0.001) in subjects with systemic diseases than in individuals with cardiac-specific conditions. These data indicate that the long-term survival rate of children with CM after HTX in experienced centers is high. A comprehensive diagnostic workup allows unraveling the basic defect in the majority of patients with CM undergoing HTX. Aetiology of CM affects morbidity and mortality in subjects necessitating HTX.
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http://dx.doi.org/10.3390/jpm10040251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712803PMC
November 2020

Conditional Generative Adversarial Networks Aided Motion Correction of Dynamic F-FDG PET Brain Studies.

J Nucl Med 2021 Jun 27;62(6):871-880. Epub 2020 Nov 27.

QIMP Team, Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria.

This work set out to develop a motion-correction approach aided by conditional generative adversarial network (cGAN) methodology that allows reliable, data-driven determination of involuntary subject motion during dynamic F-FDG brain studies. Ten healthy volunteers (5 men/5 women; mean age ± SD, 27 ± 7 y; weight, 70 ± 10 kg) underwent a test-retest F-FDG PET/MRI examination of the brain ( = 20). The imaging protocol consisted of a 60-min PET list-mode acquisition contemporaneously acquired with MRI, including MR navigators and a 3-dimensional time-of-flight MR angiography sequence. Arterial blood samples were collected as a reference standard representing the arterial input function (AIF). Training of the cGAN was performed using 70% of the total datasets ( = 16, randomly chosen), which was corrected for motion using MR navigators. The resulting cGAN mappings (between individual frames and the reference frame [55-60 min after injection]) were then applied to the test dataset (remaining 30%, = 6), producing artificially generated low-noise images from early high-noise PET frames. These low-noise images were then coregistered to the reference frame, yielding 3-dimensional motion vectors. Performance of cGAN-aided motion correction was assessed by comparing the image-derived input function (IDIF) extracted from a cGAN-aided motion-corrected dynamic sequence with the AIF based on the areas under the curves (AUCs). Moreover, clinical relevance was assessed through direct comparison of the average cerebral metabolic rates of glucose (CMRGlc) values in gray matter calculated using the AIF and the IDIF. The absolute percentage difference between AUCs derived using the motion-corrected IDIF and the AIF was (1.2% + 0.9%). The gray matter CMRGlc values determined using these 2 input functions differed by less than 5% (2.4% + 1.7%). A fully automated data-driven motion-compensation approach was established and tested for F-FDG PET brain imaging. cGAN-aided motion correction enables the translation of noninvasive clinical absolute quantification from PET/MR to PET/CT by allowing the accurate determination of motion vectors from the PET data itself.
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http://dx.doi.org/10.2967/jnumed.120.248856DOI Listing
June 2021

[Expert recommendation: treatment of nonambulatory patients with Duchenne muscular dystrophy].

Nervenarzt 2021 Apr 19;92(4):359-366. Epub 2020 Nov 19.

Friedrich-Baur-Institut, Neurologische Klinik und Poliklinik, Klinikum der Ludwig-Maximilians-Universität München, Ziemssenstr. 1, 80336, München, Deutschland.

Background: Duchenne muscular dystrophy (DMD) is the most frequent genetic neuromuscular disease in childhood with loss of ambulation usually occurring around the age of 9-11 years.

Objective, Material And Methods: Based on current guidelines and clinical trials, neuropediatric and neurological experts developed recommendations for the treatment of nonambulatory DMD patients focusing on drug treatment of adults. This advisory board was sponsored by PTC Therapeutics, the distributers of the substance ataluren.

Results And Conclusion: Loss of ambulation is heterogeneously defined across clinical trials. Among others, the need of a wheelchair, ambulation without mobility aids or maximum walking distance can be suitable parameters for assessment. Treatment of DMD patients at any stage of the disease is based on supportive and symptomatic measures, which should be continued after loss of ambulation. In addition, disease-modifying drugs are available for the treatment of DMD and glucocorticoids are the usual standard of care treatment even beyond the loss of ambulation. Ataluren, a potentially dystrophin restorative, disease-modifying treatment, has been approved for patients with DMD due to a nonsense mutation (nmDMD), which applies to approximately 13% of DMD patients and is usually combined with steroids. Clinical data from the STRIDE registry demonstrated a delayed disease progression even after loss of ambulation. Currently, no reliable data are available for exon skipping approaches in adult DMD patients. The antioxidant idebenone could be an option in nonambulant adolescent patients not treated with glucocorticoids and without other therapeutic options. A combination treatment of idebenone and glucocorticoids is currently being investigated in a clinical trial. Add-on treatment with idebenone in addition to ataluren may be considered for nonambulant nmDMD patients. Some of the discussed treatment options are still in clinical trials or there are not enough data for older DMD patients; therefore, these expert recommendations correspond to evidence class IV.
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http://dx.doi.org/10.1007/s00115-020-01019-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026471PMC
April 2021

Predicting Antidepressant Citalopram Treatment Response via Changes in Brain Functional Connectivity After Acute Intravenous Challenge.

Front Comput Neurosci 2020 6;14:554186. Epub 2020 Oct 6.

Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.

