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Background: Transfusion of red blood cell concentrate can be life-saving, but requires accurate dose calculations in children. Aims: We tested the hypothesis that cognitive aids would improve identification of the correct recommended volumes and products, according to the German National Transfusion guidelines, in pediatric transfusion scenarios. Methods: Four online questionnaire-based scenarios, two with hemodynamically stable and two with hemodynamically unstable children, were sent to German and international pediatric anesthetists for completion. In the two stable scenarios, participants were given pre-filled tables that contained all required information. For the two emergency scenarios, existing algorithms were used and required calculation by the user. The results were classified into three categories of deviations from the recommended values (DRV): DRV120 (<80% or >120%), as the acceptable variation; DRV 300 (<33% or >300%), the deviation of concern for potential harm; and DRV 1000 (<10% or >1000%), the excessive deviation with a high probability of harm. Results: A total of 1.458 pediatric anesthetists accessed this simulation questionnaire, and 402 completed questionnaires were available for analysis. A pre-filled tabular aid, avoiding calculations, led to a reduction in deviation rates in the category of DRV120 by 60% for each and of DRV300 by 17% and 20%, respectively. The use of algorithms as aids for unstable emergencies led to a reduction in the deviation rate only for DRV120 (20% and 15% respectively). In contrast, the deviation rates for DRV300 and DRV1000 rose by 37% and 16%, respectively. Participants used higher transfusion thresholds for the emergency case of a 2-year-old compromised child than for the stable case with a patient of the same age (on average, 8.6 g/dL, 95% CI 8.5–8.8 versus 7.1 g/dL, 95% CI 7.0–7.2, p < 0.001) if not supported by our aids. Participants also used a higher transfusion threshold for unstable children aged 3 months than for stable children of the same age (on average, 8.9 g/dL, 95% CI 8.7–9.0 versus 7.9 g/dL, 95% CI 7.7–8.0, p < 0.001). Conclusions: The use of cognitive aids with precalculated transfusion volumes for determining transfusion doses in children may lead to improved adherence to published recommendations, and could potentially reduce dosing deviations outside those recommended by the German national transfusion guidelines.
Distinct immune patterns of hepatocellular carcinoma (HCC) may have prognostic implications in the response to transarterial chemoembolization (TACE). Thus, we aimed to exploratively analyze tumor tissue of HCC patients who do or do not respond to TACE, and to identify novel prognostic biomarkers predictive of response to TACE. We retrospectively included 15 HCC patients who had three consecutive TACE between January 2019 and November 2019. Eight patients had a response while seven patients had no response to TACE. All patients had measurable disease according to mRECIST. Corresponding tumor tissue samples were processed for differential expression profiling using NanoString nCounter® PanCancer immune profiling panel. Immune-related pathways were broadly upregulated in TACE responders. The top differentially regulated genes were the upregulated CXCL1 (log2fc 4.98, Benjamini–Hochberg (BH)-p < 0.001), CXCL6 (log2fc 4.43, BH-p = 0.016) and the downregulated MME (log2fc −4.33, BH-p 0.001). CD8/T-regs was highly increased in responders, whereas the relative number of T-regs to tumor-infiltrating lymphocytes (TIL) was highly decreased. We preliminary identified CXCL1 and CXCL6 as candidate genes that might have the potential to serve as therapeutically relevant biomarkers in HCC patients. This might pave the way to improve patient selection for TACE in HCC patients beyond expert consensus.
For acute and chronic soft tissue infections, radical surgical debridement is required and is considered the gold standard, along with its immediate systemic antibiotic therapy. Treatment with local antibiotics and/or antibiotic-containing materials is commonly used as an additional tool in clinical practice. Spraying with fibrin and antibiotics is a newer technique that has been studied for some antibiotics. However, for gentamicin, data are not yet available on absorption, optimal application, antibiotic fate at the site and transfer of antibiotic into the blood. In an animal study involving 29 Sprague Dawley rats, 116 back wounds were sprayed with gentamicin using either gentamicin alone or one of two possible spray combinations of gentamicin and fibrin. Simultaneous application of gentamicin and fibrin via a spray system to soft tissue wounds resulted in significant antibiotic concentration over a long period of time. The technique is easy and cost-effective. The systemic crossover was significantly minimized in our study, which may have led to fewer side effects in patients. These results could lead to an improvement in local antibiotic therapy.
