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The incidence of FIX inhibitors in severe hemophilia B (SHB) is not well defined. Frequencies of 3-5% have been reported but most studies to date were small, including patients with different severities, and without prospective follow-up for inhibitor incidence. Study objective was to investigate inhibitor incidence in patients with SHB followed up to 500 exposure days (ED), the frequency of allergic reactions, and the relationship with genotypes. Consecutive previously untreated patients (PUPs) with SHB enrolled into the PedNet cohort were included. Detailed data was collected for the first 50 ED, followed by annual collection of inhibitor status and allergic reactions. Presence of inhibitors was defined by at least two consecutive positive samples. Additionally, data on factor IX gene mutation was collected. 154 PUPs with SHB were included; 75% were followed until 75 ED, and 43% until 500 ED. Inhibitors developed in 14 patients (7 high-titre). Median number of ED at inhibitor manifestation was 11 (IQR 6.5-36.5). Cumulative inhibitor incidence was 9.3% (95%CI 4.4-14.1) at 75 ED, and 10.2% (5.1-15.3) at 500 ED. Allergic reactions occurred in 4 (28.6%) inhibitor patients. Missense mutations were most frequent (46.8%) overall but not associated with inhibitors. Nonsense mutations and deletions with large structural changes comprised all mutations among inhibitor patients and were associated with an inhibitor risk of 26.9% and 33.3%, respectively. In an unselected, well-defined cohort of PUPs with SHB, cumulative inhibitor incidence was 10.2% at 500 ED. Nonsense mutations and large deletions were strongly associated with the risk of inhibitor development. The PedNet Registry is registered at clinicaltrials.gov; identifier: NCT02979119
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.
Management of decompensated cirrhosis is currently geared towards the treatment of complications once they occur. To date there is no established disease-modifying therapy aimed at halting progression of the disease and preventing the development of complications in patients with decompensated cirrhosis. The design of clinical trials to investigate new therapies for patients with decompensated cirrhosis is complex. The population of patients with decompensated cirrhosis is heterogeneous (i.e., different etiologies, comorbidities and disease severity), leading to the inclusion of diverse populations in clinical trials. In addition, primary endpoints selected for trials that include patients with decompensated cirrhosis are not homogeneous and at times may not be appropriate. This leads to difficulties in comparing results obtained from different trials. Against this background, the LiverHope Consortium organized a meeting of experts, the goal of which was to develop recommendations for the design of clinical trials and to define appropriate endpoints, both for trials aimed at modifying the natural history and preventing progression of decompensated cirrhosis, as well as for trials aimed at managing the individual complications of cirrhosis.
Objectives: An increasing number of treatment-determining biomarkers has been identified in non-small cell lung cancer (NSCLC) and molecular testing is recommended to enable optimal individualized treatment. However, data on implementation of these recommendations in the “real-world” setting are scarce. This study presents comprehensive details on the frequency, methodology and results of biomarker testing of advanced NSCLC in Germany.
Patients and methods: This analysis included 3,717 patients with advanced NSCLC (2,921 non-squamous; 796 squamous), recruited into the CRISP registry at start of systemic therapy by 150 German sites between December 2015 and June 2019. Evaluated were the molecular biomarkers EGFR, ALK, ROS1, BRAF, KRAS, MET, TP53, RET, HER2, as well as expression of PD-L1.
Results: In total, 90.5 % of the patients were tested for biomarkers. Testing rates were 92.2 % (non-squamous), 70.7 % (squamous) and increased from 83.2 % in 2015/16 to 94.2% in 2019. Overall testing rates for EGFR, ALK, ROS1, and BRAF were 72.5 %, 74.5 %, 66.1 %, and 53.0 %, respectively (non-squamous). Testing rates for PD-L1 expression were 64.5 % (non-squamous), and 58.5 % (squamous). The most common testing methods were immunohistochemistry (68.5 % non-squamous, 58.3 % squamous), and next-generation sequencing (38.7 % non-squamous, 14.4 % squamous). Reasons for not testing were insufficient tumor material or lack of guideline recommendations (squamous). No alteration was found in 37.8 % (non-squamous), and 57.9 % (squamous), respectively. Most common alterations in non-squamous tumors (all patients/all patients tested for the respective biomarker): KRAS (17.3 %/39.2 %), TP53 (14.1 %/51.4 %), and EGFR (11.0 %/15.1 %); in squamous tumors: TP53 (7.0 %/69.1 %), MET (1.5 %/11.1 %), and EGFR (1.1 %/4.4 %). Median PFS (non-squamous) was 8.7 months (95 % CI 7.4–10.4) with druggable EGFR mutation, and 8.0 months (95 % CI 3.9–9.2) with druggable ALK alterations.
Conclusion: Testing rates in Germany are high nationwide and acceptable in international comparison, but still leave out a significant portion of patients, who could potentially benefit. Thus, specific measures are needed to increase implementation.
Human lymph nodes play a central part of immune defense against infection agents and tumor cells. Lymphoid follicles are compartments of the lymph node which are spherical, mainly filled with B cells. B cells are cellular components of the adaptive immune systems. In the course of a specific immune response, lymphoid follicles pass different morphological differentiation stages. The morphology and the spatial distribution of lymphoid follicles can be sometimes associated to a particular causative agent and development stage of a disease. We report our new approach for the automatic detection of follicular regions in histological whole slide images of tissue sections immuno-stained with actin. The method is divided in two phases: (1) shock filter-based detection of transition points and (2) segmentation of follicular regions. Follicular regions in 10 whole slide images were manually annotated by visual inspection, and sample surveys were conducted by an expert pathologist. The results of our method were validated by comparing with the manual annotation. On average, we could achieve a Zijbendos similarity index of 0.71, with a standard deviation of 0.07.
Mental imagery provides an essential simulation tool for remembering the past and planning the future, with its strength affecting both cognition and mental health. Research suggests that neural activity spanning prefrontal, parietal, temporal, and visual areas supports the generation of mental images. Exactly how this network controls the strength of visual imagery remains unknown. Here, brain imaging and transcranial magnetic phosphene data show that lower resting activity and excitability levels in early visual cortex (V1-V3) predict stronger sensory imagery. Further, electrically decreasing visual cortex excitability using tDCS increases imagery strength, demonstrating a causative role of visual cortex excitability in controlling visual imagery. Together, these data suggest a neurophysiological mechanism of cortical excitability involved in controlling the strength of mental images.
Background: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein in development for the prophylaxis of hereditary angioedema (HAE) attacks.
Objective: Our aim was to determine the efficacy, safety, and tolerability of berotralstat in patients with HAE over a 24-week treatment period (the phase 3 APeX-2 trial).
Methods: APeX-2 was a double-blind, parallel-group study that randomized patients at 40 sites in 11 countries 1:1:1 to receive once-daily berotralstat in a dose of 110 mg or 150 mg or placebo (Clinicaltrials.gov identifier NCT03485911). Patients aged 12 years or older with HAE due to C1 inhibitor deficiency and at least 2 investigator-confirmed HAE attacks in the first 56 days of a prospective run-in period were eligible. The primary efficacy end point was the rate of investigator-confirmed HAE attacks during the 24-week treatment period.
Results: A total of 121 patients were randomized; 120 of them received at least 1 dose of the study drug (n = 41, 40, and 39 in the 110-mg dose of berotralstat, 150-mg of dose berotralstat, and placebo groups, respectively). Berotralstat demonstrated a significant reduction in attack rate at both 110 mg (1.65 attacks per month; P = .024) and 150 mg (1.31 attacks per month; P < .001) relative to placebo (2.35 attacks per month). The most frequent treatment-emergent adverse events that occurred more with berotralstat than with placebo were abdominal pain, vomiting, diarrhea, and back pain. No drug-related serious treatment-emergent adverse events occurred.
Conclusion: Both the 110-mg and 150-mg doses of berotralstat reduced HAE attack rates compared with placebo and were safe and generally well tolerated. The most favorable benefit-to-risk profile was observed at a dose of 150 mg per day.
The in vivo firing patterns of ventral midbrain dopamine neurons are controlled by afferent and intrinsic activity to generate sensory cue and prediction error signals that are essential for reward-based learning. Given the absence of in vivo intracellular recordings during the last three decades, the subthreshold membrane potential events that cause changes in dopamine neuron firing patterns remain unknown. To address this, we established in vivo whole-cell recordings and obtained over 100 spontaneously active, immunocytochemically-defined midbrain dopamine neurons in isoflurane-anaesthetized adult mice. We identified a repertoire of subthreshold membrane potential signatures associated with distinct in vivo firing patterns. Dopamine neuron activity in vivo deviated from single-spike pacemaking by phasic increases in firing rate via two qualitatively distinct biophysical mechanisms: 1) a prolonged hyperpolarization preceding rebound bursts, accompanied by a hyperpolarizing shift in action potential threshold; and 2) a transient depolarization leading to high-frequency plateau bursts, associated with a depolarizing shift in action potential threshold. Our findings define a mechanistic framework for the biophysical implementation of dopamine neuron firing patterns in the intact brain.
Purpose of Review: To review the latest developments and the current role of the cardiac magnetic resonance (CMR) in pericardial diseases and their complications.
Recent Findings: Cardiac Magnetic Resonance (CMR) has the ability to incorporate anatomy, physiology, and “virtual histology” strategies to achieve the most accurate diagnosis for even the most demanding, pericardial diseases.
Summary: Acute, chronic, recurrent, and constrictive pericarditis as well as pericarditis related complications, pericardial masses and congenital pericardial defects are commonly encountered in clinical practice with relatively significant morbidity and mortality. Owing to the challenging diagnosis, CMR imaging is often employed in confirming the diagnosis and elucidating the underling pathophysiology. In this review we outline the common CMR techniques and their expected diagnostic outcomes.
Die Bestimmung von ACE im Serum oder Heparinplasma stellt einen wesentlichen Bestandteil der Diagnostik, Verlaufskontrolle und Therapieüberwachung von benignen Lungenerkrankungen dar. ACE ist ein Marker, der bei Sarkoidose wertvolle Aussagen zur Diagnosefindung ermöglicht. Hier zeichnet er sich durch hohe Sensitivität und Spezifität aus.
Purpose: In this study, we examined distress levels and quality of life (QoL) of patients with hematologic malignancies under treatment in an acute setting. We used external- and self-assessment instruments for distress. Additionally, we investigated the relation between distress and QoL as well as whether highly distressed patients differed from less distressed patients concerning their QoL.
Methods: A cross-sectional study with patients of the Medical Clinic II of the University Hospital Frankfurt was conducted. One hundred and nine patients were assessed with an expert rating scale and completed self-report questionnaires. Data were exploratively analyzed and group comparisons between patients who scored above the cut-off of the respective screening instruments and those who did not were conducted.
Results: Patients with hematologic malignancies experience high levels of distress and low QoL. Especially, role and social functioning are affected. Patients suffer most from fatigue, appetite loss, and insomnia. Using established cut-offs, all screening instruments were able to differentiate between patients regarding distress and QoL. Patients scoring above the cut-off were significantly more distressed and had a lower QoL. There was a medium-to-strong correlation between distress and QoL indicators.
Conclusion: Cancer-specific screening instruments seem to be able to identify treatment needs more specifically. They also allowed a better differentiation concerning QoL. The close link between distress and QoL needs to be recognized to enable a holistic approach to treatment and thereby optimize the quality of treatment.
Purpose: The coronavirus disease 2019 (COVID-19) poses major challenges to health-care systems worldwide. This pandemic demonstrates the importance of timely access to intensive care and, therefore, this study aims to explore the accessibility of intensive care beds in 14 European countries and its impact on the COVID-19 case fatality ratio (CFR).
Methods: We examined access to intensive care beds by deriving (1) a regional ratio of intensive care beds to 100,000 population capita (accessibility index, AI) and (2) the distance to the closest intensive care unit. The cross-sectional analysis was performed at a 5-by-5 km spatial resolution and results were summarized nationally for 14 European countries. The relationship between AI and CFR was analyzed at the regional level.
Results: We found national-level differences in the levels of access to intensive care beds. The AI was highest in Germany (AI = 35.3), followed by Estonia (AI = 33.5) and Austria (AI = 26.4), and lowest in Sweden (AI = 5) and Denmark (AI = 6.4). The average travel distance to the closest hospital was highest in Croatia (25.3 min by car) and lowest in Luxembourg (9.1 min). Subnational results illustrate that capacity was associated with population density and national-level inventories. The correlation analysis revealed a negative correlation of ICU accessibility and COVID-19 CFR (r = − 0.57; p < 0.001).
Conclusion: Geographical access to intensive care beds varies significantly across European countries and low ICU accessibility was associated with a higher proportion of COVID-19 deaths to cases (CFR). Important differences in access are due to the sizes of national resource inventories and the distribution of health-care facilities relative to the human population. Our findings provide a resource for officials planning public health responses beyond the current COVID-19 pandemic, such as identifying potential locations suitable for temporary facilities or establishing logistical plans for moving severely ill patients to facilities with available beds.
Improving spatial accessibility to hospitals is a major task for health care systems which can be facilitated using recent methodological improvements of spatial accessibility measures. We used the integrated floating catchment area (iFCA) method to analyze spatial accessibility of general inpatient care (internal medicine, surgery and neurology) on national level in Germany determining an accessibility index (AI) by integrating distances, hospital beds and morbidity data. The analysis of 358 million distances between hospitals and population locations revealed clusters of lower accessibility indices in areas in north east Germany. There was a correlation of urbanity and accessibility up to r = 0.31 (p < 0.001). Furthermore, 10% of the population lived in areas with significant clusters of low spatial accessibility for internal medicine and surgery (neurology: 20%). The analysis revealed the highest accessibility for heart failure (AI = 7.33) and the lowest accessibility for stroke (AI = 0.69). The method applied proofed to reveal important aspects of spatial accessibility i.e. geographic variations that need to be addressed. However, for the majority of the German population, accessibility of general inpatient care was either high or at least not significantly low, which suggests rather adequate allocation of hospital resources for most parts of Germany.
This focus issue of the European Journal of Trauma and Emergency Surgery compiles a collection of outstanding clinical research using the immense dataset of the German TraumaRegister DGU® (TR-DGU). The TR-DGU of the German Trauma Society (Deutsche Gesellschaft für Unfallchirurgie, DGU) was founded in 1993. Currently, approximately 40,000 cases from more than 600 hospitals are entered into the database every year. The selected articles of this focus on issue highlight the immense value the TR-DGU constitutes for the current, but also for the future trauma research.
Zielsetzung: Die Daten für das Jahr 2019 des Registers „Abdominelles Aortenaneurysma“ (AAA) des Deutschen Instituts für Gefäßmedizinische Gesundheitsforschung (DIGG) der Deutschen Gesellschaft für Gefäßchirurgie und Gefäßmedizin werden vorgestellt.
Methodik: Im Jahr 2019 beteiligten sich an dem Register insgesamt 109 Kliniken. Für die offene Versorgung (OR) des intakten AAA (iAAA) gaben 78 (71,6 %) Kliniken, für die endovaskuläre Versorgung (EVAR) des iAAA 102 (93,6 %) Kliniken Daten ein. Für das rupturierte AAA (rAAA) wurden von 36 Kliniken (33,0 %) (EVAR) bzw. 50 (45,9 %) Kliniken (OR) Patienten gemeldet. Ausgewertet wurden die Daten von 1967 stationär behandelten Patienten. Von den insgesamt 1793 iAAA waren 1501 infrarenal (83,7 %) und 292 (16,3 %) juxtarenal gelegen.