The early and therapy-specific prediction of treatment success in major depressive disorder is of paramount importance due to high lifetime prevalence, and heterogeneity of response to standard medication and symptom expression. Hence, this study assessed the predictability of long-term antidepressant effects of escitalopram based on the short-term influence of citalopram on functional connectivity. Twenty nine subjects suffering from major depression were scanned twice with resting-state functional magnetic resonance imaging under the influence of intravenous citalopram and placebo in a randomized, double-blinded cross-over fashion. Symptom factors were identified for the Hamilton depression rating scale (HAM-D) and Beck's depression inventory (BDI) taken before and after a median of seven weeks of escitalopram therapy. Predictors were calculated from whole-brain functional connectivity, fed into robust regression models, and cross-validated. Significant predictive power could be demonstrated for one HAM-D factor describing insomnia and the total score ( = 0.45-0.55). Remission and response could furthermore be predicted with an area under the receiver operating characteristic curve of 0.73 and 0.68, respectively. Functional regions with high influence on the predictor were located especially in the ventral attention, fronto-parietal, and default mode networks. It was shown that medication-specific antidepressant symptom improvements can be predicted using functional connectivity measured during acute pharmacological challenge as an easily assessable imaging marker. The regions with high influence have previously been related to major depression as well as the response to selective serotonin reuptake inhibitors, corroborating the advantages of the current approach of focusing on treatment-specific symptom improvements.
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http://dx.doi.org/10.3389/fncom.2020.554186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573155PMC
October 2020

Multicenter Experience with Nusinersen Application via an Intrathecal Port and Catheter System in Spinal Muscular Atrophy.

Neuropediatrics 2020 12 22;51(6):401-406. Epub 2020 Oct 22.

Department of Neuropediatrics, University Hospitals of the Ruhr University of Bochum, Bochum, Germany.

Nusinersen, an antisense oligonucleotide enhancing the production of the survival motor neuron protein, is approved for the treatment of spinal muscular atrophy (SMA) but requires repetitive lumbar punctures. Application via a subcutaneous port connected to a permanent intrathecal catheter has been proposed as an alternative for patients with severe scoliosis, spinal fusion, or comorbidities, rendering serial interlaminar punctures complicated and risky. Since experience with this technique is sparse and follow-up data are lacking, we assessed feasibility, safety, and tolerability of this approach in eight patients with SMA II/SMA III receiving Nusinersen in a multicenter study. Median age at port implantation was 21 years (range: 10-30 years), and median follow-up time thereafter was 19 months (range: 7-24 months). Leakage of the port catheter occurred in two patients, promptly resolving after resuturing. No further complications such as infection, dislocation, kinking, or obstruction of the port were noted in any of the patients. These findings suggest that application via an intrathecal port and catheter system represents a safe and feasible option for Nusinersen treatment in subjects with SMA. However, to detect rare adverse events longer term follow-up in a larger study cohort is warranted.
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http://dx.doi.org/10.1055/s-0040-1715481DOI Listing
December 2020

Evaluation of the Xiamen AmonMed Biotechnology rapid diagnostic test COVID-19 IgM/IgG test kit (Colloidal gold).

Eur J Microbiol Immunol (Bp) 2020 Sep 25. Epub 2020 Sep 25.

1Institute for Medical Microbiology, University Medical Center Göttingen, Göttingen, Germany.

Introduction: To efficiently monitor the COVID-19 pandemic for surveillance purposes, reliable serological rapid diagnostic tests (RDTs) are desirable for settings where well-established high-throughput bench-top solutions are not available. Here, we have evaluated such an RDT.

Methods: We have assessed the Xiamen AmonMed Biotechnology COVID-19 IgM/IgG test kit (Colloidal gold) and the EUROIMMUN benchtop assay with serum samples from patients with polymerase chain reaction (PCR)-confirmed COVID-19 disease. Samples from patients with Epstein-Barr-virus (EBV) infection and blood donors were used for specificity testing.

Results: For the colloid gold rapid test and the EUROIMMUN assay, the study indicated overall sensitivity of 15.2% and 67.4%, respectively, while specificity of 99.0% and 97.9% with the blood donor sera, as well as 100% and 96.8% with the EBV-patients, were observed, respectively. An association of the time period between positive PCR results and serum acquisition with serological test positivity could be observed for the immunologlobulin G subclass of the EUROIMMUN assay only.

Conclusions: In spite of acceptable specificity of the assessed RDT, the detected poor sensitivity leaves room for improvement. The test results remain difficult to interpret and therefore the RDT can currently not be recommended for routine diagnostic or surveillance use.
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http://dx.doi.org/10.1556/1886.2020.00029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592516PMC
September 2020

Reasons for and Consequences of Low Energy Availability in Female and Male Athletes: Social Environment, Adaptations, and Prevention.

Sports Med Open 2020 Sep 10;6(1):44. Epub 2020 Sep 10.

Institute of Sports Science, Department of Exercise Physiology and Sports Therapy, Justus-Liebig University Giessen, Kugelberg 62, 35394, Giessen, Germany.

Low energy availability (LEA) represents a state in which the body does not have enough energy left to support all physiological functions needed to maintain optimal health. When compared to the normal population, athletes are particularly at risk to experience LEA and the reasons for this are manifold. LEA may result from altered dietary behaviours that are caused by body dissatisfaction, the belief that a lower body weight will result in greater performance, or social pressure to look a certain way. Pressure can also be experienced from the coach, teammates, and in this day and age through social media platforms. While LEA has been extensively described in females and female athletes have started fighting against the pressure to be thin using their social media platforms, evidence shows that male athletes are at risk as well. Besides those obvious reasons for LEA, athletes engaging in sports with high energy expenditure (e.g. rowing or cycling) can unintentionally experience LEA; particularly, when the athletes' caloric intake is not matched with exercise intensity. Whether unintentional or not, LEA may have detrimental consequences on health and performance, because both short-term and long-term LEA induces a variety of maladaptations such as endocrine alterations, suppression of the reproductive axis, mental disorders, thyroid suppression, and altered metabolic responses. Therefore, the aim of this review is to increase the understanding of LEA, including the role of an athlete's social environment and the performance effects related to LEA.
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http://dx.doi.org/10.1186/s40798-020-00275-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483688PMC
September 2020