@article{KuhtzSchneiderElHajjetal.2014, author = {Kuhtz, Juliane and Schneider, Eberhard and El Hajj, Nady and Zimmermann, Lena and Fust, Olga and Linek, Bartosz and Seufert, Rudolf and Hahn, Thomas and Schorsch, Martin and Haaf, Thomas}, title = {Epigenetic heterogeneity of developmentally important genes in human sperm: Implications for assisted reproduction outcome}, series = {Epigenetics}, volume = {9}, journal = {Epigenetics}, number = {12}, doi = {10.4161/15592294.2014.988063}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-150261}, pages = {1648-1658}, year = {2014}, abstract = {The molecular basis of male infertility is poorly understood, the majority of cases remaining unsolved. The association of aberrant sperm DNA methylation patterns and compromised semen parameters suggests that disturbances in male germline epigenetic reprogramming contribute to this problem. So far there are only few data on the epigenetic heterogeneity of sperm within a given sample and how to select the best sperm for successful infertility treatment. Limiting dilution bisulfite sequencing of small pools of sperm from fertile donors did not reveal significant differences in the occurrence of abnormal methylation imprints between sperm with and without morphological abnormalities. Intracytoplasmic morphologically selected sperm injection was not associated with an improved epigenetic quality, compared to standard intracytoplasmatic sperm injection. Deep bisulfite sequencing (DBS) of 2 imprinted and 2 pluripotency genes in sperm from men attending a fertility center showed that in both samples with normozoospermia and oligoasthenoteratozoospermia (OAT) the vast majority of sperm alleles was normally (de)methylated and the percentage of epimutations (allele methylation errors) was generally low (<1\%). However, DBS allowed one to identify and quantify these rare epimutations with high accuracy. Sperm samples not leading to a pregnancy, in particular in the OAT group, had significantly more epimutations in the paternally methylated GTL2 gene than samples leading to a live birth. All 13 normozoospermic and 13 OAT samples leading to a child had <1\% GTL2 epimutations, whereas one (7\%) of 14 normozoospermic and 7 (50\%) of 14 OAT samples without pregnancy displayed 1-14\% GTL2 epimutations.}, language = {en} } @article{FabritiusWoelferHerzbergetal.2021, author = {Fabritius, Matthias Philipp and W{\"o}lfer, Teresa A. and Herzberg, Moriz and Tiedt, Steffen and Puhr-Westerheide, Daniel and Grosu, Sergio and Maurus, Stefan and Geyer, Thomas and Curta, Adrian and Kellert, Lars and K{\"u}pper, Clemens and Liebig, Thomas and Ricke, Jens and Dimitriadis, Konstantinos and Kunz, Wolfgang G. and Zimmermann, Hanna and Reidler, Paul}, title = {Course of early neurologic symptom severity after endovascular treatment of anterior circulation large vessel occlusion stroke: association with baseline multiparametric CT imaging and clinical parameters}, series = {Diagnostics}, volume = {11}, journal = {Diagnostics}, number = {7}, issn = {2075-4418}, doi = {10.3390/diagnostics11071272}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-242681}, year = {2021}, abstract = {Background: Neurologic symptom severity and deterioration at 24 hours (h) predict long-term outcomes in patients with acute large vessel occlusion (LVO) stroke of the anterior circulation. We aimed to examine the association of baseline multiparametric CT imaging and clinical factors with the course of neurologic symptom severity in the first 24 h after endovascular treatment (EVT). Methods: Patients with LVO stroke of the anterior circulation were selected from a prospectively acquired consecutive cohort of patients who underwent multiparametric CT, including non-contrast CT, CT angiography and CT perfusion before EVT. The symptom severity was assessed on admission and after 24 h using the 42-point