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Purpose: Acute-on-chronic subdural hematoma (acSDH) describes acute bleeding into a chronic subdural hematoma (SDH), after surgery or second trauma. Because seizures are a well-known complication of SDH, associated with substantial morbidity and mortality, we aimed to analyze the incidence of acute symptomatic seizures (ASz), including status epilepticus, and determine the functional outcomes in this specific cohort of patients.
Methods: A retrospective analysis was performed, including patients with acSDH who were admitted to our department between 2010 and 2019. The incidence and timely onset of ASz and status epilepticus were evaluated. Functional outcomes at discharge and at 3–6 month follow-up were analyzed based on the modified Rankin scale.
Results: Of 506 patients with chronic SDH, 29 patients (5.7%) were diagnosed with acSDH. The overall incidence of ASz and status epilepticus were 72.4% and 10.3%, respectively. Favorable outcomes were identified in 11 patients (52.4%) in the ASz group compared with 6 patients (75%) in the non-ASz group. The mortality rate was higher in the ASz group compared with that in the control group (29% vs 0%). At follow-up, favorable outcomes were similar to those observed at discharge (52.4% in the ASz group and 71.4% in the control group). The mortality rate was still higher in the ASz group, at 32% compared with 14% for the control group.
Conclusion: AcSDH has a high risk for ASz, including status epilepticus, and is associated with unfavorable outcomes and high mortality. Thus, prophylactic treatment with antiepileptic drugs should be considered among this specific cohort of patients.
Needlestick injuries: a density-equalizing mapping and socioeconomic analysis of the global research
(2020)
Background: Needlestick injuries have caused a deleterious effect on the physical and mental health of millions of health-care workers over the past decades, being responsible for occupational infections with viruses such as HIV or hepatis C. Despite this heavy burden of disease, no concise studies have been published on the global research landscape so far.
Methods: We used the New Quality and Quantity Indices in Science platform to analyze global NSI research (n = 2987 articles) over the past 115 years using the Web of Science and parameters such as global versus country-specific research activities, semi-qualitative issues, and socioeconomic figures.
Results: Density-equalizing mapping showed that although a total of n = 106 countries participated in NSI research, large parts of Africa and South America were almost invisible regarding global participation in NSI research. Average citation rate (cr) analysis indicated a high rate for Switzerland (cr = 25.1), Italy (cr = 23.5), and Japan (cr = 19.2). Socioeconomic analysis revealed that the UK had the highest quotient QGDP of 0.13 NSI-specific publications per bill. US-$ gross domestic product (GDP), followed by South Africa (QGDP = 0.12). Temporal analysis of HIV versus hepatitis research indicated that NSI-HIV research culminated in the early 1990s, whereas NSI-hepatitis research increased over the observed period from the 1980s until the last decade.
Conclusion: Albeit NSI research activity is generally increasing, the growth is asymmetrical from a global viewpoint. International strategies should be followed that put a focus on NSI in non-industrialized areas of the world.
Due to anticipated postoperative neuropsychological sequelae, patients with gliomas infiltrating the corpus callosum rarely undergo tumor resection and mostly present in a poor neurological state. We aimed at investigating the benefit of glioma resection in the corpus callosum, hypothesizing neuropsychological deficits were mainly caused by tumor presence. Between 01/2017 and 1/2020, 21 patients who underwent glioma resection in the corpus callosum were prospectively enrolled into this study. Neuropsychological function was assessed preoperatively, before discharge and after 6 months. Gross total tumor resection was possible in 15 patients, and in 6 patients subtotal tumor resection with a tumor reduction of 97.7% could be achieved. During a median observation time of 12.6 months 9 patients died from glioblastoma after a median of 17 months. Preoperatively, all cognitive domains were affected in up to two thirds of patients, who presented a median KPS of 100% (range 60–100%). After surgery, the proportion of impaired patients increased in all neurocognitive domains. Most interestingly, after 6 months, significantly fewer patients showed impairments in attention, executive functioning, memory and depression, which are domains considered crucial for everyday functionality. Thus, the results of our study strongly support our hypothesis that in patients with gliomas infiltrating the corpus callosum the benefit of tumor resection might outweigh morbidity.
Purpose: The diagnosis of abusive head trauma (AHT) is complex and neuroimaging plays a crucial role. Our goal was to determine whether non-neuroradiologists with standard neuroradiology knowledge perform as well as neuroradiologists with experience in pediatric neuroimaging in interpreting MRI in cases of presumptive AHT (pAHT).
Methods: Twenty children were retrospectively evaluated. Patients had been diagnosed with pAHT (6 patients), non-abusive head trauma-NAHT (5 patients), metabolic diseases (3 patients), and benign enlargement of the subarachnoid spaces (BESS) (6 patients). The MRI was assessed blindly, i.e., no clinical history was given to the 3 non-neuroradiologists and 3 neuroradiologists from 2 different institutions.
Results: Blindly, neuroradiologists demonstrated higher levels of sensitivity and positive predictive value in the diagnosis of pAHT (89%) than non-neuroradiologists (50%). Neuroradiologists chose correctly pAHT as the most probable diagnosis 16 out of 18 times; in contrast, non-neuroradiologists only chose 9 out of 18 times. In our series, the foremost important misdiagnosis for pAHT was NAHT (neuroradiologists twice and non-neuroradiologists 5 times). Only victims of motor vehicle accidents were blindly misdiagnosed as pAHT. No usual household NAHT was not misdiagnosed as pAHT. Neuroradiologists correctly ruled out pAHT in all cases of metabolic diseases and BESS.
Conclusion: MRI in cases of suspected AHT should be evaluated by neuroradiologists with experience in pediatric neuroimaging. Neuroradiologists looked beyond the subdural hemorrhage (SDH) and were more precise in the assessment of pAHT and its differential diagnosis than non-neuroradiologists were. It seems that non-neuroradiologists mainly assess whether or not a pAHT is present depending on the presence or absence of SDH.
Patients with acute myeloid leukemia (AML) are often exposed to broad-spectrum antibiotics and thus at high risk of Clostridioides difficile infections (CDI). As bacterial infections are a common cause for treatment-related mortality in these patients, we conducted a retrospective study to analyze the incidence of CDI and to evaluate risk factors for CDI in a large uniformly treated AML cohort. A total of 415 AML patients undergoing intensive induction chemotherapy between 2007 and 2019 were included in this retrospective analysis. Patients presenting with diarrhea and positive stool testing for toxin-producing Clostridioides difficile were defined to have CDI. CDI was diagnosed in 37 (8.9%) of 415 AML patients with decreasing CDI rates between 2013 and 2019 versus 2007 to 2012. Days with fever, exposition to carbapenems, and glycopeptides were significantly associated with CDI in AML patients. Clinical endpoints such as length of hospital stay, admission to ICU, response rates, and survival were not adversely affected. We identified febrile episodes and exposition to carbapenems and glycopeptides as risk factors for CDI in AML patients undergoing induction chemotherapy, thereby highlighting the importance of interdisciplinary antibiotic stewardship programs guiding treatment strategies in AML patients with infectious complications to carefully balance risks and benefits of anti-infective agents.
Background: The ability to approximate intra-operative hemoglobin loss with reasonable precision and linearity is prerequisite for determination of a relevant surgical outcome parameter: This information enables comparison of surgical procedures between different techniques, surgeons or hospitals, and supports anticipation of transfusion needs. Different formulas have been proposed, but none of them were validated for accuracy, precision and linearity against a cohort with precisely measured hemoglobin loss and, possibly for that reason, neither has established itself as gold standard. We sought to identify the minimal dataset needed to generate reasonably precise and accurate hemoglobin loss prediction tools and to derive and validate an estimation formula.
Methods: Routinely available clinical and laboratory data from a cohort of 401 healthy individuals with controlled hemoglobin loss between 29 and 233 g were extracted from medical charts. Supervised learning algorithms were applied to identify a minimal data set and to generate and validate a formula for calculation of hemoglobin loss.
Results: Of the classical supervised learning algorithms applied, the linear and Ridge regression models performed at least as well as the more complex models. Most straightforward to analyze and check for robustness, we proceeded with linear regression. Weight, height, sex and hemoglobin concentration before and on the morning after the intervention were sufficient to generate a formula for estimation of hemoglobin loss. The resulting model yields an outstanding R2 of 53.2% with similar precision throughout the entire range of volumes or donor sizes, thereby meaningfully outperforming previously proposed medical models.
Conclusions: The resulting formula will allow objective benchmarking of surgical blood loss, enabling informed decision making as to the need for pre-operative type-and-cross only vs. reservation of packed red cell units, depending on a patient’s anemia tolerance, and thus contributing to resource management.
Purpose: The Masquelet technique for the treatment of large bone defects is a two-stage procedure based on an induced membrane. Compared to mature periosteum, the induced membrane differs significantly. However, both play a crucial role in bone regeneration. As part of a histological and radiological post-evaluation of an earlier project, we analyzed the influence of the granule size of the bone void filler Herafill® on development of periosteum regrowth in a critical size defect.
Methods: We compared three different sizes of Herafill® granules (Heraeus Medical GmbH, Wehrheim) in vivo in a rat femoral critical size defect (10 mm) treated with the induced membrane technique. After 8 weeks healing time, femurs were harvested and taken for histological and radiological analysis.
