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Purpose: Discordance between pre-operative biopsy and final pathology for Upper Tract Urothelial Carcinoma (UTUC) is high and optimal management remains controversial. The aim of this study is to evaluate the accuracy of pre-operative biopsy, to identify prognostic factors and to evaluate the effect of adjuvant chemotherapy on survival and oncologic outcome in UTUC.
Methods: We analyzed records of patients receiving surgical treatment for UTUC. Pathology of pre-operative biopsy was compared to surgical specimen. We used Kaplan-Meier method to estimate survival probabilities and Cox's proportional hazards models to estimate the association between covariates and event times. Primary endpoint was overall survival (OS). A matched-pair analysis was performed to evaluate the effect of adjuvant chemotherapy.
Results: 151 patients underwent surgical treatment (28% open, 36% laparoscopic, 17% robotic radical nephroureterectomy; 14% segmental ureteral resections and 5% palliative nephrectomy) for UTUC and were included in the analysis. Upstaging from <pT1 in endoscopic biopsy to ≥pT1 in final pathology occurred in 61% of patients and upgrading from low-grade to high-grade occurred in 30% of patients. Five-year OS was 59.5%. In the univariate Cox-regression model pathological stage, grade, lymphovascular invasion and positive surgical margins were associated with OS. Matched pair analysis for stage (<pT3; ≥pT3; pN+) and age revealed a significant survival benefit for adjuvant chemotherapy (HR 0.40, 0.14–0.77, p < 0.018) in this cohort.
Conclusion: UTUC is often underestimated in pre-operative biopsy, and it is associated with significant mortality. Pathological stage and grade, lymphovascular invasion and lymph node metastases are predictors of oncologic outcome and survival.
Objective: Liver stiffness measurement (LSM) is a tool used to screen for significant fibrosis and portal hypertension. The aim of this retrospective multicentre study was to develop an easy tool using LSM for clinical outcomes in advanced chronic liver disease (ACLD) patients.
Design: This international multicentre cohort study included a derivation ACLD patient cohort with valid two-dimensional shear wave elastography (2D-SWE) results. Clinical and laboratory parameters at baseline and during follow-up were recorded. LSM by transient elastography (TE) was also recorded if available. The primary outcome was overall mortality. The secondary outcome was the development of first/further decompensation.
Results: After screening 2148 patients (16 centres), 1827 patients (55 years, 62.4% men) were included in the 2D-SWE cohort, with median liver SWE (L-SWE) 11.8 kPa and a model for end stage liver disease (MELD) score of 8. Combination of MELD score and L-SWE predict independently of mortality (AUC 0.8). L-SWE cut-off at ≥20 kPa combined with MELD ≥10 could stratify the risk of mortality and first/further decompensation in ACLD patients. The 2-year mortality and decompensation rates were 36.9% and 61.8%, respectively, in the 305 (18.3%) high-risk patients (with L-SWE ≥20 kPa and MELD ≥10), while in the 944 (56.6%) low-risk patients, these were 1.1% and 3.5%, respectively. Importantly, this M10LS20 algorithm was validated by TE-based LSM and in an additional cohort of 119 patients with valid point shear SWE-LSM.
Conclusion: The M10LS20 algorithm allows risk stratification of patients with ACLD. Patients with L-SWE ≥20 kPa and MELD ≥10 should be followed closely and receive intensified care, while patients with low risk may be managed at longer intervals.
Glecaprevir/pibrentasvir, a pangenotypic, direct-acting antiviral combination approved for chronic hepatitis C virus treatment, has limited real-world evidence supporting 8-week therapy in compensated cirrhosis. We investigated effectiveness and safety of 187 hepatitis C virus-infected, treatment-naïve, patients with compensated cirrhosis receiving 8-week glecaprevir/pibrentasvir therapy in the German Hepatitis C-Registry between 2 August 2017 and 1 January 2020. Sustained virologic response was 98.4% (127/129) in the per-protocol analysis (excluding patients lost to follow-up or who discontinued treatment due to compliance) and was 85.8% (127/148) in patients with data available in an intention-to-treat analysis. Nineteen patients were lost to follow-up; nine genotype 3 patients, nine nongenotype 3 patients and one mixed genotype patient. One patient relapsed, and one died, unrelated to treatment. Adverse events (>5%) were fatigue and headache. Two serious adverse events occurred; no adverse events resulted in drug discontinuation. An 8-week glecaprevir/pibrentasvir therapy was effective and well-tolerated in this real-world analysis.
Understanding how epigenetic variation in non-coding regions is involved in distal gene-expression regulation is an important problem. Regulatory regions can be associated to genes using large-scale datasets of epigenetic and expression data. However, for regions of complex epigenomic signals and enhancers that regulate many genes, it is difficult to understand these associations. We present StitchIt, an approach to dissect epigenetic variation in a gene-specific manner for the detection of regulatory elements (REMs) without relying on peak calls in individual samples. StitchIt segments epigenetic signal tracks over many samples to generate the location and the target genes of a REM simultaneously. We show that this approach leads to a more accurate and refined REM detection compared to standard methods even on heterogeneous datasets, which are challenging to model. Also, StitchIt REMs are highly enriched in experimentally determined chromatin interactions and expression quantitative trait loci. We validated several newly predicted REMs using CRISPR-Cas9 experiments, thereby demonstrating the reliability of StitchIt. StitchIt is able to dissect regulation in superenhancers and predicts thousands of putative REMs that go unnoticed using peak-based approaches suggesting that a large part of the regulome might be uncharted water.
With the introduction of the virtual allocation crossmatch in the Eurotransplant (ET) region in 2023, the determination of unacceptable antigen mismatches (UAM) in kidney transplant recipients is of utmost importance for histocompatibility laboratories and transplant centers. Therefore, a joined working group of members from the German Society for Immunogenetics (Deutsche Gesellschaft für Immungenetik, DGI) and the German Transplantation Society (Deutsche Transplantationsgesellschaft, DTG) revised and updated the previous recommendations from 2015 in light of recently published evidence. Like in the previous version, a wide range of topics is covered from technical issues to clinical risk factors. This review summarizes the evidence about the prognostic value of contemporary methods for HLA antibody detection and identification, as well as the impact of UAM on waiting time, on which these recommendations are based. As no clear criteria could be determined to differentiate potentially harmful from harmless HLA antibodies, the general recommendation is to assign all HLA against which plausible antibodies are found as UAM. There is, however, a need for individualized solutions for highly immunized patients. These revised recommendations provide a list of aspects that need to be considered when assigning UAM to enable a fair and comprehensible procedure and to harmonize risk stratification prior to kidney transplantation between transplant centers.
DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10−7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3–82%) of the aggression–methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.
Tuberous sclerosis complex (TSC) is a rare genetic disease that is, besides cutaneous and visceral organ manifestations, typically associated with a severe, usually drug refractory epilepsy at a very early stage of the disease. Due to its direct effect on the mTOR signaling pathway dysregulated by TSC and its synergistic effects on other organ manifestations, the rapamycin derivative everolimus (EVE) is increasingly being used. The aim of this systematic review is to evaluate the efficacy, safety and tolerability of EVE in patients with TSC-associated, refractory epilepsy.
The hydrothermal vent tubeworm Riftia pachyptila hosts a single 16S rRNA phylotype of intracellular sulfur-oxidizing symbionts, which vary considerably in cell morphology and exhibit a remarkable degree of physiological diversity and redundancy, even in the same host. To elucidate whether multiple metabolic routes are employed in the same cells or rather in distinct symbiont subpopulations, we enriched symbionts according to cell size by density gradient centrifugation. Metaproteomic analysis, microscopy, and flow cytometry strongly suggest that Riftia symbiont cells of different sizes represent metabolically dissimilar stages of a physiological differentiation process: While small symbionts actively divide and may establish cellular symbiont-host interaction, large symbionts apparently do not divide, but still replicate DNA, leading to DNA endoreduplication. Moreover, in large symbionts, carbon fixation and biomass production seem to be metabolic priorities. We propose that this division of labor between smaller and larger symbionts benefits the productivity of the symbiosis as a whole.
Highlights
• Prevalence of probable DS identified from German healthcare data: 4.7 per 100,000.
• Healthcare costs: €11,048 per patient-year, mostly inpatient care 47%, medication 26%.
• Costs and hospitalizations greater in patients with rescue medication than without.
• Mean (SD) of 5.0 (2.5) different ASMs prescribed per patient over study period.
• Patients with probable DS had significantly higher mortality risk vs. controls (11.88% vs. 1.19%).
Abstract
Objective: Ten-year retrospective study to assess burden of illness in patients with probable Dravet syndrome (DS) identified from German healthcare data.
Methods: In the absence of an International Classification of Diseases code, patients with probable DS were identified using a selection algorithm considering diagnoses and drug prescriptions. Primary analyses were prevalence and demographics; secondary analyses included healthcare costs, annual hospitalization rate (AHR) and length of stay (LOS), medication use, and mortality.
Results: In the final study year, 64 patients with probable DS (mean [range] age: 33.2 [3–82] years; male: 48%) were identified. Prevalence: 4.7 per 100,000 people. During the study, 160 patients with probable DS were identified and followed up for 1,261 patient-years. Mean cost of healthcare was €11,048 per patient-year (PPY), mostly attributable to inpatient care (47%), medication (26%), and services and devices (19%). Annual healthcare costs were significantly greater for those with prescribed rescue medication (15% of patient-years) vs. without (€16,123 vs. €10,125 PPY, p < 0.001). Mean (standard deviation [SD]) AHR and LOS were 1.1 (1.7) and 17.5 (33.5) days PPY. AHR was significantly greater in patients with prescribed rescue medication vs. without (1.6 [2.0] vs. 1.0 [1.6] PPY, p < 0.001). Mean (SD) number of antiseizure medications prescribed was 2.6 (1.2) PPY and 5.0 (2.5) over the entire observable time for each patient. Mortality rate was significantly higher for probable DS vs. matched controls (11.88% [19 events] vs. 1.19% [172 events], p < 0.001).
Conclusion: Probable DS is associated with substantial healthcare costs in Germany.
The Board of Directors of the German Society of Epileptology and the committee on epilepsy and syncope of the German Society of Neurology have reviewed the current data on vaccination to prevent coronavirus disease 2019 (COVID-19) and vaccination prioritization in people with epilepsy and provide a summary and recommendations.
Influence of macrophage polarization on the effectiveness of surgical therapy of peri-implantitis
(2021)
Purpose: To evaluate the influence of macrophage expression and polarization on the effectiveness of surgical therapy of peri-implantitis over a 6 month follow-up.
Methods: A total of fourteen patients (n = 14 implants) diagnosed with peri-implantitis underwent access flap surgery, granulation tissue removal, implantoplasty, and augmentation at intra-bony components using a natural derived bone mineral and application of a native collagen membrane during a standardized surgical procedure. Granulation tissue biopsies were prepared for immunohistochemical characterization and macrophage polarization assessment. M1 and M2 phenotype expression was identified and quantified through immunohistochemical markers and histomorphometrical analyses. Clinical evaluation and data collection were performed initially and after a healing period of 6 months. Statistical analyses were performed to associate infiltrated area, macrophage, and M1/M2 phenotype influence on peri-implant tissue healing parameters after a 6-month follow-up.
Results: Mean infiltrated compartment (ICT) values occupied a total percentage of 70.3% ± 13.0 in the analyzed granulation tissue biopsies. Macrophages occupied a mean area of 15.3% ± 7.0. M1 and M2 phenotypes were present in 7.1 ± 4.1% and 5.5 ± 3.7%, respectively. No statistically significant difference was observed between M1 and M2% expression (p = 0.16). The mean M1/ M2 ratio amounted to 1.5 ± 0.8. Surgical therapy was associated with statistically significant reductions in mean bleeding on probing (BOP), probing depth (PD) and suppuration (SUPP) scores at 6 months (p < 0.05). Linear regression analyses revealed a significant correlation between macrophage expression (CD68%) and changes in PD scores and M1 (%) expression and changes in mucosal recession (MR) scores at 6 months.
Conclusions: The present data suggest that macrophages might influence peri-implant tissue healing mechanisms following surgical therapy of peri-implantitis over a short-term period. Particularly, changes in PD and MR scores were statistically significantly associated with macrophage expression and phenotype.
Fendrr synergizes with Wnt signalling to regulate fibrosis related genes during lung development
(2021)
Long non-coding RNAs are a very versatile class of molecules that can have important roles in regulating a cells function, including regulating other genes on the transcriptional level. One of these mechanisms is that RNA can directly interact with DNA thereby recruiting additional components such as proteins to these sites via a RNA:dsDNA triplex formation. We genetically deleted the triplex forming sequence (FendrrBox) from the lncRNA Fendrr in mice and find that this FendrrBox is partially required for Fendrr function in vivo. We find that the loss of the triplex forming site in developing lungs causes a dysregulation of gene programs, associated with lung fibrosis. A set of these genes contain a triplex site directly at their promoter and are expressed in fibroblasts. We find that Fendrr with the Wnt signaling pathway regulates these genes, implicating that Fendrr synergizes with Wnt signaling in lung fibrosis.
Background: During the current second wave of COVID-19, the radiologists are expected to face great challenges in differentiation between COVID-19 and other virulent influenza viruses, mainly H1N1. Accordingly, this study was performed in order to find any differentiating CT criteria that would help during the expected clinical overlap during the current Influenza season.
Results: This study was retrospectively conducted during the period from June till November 2020, on acute symptomatic 130 patients with no history of previous pulmonary diseases; 65 patients had positive PCR for COVID-19 including 50 mild patients and 15 critical or severe patients; meanwhile, the other 65 patients had positive PCR for H1N1 including 50 mild patients and 15 critical or severe patients. They included 74 males and 56 females (56.9%:43.1%). Their age ranged 14–90 years (mean age 38.9 ± 20.3 SD). HRCT findings were analyzed by four expert consultant radiologists in consensus. All patients with COVID-19 showed parenchymal or alveolar HRCT findings; only one of them had associated airway involvement. Among the 65 patients with H1N1; 56 patients (86.2%) had parenchymal or alveolar HRCT findings while six patients (9.2%) presented only by HRCT signs of airway involvement and three patients (4.6%) had mixed parenchymal and airway involvement. Regarding HRCT findings of airway involvement (namely tree in bud nodules, air trapping, bronchial wall thickening, traction bronchiectasis, and mucous plugging), all showed significant p value (ranging from 0.008 to 0.04). On the other hand, HRCT findings of parenchymal or alveolar involvement (mainly ground glass opacities) showed no significant relation.
Conclusion: HRCT can help in differentiation between non-severe COVID-19 and H1N1 based on signs of airway involvement.
Background/Objective: Evidence-based clinical pathways can be a useful tool for guideline implementation. However, there seem to be barriers to the use of clinical pathways. The aim of the present questionnaire survey was to assess the perceived usability of the clinical pathway “Overweight/obesity in children and adolescents at primary care level” and to identify factors promoting and hindering the use of the clinical pathway.
Methods: In January 2020, an online questionnaire survey was sent out to 3,916 general practitioners and 470 pediatricians in Austria. The data collected were analysed descriptively.
Results: A total of 148 people took part in the questionnaire survey (response rate 3.7 %). The majority of respondents indicated that they, in general, perceive evidence-based clinical pathways as helpful (90 %) and also make use of them (57 %). Few respondents (9 %) felt well-informed about new clinical pathways developed in Austria. Most of the respondents considered the clinical pathway “Overweight/obesity in children and adolescents at primary care level” as a useful support (60 %), as a reference work (72 %) or as a facilitator for justifying their approach to their patients (68 %). However, a large proportion of the respondents stated that the clinical pathway is not easily applicable in everyday practice. The three most frequently cited barriers to using the clinical pathway were lack of time resources, lack of structures and lack of financial incentives. Other display and access options (e. g., individualisation, integration into practice software) were most frequently cited as factors that might promote the use of the pathway.
Conclusion: Although the majority of the respondents had positive expectations regarding the use of the clinical pathway “Overweight/obesity in children and adolescents at primary care level”, many of them still perceived its usability in everyday clinical practice as difficult. The necessary next steps to improve the use of evidence-based clinical pathways seem to be: an economic and practicable design, easy accessibility of clinical pathways and the creation of framework conditions that facilitate their use in everyday practice.