National Institutes of Health Stroke Scale (NIHSS). Clinical and imaging data were compared between patients with and without early neurological deterioration (END). END was defined as an increase in ≥4 points, and a significant clinical improvement as a decrease in ≥4 points, compared to NIHSS on admission. Multivariate regression analyses were used to determine independent associations of imaging and clinical parameters with NIHSS score increase or decrease in the first 24 h. Results: A total of 211 patients were included, of whom 38 (18.0\%) had an END. END was significantly associated with occlusion of the internal carotid artery (odds ratio (OR), 4.25; 95\% CI, 1.90-9.47) and the carotid T (OR, 6.34; 95\% CI, 2.56-15.71), clot burden score (OR, 0.79; 95\% CI, 0.68-0.92) and total ischemic volume (OR, 1.01; 95\% CI, 1.00-1.01). In a comprehensive multivariate analysis model including periprocedural parameters and complications after EVT, carotid T occlusion remained independently associated with END, next to reperfusion status and intracranial hemorrhage. Favorable reperfusion status and small ischemic core volume were associated with clinical improvement after 24 h. Conclusions: The use of imaging parameters as a surrogate for early NIHSS progression in an acute LVO stroke after EVT reached limited performance with only carotid T occlusion as an independent predictor of END. Reperfusion status and early complications in terms of intracranial hemorrhage are critical factors that influence patient outcome in the acute stroke phase after EVT.}, language = {en} } @article{PacheZimmermannMikolajczaketal.2016, author = {Pache, Florence and Zimmermann, Hanna and Mikolajczak, Janine and Schumacher, Sophie and Lacheta, Anna and Oertel, Frederike C. and Bellmann-Strobl, Judith and Jarius, Sven and Wildemann, Brigitte and Reindl, Markus and Waldman, Amy and Soelberg, Kerstin and Asgari, Nasrin and Ringelstein, Marius and Aktas, Orhan and Gross, Nikolai and Buttmann, Mathias and Ach, Thomas and Ruprecht, Klemens and Paul, Friedemann and Brandt, Alexander U.}, title = {MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 4: Afferent visual system damage after optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patients}, series = {Journal of Neuroinflammation}, volume = {13}, journal = {Journal of Neuroinflammation}, number = {282}, doi = {10.1186/s12974-016-0720-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165551}, year = {2016}, abstract = {Background Antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) have been reported in patients with aquaporin-4 antibody (AQP4-IgG)-negative neuromyelitis optica spectrum disorders (NMOSD). The objective of this study was to describe optic neuritis (ON)-induced neuro-axonal damage in the retina of MOG-IgG-positive patients in comparison with AQP4-IgG-positive NMOSD patients. Methods Afferent visual system damage following ON was bilaterally assessed in 16 MOG-IgG-positive patients with a history of ON and compared with that in 16 AQP4-IgG-positive NMOSD patients. In addition, 16 healthy controls matched for age, sex, and disease duration were analyzed. Study data included ON history, retinal optical coherence tomography, visual acuity, and visual evoked potentials. Results Eight MOG-IgG-positive patients had a previous diagnosis of AQP4-IgG-negative NMOSD with ON and myelitis, and eight of (mainly recurrent) ON. Twenty-nine of the 32 eyes of the MOG-IgG-positive patients had been affected by at least one episode of ON. Peripapillary retinal nerve fiber layer thickness (pRNFL) and ganglion cell and inner plexiform layer volume (GCIP) were significantly reduced in ON eyes of MOG-IgG-positive patients (pRNFL = 59 ± 23 μm; GCIP = 1.50 ± 0.34 mm3) compared with healthy controls (pRNFL = 99 ± 6 μm, p < 0.001; GCIP = 1.97 ± 0.11 mm3, p < 0.001). Visual acuity was impaired in eyes after