Results: A significantly increased regrowth of periosteum into the defect was found when small granules were used. Large granules showed significantly increased occurrence of bone capping. Small granules lead to significant increase in callus formation in the vicinity to the membrane.
Conclusion: The size of Herafill® granules has significant impact on the development of periosteal-like structures around the defect using Masquelet’s induced membrane technique. Small granules show significantly increased regrowth of periosteum and improved bone formation adjacent to the induced membrane.
Enhanced LTP of population spikes in the dentate gyrus of mice haploinsufficient for neurobeachin
(2020)
Deletion of the autism candidate molecule neurobeachin (Nbea), a large PH-BEACH-domain containing neuronal protein, has been shown to affect synaptic function by interfering with neurotransmitter receptor targeting and dendritic spine formation. Previous analysis of mice lacking one allele of the Nbea gene identified impaired spatial learning and memory in addition to altered autism-related behaviours. However, no functional data from living heterozygous Nbea mice (Nbea+/−) are available to corroborate the behavioural phenotype. Here, we explored the consequences of Nbea haploinsufficiency on excitation/inhibition balance and synaptic plasticity in the intact hippocampal dentate gyrus of Nbea+/− animals in vivo by electrophysiological recordings. Based on field potential recordings, we show that Nbea+/− mice display enhanced LTP of the granule cell population spike, but no differences in basal synaptic transmission, synapse numbers, short-term plasticity, or network inhibition. These data indicate that Nbea haploinsufficiency causes remarkably specific alterations to granule cell excitability in vivo, which may contribute to the behavioural abnormalities in Nbea+/− mice and to related symptoms in patients.
White matter abnormalities across different epilepsy syndromes in adults: an ENIGMA Epilepsy study
(2019)
The epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre sample of adult epilepsy patients. Diffusion-weighted MRI data were analyzed from 1,069 non-epileptic controls and 1,249 patients: temporal lobe epilepsy with hippocampal sclerosis (N=599), temporal lobe epilepsy with normal MRI (N=275), genetic generalized epilepsy (N=182) and nonlesional extratemporal epilepsy (N=193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fiber tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at p<0.001). Across “all epilepsies” lower fractional anisotropy was observed in most fiber tracts with small to medium effect sizes, especially in the corpus callosum, cingulum and external capsule. Less robust effects were seen with mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippocampal sclerosis in the ipsilateral parahippocampal cingulum and external capsule, with smaller effects across most other tracts. Those with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hippocampal sclerosis. Patients with generalized and extratemporal epilepsies had pronounced differences in fractional anisotropy in the corpus callosum, corona radiata and external capsule, and in mean diffusivity of the anterior corona radiata. Earlier age of seizure onset and longer disease duration were associated with a greater extent of microstructural abnormalities in patients with hippocampal sclerosis. We demonstrate microstructural abnormalities across major association, commissural, and projection fibers in a large multicentre study of epilepsy. Overall, epilepsy patients showed white matter abnormalities in the corpus callosum, cingulum and external capsule, with differing severity across epilepsy syndromes. These data further define the spectrum of white matter abnormalities in common epilepsy syndromes, yielding new insights into pathological substrates that may be used to guide future therapeutic and genetic studies.
Our lives (and deaths) have by now been dominated for two years by COVID-19, a pandemic that has caused hundreds of millions of disease cases, millions of deaths, trillions in economic costs, and major restrictions on our freedom. Here we suggest a novel tool for controlling the COVID-19 pandemic. The key element is a method for a population-scale PCR-based testing, applied on a systematic and repeated basis. For this we have developed a low cost, highly sensitive virus-genome-based test. Using Germany as an example, we demonstrate by using a mathematical model, how useful this strategy could have been in controlling the pandemic. We show using real-world examples how this might be implemented on a mass scale and discuss the feasibility of this approach.
Our lives (and deaths) have been dominated for more than a year by COVID-19, a pandemic that has caused hundreds of millions of disease cases, millions of deaths, trillions in economic costs, and major restrictions on our freedom. We argue that much of this could have been avoided by repeated and systematic population-scale PCR-based testing and targeted quarantine. We describe key elements of the current implementations of such a system and demonstrate (with Germany as an example), that this strategy could have suppressed the pandemic within weeks, eliminating the vast majority of its overall impact in terms of deaths, economic costs and restrictions. It can, however, still play a major role in further reducing the worldwide impact of the current phase of the pandemic, and remain as a key protection against similar dangers in the future.
Predicting adult Attention Deficit Hyperactivity Disorder (ADHD) using vocal acoustic features
(2021)
Background: It is a key concern in psychiatric research to investigate objective measures to support and ultimately improve diagnostic processes. Current gold standard diagnostic procedures for attention deficit hyperactivity disorder (ADHD) are mainly subjective and prone to bias. Objective measures such as neuropsychological measures and EEG markers show limited specificity. Recent studies point to alterations of voice and speech production to reflect psychiatric symptoms also related to ADHD. However, studies investigating voice in large clinical samples allowing for individual-level prediction of ADHD are lacking. The aim of this study was to explore a role of prosodic voice measures as objective marker of ADHD.
Methods: 1005 recordings were analyzed from 387 ADHD patients, 204 healthy controls, and 100 clinical (psychiatric) controls. All participants (age range 18-59 years, mean age 34.4) underwent an extensive diagnostic examination according to gold standard methods and provided speech samples (3 min in total) including free and given speech. Paralinguistic features were calculated, and random forest based classifications were performed using a 10-fold cross-validation with 100 repetitions controlling for age, sex, and education. Association of voice features and ADHD-symptom severity assessed in the clinical interview were analyzed using random forest regressions.
Results and Conclusion ADHD was predicted with AUC = 0.76. The analysis of a non-comorbid sample of ADHD resulted in similar classification performance. Paralinguistic features were associated with ADHD-symptom severity as indicated by random forest regression. In female participants, particularly with age < 32 years, paralinguistic features showed the highest classification performance (AUC = 0.86).
Paralinguistic features based on derivatives of loudness and fundamental frequency seem to be promising candidates for further research into vocal acoustic biomarkers of ADHD. Given the relatively good performance in female participants independent of comorbidity, vocal measures may evolve as a clinically supportive option in the complex diagnostic process in this patient group.
Competing Interest Statement: EA participated and received payments in the national advisory board ADHD of Shire/Takeda. JL is co-founder and CTO of PeakProfiling GmbH. He created audio-features used in this study, that are intellectual property of PeakProfiling GmbH. FH received payments by PeakProfiling GmbH.
Clinical Trial: NCT01104623
Gastroschisis und Omphalozele zählen zu den häufigsten angeborenen Bauchwanddefekten. Dabei wird zwischen einfacher (ohne sekundäre Darmveränderungen) und komplexer (mit sekundären Darmveränderungen) Gastroschisis unterschieden. Bei der Omphalozele ist es wichtig, ob eine Protrusion der Leber vorliegt. Die Therapie beider Fehlbildungen besteht aus der Reposition der Bauchorgane in den Bauchraum und einem operativen Bauchdeckenverschluss in den ersten Lebenstagen.
Daten zu Langzeitverläufen nach dem operativen Bauchdeckenverschluss, insbesondere in Hinblick auf gastrointestinale Komplikationen mit erneutem chirurgischen Interventionsbedarf, sind in der Literatur rar.
Ziel dieser Studie ist es daher, die Inzidenz und die Art von operativen Eingriffen nach dem Bauchdeckenverschluss bei Patienten mit einer Gastroschisis und einer Omphalozele nach einem Bauchdeckenverschluss am eigenen Patientenkollektiv zu untersuchen. Hierzu wurden die Akten aller Patienten mit Gastroschisis und Omphalozele, die in der Klinik für Kinderchirurgie und Kinderurologie des Universitätsklinikums Frankfurt von 2010 bis 2019 behandelt wurden, retrospektiv ausgewertet. Die Inzidenz von Operationen nach Bauchdeckenverschluss wurde anhand der mittleren kumulativen Ein-Jahres-Anzahl an Operationen pro Patienten und der kumulativen Ein-Jahres-Inzidenz der Operationen ermittelt.
Insgesamt wurden 61 Patienten identifiziert. Nach Ausschluss von vier Patienten (Krankenhausverlegung (ein Patient) und Versterben (drei Patienten)) konnten die Verläufe von 33 Patienten mit Gastroschisis (18 mit einfacher und 15 mit komplexer Gastroschisis) und 24 Patienten mit Omphalozele (je zwölf mit und ohne Leberprotrusion) ausgewertet werden.
Bei 23 Patienten mit Gastroschisis und bei 20 Patienten mit Omphalozele kam es innerhalb des ersten Jahres nach Bauchdeckenverschluss zu erneuten Operationen. Das Risiko sich einer erneuten Operation unterziehen zu müssen, war bei Patienten mit komplexer Gastroschisis signifikant höher als bei Patienten mit einfacher Gastroschisis (kumulative Ein-Jahres-Inzidenz: 64,3% vs. 24,4%; p= 0,05). Zwischen den beiden 6 Formen der Omphalozele bestand kein Unterschied in der Inzidenz chirurgischer Eingriffe. Im Median kam es bei Patienten mit Gastroschisis nach 84 Tagen und bei Patienten mit Omphalozele nach 114,5 Tagen zu einer erneuten Operation.