The adult human body contains about 4 g of iron. About 1–2 mg of iron is absorbed every day, and in healthy individuals, the same amount is excreted. We describe a patient who presents with severe iron deficiency anemia with hemoglobin levels below 6 g/dL and ferritin levels below 30 ng/mL. Although red blood cell concentrates and intravenous iron have been substituted every month for years, body iron stores remain depleted. Diagnostics have included several esophago-gastro-duodenoscopies, colonoscopies, MRI of the liver, repetitive bone marrow biopsies, psychological analysis, application of radioactive iron to determine intact erythropoiesis, and measurement of iron excretion in urine and feces. Typically, gastrointestinal bleeding is a major cause of iron loss. Surprisingly, intestinal iron excretion in stool in the patient was repetitively increased, without gastrointestinal bleeding. Furthermore, whole exome sequencing was performed in the patient and additional family members to identify potential causative genetic variants that may cause intestinal iron loss. Under different inheritance models, several rare mutations were identified, two of which (in CISD1 and KRI1) are likely to be functionally relevant. Intestinal iron loss in the current form has not yet been described and is, with high probability, the cause of the severe iron deficiency anemia in this patient.
Gram-negative Tripartite Resistance Nodulation and cell Division (RND) superfamily efflux pumps confer various functions, including multidrug and bile salt resistance, quorum-sensing, virulence and can influence the rate of mutations on the chromosome. Multidrug RND efflux systems are often characterized by a wide substrate specificity. Similarly to many other RND efflux pump systems, AcrAD-TolC confers resistance toward SDS, novobiocin and deoxycholate. In contrast to the other pumps, however, it in addition confers resistance against aminoglycosides and dianionic β-lactams, such as sulbenicillin, aztreonam and carbenicillin. Here, we could show that AcrD from Salmonella typhimurium confers resistance toward several hitherto unreported AcrD substrates such as temocillin, dicloxacillin, cefazolin and fusidic acid. In order to address the molecular determinants of the S. typhimurium AcrD substrate specificity, we conducted substitution analyses in the putative access and deep binding pockets and in the TM1/TM2 groove region. The variants were tested in E. coli ΔacrBΔacrD against β-lactams oxacillin, carbenicillin, aztreonam and temocillin. Deep binding pocket variants N136A, D276A and Y327A; access pocket variant R625A; and variants with substitutions in the groove region between TM1 and TM2 conferred a sensitive phenotype and might, therefore, be involved in anionic β-lactam export. In contrast, lower susceptibilities were observed for E. coli cells harbouring deep binding pocket variants T139A, D176A, S180A, F609A, T611A and F627A and the TM1/TM2 groove variant I337A. This study provides the first insights of side chains involved in drug binding and transport for AcrD from S. typhimurium.
Biallelic pathogenic variants in CLPP, encoding mitochondrial matrix peptidase ClpP, cause a rare autosomal recessive condition, Perrault syndrome type 3 (PRLTS3). It is characterized by primary ovarian insufficiency and early sensorineural hearing loss, often associated with progressive neurological deficits. Mouse models showed that accumulations of (i) its main protein interactor, the substrate-selecting AAA+ ATPase ClpX, (ii) mitoribosomes, and (iii) mtDNA nucleoids are the main cellular consequences of ClpP absence. However, the sequence of these events and their validity in human remain unclear. Here, we studied global proteome profiles to define ClpP substrates among mitochondrial ClpX interactors, which accumulated consistently in ClpP-null mouse embryonal fibroblasts and brains. Validation work included novel ClpP-mutant patient fibroblast proteomics. ClpX co-accumulated in mitochondria with the nucleoid component POLDIP2, the mitochondrial poly(A) mRNA granule element LRPPRC, and tRNA processing factor GFM1 (in mouse, also GRSF1). Only in mouse did accumulated ClpX, GFM1, and GRSF1 appear in nuclear fractions. Mitoribosomal accumulation was minor. Consistent accumulations in murine and human fibroblasts also affected multimerizing factors not known as ClpX interactors, namely, OAT, ASS1, ACADVL, STOM, PRDX3, PC, MUT, ALDH2, PMPCB, UQCRC2, and ACADSB, but the impact on downstream metabolites was marginal. Our data demonstrate the primary impact of ClpXP on the assembly of proteins with nucleic acids and show nucleoid enlargement in human as a key consequence.
The accumulation of functionally impaired mitochondria is a key event in aging. Previous works with the fungal aging model Podospora anserina demonstrated pronounced age-dependent changes of mitochondrial morphology and ultrastructure, as well as alterations of transcript and protein levels, including individual proteins of the oxidative phosphorylation (OXPHOS). The identified protein changes do not reflect the level of the whole protein complexes as they function in-vivo. In the present study, we investigated in detail the age-dependent changes of assembled mitochondrial protein complexes, using complexome profiling. We observed pronounced age-depen-dent alterations of the OXPHOS complexes, including the loss of mitochondrial respiratory supercomplexes (mtRSCs) and a reduction in the abundance of complex I and complex IV. Additionally, we identified a switch from the standard complex IV-dependent respiration to an alternative respiration during the aging of the P. anserina wild type. Interestingly, we identified proteasome components, as well as endoplasmic reticulum (ER) proteins, for which the recruitment to mitochondria appeared to be increased in the mitochondria of older cultures. Overall, our data demonstrate pronounced age-dependent alterations of the protein complexes involved in energy transduction and suggest the induction of different non-mitochondrial salvage pathways, to counteract the age-dependent mitochondrial impairments which occur during aging.
Objective: To analyze the influence of biopsy Gleason score on the risk for lymph node invasion (LNI) during pelvic lymph node dissection (PLND) in patients undergoing radical prostatectomy (RP) for intermediate-risk prostate cancer (PCa).
Materials and Methods: We retrospectively analyzed 684 patients, who underwent RP between 2014 and June 2020 due to PCa. Univariable and multivariable logistic regression, as well as binary regression tree models were used to assess the risk of positive LNI and evaluate the need of PLND in men with intermediate-risk PCa.
Results: Of the 672 eligible patients with RP, 80 (11.9%) men harbored low-risk, 32 (4.8%) intermediate-risk with international society of urologic pathologists grade (ISUP) 1 (IR-ISUP1), 215 (32.0%) intermediate-risk with ISUP 2 (IR-ISUP2), 99 (14.7%) intermediate-risk with ISUP 3 (IR-ISUP3), and 246 (36.6%) high-risk PCa. Proportions of LNI were 0, 3.1, 3.7, 5.1, and 24.0% for low-risk, IR-ISUP1, IR-ISUP 2, IR-ISUP-3, and high-risk PCa, respectively (p < 0.001). In multivariable analyses, after adjustment for patient and surgical characteristics, IR-ISUP1 [hazard ratio (HR) 0.10, p = 0.03], IR-ISUP2 (HR 0.09, p < 0.001), and IR-ISUP3 (HR 0.18, p < 0.001) were independent predictors for lower risk of LNI, compared with men with high-risk PCa disease.
Conclusions: The international society of urologic pathologists grade significantly influence the risk of LNI in patients with intermediate- risk PCa. The risk of LNI only exceeds 5% in men with IR-ISUP3 PCa. In consequence, the need for PLND in selected patients with IR-ISUP 1 or IR-ISUP2 PCa should be critically discussed.
Endogenous nitro-fatty acids (NFA) are potent electrophilic lipid mediators that exert biological effects in vitro and in vivo via selective covalent modification of thiol-containing target proteins. The cytoprotective, anti-inflammatory, and anti-tumorigenic effects of NFA in animal models of disease caused by targeted protein nitroalkylation are a valuable basis for the development of future anti-phlogistic and anti-neoplastic drugs. Considering the complexity of diseases and accompanying comorbidities there is an urgent need for clinically effective multifunctional drugs. NFA are composed of a fatty acid backbone containing a nitroalkene moiety triggering Michael addition reactions. However, less is known about the target-specific structure–activity relationships and selectivities comparing different NFA targets. Therefore, we analyzed 15 NFA derivatives and compared them with the lead structure 9-nitro-oleic acid (9NOA) in terms of their effect on NF-κB (nuclear factor kappa B) signaling inhibition, induction of Nrf-2 (nuclear factor erythroid 2-related factor 2) gene expression, sEH (soluble epoxide hydrolase), LO (lipoxygenase), and COX-2 (cyclooxygenase-2) inhibition, and their cytotoxic effects on colorectal cancer cells. Minor modifications of the Michael acceptor position and variation of the chain length led to drugs showing increased target preference or enhanced multi-targeting, partly with higher potency than 9NOA. This study is a significant step forward to better understanding the biology of NFA and their enormous potential as scaffolds for designing future anti-inflammatory drugs.
The complex and adaptive nature of malignant neoplasm constitute a major challenge for the development of effective anti-oncogenic therapies. Emerging evidence has uncovered the pivotal functions exerted by the small leucine-rich proteoglycans, decorin and biglycan, in affecting tumor growth and progression. In their soluble forms, decorin and biglycan act as powerful signaling molecules. By receptor-mediated signal transduction, both proteoglycans modulate key processes vital for tumor initiation and progression, such as autophagy, inflammation, cell-cycle, apoptosis, and angiogenesis. Despite of their structural homology, these two proteoglycans interact with distinct cell surface receptors and thus modulate distinct signaling pathways that ultimately affect cancer development. In this review, we summarize growing evidence for the complex roles of decorin and biglycan signaling in tumor biology and address potential novel therapeutic implications.
Effect of chemotherapy on overall survival in contemporary metastatic prostate cancer patients
(2021)
Introduction: Randomized clinical trials demonstrated improved overall survival in chemotherapy exposed metastatic prostate cancer patients. However, real-world data validating this effect with large scale epidemiological data sets are scarce and might not agree with trials. We tested this hypothesis.
Materials and Methods: We identified de novo metastatic prostate cancer patients within the Surveillance, Epidemiology, and End Results (SEER) database (2014-2015). Kaplan-Meier plots and Cox regression models tested for overall survival differences between chemotherapy-exposed patients vs chemotherapy-naïve patients. All analyses were repeated in propensity-score matched cohorts. Additionally, landmark analyses were applied to account for potential immortal time bias.
Results: Overall, 4295 de novo metastatic prostate cancer patients were identified. Of those, 905 (21.1%) patients received chemotherapy vs 3390 (78.9%) did not. Median overall survival was not reached at 30 months follow-up. Chemotherapy-exposed patients exhibited significantly better overall survival (61.6 vs 54.3%, multivariable HR:0.82, CI: 0.72-0.96, p=0.01) at 30 months compared to their chemotherapy-naïve counterparts. These findings were confirmed in propensity score matched analyses (multivariable HR: 0.77, CI:0.66-0.90, p<0.001). Results remained unchanged after landmark analyses were applied in propensity score matched population.
Conclusions: In this contemporary real-world population-based cohort, chemotherapy for metastatic prostate cancer patients was associated with better overall survival. However, the magnitude of overall survival benefit was not comparable to phase 3 trials.
Introduction: To evaluate the oncological outcome of high dose rate (HDR) brachytherapy (BRT) as monotherapy for clinically localised prostate cancer (PCA).
Material and Methods: Between January 2002 and February 2004, 141 consecutive patients with clinically localised PCA were treated with HDR-BRT monotherapy. The cohort comprised 103 (73%) low-, 32 (22.7%) intermediate- and 6 (4.3%) high risk patients according to D’Amico classification or 104 (73.8%) low-, 24 (17.0%) intermediate favourable-, 12 (8.5%) intermediate unfavourable- and one (0.7%) very high risk patient according to National Comprehensive Cancer Network (NCCN) one. Patients received four fractions of 9.5 Gy delivered within a single implant up to a total physical dose of 38 Gy. Catheter-implantation was transrectal ultrasound-based whereas treatment planning CT-based. Thirty-three patients (23.4%) received ADT neoadjuvantly and continued concurrently with BRT. Biochemical relapse-free survival (BRFS) was defined according to the Phoenix Consensus Criteria and genitourinary (GU)/gastrointestinal (GI) toxicity evaluated using the Common Toxicity Criteria for Adverse Events version 5.0.
Results: Median age at treatment and median follow-up time was 67.2 and 15.2 years, respectively. Twenty-three (16.3%) patients experienced a biochemical relapse and 5 (3.5%) developed distant metastases, with only one patient dying of PCA. The BRFS was 85.1% at 15 years and 78.7% at 18 years. The corresponding overall survival, metastases-free survival, and prostate cancer specific mortality at 15- and 18-years was 73.9%/59.1%, 98.3%/90.6%, and 100%/98.5% respectively. Late grade 3 GI and GU toxicity was 4.2% and 5.6% respectively. Erectile dysfunction grade 3 was reported by 27 (19%) patients. From the prognostic factors evaluated, tumor stage (≤T2b compared to ≥T2c) along with the risk group (low-intermediate vs. high) when using the D’Amico classification but not when the NCCN one was taken into account, correlated significantly with BRFS.
Conclusion: Our long-term results confirm HDR-BRT to be a safe and effective monotherapeutic treatment modality for low- and intermediate risk PCA.
The analysis of ethanol and of its congeners in blood plays an important role in forensic cases, especially when allegations are made that alcohol has been consumed after an accident. In alcoholic beverages, congener alcohols are by-products and are generated during fermentation. The assay of these compounds in serum samples and beverages has been previously performed using headspace-gas chromatography-flame ionization detection methods (HS-GC-FID). As an alternative, a robust headspace-gas chromatography-mass spectrometry (HS-GC-MS) procedure was developed and validated, which has the following advantages:
- Simultaneous determination of ethanol, congener alcohols and other
endogenous substances.
- Reduction of matrix interference by increasing selectivity and
specificity.
- Clear separation of the positional isomers 3-methyl-1-butanol and
2-methyl-1-butanol.
The Q80K polymorphism in the NS3-4A protease of the hepatitis C virus is associated with treatment failure of direct-acting antiviral agents. This polymorphism is highly prevalent in genotype 1a infections and stably transmitted between hosts. Here, we investigated the underlying molecular mechanisms of evolutionarily conserved coevolving amino acids in NS3-Q80K and revealed potential implications of epistatic interactions in immune escape and variants persistence. Using purified protein, we characterized the impact of epistatic amino acid substitutions on the physicochemical properties and peptide cleavage kinetics of the NS3-Q80K protease. We found that Q80K destabilized the protease protein fold (p < 0.0001). Although NS3-Q80K showed reduced peptide substrate turnover (p < 0.0002), replicative fitness in an H77S.3 cell culture model of infection was not significantly inferior to the WT virus. Epistatic substitutions at residues 91 and 174 in NS3-Q80K stabilized the protein fold (p < 0.0001) and leveraged the WT protease stability. However, changes in protease stability inversely correlated with enzymatic activity. In infectious cell culture, these secondary substitutions were not associated with a gain of replicative fitness in NS3-Q80K variants. Using molecular dynamics, we observed that the total number of residue contacts in NS3-Q80K mutants correlated with protein folding stability. Changes in the number of contacts reflected the compensatory effect on protein folding instability by epistatic substitutions. In summary, epistatic substitutions in NS3-Q80K contribute to viral fitness by mechanisms not directly related to RNA replication. By compensating for protein-folding instability, epistatic interactions likely protect NS3-Q80K variants from immune cell recognition.
The development of resistance to chemotherapeutic agents, such as Doxorubicin (DOX) and cytarabine (AraC), is one of the greatest challenges to the successful treatment of Acute Myeloid Leukemia (AML). Such acquisition is often underlined by a metabolic reprogramming that can provide a therapeutic opportunity, as it can lead to the emergence of vulnerabilities and dependencies to be exploited as targets against the resistant cells. In this regard, genome-scale metabolic models (GSMMs) have emerged as powerful tools to integrate multiple layers of data to build cancer-specific models and identify putative metabolic vulnerabilities. Here, we use genome-scale metabolic modelling to reconstruct a GSMM of the THP1 AML cell line and two derivative cell lines, one with acquired resistance to AraC and the second with acquired resistance to DOX. We also explore how, adding to the transcriptomic layer, the metabolomic layer enhances the selectivity of the resulting condition specific reconstructions. The resulting models enabled us to identify and experimentally validate that drug-resistant THP1 cells are sensitive to the FDA-approved antifolate methotrexate. Moreover, we discovered and validated that the resistant cell lines could be selectively targeted by inhibiting squalene synthase, providing a new and promising strategy to directly inhibit cholesterol synthesis in AML drug resistant cells.