ON in MOG-IgG-positive patients (0.35 ± 0.88 logMAR). There were no significant differences in any structural or functional visual parameters between MOG-IgG-positive and AQP4-IgG-positive patients (pRNFL: 59 ± 21 μm; GCIP: 1.41 ± 0.27 mm3; Visual acuity = 0.72 ± 1.09 logMAR). Importantly, MOG-IgG-positive patients had a significantly higher annual ON relapse rate than AQP4-IgG-positive patients (median 0.69 vs. 0.29 attacks/year, p = 0.004), meaning that on average a single ON episode caused less damage in MOG-IgG-positive than in AQP4-IgG-positive patients. pRNFL and GCIP loss correlated with the number of ON episodes in MOG-IgG-positive patients (p < 0.001), but not in AQP4-IgG-positive patients. Conclusions Retinal neuro-axonal damage and visual impairment after ON in MOG-IgG-positive patients are as severe as in AQP4-IgG-positive NMOSD patients. In MOG-IgG-positive patients, damage accrual may be driven by higher relapse rates, whereas AQP4-IgG-positive patients showed fewer but more severe episodes of ON. Given the marked damage in some of our MOG-IgG-positive patients, early diagnosis and timely initiation and close monitoring of immunosuppressive therapy are important.}, language = {en} } @article{ChumakRuettigerLeeetal.2016, author = {Chumak, Tetyana and R{\"u}ttiger, Lukas and Lee, Sze Chim and Campanelli, Dario and Zuccotti, Annalisa and Singer, Wibke and Popel{\´a}ř, Jiř{\´i} and Gutsche, Katja and Geisler, Hyun-Soon and Schraven, Sebastian Philipp and Jaumann, Mirko and Panford-Walsh, Rama and Hu, Jing and Schimmang, Thomas and Zimmermann, Ulrike and Syka, Josef and Knipper, Marlies}, title = {BDNF in Lower Brain Parts Modifies Auditory Fiber Activity to Gain Fidelity but Increases the Risk for Generation of Central Noise After Injury}, series = {Molecular Neurobiology}, volume = {53}, journal = {Molecular Neurobiology}, number = {8}, doi = {10.1007/s12035-015-9474-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-187341}, pages = {5607-5627}, year = {2016}, abstract = {For all sensory organs, the establishment of spatial and temporal cortical resolution is assumed to be initiated by the first sensory experience and a BDNF-dependent increase in intracortical inhibition. To address the potential of cortical BDNF for sound processing, we used mice with a conditional deletion of BDNF in which Cre expression was under the control of the Pax2 or TrkC promoter. BDNF deletion profiles between these mice differ in the organ of Corti (BDNF \(^{Pax2}\) -KO) versus the auditory cortex and hippocampus (BDNF \(^{TrkC}\) -KO). We demonstrate that BDNF \(^{Pax2}\) -KO but not BDNF \(^{TrkC}\) -KO mice exhibit reduced sound-evoked suprathreshold ABR waves at the level of the auditory nerve (wave I) and inferior colliculus (IC) (wave IV), indicating that BDNF in lower brain regions but not in the auditory cortex improves sound sensitivity during hearing onset. Extracellular recording of IC neurons of BDNF \(^{Pax2}\) mutant mice revealed that the reduced sensitivity of auditory fibers in these mice went hand in hand with elevated thresholds, reduced dynamic range, prolonged latency, and increased inhibitory strength in IC neurons. Reduced parvalbumin-positive contacts were found in the ascending auditory circuit, including the auditory cortex and hippocampus of BDNF \(^{Pax2}\) -KO, but not of BDNF \(^{TrkC}\) -KO mice. Also, BDNF \(^{Pax2}\) -WT but not BDNF \(^{Pax2}\) -KO mice did lose basal inhibitory strength in IC neurons after acoustic trauma. These findings suggest that BDNF in the lower parts of the auditory system drives auditory fidelity along the entire ascending pathway up to the cortex by increasing inhibitory strength in behaviorally relevant frequency regions. Fidelity and inhibitory strength can be lost following auditory nerve injury leading to diminished sensory outcome and increased central noise.