74% der Patienten mit Gastroschisis und 30% der Patienten mit Omphalozele wurden aufgrund einer gastrointestinalen Komplikation operiert. Die Patienten mit komplexer Gastroschisis hatten im Vergleich zu Patienten mit einfacher Gastroschisis ein signifikant erhöhtes Risiko für eine Operation zur Behandlung einer gastrointestinalen Komplikation (kumulative Ein-Jahres-Inzidenz 64,3% vs. 11,1%; p= 0,015). In Bezug auf die Anzahl der Operationen pro Patienten und Jahr hatten die Patienten mit komplexer Gastroschisis und Patienten mit Omphalozele und Leberprotrusion die meisten operativen Eingriffe (kumulative Ein-Jahres-Anzahl 1,664 und 1,417 vs. einfache Gastroschisis (0,326) und Omphalozele ohne Leberprotrusion (0,333)). Dieses Verhältnis spiegelt sich auch in der kumulativen Ein-Jahres-Anzahl an Operationen mit gastrointestinalen Indikationen wider (komplexe Gastroschisis: 1,462 Operationen; Omphalozele mit Leberprotrusion: 0,500 Operationen; einfache Gastroschisis: 0,111 Operationen; Omphalozele ohne Leberprotrusion: keine Operation)
Nach dem Bauchdeckenverschluss kam es zu zwei Todesfällen bei Patienten mit komplexer Gastroschisis und zu drei Todesfällen bei den Patienten mit Omphalozele und Leberprotrusion. Bei den beiden Patienten mit komplexer Gastroschisis lag eine gastrointestinale Ursache vor (Leberversagen, Dünndarmvolvulus). Die Patienten mit der Omphalozele verstarben aufgrund assoziierter kardialer und pulmonaler Erkrankungen. Die Daten zeigen, dass Patienten mit Gastroschisis und Omphalozele im ersten Lebensjahr nach dem Bauchdeckenverschluss ein hohes Risiko für weitere Operationen haben. Patienten mit komplexer Gastroschisis und mit einer Omphalozele und Leberprotrusion haben das größte Risiko für eine erneute Operation nach Bauchdeckenverschluss. Bei Patienten mit einfacher Gastroschisis und Omphalozele ohne Leberprotrusion ist dieses Risiko gering. Die Mehrzahl der Operationen erfolgt aufgrund von gastrointestinalen Ursachen. Nur bei Patienten mit komplexer Gastroschisis tragen gastrointestinale Komplikationen zu einer erhöhten Mortalitätsrate bei. Die Ergebnisse dieser Arbeit können für Aufklärungs- und Beratungsgespräche von Eltern von Kindern mit Gastroschisis und Omphalozele herangezogen werden.
Neuroendokrine Tumoren (NET) sind eine seltene Krankheit mit einem breitgefächerten heterogenen Erscheinungsbild, wodurch sich die Diagnose der Tumoren aus einer Vielzahl aus Gründen häufig um Jahre verzögert (1). In dieser Arbeit analysierten wir einen großen Datensatz in einem tertiären Referenzzentrum (UKF) von 1984-2019, um die Symptomatik vor der Diagnose des Tumors sowie den Zeitraum von der Tumormanifestation bis zur Diagnose weiter zu klären. Für die deskriptiven Analysen kamen SPSS, Cox-Regression und Log-Rank-Test zur Anwendung.
Insgesamt schloss die retrospektive Studie 488 gastroenteropankreastische (GEP)-NET mit 486 Patienten ≥ 18 Jahren ein, wovon knapp mehr als die Hälfte männlich (52,9%) waren. Das mittlere Alter bei Erstdiagnose (ED) betrug 58 Jahre (477/486, 9 unbekannt). Die häufigsten Primärtumorlokalisationen stellten Pankreas (143/488 Patienten) und Dünndarm (145/488 Patienten) dar. Die Mehrheit der NET waren langsam wachsende G1-Tumoren mit einem Ki67 < 3% (155/330). Die Hälfte der Patienten entwickelten im Verlauf Fernmetastasen, wobei die meisten bereits bei der ED vorlagen und insbesondere die Leber als Metastasierungsorgan dominierte. Bei mehr als 60% der Patienten konnten Angaben zur klinischen Symptomatik vor der ED detektiert werden, wovon wiederum mehr als die Hälfte symptomatisch waren. 42% der symptomatischen Patienten zeigten NET-spezifische Symptome (Bauchschmerzen 77/128; 60,2%, Durchfall 51/128; 39,8%, Flush 19/128; 14,8%, Karzinoidsyndrom 8/128; 6,3% Tachykardie 6/128; 4,7%). In der primären bildgebenden Diagnostik dominierten konventionelle Bildgebungen wie Sonographie und Computertomographie (CT), wobei nuklearmedizinische Diagnostik eine Seltenheit darstellte. Mehr als 30% der Tumoren wurden als Zufallsbefunde im Rahmen einer bildgebenden Diagnostik oder Operation diagnostiziert. Die Mehrheit der Patienten stellte sich initial außerhalb unserer Klinik vor, nur etwa 15% wurden innerhalb unserer Klinik insbesondere in der Gastroenterologie vorstellig, wo der NET diagnostiziert wurde.
Die Phase von der Tumormanifestation bis zur ED aller NET betrug im Median 17 Tage. Das Vorhandensein von Fernmetastasen sowie Symptomen führte zu keiner signifikanten Kürzung der Phase und einer schnelleren ED des NET (Median 65,5 vs. 90 Tage, p = 0,4).
The present guidelines comprise relevant aspects of the use of compression therapy with medical compression stockings (MCS), phlebological compression bandages (PCB), and medical adaptive compression systems (MAC) based on an extensive literature search based on the state of scientific knowledge as of December 2018.
These guidelines were prepared by experts within the framework of an electronic consensus process and a consensus conference which took place in Bielefeld, Germany, on September 27, 2018, on the initiative of the German Society of Phlebology (DGP) and the Professional Association of Phlebologists (BVP). The guidelines were adopted by the boards and advisory councils of the DGP and the BVP, and of the participating professional associations, after preparation by the group of experts and extensive debate, on December 31, 2018.
These guidelines do not cover compression therapy with medical thrombosis prophylaxis stockings (MTPS) or with intermittent pneumatic compression (IPC), which are treated in other guidelines (AWMF 003-001, S3; AWMF 037-001, S1).
The recommendations of the AWMF guidelines “Diagnostics and Treatment of Lymphedema” (registration number 058-001) and “Lipedema” (registration number 037-012) shall also be taken into account where appropriate: https://www.awmf.org/uploads/tx_szleitlinien/058-001l_S2k_Diagnostik_und_Therapie_der_Lymphoedeme_2017-05.pdf, https://www.awmf.org/uploads/tx_szleitlinien/037-012l_S1_Lipoedem_2016-01.pdf.
Purpose: Dosimetric treatment planning evaluations concerning patient-adapted moulds for iridium-192 highdose-rate brachytherapy are presented in this report.
Material and methods: Six patients with perinasal skin tumors were treated with individual moulds made of biocompatible epithetic materials with embedded plastic applicators. Treatment plans were optimized with regard to clinical requirements, and dose was calculated using standard water-based TG-43 formalism. In addition, retrospective material-dependent collapsed cone calculations according to TG-186 protocol were evaluated to quantify the limitations of TG-43 protocol for this superficial brachytherapy technique.
Results: The dose-volume parameters D90, V100, and V150 of the planning target volumes (PTVs) for TG-43 dose calculations yielded 92.2% to 102.5%, 75.1% to 93.1%, and 7.4% to 41.7% of the prescribed dose, respectively. The maximum overall dose to the ipsilateral eyeball as the most affected organ at risk (OAR) varied between 8.9 and 36.4 Gy. TG-186 calculations with Hounsfield unit-based density allocation resulted in down by –6.4%, –16.7%, and –30.0% lower average D90, V100, and V150 of the PTVs, with respect to the TG-43 data. The corresponding calculated OAR doses were also lower. The model-based TG-186 dose calculations have considered reduced backscattering due to environmental air as well as the dose-to-medium influenced by the mould materials and tissue composition. The median PTV dose was robust within 0.5% for simulated variations of mould material densities in the range of 1.0 g/cm³ to 1.26 g/cm³ up to 7 mm total mould thickness.
Conclusions: HDR contact BT with individual moulds is a safe modality for routine treatment of perinasal skin tumors. The technique provides good target coverage and OARs’ protection, while being robust against small variances in mould material density. Model-based dose calculations (TG-186) should complement TG-43 dose calculations for verification purpose and quality improvement.
On the current psychotherapeutic situation for persons with pornography use disorder in Germany
(2023)
Background and aims: For the first time, the ICD-11 provides the diagnosis compulsive sexual behavior disorder (CSBD) that can be assigned for pornography use disorder (PUD). This study aimed to estimate the prevalence of PUD and associated consequences in Germany, to identify the psychotherapy demand among likely PUD (lPUD) cases and the treatment supply in different psychotherapeutic settings, to survey psychotherapists' level of expertise regarding PUD, and to identify predictors for psychotherapy demand.