Ergebnisse: 1429 iAAA (79,7 %) wurden endovaskulär und 364 (20,3 %) offen versorgt. Bei den endovaskulär versorgten Patienten mit iAAA verlief der Eingriff in 86,3 % der Fälle komplikationslos. Es verstarben insgesamt 15 Patienten (1,0 %) bis zur Entlassung. Bei den offen versorgten Patienten wiesen 67,0 % der Patienten keine Komplikationen auf. Verstorben sind insgesamt 20 Patienten (5,5 %). Bei EVAR war die Klinikletalität bei Versorgung juxtarenaler AAA mit 3,7 % signifikant höher als bei Versorgung infrarenaler AAA mit 0,6 % (p = 0,002), bei OR konnten hingegen keine signifikanten Unterschiede hinsichtlich der Klinikletalität aufgezeigt werden (juxtarenal 4,8 %, infrarenal 5,8 %; p = 0,470). Von den 174 Patienten mit rAAA wurden 80 (46,0 %) endovaskulär und 94 (54,0 %) offen versorgt. Bei EVAR sind 20,0 % der Patienten während des stationären Aufenthalts verstorben, bei OR 36,2 %.
Schlussfolgerung: Die Ergebnisse des Jahres 2019 zu Klinikletalität und Morbidität bei endovaskulärer und offener Versorgung des iAAA bestätigen weitgehend die publizierten Ergebnisse für die Jahre 2013 bis 2018. Beim rAAA sind die Ergebnisse der einzelnen Jahresberichte hingegen widersprüchlich, die kleinen berichteten jährlichen Fallzahlen erlauben nur Aussagen über größere Zeiträume.
Introduction: The induced membrane technique for the treatment of large bone defects is a two-step procedure. In the first operation, a foreign body membrane is induced around a spacer, then, in the second step, several weeks or months later, the spacer is removed and the Membrane pocket is filled with autologous bone material. Induction of a functional biological membrane might be avoided by initially using a biological membrane. In this study, the effect of a human acellular dermis (hADM, Epiflex, DIZG gGmbH) was evaluated for the treatment of a large (5 mm), plate-stabilised femoral bone defect.
Material and Methods: In an established rat model, hADM was compared to the two-stage induced membrane technique and a bone defect without membrane cover. Syngeneous spongiosa from donor animals was used for defect filling in all groups. The group size in each case was n = 5, the induction time of the membrane was 3–4 weeks and the healing time after filling of the defect was 8 weeks.
Results: The ultimate loads were increased to levels comparable with native bone in both membrane groups (hADM: 63.2% ± 29.6% of the reference bone, p < 0.05 vs. no membrane, induced membrane: 52.1% ± 25.8% of the reference bone, p < 0.05 vs. no membrane) and were significantly higher than the control group without membrane (21.5%). The membrane groups were radiologically and histologically almost completely bridged by new bone formation, in contrast to the control Group where no closed osseous bridging could be observed.
Conclusion: The use of the human acellular dermis leads to equivalent healing results in comparison to the two-stage induced membrane technique. This could lead to a shortened therapy duration of large bone defects.
Background: The prevalence of multimorbidity is increasing in recent years, and patients with multimorbidity often have a decrease in quality of life and require more health care. The aim of this study was to explore the evolution of multimorbidity taking the sequence of diseases into consideration.
Methods: We used a Belgian database collected by extracting coded parameters and more than 100 chronic conditions from the Electronic Health Records of general practitioners to study patients older than 40 years with multiple diagnoses between 1991 and 2015 (N = 65 939). We applied Markov chains to estimate the probability of developing another condition in the next state after a diagnosis. The results of Weighted Association Rule Mining (WARM) allow us to show strong associations among multiple conditions.
Results: About 66.9% of the selected patients had multimorbidity. Conditions with high prevalence, such as hypertension and depressive disorder, were likely to occur after the diagnosis of most conditions. Patterns in several disease groups were apparent based on the results of both Markov chain and WARM, such as musculoskeletal diseases and psychological diseases. Psychological diseases were frequently followed by irritable bowel syndrome.
Conclusions: Our study used Markov chains and WARM for the first time to provide a comprehensive view of the relations among 103 chronic conditions, taking sequential chronology into consideration. Some strong associations among specific conditions were detected and the results were consistent with current knowledge in literature, meaning the approaches were valid to be used on larger data sets, such as National Health care Systems or private insurers.
Introduction: Dravet syndrome (DS), a prototypic developmental and genetic epileptic encephalopathy (DEE), is characterized by an early onset of treatment-refractory seizures, together with impairments in motor control, behavior, and cognition. Even with multiple conventional anti-epileptic drugs, seizures remain poorly controlled, and there has been a considerable unmet need for effective and tolerable treatments. Areas covered: This targeted literature review aims to highlight recent changes to the therapeutic landscape for DS by summarizing the most up-to-date, evidence-based research, including pivotal data from the clinical development of stiripentol, cannabidiol, and fenfluramine, which are important milestones for DS treatment, together with the latest findings of other pharmacotherapies in development. In phase III, double-blind, placebo-controlled randomized controlled trials stiripentol, cannabidiol, and fenfluramine have shown clinically relevant reductions in convulsive seizure frequency, and are generally well tolerated. Stiripentol was associated with responder rates (greater than 50% reduction in convulsive seizure frequency) of 67%-71%, when added to valproic acid and clobazam; cannabidiol was associated with responder rates of 43%-49% (48%-63% in conjunction with clobazam), and fenfluramine of 54%-68% across studies. Therapies in development include soticlestat, ataluren, verapamil, and clemizole, with strategies to treat the underlying cause of DS, including gene therapy and antisense oligonucleotides beginning to emerge from preclinical studies. Expert opinion: Despite the challenges of drug development in rare diseases, this is an exciting time for the treatment of DS, with the promise of new efficacious and well-tolerated therapies, which may pave the way for treatment advances in other DEEs.
Study design: Systematic review. Background and objectives: Preoperative neuromuscular function is predictive for knee function and return to sports (RTS) after reconstruction of the anterior cruciate ligament (ACL). The aim of this review was to examine the potential benefits of prehabilitation on pre-/postoperative objective, self-reported and RTS-specific outcomes. Methods: A systematic search was conducted within three databases. From the 1.071 studies screened, two randomized control trials (RCTs), two control trials (CTs) and two cohort studies (CS) met the inclusion criteria. Methodological quality rating adopted the PEDro- (RCT, CT) or Newcastle-Ottawa-Scale (CS). Results and conclusions: Methodological quality of the included studies was moderate (PEDro score: 6.5 ± 1.7; range 4 to 9). Two studies reported higher increases of the maximal quadriceps torque from baseline to pre-reconstruction: one study in the limb symmetry index (LSI), and one in both legs of the prehabilitation group compared to the controls. At 12-weeks post-reconstruction, one study (from two) indicated that the prehabilitation group had a lesser post-operative decline in the single-leg-hop for distance LSI (clinically meaningful). Similar findings were found in terms of quadriceps strength LSI (one study). At both pre-reconstruction (three studies) and two-year post-surgery (two studies), the prehabilitation groups reached significantly higher self-reported knee function (clinically meaningful) than the controls. RTS tended to be faster (one study). At two years post-surgery, RTS rates (one study) were higher in the prehabilitation groups. The results provide evidence for the relevance of prehabilitation prior to ACL-reconstruction to improve neuromuscular and self-reported knee function as well as RTS. More high quality confirmatory RCTs are warranted.
Class I and II histone deacetylases (HDAC) are considered important regulators of immunity and inflammation. Modulation of HDAC expression and activity is associated with altered inflammatory responses but reports are controversial and the specific impact of single HDACs is not clear. We examined class I and II HDACs in TLR-4 signaling pathways in murine macrophages with a focus on IκB kinase epsilon (IKKε) which has not been investigated in this context before. Therefore, we applied the pan-HDAC inhibitors (HDACi) trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) as well as HDAC-specific siRNA. Administration of HDACi reduced HDAC activity and decreased expression of IKKε although its acetylation was increased. Other pro-inflammatory genes (IL-1β, iNOS, TNFα) also decreased while COX-2 expression increased. HDAC 2, 3 and 4, respectively, might be involved in IKKε and iNOS downregulation with potential participation of NF-κB transcription factor inhibition. Suppression of HDAC 1–3, activation of NF-κB and RNA stabilization mechanisms might contribute to increased COX-2 expression. In conclusion, our results indicate that TSA and SAHA exert a number of histone- and HDAC-independent functions. Furthermore, the data show that different HDAC enzymes fulfill different functions in macrophages and might lead to both pro- and anti-inflammatory effects which have to be considered in therapeutic approaches.
Objectives: The ongoing coronavirus pandemic is challenging, especially in severely affected patients who require intubation and sedation. Although the potential benefits of sedation with volatile anesthetics in coronavirus disease 2019 patients are currently being discussed, the use of isoflurane in patients with coronavirus disease 2019–induced acute respiratory distress syndrome has not yet been reported. Design: We performed a retrospective analysis of critically ill patients with hypoxemic respiratory failure requiring mechanical ventilation. Setting: The study was conducted with patients admitted between April 4 and May 15, 2020 to our ICU. Patients: We included five patients who were previously diagnosed with severe acute respiratory syndrome coronavirus 2 infection. Intervention: Even with high doses of several IV sedatives, the targeted level of sedation could not be achieved. Therefore, the sedation regimen was switched to inhalational isoflurane. Clinical data were recorded using a patient data management system. We recorded demographical data, laboratory results, ventilation variables, sedative dosages, sedation level, prone positioning, duration of volatile sedation and outcomes. Measurements & Main Results: Mean age (four men, one women) was 53.0 (± 12.7) years. The mean duration of isoflurane sedation was 103.2 (± 66.2) hours. Our data demonstrate a substantial improvement in the oxygenation ratio when using isoflurane sedation. Deep sedation as assessed by the Richmond Agitation and Sedation Scale was rapidly and closely controlled in all patients, and the subsequent discontinuation of IV sedation was possible within the first 30 minutes. No adverse events were detected. Conclusions: Our findings demonstrate the feasibility of isoflurane sedation in five patients suffering from severe coronavirus disease 2019 infection. Volatile isoflurane was able to achieve the required deep sedation and reduced the need for IV sedation.
Background: Non-clear cell renal cell cancers (nccRCC) are rare entities, and the optimal therapy in metastatic disease has still to be defined. Methods: In this small prospectively randomized phase IIa multicenter trial, we investigated temsirolimus (TEM) versus sunitinib (SUN) as first-line therapy in patients with metastatic nccRCC. The patients were randomized 1:1 to either TEM in a dose of 25 mg i.v. once a week or SUN with 50 mg p.o. daily for 4 weeks on and 2 weeks off. Primary endpoint was progression-free survival (PFS). In total, 22 patients were included with predominantly papillary RCC (16/22) followed by chromophobe RCC and others. Results: The male to female ratio was 16:6. The tumor control rate (CR + PR + SD) was 58% for TEM and 90% for SUN-treated patients. There was also a trend for improved PFS with 9.3 versus 13.2 months (HR 1.64; 95% CI 0.65–4.18) in favor of SUN. There was no trend for overall survival. Conclusions: Despite this trial had to be terminated earlier due to low recruitment, the results match the other studies published so far with the mTOR inhibitor everolimus and SUN, which show a trend in favor of SUN for ORR and PFS.
Im Rahmen der Serie „Biomarker“, die im Zentralblatt für Arbeitsmedizin und Ergonomie publiziert wird, ist das Angiotensin-Converting Enzyme (ACE) zugehörig als häufiger Marker in der Diagnostik von pulmonalen und extrapulmonalen Erkrankungen. Die Bestimmung von ACE stellt einen wesentlichen Bestandteil der Diagnostik von pulmonalen und extrapulmonalen Erkrankungen dar. Der Einfluss von Tabakkonsum, Medikamenten, Zink-Chelatoren auf die ACE-Konzentration wird eruiert. ACE erwies sich als Marker mit einer hohen Sensitivität und Spezifität bei Lungenerkrankungen.
Introduction: Gastroesophageal reflux disease (GERD) is associated with accelerated decline in lung health in children with cystic fibrosis (CF). Thus, antireflux surgery (ARS) is offered to a selected CF cohort with refractory GERD, but outcomes remain poorly investigated. This study aimed to determine the incidence of GERD in children with CF and to evaluate complications and outcomes of ARS. Materials and Methods: A systematic literature-based search was conducted using various online databases according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The number of GERD cases in pediatric CF cohorts who underwent diagnostic investigation(s) was recorded. Data on postoperative complications and outcomes (including symptoms, lung function, and nutritional status) following ARS were analyzed. Results: Ten articles (n = 289 patients) met the defined inclusion criteria (51% male; age range, 0.5 month–36 years). The overall incidence of GERD was 46% (range, 19–81%), derived from seven studies (n = 212 patients). Four publications (n = 82 patients) reported on ARS due to uncontrolled GERD. All ARSs were Nissen fundoplication (majority with gastrostomy placement). Major postoperative complications occurred in 15 (18%) patients, two required redo-ARS. Median follow-up time was 2 years (range, 3 months–6 years); 59% showed symptom improvement, and pulmonary exacerbations and decline in lung function were reduced. Nutritional status mainly improved in milder CF cases. There were no deaths related to ARS. Conclusion: Approximately half of pediatric CF patients have GERD. Published data for children with CF are limited and heterogeneous in terms of GERD diagnosis and outcomes following ARS. However, ARS has shown to slow the deterioration of lung function in CF.
Background: Current literature is inconsistent regarding the risk of severe side effects using accelerated induction protocols in Hymenoptera venom immunotherapy (VIT). In addition, several data indicate the influence of purity grade of venom preparation on tolerability. We evaluated the safety and tolerability of ultra-rush and rush build-up protocols using purified and non-purified venom preparations. Methods: Retrospective single-center study of 581 VIT inductions (325 ultra-rush and 256 rush protocols) from 2005 to 2018 in 559 patients with bee and vespid venom allergy using aqueous purified (ALK SQ®) for ultra-rush protocol and aqueous non-purified (ALK Reless®) venom preparations for rush protocol. Results: Urticaria (8% vs. 3.1%, p = 0,013) and dose reductions (4.3% vs. 1.2%, p = 0,026) were significantly more frequent in the ultra-rush group. Overall rate of moderate-to-severe side effects (anaphylaxis ≥grade 2 according to Ring and Meβmer) was low and did not differ significantly between protocols (p = 0.105). Severe events (grade 4 anaphylaxis) were not reported. Discontinuation rate was very low in both cohorts (0.6% vs 1.2%). The higher purity grade of venom preparations in the ultra-rush cohort did not improve tolerability. The bee venom group showed a non-significant trend towards higher incidence of mild reactions (urticaria), resulting in more frequent dose reductions and antiallergic therapy. Conclusion: Rush and ultra-rush protocols show an excellent safety profile with only infrequent and mild anaphylactic reactions in bee and vespid venom allergy. Ultra-rush immunotherapy reduces the duration of the inpatient build-up phase setting and thus is viewed by the authors as preferred treatment in Hymenoptera venom allergic patients.
Background: Dental professionals are subjected to higher risks for musculoskeletal disorders (MSDs) than other professional groups, especially the hand region. This study aims to investigate the prevalence of hand complaints among dentists (Ds) and dental assistants (DAs) and examines applied therapies. Methods: For this purpose, an online questionnaire analysed 389 Ds (240female/149male) and 406 DAs (401female/5male) working in Germany. The self-reported data of the two occupational groups were compared with regard to the topics examined. The questionnaire was based on the Nordic Questionnaire (self-reported lifetime, 12-month and 7-day MSDs prevalence of the hand, the conducted therapy and its success), additional occupational and sociodemographic questions as well as questions about specific medical conditions. Results: 30.8% of Ds affirmed MSDs in the hand at any time in their lives, 20.3% in the last twelve months and 9.5% in the last seven days. Among DAs, 42.6% reported a prevalence of MSDs in the hand at any time in their lives, 31.8% in the last 12 months and 15.3% in the last seven days. 37.5% of the Ds and 28.3% of the DAs stated that they had certain treatments. For both, Ds and DAs, physiotherapy was the most frequently chosen form of therapy. 89.7% of Ds and 63.3% of DAs who received therapy reported an improvement of MSDs. Conclusion: Although the prevalence of MSDs on the hand is higher among DAs than among Ds, the use of therapeutic options and the success of therapy is lower for DAs compared to Ds.