}, language = {en} } @article{HerzbergScherlingStahletal.2021, author = {Herzberg, Moritz and Scherling, Korbinian and Stahl, Robert and Tiedt, Steffen and Wollenweber, Frank A. and K{\"u}pper, Clemens and Feil, Katharina and Forbrig, Robert and Patzig, Maximilian and Kellert, Lars and Kunz, Wolfgang G. and Reidler, Paul and Zimmermann, Hanna and Liebig, Thomas and Dieterich, Marianne and Dorn, Franziska}, title = {Late Thrombectomy in Clinical Practice: Retrospective Application of DAWN/DEFUSE3 Criteria within the German Stroke Registry}, series = {Clinical Neuroradiology}, volume = {31}, journal = {Clinical Neuroradiology}, number = {3}, doi = {10.1007/s00062-021-01033-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-264765}, pages = {799-810}, year = {2021}, abstract = {Background and Purpose To provide real-world data on outcome and procedural factors of late thrombectomy patients. Methods We retrospectively analyzed patients from the multicenter German Stroke Registry. The primary endpoint was clinical outcome on the modified Rankin scale (mRS) at 3 months. Trial-eligible patients and the subgroups were compared to the ineligible group. Secondary analyses included multivariate logistic regression to identify predictors of good outcome (mRS ≤ 2). Results Of 1917 patients who underwent thrombectomy, 208 (11\%) were treated within a time window ≥ 6-24 h and met the baseline trial criteria. Of these, 27 patients (13\%) were eligible for DAWN and 39 (19\%) for DEFUSE3 and 156 patients were not eligible for DAWN or DEFUSE3 (75\%), mainly because there was no perfusion imaging (62\%; n = 129). Good outcome was not significantly higher in trial-ineligible (27\%) than in trial-eligible (20\%) patients (p = 0.343). Patients with large trial-ineligible CT perfusion imaging (CTP) lesions had significantly more hemorrhagic complications (33\%) as well as unfavorable outcomes. Conclusion In clinical practice, the high number of patients with a good clinical outcome after endovascular therapy ≥ 6-24 h as in DAWN/DEFUSE3 could not be achieved. Similar outcomes are seen in patients selected for EVT ≥ 6 h based on factors other than CTP. Patients triaged without CTP showed trends for shorter arrival to reperfusion times and higher rates of independence.}, language = {en} } @article{HerzbergDornTrummetal.2022, author = {Herzberg, Moriz and Dorn, Franziska and Trumm, Christoph and Kellert, Lars and Tiedt, Steffen and Feil, Katharina and K{\"u}pper, Clemens and Wollenweber, Frank and Liebig, Thomas and Zimmermann, Hanna}, title = {Middle cerebral artery M2 thrombectomy: safety and technical considerations in the German Stroke Registry (GSR)}, series = {Journal of Clinical Medicine}, volume = {11}, journal = {Journal of Clinical Medicine}, number = {15}, issn = {2077-0383}, doi = {10.3390/jcm11154619}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-286052}, year = {2022}, abstract = {There is ongoing debate concerning the safety and efficacy of various mechanical thrombectomy (MT) approaches for M2 occlusions. We compared these for MT in M2 versus M1 occlusions. Subgroup analyses of different technical approaches within the M2 MT cohort were also performed. Patients were included from the German Stroke Registry (GSR), a multicenter registry of consecutive MT patients. Primary outcomes were reperfusion success events. Secondary outcomes were early clinical improvement (improvement in NIHSS score > 4) and independent survival at 90 days (mRS 0-2). Out of 3804 patients, 2689 presented with M1 (71\%) and 1115 with isolated M2 occlusions (29\%). The mean age was 76 (CI 65-82) and 77 (CI 66-83) years, respectively. Except for baseline NIHSS (15 (CI 10-18) vs. 11 (CI 6-16), p < 0.001) and ASPECTS (9 (CI 7-10) vs. 9 (CI 8-10, p < 0.001), baseline demographics were balanced. Apart from a more frequent use of dedicated small vessel stent retrievers (svSR) in