Methods: Four studies were conducted: 1. Online study in the general population (n = 2070; m = 48.9%, f = 50.8%, d = 0.2%), 2. Survey among practicing psychotherapists (n = 983), 3. Survey of psychotherapists in psychotherapeutic outpatient clinics (n = 185), 4. Interviews with psychotherapeutic inpatient clinics (n = 28).
Results: The estimated prevalence of lPUD in the online study was 4.7% and men were 6.3 times more often affected than women. Compared to individuals without PUD, individuals with lPUD more often indicated negative consequences in performance-related areas. Among lPUD cases, 51.2% of men and 64.3% of women were interested in a specialized PUD treatment. Psychotherapists reported 1.2%–2.9% of lPUD cases among their patients. 43.2%–61.5% of psychotherapists stated to be poorly informed about PUD. Only 7% of psychotherapeutic inpatient clinics provided specific treatments to patients with PUD. While, among other factors, negative consequences attributed to lPUD were predictive for psychotherapy demand, weekly pornography consumption, subjective well-being, and religious attachment were not.
Discussion and conclusions: Although PUD occurs quite often in Germany, availability of mental health care services for PUD is poor. Specific PUD treatments are urgently needed.
The capacity of convalescent and vaccine-elicited sera and monoclonal antibodies (mAb) to neutralize SARS-CoV-2 variants is currently of high relevance to assess the protection against infections.
We performed a cell culture-based neutralization assay focusing on authentic SARS-CoV-2 variants B.1.617.1 (Kappa), B.1.617.2 (Delta), B.1.427/B.1.429 (Epsilon), all harboring the spike substitution L452R.
We found that authentic SARS-CoV-2 variants harboring L452R had reduced susceptibility to convalescent and vaccine-elicited sera and mAbs. Compared to B.1, Kappa and Delta showed a reduced neutralization by convalescent sera by a factor of 8.00 and 5.33, respectively, which constitutes a 2-fold greater reduction when compared to Epsilon. BNT2b2 and mRNA1273 vaccine-elicited sera were less effective against Kappa, Delta, and Epsilon compared to B.1. No difference was observed between Kappa and Delta towards vaccine-elicited sera, whereas convalescent sera were 1.5-fold less effective against Delta, respectively. Both B.1.617 variants Kappa (+E484Q) and Delta (+T478K) were less susceptible to either casirivimab or imdevimab.
In conclusion, in contrast to the parallel circulating Kappa variant, the neutralization efficiency of convalescent and vaccine-elicited sera against Delta was moderately reduced. Delta was resistant to imdevimab, which however, might be circumvented by a combination therapy with casirivimab together.
Knowledge is limited as to how prior SARS-CoV-2 infection influences cellular and humoral immunity after booster-vaccination with bivalent BA.4/5-adapted mRNA-vaccines, and whether vaccine-induced immunity correlates with subsequent infection. In this observational study, individuals with prior infection (n=64) showed higher vaccine-induced anti-spike IgG antibodies and neutralizing titers, but the relative increase was significantly higher in non-infected individuals (n=63). In general, both groups showed higher neutralizing activity towards the parental strain than towards Omicron subvariants BA.1, BA.2 and BA.5. In contrast, CD4 or CD8 T-cell levels towards spike from the parental strain and the Omicron subvariants, and cytokine expression profiles were similar irrespective of prior infection. Breakthrough infections occurred more frequently among previously non-infected individuals, who had significantly lower vaccine-induced spike-specific neutralizing activity and CD4 T-cell levels. Thus, the magnitude of vaccine-induced neutralizing activity and specific CD4 T-cells after bivalent vaccination may serve as a correlate for protection in previously non-infected individuals.
The NVX-CoV2373-vaccine has recently been licensed, although data on vaccine-induced humoral and cellular immunity towards the parental strain and variants of concern (VOCs) in comparison to dual-dose mRNA-regimens are limited. In this observational study including 66 participants, we show that NVX-CoV2373-induced IgG-levels were lower than after vaccination with BNT162b2 or mRNA-1273 (n=22 each, p=0.006). Regardless of the vaccine and despite different IgG-levels, neutralizing activity towards VOCs was highest for Delta, followed by BA.2 and BA.1. Interestingly, spike-specific CD8 T-cell levels after NVX-CoV2373-vaccination were significantly lower and were detectable in 3/22 (14%) individuals only. In contrast, spike-specific CD4 T-cells were induced in 18/22 (82%) individuals. However, CD4 T-cell levels were lower (p<0.001), had lower CTLA-4 expression (p<0.0001) and comprised less multifunctional cells co-expressing IFNγ, TNFαα and IL-2 (p=0.0007) as compared to mRNA-vaccinated individuals. Unlike neutralizing antibodies, NVX-CoV2373-induced CD4 T cells cross-reacted to all tested VOCs from Alpha to Omicron, which may hold promise to protect from severe disease.
Background: Leukocyte progenitors derived from clonal hematopoiesis of undetermined potential (CHIP) are associated with increased cardiovascular events. However, the prevalence and functional relevance of CHIP in coronary artery disease (CAD) are unclear, and cells affected by CHIP have not been detected in human atherosclerotic plaques.
Methods: CHIP mutations in blood and tissues were identified by targeted deep-DNA-sequencing (DNAseq: coverage >3,000) and whole-genome-sequencing (WGS: coverage >35). CHIP-mutated leukocytes were visualized in human atherosclerotic plaques by mutaFISHTM. Functional relevance of CHIP mutations was studied by RNAseq.
Results: DNAseq of whole blood from 540 deceased CAD patients of the Munich cardIovaScular StudIes biObaNk (MISSION) identified 253 (46.9%) CHIP mutation carriers (mean age 78.3 years). DNAseq on myocardium, atherosclerotic coronary and carotid arteries detected identical CHIP mutations in 18 out of 25 mutation carriers in tissue DNA. MutaFISHTM visualized individual macrophages carrying DNMT3A CHIP mutations in human atherosclerotic plaques. Studying monocyte-derived macrophages from Stockholm-Tartu Atherosclerosis Reverse Networks Engineering Task (STARNET; n=941) by WGS revealed CHIP mutations in 14.2% (mean age 67.1 years). RNAseq of these macrophages revealed that expression patterns in CHIP mutation carriers differed substantially from those of non-carriers. Moreover, patterns were different depending on the underlying mutations, e.g. those carrying TET2 mutations predominantly displayed upregulated inflammatory signaling whereas ASXL1 mutations showed stronger effects on metabolic pathways.
Conclusions: Deep-DNA-sequencing reveals a high prevalence of CHIP mutations in whole blood of CAD patients. CHIP-affected leukocytes invade plaques in human coronary arteries. RNAseq data obtained from macrophages of CHIP-affected patients suggest that pro-atherosclerotic signaling differs depending on the underlying mutations. Further studies are necessary to understand whether specific pathways affected by CHIP mutations may be targeted for personalized treatment.
Standard reference values of the upper body posture in healthy middle-aged female adults in Germany
(2021)
In order to classify and analyze the parameters of upper body posture, a baseline in form of standard values is demanded. To this date, standard values have only been published for healthy young women. Data for female adults between 51 and 60 years are lacking. 101 symptom-free female volunteers aged 51–60 (55.16 ± 2.89) years. The mean height of the volunteers was 1.66 ± 0.62 m, with a mean body weight of 69.3 ± 11.88 kg and an average BMI of 25.02 ± 4.55 kg/m2. By means of video raster stereography, a 3D-scan of the upper back surface was measured in a habitual standing position. The confidence interval, tolerance range and ICCs were calculated for all parameters. The habitual standing position is almost symmetrical in the frontal plane the most prominent deviation being a slightly more ventral position of the left shoulder blade in comparison to the right. The upper body (spine position) is inclined ventrally with a minor tilt to the left. In the sagittal plane, the kyphosis angle of the thoracic spine is greater than the lordosis angle of the lumbar spine. The pelvis is virtually evenly balanced with deviations from an ideal position falling under the measurement error margin of 1 mm/1°. There were also BMI influenced postural variations in the sagittal plane and shoulder distance. The ICCs are calculated from three repeated measurements and all parameters can be classified as "almost perfect". Deflections from an ideally symmetric spinal alignment in women aged 51–60 years are small-scaled, with a minimal frontal-left inclination and accentuated sigmoidal shape of the spine. Postural parameters presented in this survey allow for comparisons with other studies as well as the evaluation of clinical diagnostics and applications.
Background: The aim is to investigate to what extent the different oral protections compared to the habitual occlusion affect the upper body posture in statics and during taekwondo-specific movement.
Methods: 12 Taekwondoka (5 f/7 m) of German national team were measured by using a 3d back scanner and an ultrasonic distance measuring (upright stand, taekwondo attack and defense movement, two taekwondo specific combinations) in habitual occlusion, with a custom-made and ready-made mouth protection
Results: There are no significant changes in the upper body posture (p ≥ 0.05). Depending on the dynamic measurements, different significant reactions of the spinal position were found while wearing the custom made mouthguard or the ready-made mouthguard according to the conducted movement.
Conclusion: The measured changes in dynamic movements are not clinical relevant. Based on the positive responses from the participants, the custom-made mouth protection can be recommended combined with an individual analysis.