Background: The increasing number of cases and hospital admissions due to COVID-19 created an urgent need for rapid, reliable testing procedures for SARS-CoV-2 in Emergency Departments (ED) in order to effectively manage hospital resources, allocate beds and prevent nosocomial spread of infection. The ID NOW™ COVID-19 assay is a simple, user-friendly, rapid molecular test run on an instrument with a small footprint enabling point-of-care diagnostics.
Methods: In the first wave, outsourced RT-PCR testing regularly required 36-48 hours before results were available. This prospective study was conducted in the second wave (October 2020-April 2021) and evaluated the impact the implementation of the ID NOW™ COVID-19 test in the ED had on clinical care processes and patient pathways. 710 patients were recruited upon arrival at the ED which included those presenting clinical symptoms, asymptomatic individuals or persons fulfilling epidemiological criteria. The first anterior nasal swab was taken by trained nurses in the ambulance or a separate consultation room. The ID NOW™ COVID-19 test was performed in the ED in strict compliance with the manufacturer’s instructions and positive or suspected cases were additionally tested with RT_PCR (cobas SARS-COV-2 RT-PCR, Roche) following collection of a second nasopharyngeal NP specimen.
Results: Swabs directly tested with the ID NOW™ COVID-19 test showed a diagnostic concordance of 98 % (sensitivity 99.59 %, specificity 94.55 %, PPV 97.6 %, NPV 99.05 %) compared to RT-PCR as reference. The 488 patients that tested positive with the ID NOW™ COVID-19 had a Ct range in RT-PCR results between 7.94 to 37.42 (in 23.2 % > 30). Two false negative results (0.28%) were recorded from patients with Ct values > 30. 14 (1.69%) discordant results were reviewed case-by-case and usually associated with either very early or very advanced stages of infection. Furthermore, patients initially negative with the ID NOW™ COVID-19 test and admitted to the hospital were tested again on days 5 and 12: no patient became positive.
Discussion: The ID NOW™ COVID-19 test for detection of SARS-CoV-2 demonstrated excellent diagnostic agreement with RT-PCR under the above-mentioned patients pathways implemented during the second wave. The main advantage of the system was the provision of reliable results within a few minutes. This not only allowed immediate initiative of appropriate therapy and care for COVID-19 (patient benefit) but provided essential information on isolation and thus available beds. This drastically helped the overall finances of the department and additionally allowed more patients to be admitted including those requiring immediate attention; this was not possible during the first wave since beds were blocked waiting for diagnostic confirmation. Our findings also show that when interpreting the results, the clinical condition and epidemiological history of the patient must be taken into account, as with any test procedure. Overall, the ID NOW™ COVID-19 test for SARS-CoV-2 provided a rapid and reliable alternative to laboratory-based RT-PCR in the real clinical setting which became an acceptable part of the daily routine within the ED and demonstrated that early patient management can mitigate the impact of the pandemic on the hospital.
Relationship between regional white matter hyperintensities and alpha oscillations in older adults
(2021)
Aging is associated with increased white matter hyperintensities (WMHs) and with the alterations of alpha oscillations (7–13 Hz). However, a crucial question remains, whether changes in alpha oscillations relate to aging per se or whether this relationship is mediated by age-related neuropathology like WMHs. Using a large cohort of cognitively healthy older adults (N=907, 60-80 years), we assessed relative alpha power, alpha peak frequency, and long-range temporal correlations (LRTC) from resting-state EEG. We further associated these parameters with voxel-wise WMHs from 3T MRI. We found that a higher prevalence of WMHs in the superior and posterior corona radiata as well as in the thalamic radiation was related to elevated alpha power, with the strongest association in the bilateral occipital cortex. In contrast, we observed no significant relation of the WMHs probability with alpha peak frequency and LRTC. Finally, higher age was associated with elevated alpha power via total WMH volume. Although an increase in alpha oscillations due to WMH can have a compensatory nature, we rather suggest that an elevated alpha power is a consequence of WMH affecting a spatial organization of alpha sources.
Background: Nitric oxide synthase 1 adaptor protein (NOS1AP; previously named CAPON) is linked to the glutamatergic postsynaptic density through interaction with neuronal nitric oxide synthase (nNOS). NOS1AP and its interaction with nNOS have been associated with several mental disorders. Despite the high levels of NOS1AP expression in the hippocampus and the relevance of this brain region in glutamatergic signalling as well as mental disorders, a potential role of hippocampal NOS1AP in the pathophysiology of these disorders has not been investigated yet.
Methods: To uncover the function of NOS1AP in hippocampus, we made use of recombinant adeno-associated viruses to overexpress murine full-length NOS1AP or the NOS1AP carboxyterminus in the hippocampus of mice. We investigated these mice for changes in gene expression, neuronal morphology, and relevant behavioural phenotypes.
Findings: We found that hippocampal overexpression of NOS1AP markedly increased the interaction of nNOS with PSD-95, reduced dendritic spine density, and changed dendritic spine morphology at CA1 synapses. At the behavioural level, we observed an impairment in social memory and decreased spatial working memory capacity.
Interpretation: Our data provide a mechanistic explanation for a highly selective and specific contribution of hippocampal NOS1AP and its interaction with the glutamatergic postsynaptic density to cross-disorder pathophysiology. Our findings allude to therapeutic relevance due to the druggability of this molecule.
Attention-deficit hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder characterized by hyperactivity, impulsivity, and/or inattention, which are symptoms also observed in many rare genetic disorders. We searched for genes involved in Mendelian disorders presenting with ADHD symptoms in the Online Mendelian Inheritance in Man (OMIM) database, to curate a list of new candidate risk genes for ADHD. We explored the enrichment of functions and pathways in this gene list, and tested whether rare or common variants in these genes are associated with ADHD or with its comorbidities. We identified 139 genes, causal for 137 rare disorders, mainly related to neurodevelopmental and brain function. Most of these Mendelian disorders also present with other psychiatric traits that are often comorbid with ADHD. Using whole exome sequencing (WES) data from 668 ADHD cases, we found rare variants associated with the dimension of the severity of inattention symptoms in three genes: KIF11, WAC, and CRBN. Then, we focused on common variants and identified six genes associated with ADHD (in 19,099 cases and 34,194 controls): MANBA, UQCC2, HIVEP2, FOPX1, KANSL1, and AUH. Furthermore, HIVEP2, FOXP1, and KANSL1 were nominally associated with autism spectrum disorder (ASD) (18,382 cases and 27,969 controls), as well as HIVEP2 with anxiety (7016 cases and 14,475 controls), and FOXP1 with aggression (18,988 individuals), which is in line with the symptomatology of the rare disorders they are responsible for. In conclusion, inspecting Mendelian disorders and the genes responsible for them constitutes a valuable approach for identifying new risk genes and the mechanisms of complex disorders.
Background. The guidelines on antithrombotic treatment in patients with symptomatic peripheral artery disease (PAD) undergoing peripheral revascularization of the lower extremities were developed based on heterogeneous trials, assessing various dose regimens and recruiting patients who were subjected to different revascularization procedures. Objective. To compare efficacy and safety of treatments used in patients with PAD undergoing peripheral revascularization accounting for between-trial heterogeneity and large dispersion of the quality of evidence. Methods. A systematic literature review of randomised controlled trials (RCTs) recruiting adult patients with PAD receiving antithrombotics was conducted until January 2020. Hazard ratios (HR) were pooled using Bayesian network meta-analysis. The estimated between-treatment effects were presented as HR together with 95% credible intervals. The base case analysis included studies recruiting patients following recent peripheral revascularization, who received treatment regimens administered within the recommended therapeutic window, while a sensitivity scenario included all identified trials. Results. Thirteen RCTs were identified (8 RCTs enrolled patients following peripheral revascularization and 5 RCTs regardless of the previous revascularization). Five trials, recruiting an overall of 8349 patients, were considered for the base case analysis. Of those, 6564 patients were recruited in the VOYAGER PAD trial comparing rivaroxaban plus aspirin (RIV plus ASA) versus ASA. RIV plus ASA was associated with a lower risk of repeated peripheral revascularization versus ASA monotherapy (HR = 0.88 [0.79, 0.99]), however having a trend towards an increased rate of major bleeding (HR = 1.43 [0.98, 2.11]). There was no evidence for differences between RIV plus ASA and dual antiplatelet therapy and vitamin K antagonists plus ASA. Similar results were observed in sensitivity analyses. Conclusions. RIV plus ASA is associated with reduced risk of revascularization compared with ASA monotherapy, but the evidence for other comparators, in particular antiplatelet regimens, was insufficient to guide treatment decisions and highlights the challenge in establishing the magnitude of comparative efficacy using existing RCTs.
Objective: Management and outcomes of superficial vein thrombosis (SVT) are highly variable and not well described. Therefore, the INvestigating SIGnificant Health TrendS in the management of SVT (INSIGHTS-SVT) study collected prospective data under real life conditions.
Methods: Prospective observational study of objectively confirmed acute isolated SVT. The primary outcome was a composite of symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE), and extension or recurrence of SVT at three months. The primary safety outcome was clinically relevant bleeding.
Results: A total of 1 150 patients were included (mean age 60.2 ± 14.7 years; 64.9% women; mean BMI 29.4 ± 6.3 kg/m2). SVT was below the knee in 54.5%, above the knee in 26.7%, above and below the knee in 18.8%. At baseline, 93.6% received pharmacological treatment (65.7% fondaparinux, 23.2% heparins, 4.3% direct oral anticoagulants [DOACs], 14.5% analgesics), 77.0% compression treatment, and 1.9% surgery; 6.4% did not receive any anticoagulation. The primary outcome occurred in 5.8%; 4.7% had recurrent or extended SVT, 1.7% DVT, and 0.8% PE. Clinically relevant non-major bleeding occurred in 1.2% and major bleeding in 0.3%. Complete clinical recovery of SVT was reported in 708 patients (62.4%). Primary outcome adjusted by propensity score and for treatment duration was lower with fondaparinux compared with low molecular weight heparin (4.4% vs. 9.6%; hazard ratio [HR] 0.51; 95% confidence interval [CI] 0.3 - 0.9; p = .017). On multivariable analysis, associated factors for primary outcome included another SVT prior to the present SVT event (HR 2.3), age per year (HR 0.97), duration of drug treatment per week (HR 0.92), and thrombus length (HR 1.03).
Conclusion: At three month follow up, patients with isolated SVT are at risk of thromboembolic complications (mainly recurrent or extended SVT), despite anticoagulation. In this real life study, about one third had received either heparins, oral anticoagulants, or no anticoagulation.
Highlights
• Forensic experts should be questioned about their education and experience.
• Reliability of methods used to estimate the PMI should be evident when exposed in court.
• Judges should question if the right method was used in the right manner.
• The PMI is an estimate and cannot be interpreted as the actual time of death.
Abstract
When a capital crime is committed the post-mortem interval (PMI) is of particular importance in investigating a suspect’s alibi in court. A forensic expert can use different methods to estimate the PMI. This research focuses on who is considered an expert in court and whether the methods used to estimate the PMI are reliable. In this study, the methods used to estimate the PMI and the experts consulted, available in Dutch jurisprudence, in the period 2010–2019 were investigated. Ninety-four judicial cases were included and multiple experts and methods of estimating the PMI were found. As part of this study, the methods that were used to estimate the PMI in court were subjected to the Daubert criteria. Of these methods, only the Henssge nomogram and entomological methods met the Daubert criteria. However, the methods are only useful when applied by the right forensic expert and in the right manner. Unfortunately, this was not always the case.
Purpose: The role of hypoalbuminemia and raised C-reactive protein (CRP) levels in predicting critical prognosis has been described extensively in adult literature. However, there are limited studies in pediatrics, particularly neonates. The CRP/albumin (CRP/ALB) ratio is often associated with higher mortality, organ failure and prolonged hospital stay. We hypothesized that the serum CRP/ALB ratio has a prognostic value in predicting surgery and mortality in neonates with necrotizing enterocolitis (NEC).
Methods: Retrospective review of all neonates with clinical and radiological evidence of non-perforated NEC that were treated in a tertiary-level referral hospital between 2009 and 2018. General patient demographics, laboratory parameters and outcomes were recorded. Receiver operating characteristics analysis was performed to evaluated optimal cut-offs and area under the curve (AUC) with 95% confidence intervals (CI).
Results: A total of 191 neonates were identified. Of these, 103 (53.9%) were born at ≤ 28 weeks of gestation and 101 (52.9%) had a birth weight of ≤ 1000 g. Eighty-four (44.0%) patients underwent surgical intervention for NEC. The overall survival rate was 161/191 (84.3%). A CRP/ALB ratio of ≥ 3 on day 2 of NEC diagnosis was associated with a statistically significant higher likelihood for surgery [AUC 0.71 (95% CI 0.63–0.79); p < 0.0001] and mortality [AUC 0.66 (95% CI 0.54–0.77); p = 0.0150], respectively.
Conclusions : A CRP/ALB ratio of ≥ 3 on day 2 is indicative of a critical pathway in neonates with radiologically confirmed, non-perforated NEC. This could be used as an additional criterion to guide parental counselling in NEC for surgical intervention and mortality.
Activation of the tumor-associated stroma to support tumor growth is a common feature observed in different cancer entities. This principle is exemplified by cancer-associated fibroblasts (CAFs), which are educated by the tumor to shape its development across all stages. CAFs can alter the extracellular matrix (ECM) and secrete a variety of different molecules. In that manner they have the capability to affect activation, survival, proliferation, and migration of other stromal cells and cancer cell themselves. Alteration of the ECM, desmoplasia, is a common feature of breast cancer, indicating a prominent role for CAFs in shaping tumor development in the mammary gland. In this review, we summarize the multiple roles CAFs play in mammary carcinoma. We discuss experimental and clinical strategies to interfere with CAFs function in breast cancer. Moreover, we highlight the issues arising from CAFs heterogeneity and the need for further research to identify CAFs subpopulation(s) that can be targeted to improve breast cancer therapy.
Background: Intraoperative blood salvage (IBS) is regarded as an alternative to allogeneic blood transfusion excluding the risks associated with allogeneic blood. Currently, IBS is generally avoided in tumor surgeries due to concern for potential metastasis caused by residual tumor cells in the erythrocyte concentrate.
Methods: The feasibility, efficacy and safety aspects of the new developed Catuvab procedure using the bispecific trifunctional antibody Catumaxomab was investigated in an ex-vivo pilot study in order to remove residual EpCAM positive tumor cells from the autologous erythrocyte concentrates (EC) from various cancer patients, generated by a IBS device.
Results: Tumor cells in intraoperative blood were detected in 10 of 16 patient samples in the range of 69–2.6 × 105 but no residual malignant cells in the final erythrocyte concentrates after Catuvab procedure. IL-6 and IL-8 as pro-inflammatory cytokines released during surgery, were lowered in mean 28-fold and 52-fold during the Catuvab procedure, respectively, whereas Catumaxomab antibody was detected in 8 of 16 of the final EC products at a considerable decreased and uncritical residual amount (37 ng in mean).
Conclusion: The preliminary study results indicate efficacy and feasibility of the new medical device Catuvab allowing potentially the reinfusion of autologous erythrocyte concentrates (EC) produced by IBS device during oncological high blood loss surgery. An open-label, multicenter clinical study on the removal of EpCAM-positive tumor cells from blood collected during tumor surgery using the Catuvab device is initiated to validate these encouraging results.
Background: Orthodontic root resorptions are frequently investigated in small animals, and micro-computed tomography (μCT) enables volumetric comparison. Despite, due to overlapping histograms from dentine and bone, accurate quantification of root resorption is challenging. The present study aims at (i) validating a novel automated approach for tooth segmentation (ATS), (ii) to indicate that matching of contralateral teeth is eligible to assess orthodontic tooth movement (OTM) and root resorption (RR), (iii) and to apply the novel approach in an animal trial performing orthodontic tooth movement.
Methods: The oral apparatus of three female mice were scanned with a μCT. The first molars of each jaw and animal were segmented using ATS (test) and manually (control), and contralateral volumes were compared. Agreement in root volumes and time efficiency were assessed for method validation. In another n = 14 animals, the left first upper molar was protracted for 11 days at 0.5 N, whereas the contralateral molar served as control. Following ATS, OTM and RR were estimated.
Results: ATS was significantly more time efficient compared to the manual approach (81% faster, P < 0.01), accurate (volume differences: − 0.01 ± 0.04 mm3), and contralateral roots had comparable volumes. Protracted molars had significantly lower root volumes (P = 0.03), whereas the amount of OTM failed to reveal linear association with RR (P > 0.05).