Purpose: To evaluate the efficacy and safety of microwave ablation (MWA) as a treatment for recurrent hepatocellular carcinoma (HCC) after initial successful surgical resection. Methods: This retrospective study included 40 patients (11 women and 29 men; mean age: 62.3 ± 11.7 years) with 48 recurrent lesions of HCC after initial surgical resection that were treated by percutaneous MWA. Several parameters including complications, technical success, local tumor progression (LTP), intrahepatic distant recurrence (IDR), overall survival (OS), and progression-free survival (PFS) were evaluated in order to investigate the safety and efficacy of MWA for these recurrent HCC lesions after surgical treatment. Results: All MWA treatments were performed without complications or procedure-related deaths. Technical success was achieved in all cases. Two cases developed LTP at a rate of 5%, and IDR occurred in 23 cases at a rate of 57.5% (23/40). The 1-, 2-, 3-, 4-, and 6-year OS rates were 97%, 89.2%, 80.3%, 70.2%, and 60.2%, respectively. The 1- and 3-year PFS rates were 50.2% and 34.6%, respectively. Conclusion: MWA is effective and safe as a local treatment for recurrent HCC after initial surgical resection.
CEND-1 (iRGD) is a bifunctional cyclic peptide that can modulate the solid tumour microenvironment, enhancing the delivery and therapeutic index of co-administered anti-cancer agents. This study explored CEND-1’s pharmacokinetic (PK) properties pre-clinically and clinically, and assessed CEND-1 distribution, tumour selectivity and duration of action in pre-clinical tumour models. Its PK properties were assessed after intravenous infusion of CEND-1 at various doses in animals (mice, rats, dogs and monkeys) and patients with metastatic pancreatic cancer. To assess tissue disposition, [3H]-CEND-1 radioligand was administered intravenously to mice bearing orthotopic 4T1 mammary carcinoma, followed by tissue measurement using quantitative whole-body autoradiography or quantitative radioactivity analysis. The duration of the tumour-penetrating effect of CEND-1 was evaluated by assessing tumour accumulation of Evans blue and gadolinium-based contrast agents in hepatocellular carcinoma (HCC) mouse models. The plasma half-life was approximately 25 min in mice and 2 h in patients following intravenous administration of CEND-1. [3H]-CEND-1 localised to the tumour and several healthy tissues shortly after administration but was cleared from most healthy tissues by 3 h. Despite the rapid systemic clearance, tumours retained significant [3H]-CEND-1 several hours post-administration. In mice with HCC, the tumour penetration activity remained elevated for at least 24 h after the injection of a single dose of CEND-1. These results indicate a favourable in vivo PK profile of CEND-1 and a specific and sustained tumour homing and tumour penetrability. Taken together, these data suggest that even single injections of CEND-1 may elicit long-lasting tumour PK improvements for co-administered anti-cancer agents.
Significant progress has been made in the management of Wilms tumor (WT) in recent years, mostly as a result of collaborative efforts and the implementation of protocol-driven, multimodal therapy. This article offers a comprehensive overview of current multidisciplinary treatment strategies for WT, whilst also addressing recent technical innovations including nephron-sparing surgery (NSS) and minimally invasive approaches. In addition, surgical concepts for the treatment of metastatic disease, advances in tumor imaging technology and potentially prognostic biomarkers will be discussed. Current evidence suggests that, in experienced hands and selected cases, laparoscopic radical nephrectomy and laparoscopic-assisted partial nephrectomy for WT may offer the same outcome as the traditional open approach. While NSS is the standard procedure for bilateral WT, NSS has evolved as an alternative technique in patients with smaller unilateral WT and in cases with imminent renal failure. Metastatic disease of the lung or liver that is associated with WT is preferably treated with a three-drug chemotherapy and local radiation therapy. However, surgical sampling of lung nodules may be advisable in persistent nodules before whole lung irradiation is commenced. Several tumor markers such as loss of heterozygosity of chromosomes 1p/16q, 11p15 and gain of function at 1q are associated with an increased risk of recurrence or a decreased risk of overall survival in patients with WT. In summary, complete resection with tumor-free margins remains the primary surgical aim in WT, while NSS and minimally invasive approaches are only suitable in a subset of patients with smaller WT and low-risk disease. In the future, advances in tumor imaging technology may assist the surgeon in defining surgical resection margins and additional biomarkers may emerge as targets for development of new diagnostic tests and potential therapies.