Herz- und Lungenerkrankungen sind weltweit eine der häufigsten Todesursachen. Das Cardio-Pulmonary Institute (CPI) widmet sich der Erforschung dieser Krankheiten auf molekularer Ebene, um innovative Behandlungsmethoden für Patient*innen zu entwickeln. Als interdisziplinäres Forschungsinstitut der Goethe-Universität Frankfurt, der Justus-Liebig-Universität Gießen und des Max-Planck-Instituts für Herz- und Lungenforschung in Bad Nauheim ist das CPI ein einzigartiges Zentrum.
Background: MDM2 inhibitors are under investigation for the treatment of acute myeloid leukaemia (AML) patients in phase III clinical trials. To study resistance formation to MDM2 inhibitors in AML cells, we here established 45 sub-lines of the AML TP53 wild-type cell lines MV4-11 (15 sub-lines), OCI-AML-2 (10 sub-lines), OCI-AML-3 (12 sub-lines), and SIG-M5 (8 sub-lines) with resistance to the MDM2 inhibitor nutlin-3.
Methods: Nutlin-3-resistant sub-lines were established by continuous exposure to stepwise increasing drug concentrations. The TP53 status was determined by next generation sequencing, cell viability was measured by MTT assay, and p53 was depleted using lentiviral vectors encoding shRNA.
Results: All MV4-11 sub-lines harboured the same R248W mutation and all OCI-AML-2 sub-lines the same Y220C mutation, indicating the selection of pre-existing TP53-mutant subpopulations. In concordance, rare alleles harbouring the respective mutations could be detected in the parental MV4-11 and OCI-AML-2 cell lines. The OCI-AML-3 and SIG-M5 sub-lines were characterised by varying TP53 mutations or wild type TP53, indicating the induction of de novo TP53 mutations. Doxorubicin, etoposide, gemcitabine, cytarabine, and fludarabine resistance profiles revealed a noticeable heterogeneity among the sub-lines even of the same parental cell lines. Loss-of-p53 function was not generally associated with decreased sensitivity to cytotoxic drugs.
Conclusion: We introduce a substantial set of models of acquired MDM2 inhibitor resistance in AML. MDM2 inhibitors select, in dependence on the nature of a given AML cell population, pre-existing TP53-mutant subpopulations or induce de novo TP53 mutations. Although loss-of-p53 function has been associated with chemoresistance in AML, nutlin-3-adapted sub-lines displayed in the majority of experiments similar or increased drug sensitivity compared to the respective parental cells. Hence, chemotherapy may remain an option for AML patients after MDM2 inhibitor therapy failure. Even sub-lines of the same parental cancer cell line displayed considerable heterogeneity in their response to other anti-cancer drugs, indicating the need for the detailed understanding and monitoring of the evolutionary processes in cancer cell populations in response to therapy as part of future individualised treatment protocols.
Recent findings in permanent cell lines suggested that SARS-CoV-2 Omicron BA.1 induces a stronger interferon response than Delta. Here, we show that BA.1 and BA.5 but not Delta induce an antiviral state in air-liquid interface (ALI) cultures of primary human bronchial epithelial (HBE) cells and primary human monocytes. Both Omicron subvariants caused the production of biologically active type I (α/β) and III (λ) interferons and protected cells from super-infection with influenza A viruses. Notably, abortive Omicron infection of monocytes was sufficient to protect monocytes from influenza A virus infection. Interestingly, while influenza-like illnesses surged during the Delta wave in England, their spread rapidly declined upon the emergence of Omicron. Mechanistically, Omicron-induced interferon signalling was mediated via double-stranded RNA recognition by MDA5, as MDA5 knock-out prevented it. The JAK/ STAT inhibitor baricitinib inhibited the Omicron-mediated antiviral response, suggesting it is caused by MDA5-mediated interferon production, which activates interferon receptors that then trigger JAK/ STAT signalling. In conclusion, our study 1) demonstrates that only Omicron but not Delta induces a substantial interferon response in physiologically relevant models, 2) shows that Omicron infection protects cells from influenza A virus super-infection, and 3) indicates that BA.1 and BA.5 induce comparable antiviral states.
The COVID-19 pandemic and the associated prevention measures did not only impact on the transmission of COVID-19 but also on the spread of other infectious diseases in an unprecedented natural experiment. Here, we analysed the transmission patterns of 22 different infectious diseases during the COVID-19 pandemic in England. Our results show that the COVID-19 prevention measures generally reduced the spread of pathogens that are transmitted via the air and the faecal-oral route. Moreover, the COVID-19 prevention measures resulted in the sustained suppression of vaccine-preventable infectious diseases also after the removal of restrictions, while non-vaccine preventable diseases displayed a rapid rebound. Despite concerns that a lack of exposure to common pathogens may affect population immunity and result in large outbreaks by various pathogens post-COVID-19, only four of the 22 investigated diseases and disease groups displayed higher post-than pre-pandemic levels without an obvious causative relationship. Notably, this included chickenpox for which an effective vaccine is available but not used in the UK, which provides strong evidence supporting the inclusion of the chickenpox vaccination into the routine vaccination schedule in the UK. In conclusion, our findings provide unique, novel insights into the impact of non-pharmaceutical interventions on the spread of a broad range of infectious diseases.
Visual processing begins at the first synapse of the visual system. In the mouse retina, three different types of photoreceptors provide input to 14 bipolar cell (BC) types. Classically, most BC types are thought to contact all cones within their dendritic field; ON BCs would contact cones exclusively via so-called invaginating synapses, while OFF BCs would form basal synapses. By mining publically available electron microscopy data, we discovered interesting violations of these rules of outer retinal connectivity: ON BC type X contacted only ~20% of the cones in its dendritic field and made mostly atypical non-invaginating contacts. Types 5T, 5O and 8 also contacted fewer cones than expected. In addition, we found that rod BCs received input from cones, providing anatomical evidence that rod and cone pathways are interconnected in both directions. This suggests that the organization of the outer plexiform layer is more complex than classically thought.
In the mouse retina, three different types of photoreceptors provide input to 14 bipolar cell (BC) types. Classically, most BC types are thought to contact all cones within their dendritic field; ON-BCs would contact cones exclusively via so-called invaginating synapses, while OFF-BCs would form basal synapses. By mining publically available electron microscopy data, we discovered interesting violations of these rules of outer retinal connectivity: ON-BC type X contacted only ~20% of the cones in its dendritic field and made mostly atypical non-invaginating contacts. Types 5T, 5O and 8 also contacted fewer cones than expected. In addition, we found that rod BCs received input from cones, providing anatomical evidence that rod and cone pathways are interconnected in both directions. This suggests that the organization of the outer plexiform layer is more complex than classically thought.
Individual differences in perception are widespread. Considering inter-individual variability, synesthetes experience stable additional sensations; schizophrenia patients suffer perceptual deficits in, eg, perceptual organization (alongside hallucinations and delusions). Is there a unifying principle explaining inter-individual variability in perception? There is good reason to believe perceptual experience results from inferential processes whereby sensory evidence is weighted by prior knowledge about the world. Perceptual variability may result from different precision weighting of sensory evidence and prior knowledge. We tested this hypothesis by comparing visibility thresholds in a perceptual hysteresis task across medicated schizophrenia patients (N = 20), synesthetes (N = 20), and controls (N = 26). Participants rated the subjective visibility of stimuli embedded in noise while we parametrically manipulated the availability of sensory evidence. Additionally, precise long-term priors in synesthetes were leveraged by presenting either synesthesia-inducing or neutral stimuli. Schizophrenia patients showed increased visibility thresholds, consistent with overreliance on sensory evidence. In contrast, synesthetes exhibited lowered thresholds exclusively for synesthesia-inducing stimuli suggesting high-precision long-term priors. Additionally, in both synesthetes and schizophrenia patients explicit, short-term priors—introduced during the hysteresis experiment—lowered thresholds but did not normalize perception. Our results imply that perceptual variability might result from differences in the precision afforded to prior beliefs and sensory evidence, respectively.
Sowohl die Lebenserwartung als auch die Prävalenz HIV-infizierter Patient*innen ist stetig ansteigend,aufgrund der HAART und durch verbesserte diagnostische Methoden. Nicht-AIDS-definierenden Erkrankungen sind heutzutage die führenden Todesursachen. Durch verzögerte Diagnosestellung und zurückhaltenden Therapien gynäkologischer Malignome ist die Prognose im Vergleich zur Normalbevölkerung schlechter.
In dieser retrospektiven Fall-Kontroll-Studie des Universitätsklinikums Frankfurt am Mains wurden die Therapie und das Outcome gynäkologischer Malignome von 23 HIV-infizierten Patientinnen aus den Jahren 2009-2019 mit einer Kontrollgruppe aus dem gynäkologischen Krebszentrum der Klinik Essen Mitte verglichen, um herauszufinden, inwiefern eine HIV-Infektion das Outcome der Patientinnen beeinflusst.
Das gynäkologische Malignom, dominierend das Zervixkarzinom, trat durchschnittlich ein Jahrzehnt nach der HIV-Diagnose auf. Im Unterschied zu anderen Studien, ist unser Kollektiv überwiegend hellhäutig. Ein bekannter Drogenabusus ist häufig und zusammenhängend mit weiteren Koinfektionen.