This study deals with 3D laser investigation on the border between the human lymph node T-zone and germinal centre. Only a few T-cells specific for antigen selected B-cells are allowed to enter germinal centres. This selection process is guided by sinus structures, chemokine gradients and inherent motility of the lymphoid cells. We measured gaps and wall-like structures manually, using IMARIS, a 3D image software for analysis and interpretation of microscopy datasets. In this paper, we describe alpha-actin positive and semipermeable walls and wall-like structures that may hinder T-cells and other cell types from entering germinal centres. Some clearly defined holes or gaps probably regulate lymphoid traffic between T- and B-cell areas. In lymphadenitis, the morphology of this border structure is clearly defined. However, in case of malignant lymphoma, the wall-like structure is disrupted. This has been demonstrated exemplarily in case of angioimmunoblastic T-cell lymphoma. We revealed significant differences of lengths of the wall-like structures in angioimmunoblastic T-cell lymphoma in comparison with wall-like structures in reactive tissue slices. The alterations of morphological structures lead to abnormal and less controlled T- and B-cell distributions probably preventing the immune defence against tumour cells and infectious agents by dysregulating immune homeostasis.
Background: The intraoperative blood loss is estimated daily in the operating room and is mainly done by visual techniques. Due to local standards, the surgical sponge colours can vary (e.g. white in US, green in Germany). The influence of sponge colour on accuracy of estimation has not been in the focus of research yet. Material and methods: A blood loss simulation study containing four “bleeding” scenarios each per sponge colour were created by using expired whole blood donation samples. The blood donations were applied to white and green surgical sponges after dilution with full electrolyte solution. Study participants had to estimate the absorbed blood loss in sponges in all scenarios. The difference to the reference blood loss was analysed. Multivariate linear regression analysis was performed to investigate other influence factors such as staff experience and sponge colour. Results: A total of 53 anaesthesists participated in the study. Visual estimation correlated moderately with reference blood loss in white (Spearman's rho: 0.521; p = 3.748*10−16) and green sponges (Spearman's rho: 0.452; p = 4.683*10−12). The median visually estimated blood loss was higher in white sponges (250ml IRQ 150–412.5ml) than in green sponges (150ml IQR 100-300ml), compared to reference blood loss (103ml IQR 86–162.8). For both colour types of sponges, major under- and overestimation was observed. The multivariate statistics demonstrates that fabric colours have a significant influence on estimation (p = 3.04*10−10), as well as clinician’s qualification level (p = 2.20*10−10, p = 1.54*10−08) and amount of RBL to be estimated (p < 2*10−16). Conclusion: The deviation of correct blood loss estimation was smaller with white surgical sponges compared to green sponges. In general, deviations were so severe for both types of sponges, that it appears to be advisable to refrain from visually estimating blood loss whenever possible and instead to use other techniques such as e.g. colorimetric estimation.
Objectives: In this study, localization accuracy and sensitivity to acoustic interaural time differences (ITDs) in subjects using cochlear implants with combined electric-acoustic stimulation (EAS) were assessed and compared with the results of a normal hearing control group. Methods: Eight CI users with EAS (2 bilaterally implanted, 6 unilaterally implanted) and symmetric binaural acoustic hearing and 24 normal hearing subjects participated in the study. The first experiment determined mean localization error (MLE) for different angles of sound incidence between ± 60° (frontal and dorsal presentation). The stimuli were either low-pass, high-pass or broadband noise bursts. In a second experiment, just noticeable differences (JND) of ITDs were measured for pure tones of 125 Hz, 250 Hz and 500 Hz (headphone presentation). Results: Experiment 1: MLE of EAS subjects was 8.5°, 14.3° and 14.7°, (low-, high-pass and broadband stimuli respectively). In the control group, MLE was 1.8° (broadband stimuli). In the differentiation between sound incidence from front and back, EAS subjects performed on chance level. Experiment 2: The JND-ITDs were 88.7 μs for 125 Hz, 48.8 μs for 250 Hz and 52.9 μs for 500 Hz (EAS subjects). Compared to the control group, JND-ITD for 125 Hz was on the same level of performance. No statistically significant correlation was found between MLE and JND-ITD in the EAS cohort. Conclusions: Near to normal ITD sensitivity in the lower frequency acoustic hearing was demonstrated in a cohort of EAS users. However, in an acoustic localization task, the majority of the subjects did not reached the level of accuracy of normal hearing. Presumably, signal processing time delay differences between devices used on both sides are deteriorating the transfer of precise binaural timing cues.
Background: Anemia is the most important complication during major surgery and transfusion of red blood cells is the mainstay to compensate for life threating blood loss. Therefore, accurate measurement of hemoglobin (Hb) concentration should be provided in real-time. Blood Gas Analysis (BGA) provides rapid point-of-care assessment using smaller sampling tubes compared to central laboratory (CL) services. Objective: This study aimed to investigate the accuracy of BGA hemoglobin testing as compared to CL services. Methods: Data of the ongoing LIBERAL-Trial (Liberal transfusion strategy to prevent mortality and anemia-associated ischemic events in elderly non-cardiac surgical patients, LIBERAL) was used to assess the bias for Hb level measured by BGA devices (ABL800 Flex analyzer®, GEM series® and RapidPoint 500®) and CL as the reference method. For that, we analyzed pairs of Hb level measured by CL and BGA within two hours. Furthermore, the impact of various confounding factors including age, gender, BMI, smoker status, transfusion of RBC, intraoperative hemodilution, and co-medication was elucidated. In order to ensure adequate statistical analysis, only data of participating centers providing more than 200 Hb pairs were used. Results: In total, three centers including 963 patients with 1,814 pairs of Hb measurements were analyzed. Mean bias was comparable between ABL800 Flex analyzer® and GEM series®: - 0.38 ± 0.15 g/dl whereas RapidPoint 500® showed a smaller bias (-0.09 g/dl) but greater median absolute deviation (± 0.45 g/dl). In order to avoid interference with different standard deviations caused by the different analytic devices, we focused on two centers using the same BGA technique (309 patients and 1,570 Hb pairs). A Bland-Altman analysis and LOWESS curve showed that bias decreased with smaller Hb values in absolute numbers but increased relatively. The smoker status showed the greatest reduction in bias (0.1 g/dl, p<0.001) whereas BMI (0.07 g/dl, p = 0.0178), RBC transfusion (0.06 g/dl, p<0.001), statins (0.04 g/dl, p<0.05) and beta blocker (0.03 g/dl, p = 0.02) showed a slight effect on bias. Intraoperative substitution of volume and other co-medications did not influence the bias significantly. Conclusion: Many interventions like substitution of fluids, coagulating factors or RBC units rely on the accuracy of laboratory measurement devices. Although BGA Hb testing showed a consistently stable difference to CL, our data confirm that BGA devices are associated with different bias. Therefore, we suggest that hospitals assess their individual bias before implementing BGA as valid and stable supplement to CL. However, based on the finding that bias decreased with smaller Hb values, which in turn are used for transfusion decision, we expect no unnecessary or delayed RBC transfusion, and no major impact on the LIBERAL trial performance.
Objectives: To review systematically the past 10 years of research activity into the healthcare experiences (HCX) of patients with chronic heart failure (CHF) in Germany, in order to identify research foci and gaps and make recommendations for future research. Design: In this scoping review, six databases and grey literature sources were systematically searched for articles reporting HCX of patients with CHF in Germany that were published between 2008 and 2018. Extracted results were summarised using quantitative and qualitative descriptive analysis. Results: Of the 18 studies (100%) that met the inclusion criteria, most were observational studies (60%) that evaluated findings quantitatively (60%). HCX were often concerned with patient information, global satisfaction as well as relationships and communication between patients and providers and generally covered ambulatory care, hospital care and rehabilitation services. Overall, the considerable heterogeneity of the included studies’ outcomes only permitted relatively trivial levels of synthesis. Conclusion: In Germany, research on HCX of patients with CHF is characterised by missing, inadequate and insufficient information. Future research would benefit from qualitative analyses, evidence syntheses, longitudinal analyses that investigate HCX throughout the disease trajectory, and better reporting of sociodemographic data. Furthermore, research should include studies that are based on digital data, reports of experiences gained in under-investigated yet patient-relevant healthcare settings and include more female subjects.
The intestinal epithelium acts as a selective barrier for the absorption of water, nutrients and orally administered drugs. To evaluate the gastrointestinal permeability of a candidate molecule, scientists and drug developers have a multitude of cell culture models at their disposal. Static transwell cultures constitute the most extensively characterized intestinal in vitro system and can accurately categorize molecules into low, intermediate and high permeability compounds. However, they lack key aspects of intestinal physiology, including the cellular complexity of the intestinal epithelium, flow, mechanical strain, or interactions with intestinal mucus and microbes. To emulate these features, a variety of different culture paradigms, including microfluidic chips, organoids and intestinal slice cultures have been developed. Here, we provide an updated overview of intestinal in vitro cell culture systems and critically review their suitability for drug absorption studies. The available data show that these advanced culture models offer impressive possibilities for emulating intestinal complexity. However, there is a paucity of systematic absorption studies and benchmarking data and it remains unclear whether the increase in model complexity and costs translates into improved drug permeability predictions. In the absence of such data, conventional static transwell cultures remain the current gold-standard paradigm for drug absorption studies.
Background: Dentists are at a higher risk of suffering from musculoskeletal disorders (MSD) than the general population. However, the latest study investigating MSD in the dental profession in Germany was published about 20 years ago. Therefore, the aim of this study was to reveal the current prevalence of MSD in dentists and dental students in Germany. Methods: The final study size contained 450 (287 f/163 m) subjects of different areas of specialization. The age of the participants ranged from 23 to 75 years. The questionnaire consisted of a modified version of the Nordic Questionnaire, work-related questions from the latest questionnaire of German dentists, typical medical conditions and self-developed questions. Results: The overall prevalence showed that dentists suffered frequently from MSD (seven days: 65.6%, twelve months: 92%, lifetime: 95.8%). The most affected body regions included the neck (42.7%–70.9%–78.4%), shoulders (29.8%–55.6%–66.2%) and lower back (22.9%–45.8%–58.7%). Overall, female participants stated that they suffered from pain significantly more frequently, especially in the neck, shoulders and upper back. Conclusion: The prevalence of MSD among dentists, especially in the neck, shoulder and back area, was significantly higher than in the general population. In addition, women suffered more frequently from MSD than men in almost all body regions.
Large spines are stable and important for memory trace formation. The majority of large spines also contains synaptopodin (SP), an actin-modulating and plasticity-related protein. Since SP stabilizes F-actin, we speculated that the presence of SP within large spines could explain their long lifetime. Indeed, using 2-photon time-lapse imaging of SP-transgenic granule cells in mouse organotypic tissue cultures we found that spines containing SP survived considerably longer than spines of equal size without SP. Of note, SP-positive (SP+) spines that underwent pruning first lost SP before disappearing. Whereas the survival time courses of SP+ spines followed conditional two-stage decay functions, SP-negative (SP-) spines and all spines of SP-deficient animals showed single-phase exponential decays. This was also the case following afferent denervation. These results implicate SP as a major regulator of long-term spine stability: SP clusters stabilize spines, and the presence of SP indicates spines of high stability.
Prostate cancer patients whose tumors develop resistance to conventional treatment often turn to natural, plant-derived products, one of which is sulforaphane (SFN). This study was designed to determine whether anti-tumor properties of SFN, identified in other tumor entities, are also evident in cultivated DU145 and PC3 prostate cancer cells. The cells were incubated with SFN (1–20 µM) and tumor cell growth and proliferative activity were evaluated. Having found a considerable anti-growth, anti-proliferative, and anti-clonogenic influence of SFN on both prostate cancer cell lines, further investigation into possible mechanisms of action were performed by evaluating the cell cycle phases and cell-cycle-regulating proteins. SFN induced a cell cycle arrest at the S- and G2/M-phase in both DU145 and PC3 cells. Elevation of histone H3 and H4 acetylation was also evident in both cell lines following SFN exposure. However, alterations occurring in the Cdk-cyclin axis, modification of the p19 and p27 proteins and changes in CD44v4, v5, and v7 expression because of SFN exposure differed in the two cell lines. SFN, therefore, does exert anti-tumor properties on these two prostate cancer cell lines by histone acetylation and altering the intracellular signaling cascade, but not through the same molecular mechanisms.
Human placentation is a highly invasive process. Deficiency in the invasiveness of trophoblasts is associated with a spectrum of gestational diseases, such as preeclampsia (PE). The oncogene B-cell lymphoma 6 (BCL6) is involved in the migration and invasion of various malignant cells. Intriguingly, its expression is deregulated in preeclamptic placentas. We have reported that BCL6 is required for the proliferation, survival, fusion, and syncytialization of trophoblasts. In the present work, we show that the inhibition of BCL6, either by its gene silencing or by using specific small molecule inhibitors, impairs the migration and invasion of trophoblastic cells, by reducing cell adhesion and compromising the dynamics of the actin cytoskeleton. Moreover, the suppression of BCL6 weakens the signals of the phosphorylated focal adhesion kinase, Akt/protein kinase B, and extracellular regulated kinase 1/2, accompanied by more stationary, but less migratory, cells. Interestingly, transcriptomic analyses reveal that a small interfering RNA-induced reduction of BCL6 decreases the levels of numerous genes, such as p21 activated kinase 1, myosin light chain kinase, and gamma actin related to cell adhesion, actin dynamics, and cell migration. These data suggest BCL6 as a crucial player in the migration and invasion of trophoblasts in the early stages of placental development through the regulation of various genes associated with the migratory machinery.
Background: MitraClip ® (MC) is an established procedure for severe mitral regurgitation (MR) in patients deemed unsuitable for surgery. Right ventricular dysfunction (RVD) is associated with a higher mortality risk. The prognostic accuracy of heart failure risk scores like the Seattle heart failure model (SHFM) and Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score in pts undergoing MC with or without RVD has not been investigated so far. Methods: SHFM and MAGGIC score were calculated retrospectively. RVD was determined as tricuspid annular plane systolic excursion (TAPSE) ≤15 mm. Area under receiver operating curves (AUROC) of SHFM and MAGGIC were performed for one-year all-cause mortality after MC. Results: N = 103 pts with MR III° (73 ± 11 years, LVEF 37 ± 17%) underwent MC with a reduction of at least I° MR. One-year mortality was 28.2%. In Kaplan-Meier analysis, one- year mortality was significantly higher in RVD-pts (34.8% vs 2.8%, p = 0.009). Area under the Receiver Operating Characteristic (AUROC) for SHFM and MAGGIC were comparable for both scores (SHFM: 0.704, MAGGIC: 0.692). In pts without RVD, SHFM displayed a higher AUROC and therefore better diagnostic accuracy (SHFM: 0.776; MAGGIC: 0.551, p < 0.05). In pts with RVD, MAGGIC and SHFM displayed comparable AUROCs. Conclusion: RVD is an important prognostic marker in pts undergoing MC. SHFM and MAGGIC displayed adequate over-all prognostic power in these pts. Accuracy differed in pts with and without RVD, indicating higher predictive power of the SHFM score in pts without RVD.
During the course of sepsis in critically ill patients, kidney dysfunction and damage are among the first events of a complex scenario toward multi-organ failure and patient death. Acute kidney injury triggers the release of lipocalin-2 (Lcn-2), which is involved in both renal injury and recovery. Taking into account that Lcn-2 binds and transports iron with high affinity, we aimed at clarifying if Lcn-2 fulfills different biological functions according to its iron-loading status and its cellular source during sepsis-induced kidney failure. We assessed Lcn-2 levels both in serum and in the supernatant of short-term cultured renal macrophages (MΦ) as well as renal tubular epithelial cells (TEC) isolated from either Sham-operated or cecal ligation and puncture (CLP)-treated septic mice. Total kidney iron content was analyzed by Perls’ staining, while Lcn-2-bound iron in the supernatants of short-term cultured cells was determined by atomic absorption spectroscopy. Lcn-2 protein in serum was rapidly up-regulated at 6 h after sepsis induction and subsequently increased up to 48 h. Lcn-2-levels in the supernatant of TEC peaked at 24 h and were low at 48 h with no change in its iron-loading. In contrast, in renal MΦ Lcn-2 was low at 24 h, but increased at 48 h, where it mainly appeared in its iron-bound form. Whereas TEC-secreted, iron-free Lcn-2 was associated with renal injury, increased MΦ-released iron-bound Lcn-2 was linked to renal recovery. Therefore, we hypothesized that both the cellular source of Lcn-2 as well as its iron-load crucially adds to its biological function during sepsis-induced renal injury.