Conclusions: Within the limits of the study, it was demonstrated that the combination of ATS and registration of contralateral jaws enables measurements of OTS and associated RR in μCT scans.
The disruption in blood supply due to myocardial infarction is a critical determinant for infarct size and subsequent deterioration in function. The identification of factors that enhance cardiac repair by the restoration of the vascular network is, therefore, of great significance. Here, we show that the transcription factor Zinc finger E-box-binding homeobox 2 (ZEB2) is increased in stressed cardiomyocytes and induces a cardioprotective cross-talk between cardiomyocytes and endothelial cells to enhance angiogenesis after ischemia. Single-cell sequencing indicates ZEB2 to be enriched in injured cardiomyocytes. Cardiomyocyte-specific deletion of ZEB2 results in impaired cardiac contractility and infarct healing post-myocardial infarction (post-MI), while cardiomyocyte-specific ZEB2 overexpression improves cardiomyocyte survival and cardiac function. We identified Thymosin β4 (TMSB4) and Prothymosin α (PTMA) as main paracrine factors released from cardiomyocytes to stimulate angiogenesis by enhancing endothelial cell migration, and whose regulation is validated in our in vivo models. Therapeutic delivery of ZEB2 to cardiomyocytes in the infarcted heart induces the expression of TMSB4 and PTMA, which enhances angiogenesis and prevents cardiac dysfunction. These findings reveal ZEB2 as a beneficial factor during ischemic injury, which may hold promise for the identification of new therapies.
Background: Tisagenlecleucel, an anti-CD19 chimeric antigen receptor T cell therapy, has demonstrated efficacy in children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) in two multicenter phase 2 trials (ClinicalTrials.gov, NCT02435849 (ELIANA) and NCT02228096 (ENSIGN)), leading to commercialization of tisagenlecleucel for the treatment of patients up to age 25 years with B-ALL that is refractory or in second or greater relapse.
Methods: A pooled analysis of 137 patients from these trials (ELIANA: n=79; ENSIGN: n=58) was performed to provide a comprehensive safety profile for tisagenlecleucel.
Results: Grade 3/4 tisagenlecleucel-related adverse events (AEs) were reported in 77% of patients. Specific AEs of interest that occurred ≤8 weeks postinfusion included cytokine-release syndrome (CRS; 79% (grade 4: 22%)), infections (42%; grade 3/4: 19%), prolonged (not resolved by day 28) cytopenias (40%; grade 3/4: 34%), neurologic events (36%; grade 3: 10%; no grade 4 events), and tumor lysis syndrome (4%; all grade 3). Treatment for CRS included tocilizumab (40%) and corticosteroids (23%). The frequency of neurologic events increased with CRS severity (p<0.001). Median time to resolution of grade 3/4 cytopenias to grade ≤2 was 2.0 (95% CI 1.87 to 2.23) months for neutropenia, 2.4 (95% CI 1.97 to 3.68) months for lymphopenia, 2.0 (95% CI 1.87 to 2.27) months for leukopenia, 1.9 (95% CI 1.74 to 2.10) months for thrombocytopenia, and 1.0 (95% CI 0.95 to 1.87) month for anemia. All patients who achieved complete remission (CR)/CR with incomplete hematologic recovery experienced B cell aplasia; however, as nearly all responders also received immunoglobulin replacement, few grade 3/4 infections occurred >1 year postinfusion.
Conclusions: This pooled analysis provides a detailed safety profile for tisagenlecleucel during the course of clinical trials, and AE management guidance, with a longer follow-up duration compared with previous reports.
Patients with unilateral hip osteoarthritis show a characteristic gait pattern in which they unload the affected leg and overload the unaffected leg. Information on the gait characteristics of patients with bilateral hip osteoarthritis is very limited. The main purposes of this study were to investigate whether the gait pattern of both legs of patients with bilateral hip osteoarthritis deviates from healthy controls and whether bilateral hip osteoarthritis patients show a more symmetrical joint load compared to unilateral hip osteoarthritis patients. In this prospective study, 26 patients with bilateral hip osteoarthritis, 26 patients with unilateral hip osteoarthritis and 26 healthy controls were included. The three groups were matched for gender, age and walking speed. Patients were scheduled for a unilateral total hip arthroplasty on the more affected/more painful side. All participants underwent a three-dimensional gait analysis. Gait kinematics and gait kinetics of patients and controls were compared using Statistical Parametric Mapping. Corrected for speed, the gait kinematics and kinetics of both legs of patients with bilateral hip osteoarthritis differed from healthy controls. Bilateral patients had symmetrical knee joint loading, in contrast to the asymmetrical knee joint loading in unilateral hip osteoarthritis patients. The ipsilateral leg of the bilateral patients could be included in studies in addition to unilateral hip osteoarthritis patients as no differences were found. Although patients with bilateral hip osteoarthritis show more symmetrical frontal plane knee joint moments, a pathological external knee adduction moment in the second half of stance was present in the ipsilateral leg in patients with unilateral and bilateral hip osteoarthritis. The lateral adjustment of the knee adduction moment may initiate or accelerate progression of degenerative changes in the lateral compartment of the knee.
Ataxia telangiectasia (A-T) is a progressive and life-limiting disease associated with cerebellar ataxia due to progressive cerebellar degeneration. In addition to ataxia, which is described in detail, the presence of chorea, dystonia, oculomotor apraxia, athetosis, parkinsonism, and myoclonia are typical manifestations of the disease. The study aimed to evaluate the specificity and sensitivity of neurofilament light chain (NfL) as a biomarker of neurodegeneration in relation to SARA score. In this prospective trial, one visit of 42 A-T patients aged 1.3–25.6 years (mean 11.6 ± 7.3 years) was performed, in which NfL was determined from serum by ELISA. Additionally, a neurological examination of the patients was performed. Blood was collected from 19 healthy volunteers ≥ 12 years of age. We found significantly increased levels of NfL in patients with A-T compared to healthy controls (21.5 ± 3.6 pg/mL vs. 9.3 ± 0.49 pg/mL, p ≤ 0.01). There was a significant correlation of NfL with age, AFP, and SARA. NfL is a new potential progression biomarker in blood for neurodegeneration in A-T which increases with age.
Background: The correct performance of a structured facial examination presents a fundamental clinical skill to detect facial pathologies. However, many students are not adequately prepared in this basic clinical skill. Many argue that the traditional ‘See One, Do One’ approach is not sufficient to fully master a clinical skill. ‘Mental Training’ has successfully been used to train psychomotor and technical skills in sports and other surgical fields, but its use in Oral and Maxillofacial Surgery is not described. We conducted a quasi-experimental to determine if ‘Mental Training’ was effective in teaching a structured facial examination.
Methods: Sixty-seven students were randomly assigned to a ‘Mental Training’ and ‘See One, Do One’ group. Both groups received standardized video instruction on how to perform a structured facial examination. The ‘See One, Do One’ group then received 60 min of guided physical practice while the ‘Mental Training’ group actively developed a detailed, stepwise sequence of the performance of a structured facial examination and visualized this sequence subvocally before practicing the skill. Student performance was measured shortly after (T1) and five to 10 weeks (T2) after the training by two blinded examiners (E1 and E2) using a validated checklist.
Results: Groups did not differ in gender, age or in experience. The ‘Mental Training’ group averaged significantly more points in T1 (pE1 = 0.00012; pE2 = 0.004; dE1 = 0.86; dE2 = 0.66) and T2 (pE1 = 0.04; pE2 = 0.008, dE1 = 0.37; dE2 = 0.64) than the ‘See One, Do One’ group. The intragroup comparison showed a significant (pE1 = 0.0002; pE2 = 0.06, dE1 = 1.07; dE2 = 0.50) increase in clinical examination skills in the ‘See One, Do One’ group, while the ‘Mental Training’ group maintained an already high level of clinical examination skills between T1 and T2.
Discussion: ‘Mental Training’ is an efficient tool to teach and maintain basic clinical skills. In this study ‘Mental Training’ was shown to be superior to the commonly used ‘See One, Do One’ approach in learning how to perform a structured facial examination and should therefore be considered more often to teach physical examination skills.
This study highlights the importance of insect evidence by evaluating 949 insect-associated cases, including 139 entomological reports, from 2001 to 2019 at the Institute of Legal Medicine Frankfurt/Germany. With a high number of cases in the summer months and a low number in the colder season, 78.5% of the bodies were found indoors, regardless of year or month. In more than 80% of the cases, where PMI information was available (n = 704), the presumed PMI ranged from 1 to 21 days, a period during which entomological evidence can provide a day-specific estimate of PMImin. In cases where insects have been identified to species level (n = 279), most bodies were infested by one or two species with a maximum of 10 different species. Overall, a total of 55 insect species were found. Information on biology, activity and distribution of the most abundant taxa is given and applied for 5 case histories estimating different PMImins of up to over 6 months. Despite proved importance and scientific development of forensic entomology, insects are still rarely considered as a tool in forensic case work. The main reasons are a lack of awareness and (too) late involvement of a forensic entomologist. Our work shows that forensic entomology is an independent discipline that requires specialist expertise.
Physical activity and well-being during the second COVID19-related lockdown in Germany in 2021
(2021)
In the second wave of the COVID-19 pandemic in Germany, lockdown measures were reinstalled and were in place between November 2020 and April 2021, including the closure of physical activity facilities. The aim of the current online survey was to assess the lockdown effects on physical activity and well-being in the general population. Pre-lockdown vs. lockdown differences were tested with the Χ2 test and the Student’s t-test for paired data. Predictor variables to explain compliance with physical activity recommendations were identified using a fixed-effects binary logistic regression analysis. Data of 993 respondents were analyzed. Transport-related and leisure-time physical activity decreased (p < 0.001, d = 0.25, and p < 0.001, d = 0.33, respectively). Compliance with physical activity recommendations decreased from 42.2% to 29.4% (chi2 (1, 1986) = 35.335, p < 0.001, V = 0.13). Well-being decreased significantly (t (990) = 23.405, p < 0.001) by 16.3 points (d = 0.74). Physical activity and well-being declined in German adults during the second COVID-19-related lockdown. Physical activity should be promoted also in light of the emerging evidence on its protective effects against COVID-19.
Background and Objectives: We tested if a novel combination of predictors could improve the accuracy of outcome prediction after transfemoral transcatheter aortic valve implantation (TAVI). Materials and Methods: This prospective study recruited 169 participants (49% female; median age 81 years). The primary endpoint was midterm mortality; secondary endpoints were acute Valve Academic Research Consortium (VARC)-3 complication rate and post-TAVI in-hospital length of stay (LoS). EuroSCORE II (ESII), comorbidities (e.g., coronary artery disease), eGFR (estimated glomerular filtration rate; based on cystatin C), hemoglobin, creatinine, N-Terminal pro-Brain Natriuretic Peptide (NTproBNP) levels and patient-reported outcome measures (PROMs, namely EuroQol-5-Dimension-5-Levels, EQ5D5L; Kansas City Cardiomyopathy Questionnaire, KCCQ; clinical frailty scale, CFS) at baseline were tested as predictors. Regression (uni- and multi-variate Cox; linear; binary logistic) and receiver operating characteristic (ROC)-curve analysis were applied. Results: Within a median follow-up of 439 (318–585) days, 12 participants died (7.1%). Independent predictors of mortality using multivariate Cox regression were baseline eGFR (p = 0.001) and KCCQ (p = 0.037). Based on these predictors, a Linear Prediction Score (LPS1) was calculated. The LPS1-area under the curve (AUC)-value (0.761) was significantly higher than the ESII-AUC value (0.597; p = 0.035). Independent predictors for LoS > 6 days (the median LoS) were eGFR (p = 0.028), NTproBNP (p = 0.034), and EQ5D5L values (p = 0.002); a respective calculated LPS2 provided an AUC value of 0.677 (p < 0.001). Eighty participants (47.3%) experienced complications. Male sex predicted complications only in the univariate analysis. Conclusions: The combination of KCCQ and eGFR can better predict midterm mortality than ES II alone. Combining eGFR, NTproBNP, and EQ5D5L can reliably predict LoS after TAVI. This novel method improves personalized TAVI risk stratification and hence may help reduce post-TAVI risk.
Aims: Patients with cardiovascular comorbidities have a significantly increased risk for a critical course of COVID-19. As the SARS-CoV2 virus enters cells via the angiotensin-converting enzyme receptor II (ACE2), drugs which interact with the renin angiotensin aldosterone system (RAAS) were suspected to influence disease severity.
Methods and results: We analyzed 1946 consecutive patients with cardiovascular comorbidities or hypertension enrolled in one of the largest European COVID-19 registries, the Lean European Open Survey on SARS-CoV-2 (LEOSS) registry. Here, we show that angiotensin II receptor blocker intake is associated with decreased mortality in patients with COVID-19 [OR 0.75 (95% CI 0,59–0.96; p = 0.013)]. This effect was mainly driven by patients, who presented in an early phase of COVID-19 at baseline [OR 0,64 (95% CI 0,43–0,96; p = 0.029)]. Kaplan-Meier analysis revealed a significantly lower incidence of death in patients on an angiotensin receptor blocker (ARB) (n = 33/318;10,4%) compared to patients using an angiotensin-converting enzyme inhibitor (ACEi) (n = 60/348;17,2%) or patients who received neither an ACE-inhibitor nor an ARB at baseline in the uncomplicated phase (n = 90/466; 19,3%; p<0.034). Patients taking an ARB were significantly less frequently reaching the mortality predicting threshold for leukocytes (p<0.001), neutrophils (p = 0.002) and the inflammatory markers CRP (p = 0.021), procalcitonin (p = 0.001) and IL-6 (p = 0.049). ACE2 expression levels in human lung samples were not altered in patients taking RAAS modulators.
Conclusion: These data suggest a beneficial effect of ARBs on disease severity in patients with cardiovascular comorbidities and COVID-19, which is linked to dampened systemic inflammatory activity.
Autophagy is an important survival mechanism that allows recycling of nutrients and removal of damaged organelles and has been shown to contribute to the proliferation of acute myeloid leukemia (AML) cells. However, little is known about the mechanism by which autophagy- dependent AML cells can overcome dysfunctional autophagy. In our study we identified autophagy related protein 3 (ATG3) as a crucial autophagy gene for AML cell proliferation by conducting a CRISPR/Cas9 dropout screen with a library targeting around 200 autophagy-related genes. shRNA-mediated loss of ATG3 impaired autophagy function in AML cells and increased their mitochondrial activity and energy metabolism, as shown by elevated mitochondrial ROS generation and mitochondrial respiration. Using tracer-based NMR metabolomics analysis we further demonstrate that the loss of ATG3 resulted in an upregulation of glycolysis, lactate production, and oxidative phosphorylation. Additionally, loss of ATG3 strongly sensitized AML cells to the inhibition of mitochondrial metabolism. These findings highlight the metabolic vulnerabilities that AML cells acquire from autophagy inhibition and support further exploration of combination therapies targeting autophagy and mitochondrial metabolism in AML.
Uterine cervical cancer is one of the leading causes of cancer-related mortality in women worldwide. Each year, over half a million new cases are estimated, resulting in more than 300,000 deaths. While less-invasive, fertility-preserving surgical procedures can be offered to women in early stages, treatment for locally advanced disease may include radical hysterectomy, primary chemoradiotherapy (CRT) or a combination of these modalities. Concurrent platinum-based chemoradiotherapy regimens remain the first-line treatments for locally advanced cervical cancer. Despite achievements such as the introduction of angiogenesis inhibitors, and more recently immunotherapies, the overall survival of women with persistent, recurrent or metastatic disease has not been extended significantly in the last decades. Furthermore, a broad spectrum of molecular markers to predict therapy response and survival and to identify patients with high- and low-risk constellations is missing. Implementation of these markers, however, may help to further improve treatment and to develop new targeted therapies. This review aims to provide comprehensive insights into the complex mechanisms of cervical cancer pathogenesis within the context of molecular markers for predicting treatment response and prognosis.