Die HIV-Erkrankung ist bei mehr als der Hälfte der Patientinnen bereits fortgeschritten, jedoch ließ sich kein Zusammenhang zwischen dem Auftreten gynäkologischer Malignome und einer CD4-Zellzahl <500 CD4-Zellen/µl nachweisen. Die antiretrovirale Therapie entsprach größtenteils nicht den aktuellen Leitlinien.
Bis auf fünf Frauen wurden alle Frauen leitliniengerecht therapiert. Eine Korrelation zwischen der Therapie und der Tumorentität, der CD4-Zellzahl, dem Alter oder dem Stadium des Malignoms konnte nicht gezeigt werden.
Insgesamt liegt die 5-Jahresüberlebensrate der Kohorte bei 74.8%. Eine nicht leitliniengerechte Therapie ist nicht direkt mit einem schlechteren Outcome verbunden, jedoch mit einem weitaus kürzeren Follow-Up-Zeitraum von durchschnittlich 0.22 Jahren im Vergleich zu 4.85 Jahren bei leitlinienkonform therapierten Patientinnen. Es liegt ein statistisch signifikanter Unterschied zwischen der Kontrollgruppe und unserer Kohorte vor, sodass angenommen werden kann, dass bei Vorliegen einer HIV-Infektion die Therapie des gynäkologischen Malignoms häufiger nicht leitliniengerecht ist.
Bislang existieren nur wenige Studien, die die Therapie und das Outcome gynäkologischer Malignome bei HIV-infizierten Patientinnen untersuchen. Die Interaktion einer ART mit antineoplastischen Medikamenten und die Anwendung von Checkpointinhibitoren und einer „targeted therapy“ sollten Gegenstand weiterer Untersuchungen sein. Dafür sollten HIV-Patientinnen in Therapiestudien inkludiert werden, sodass geeignete Leitlinien erarbeitet werden können.
Background Reward processing has been proposed to underpin atypical social behavior, a core feature of autism spectrum disorder (ASD). However, previous neuroimaging studies have yielded inconsistent results regarding the specificity of atypicalities for social rewards in ASD. Utilizing a large sample, we aimed to assess altered reward processing in response to reward type (social, monetary) and reward phase (anticipation, delivery) in ASD.
Methods Functional magnetic resonance imaging during social and monetary reward anticipation and delivery was performed in 212 individuals with ASD (7.6-30.5 years) and 181 typically developing (TD) participants (7.6-30.8 years).
Results Across social and monetary reward anticipation, whole-brain analyses (p<0.05, family-wise error-corrected) showed hypoactivation of the right ventral striatum (VS) in ASD. Further, region of interest (ROI) analysis across both reward types yielded hypoactivation in ASD in both the left and right VS. Across delivery of social and monetary reward, hyperactivation of the VS in individuals with ASD did not survive correction for multiple comparisons. Reward type by diagnostic group interactions, and a dimensional analysis of autism trait scores were not significant during anticipation or delivery. Levels of attention-deficit/hyperactivity disorder (ADHD) symptoms did not affect reward processing in ASD.
Conclusions Our results do not support current theories linking atypical social interaction in ASD to specific alterations in processing of social rewards. Instead, they point towards a generalized hypoactivity of VS in ASD during anticipation of both social and monetary rewards. We suggest that this indicates attenuated subjective reward value in ASD independent of social content and ADHD symptoms.
Background: Autism Spectrum Disorder (henceforth ‘autism’) is a highly heterogeneous neurodevelopmental condition with few effective treatments for core and associated features. To make progress we need to both identify and validate neural markers that help to parse heterogeneity to tailor therapies to specific neurobiological profiles. Atypical hemispheric lateralization is a stable feature across studies in autism, however its potential of lateralization as a neural stratification marker has not been widely examined.
Methods: In order to dissect heterogeneity in lateralization in autism, we used the large EU-AIMS Longitudinal European Autism Project dataset comprising 352 individuals with autism and 233 neurotypical (NT) controls as well as a replication dataset from ABIDE (513 autism, 691 NT) using a promising approach that moves beyond mean-group comparisons. We derived grey matter voxelwise laterality values for each subject and modelled individual deviations from the normative pattern of brain laterality across age using normative modeling.
Results: Results showed that individuals with autism had highly individualized patterns of both extreme right- and leftward deviations, particularly in language-, motor- and visuospatial regions, associated with symptom severity. Language delay (LD) explained most variance in extreme rightward patterns, whereas core autism symptom severity explained most variance in extreme leftward patterns. Follow-up analyses showed that a stepwise pattern emerged with individuals with autism with LD showing more pronounced rightward deviations than autism individuals without LD.
Conclusion: Our analyses corroborate the need for novel (dimensional) approaches to delineate the heterogeneous neuroanatomy in autism, and indicate atypical lateralization may constitute a neurophenotype for clinically meaningful stratification in autism.
Background: Marked sex differences in autism prevalence accentuate the need to understand the role of biological sex-related factors in autism. Efforts to unravel sex differences in the brain organization of autism have, however, been challenged by the limited availability of female data.
Methods: We addressed this gap by using a large sample of males and females with autism and neurotypical (NT) control individuals (ABIDE; Autism: 362 males, 82 females; NT: 409 males, 166 females; 7-18 years). Discovery analyses examined main effects of diagnosis, sex and their interaction across five resting-state fMRI (R-fMRI) metrics (voxel-level Z > 3.1, cluster-level P < 0.01, gaussian random field corrected). Secondary analyses assessed the robustness of the results to different pre-processing approaches and their replicability in two independent samples: the EU-AIMS Longitudinal European Autism Project (LEAP) and the Gender Explorations of Neurogenetics and Development to Advance Autism Research (GENDAAR).
Results: Discovery analyses in ABIDE revealed significant main effects across the intrinsic functional connectivity (iFC) of the posterior cingulate cortex, regional homogeneity and voxel-mirrored homotopic connectivity (VMHC) in several cortical regions, largely converging in the default network midline. Sex-by-diagnosis interactions were confined to the dorsolateral occipital cortex, with reduced VMHC in females with autism. All findings were robust to different pre-processing steps. Replicability in independent samples varied by R-fMRI measures and effects with the targeted sex-by-diagnosis interaction being replicated in the larger of the two replication samples – EU-AIMS LEAP.
Limitations: Given the lack of a priori harmonization among the discovery and replication datasets available to date, sample-related variation remained and may have affected replicability.
Conclusions: Atypical cross-hemispheric interactions are neurobiologically relevant to autism. They likely result from the combination of sex-dependent and sex-independent factors with a differential effect across functional cortical networks. Systematic assessments of the factors contributing to replicability are needed and necessitate coordinated large-scale data collection across studies.
Competing Interest Statement: ADM receives royalties from the publication of the Italian version of the Social Responsiveness Scale Child Version by Organization Speciali, Italy. JKB has been a consultant to, advisory board member of, and a speaker for Takeda/Shire, Medice, Roche, and Servier. He is not an employee of any of these companies and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, or royalties. CFB is director and shareholder in SBGneuro Ltd. TC has received consultancy from Roche and Servier and received book royalties from Guildford Press and Sage. DM has been a consultant to, and advisory board member, for Roche and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. TB served in an advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Shire, and Infectopharm. He received conference support or speakers fee by Lilly, Medice, and Shire. He received royalties from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press; the present work is unrelated to these relationships. JT is a consultant to Roche. The remaining authors declare no competing interests.
Individual differences in perception are widespread. Considering inter-individual variability, synesthetes experience stable additional sensations; schizophrenia patients suffer perceptual deficits in e.g. perceptual organization (alongside hallucinations and delusions). Is there a unifying principle explaining inter-individual variability in perception? There is good reason to believe perceptual experience results from inferential processes whereby sensory evidence is weighted by prior knowledge about the world. Different perceptual phenotypes may result from different precision weighting of sensory evidence and prior knowledge. We tested this hypothesis by comparing visibility thresholds in a perceptual hysteresis task across medicated schizophrenia patients, synesthetes, and controls. Participants rated the subjective visibility of stimuli embedded in noise while we parametrically manipulated the availability of sensory evidence. Additionally, precise long-term priors in synesthetes were leveraged by presenting either synesthesia-inducing or neutral stimuli. Schizophrenia patients showed increased visibility thresholds, consistent with overreliance on sensory evidence. In contrast, synesthetes exhibited lowered thresholds exclusively for synesthesia-inducing stimuli suggesting high-precision long-term priors. Additionally, in both synesthetes and schizophrenia patients explicit, short-term priors – introduced during the hysteresis experiment – lowered thresholds but did not normalize perception. Our results imply that distinct perceptual phenotypes might result from differences in the precision afforded to prior beliefs and sensory evidence, respectively.
Electrocardiograms (ECG) record the heart activity and are the most common and reliable method to detect cardiac arrhythmias, such as atrial fibrillation (AFib). Lately, many commercially available devices such as smartwatches are offering ECG monitoring. Therefore, there is increasing demand for designing deep learning models with the perspective to be physically implemented on these small portable devices with limited energy supply. In this paper, a workflow for the design of small, energy-efficient recurrent convolutional neural network (RCNN) architecture for AFib detection is proposed. However, the approach can be well generalized to every type of long time series. In contrast to previous studies, that demand thousands of additional network neurons and millions of extra model parameters, the logical steps for the generation of a CNN with only 114 trainable parameters are described. The model consists of a small segmented CNN in combination with an optimal energy classifier. The architectural decisions are made by using the energy consumption as a metric in an equally important way as the accuracy. The optimization steps are focused on the software which can be embedded afterwards on a physical chip. Finally, a comparison with some previous relevant studies suggests that the widely used huge CNNs for similar tasks are mostly redundant and unessentially computationally expensive.