Background Polypharmacy interventions are resource-intensive and should be targeted to those at risk of negative health outcomes. Our aim was to develop and internally validate prognostic models to predict health-related quality of life (HRQoL) and the combined outcome of falls, hospitalisation, institutionalisation and nursing care needs, in older patients with multimorbidity and polypharmacy in general practices.
Methods Design: two independent data sets, one comprising health insurance claims data (n=592 456), the other data from the PRIoritising MUltimedication in Multimorbidity (PRIMUM) cluster randomised controlled trial (n=502). Population: ≥60 years, ≥5 drugs, ≥3 chronic diseases, excluding dementia. Outcomes: combined outcome of falls, hospitalisation, institutionalisation and nursing care needs (after 6, 9 and 24 months) (claims data); and HRQoL (after 6 and 9 months) (trial data). Predictor variables in both data sets: age, sex, morbidity-related variables (disease count), medication-related variables (European Union-Potentially Inappropriate Medication list (EU-PIM list)) and health service utilisation. Predictor variables exclusively in trial data: additional socio-demographics, morbidity-related variables (Cumulative Illness Rating Scale, depression), Medication Appropriateness Index (MAI), lifestyle, functional status and HRQoL (EuroQol EQ-5D-3L). Analysis: mixed regression models, combined with stepwise variable selection, 10-fold cross validation and sensitivity analyses.
Results Most important predictors of EQ-5D-3L at 6 months in best model (Nagelkerke’s R² 0.507) were depressive symptoms (−2.73 (95% CI: −3.56 to −1.91)), MAI (−0.39 (95% CI: −0.7 to −0.08)), baseline EQ-5D-3L (0.55 (95% CI: 0.47 to 0.64)). Models based on claims data and those predicting long-term outcomes based on both data sets produced low R² values. In claims data-based model with highest explanatory power (R²=0.16), previous falls/fall-related injuries, previous hospitalisations, age, number of involved physicians and disease count were most important predictor variables.
Conclusions Best trial data-based model predicted HRQoL after 6 months well and included parameters of well-being not found in claims. Performance of claims data-based models and models predicting long-term outcomes was relatively weak. For generalisability, future studies should refit models by considering parameters representing well-being and functional status.
Background: Rates of permanent pacemaker implantation (PPI) have been low using the self‐expanding ACURATE neo device, but data regarding risk factors of PPI for this specific device are scarce.
Methods: The study cohort consisted of patients (n = 1000) with severe aortic stenosis undergoing transfemoral transcatheter aortic valve implantation (TAVI) using the ACURATE neo prosthesis in our center between May 2012 and December 2019. For the present analysis, we excluded patients with previous permanent pacemaker (n = 110), high‐grade AV block prior to TAVI (n = 3), and patients requiring conversion to surgical valve replacement (n = 4) or the implantation of a second prosthesis as valve‐in‐valve (n = 15). Preexisting conduction abnormalities were determined, and the implantation depth of the prosthesis was measured on final angiography. Differences across quartiles based on the original consecutive cohort were analyzed with respect to implantation depth and PPI rate. Predictors of PPI were identified using logistic regression.
Results: The PPI rate was 10%. Preexisting AV block I°, right bundle branch block (RBBB), and the implantation depth were independent predictors of PPI. Across quartiles, the implantation depth differed significantly with lowest values in the last quartile, whereas differences of PPI rates across quartiles were not statistically significant, but showed a notable decrease in the last quartile.
Conclusion: Preexisting RBBB, AV block I°, and low implantation depth were independent predictors of PPI following TAVI using the ACURATE neo device. Instead of deliberately aiming at a high position, avoidance of a low implantation depth may represent a reasonable compromise to reduce the rate of PPI without increasing the risk of malpositioning.
Background: The aim of this study was to evaluate post‐irradiation changes in the central nervous system (CNS) detected using magnetic resonance (MR) imaging.
Methods: Magnetic resonance images of 15 children with CNS tumors treated through whole‐brain irradiation over 10 years were reviewed retrospectively. Variables such as age at the time of irradiation, total radiation dose, treatment length, and time interval between irradiation and MR changes, were evaluated.
Results: All patients included in the study had imaging abnormalities of the CNS. Eight patients (53%) developed CNS abnormalities within a short period of time – only a few months after irradiation (mean 4.8 months). Seven patients (47%) developed CNS abnormalities within a long time interval after treatment (mean 4.6 years). In almost all patients, a T2 increase in supra‐ and infratentorial white matter was observed. Follow‐up examinations showed nine patients (60%) with cerebellar atrophy.
Conclusions: In this sample of pediatric patients who underwent whole‐brain irradiation, the time receiving irradiation was not related to the severity of the MR changes. A correlation between the age of the child or the length of the radiotherapy and the extent of the changes could not be confirmed. However, we observed a trend towards stronger brain parenchymal degeneration with cystic changes in the younger age group of children in our sample. Older children who received irradiation seem to be more susceptible to vascular dysplasia with cavernous hemangiomas and microbleeding.
Background: Conditions during blood product storage and transportation should maintain quality. The aim of this in vitro study was to investigate the effect of interruption of agitation, temporary cooling (TC), and pneumatic tube system transportation (PTST) on the aggregation ability (AA) and mitochondrial function (MF) of platelet concentrates (PC).
Study Design and Methods: A PC was divided equally into four subunits and then allocated to four test groups. The control group (I) was stored as recommended (continuous agitation, 22 ± 2°C) for 4 days. The test groups were stored without agitation (II), stored as recommended, albeit 4°C for 60 minutes on day (d)2 (III) and PTST (IV). Aggregometry was measured using Multiplate (RocheAG; ADPtest, ASPItest, TRAPtest, COLtest) and MF using Oxygraph‐2k (Oroboros Instruments). The basal and maximum mitochondrial respiratory rate (MMRR) were determined. AA and MF were measured daily in I and II and AA in III and IV on d2 after TC/PTST. Statistical analysis was performed using tests for matched observations.
Results: Eleven PCs were used. TRAP‐6 induced AA was significantly lower in II when compared to I on d4 (P = 0.015*). In III the ASPItest was significantly lower (P = 0.032*). IV showed no significant differences. The basal and MMRR were significantly reduced over 4 days in I and II (for both rates in both groups: P = <0.0001*). No significant differences occurred on d4 (P = 0.495).
Conclusion: Our results indicate that ex vivo AA and MF of PCs are unaffected, even in no‐ideal storage and transport circumstances with respect to agitation, temperature, and force.
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that is accompanied by neurodevelopmental differences in regional cortical volume (CV), and a potential layer‐specific pathology. Conventional measures of CV, however, do not indicate how volume is distributed across cortical layers. In a sample of 92 typically developing (TD) controls and 92 adult individuals with ASD (aged 18–52 years), we examined volumetric gradients by quantifying the degree to which CV is weighted from the pial to the white surface of the brain. Overall, the spatial distribution of Frustum Surface Ratio (FSR) followed the gyral and sulcal pattern of the cortex and approximated a bimodal Gaussian distribution caused by a linear mixture of vertices on gyri and sulci. Measures of FSR were highly correlated with vertex‐wise estimates of mean curvature, sulcal depth, and pial surface area, although none of these features explained more than 76% variability in FSR on their own. Moreover, in ASD, we observed a pattern of predominant increases in the degree of FSR relative to TD controls, with an atypical neurodevelopmental trajectory. Our findings suggest a more outward‐weighted gradient of CV in ASD, which may indicate a larger contribution of supragranular layers to regional differences in CV.
Introduction: Haemophilia (HA) and rheumatoid arthritis (RA) patients may develop joint damage caused by recurrent joint bleedings in HA or by chronic inflammation in RA. Only few data exist for biomarker studies in these patients.
Aim: The objective of the present study is to assess a large array of biomarkers in peripheral blood samples obtained from HA patients without or with arthropathy and to compare pattern to RA patients and healthy controls.
Methods: A panel of biomarkers was assessed in 129 men (40 HA patients without arthropathy, 23 HA patients with arthropathy, 23 RA patients and 43 control subjects). 37 different biomarkers (cytokines, angiogenesis‐related proteins) were analysed using a multiple analyte profiling technology and supplemented by acute phase proteins, coagulation and immunological parameters.
Results: Evidence for systemic inflammation was obtained by increased acute phase reactants in all patient groups. 13 or 14 from 42 soluble parameters demonstrated significant differences (p < .05) between HA patients without arthropathy and healthy controls, or between HA patients with arthropathy and healthy controls, respectively. Largely overlapping patterns were obtained except for interleukin‐7 being increased in HA patients without arthropathy and being decreased in HA in the presence of arthropathy.
Conclusions: In addition to data supporting systemic inflammation, we provide evidence for a common biomarker profile in HA patients and RA patients compared to healthy controls. A distinctive biomarker profile for HA patients with arthropathy did not appear except for interleukin‐7 demonstrating specific changes depending on the absence or presence of arthropathy in HA patients.
Background: In pain research and clinics, it is common practice to subgroup subjects according to shared pain characteristics. This is often achieved by computer‐aided clustering. In response to a recent EU recommendation that computer‐aided decision making should be transparent, we propose an approach that uses machine learning to provide (1) an understandable interpretation of a cluster structure to (2) enable a transparent decision process about why a person concerned is placed in a particular cluster.
Methods: Comprehensibility was achieved by transforming the interpretation problem into a classification problem: A sub‐symbolic algorithm was used to estimate the importance of each pain measure for cluster assignment, followed by an item categorization technique to select the relevant variables. Subsequently, a symbolic algorithm as explainable artificial intelligence (XAI) provided understandable rules of cluster assignment. The approach was tested using 100‐fold cross‐validation.
Results: The importance of the variables of the data set (6 pain‐related characteristics of 82 healthy subjects) changed with the clustering scenarios. The highest median accuracy was achieved by sub‐symbolic classifiers. A generalized post‐hoc interpretation of clustering strategies of the model led to a loss of median accuracy. XAI models were able to interpret the cluster structure almost as correctly, but with a slight loss of accuracy.
Conclusions: Assessing the variables importance in clustering is important for understanding any cluster structure. XAI models are able to provide a human‐understandable interpretation of the cluster structure. Model selection must be adapted individually to the clustering problem. The advantage of comprehensibility comes at an expense of accuracy.
Ionizing radiation interacts with the immune system in many ways with a multiplicity that mirrors the complexity of the immune system itself: namely the need to maintain a delicate balance between different compartments, cells and soluble factors that work collectively to protect, maintain, and restore tissue function in the face of severe challenges including radiation damage. The cytotoxic effects of high dose radiation are less relevant after low dose exposure, where subtle quantitative and functional effects predominate that may go unnoticed until late after exposure or after a second challenge reveals or exacerbates the effects. For example, low doses may permanently alter immune fitness and therefore accelerate immune senescence and pave the way for a wide spectrum of possible pathophysiological events, including early-onset of age-related degenerative disorders and cancer. By contrast, the so called low dose radiation therapy displays beneficial, anti-inflammatory and pain relieving properties in chronic inflammatory and degenerative diseases. In this review, epidemiological, clinical and experimental data regarding the effects of low-dose radiation on the homeostasis and functional integrity of immune cells will be discussed, as will be the role of immune-mediated mechanisms in the systemic manifestation of localized exposures such as inflammatory reactions. The central conclusion is that ionizing radiation fundamentally and durably reshapes the immune system. Further, the importance of discovery of immunological pathways for modifying radiation resilience amongst other research directions in this field is implied.
Objective: Combination antiretroviral therapy (cART) has markedly increased survival and quality of life in people living with HIV. With the advent of new treatment options, including single-tablet regimens, durability and efficacy of first-line cART regimens are evolving.
Methods: We analyzed data from the prospective multicenter German Clinical Surveillance of HIV Disease (ClinSurv) cohort of the Robert-Koch Institute. Kaplan–Meier and Cox proportional hazards models were run to examine the factors associated with treatment modification. Recovery after treatment initiation was analyzed comparing pre-cART viral load and CD4+ T-cell counts with follow-up data.
Results: We included 8788 patients who initiated cART between 2005 and 2017. The sample population was predominantly male (n = 7040; 80.1%), of whom 4470 (63.5%) were reporting sex with men as the transmission risk factor. Overall, 4210 (47.9%) patients modified their first-line cART after a median time of 63 months (IQR 59–66). Regimens containing integrase strand transfer inhibitors (INSTI) were associated with significantly lower rates of treatment modification (adjusted hazard ratio 0.44; 95% CI 0.39–0.50) compared to protease inhibitor (PI)-based regimens. We found a decreased durability of first-line cART significantly associated with being female, a low CD4+ T-cell count, cART initiation in the later period (2011–2017), being on a multi-tablet regimen (MTR).
Conclusions: Drug class and MTRs are significantly associated with treatment modification. INSTI-based regimens showed to be superior compared to PI-based regimens in terms of durability.
Zur ergonomischen Beurteilung von Arbeitsplätzen werden „ergonomic risk assessment tools“ (ERAT) verwendet. Mithilfe dieser kann die körperliche Belastung evaluiert und hinsichtlich eines biomechanischen Überlastungsrisikos bewertet werden. Dazu gehören neben Eigenangaben auch observatorische Methoden, deren Ergebnisse in Punktwerten („Scores“) zusammengefasst werden, wie z. B. die RULAMethode („rapid upper limb assessment“). Durch die technische Weiterentwicklung direkter Messmethoden können inertiale Motion-Capture-Systeme im 21. Jahrhundert präzise und kontinuierliche objektive Daten liefern. In einem neuen Ansatz wurde die observatorische Scoring-Methode RULA modifiziert und auf die digital erhobenen Daten angewendet, was differenzierte ergonomische Betrachtungen ganzer Arbeitsabläufe ermöglicht.
Purpose: Does surgical approach (minimally invasive vs. open) and type (radical vs. partial nephrectomy) affects opioid use and workplace absenteeism.
Materials and Methods: Retrospective multivariable regression analysis of 2,646 opioid-naïve patients between 18 and 64 undergoing radical or partial nephrectomy via either a minimally invasive vs. open approach for kidney cancer in the United States between 2012 and 2017 drawn from the IBM Watson Health Database was performed. Outcomes included: (1) opioid use in opioid-naïve patients as measured by opioid prescriptions in the post-operative setting at early, intermediate and prolonged time periods and (2) workplace absenteeism after surgery.
Results: Patients undergoing minimally invasive surgery had a lower odds of opioid use in the early and intermediate post-operative periods (early: odds ratio [OR], 0.77; 95% confidence interval [CI], 0.62–0.97; p=0.02, intermediate: OR, 0.60; 95% CI, 0.48–0.75; p<0.01), but not in the prolonged setting (prolonged: OR, 1.00; 95% CI, 0.75–1.34; p=0.98) and had earlier return to work (minimally invasive vs. open: −10.53 days; 95% CI, −17.79 to −3.26; p<0.01). Controlling for approach, patient undergoing partial nephrectomy had lower rates of opioid use across all time periods examined and returned to work earlier than patients undergoing radical nephrectomy (partial vs. radical: −14.41 days; 95% CI, −21.22 to −7.60; p<0.01).
Conclusions: Patients undergoing various forms of surgery for kidney cancer had lower rates of peri-operative opioid use, fewer days of workplace absenteeism, but no difference in long-term rates of opioid use in patients undergoing minimally invasive as compared to open surgery.