M2 (17.4\% vs. 3.0; p < 0.001), intraprocedural aspects were balanced. There was no difference in ICH at 24 h (11\%; p = 1.0), adverse events (14.4\% vs. 18.1\%; p = 0.63), clinical improvement (62.5\% vs. 61.4 \%; p = 0.57), mortality (26.9\% vs. 22.9\%; p = 0.23). In M2 MT, conventional stent retriever (cSR) achieved higher rates of mTICI3 (54.0\% vs. 37.7-42.0\%; p < 0.001), requiring more MT-maneuvers (7, CI 2-8) vs. 2 (CI 2-7)/(CI 2-2); p < 0.001) and without impact on efficacy and outcome. Real-life MT in M2 can be performed with equal safety and efficacy as in M1 occlusions. Different recanalization techniques including the use of svSR did not result in significant differences regarding safety, efficacy and outcome.}, language = {en} } @article{TutovChenWerneretal.2023, author = {Tutov, Anna and Chen, Xinyu and Werner, Rudolf A. and M{\"u}hlig, Saskia and Zimmermann, Thomas and Nose, Naoko and Koshino, Kazuhiro and Lapa, Constantin and Decker, Michael and Higuchi, Takahiro}, title = {Rationalizing the binding modes of PET radiotracers targeting the norepinephrine transporter}, series = {Pharmaceutics}, volume = {15}, journal = {Pharmaceutics}, number = {2}, issn = {1999-4923}, doi = {10.3390/pharmaceutics15020690}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-303949}, year = {2023}, abstract = {Purpose: A new PET radiotracer \(^{18}\)F-AF78 showing great potential for clinical application has been reported recently. It belongs to a new generation of phenethylguanidine-based norepinephrine transporter (NET)-targeting radiotracers. Although many efforts have been made to develop NET inhibitors as antidepressants, systemic investigations of the structure-activity relationships (SARs) of NET-targeting radiotracers have rarely been performed. Methods: Without changing the phenethylguanidine pharmacophore and 3-fluoropropyl moiety that is crucial for easy labeling, six new analogs of \(^{18}\)F-AF78 with different meta-substituents on the benzene-ring were synthesized and evaluated in a competitive cellular uptake assay and in in vivo animal experiments in rats. Computational modeling of these tracers was established to quantitatively rationalize the interaction between the radiotracers and NET. Results: Using non-radiolabeled reference compounds, a competitive cellular uptake assay showed a decrease in NET-transporting affinity from meta-fluorine to iodine (0.42 and 6.51 µM, respectively), with meta-OH being the least active (22.67 µM). Furthermore, in vivo animal studies with radioisotopes showed that heart-to-blood ratios agreed with the cellular experiments, with AF78(F) exhibiting the highest cardiac uptake. This result correlates positively with the electronegativity rather than the atomic radius of the meta-substituent. Computational modeling studies revealed a crucial influence of halogen substituents on the radiotracer-NET interaction, whereby a T-shaped π-π stacking interaction between the benzene-ring of the tracer and the amino acid residues surrounding the NET binding site made major contributions to the different affinities, in accordance with the pharmacological data. Conclusion: The SARs were characterized by in vitro and in vivo evaluation, and computational modeling quantitatively rationalized the interaction between radiotracers and the NET binding site. These findings pave the way for further evaluation in different species and underline the potential of AF78(F) for clinical application, e.g., cardiac innervation imaging or molecular imaging of neuroendocrine tumors.