Electrocardiograms (ECG) record the heart activity and are the most common and reliable method to detect cardiac arrhythmias, such as atrial fibrillation (AFib). Lately, many commercially available devices such as smartwatches are offering ECG monitoring. Therefore, there is increasing demand for designing deep learning models with the perspective to be physically implemented on these small portable devices with limited energy supply. In this paper, a workflow for the design of small, energy-efficient recurrent convolutional neural network (RCNN) architecture for AFib detection is proposed. However, the approach can be well generalized to every type of long time series. In contrast to previous studies, that demand thousands of additional network neurons and millions of extra model parameters, the logical steps for the generation of a CNN with only 114 trainable parameters are described. The model consists of a small segmented CNN in combination with an optimal energy classifier. The architectural decisions are made by using the energy consumption as a metric in an equally important way as the accuracy. The optimisation steps are focused on the software which can be embedded afterwards on a physical chip. Finally, a comparison with some previous relevant studies suggests that the widely used huge CNNs for similar tasks are mostly redundant and unessentially computationally expensive.
Das Verständnis von Tumorerkrankungen wurde durch neue technologische und ökonomische Verbesserungen für die Next-Generation-Sequencing Analyse (NGS) gefördert. Die Komplexität der Interpretation genomischer Daten erschwert jedoch die Anwendung von NGS-Analysen im klinischen Kontext. Die Herausforderung besteht darin bei stetig wachsendem medizinischem Wissen dieses im klinischen Kontext zu interpretieren und eine personalisierte Therapieempfehlung abzugeben. Einen ressourcensparenden Ansatz können KI-unterstützende Software-Programme bieten, welche die genomischen Varianten mit der aktuellen Literatur vergleichen, eine Bewertung der Therapieoptionen geben und klinische Studien empfehlen können. In dieser retrospektiven Arbeit wurden Patient:innen mit metastasiertem Brustkrebs (n=77) mittels gezielter NGS-Analyse anhand von sogenannten Genpanels mit 126 bzw. 540 krebsrelevanten Genen im Zeitraum von 01/2019-02/2022 untersucht. Mit Hilfe von bioinformatischen Methoden wurden patientenspezifische genomische Veränderungen mit Behandlungsoptionen abgeglichen. Diese Methoden stützen sich vollständig auf öffentliche Datenbanken über somatische Varianten mit prädiktiver Evidenz für das Ansprechen auf bestimmte Medikamente. Diese Versorgungsforschung einer repräsentativen Kohorte des Universitätsklinikums Frankfurt in Kooperation mit Regionalverbund OncoNet Rhein-Main wurden systematisch ausgewertet inklusive der Bedeutung genomischer Varianten. Das OncoNet Rhein-Main ist eine Kooperation aus führenden onkologischen Zentren und Praxen im Rhein-Main-Gebiet, welche sich als Netzwerk der Aufgabe angenommen haben Patient:innen optimal therapeutisch zu versorgen. Für 51% (39/77) der Patient:innen konnte mindestens eine gezielte Therapieoption mit einem effektivem Biomarker im gleichen Tumortyp gemäß Zulassung der Europäischen Arzneimittelbehörde (EMA) gefunden werden.
Bei 12/77 (16%) wurde mindestens eine Alteration mit einem effektivem Biomarker und einer OFF-Label Therapieoption gefunden. Bei 30% der Patient:innen wurden Veränderungen in optionalen Biomarkern gefunden, welche Resistenzmechanismen erklären. Die umfassende molekulare Analyse von Patient:innen mit fortgeschrittenem Brustkrebs erlaubt die Behandlungsoption zu verbessern und ermöglicht durch die Analyse von bekannten Resistenzmarkern auch den klinischen Verlauf besser zu verstehen. Die interdisziplinäre Besprechung der Befunde im molekularem Tumorboard ist im Hinblick auf kontinuierliches Lernen aller Beteiligten sowie zur Qualitätssicherung eine entscheidende obligate Maßnahme.
We studied oscillatory mechanisms of memory formation in 48 younger and 51 older adults in an intentional associative memory task with cued recall. While older adults showed lower memory performance than young adults, we found subsequent memory effects (SME) in alpha/beta and theta frequency bands in both age groups. Using logistic mixed effects models, we investigated whether interindividual differences in structural integrity of key memory regions could account for interindividual differences in the strength of the SME. Structural integrity of inferior frontal gyrus (IFG) and hippocampus was reduced in older adults. SME in the alpha/beta band were modulated by the cortical thickness of IFG, in line with its hypothesized role for deep semantic elaboration. Importantly, this structure–function relationship did not differ by age group. However, older adults were more frequently represented among the participants with low cortical thickness and consequently weaker SME in the alpha band. Thus, our results suggest that differences in the structural integrity of the IFG contribute not only to interindividual, but also to age differences in memory formation.
Background: Peanuts are a member of the legume family (botanical family Leguminosae) and peanut allergies are the most common cause of food anaphylaxis in many countries. The prevalence of peanut allergy is increasing.
Methods: Experts from Germany and Austria performed a standardized literature search and published their consensus recommendations in a White Paper on Peanut Allergy, which this care pathway is based upon, thus, providing a comprehensive diagnosis and treatment algorithm.
Results: The most important diagnostic key elements include a detailed clinical medical history, evidence of peanut-specific sensitization by means of skin prick testing and/or in vitro determination of the peanut (extract)-specific IgE and/or the molecular component diagnostics (most important Ara h 2-specific IgE, sometimes also Ara h1-, 3-, 6-, 8- and 9-specific IgE) as well as the gold standard, the double-blind, placebo-controlled food challenge. The diagnostic algorithms were created for the following constellations: Suspected primary peanut allergy with a clear history of systemic immediate-type reaction, suspected primary peanut allergy with questionable symptoms, suspected secondary (possibly pollen-associated) peanut allergy with a history of solely oropharyngeal symptoms and incidental finding of sensitization and no peanut ingestion so far.
Conclusions: After established diagnosis the standard of care is counseling to avoid peanut contact and prescription of emergency medications (oral antihistamines, oral steroids, inhaled β2-agonists, injectable intramuscular epinephrine) as needed. Instruction on the use of these emergency medications should be provided. A preparation for oral immunotherapy (OIT) for 4 to 17 years old peanut allergic children/ adolescents has been recently approved by the regulatory authorities. OIT for peanut allergy shows high efficacy and an acceptable safety profile, improves quality of life, and health economic aspects. Thus it offers a therapeutic option for peanut allergic children and adolescents.
The current management of a primary IgE-mediated peanut allergy consists of the two basic pillars “exposure prophylaxis” with avoidance of the allergen and “emergency therapy” with short-term treatment of an acute allergic reaction after accidental ingestion. Accidental reactions are common despite attempted avoidance. The severity of an allergic or even anaphylactic reaction after accidental ingestion is difficult to assess prior to reaction. In addition, reaction thresholds may vary depending on the accompanying augmentation factor. Therefore, every peanut allergic patient should receive individual dietary counseling as well as instructions for the use of the emergency kit and a structured patient education program (anaphylaxis group training), if necessary. For the first time, since fall 2021 a causal treatment option with a drug for oral immunotherapy will now be available for 4‑ to 17-year-old peanut-allergic children and adolescents. The oral immunotherapy with peanut protein as defatted powder of Arachis hypogaea L., semen (peanuts) leads to desensitization with a good efficacy record and an acceptable safety profile. Other treatment options with different therapeutic approaches are also under development and will probably expand the range for treatment in the coming years.
Based on Eysenck’s pioneering work, CNS arousal has long been considered an encouraging biological candidate that may explain individual differences in human personality. Yet, results from empirical studies remained inconclusive. Notably, the vast majority of published results have been derived from small samples, and EEG alpha power has usually served as exclusive indicator for CNS arousal. In this study, we selected N = 468 individuals of the LIFE-Adult cohort and investigated the associations between the Big Five personality traits and CNS arousal by using the low-resolution electromagnetic tomography-based analysis tool VIGALL. Our analyses revealed that subjects who reported higher levels of extraversion and openness to experience, respectively, exhibited lower levels of CNS arousal in the resting state. Bayesian and frequentist analysis results were especially convincing for openness to experience. Among the lower-order personality traits, we obtained strongest evidence for neuroticism facet ‘impulsivity’ and reduced CNS arousal. We regard these findings as well in line with the postulations of Eysenck and Zuckerman and consistent with the assumptions of the ‘arousal regulation model’. Our results also agree with meta-analytically derived effect sizes in the field of individual differences research, highlighting the need for large studies with at least several hundreds of subjects.