Cisplatin, which induces DNA damage, is standard chemotherapy for advanced bladder cancer (BCa). However, efficacy is limited due to resistance development. Since artesunate (ART), a derivative of artemisinin originating from Traditional Chinese Medicine, has been shown to exhibit anti-tumor activity, and to inhibit DNA damage repair, the impact of artesunate on cisplatin-resistant BCa was evaluated. Cisplatin-sensitive (parental) and cisplatin-resistant BCa cells, RT4, RT112, T24, and TCCSup, were treated with ART (1–100 µM). Cell growth, proliferation, and cell cycle phases were investigated, as were apoptosis, necrosis, ferroptosis, autophagy, metabolic activity, and protein expression. Exposure to ART induced a time- and dose-dependent significant inhibition of tumor cell growth and proliferation of parental and cisplatin-resistant BCa cells. This inhibition was accompanied by a G0/G1 phase arrest and modulation of cell cycle regulating proteins. ART induced apoptos is by enhancing DNA damage, especially in the resistant cells. ART did not induce ferroptosis, but led to a disturbance of mitochondrial respiration and ATP generation. This impairment correlated with autophagy accompanied by a decrease in LC3B-I and an increase in LC3B-II. Since ART significantly inhibits proliferative and metabolic aspects of cisplatin-sensitive and cisplatin-resistant BCa cells, it may hold potential in treating advanced and therapy-resistant BCa.
Background: The spontaneously diabetic “non-obese diabetic” (NOD) mouse is a faithful model of human type-1 diabetes (T1D). Methods: Given the pivotal role of α4 integrin (CD49d) in other autoimmune diseases, we generated NOD mice with α4-deficient hematopoiesis (NOD.α4-/-) to study the role of α4 integrin in T1D. Results: NOD.α4-/- mice developed islet-specific T-cells and antibodies, albeit quantitatively less than α4+ counterparts. Nevertheless, NOD.α4-/- mice were completely and life-long protected from diabetes and insulitis. Moreover, transplantation with isogeneic α4-/- bone marrow prevented progression to T1D of pre-diabetic NOD.α4+ mice despite significant pre-existing islet cell injury. Transfer of α4+/CD3+, but not α4+/CD4+ splenocytes from diabetic to NOD.α4-/- mice induced diabetes with short latency. Despite an only modest contribution of adoptively transferred α4+/CD3+ cells to peripheral blood, pancreas-infiltrating T-cells were exclusively graft derived, i.e., α4+. Microbiota of diabetes-resistant NOD.α4-/- and pre-diabetic NOD.α4+ mice were identical. Co- housed diabetic NOD.α4+ mice showed the characteristic diabetic dysbiosis, implying causality of diabetes for dysbiosis. Incidentally, NOD.α4-/- mice were protected from autoimmune sialitis. Conclusion: α4 is a potential target for primary or secondary prevention of T1D.
Unpredictable disease trajectories make early clarification of end-of-life (EoL) care preferences in older patients with multimorbidity advisable. This mixed methods systematic review synthesizes studies and assesses such preferences. Two independent reviewers screened title/abstracts/full texts in seven databases, extracted data and used the Mixed Methods Appraisal Tool to assess risk of bias (RoB). We synthesized findings from 22 studies (3243 patients) narratively and, where possible, quantitatively. Nineteen studies assessed willingness to receive life-sustaining treatments (LSTs), six, the preferred place of care, and eight, preferences regarding shared decision-making processes. When unspecified, 21% of patients in four studies preferred any LST option. In three studies, fewer patients chose LST when faced with death and deteriorating health, and more when treatment promised life extension. In 13 studies, 67% and 48% of patients respectively were willing to receive cardiopulmonary resuscitation and mechanical ventilation, but willingness decreased with deteriorating health. Further, 52% of patients from three studies wished to die at home. Seven studies showed that unless incapacitated, most patients prefer to decide on their EoL care themselves. High non-response rates meant RoB was high in most studies. Knowledge of EoL care preferences of older patients with multimorbidity increases the chance such care will be provided.
Background: Surgical complications are associated with a significant burden to patients and hospitals and are increasingly discussed in recent literature. This cohort study reviewed surgery-related complications in a Level I trauma center. The effect of a complication avoidance care bundle on the rate of surgical complications was analyzed. Methods: All complications (surgical and nonsurgical) that occur in our trauma department are prospectively captured using a standardized documentation form and are discussed and analyzed in a weekly trauma Morbidity and Mortality (M&M) conference. Surgical complication rates are calculated using the annual surgical procedure numbers. Based on discussions in the M&M conference, a complication avoidance care bundle consisting of five measures was established: (1) Improving team situational awareness; (2) reducing operating room traffic by staff members and limiting door-opening events; (3) preoperative screening for infectious foci; (4) adapted preoperative antibiotic prophylaxis in anatomic regions with a high risk of infectious complications; and (5) use of iodine-impregnated adhesive drape. Results: The number of surgical procedures steadily increased over the study years, from 3587 in 2015 to 3962 in 2019 (an increase of 10.5%). Within this 5-year study period, the overall rate of surgical complications was 0.8%. Surgical site infections were the most frequently found complications (n = 40, 24.8% of all surgical complications), followed by screw malposition (n = 20, 12.4%), postoperative dislocations of arthroplasties (n = 18, 11.2%), and suboptimal fracture reduction (n = 18, 11.2%). Following implementation of the complication avoidance care bundle, the overall rate of surgical complications significantly decreased, from 1.14% in the year 2016 to 0.56% in the study year 2019, which represents a reduction of 51% within a 3-year time period. Conclusions: A multimodal strategy targeted at reducing the surgical complication rate can be successfully established based on a transparent discussion of adverse surgical outcomes. The combination of the different preventive measures was associated with reducing the overall complication rate by half within a 3-year time period.
The main goal of the present study was the identification of cellular phenotypes in attention-deficit-/hyperactivity disorder (ADHD) patient-derived cellular models from carriers of rare copy number variants (CNVs) in the PARK2 locus that have been previously associated with ADHD. Human-derived fibroblasts (HDF) were cultured and human-induced pluripotent stem cells (hiPSC) were reprogrammed and differentiated into dopaminergic neuronal cells (mDANs). A series of assays in baseline condition and in different stress paradigms (nutrient deprivation, carbonyl cyanide m-chlorophenyl hydrazine (CCCP)) focusing on mitochondrial function and energy metabolism (ATP production, basal oxygen consumption rates, reactive oxygen species (ROS) abundance) were performed and changes in mitochondrial network morphology evaluated. We found changes in PARK2 CNV deletion and duplication carriers with ADHD in PARK2 gene and protein expression, ATP production and basal oxygen consumption rates compared to healthy and ADHD wildtype control cell lines, partly differing between HDF and mDANs and to some extent enhanced in stress paradigms. The generation of ROS was not influenced by the genotype. Our preliminary work suggests an energy impairment in HDF and mDAN cells of PARK2 CNV deletion and duplication carriers with ADHD. The energy impairment could be associated with the role of PARK2 dysregulation in mitochondrial dynamics.
In the absence of an active prophylactic vaccine against HIV-1, passively administered, broadly neutralizing antibodies (bnAbs) identified in some chronically infected persons were shown to prevent HIV-1 infection in animal models. However, passive administration of bnAbs may not be suited to prevent sexual HIV-1 transmission in high-risk cohorts, as a continuous high level of active bnAbs may be difficult to achieve at the primary site of sexual transmission, the human vagina with its acidic pH. Therefore, we used Lactobacillus, a natural commensal in the healthy vaginal microbiome, to express bn nanobodies (VHH) against HIV-1 that we reported previously. After demonstrating that recombinant VHHA6 expressed in E. coli was able to protect humanized mice from mucosal infection by HIV-1Bal, we expressed VHHA6 in a soluble or in a cell-wall-anchored form in Lactobacillus rhamnosus DSM14870. This strain is already clinically applied for treatment of bacterial vaginosis. Both forms of VHHA6 neutralized a set of primary epidemiologically relevant HIV-1 strains in vitro. Furthermore, VHHA6 was still active at an acidic pH. Thus, lactobacilli expressing bn VHH potentially represent an attractive vector for the passive immunization of women in cohorts at high risk of HIV-1 transmission.
The transcription factor NF-E2 p45-related factor 2 (Nrf2) is an established master regulator of the anti-oxidative and detoxifying cellular response. Thus, a role in inflammatory diseases associated with the generation of large amounts of reactive oxygen species (ROS) seems obvious. In line with this, data obtained in cell culture experiments and preclinical settings have shown that Nrf2 is important in regulating target genes that are necessary to ensure cellular redox balance. Additionally, Nrf2 is involved in the induction of phase II drug metabolizing enzymes, which are important both in degrading and converting drugs into active forms, and into putative carcinogens. Therefore, Nrf2 has also been implicated in tumorigenesis. This must be kept in mind when new therapy approaches are planned for the treatment of sepsis. Therefore, this review highlights the function of Nrf2 in sepsis with a special focus on the translation of rodent-based results into sepsis patients in the intensive care unit (ICU).
People with Parkinson’s disease (PD) experience a gradual loss of functional abilities that affects all facets of their daily life. There is a lack of longitudinal studies on coping styles in relation to the disease progression among people with PD. The aim of this study was to explore how coping styles in PD evolve over a 3-year period. Data from the longitudinal project “Home and Health in People Ageing with PD” was utilized (N = 158), including baseline and 3-year follow-up assessments. Coping was captured by ratings of 13 different coping styles. A factor analysis was conducted to analyse patterns of coping styles. Stability and change were analysed for each of the 13 styles with respect to the course of the disease. The factor analysis revealed four coping patterns: pessimistic, optimistic, persistent and support-seeking. The stability of each coping style over time ranged from 75.3% to 90.5%. Those who experienced a worsening of the disease were most inclined to change their coping style (p = 0.006). The results suggest that even when facing severe challenges due to PD in daily life, coping styles remain relatively stable over time. However, a worsening in PD severity appeared to trigger a certain re-evaluation of coping styles.
Echovirus-30 (E-30) is a non-polio enterovirus responsible for meningitis outbreaks in children worldwide. To gain access to the central nervous system (CNS), E-30 first has to cross the blood-brain barrier (BBB) or the blood-cerebrospinal fluid barrier (BCSFB). E-30 may use lipid rafts of the host cells to interact with and to invade the BCSFB. To study enteroviral infection of the BCSFB, an established in vitro model based on human immortalized brain choroid plexus papilloma (HIBCPP) cells has been used. Here, we investigated the impact of E-30 infection on the protein content of the lipid rafts at the BCSFB in vitro. Mass spectrometry analysis following E-30 infection versus uninfected conditions revealed differential abundancy in proteins implicated in cellular adhesion, cytoskeleton remodeling, and endocytosis/vesicle budding. Further, we evaluated the blocking of endocytosis via clathrin/dynamin blocking and its consequences for E-30 induced barrier disruption. Interestingly, blocking of endocytosis had no impact on the capacity of E-30 to induce loss of barrier properties in HIBCPP cells. Altogether, these data highlight the impact of E-30 on HIBCPP cells microdomain as an important factor for host cell alteration.
Simple Summary
Endometrial cancer is the most frequent gynecologic tumor in developed countries. Obesity is an established risk factor for this disease. This work provides an overview of pathophysiological interactions and pathways in obese women initiating tumorigenesis. Furthermore, the clinical impact of adiposity on the treatment of endometrial cancer is discussed as well therapeutic and preventive options.
Abstract
Endometrial cancer (EC) is the most frequently observed malignant gynecologic disease in developed countries. There is a strong association between the established risk factor obesity and the incidence of EC. Furthermore, the rate of women with a body mass index (BMI) > 30 kg/m2 is increasing worldwide, correspondingly leading to a higher prevalence of EC. Understanding the adipose tissue as an endocrine organ, elementary pathophysiological pathways of tumorigenesis have been revealed. This includes the fundamental role of hyperglycemia, insulin resistance, and hyperestrogenemia, as well as interactions with a chronic proinflammatory microenvironment. Therapeutic options potentially include metformin or bariatric surgery. Moreover, changes in individual lifestyle such as weight reduction, physical activity, and an awareness of healthy nutrition are effective in preventing the disease.
Background: Despite a large body of evidence demonstrating the effectiveness of psychotherapy for posttraumatic stress for children and adolescents, the adoption of empirically supported treatments (ESTs) in routine care is low.
Objective: This implementation study aims to evaluate the dissemination of Trauma-Focused Cognitive Behavioural Therapy (TF-CBT) for children and adolescents with posttraumatic stress symptoms (PTSS) after child abuse and neglect (CAN) with a focus on supervision.
Method: In a cluster-randomized controlled trial, the study will evaluate the implementation of TF-CBT focussing on the training of therapists including the provision of supervision. The effectiveness of specialized trauma-focused supervision will be compared to supervision as usual with respect to the successful implementation of TF-CBT for youths with PTSS administered by psychotherapists with different levels of professional experience. The primary outcome is whether the patient receives a treatment with sufficient adherence to the TF-CBT manual. The unit of randomization will be the therapists. The main outcome will be analysed using multilevel logistic regressions. Secondary outcomes will concern further patient-related (reduction of PTSS and depressive symptoms) and therapist-related (professional quality of life) variables. Additional exploratory analyses are planned.
Discussion: Since the trial is designed as an implementation study, it permits naturalistic referrals to the participating therapists by patients, caregivers, child and youth welfare agencies and paediatricians. The strict primary outcome will help evaluating the role of model-based supervision in the implementation process. The explorative outcomes will evaluate whether implementation success translates into better patient outcomes. We expect that the dissemination measures will lead to a successful implementation of TF-CBT and promote sustainable structures in routine care that will remain in place after study completion and offer access to ESTs for future children and youths with a history of CAN.
The influence of biological maturity status (BMS) on talent identification and development within elite youth soccer is critically debated. During adolescence, maturity-related performance differences within the same age group may cause greater chances of being selected for early maturing players. Therefore, coaches need to consider players' BMS. While standard methods for assessing BMS in adolescents are expensive and time-consuming imaging techniques (i.e., X-ray and MRI), there also exist more pragmatic procedures. This study aimed to evaluate commonly used methods to assess BMS within a highly selected sample of youth soccer players. A total of N = 63 elite male soccer players (U12 and U14) within the German Soccer Association's talent promotion program completed a test battery assessing BMS outcomes. Utilizing MRI diagnostics, players' skeletal age (SAMRI) was determined by radiologists and served as the reference method. Further commonly used methods included skeletal age measured by an ultrasound device (SAUS), the maturity offset (MOMIR), and the percentage of adult height (PAHKR). The relation of these alternative BMS outcomes to SAMRI was examined using different perspectives: performing bivariate correlation analyses (1), modeling BMS as a latent variable (BMSlat) based on the multiple alternative diagnostics (2), and investigating individual differences in agreement (3). (1) Correlations of SAMRI and the further BMS variables ranked from r = 0.80 to r = 0.84 for the total sample and were lower for U12 (0.56 ≤ r ≤ 0.66), and U14 (0.61 ≤ r ≤ 0.74) (2). The latent structural equation modeling (SEM) (R2 = 51%) revealed a significant influence on BMSlat for MOMIR (β = 0.51, p <0.05). The additional contribution of PAHKR (β = 0.27, p = 0.06) and SAUS (β = −0.03, p = 0.90) was rather small (3). The investigation of individual differences between the reference method and alternative diagnostics indicated a significant bias for MOMIR (p <0.01). The results support the use of economical and time-efficient methods for assessing BMS within elite youth soccer. Bivariate correlation analyses as well as the multivariate latent variable approach highlight the measures' usefulness. However, the observed individual level differences for some of the utilized procedures led to the recommendation for practitioners to use at least two alternative assessment methods in order to receive more reliable information about players' BMS within the talent promotion process.