}, language = {en} } @article{ElHelouBiegnerBodeetal.2019, author = {El-Helou, Sabine M. and Biegner, Anika-Kerstin and Bode, Sebastian and Ehl, Stephan R. and Heeg, Maximilian and Maccari, Maria E. and Ritterbusch, Henrike and Speckmann, Carsten and Rusch, Stephan and Scheible, Raphael and Warnatz, Klaus and Atschekzei, Faranaz and Beider, Renata and Ernst, Diana and Gerschmann, Stev and Jablonka, Alexandra and Mielke, Gudrun and Schmidt, Reinhold E. and Sch{\"u}rmann, Gesine and Sogkas, Georgios and Baumann, Ulrich H. and Klemann, Christian and Viemann, Dorothee and Bernuth, Horst von and Kr{\"u}ger, Renate and Hanitsch, Leif G. and Scheibenbogen, Carmen M. and Wittke, Kirsten and Albert, Michael H. and Eichinger, Anna and Hauck, Fabian and Klein, Christoph and Rack-Hoch, Anita and Sollinger, Franz M. and Avila, Anne and Borte, Michael and Borte, Stephan and Fasshauer, Maria and Hauenherm, Anja and Kellner, Nils and M{\"u}ller, Anna H. and {\"U}lzen, Anett and Bader, Peter and Bakhtiar, Shahrzad and Lee, Jae-Yun and Heß, Ursula and Schubert, Ralf and W{\"o}lke, Sandra and Zielen, Stefan and Ghosh, Sujal and Laws, Hans-Juergen and Neubert, Jennifer and Oommen, Prasad T. and H{\"o}nig, Manfred and Schulz, Ansgar and Steinmann, Sandra and Klaus, Schwarz and D{\"u}ckers, Gregor and Lamers, Beate and Langemeyer, Vanessa and Niehues, Tim and Shai, Sonu and Graf, Dagmar and M{\"u}glich, Carmen and Schmalzing, Marc T. and Schwaneck, Eva C. and Tony, Hans-Peter and Dirks, Johannes and Haase, Gabriele and Liese, Johannes G. and Morbach, Henner and Foell, Dirk and Hellige, Antje and Wittkowski, Helmut and Masjosthusmann, Katja and Mohr, Michael and Geberzahn, Linda and Hedrich, Christian M. and M{\"u}ller, Christiane and R{\"o}sen-Wolff, Angela and Roesler, Joachim and Zimmermann, Antje and Behrends, Uta and Rieber, Nikolaus and Schauer, Uwe and Handgretinger, Rupert and Holzer, Ursula and Henes, J{\"o}rg and Kanz, Lothar and Boesecke, Christoph and Rockstroh, J{\"u}rgen K. and Schwarze-Zander, Carolynne and Wasmuth, Jan-Christian and Dilloo, Dagmar and H{\"u}lsmann, Brigitte and Sch{\"o}nberger, Stefan and Schreiber, Stefan and Zeuner, Rainald and Ankermann, Tobias and Bismarck, Philipp von and Huppertz, Hans-Iko and Kaiser-Labusch, Petra and Greil, Johann and Jakoby, Donate and Kulozik, Andreas E. and Metzler, Markus and Naumann-Bartsch, Nora and Sobik, Bettina and Graf, Norbert and Heine, Sabine and Kobbe, Robin and Lehmberg, Kai and M{\"u}ller, Ingo and Herrmann, Friedrich and Horneff, Gerd and Klein, Ariane and Peitz, Joachim and Schmidt, Nadine and Bielack, Stefan and Groß-Wieltsch, Ute and Classen, Carl F. and Klasen, Jessica and Deutz, Peter and Kamitz, Dirk and Lassy, Lisa and Tenbrock, Klaus and Wagner, Norbert and Bernbeck, Benedikt and Brummel, Bastian and Lara-Villacanas, Eusebia and M{\"u}nstermann, Esther and Schneider, Dominik T. and Tietsch, Nadine and Westkemper, Marco and Weiß, Michael and Kramm, Christof and K{\"u}hnle, Ingrid and Kullmann, Silke and Girschick, Hermann and Specker, Christof and Vinnemeier-Laubenthal, Elisabeth and Haenicke, Henriette and Schulz, Claudia and Schweigerer, Lothar and M{\"u}ller, Thomas G. and Stiefel, Martina and Belohradsky, Bernd H. and Soetedjo, Veronika and Kindle, Gerhard and Grimbacher, Bodo}, title = {The German national registry of primary immunodeficiencies (2012-2017)}, series = {Frontiers in Immunology}, volume = {10}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2019.01272}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226629}, year = {2019}, abstract = {Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1-25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57\% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36\% of patients. Familial cases were observed in 21\% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0-88 years). Presenting symptoms comprised infections (74\%) and immune dysregulation (22\%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE-syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49\% of all patients received immunoglobulin G (IgG) substitution (70\%-subcutaneous; 29\%-intravenous; 1\%-unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.}, language = {en} }