Progranulin deficiency in mice is associated with deregulations of the scavenger receptor signaling of CD36/SCARB3 in immune disease models, and CD36 is a dominant receptor in taste bud cells in the tongue and contributes to the sensation of dietary fats. Progranulin-deficient mice (Grn−/−) are moderately overweight during middle age. We therefore asked if there was a connection between progranulin/CD36 in the tongue and fat taste preferences. By using unbiased behavioral analyses in IntelliCages and Phenomaster cages we showed that progranulin-deficient mice (Grn−/−) developed a strong preference of fat taste in the form of 2% milk over 0.3% milk, and for diluted MCTs versus tap water. The fat preference in the 7d-IntelliCage observation period caused an increase of 10% in the body weight of Grn−/− mice, which did not occur in the wildtype controls. CD36 expression in taste buds was reduced in Grn−/− mice at RNA and histology levels. There were no differences in the plasma or tongue lipids of various classes including sphingolipids, ceramides and endocannabinoids. The data suggest that progranulin deficiency leads to a lower expression of CD36 in the tongue resulting in a stronger urge for fatty taste and fatty nutrition.
Background: Antibody detection of SARS-CoV-2 requires an understanding of its variation, course, and duration.
Methods: Antibody response to SARS-CoV-2 was evaluated over 5–430 days on 828 samples across COVID-19 severity levels, for total antibody (TAb), IgG, IgA, IgM, neutralizing antibody (NAb), antibody avidity, and for receptor-binding-domain (RBD), spike (S), or nucleoprotein (N). Specificity was determined on 676 pre-pandemic samples.
Results: Sensitivity at 30–60 days post symptom onset (pso) for TAb-S/RBD, TAb-N, IgG-S, IgG-N, IgA-S, IgM-RBD, and NAb was 96.6%, 99.5%, 89.7%, 94.3%, 80.9%, 76.9% and 92.8%, respectively. Follow-up 430 days pso revealed: TAb-S/RBD increased slightly (100.0%); TAb-N decreased slightly (97.1%); IgG-S and IgA-S decreased moderately (81.4%, 65.7%); NAb remained positive (94.3%), slightly decreasing in activity after 300 days; there was correlation with IgG-S (Rs = 0.88) and IgA-S (Rs = 0.71); IgG-N decreased significantly from day 120 (15.7%); IgM-RBD dropped after 30–60 days (22.9%). High antibody avidity developed against S/RBD steadily with time in 94.3% of patients after 430 days. This correlated with persistent antibody detection depending on antibody-binding efficiency of the test design. Severe COVID-19 correlated with earlier and higher antibody response, mild COVID-19 was heterogeneous with a wide range of antibody reactivities. Specificity of the tests was ≥99%, except for IgA (96%).
Conclusion: Sensitivity of anti-SARS-CoV-2 assays was determined by test design, target antigen, antibody avidity, and COVID-19 severity. Sustained antibody detection was mainly determined by avidity progression for RBD and S. Testing by TAb and for S/RBD provided the highest sensitivity and longest detection duration of 14 months so far.
Probably, patients with de novo (synchronous) and recurrent (metachronous) oligometastatic hormone-sensitive prostate cancer have different oncologic outcomes. Thus, we are challenged with different scenarios in clinical practice, where different treatment options may apply. In the last years, several prospective studies have focused on the treatment of patients with de novo oligometastatic hormone-sensitive prostate cancer. Not only the addition of systemic therapeutic treatments, such as chemotherapy with docetaxel, abiraterone, enzalutamide, and apalutamide, next to androgen deprivation therapy, demonstrated to improve outcomes in these patients but also local therapy of the primary has been demonstrated to improve outcomes of low-volume metastatic disease. Next to radiotherapy, also radical prostatectomy has been reported as a feasible and safe treatment option. Additional metastasis-directed therapy in de novo metastatic disease is currently examined by four trials. In the recurrent metastatic setting, less data are available, and it remains uncertain if patients can be treated in the same way as synchronous oligometastatic disease. Metastasis-directed therapy has demonstrated to prolong outcomes, while data on survival are still missing.
Objectives: The aim of this study was to evaluate the development and status quo of the quality of high throughput in vitro diagnostic testing for tetanus and diphtheria antitoxin antibody (ATX) concentrations based on external quality assessment (EQA) data.
Methods: We analyzed manufacturer-specific data of 22 EQA surveys—each for the detection of tetanus and diphtheria ATX—to check the diagnostic strength of the corresponding in vitro diagnostic systems.
Results: While the results were mostly well aligned, individual surveys showed widely dispersed ATX concentrations. The medians of manufacturer collectives deviated from the overall median by up to 8.9-fold in the case of diphtheria ATX and by up to 3.5-fold in the case of tetanus ATX. Such a distribution in the results is particularly critical in the cut-off range for immunity and may lead to an incorrect assessment of vaccination status.
Conclusion: These results were surprising as there are International Standards for both ATX; however, the results may be linked to the high ATX concentration of the reference material, which deviates considerably from clinically significant concentrations. To increase the accuracy and diagnostic strength of both assays, we recommend a recalibration of the test systems and verification of their traceability to the International Standards.
Objectives: To prospectively evaluate lung ultrasound in comparison with radiography and computed tomography (CT) for detecting HIV-related lung diseases.
Methods: Ultrasound examinations in HIV-positive patients were evaluated by three raters; available conventional imaging was evaluated by another rater. Results were compared with each other and the definite diagnosis. Interrater reliability was calculated for each finding.
Results: Eighty HIV-positive patients received lung ultrasound examinations; 74 received conventional imaging. The overall sensitivity was 97.5% for CT, 90.7% for ultrasound and 78.1% for radiography. The most common diagnoses were Pneumocystis jirovecii pneumonia (21 cases) and bacterial pneumonia (17 cases). The most frequent and sensitive ultrasonographic findings were interstitial abnormalities indicated by B-lines, independent of the aetiology. Interrater reliability was high for interstitial abnormalities (ICC=0.82). The interrater reliability for consolidations and effusion increased during the study (r=0.88 and r=0.37, respectively).
Conclusions: Ultrasound is a fast, reliable and sensitive point-of-care tool, particularly in detecting interstitial lung disease, which is common in HIV-associated illness. It does not effectively discriminate between different aetiologies. A longer learning period might be required to reliably identify consolidations and effusions.
Background: The surgical treatment of giant olfactory groove meningiomas (OGMs) with marked perilesional brain oedema is still a surgical challenge. After tumour resection, increase of brain oedema may occur causing dramatic neurological deterioration and even death of the patient. The objective of this paper is to describe surgical features of a two-step staged resection of these tumours performed to counter increase of postoperative brain oedema.
Methods: This two-step staged resection procedure was carried out in a consecutive series of 19 patients harbouring giant OGMs. As first step, a bifrontal craniectomy was performed followed by a right-sided interhemispherical approach. About 80% of the tumour mass was resected leaving behind a shell-shaped tumour remnant. In the second step, carried out after the patients’ recovery from the first surgery and decline of oedema, the remaining part of the tumour was removed completely followed by duro- and cranioplasty.
Results: Ten patients recovered quickly from first surgery and the second operation was performed after a mean of 12.4 days. In eight patients, the second operation was carried out later between day 25 and 68 due to surgery-related complications, development of a trigeminal zoster, or to a persisting frontal brain oedema. Mean follow-up was 49.3 months and all but one patient had a good outcome regardless of surgery-related complications.
Conclusions: Our results suggest that a two-step staged resection of giant OGMs minimizes the increase of postoperative brain oedema as far as possible and translates into lower morbidity and mortality.
Acute kidney injury (AKI) complicates the clinical course of hospitalized patients by increasing need for intensive care treatment and mortality. There is only little data about its impact on AML patients undergoing intensive induction chemotherapy. In this study, we analyzed the incidence as well as risk factors for AKI development and its impact on the clinical course of AML patients undergoing induction chemotherapy. We retrospectively analyzed data from 401 AML patients undergoing induction chemotherapy between 2007 and 2019. AKI was defined and stratified according to KIDGO criteria by referring to a defined baseline serum creatinine measured on day 1 of induction chemotherapy. Seventy-two of 401 (18%) AML patients suffered from AKI during induction chemotherapy. AML patients with AKI had more days with fever (7 vs. 5, p = 0.028) and were more often treated on intensive care unit (45.8% vs. 10.6%, p < 0.001). AML patients with AKI had a significantly lower complete remission rate after induction chemotherapy and, with 402 days, a significantly shorter median overall survival (OS) (median OS for AML patients without AKI not reached). In this study, we demonstrate that the KIDGO classification allows mortality risk stratification for AML patients undergoing induction chemotherapy. Relatively mild AKI episodes have impact on the clinical course of these patients and can lead to chronic impairment of kidney function. Therefore, we recommend incorporating risk factors for AKI in decision-making considering nutrition, fluid management, as well as the choice of potentially nephrotoxic medication in order to decrease the incidence of AKI.
Purpose: Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) replicates predominantly in the upper respiratory tract and is primarily transmitted by droplets and aerosols. Taking the medical history for typical COVID-19 symptoms and PCR-based SARS-CoV-2 testing have become established as screening procedures. The aim of this work was to describe the clinical appearance of SARS-CoV-2-PCR positive patients and to determine the SARS-CoV-2 contact risk for health care workers (HCW).
Methods: The retrospective study included n = 2283 SARS-CoV-2 PCR tests from n = 1725 patients with otorhinolaryngological (ORL) diseases performed from March to November 2020 prior to inpatient treatment. In addition, demographic data and medical history were assessed.
Results: n = 13 PCR tests (0.6%) were positive for SARS-CoV-2 RNA. The positive rate showed a significant increase during the observation period (p < 0.01). None of the patients had clinical symptoms that led to a suspected diagnosis of COVID-19 before PCR testing. The patients were either asymptomatic (n = 4) or had symptoms that were interpreted as symptoms typical of the ORL disease or secondary diagnoses (n = 9).
Conclusion: The identification of SARS-CoV-2-positive patients is a considerable challenge in clinical practice. Our findings illustrate that taking a medical history alone is of limited value and cannot replace molecular SARS-CoV-2 testing, especially for patients with ORL diseases. Our data also demonstrate that there is a high probability of contact with SARS-CoV-2-positive patients in everyday clinical practice, so that the use of personal protective equipment, even in apparently “routine cases”, is highly recommended.
Estimating intraoperative blood loss is one of the daily challenges for clinicians. Despite the knowledge of the inaccuracy of visual estimation by anaesthetists and surgeons, this is still the mainstay to estimate surgical blood loss. This review aims at highlighting the strengths and weaknesses of currently used measurement methods. A systematic review of studies on estimation of blood loss was carried out. Studies were included investigating the accuracy of techniques for quantifying blood loss in vivo and in vitro. We excluded nonhuman trials and studies using only monitoring parameters to estimate blood loss. A meta-analysis was performed to evaluate systematic measurement errors of the different methods. Only studies that were compared with a validated reference e.g. Haemoglobin extraction assay were included. 90 studies met the inclusion criteria for systematic review and were analyzed. Six studies were included in the meta-analysis, as only these were conducted with a validated reference. The mixed effect meta-analysis showed the highest correlation to the reference for colorimetric methods (0.93 95% CI 0.91–0.96), followed by gravimetric (0.77 95% CI 0.61–0.93) and finally visual methods (0.61 95% CI 0.40–0.82). The bias for estimated blood loss (ml) was lowest for colorimetric methods (57.59 95% CI 23.88–91.3) compared to the reference, followed by gravimetric (326.36 95% CI 201.65–450.86) and visual methods (456.51 95% CI 395.19–517.83). Of the many studies included, only a few were compared with a validated reference. The majority of the studies chose known imprecise procedures as the method of comparison. Colorimetric methods offer the highest degree of accuracy in blood loss estimation. Systems that use colorimetric techniques have a significant advantage in the real-time assessment of blood loss.
Background: To determine the correlation between urine loss in PAD-test after catheter removal, and early urinary continence (UC) in RP treated patients. Methods: Urine loss was measured by using a standardized, validated PAD-test within 24 h after removal of the transurethral catheter, and was grouped as a loss of <1, 1–10, 11–50, and >50 g of urine, respectively. Early UC (median: 3 months) was defined as the usage of no or one safety-pad. Uni- and multivariable logistic regression models tested the correlation between PAD-test results and early UC. Covariates consisted of age, BMI, nerve-sparing approach, prostate volume, and extraprostatic extension of tumor. Results: From 01/2018 to 03/2021, 100 patients undergoing RP with data available for a PAD-test and early UC were retrospectively identified. Ultimately, 24%, 47%, 15%, and 14% of patients had a loss of urine <1 g, 1–10 g, 11–50 g, and >50 g in PAD-test, respectively. Additionally, 59% of patients reported to be continent. In multivariable logistic regression models, urine loss in PAD-test predicted early UC (OR: 0.21 vs. 0.09 vs. 0.03; for urine loss 1–10 g vs. 11–50 g vs. >50 g, Ref: <1 g; all p < 0.05). Conclusions: Urine loss after catheter removal strongly correlated with early continence as well as a severity in urinary incontinence.
Epoxyeicosatrienoic acids (EET) facilitate regeneration in different tissues, and their benefit in dermal wound healing has been proven under normal conditions. In this study, we investigated the effect of 11,12 EET on dermal wound healing in diabetes. We induced diabetes by i.p. injection of streptozotocin 2 weeks prior to wound creation on the dorsal side of the mouse ear. 11,12 EET was applied every second day on the wound, whereas the control groups received only solvent. Epithelialization was monitored every second day intravitally up to wound closure. Wounds were stained for VEGF, CD31, TGF-β, TNF-α, SDF-1α, NF-κB, and Ki-67, and fibroblasts were counted after hematoxylin-eosin stain on days 3, 6, 9, and 16 after wounding. After induction of diabetes, wounds closed on day 13.00 ± 2.20 standard deviation (SD). Local 11,12 ETT application improved wound closure significantly to day 8.40 ± 1.39 SD. EET treatment enhanced VEGF and CD31 expression in wounds on day 3. It also seemed to raise TNF-α level on all days investigated as well as TGF-β level on days 3 and 6. A decrease in NF-κB could be observed on days 9 and 16 after EET application. The latter findings were not significant. SDF-1α expression was not influenced by EET application, and Ki-67 was significantly less in the EET group on day 9 after EET application. The number of fibroblasts was significantly increased on day 9 after the 11,12 EET application. 11,12 EET improve deteriorated wound healing in diabetes by enhancing neoangiogenesis, especially in the early phase of wound healing. Furthermore, they contribute to the dissolution of the initial inflammatory reaction, allowing the crucial transition from the inflammatory to proliferative phase in wound healing.
Short- and long-term effects of rehabilitation after perimesencephalic subarachnoid hemorrhage
(2021)
n about 25% of patients with spontaneous subarachnoid hemorrhage (SAH), a bleeding source cannot be identified during radiological diagnostics. Generally, the outcome of perimesencephalic or prepontine (PM) SAH is known to be significantly better than after non-PM SAH. Data about long-term follow-up concerning physical and mental health are scarce, so this study is reports on long-term results. We measured the influence of PM SAH on a quality-of-life modified Rankin (mRs) scale after six months. For long-term follow-up, a SF-36 questionnaire was used. Questionnaires were sent out between 18 and 168 months after ictus. In 37 patients, a long-term follow-up was available (up to 14 years after SAH). Data detected with the SF-36 questionnaire are compared to reference applicability to the standard population. In total, 37 patients were included for further analysis and divided in 2 subgroups; 13 patients (35%) received subsequent rehabilitation after clinical stay and 24 (65%) did not. In the short-term outcome, a significant improvement from discharge until follow-up was identified in patients with subsequent rehabilitation, but not in the matched pair group without rehabilitation. When PM SAH was compared to the standard population, a reduction in quality of life was identified in physical items (role limitations because of physical health problems, physical functioning) as well as in psychological items (role limitations because of emotional problems). Subsequent rehabilitation on PM SAH patients probably leads to an increase in independence and better mRs. While better mRs was shown at discharge in patients without subsequent rehabilitation, the mRs of rehabilitants was nearly identical after rehabilitation. Patients with good mRs also reached high levels of health-related quality of life (HRQoL) without rehabilitation. Thus, subsequent rehabilitation needs to be encouraged on an individual basis. Indication criteria for subsequent rehabilitation should be defined in further studies to improve patient treatment and efficiency in health care.