Systemic inflammation is associated with alterations in complex brain functions such as learning and memory. However, diagnostic approaches to functionally assess and quantify inflammation-associated alterations in synaptic plasticity are not well-established. In previous work, we demonstrated that bacterial lipopolysaccharide (LPS)-induced systemic inflammation alters the ability of hippocampal neurons to express synaptic plasticity, i.e., the long-term potentiation (LTP) of excitatory neurotransmission. Here, we tested whether synaptic plasticity induced by repetitive magnetic stimulation (rMS), a non-invasive brain stimulation technique used in clinical practice, is affected by LPS-induced inflammation. Specifically, we explored brain tissue cultures to learn more about the direct effects of LPS on neural tissue, and we tested for the plasticity-restoring effects of the anti-inflammatory cytokine interleukin 10 (IL10). As shown previously, 10 Hz repetitive magnetic stimulation (rMS) of organotypic entorhino-hippocampal tissue cultures induced a robust increase in excitatory neurotransmission onto CA1 pyramidal neurons. Furthermore, LPS-treated tissue cultures did not express rMS-induced synaptic plasticity. Live-cell microscopy in tissue cultures prepared from a novel transgenic reporter mouse line [C57BL/6-Tg(TNFa-eGFP)] confirms that ex vivo LPS administration triggers microglial tumor necrosis factor alpha (TNFα) expression, which is ameliorated in the presence of IL10. Consistent with this observation, IL10 hampers the LPS-induced increase in TNFα, IL6, IL1β, and IFNγ and restores the ability of neurons to express rMS-induced synaptic plasticity in the presence of LPS. These findings establish organotypic tissue cultures as a suitable model for studying inflammation-induced alterations in synaptic plasticity, thus providing a biological basis for the diagnostic use of transcranial magnetic stimulation in the context of brain inflammation.
Andropogon virginicus is an invasive weed that seriously threatens agricultural production and economics worldwide. In this research, dried aerial parts of A. virginicus were extracted, applying Soxhlet and liquid-liquid phase methods to acquire the total crude (T-Anvi), hexane (H-Anvi), ethyl acetate (E-Anvi), butanol (B-Anvi), and water (W-Anvi) extracts, respectively. In which, T-Anvi contains the highest total phenolic and flavonoid contents (24.80 mg gallic acid and 37.40 mg rutin equivalents per g dry weight, respectively). Via anti-radical (ABTS and DPPH), and reducing power assays, E-Anvi exhibits the most potent activities (IC50 = 13.96, 43.59 and 124.11 µg/mL, respectively), stronger than butylated hydroxytoluene (BHT), a standard antioxidant, while the lipid peroxidation inhibitory effect of E-Anvi (LPI = 90.85% at the concentration of 500 µg/mL) is close to BHT. E-Anvi shows the most substantial inhibition (IC50 = 2.58 mg/mL) on tyrosinase. Notably, α-amylase is significantly suppressed by H-Anvi (IC50 = 0.72 mg/mL), over twice stronger than the positive control, palmitic acid. In the cytotoxic assay, E-Anvi is the strongest extract inhibiting K562 cells (IC50 = 112.01 µg/mL). Meanwhile, T-Anvi shows the highest prevention on Meg-01 expansion (IC50 = 91.40 µg/mL). Dominant compounds detected in E-Anvi by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) are identified as flavonoids. However, among four major compounds identified in H-Anvi by gas chromatography-mass spectrometry (GC-MS), palmitic acid and phytol are the most abundant compounds with peak areas of 27.97% and 16.42%, respectively. In essence, this is the first report describing that A. virginicus is a potential natural source of antioxidants, tyrosinase and α-amylase inhibitors, and anti-chronic myeloid leukemia (CML) agents which may be useful in future therapeutics as promising alternative medicines.
Largely unnoticed, all life on earth is constantly exposed to low levels of ionizing radiation. Radon, an imperceptible natural occurring radioactive noble gas, contributes as the largest single fraction to radiation exposure from natural sources. For that reason, radon represents a major issue for radiation protection. Nevertheless, radon is also applied for the therapy of inflammatory and degenerative diseases in galleries and spas to many thousand patients a year. In either case, chronic environmental exposure or therapy, the effect of radon on the organism exposed is still under investigation at all levels of interaction. This includes the physical stage of diffusion and energy deposition by radioactive decay of radon and its progeny and the biological stage of initiating and propagating a physiologic response or inducing cancer after chronic exposure. The purpose of this manuscript is to comprehensively review the current knowledge of radon and its progeny on physical background, associated cancer risk and potential therapeutic effects.
We sought to determine the effects of the use of a Bioengineered Combo Dual-Therapy CD34 Antibody-Covered Sirolimus-Eluting Coronary Stent (Combo® DTS) in patients with chronic total occlusion (CTO) by evaluating clinical outcomes and by performing an optical coherence tomography (OCT) analysis. We retrospectively analyzed data from 39 patients who had successfully undergone OCT-guided revascularization of a CTO being treated with a Combo® DTS. Clinical assessment, angiography (with quantitative coronary angiography analysis) and OCT examination were performed at baseline and at follow-up. The median follow-up period was 189 days, ranging from 157 to 615 days. At follow-up, revascularization was required due to angiographic restenosis in 40% (14 of 35) of patients. OCT analysis detected neointima proliferation in 23 (76.6%) patients. Neointima formation was often associated with microvessels in 18 patients (60%). Neoatheroslcerosis was observed in 2 (6.6%) patients. Malapposition was found in 4 patients (13.3%), and stent fractures were found in 11 patients (36.6%). Rate of strut coverage was 96.3% at follow-up. In conclusion, the implantation of a Combo® DTS after successful CTO recanalization was associated with a restenosis rate of 40% despite good stent implantation at baseline, proven by OCT. Neointima formation was found as a main contributor to restenosis. Nevertheless, we observed a low rate of major cardiovascular events in our follow-up.
Introduction: In patients with severe pelvic ring injuries, exsanguination still is the leading cause of death in the early post-injury phase. While mechanical pelvic ring stabilization and pre-peritoneal pelvic packing are mainly addressing venous bleeding, angio-embolization aims to control arterial bleeding. The goal of the present study was to evaluate the rate of postoperative angio-embolization after mechanical pelvic ring injury stabilization and pre-peritoneal pelvic packing. Bleeding sources detected in the angiography and the patient's outcome were investigated. Patients and Methods: Retrospective observational cohort study at a single academic level I trauma center, reviewing all patients with pelvic ring injuries admitted from 01/2010 to 12/2019. Patients with emergent mechanical pelvic ring stabilization (supraacetabular external fixator and/or pelvic C-clamp) and direct pre-peritoneal pelvic packing were further analyzed. Patients that underwent postoperative angio-embolization were compared with those that did not. All postoperative angio-embolizations were evaluated with regards to bleeding sources and type of embolization. Results: During the study period, a total of 39 patients required immediate mechanical pelvic stabilization and direct pre-peritoneal pelvic packing. Of these, 12 patients (30.8%) underwent a postoperative angio-embolization. The following vessels were identified as bleeding sources: superior gluteal artery (n = 6), obturator artery (n = 2), internal pudendal artery (n = 2), unnamed branches of the internal iliac artery (n = 3). A selective embolization was successful in 11 patients; in 1 patient, an unilateral complete occlusion of the internal iliac artery was performed to control the bleeding. Mean time from hospital admission to the surgical procedure was 52.8 ± 14.7 min and the mean time from admission to angio-embolization was 189.1 ± 55.5 min. The in-hospital mortality rate of patients with angio-embolization was 25.0% (n = 3). Of these, 2 patients died due to multiple organ failure and 1 patient due to severe head injury. Conclusion: Secondary angio-embolization after external pelvic fixation and pre-peritoneal pelvic packing was effective in controlling ongoing bleeding. The most frequently detected bleeding vessel was the superior gluteal artery, which is difficult to surgically address, further highlighting the importance of angio-embolization in the management algorithm.
New innovative neuropsychological tests in attention deficit hyperactivity disorder ADHD have been proposed as objective measures for diagnosis and therapy. The current study aims to investigate two different commercial continuous performance tests (CPT) in a head-to-head comparison regarding their comparability and their link with clinical parameters. The CPTs were evaluated in a clinical sample of 29 adult patients presenting in an ADHD outpatient clinic. Correlational analyses were performed between neuropsychological data, clinical rating scales, and a personality-based measure. Though inattention was found to positively correlate between the two tests (r = 0.49, p = 0.01), no association with clinical measures and inattention was found for both tests. While hyperactivity did not correlate between both tests, current ADHD symptoms were positively associated with Nesplora Aquarium’s motor activity (r = 0.52 to 0.61, p < 0.05) and the Qb-Test’s hyperactivity (r = 0.52 to 0.71, p < 0.05). Conclusively, the overall comparability of the tests was limited and correlation with clinical parameters was low. While our study shows some interesting correlation between clinical symptoms and sub-scales of these tests, usage in clinical practice is not recommended.
The float serve is an effective weapon to impede the attack of the opposing team. Because of its great importance in indoor and beach volleyball, we measured and quantified the float effect. We recorded 24 float serves of 12 top athletes in beach volleyball and indoor volleyball, respectively, and analyzed them using video analysis. We determined the 3D trajectories of the ball flight and developed two measures to describe the size of the float effect, the mean residuals and the anticipation error. Both were derived from regression models. These measures suggest that the float effect is greater in the vertical plane than in the horizontal plane, both for indoor and beach volleyball. Analyses of ball release velocities suggest that a certain ball release velocity is a necessary, but not sufficient, condition for ball floating. A validation of the float measurements with subjective expert ratings showed a correlation with the horizontal deviations. This study provides a new approach to analyze floating in on-court volleyball serves and broadens the knowledge for float effects in sports.
Tumor-associated macrophages (TAMs) influence lung tumor development by inducing immunosuppression. Transcriptome analysis of TAMs isolated from human lung tumor tissues revealed an up-regulation of the Wnt/β-catenin pathway. These findings were reproduced in a newly developed in vitro “trained” TAM model. Pharmacological and macrophage-specific genetic ablation of β-catenin reprogrammed M2-like TAMs to M1-like TAMs both in vitro and in various in vivo models, which was linked with the suppression of primary and metastatic lung tumor growth. An in-depth analysis of the underlying signaling events revealed that β-catenin–mediated transcriptional activation of FOS-like antigen 2 (FOSL2) and repression of the AT-rich interaction domain 5A (ARID5A) drive gene regulatory switch from M1-like TAMs to M2-like TAMs. Moreover, we found that high expressions of β-catenin and FOSL2 correlated with poor prognosis in patients with lung cancer. In conclusion, β-catenin drives a transcriptional switch in the lung tumor microenvironment, thereby promoting tumor progression and metastasis.
Background: Since January 2018 performance of urethroplasties is done on regular basis at the University Hospital Frankfurt (UKF). We aimed to implement and transfer an institutional standardized perioperative algorithm for urethral surgery (established at the University Hospital Hamburg-Eppendorf—UKE) using a validated Urethral Stricture Surgery Patient-Reported Outcome Measure (USS-PROM) in patients undergoing urethroplasty at UKF. Materials and Methods: We retrospectively analyzed all patients who underwent urethroplasty for urethral stricture disease between January 2018 and January 2020 at UKF. All patients were offered to revisit for clinical follow-up (FU) and completion of USS-PROM. Primary end point was stricture recurrence-free survival (RFS). Secondary endpoints were functional outcomes, quality of life (QoL), and patient satisfaction. Results: In total, 50 patients underwent urethroplasty and 74 and 24% had a history of previous urethrotomy or urethroplasty, respectively. A buccal mucosal graft urethroplasty was performed in 86% (n = 43). After patient's exclusion due to lost of FU, FU <3 months, and/or a pending second stage procedure, 40 patients were eligible for final analysis. At median FU of 10 months (interquartile-range 5.0–18.0), RFS was 83%. After successful voiding trial, the postoperative median Qmax significantly improved (24.0 vs. 7.0 mL/s; p < 0.01). Conversely, median residual urine decreased significantly (78 vs. 10 mL; p < 0.01). Overall, 95% of patients stated that QoL improved and 90% were satisfied by the surgical outcome. Conclusions: We demonstrated a successful implementation and transfer of an institutional standardized perioperative algorithm for urethral surgery from one location (UKE) to another (UKF). In our short-term FU, urethroplasty showed excellent RFS, low complication rates, good functional results, improvement of QoL and high patient satisfaction. PROMs allow an objective comparison between different centers.
While impulsivity is a basic feature of attention-deficit / hyperactivity disorder (ADHD), no study explored the effect of different components of the Impulsiveness (Imp) and Venturesomeness (Vent) scale (IV7) on psychiatric comorbidities and an ADHD polygenic risk score (PRS). We used the IV7 self-report scale in an adult ADHD sample of 903 patients, 70% suffering from additional comorbid disorders, and in a subsample of 435 genotyped patients. Venturesomeness, unlike immediate Impulsivity, is not specific to ADHD. We consequently analyzed the influence of Imp and Vent also in the context of a PRS on psychiatric comorbidities of ADHD. Vent shows a distinctly different distribution of comorbidities, e.g., less anxiety and depression. PRS showed no effect on different ADHD comorbidities, but correlated with childhood hyperactivity. In a complementary analysis using principal component analysis with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition ADHD criteria, revised NEO Personality Inventory, Imp, Vent, and PRS, we identified three ADHD subtypes. These are an impulsive–neurotic type, an adventurous–hyperactive type with a stronger genetic component, and an anxious–inattentive type. Our study thus suggests the importance of adventurousness and the differential consideration of impulsivity in ADHD. The genetic risk is distributed differently between these subtypes, which underlines the importance of clinically motivated subtyping. Impulsivity subtyping might give insights into the organization of comorbid disorders in ADHD and different genetic background.
Purpose: To develop and validate a CT-based radiomics signature for the prognosis of loco-regional tumour control (LRC) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated by primary radiochemotherapy (RCTx) based on retrospective data from 6 partner sites of the German Cancer Consortium - Radiation Oncology Group (DKTK-ROG).
Material and methods: Pre-treatment CT images of 318 patients with locally advanced HNSCC were collected. Four-hundred forty-six features were extracted from each primary tumour volume and then filtered through stability analysis and clustering. First, a baseline signature was developed from demographic and tumour-associated clinical parameters. This signature was then supplemented by CT imaging features. A final signature was derived using repeated 3-fold cross-validation on the discovery cohort. Performance in external validation was assessed by the concordance index (C-Index). Furthermore, calibration and patient stratification in groups with low and high risk for loco-regional recurrence were analysed.
Results: For the clinical baseline signature, only the primary tumour volume was selected. The final signature combined the tumour volume with two independent radiomics features. It achieved moderately good discriminatory performance (C-Index [95% confidence interval]: 0.66 [0.55–0.75]) on the validation cohort along with significant patient stratification (p = 0.005) and good calibration.
Conclusion: We identified and validated a clinical-radiomics signature for LRC of locally advanced HNSCC using a multi-centric retrospective dataset. Prospective validation will be performed on the primary cohort of the HNprädBio trial of the DKTK-ROG once follow-up is completed.
The β-carboline alkaloid harmine is a potent DYRK1A inhibitor, but suffers from undesired potent inhibition of MAO-A, which strongly limits its application. We synthesized more than 60 analogues of harmine, either by direct modification of the alkaloid or by de novo synthesis of β-carboline and related scaffolds aimed at learning about structure-activity relationships for inhibition of both DYRK1A and MAO-A, with the ultimate goal of separating desired DYRK1A inhibition from undesired MAO-A inhibition. Based on evidence from published crystal structures of harmine bound to each of these enzymes, we performed systematic structure modifications of harmine yielding DYRK1A-selective inhibitors characterized by small polar substituents at N-9 (which preserve DYRK1A inhibition and eliminate MAO-A inhibition) and beneficial residues at C-1 (methyl or chlorine). The top compound AnnH75 remains a potent DYRK1A inhibitor, and it is devoid of MAO-A inhibition. Its binding mode to DYRK1A was elucidated by crystal structure analysis, and docking experiments provided additional insights for this attractive series of DYRK1A and MAO-A inhibitors.