Introduction: In recent years, resource-saving handling of allogeneic blood products and a reduction of transfusion rates in adults has been observed. However, comparable published national data for transfusion practices in pediatric patients are currently not available. In this study, the transfusion rates for children and adolescents were analyzed based on data from the Federal Statistical Office of Germany during the past 2 decades. Methods: Data were queried via the database of the Federal Statistical Office (Destasis). The period covered was from 2005 to 2018, and those in the sample group were children and adolescents aged 0–17 years receiving inpatient care. Operation and procedure codes (OPS) for transfusions, procedures, or interventions with increased transfusion risk were queried and evaluated in detail. Results: In Germany, 0.9% of the children and adolescents treated in hospital received a transfusion in 2018. A reduction in transfusion rates from 1.02% (2005) to 0.9% (2018) was observed for the total collective of children and adolescents receiving inpatient care. Increases in transfusion rates were recorded for 1- to 4- (1.41–1.45%) and 5- to 10-year-olds (1.24–1.33%). Children under 1 year of age were most frequently transfused (in 2018, 40.2% of the children were cared for in hospital). Transfusion-associated procedures such as chemotherapy or machine ventilation and respiratory support for newborns and infants are on the rise. Conclusion: Transfusion rates are declining in children and adolescents, but the reasons for increases in transfusion rates in other groups are unclear. Prospective studies to evaluate transfusion rates and triggers in children are urgently needed.
Background: Plasma transfusions are most commonly used therapeutically for bleeding or prophylactically in non-bleeding patients prior to invasive procedures or surgery. Although plasma transfusions generally seem to decline, plasma usage for indications that lack evidence of efficacy prevail. Summary: There is wide international, interinstitutional, and interindividual variance regarding the compliance with guidelines based on published references, supported by appropriate testing. There is furthermore a profound lack of evidence from randomized controlled trials comparing the effect of plasma transfusion with that of other therapeutic interventions for most indications, including massive bleeding. The expected benefit of a plasma transfusion needs to be balanced carefully against the associated risk of adverse events. In light of the heterogeneous nature of bleeding conditions and their rapid evolvement over time, fibrinogen and factor concentrate therapy, directed at specific phases of coagulation identified by alternative laboratory assays, may offer advantages over conventional blood product ratio-driven resuscitation. However, their outcome benefit has not been demonstrated in well-powered prospective trials. This systematic review will detail the current evidence base for plasma transfusion in adult surgical patients.
Based on Eysenck’s biopsychological trait theory, brain arousal has long been considered to explain individual differences in human personality. Yet, results from empirical studies remained inconclusive. However, most published results have been derived from small samples and, despite inherent limitations, EEG alpha power has usually served as an exclusive indicator for brain arousal. To overcome these problems, we here selected N = 468 individuals of the LIFE-Adult cohort and investigated the associations between the Big Five personality traits and brain arousal by using the validated EEG- and EOG-based analysis tool VIGALL. Our analyses revealed that participants who reported higher levels of extraversion and openness to experience, respectively, exhibited lower levels of brain arousal in the resting state. Bayesian and frequentist analysis results were especially convincing for openness to experience. Among the lower-order personality traits, we obtained the strongest evidence for neuroticism facet ‘impulsivity’ and reduced brain arousal. In line with this, both impulsivity and openness have previously been conceptualized as aspects of extraversion. We regard our findings as well in line with the postulations of Eysenck and consistent with the recently proposed ‘arousal regulation model’. Our results also agree with meta-analytically derived effect sizes in the field of individual differences research, highlighting the need for large (collaborative) studies.
Eine Erkrankung zählt in der Europäischen Union zu den Seltenen Erkrankungen (SE), wenn diese nicht mehr als 5 von 10.000 Menschen betrifft. Derzeit existiert mit mehr als 6000 SE eine sowohl große als auch heterogene Menge an unterschiedlichen Krankheitsbilder, die in ihrer Symptomatik komplex, vielschichtig und damit im medizinischen Alltag schwierig einzuordnen sind. Dies erschwert Diagnosefindung und Behandlung sowie das Auffinden eines passenden Ansprechpartners, da es nur wenige Experten für jede einzelne SE gibt. Der medizinische Versorgungsatlas für Seltene Erkrankungen www.se-atlas.de ermöglicht anhand von Erkrankungsnamen die Suche nach Versorgungseinrichtungen und Selbsthilfeorganisationen zu bestimmten SE und stellt die Suchergebnisse geografisch dar. Ebenso gibt er einen Überblick über alle deutschen Zentren für SE, die eine Anlaufstelle für betroffene Personen mit unklarer Diagnose darstellen. Der se-atlas dient als Kompass durch die heterogene Menge an Informationen über Versorgungseinrichtungen für SE und stellt niederschwellig Informationen für eine breite Nutzergruppe von Betroffenen bis hin zu Mitgliedern des medizinischen Versorgungsteams bereit.
The unicellular ciliate Paramecium contains a large vegetative macronucleus with several unusual characteristics including an extremely high coding density and high polyploidy. As macronculear chromatin is devoid of heterochromatin our study characterizes the functional epigenomic organisation necessary for gene regulation and proper PolII activity. Histone marks (H3K4me3, H3K9ac, H3K27me3) revealed no narrow peaks but broad domains along gene bodies, whereas intergenic regions were devoid of nucleosomes. Our data implicates H3K4me3 levels inside ORFs to be the main factor to associate with gene expression and H3K27me3 appears to occur as a bistable domain with H3K4me3 in plastic genes. Surprisingly, silent and lowly expressed genes show low nucleosome occupancy suggesting that gene inactivation does not involve increased nucleosome occupancy and chromatin condensation. Due to a high occupancy of Pol II along highly expressed ORFs, transcriptional elongation appears to be quite different to other species. This is supported by missing heptameric repeats in the C-terminal domain of Pol II and a divergent elongation system. Our data implies that unoccupied DNA is the default state, whereas gene activation requires nucleosome recruitment together with broad domains of H3K4me3. This could represent a buffer for paused Pol II along ORFs in absence of elongation factors of higher eukaryotes.
Long non-coding RNAs (lncRNAs) can act as regulatory RNAs which, by altering the expression of target genes, impact on the cellular phenotype and cardiovascular disease development. Endothelial lncRNAs and their vascular functions are largely undefined. Deep RNA-Seq and FANTOM5 CAGE analysis revealed the lncRNA LINC00607 to be highly enriched in human endothelial cells. LINC00607 was induced in response to hypoxia, arteriosclerosis regression in non-human primates and also in response to propranolol used to induce regression of human arteriovenous malformations. siRNA knockdown or CRISPR/Cas9 knockout of LINC00607 attenuated VEGF-A-induced angiogenic sprouting. LINC00607 knockout in endothelial cells also integrated less into newly formed vascular networks in an in vivo assay in SCID mice. Overexpression of LINC00607 in CRISPR knockout cells restored normal endothelial function. RNA- and ATAC-Seq after LINC00607 knockout revealed changes in the transcription of endothelial gene sets linked to the endothelial phenotype and in chromatin accessibility around ERG-binding sites. Mechanistically, LINC00607 interacted with the SWI/SNF chromatin remodeling protein BRG1. CRISPR/Cas9-mediated knockout of BRG1 in HUVEC followed by CUT&RUN revealed that BRG1 is required to secure a stable chromatin state, mainly on ERG-binding sites. In conclusion, LINC00607 is an endothelial-enriched lncRNA that maintains ERG target gene transcription by interacting with the chromatin remodeler BRG1.
Aims: Chronic pressure or volume overload induce concentric vs. eccentric left ventricular (LV) remodelling, respectively. Previous studies suggest that distinct signalling pathways are involved in these responses. NADPH oxidase-4 (Nox4) is a reactive oxygen species-generating enzyme that can limit detrimental cardiac remodelling in response to pressure overload. This study aimed to assess its role in volume overload-induced remodelling.
Methods and results: We compared the responses to creation of an aortocaval fistula (Shunt) to induce volume overload in Nox4-null mice (Nox4−/−) vs. wild-type (WT) littermates. Induction of Shunt resulted in a significant increase in cardiac Nox4 mRNA and protein levels in WT mice as compared to Sham controls. Nox4−/− mice developed less eccentric LV remodelling than WT mice (echocardiographic relative wall thickness: 0.30 vs. 0.27, P < 0.05), with less LV hypertrophy at organ level (increase in LV weight/tibia length ratio of 25% vs. 43%, P < 0.01) and cellular level (cardiomyocyte cross-sectional area: 323 µm2 vs. 379 μm2, P < 0.01). LV ejection fraction, foetal gene expression, interstitial fibrosis, myocardial capillary density, and levels of myocyte apoptosis after Shunt were similar in the two genotypes. Myocardial phospho-Akt levels were increased after induction of Shunt in WT mice, whereas levels decreased in Nox4−/− mice (+29% vs. −21%, P < 0.05), associated with a higher level of phosphorylation of the S6 ribosomal protein (S6) and the eIF4E-binding protein 1 (4E-BP1) in WT compared to Nox4−/− mice. We identified that Akt activation in cardiac cells is augmented by Nox4 via a Src kinase-dependent inactivation of protein phosphatase 2A.
Conclusion: Endogenous Nox4 is required for the full development of eccentric cardiac hypertrophy and remodelling during chronic volume overload. Nox4-dependent activation of Akt and its downstream targets S6 and 4E-BP1 may be involved in this effect.