Anti-inflammatory effects of low-dose irradiation often follow a non-linear dose–effect relationship. These characteristics were also described for the modulation of leukocyte adhesion to endothelial cells. Previous results further revealed a contribution of reactive oxygen species (ROS) and anti-oxidative factors to a reduced leukocyte adhesion. Here, we evaluated the expression of anti-oxidative enzymes and the transcription factor Nrf2 (Nuclear factor-erythroid-2-related factor 2), intracellular ROS content, and leukocyte adhesion in primary human microvascular endothelial cells (HMVEC) upon low-dose irradiation under physiological laminar shear stress or static conditions after irradiation with X-ray or Carbon (C)-ions (0–2 Gy). Laminar conditions contributed to increased mRNA expression of anti-oxidative factors and reduced ROS in HMVEC following a 0.1 Gy X-ray and 0.5 Gy C-ion exposure, corresponding to reduced leukocyte adhesion and expression of adhesion molecules. By contrast, mRNA expression of anti-oxidative markers and adhesion molecules, ROS, and leukocyte adhesion were not altered by irradiation under static conditions. In conclusion, irradiation of endothelial cells with low doses under physiological laminar conditions modulates the mRNA expression of key factors of the anti-oxidative system, the intracellular ROS contents of which contribute at least in part to leucocyte adhesion, dependent on the radiation source.
Mechanotransduction is elicited in cells upon the perception of physical forces transmitted via the extracellular matrix in their surroundings and results in signaling events that impact cellular functions. This physiological process is a prerequisite for maintaining the integrity of diarthrodial joints, while excessive loading is a factor promoting the inflammatory mechanisms of joint destruction. Here, we describe a mechanotransduction pathway in synovial fibroblasts (SF) derived from the synovial membrane of inflamed joints. The functionality of this pathway is completely lost in the absence of the disintegrin metalloproteinase ADAM15 strongly upregulated in SF. The mechanosignaling events involve the Ca2+-dependent activation of c-Jun-N-terminal kinases, the subsequent downregulation of long noncoding RNA HOTAIR, and upregulation of the metabolic energy sensor sirtuin-1. This afferent loop of the pathway is facilitated by ADAM15 via promoting the cell membrane density of the constitutively cycling mechanosensitive transient receptor potential vanilloid 4 calcium channels. In addition, ADAM15 reinforces the Src-mediated activation of pannexin-1 channels required for the enhanced release of ATP, a mediator of purinergic inflammation, which is increasingly produced upon sirtuin-1 induction.
Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors predominate as first-line therapy options for renal cell carcinoma. When first-line TKI therapy fails due to resistance development, an optimal second-line therapy has not yet been established. The present investigation is directed towards comparing the anti-angiogenic properties of the TKIs, sorafenib and axitinib on human endothelial cells (HUVECs) with acquired resistance towards the TKI sunitinib. HUVECs were driven to resistance by continuously exposing them to sunitinib for six weeks. They were then switched to a 24 h or further six weeks treatment with sorafenib or axitinib. HUVEC growth, as well as angiogenesis (tube formation and scratch wound assay), were evaluated. Cell cycle proteins of the CDK-cyclin axis (CDK1 and 2, total and phosphorylated, cyclin A and B) and the mTOR pathway (AKT, total and phosphorylated) were also assessed. Axitinib (but not sorafenib) significantly suppressed growth of sunitinib-resistant HUVECs when they were exposed for six weeks. This axinitib-associated growth reduction was accompanied by a cell cycle block at the G0/G1-phase. Both axitinib and sorafenib reduced HUVEC tube length and prevented wound closure (sorafenib > axitinib) when applied to sunitinib-resistant HUVECs for six weeks. Protein analysis revealed diminished phosphorylation of CDK1, CDK2 and pAKT, accompanied by a suppression of cyclin A and B. Both drugs modulated CDK-cyclin and AKT-dependent signaling, associated either with both HUVEC growth and angiogenesis (axitinib) or angiogenesis alone (sorafenib). Axitinib and sorafenib may be equally applicable as second line treatment options, following sunitinib resistance.
Cyclic nucleotides are important second messengers involved in cellular events, and analogues of this type of molecules are promising drug candidates. Some cyclic nucleotide analogues have become standard tools for the investigation of biochemical and physiological signal transduction pathways, such as the Rp-diastereomers of adenosine and guanosine 3′,5′-cyclic monophosphorothioate, which are competitive inhibitors of cAMP- and cGMP-dependent protein kinases. Next generation analogues exhibit a higher membrane permeability, increased resistance against degradation, and improved target specificity, or are caged or photoactivatable for fast and/or targeted cellular imaging. Novel specific nucleotide analogues activating or inhibiting cyclic nucleotide-dependent ion channels, EPAC/GEF proteins, and bacterial target molecules have been developed, opening new avenues for basic and applied research. This review provides an overview of the current state of the field, what can be expected in the future and some practical considerations for the use of cyclic nucleotide analogues in biological systems.
Background: Feedback is an essential element of learning. Despite this, students complain about receiving too little feedback in medical examinations, e.g., in an objective structured clinical examination (OSCE). This study aims to implement a written structured feedback tool for use in OSCEs and to analyse the attitudes of students and examiners towards this kind of feedback.
Methods: The participants were OSCE examiners and third-year medical students. This prospective study was conducted using a multistage design. In the first step, an unstructured interrogation of the examiners formed the basis for developing a feedback tool, which was evaluated and then adopted in the next steps.
Results: In total, 351 students and 51 examiners participated in this study. A baseline was created for each category of OSCE station and was supplemented with station-specific items. Each of these items was rated on a three-point scale. In addition to the preformulated answer options, each domain had space for individual comments.
A total of 87.5% of the students and 91.6% of the examiners agreed or rather agreed that written feedback should continue to be used in upcoming OSCEs.
Conclusion: The implementation of structured, written feedback in a curricular, summative examination is possible, and examiners and students would like the feedback to be constant.
Background: On encountering a susceptible target, natural killer (NK) cells mediate cytotoxicity through highly regulated steps of directed degranulation. Cytotoxic granules converge at the microtubule organizing center and are polarized toward the immunological synapse (IS), followed by granule exocytosis. NK cell retargeting by chimeric antigen receptors (CARs) or mAbs represents a promising strategy for overcoming tumor cell resistance. However, little is known about the lytic granule dynamics of such retargeted NK cells toward NK-cell-resistant tumors.
Methods: Here, we used spinning disk confocal microscopy for live-cell imaging to analyze granule-mediated NK cell cytotoxicity in ErbB2-targeted CAR-expressing NK-92 cells (NK-92/5.28.z) and high-affinity FcR transgenic NK-92 cells plus Herceptin toward ErbB2-positive breast cancer cells (MDA-MB-453), which are resistant to parental NK-92.
Results: Unmodified NK-92 cells cocultured with resistant cancer cells showed stable conjugate formation and granule clustering, but failed to polarize granules to the IS. In contrast, retargeting by CAR or FcR+Herceptin toward the MDA-MB-453 cells enabled granule polarization to the IS, resulting in highly effective cytotoxicity. We found that in NK-92 the phosphoinositide 3-kinase pathway was activated after contact with resistant MDA-MB-453, while phospholipase C-γ (PLCγ) and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) were not activated. In contrast, retargeting by CAR or antibody-dependent cell-mediated cytotoxicity (ADCC) provided the missing PLCγ and MEK/ERK signals.
Conclusions: These observations suggest that NK cells can create conjugates with resistant cancer cells and respond by granule clustering, but the activation signals are insufficient to induce granule polarization and consequent release of lytic enzymes. Retargeting by CAR and/or the FcR/mAb (ADCC) axis provide the necessary signals, leading to granule polarization and thereby overcoming tumor cell resistance.
Introduction Massive haemoptysis is a life-threatening event in advanced cystic fibrosis (CF) lung disease with bronchial artery embolisation (BAE) as standard of care treatment. The aim of our study was to scrutinise short-term and long-term outcomes of patients with CF and haemoptysis after BAE using coils.
Methods We carried out a retrospective cohort study of 34 adult patients treated for massive haemoptysis with super selective bronchial artery coil embolisation (ssBACE) between January 2008 and February 2015. Embolisation protocol was restricted to the culprit vessel(s) and three lobes maximum. Demographic data, functional end-expiratory volume in 1 s in % predicted (FEV1% pred.) and body mass index before and after ssBACE, sputum colonisation, procedural data, time to transplant and time to death were documented.
Results Patients treated with ssBACE showed significant improvement of FEV1% pred. after embolisation (p=0.004) with 72.8% alive 5 years post-ssBACE. Mean age of the patients was 29.9 years (±7.7). Mean FEV1% pred. was 45.7% (±20.1). Median survival to follow-up was 75 months (0–125). Severe complication rate was 0%, recanalisation rate 8.8% and 5-year-reintervention rate 58.8%. Chronic infection with Pseudomonas aeruginosa was found in 79.4%, Staphylococcus areus in 50% and Aspergillus fumigatus in 47.1%.
Discussion ssBACE is a safe and effective treatment for massive haemoptysis in patients with CF with good results for controlling haemostasis and excellent short-term and long-term survival, especially in severely affected patients with FEV<40% pred. We think the data of our study support the use of coils and a protocol of careful and prudent embolisation.
Testing for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) by RT-PCR is a vital public health tool in the pandemic. Self-collected samples are increasingly used as an alternative to nasopharyngeal swabs. Several studies suggested that they are sufficiently sensitive to be a useful alternative. However, there are limited data directly comparing several different types of self-collected materials to determine which material is preferable. A total of 102 predominantly symptomatic adults with a confirmed SARS-CoV-2 infection self-collected native saliva, a tongue swab, a mid-turbinate nasal swab, saliva obtained by chewing a cotton pad and gargle lavage, within 48 h of initial diagnosis. Sample collection was unsupervised. Both native saliva and gargling with tap water had high diagnostic sensitivity of 92.8% and 89.1%, respectively. Nasal swabs had a sensitivity of 85.1%, which was not significantly inferior to saliva (p = 0.092), but 16.6% of participants reported they had difficult in self-collection of this sample. A tongue swab and saliva obtained by chewing a cotton pad had a significantly lower sensitivity of 74.2% and 70.2%, respectively. Diagnostic sensitivity was not related to the presence of clinical symptoms or to age. When comparing self-collected specimens from different material, saliva, gargle lavage or mid-turbinate nasal swabs may be considered for most symptomatic patients. However, complementary experiments are required to verify that differences in performance observed among the five sampling modes were not attributed to collection impairment.
PAX6 is a highly conserved transcription factor and key regulator of several neurogenic processes, including the continuous generation of dopaminergic/GABAergic interneurons in the adult ventricular-subventricular (V-SVZ) neurogenic system in mice. Here we report that PAX6 cooperates with the TALE-homeodomain transcription factor PBX1 in this context. Chromatin-immunoprecipitation showed that PBX1 and PAX6 co-occupy shared genomic binding sites in adult V-SVZ stem- and progenitor cell cultures and mouse embryonic stem cells, while depletion of Pbx1 revealed that association of PAX6 with these sites requires the presence of PBX1. Expression profiling together with viral overexpression or knockdown of Pax6 or Pbx1 identified novel PBX1-PAX6 co-regulated genes, including several transcription factors. Computational modeling of genome wide expression identified novel cross-regulatory networks among these very transcription factors. Taken together, the results presented here highlight the intimate link that exists between PAX6 and TALE-HD family proteins and contribute novel insights into how the orchestrated activity of transcription factors shapes adult V-SVZ neurogenesis.
Background: Lipedema is a chronic disorder of the adipose tissue that affects mainly women, characterised by symmetrical, excessive fatty tissue on the legs and pain. Standard conservative treatment is long-term comprehensive decongestive therapy (CDT) to alleviate lipedema-related pain and to improve psychosocial well-being, mobility and physical activity. Patients may benefit from surgical removal of abnormally propagated adipose tissue by liposuction. The LIPLEG trial evaluates the efficacy and safety of liposuction compared to standard CDT.
Methods/design: LIPLEG is a randomised controlled multicentre investigator-blinded trial. Women with lipedema (n=405) without previous liposuction will be allocated 2:1 to liposuction or CDT. The primary outcome of the trial is leg pain reduction by ≥2 points on a visual analogue scale ranging 0–10 at 12 months on CDT or post-completion of liposuction. Secondary outcomes include changes in leg pain severity, health-related quality of life, depression tendency, haematoma tendency, prevalence of oedema, modification physical therapy scope, body fat percentage, leg circumference and movement restriction.
The primary analysis bases on intention-to-treat. Success proportions are compared using the Mantel-Haenszel test stratified by lipedema stage at a 5% two-sided significance level. If this test is statistically significant, the equality of the response proportions in the separate strata is evaluated by Fisher’s exact test in a hierarchical test strategy.
Discussion: LIPLEG assesses whether surgical treatment of lipedema is safe and effective to reduce pain and other lipedema-related health issues. The findings of this trial have the potential to change the standard of care in lipedema.
Trial registration: ClinicalTrials.gov NCT04272827. Registered on February 14, 2020.
Trial status: Protocol version is 02_0, December 17, 2019
Encouraging clinical results were reported on a novel cone-in-cone coupling for the fixation of dental implant-supported crowns (Acuris, Dentsply Sirona Implants, Mölndal, Sweden). However, the presence or absence of a microgap and a potential bacterial leakage at the conometric joint has not yet been investigated. A misfit and a resulting gap between the conometric components could potentially serve as a bacterial reservoir that promotes plaque formation, which in turn may lead to inflammation of the peri-implant tissues. Thus, a two-fold study set-up was designed in order to evaluate the bidirectional translocation of bacteria along conometrically seated single crowns. On conometric abutments filled with a culture suspension of anaerobic bacteria, the corresponding titanium nitride-coated (TiN) caps were fixed by friction. Each system was sterilized and immersed in culture medium to provide an optimal environment for microbial growth. Positive and negative controls were prepared. Specimens were stored in an anaerobic workstation, and total and viable bacterial counts were determined. Every 48 h, samples were taken from the reaction tubes to inoculate blood agar plates and to isolate bacterial DNA for quantification using qrt-PCR. In addition, one Acuris test system was subjected to scanning electron microscopy (SEM) to evaluate the precision of fit of the conometric coupling and marginal crown opening. Throughout the observational period of one week, blood agar plates of the specimens showed no viable bacterial growth. qrt-PCR, likewise, yielded a result approaching zero with an amount of about 0.53 × 10−4 µg/mL DNA. While the luting gap/marginal opening between the TiN-cap and the ceramic crown was within the clinically acceptable range, the SEM analysis failed to identify a measurable microgap at the cone-in-cone junction. Within the limits of the in-vitro study it can be concluded that the Acuris conometric interface does not allow for bacterial translocation under non-dynamic loading conditions.
Background: Glucose metabolism in the tumor-microenvironment is a fundamental hallmark for tumor growth and intervention therein remains an attractive option for anti-tumor therapy. Whether tumor-derived factors such as microRNAs (miRs) regulate glucose metabolism in stromal cells, especially in tumor-associated macrophages (TAMs), to hijack them for trophic support, remains elusive.
Methods: Ago-RIP-Seq identified macrophage lactate dehydrogenase B (LDHB) as a target of tumor-derived miR-375 in both 2D/3D cocultures and in murine TAMs from a xenograft mouse model. The prognostic value was analyzed by ISH and multiplex IHC of breast cancer patient tissues. Functional consequences of the miR-375-LDHB axis in TAMs were investigated upon mimic/antagomir treatment by live metabolic flux assays, GC/MS, qPCR, Western blot, lentiviral knockdown and FACS. The therapeutic potential of a combinatorial miR-375-decoy/simvastatin treatment was validated by live cell imaging.
Results: Macrophage LDHB decreased in murine and human breast carcinoma. LDHB downregulation increase aerobic glycolysis and lactagenesis in TAMs in response to tumor-derived miR-375. Lactagenesis reduced fatty acid synthesis but activated SREBP2, which enhanced cholesterol biosynthesis in macrophages. LDHB downregulation skewed TAMs to function as a lactate and sterol/oxysterol source for the proliferation of tumor cells. Restoring of LDHB expression potentiated inhibitory effects of simvastatin on tumor cell proliferation.
Conclusion: Our findings identified a crucial role of LDHB in macrophages and established tumor-derived miR-375 as a novel regulator of macrophage metabolism in breast cancer, which might pave the way for strategies of combinatorial cancer cell/stroma cell interventions.