Ataxia-Telangiectasia (A-T), a pleiotropic chromosomal breakage syndrome, is caused by the loss of the kinase Ataxia-telangiectasia mutated (ATM). ATM is not only involved in the response to DNA damage, but also in sensing and counteracting oxidative stress. Since a disturbed redox balance has been implicated in the pathophysiology of A-T lung disease, we aimed to further explore the interplay between ATM and oxidative stress in lung cells. Using a kinetic trapping approach, we could demonstrate an interaction between the trapping mutant TRX1-CS and ATM upon oxidative stress. We could further show that combined inhibition of thioredoxin reductase (TrxR) and ATM kinase activity, using Auranofin and KU55933 respectively, induced an increase in cellular reactive oxygen species (ROS) levels and protein oxidation in lung cells. Furthermore, ATM inhibition sensitized lung cells to Auranofin-induced cell death that could be rescued by ROS scavengers. As a consequence, targeted reduction of ATM by TRX1 could serve as a regulator of oxidative ATM activation and contribute to the maintenance of the cellular redox homeostasis. These results highlight the importance of the redox-active function of ATM in preventing ROS accumulation and cell death in lung cells.
Characterization of neonates born to mothers with SARS-CoV-2 infection: review and meta-analysis
(2020)
Characterization of neonates born to mothers with SARS-CoV-2 infection has been partially carried out. There has been no systematic review providing a holistic neonatal presentation including possible vertical transmission. A systematic literature search was performed using PubMed, Google Scholar and Web of Science up to June, 6 2020. Studies on neonates born to mothers with SARS-CoV-2 infection were included. A binary random effect model was used for prevalence and 95% confidence interval. 32 studies involving 261 neonates were included in meta-analysis. Most neonates born to infected mothers did not show any clinical abnormalities (80.4%). Clinical features were dyspnea in 11 (42.3%) and fever in 9 newborns (19.1%). Of 261 neonates, 120 neonates were tested for infection, of whom 12 (10.0%) tested positive. Swabs from placenta, cord blood and vaginal secretion were negative. Neonates are mostly non affected by the mother's SARS-CoV-2 infection. The risk of vertical transmission is low.
The B-cell receptor (BCR) signaling pathway is a crucial pathway of B cells, both for their survival and for antigen-mediated activation, proliferation and differentiation. Its activation is also critical for the genesis of many lymphoma types. BCR-mediated lymphoma proliferation may be caused by activating BCR-pathway mutations and/or by active or tonic stimulation of the BCR. BCRs of lymphomas have frequently been described as polyreactive. In this review, the role of specific target antigens of the BCRs of lymphomas is highlighted. These antigens have been found to be restricted to specific lymphoma entities. The antigens can be of infectious origin, such as H. pylori in gastric MALT lymphoma or RpoC of M. catarrhalis in nodular lymphocyte predominant Hodgkin lymphoma, or they are autoantigens. Examples of such autoantigens are the BCR itself in chronic lymphocytic leukemia, LRPAP1 in mantle cell lymphoma, hyper-N-glycosylated SAMD14/neurabin-I in primary central nervous system lymphoma, hypo-phosphorylated ARS2 in diffuse large B-cell lymphoma, and hyper-phosphorylated SLP2, sumoylated HSP90 or saposin C in plasma cell dyscrasia. Notably, atypical posttranslational modifications are often responsible for the immunogenicity of many autoantigens. Possible therapeutic approaches evolving from these specific antigens are discussed.
Background: Musculoskeletal disorders (MSD) are common among dental professionals. The most common areas affected are the trunk, neck, shoulders and wrists. Current evidence suggests that the causes of MSD can be found in the physical demands of the profession. Posture and movement during treatment is influenced by the arrangement of the treatment concept (patient chair, equipment and cabinets). It has not been investigated whether the ergonomic risk differs between the treatment concepts.
Methods: To evaluate the prevalence of MSD in dental professionals, 1000 responses will be collected from a nationwide (Germany) online questionnaire (mod. Nordic Questionnaire and mod. Meyer questionnaire). In order to assess the ergonomic risk of the treatment techniques used in the four treatment concepts, 3D movement analyses are carried out with inertial sensors. For this purpose, 20 teams of dentists and dental assistants from four dental fields of specializations (generalists, orthodontists, endodontists and oral surgeons) and a student control group will be recruited. Each team will execute field specific standardized treatments at a dummy head. Measurements are carried out in each of the four treatment concepts. The data will be analyzed using the Rapid Upper Limb Assessment (RULA) which will be modified for the evaluation of objective data.
Conclusions: On the basis of these investigations, a substantial gain of knowledge regarding work-related MSD in the field of dentistry and its potential biomechanical causes is possible. For the first time, objective and differentiated comparisons between the four treatment concepts are possible for different fields of dental specialization. Up to now, statically held positions of the trunk and proximal upper extremities, but also the repetitive movements of the hands have been considered a risk for MSD. Since both are included in the RULA, dental activities can be assessed in a detailed but also global manner with regard to ergonomic risks.
Background: The aim of this pilot study was to analyze postures during the work of neurologists with respect to their occupational activities.
Methods: A total data material of 64.8 h (3885.74 min) of nine (three m/six f) neurologists (assistant physicians) was collected. Kinematic data were collected using the CUELA system (electro-goniometry). In addition, the occupational tasks performed on-site were subject to a detailed objective activity analysis. All activities were assigned to the categories "Office activities" (I), "Measures on patients" (II) and "Other activities" (III). The angle values of each body region (evaluation parameters) were evaluated according to ergonomic ISO standards.
Results: Only 3.4% of the working hours were spent with (II), while 50.8% of time was spent with (I) and 45.8% with (III). All tasks of category (II) revealed an increased ergonomic risk to the head, neck, trunk and back areas. During category (I) especially neck and back movements in the sagittal plane showed higher ergonomic risk levels.
Conclusion: Despite frequently performed awkward body positions in (II), the ergonomic risk is considered as rather low, since the percentage time share totaled only 3.4%. As a result, "Office activities" have been detected as high predictor to cause stress load on the musculoskeletal system in the daily work of neurologists.
Sarcomas are rare cancers with high heterogeneity in terms of type, location, and treatment. The health-related quality of life (HRQoL) of sarcoma patients has rarely been investigated and is the subject of this analysis. Adult sarcoma patients and survivors were assessed between September 2017 and February 2019 in 39 study centers in Germany using standardized, validated questionnaires (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)). Associated factors were analyzed exploratively using multivariable linear regressions. Among 1113 patients, clinically important limitations and symptoms were most pronounced in emotional (63%, 95% CI 60–66%), physical (60%, 95% CI 57–62%), role functioning (51%, 95% CI 48–54%), and pain (56%, 95% CI 53–59%) and fatigue (51%, 95% CI 48–54%). HRQoL differed between tumor locations with lower extremities performing the worst and sarcoma types with bone sarcoma types being most affected. Additionally, female gender, higher age, lower socioeconomic status, recurrent disease, not being in retirement, comorbidities, and being in treatment were associated with lower HRQoL. Sarcoma patients are severely restricted in their HRQoL, especially in functioning scales. The heterogeneity of sarcomas with regard to type and location is reflected in HRQoL outcomes. During treatment and follow-up, close attention has to be paid to the reintegration of the patients into daily life as well as to their physical abilities and emotional distress.
Tyrosine kinase inhibitors (TKIs) are currently the standard chemotherapeutic agents for the treatment of chronic myeloid leukemia (CML). However, due to TKI resistance acquisition in CML patients, identification of new vulnerabilities is urgently required for a sustained response to therapy. In this study, we have investigated metabolic reprogramming induced by TKIs independent of BCR-ABL1 alterations. Proteomics and metabolomics profiling of imatinib-resistant CML cells (ImaR) was performed. KU812 ImaR cells enhanced pentose phosphate pathway, glycogen synthesis, serine-glycine-one-carbon metabolism, proline synthesis and mitochondrial respiration compared with their respective syngeneic parental counterparts. Moreover, the fact that only 36% of the main carbon sources were utilized for mitochondrial respiration pointed to glycerol-phosphate shuttle as mainly contributors to mitochondrial respiration. In conclusion, CML cells that acquire TKIs resistance present a severe metabolic reprogramming associated with an increase in metabolic plasticity needed to overcome TKI-induced cell death. Moreover, this study unveils that KU812 Parental and ImaR cells viability can be targeted with metabolic inhibitors paving the way to propose novel and promising therapeutic opportunities to overcome TKI resistance in CML.
The multifunctional HSP70 co-chaperone BAG3 (BCL-2-associated athanogene 3) represents a key player in the quality control of the cellular proteostasis network. In response to stress, BAG3 specifically targets aggregation-prone proteins to the perinuclear aggresome and promotes their degradation via BAG3-mediated selective macroautophagy. To adapt cellular homeostasis to stress, BAG3 modulates and functions in various cellular processes and signaling pathways. Noteworthy, dysfunction and deregulation of BAG3 and its pathway are pathophysiologically linked to myopathies, cancer, and neurodegenerative disorders. Here, we report a BAG3 proteomic signature under proteostasis stress. To elucidate the dynamic and multifunctional action of BAG3 in response to stress, we established BAG3 interactomes under basal and proteostasis stress conditions by employing affinity purification combined with quantitative mass spectrometry. In addition to the identification of novel potential BAG3 interactors, we defined proteins whose interaction with BAG3 was altered upon stress. By functional annotation and protein-protein interaction enrichment analysis of the identified potential BAG3 interactors, we confirmed the multifunctionality of BAG3 and highlighted its crucial role in diverse cellular signaling pathways and processes, ensuring cellular proteostasis and cell viability. These include protein folding and degradation, gene expression, cytoskeleton dynamics (including cell cycle and transport), as well as granulostasis, in particular.
Ferric carboxymaltose (FCM) has been shown to achieve rapid replenishment of iron stores and correction of anaemia in various populations with iron deficiency. A decrease in serum phosphate (PO43−) levels, which in most cases is asymptomatic, has been reported with IV iron preparations. Hypophosphataemia (HP) is a known adverse drug reaction with FCM. This post hoc pooled analysis investigates the frequency, duration, risk factors, and clinical signs of HP as reported in interventional clinical trials with FCM. Pooled data from subjects enrolled across 45 clinical trials in different therapy areas were included. A three-step adjudication process was utilised to identify adverse events of HP. Stratified analyses by therapy group and stepwise logistic regression analysis were used to identify predictors of HP. This pooled analysis confirms that FCM is associated with increased rates of serum PO43− lowering, but mean serum PO43− values were seen to recover at Week 4 and further recover at Week 8. Among all subjects receiving FCM therapy (n = 6879), 41.4% (n = 2847) reached a PO43− nadir value <2.5 mg/dL at any point on study and 0.7% (n = 49) reached a nadir <1 mg/dL. Although gastroenterology and women’s health subjects were identified to be at higher risk, occurrence of severe HP (<1 mg/dL [0.3 mmol/L]) following FCM administration was not observed to be common among subjects in these studies. Furthermore, there was no correlation between laboratory serum PO43− values and the occurrence of reported adverse events related to low PO43− levels.
Improving long-term patient and graft survival after liver transplantation (LT) remains a major challenge. Compared to the early phase after LT, long-term morbidity and mortality of the recipients not only depends on complications immediately related to the graft function, infections, or rejection, but also on medical factors such as de novo malignancies, metabolic disorders (e.g., new-onset diabetes, osteoporosis), psychiatric conditions (e.g., anxiety, depression), renal failure, and cardiovascular diseases. While a comprehensive post-transplant care at the LT center and the connected regional networks may improve outcome, there is currently no generally accepted standard to the post-transplant management of LT recipients in Germany. We therefore described the structure and standards of post-LT care by conducting a survey at 12 German LT centers including transplant hepatologists and surgeons. Aftercare structures and form of cost reimbursement considerably varied between LT centers across Germany. Further discussions and studies are required to define optimal structure and content of post-LT care systems, aiming at improving the long-term outcomes of LT recipients.
Transjugular intrahepatic portosystemic shunt (TIPS) is an established treatment tool in decompensated liver cirrhosis that has been shown to prolong transplant-free survival. Hepatic encephalopathy (HE) is a frequent complication of decompensated cirrhosis, eventually induced and/or aggravated by TIPS, that remains a clinical challenge especially in these patients. Therefore, patient selection for TIPS requires careful assessment of risk factors for HE. TIPS procedural parameters regarding stent size and invasive portosystemic pressure gradient measurements thereby have an important role. Endovascular shunt modification, in combination with a conservative medical approach, often results in a significant reduction of symptoms. This review summarizes HE molecular mechanisms and pathophysiology as well as diagnostic and therapeutic approaches targeting shunt-induced HE.
Lack of sensitive diagnostic tests impairs the understanding of the epidemiology of histoplasmosis, a disease whose burden is estimated to be largely underrated. Broad-range PCRs have been applied to identify fungal agents from pathology blocks, but sensitivity is variable. In this study, we compared the results of a specific Histoplasma qPCR (H. qPCR) with the results of a broad-range qPCR (28S qPCR) on formalin-fixed, paraffin-embedded (FFPE) tissue specimens from patients with proven fungal infections (n = 67), histologically suggestive of histoplasmosis (n = 36) and other mycoses (n = 31). The clinical sensitivity for histoplasmosis of the H. qPCR and the 28S qPCR was 94% and 48.5%, respectively. Samples suggestive for other fungal infections were negative with the H. qPCR. The 28S qPCR did not amplify DNA of Histoplasma in FFPE in these samples, but could amplify DNA of Emergomyces (n = 1) and Paracoccidioides (n = 2) in three samples suggestive for histoplasmosis but negative in the H. qPCR. In conclusion, amplification of Histoplasma DNA from FFPE samples is more sensitive with the H. qPCR than with the 28S qPCR. However, the 28S qPCR identified DNA of other fungi in H. qPCR-negative samples presenting like histoplasmosis, suggesting that the combination of both assays may improve the diagnosis.
Central nervous hyperarousal is as a key component of current pathophysiological concepts of chronic insomnia disorder. However, there are still open questions regarding its exact nature and the mechanisms linking hyperarousal to sleep disturbance. Here, we aimed at studying waking state hyperarousal in insomnia by the perspective of resting-state vigilance dynamics. The VIGALL (Vigilance Algorithm Leipzig) algorithm has been developed to investigate resting-state vigilance dynamics, and it revealed, for example, enhanced vigilance stability in depressive patients. We hypothesized that patients with insomnia also show a more stable vigilance regulation. Thirty-four unmedicated patients with chronic insomnia and 25 healthy controls participated in a twenty-minute resting-state electroencephalography (EEG) measurement following a night of polysomnography. Insomnia patients showed enhanced EEG vigilance stability as compared to controls. The pattern of vigilance hyperstability differed from that reported previously in depressive patients. Vigilance hyperstability was also present in insomnia patients showing only mildly reduced sleep efficiency. In this subgroup, vigilance hyperstability correlated with measures of disturbed sleep continuity and arousal. Our data indicate that insomnia disorder is characterized by hyperarousal at night as well as during daytime.
The present study considered the entire leg alignment and links static parameters to the external joint moments during gait in patients with hip osteoarthritis. Eighteen patients with unilateral hip osteoarthritis were measured using the EOS® system. Clinical leg alignment and femoral parameters were extracted from the 3D reconstruction of the EOS images. A 3D gait analysis was performed and external knee and hip adduction moments were computed and compared to 18 healthy controls in the same age group. The knee adduction moments of the involved leg were strongly correlated to the femoral offset and the varus/valgus alignment. These parameters alone explained over 50% of the variance in the knee adduction moments. Adding the pelvic drop of the contralateral side increased the model of femoral offset and varus/valgus alignment and explained 78% of the knee adduction moment during the first half of the stance phase. The hip adduction moments were best associated with the hip kinematics and not the leg alignment.