In combination with radiotherapy, immunotherapy is becoming an increasingly used strategy in treating advanced, recurrent, or metastatic cancer. The evident impact of radiotherapy on local and systemic immune response is an indication of the synergistic effect of these two modalities. There is a strong rationale to combine radiotherapy and immunotherapy to enhance response rates and overcome resistances. Therefore, the combination of radio- and immunotherapy holds a variety of opportunities as well as challenges in treating primary cancer and is progressively tested in curative settings. Brachytherapy is also known as internal radiation therapy and only offers a local therapy option at first glance: due to tumor-specific antigens, released by a high local radiation dose, a systemic immune response could be plausible and eminent. Accordingly, brachytherapy could be an underestimated partner with immuno-therapeutic approaches in both curative and palliative settings, to generate local and systemic response. In this review, we summarized the potential benefit of a potential combination of brachytherapy and immuno-therapeutic approaches vs. the background of limited data.
Background: In order to classify and analyze the parameters of upper body posture, a baseline in the form of standard values is demanded. To this date, standard values have only been published for healthy men aged 18–35 and 41–50 years. Data for male adults aged between 31 and 40 years are lacking.
Methods: The postural parameters of 101 symptom-free male volunteers aged 31–40 (35.58 ± 2.88) years were studied. The mean height of the men was 179.89 ± 7.38 cm, with a mean body weight of 86.36 ± 11.58 kg and an average BMI of 26.70 ± 3.35 kg/m2. By means of video rasterstereography, a 3-dimensional scan of the upper back surface was measured in a habitual standing position. The means or medians, confidence interval, tolerance range, and group comparisons and correlations of BMI and physical activity were calculated for all parameters.
Results: The habitual standing position was found to be almost symmetrical and the axis aligned in the spine, pelvis, and shoulder region, while the spine position was marginally inclined ventrally. The kyphosis angle of the thoracic spine was greater than the lordosis angle of the lumbar spine. All deviations fell under the measurement error margin of 1 mm/1°. The greater the BMI, the greater was the pelvic and scapular distance. The lower the BMI, the further caudally positioned was the right shoulder. The pelvic and scapular distances were also lower with the increasing athleticism of the participants.
Conclusion: The upper body posture of men between the ages of 31 and 40 years was found to be almost symmetrical and axis-conforming, with the kyphosis angle, pelvic distance, and shoulder distance enlarging with increasing BMI. Consequently, postural parameters presented in this survey allow for comparisons with other studies, as well as the evaluation of clinical diagnostics and applications.
Observed weather and projected climate change suggest an increase in the transmission of vector-borne diseases (VBDs) in the Hindu Kush Himalayan (HKH) region. In this study, we systematically explore the literature for empiric associations between the climate variables and specific VBDs and their vectors in the HKH region. We conducted a systematic synthesis of the published literature on climate variables, VBDs and vectors in the HKH region until the 8th of December 2020. The majority of studies show significant positive associations of VBDs with climatic factors, such as temperature, precipitation, relative humidity, etc. This systematic review allowed us to identify the most significant variables to be considered for evidence-based trend estimates of the effects of climate change on VBDs and their vectors in the HKH region. This evidence-based trend was set into the context of climate change as well as the observed expansion of VBDs and disease vectors in the HKH region. The geographic range of VBDs expanded into previously considered non-endemic areas of highlands (mountains) in the HKH region. Based on scarce, but clear evidence of a positive relationship of most climate variables and VBDs and the observed climatic changes, we strongly recommend an expansion of vector control and surveillance programmes in areas of the HKH region that were previously considered to be non-endemic.
Background: The number of operations by the German emergency medical service almost doubled between 1994 and 2016. The associated expenses increased by 380% in a similar period. Operations with treatment on-site, which retrospectively proved to be misallocated (OFF-Missions), have a substantial proportion of the assignment of the emergency medical service (EMS). Besides OFF-Missions, operations with patient transport play a dominant role (named as ON-Missions). The aim of this study is to work out the medical and economic relevance of both operation types.
Methods: This analysis examined N = 819,780 missions of the EMS and patient transport service (PTS) in the catchment area of the emergency medical dispatch centre (EMDC) Bad Kreuznach over the period from 01/01/2007 to 12/31/2016 in terms of triage and disposition, urban-rural distribution, duration of operations and economic relevance (p < .01).
Results: 53.4% of ON-Missions are triaged with the indication non-life-threatening patient transport; however, 63.7% are processed by the devices of the EMS. Within the OFF-Mission cohort, 78.2 and 85.8% are triaged or dispatched for the EMS. 74% of all ON-Missions are located in urban areas, 26% in rural areas; 81.3% of rural operations are performed by the EMS. 66% of OFF-Missions are in cities. 93.2% of the remaining 34% of operations in rural locations are also performed by the EMS. The odds for both ON- and OFF-Missions in rural areas are significantly higher than for PTS (ORON 3.6, 95% CI 3.21–3.30; OROFF 3.18, 95% CI 3.04–3.32). OFF-Missions last 47.2 min (SD 42.3; CI 46.9–47.4), while ON-Missions are processed after 79.7 min on average (SD 47.6; CI 79.6–79.9). ON-Missions generated a turnover of more than € 114 million, while OFF-Missions made a loss of almost € 13 million.
Conclusions: This study particularly highlights the increasing utilization of emergency devices; especially in OFF-Missions, the resources of the EMS have a higher number of operations than PTS. OFF-Missions cause immensely high costs due to misallocations from an economic point of view. Appropriate patient management appears necessary from both medical and economic perspective, which requires multiple solution approaches.
The aim of this study was to investigate gender-specific influences of different symmetric and asymmetric occlusion conditions on postural control during standing and walking. The study involved 59 healthy adult volunteers (41 f/19 m) aged between 22 and 53 years (30.2 ± 6.3 years). Postural control measurements were carried out using a pressure plate by measuring plantar pressure distribution during standing and walking test conditions. Seven different occlusion conditions were tested. Prior to a MANOVA model analysis, the relationship between the two test conditions were checked using a factor analysis with a varying number of factors (between 2 and 10). The plantar pressure distributions during walking and standing are independent test conditions. The coefficient of variance across all variables between the conditions and genders was not significant: t(46) = 1.51 (p = 0.13). No statement can be made whether, or not, the influence of gender is greater than the influence of the conditions. Healthy male and female test subjects did not show any difference between seven occlusion conditions on the plantar pressure distribution while standing or walking. No differences between the genders were found for any of the investigated variables. In contrast to custom-made occlusion splints, simple cotton rolls appear not to influence the neuromuscular system in a systematic manner.
Purpose of the Review: This review aims to summarize the current knowledge of the extracellular matrix remodeling during hepatic fibrosis. We discuss the diverse interactions of the extracellular matrix with hepatic cells and the surrounding matrix in liver fibrosis, with the focus on the molecular pathways and the mechanisms that regulate extracellular matrix remodeling.
Recent Findings: The extracellular matrix not only provides structure and support for the cells, but also controls cell behavior by providing adhesion signals and by acting as a reservoir of growth factors and cytokines.
Summary: Hepatic fibrosis is characterized by an excessive accumulation of extracellular matrix. During fibrogenesis, the natural remodeling process of the extracellular matrix varies, resulting in the excessive accumulation of its components, mainly collagens. Signals released by the extracellular matrix induce the activation of hepatic stellate cells, which are the major source of extracellular matrix and most abundant myofibroblasts in the liver.
Lennox-Gastaut syndrome (LGS), a childhood-onset severe developmental and epileptic encephalopathy (DEE), is an entity that encompasses a heterogenous group of aetiologies, with no single genetic cause. It is characterised by multiple seizure types, an abnormal EEG with generalised slow spike and wave discharges and cognitive impairment, associated with high morbidity and profound effects on the quality of life of patients and their families. Drug-refractory seizures are a hallmark and treatment is further complicated by its multiple morbidities, which evolve over the patient’s lifetime. This review provides a comprehensive overview of the current and future options for the treatment of seizures associated with LGS. Six treatments are specifically indicated as adjunct therapies for the treatment of seizures associated with LGS in the US: lamotrigine, clobazam, rufinamide, topiramate, felbamate and most recently cannabidiol. These therapies have demonstrated reductions in drop seizures in 15%–68% of patients across trials, with responder rates (≥ 50% reduction in drop seizures) of 37%–78%. Valproate is still the preferred first-line treatment, generally in combination with lamotrigine or clobazam. Other treatments frequently used off-label include the broad spectrum anti-epileptic drugs (AED) levetiracetam, zonisamide and perampanel, while recent evidence from observational studies has indicated that a newer AED, the levetiracetam analogue brivaracetam, may be effective and well tolerated in LGS patients. Other treatments in clinical development include fenfluramine in late phase III, perampanel, soticlestat–OV953/TAK-953, carisbamate and ganaxolone. Non-pharmacologic interventions include the ketogenic diet, vagus nerve stimulation and surgical interventions; these are also expanding, with the potential for less invasive techniques for corpus callosotomy that have promise for reducing complications. However, despite these advancements, patients continue to experience a significant burden. Because LGS is not a single entity, tailoring of treatment is needed as opposed to a ‘one size fits all’ approach. Further research is needed into the underlying aetiologies and pathophysiology of LGS, together with advancements in treatments that encompass the spectrum of seizures associated with this complex syndrome.
Data on the long-term behavior of computer-aided designed/computer-aided manufactured (CAD-CAM) resin-based composites are sparse. To achieve higher predictability on the mechanical behavior of these materials, the aim of the study was to establish a mathematical relationship between the material thickness of resin-based materials and their fracture load. The tested materials were Lava Ultimate (LU), Cerasmart (GC), Enamic (EN), and Telio CAD (TC). For this purpose, 60 specimens were prepared, each with five different material thicknesses between 0.4 mm and 1.6 mm (N = 60, n = 12). The fracture load of all specimens was determined using the biaxial flexural strength test (DIN EN ISO 6872). Regression curves were fitted to the results and their coefficient of determination (R2) was computed. Cubic regression curves showed the best R2 approximation (LU R2 = 0.947, GC R2 = 0.971, VE R2 = 0.981, TC R2 = 0.971) to the fracture load values. These findings imply that the fracture load of all tested resin-based materials has a cubic relationship to material thickness. By means of a cubic equation and material-specific fracture load coefficients, the fracture load can be calculated when material thickness is given. The approach enables a better predictability for resin-based restorations for the individual patient. Hence, the methodology might be reasonably applied to other restorative materials.
Introduction: Current classifications of complete knee dislocations do not capture the extent of the complex concomitant ligamentous and bony injuries, which may have an impact on future outcomes. The purpose of this retrospective study was to evaluate the epidemiology of complete knee dislocations as well as to present an updated classification system based on the author’s experience at a Level-I trauma center.
Materials and methods: Only patients with complete loss of contact of the articulating bones and ≥ 18 years of age who admitted in our level-I trauma center between 2002 and 2019 were included. Patients were identified using a retrospective systematical query in the Hospital Information System (HIS) using the International Statistical Classification of Diseases and Related Health Problems Version10 (ICD-10) codes of the German Diagnosis Related Groups (G-DRG).
Results: Final data included 80 patients, with the majority of patients being male (n = 64; 80.0%). Mean age was 34.9 years (range: 18–70 years). External protective fixation was applied in 32 patients (40.0%). Reconstruction of the posterior cruciate ligament and the anterior cruciate ligament were performed in 56.3% (n = 45) and 55.0% (n = 44) of cases, respectively. The lateral collateral ligament complex was surgically addressed in 47.5% (n = 38), while the medial collateral ligament complex was reconstructed in 40% (n = 32). Surgery of the lateral meniscus and the medial meniscus was needed in 31.1% (n = 25) and 30.0% (n = 24). Neurovascular surgery occurred in 13.8% (n = 11). From the characteristic injury-patterns the authors of this study present a new classification system that ranks the injuries from Grade-A to Grade-D according to their severity.
Conclusion: This retrospective study demonstrates that the historically used classification systems for dislocations of the knee are insufficient for these severe injuries. Concomitant ligamentous, neurovascular, bony, and meniscal injuries were frequent, and required several staged procedures. Consequently, an updated classification system is proposed.
Background: Alcohol drinking is associated with a serious risk of developing health problems as well as with a large number of traumatic injuries. Although chronic alcohol misuse is known to contribute to severe inflammatory complications, the effects of an acute alcohol misuse are still unclear. Here, the impact of acute alcohol drinking on leukocyte counts and their cellular functions were studied.
Methods: Twenty-two healthy volunteers (12 female, 10 male) received a predefined amount of a whiskey-cola mixed drink (40% v/v), at intervals of 20 min, over 4 h to achieve a blood alcohol concentration of 1‰. Blood samples were taken before drinking T0, 2 h (T2), 4 h (T4), 6 h (T6), 24 h (T24) and 48 h (T48) after starting drinking alcohol. Leukocytes, monocytes and granulocyte counts and their functions regarding the production of reactive oxidative species (ROS), phagocytosis and apoptosis were analyzed by flow cytometry.
Results: Total leukocyte counts significantly increased at T2 and T4, while granulocyte and monocyte counts decreased at T4 and T6 vs. T0. Monocytes increased significantly at T24 and T48 vs. T0. While the total number of ROS-producing leukocytes and notably granulocytes significantly increased, in parallel, the intracellular ROS intensity decreased at T2 and T6. The numbers of ROS-positive monocytes have shown a delayed modulation of ROS, with a significant reduction in the total number of ROS-producing cells at T48 and a significantly reduced intracellular ROS-intensity at T24. Phagocyting capacity of leukocytes significantly decreased at T4 and T6. In general leukocytes, and notably granulocytes demonstrated significantly increased early (T2), while monocyte exerted significantly increased late apoptosis (T24 and T48).
Conclusions: Alcohol drinking immediately impacts leukocyte functions, while the impact on monocytes occurs at even later time points. Thus, even in young healthy subjects, alcohol drinking induces immunological changes that are associated with diminished functions of innate immune cells that persist for days.
Purpose: The aim of this study was to investigate characteristics associated with ectopic pregnancy (EP) that could be utilized for predicting morbidity or mortality.
Methods: This was a retrospective analysis of pregnancy-related records from a tertiary center over a period of ten years. Data on age, gravidity, parity, EP risk, amenorrhea duration, abdominal pain presence and location, β-human chorionic gonadotropin (β-HCG) level, ultrasound findings, therapeutic intervention, exact EP implantation site and length of hospital stay (LOS) were obtained from the database. The LOS was used as a proxy for morbidity and was tested for an association with all variables. All statistical analyses were conducted with Stata® (ver. 16.1, Texas, USA).
Results: The incidence of EP in a cohort of 30,247 pregnancies over a ten-year period was 1.05%. Patients presented with lower abdominal pain in 87.9% of cases, and the likelihood of experiencing pain was tenfold higher if fluid was detectable in the pouch of Douglas. Only 5.1% of patients had a detectable embryonic heartbeat, and 18.15% had one or more risk factors for EP. While most EPs were tubal, 2% were ovarian. The LOS was 1.9 days, and laparoscopic intervention was the main management procedure. The cohort included one genetically proven dizygotic heterotopic pregnancy (incidence, 3.3 × 10− 5) that was diagnosed in the 7th gestational week. The only association found was between the β-HCG level and LOS, with a linear regression β coefficient of 0.01 and a P-value of 0.04.
Conclusion: EP is a relatively common condition affecting approximately 1% of all pregnancies. β-HCG correlates with EP-related morbidity, but the overall morbidity rate of EP is low regardless of the implantation site. Laparoscopic surgery is an effective therapeutic procedure that is safe for managing EP, even in cases of heterotopic pregnancy.
Background: While the antidepressant efficacy of guided digital interventions has been proven in randomized controlled trials, findings from routine care are less clear. Low adherence rates are common and limit the potential effectiveness. Adherence has been linked to sociodemographic variables and the amount of guidance, but the role of the guide's profession and their work setting has not yet been studied for routine care.
Methods: Routinely collected log data from a digital intervention for depressed patients (iFightDepression tool) were analyzed in an exploratory manner. The sample is a convenience sample from routine care, where guidance is provided by general practitioners (GP), certified psychotherapists (PT) or medical doctors specialized in mental health. Log data from 2184 patients were analyzed and five usage parameters were extracted to measure adherence (first-to-last login, time on tool, number of sessions, workshops completed and minimal dose). Multiple logistic regression was used to analyze relations between the guide's profession and clinical context as well as other covariates and adherence and symptom change on a brief depression questionnaire (PHQ-9).