Background: The ERGO2 (Ernaehrungsumstellung bei Patienten mit Rezidiv eines Glioblastoms) MR-spectroscopic imaging (MRSI) subtrial investigated metabolism in patients randomized to calorically restricted ketogenic diet/intermittent fasting (crKD-IF) versus standard diet (SD) in addition to re-irradiation (RT) for recurrent malignant glioma. Intracerebral concentrations of ketone bodies (KB), intracellular pH (pHi), and adenosine triphosphate (ATP) were non-invasively determined. Methods: 50 patients were randomized (1:1): Group A keeping a crKD-IF for nine days, and Group B a SD. RT was performed on day 4-8. Twenty-three patients received an extended MRSI-protocol (1H decoupled 31P MRSI with 3D chemical shift imaging (CSI) and 2D 1H point-resolved spectroscopy (PRESS)) at a 3T scanner at baseline and on day 6. Voxels were selected from the area of recurrent tumor and contralateral hemisphere. Spectra were analyzed with LCModel, adding simulated signals of 3-hydroxybutyrate (βOHB), acetone (Acn) and acetoacetate (AcAc) to the standard basis set. Results: Acn was the only reliably MRSI-detectable KB within tumor tissue and/or normal appearing white matter (NAWM). It was detected in 4/11 patients in Group A and in 0/8 patients in Group B. MRSI results showed no significant depletion of ATP in tumor tissue of patients at day 6 during crKD-IF, even though there were a significant difference in ketone serum levels between Group A and B at day 6 and a decline in fasting glucose in Group A from baseline to day 6. The tumor specific alkaline pHi was maintained. Conclusions: Our metabolic findings suggest that tumor cells maintain energy homeostasis even with reduced serum glucose levels and may generate additional ATP through other sources.r sources.
Context: Autoimmune polyglandular syndrome (APS-2: autoimmune Addison’s disease or type 1 diabetes) is conferred by predisposing HLA molecules, vitamin D deficiency, and heritable susceptibility. Organ destruction is accompanied by cytokine alterations. We addressed the monocytic cytokines of two distinct APS-2 cohorts, effects of vitamin D and HLA DQ risk.
Methods: APS-2 patients (n = 30) and healthy controls (n = 30) were genotyped for HLA DQA1/DQB1 and their CD14+ monocytes stimulated with IL1β and/or 1,25(OH)2D3 for 24 h. Immune regulatory molecules (IL-6, IL-10, IL-23A, IL-15, CCL-2, PD-L1), vitamin D pathway gene transcripts (CYP24A1, CYP27B1, VDR), and CD14 were analyzed by enzyme-linked immunosorbent assay and RTqPCR. Results: Pro-inflammatory CCL-2 was higher in APS-2 patients than in controls (p = 0.001), whereas IL-6 showed a trend – (p = 0.1). In vitro treatment with 1,25(OH)2D3 reduced proinflammatory cytokines (IL-6, CCL-2, IL-23A, IL-15) whereas anti-inflammatory cytokines (IL-10 and PD-L1) rose both in APS-type 1 diabetes and APS-Addison´s disease. Patients with adrenal autoimmunity showed a stronger response to vitamin D. Expression of IL-23A and vitamin D pathway genes VDR and CYP27B1 varied by HLA genotype and was lower in healthy individuals with high-risk HLA (p = 0.0025; p = 0.04), while healthy controls with low-risk HLA showed a stronger IL-10 and CD14 expression (p = 0.01; p = 0.03). Conclusion: 1,25(OH)2D3 regulates the monocytic response in APS-2 disorders type 1 diabetes or Addison´s disease. The monocytic cytokine profile of individuals carrying HLA high-risk alleles is proinflammatory, enhances polyglandular autoimmunity and can be targeted by vitamin D.
Background: Vacuum cleaning, which is associated with musculoskeletal complaints, is frequently carried out in private households and by professional cleaners. The aim of this pilot study was to quantify the movements during habitual vacuuming and to characterize the movement profile with regard to its variability. Methods: The data were collected from 31 subjects (21 f/10 m) using a 3D motion analysis system (XSens). Eight vacuum cleaners were used to vacuum polyvinyl chloride (PVC) and carpet floors. In 15 joints of the right upper extremity, the trunk and the lower extremities, Principal Component Analysis was used to determine the predominantly varying joints during vacuuming. Results: The movements of the trunk and the lower extremities were relatively constant and, therefore, had less influence. The shoulder, elbow and wrist joints were identified as joints that can be decisive for the movement profile and that can be influenced. These joints were represented in the course of the vacuuming cycle by the mean movement with its standard deviation. Conclusion: In summary, the generalization of a movement profile is possible for the trunk and the lower extremities due to the relative homogeneity. In future it will be necessary to identify factors influencing variability in order to draw conclusions about movement ergonomics.
The assessment of knee or hip joint loading by external joint moments is mainly used to draw conclusions on clinical decision making. However, the correlation between internal and external loads has not been systematically analyzed. This systematic review aims, therefore, to clarify the relationship between external and internal joint loading measures during gait. A systematic database search was performed to identify appropriate studies for inclusion. In total, 4,554 articles were identified, while 17 articles were finally included in data extraction. External joint loading parameters were calculated using the inverse dynamics approach and internal joint loading parameters by musculoskeletal modeling or instrumented prosthesis. It was found that the medial and total knee joint contact forces as well as hip joint contact forces in the first half of stance can be well predicted using external joint moments in the frontal plane, which is further improved by including the sagittal joint moment. Worse correlations were found for the peak in the second half of stance as well as for internal lateral knee joint contact forces. The estimation of external joint moments is useful for a general statement about the peak in the first half of stance or for the maximal loading. Nevertheless, when investigating diseases as valgus malalignment, the estimation of lateral knee joint contact forces is necessary for clinical decision making because external joint moments could not predict the lateral knee joint loading sufficient enough. Dependent on the clinical question, either estimating the external joint moments by inverse dynamics or internal joint contact forces by musculoskeletal modeling should be used.
SUMOylation is a reversible posttranslational modification pathway catalyzing the conjugation of small ubiquitin-related modifier (SUMO) proteins to lysine residues of distinct target proteins. SUMOylation modifies a wide variety of cellular regulators thereby affecting a multitude of key processes in a highly dynamic manner. The SUMOylation pathway displays a hallmark in cellular stress-adaption, such as heat or redox stress. It has been proposed that enhanced cellular SUMOylation protects the brain during ischemia, however, little is known about the specific regulation of the SUMO system and the potential target proteins during cardiac ischemia and reperfusion injury (I/R). By applying left anterior descending (LAD) coronary artery ligation and reperfusion in mice, we detect dynamic changes in the overall cellular SUMOylation pattern correlating with decreased SUMO deconjugase activity during I/R injury. Further, unbiased system-wide quantitative SUMO-proteomics identified a sub-group of SUMO targets exhibiting significant alterations in response to cardiac I/R. Notably, transcription factors that control hypoxia- and angiogenesis-related gene expression programs, exhibit altered SUMOylation during ischemic stress adaptation. Moreover, several components of the ubiquitin proteasome system undergo dynamic changes in SUMO conjugation during cardiac I/R suggesting an involvement of SUMO signaling in protein quality control and proteostasis in the ischemic heart. Altogether, our study reveals regulated candidate SUMO target proteins in the mouse heart, which might be important in coping with hypoxic/proteotoxic stress during cardiac I/R injury.
To successfully learn using open Internet resources, students must be able to critically search, evaluate and select online information, and verify sources. Defined as critical online reasoning (COR), this construct is operationalized on two levels in our study: (1) the student level using the newly developed Critical Online Reasoning Assessment (CORA), and (2) the online information processing level using event log data, including gaze durations and fixations. The written responses of 32 students for one CORA task were scored by three independent raters. The resulting score was operationalized as “task performance,” whereas the gaze fixations and durations were defined as indicators of “process performance.” Following a person-oriented approach, we conducted a process mining (PM) analysis, as well as a latent class analysis (LCA) to test whether—following the dual-process theory—the undergraduates could be distinguished into two groups based on both their process and task performance. Using PM, the process performance of all 32 students was visualized and compared, indicating two distinct response process patterns. One group of students (11), defined as “strategic information processers,” processed online information more comprehensively, as well as more efficiently, which was also reflected in their higher task scores. In contrast, the distributions of the process performance variables for the other group (21), defined as “avoidance information processers,” indicated a poorer process performance, which was also reflected in their lower task scores. In the LCA, where two student groups were empirically distinguished by combining the process performance indicators and the task score as a joint discriminant criterion, we confirmed these two COR profiles, which were reflected in high vs. low process and task performances. The estimated parameters indicated that high-performing students were significantly more efficient at conducting strategic information processing, as reflected in their higher process performance. These findings are so far based on quantitative analyses using event log data. To enable a more differentiated analysis of students’ visual attention dynamics, more in-depth qualitative research of the identified student profiles in terms of COR will be required.
Background: Both EPO levels and anemia have shown prognostic value in several cardiac disorders. An observational study with a prospective follow-up was performed to investigate their independent prognostic roles in severe aortic stenosis. Methods: An up to 36-month follow-up of consecutive patients with severe aortic stenosis undergoing TAVR in a high-volume center was performed. Patients with eGRF <30 mL/min/1.73 m2 were excluded. EPO levels and/or anemia status and its association with mid-term mortality were assessed. Results: Out of 407, 360 met eligibility criteria. Median age was 83 years, with 71.4% having a NYHA class III/IV. Anemia was present in 51.9%, and iron deficiency in 52.8%. Median (IQR) EPO levels were 14.4 (9.30–24.30) mIU/mL. Median follow-up was 566 days. Anemia was associated with overall mortality (HR 2.40, 95% CI 1.51–3.80, p < 0.001). Higher logEPO levels were associated with mid-term mortality (HR 4.05, 95% CI 2.29–7.16, p < 0.001), even after adjusting for clinically and/or statistically relevant factors (multivariate HR 2.25, 95 CI 1.09–4.66, p = 0.029). Kaplan-Meier analyses showed early diverging curves for anemia vs. non-anemia, whereas curves for patients in various EPO level quartiles started to diverge at about 100 days, with differences consistently increasing during the subsequent entire follow-up period. Conclusions: Differently from anemia, which was a strong predictor for both early and late mortality in severe aortic stenosis after TAVR, independent prognostic value of EPO only emerged after post-TAVR recovery. EPO prognostic value was independent from anemia and mild-to-moderate renal dysfunction. High EPO levels could be useful to identify patients with severe aortic stenosis showing a compromised mid-term survival in spite of TAVR use and independently from early TAVR results.
Objective: This study aims to evaluate catheter management in acute epididymitis (AE) patients requiring inpatient treatment and risk factors predicting severity of disease.
Material and Methods: Patients with diagnosed AE and inpatient treatment between 2004 and 2019 at the University Hospital Frankfurt were analyzed. A risk score, rating severity of AE, including residual urine > 100 ml, fever > 38.0°C, C-reactive protein (CRP) > 5 mg/dl, and white blood count (WBC) > 10/nl was introduced.
Results: Of 334 patients, 107 (32%) received a catheter (transurethral (TC): n = 53, 16%, suprapubic (SPC): n = 54, 16%). Catheter patients were older, exhibited more comorbidities, and had higher CRP and WBC compared with the non-catheter group (NC). Median length of stay (LOS) was longer in the catheter group (7 vs. 6 days, p < 0.001), whereas necessity of abscess surgery and recurrent epididymitis did not differ. No differences in those parameters were recorded between TC and SPC. According to our established risk score, 147 (44%) patients exhibited 0–1 (low-risk) and 187 (56%) 2–4 risk factors (high-risk). In the high-risk group, patients received a catheter significantly more often than with low-risk (TC: 22 vs. 9%; SPC: 19 vs. 12%, both p ≤ 0.01). Catheter or high-risk patients exhibited positive urine cultures more frequently than NC or low-risk patients. LOS was comparable between high-risk patients with catheter and low-risk NC patients.
Conclusion: Patients with AE who received a catheter at admission were older, multimorbid, and exhibited more severe symptoms of disease compared with the NC patients. A protective effect of catheters might be attributable to patients with adverse risk constellations or high burden of comorbidities. The introduced risk score indicates a possibility for risk stratification.
Evoked potentials in the amplitude-time spectrum of the electroencephalogram are commonly used to assess the extent of brain responses to stimulation with noxious contact heat. The magnitude of the N- and P-waves are used as a semi-objective measure of the response to the painful stimulus: the higher the magnitude, the more painful the stimulus has been perceived. The strength of the N-P-wave response is also largely dependent on the chosen reference electrode site. The goal of this study was to examine which reference technique excels both in practical and theoretical terms when analyzing noxious contact heat evoked potentials (CHEPS) in the amplitude-time spectrum. We recruited 21 subjects (10 male, 11 female, mean age of 55.79 years). We applied seven noxious contact heat stimuli using two temperatures, 51°C, and 54°C, to each subject. During EEG analysis, we aimed to identify the referencing technique which produces the highest N-wave and P-wave amplitudes with as little artifactual influence as possible. For this purpose, we applied the following six referencing techniques: mathematically linked A1/A2 (earlobes), average reference, REST, AFz, Pz, and mathematically linked PO7/PO8. We evaluated how these techniques impact the N-P amplitudes of CHEPS based on our data from healthy subjects. Considering all factors, we found that mathematically linked earlobes to be the ideal referencing site to use when displaying and evaluating CHEPS in the amplitude-time spectrum.
Aim: Left ventricular non-compaction (LVNC) is perceived as a rare high-risk cardiomyopathy characterized by excess left ventricular (LV) trabeculation. However, there is increasing evidence contesting the clinical significance of LV hyper-trabeculation and the existence of LVNC as a distinct cardiomyopathy. The aim of this study is to assess the association of LV trabeculation extent with cardiovascular morbidity and all-cause mortality in patients undergoing clinical cardiac magnetic resonance (CMR) scans across 57 European centers from the EuroCMR registry.
Methods and Results: We studied 822 randomly selected cases from the EuroCMR registry. Image acquisition was according to international guidelines. We manually segmented images for LV chamber quantification and measurement of LV trabeculation (as per Petersen criteria). We report the association between LV trabeculation extent and important cardiovascular morbidities (stroke, atrial fibrillation, heart failure) and all-cause mortality prospectively recorded over 404 ± 82 days of follow-up. Maximal non-compaction to compaction ratio (NC/C) was mean (standard deviation) 1.81 ± 0.67, from these, 17% were above the threshold for hyper-trabeculation (NC/C > 2.3). LV trabeculation extent was not associated with increased risk of the defined outcomes (morbidities, mortality, LV CMR indices) in the whole cohort, or in sub-analyses of individuals without ischaemic heart disease, or those with NC/C > 2.3.
Conclusion: Among 882 patients undergoing clinical CMR, excess LV trabeculation was not associated with a range of important cardiovascular morbidities or all-cause mortality over ~12 months of prospective follow-up. These findings suggest that LV hyper-trabeculation alone is not an indicator for worse cardiovascular prognosis.
Signature of consciousness in brain-wide synchronization patterns of monkey and human fMRI signals
(2020)
During the sleep-wake cycle, the brain undergoes profound dynamical changes, which manifest subjectively as transitions between conscious experience and unconsciousness. Yet, neurophysiological signatures that can objectively distinguish different consciousness states based are scarce. Here, we show that differences in the level of brain-wide signals can reliably distinguish different stages of sleep and anesthesia from the awake state in human and monkey fMRI resting state data. Moreover, a whole-brain computational model can faithfully reproduce changes in global synchronization and other metrics such as functional connectivity, structure-function relationship, integration and segregation across vigilance states. We demonstrate that the awake brain is close to a Hopf bifurcation, which naturally coincides with the emergence of globally correlated fMRI signals. Furthermore, simulating lesions of individual brain areas highlights the importance of connectivity hubs in the posterior brain and subcortical nuclei for maintaining the model in the awake state, as predicted by graph-theoretical analyses of structural data.