Results: The analyses showed a significant relation of guide profession and adherence. Guidance by PT was associated to the highest adherence scores (reference category). The odds ratios (ORs) of scoring above the median in each usage parameter for patients guided by GPs were 0.50–0.63 (all ps < 0.002) and 0.61–0.80 (p = .002–0.197) for MH. Higher age, initial PHQ-9 score and self-reported diagnosis of depression were also significantly associated with higher adherence scores. In a subsample providing enough data on the PHQ-9 (n = 347), no association of guide profession with symptom reduction was found. Instead, a greater reduction was observed for patients with a higher baseline PHQ-9 (β = −0. 39, t(341.75) = −8.814, p < .001) and for those who had achieved minimal dose (β = −2.42, t(340.34) = −4.174, P < .001) and those who had achieved minimal dose and scored high on time on tool (β = 0.22, t(341.75) = 1.965, P = .050).
Conclusion: Being guided by PT was associated with the highest adherence. The lowest adherence was observed in patients who were guided by GP. While no association of guide profession and symptom reduction was found in a subsample, greater adherence was associated with symptom reduction.
The detection of multiple biomolecule classes in one go is highly desirable for a wide variety of areas, and in particular for point-of-care diagnostics. For example, wound infections are a major problem for patient’s health and cause huge efforts in our healthcare system. In this regard, monitoring infected wounds through simultaneous detection of pathogens via nucleic acid analysis and detection of local inflammation biomarkers is key in order to enable a personalized therapy, improve the clinical outcome and thus, leading to a reduction of overall healthcare costs. In this regard, wound exudate offers an attractive sample material which can be collected in a non-invasive manner. Here, we report the development of a Multianalyte-Assay detecting inflammation biomarkers and pathogen DNA simultaneously from one sample within 35 min. Protein-compatible amplification and labeling transforms nucleic acid information into the measurement principle for protein detection. The combination with rapid detection via lateral flow immunoassay enables a fast and straightforward analysis of multiple biomolecule classes using identical assay conditions. To demonstrate the feasibility of the Multianalyte-Assay, the proinflammatory cytokine interleukin-6 (IL-6) and gDNA of the opportunistic pathogen Pseudomonas aeruginosa (P. aeruginosa) are used. The detection limits of 4 ng/mL IL-6 and 70 copies/reaction P. aeruginosa gDNA meet the clinically relevant range and thus, having tremendous potential to improve the wound management at the point-of-care.
Studies have demonstrated an increased risk of accidents and injuries in children, adolescents and adults with attention-deficit/hyperactivity disorder (ADHD). However, little is known about how accident risk may alter over the lifespan. Additionally, it would be important to know if the most common types of accidents and injuries differ in ADHD patients over different age groups. Furthermore, there is increasing evidence of an ameliorating effect of ADHD medication on accident risk. Lastly, the underlying risk factors and causal mechanisms behind increased accident risk remain unclear. We therefore conducted a systematic review focusing on the above described research questions. Our results suggested that accident/injury type and overall risk changes in ADHD patients over the lifespan. ADHD medication appeared to be similarly effective at reducing accident risk in all age groups. However, studies with direct comparisons of accident/injuries and effects of medication at different age groups or in old age are still missing. Finally, comorbidities associated with ADHD such as substance abuse appear to further increase the accident/injury risk.
Purpose: To evaluate the potential impact of rebubbling on the anterior segment parameters and refractive outcomes in patients with graft detachment following uneventful DMEK for Fuchs endothelial dystrophy (FED).
Methods: Retrospective institutional cohort study of comparing 34 eyes of 31 patients with rebubbling for graft detachment following Descemet membrane endothelial keratoplasty (DMEK) to 33 eyes of 28 patients with uneventful DMEK. Main outcome parameters were various corneal parameters obtained by Scheimpflug imaging, refractive outcome, corrected distance visual acuity (CDVA), and endothelial cell density (ECD).
Results: Anterior and posterior corneal astigmatism, corneal densitometry, central corneal thickness, and anterior chamber depth and volume showed no significant differences. Preoperative distribution of astigmatism axis orientations showed a high proportion of anterior corneal with-the-rule astigmatism (71%) in eyes requiring rebubbling. Mean postoperative cylinder in the rebubbling group (1.21 ± 0.85 D) was significantly higher compared to the controls (p = 0.04), while differences in spherical equivalent (SE) were insignificant (p = 0.24). Postoperative CDVA was 0.11 ± 0.11 in the control group compared to 0.21 ± 0.17 in the rebubbling group (p = 0.03). Eyes with subsequent rebubbling demonstrated a significantly higher endothelial cell loss (56% versus 37%) (p < 0.001).
Conclusion: Apart from higher cylinder values, refractive outcome and corneal parameters assessed by Scheimpflug imaging were comparable in eyes with rebubbling and controls. However, a reduced visual acuity and an increased endothelial cell loss should be taken into consideration prior to rebubbling especially in eyes with circumscribed graft detachment.
Neurometabolic diseases (NMDs) are typically caused by genetic abnormalities affecting enzyme functions, which in turn interfere with normal development and activity of the nervous system. Although the individual disorders are rare, NMDs are collectively relatively common and often lead to lifelong difficulties and high societal costs. Neuropsychiatric manifestations, including ADHD symptoms, are prominent in many NMDs, also when the primary biochemical defect originates in cells and tissues outside the nervous system. ADHD symptoms have been described in phenylketonuria, tyrosinemias, alkaptonuria, succinic semialdehyde dehydrogenase deficiency, X-linked ichthyosis, maple syrup urine disease, and several mitochondrial disorders, but are probably present in many other NMDs and may pose diagnostic and therapeutic challenges. Here we review current literature linking NMDs with ADHD symptoms. We cite emerging evidence that many NMDs converge on common neurochemical mechanisms that interfere with monoamine neurotransmitter synthesis, transport, metabolism, or receptor functions, mechanisms that are also considered central in ADHD pathophysiology and treatment. Finally, we discuss the therapeutic implications of these findings and propose a path forward to increase our understanding of these relationships.
Background: An experienced life-threating anaphylactic reaction to hymenoptera venom can sustainably impair patients’ quality of life (QoL). Besides carrying emergency medication, venom-specific immunotherapy (VIT) exists as a causal treatment of allergy.
Objective: This study aimed to examine QoL, anxiety, depression, and physical and mental health in patients allergic to hymenoptera venom before and during VIT and the impact of a tolerated sting challenge (SC).
Methods: Between July 2017 and August 2017, 142 patients with venom allergy were analyzed using validated questionnaires as the: Vespid Allergy Quality for Life Questionnaire" (VQLQ-d), the "Hospital Anxiety and Depression Scale" (HADS-D) and the "Short Form 36" (SF-36). To evaluate the impact of VIT and SC on the QoL, patients were divided into 3 groups: (A) VIT and tolerated SC (n = 45), (B) VIT before carrying out SC (n = 73), and (C) therapy-naïve before VIT (n = 20). Further parameters like gender, age, insect species, and severity of the anaphylactic reaction were assessed.
Results: A significant correlation between the health-related QoL and the parameters of gender and state of treatment was seen. Especially male patients, as well as patients allergic to yellow jacket venom, benefit from a SC in terms of a significant increase in their QoL. In the total study cohort, a clear trend was observed towards a higher QoL in patients under VIT who tolerated a SC. Overall, neither the patients’ age nor the insect species exerted a relevant influence on QoL, depression or anxiety. However, women showed a lower QoL combined with higher anxiety and depression scores than men.
Conclusion: Immunotherapy leads to an improved QoL, which can be further increased by a SC. A tolerated SC conceivably reassures the patients by objectifying the treatment success. Female patients appear to have a stronger impaired QoL per se. Taken together, a SC can be performed during VIT to strengthen the patients’ QoL.
Background: Cirrhosis is known to have a high prevalence and mortality worldwide. However, in Europe, the epidemiology of cirrhosis is possibly undergoing demographic changes, and etiologies may have changed due to improvements in standard of care. The aim of this population-based study was to analyze the trends and the course of liver cirrhosis and its complications in recent years in Germany.
Methods: We analyzed the data of all hospital admissions in Germany within diagnosis-related groups from 2005 to 2018. The diagnostic records of cirrhosis and other categories of diseases were based on ICD-10-GM codes. The primary outcome measurement was in-hospital mortality. Trends were analyzed through Poisson regression of annual number of admissions. The impact of cirrhosis on overall in-hospital mortality were assessed through the multivariate multilevel logistic regression model adjusted for age, sex, and comorbidities.
Findings: Of the 248,085,936 admissions recorded between 2005 and 2018, a total of 2,302,171(0•94%) were admitted with the diagnosis of cirrhosis, mainly as a comorbidity. Compared with other chronic diseases, patients admitted with cirrhosis were younger, mainly male and had the highest in-hospital mortality rate. Diagnosis of cirrhosis was an independent risk factor of in-hospital mortality with the highest odds ratio (OR:6•2[95%CI:6.1-6•3]) among all diagnoses. The prevalence of non-alcoholic fatty liver disease has increased four times from 2005 to 2018, while alcoholic cirrhosis is 20 times than other etiologies. Bleeding was found to be decreasing over time, but ascites remained the most common complication and was increasing.
Interpretation: This nationwide study demonstrates that cirrhosis represents a considerable healthcare burden, as shown by the increasing in-hospital mortality, also in combination with other chronic diseases. Alcohol-related cirrhosis and complications are on the rise. More resources and better management strategies are warranted.
Background: Transfusion of red blood cells (RBC) in patients undergoing major elective cranial surgery is associated with increased morbidity, mortality and prolonged hospital length of stay (LOS). This retrospective single center study aims to identify the impact of RBC transfusions on skull-base and non-skull-base meningioma patients including the identification of risk factors for RBC transfusion.
Methods: From October 2009 - October 2016 we retrospectively analyzed 423 primary meningioma patients undergoing surgery for primary meningioma resection our department.
Results: Of these 423 patients, 68 (16.1%) received RBC transfusion and 355 (83.9%) did not receive RBC units. Preoperative anaemia rate was significantly higher in transfused patients (17.7%) compared to patients without RBC transfusion (6.2%; p = 0.0015). In transfused patients, postoperative complications as well as hospital LOS was significantly higher (p < 00001) compared to non-transfused patients. After multivariate analyses, risk factors for RBC transfusion were preoperative American Society of Anesthesiologists (ASA) physical status score (p = 0.0247), tumor size (p = 0.0006), surgical time (p = 0.0018) and intraoperative blood loss (p < 0.001). Kaplan-Meier curves revealed significant influence on overall survival by preoperative anaemia, RBC transfusion, smoking, cardiovascular disease, preoperative KPS ≤ 60% and age (elderly ≥ 75 years).
Conclusion: We concluded that blood loss due to large tumors or localization near large vessels are the main triggers for RBC transfusion in meningioma patients paired with a potential preselection that masks the effect of preoperative anaemia in multivariate analysis. Further studies evaluating the impact of preoperative anaemia management for reduction of RBC transfusion are needed to improve clinical outcomes of meningioma patients.
Study Design: Cross-sectional survey
Objective: To determine the influence of surgeons’ level of experience and subspeciality training on the reliability, reproducibility, and accuracy of sacral fracture classification using the AO Spine Sacral Injury Classification System.
Summary of Background Data: An ideal classification system is easily comprehensible and reliable amongst the diverse group of surgeons. A surgeons’ level of experience may have a significant effect on the reliability and accuracy of a classification system. Moreover, surgeons of different subspecialities may have various levels of comfort with imaging assessment of sacral injuries required for accurate diagnosis and classification.
Methods: High-resolution computerized tomography (CT) images from 26 cases were assessed by 172 investigators from a diverse array of surgical subspecialities (general orthopaedics, neurosurgery, orthopaedic spine, orthopaedic trauma) and experience (<5, 5-10, 11-20, >20 years). Validation assessments were performed via web conference using high-resolution images, as well as axial/sagittal/coronal CT scan sequences. Two assessments were performed by each investigator independently three weeks apart in randomized order. Reliability and reproducibility were calculated with cohen’s kappa coefficient (k) and gold standard classification agreement was determined for each fracture morphology and subtype and stratified by experience and subspeciality.
Results: Respondents achieved an overall k = 0.87 for morphology and k = 0.77 for subtype classification, representing excellent and substantial intraobserver reproducibility, respectively. Respondents from all four practice experience groups demonstrated excellent interobserver reliability when classifying overall morphology (k=0.842/0.850, Assessment 1/Assessment 2) and substantial interobserver reliability in overall subtype (k=0.719/0.751) in both assessments. General orthopaedists, neurosurgeons, and orthopaedic spine surgeons exhibited excellent interobserver reliability in overall morphology classification and substantial interobserver reliability in overall subtype classification. Surgeons in each experience category and subspecialty correctly classified fracture morphology in over 90% of cases and fracture subtype in over 80% of cases according to the gold standard. Correct overall classification of fracture morphology (Assessment 1: p= 0.024, Assessment 2: p=0.006) and subtype (p2<0.001) differed significantly with surgeons with >20 years of experience demonstrating increased difficulty correctly classifying all fracture subtypes overall in comparison to the other experience groups. Correct overall classification did not significantly differ by subspecialty.
Conclusions: Overall, the AO Spine Sacral Injury Classification System appears to be universally applicable among surgeons of various subspecialties and levels of experience with acceptable reliability, reproducibility, and accuracy.
Disclosures: author 1: none; author 2: consultant=Medtronic, Nuvasive, ISD, Asutra, Stryker, Bioventus, Zimmer, teledocs, Clinical Spine Surgery, AOSpine ; author 3: none; author 4: grants/research support=AOSpine, consultant=DPS, icotec; author 5: none; author 6: none; author 7: grants/research support=DPS; author 8: none; author 9: grants/research support=NIH, RTI, CSRS, royalties=Inion ; author 10: stock/shareholder=Advanced Spinal Intellectual Properties; Atlas Spine; Avaz Surgical; Bonovo Orthopaedics; Computational Biodynamics; Cytonics; Deep Health; Dimension Orthotics LLC; Electrocore; Flagship Surgical; FlowPharma; Globus; Innovative Surgical Design; Insight Therapeutics; Jushi; Nuvasive; Orthobullets; Paradigm Spine; Parvizi Surgical Innovation; Progressive Spinal Technologies; Replication Medica; Spine Medica; Spineology; Stout Medical; Vertiflex; ViewFi Health, royalties=Aesculap; Atlas Spine; Globus; Medtronics; SpineWave; Stryker Spine,other financial report=AO Spine
Background: To investigate whether patients with critical emergency conditions are seeking or receiving the medical care that they require we characterized the reality of care for patients presenting with Neuro-emergencies during the first phase of the COVID-19 pandemic.
Methods: In this observational, longitudinal cohort study, all neurosurgical admissions that presented to our Department between February 1st and April 15th during the COVID-19 pandemic and during the same time-period in 2019 were identified and categorized according to the presence of a Neuro-emergency, the route of admission, management, and the category of disease. Further, the clinical course of patients with chronic subdural hematoma (cSDH) was investigated as a Neuro-emergency representative for a wide variety of semi-urgent symptoms.
Results: During the pandemic, the percentage of Neuro-emergencies among all neurosurgical admissions remained similar as in 2019 but a larger proportion presented through the emergency department than through the outpatient clinic or by referral (*p=0.009). The total number of Neuro-emergencies was significantly reduced (*p=0.0007) across all types of disease, particularly in severe vascular (*p=0.036) but also in spinal (*p=0.007) and hydrocephalus (*p=0.048) emergencies. Strikingly, elderly patients with cSDH and mild to moderate symptoms presented less frequently, with more severe symptoms (*p=0.046) and were less likely to reach favorable outcome (*p=0.003).
Conclusions: Despite pandemic-related restrictive measures and reallocation of resources, patients with Neuro-emergencies should be encouraged to present regardless of the severity of symptoms because deferred presentation may result in adverse outcome. Thus, conservation of critical healthcare resources remains essential in spite fighting COVID-19.
Within the scope of this technical report, the feasibility of indocyanine green (ICG) as a fluorescent agent for postmortem angiography of the heart is tested. The study included 4 deceased persons with no respective medical history of heart diseases. The basic patterns of findings in ICG fluorescence angiography associated with healthy hearts are presented. The method can easily be integrated into a workflow without restricting the macroscopic or histologic diagnostics. This paper represents the fundamental technical and analytical basis for upcoming studies concerning the possibilities and limitations of fluorescence angiography in the diagnosis of heart pathology.