Objectiv:e To explore the association of physical activity (PA) with musculoskeletal pain (MSK pain).
Design: Cross-sectional study
Setting: 14 countries (Argentina, Australia, Austria, Brazil, Chile, France, Germany, Italy, the Netherlands, Singapore, South Africa, Spain, Switzerland and the USA).
Participants: Individuals aged 18 or older.
Primary and secondary outcome measures: PA volumes were assessed with an adapted version of the Nordic Physical Activity Questionnaire-short. Prevalence of MSK pain was captured by means of a 20-item checklist of body locations. Based on the WHO recommendation on PA, participants were classified as non-compliers (0–150 min/week), compliers (150–300 min/week), double compliers (300–450 min/week), triple compliers (450–600 min/week), quadruple compliers (600–750 min/week), quintuple compliers (750–900 min/week) and top compliers (more than 900 min/week). Multivariate logistic regression was used to obtain adjusted ORs of the association between PA and MSK pain for each body location, correcting for age, sex, employment status and depression risk.
Results: A total of 13 741 participants completed the survey. Compared with non-compliers, compliers had smaller odds of MSK pain in one location (thoracic pain, OR 0.77, 95% CI 0.64 to 0.93). Double compliance was associated with reduced pain occurrence in six locations (elbow, OR 0.70, 95% CI 0.50 to 0.98; forearm, OR 0.63, 95% CI 0.40 to 0.99; wrist, OR 0.74, 95% CI 0.57 to 0.98; hand, OR 0.57, 95% CI 0.40 to 0.79; fingers, OR 0.72, 95% CI 0.52 to 0.99; abdomen, OR 0.61, 95% CI 0.41 to 0.91). Triple to top compliance was also linked with lower odds of MSK pain (five locations in triple compliance, three in quadruple compliance, two in quintuple compliance, three in top compliance), but, at the same time, presented increased odds of MSK pain in some of the other locations.
Conclusion: A dose of 300–450 min WHO-equivalent PA/week was associated with lower odds of MSK pain in six body locations. On the other hand, excessive doses of PA were associated with higher odds of pain in certain body locations.
The correction of valgus leg malalignment in children using implant-mediated growth guidance is widely used and effective. Despite the minimal invasive character of the procedure, a relevant number of patients sustain prolonged pain and limited mobility after temporary hemiepiphysiodesis. Our aim was to investigate implant-associated risk factors (such as implant position and screw angulation), surgical- or anesthesia-related risk factors (such as type of anesthesia, use, and duration), and pressure of tourniquet or duration of surgery for these complications. Thirty-four skeletally immature patients with idiopathic valgus deformities undergoing hemiepiphysiodesis plating from October 2018–July 2022 were enrolled in this retrospective study. Participants were divided into groups with and without prolonged complications (persistent pain, limited mobility of the operated knee between five weeks and six months) after surgery. Twenty-two patients (65%) had no notable complications, while twelve patients (35%) had prolonged complications. Both groups differed significantly in plate position relative to physis (p = 0.049). In addition, both groups showed significant differences in the distribution of implant location (p = 0.016). Group 1 had a shorter duration of surgery than group 2 (32 min vs. 38 min, p = 0.032) and a lower tourniquet pressure (250 mmHg vs. 270 mmHg, p = 0.019). In conclusion, simultaneous plate implantation at the femur and tibia and metaphyseal plate positioning resulted in prolonged pain and a delay of function. In addition, the amplitude of tourniquet pressure or duration of surgery could play a factor.
Background: Malalignments of the lower extremity are common reasons for orthopedic consultation because it may lead to osteoarthritis in adulthood. An accurate and reliable radiological assessment of lower limb alignment in children and adolescents is essential for clinical decision-making on treatment of limb deformities and for regular control after a surgical intervention.
Objective: First, does the analysis of full-length standing anteroposterior radiographs show a good intra- and interobserver reliability? Second, which parameter is most susceptible to observer-dependent errors? Third, what is the Standard Error of Measurement (SEM95%) of the absolute femoral and tibial length?
Methods: Two observers evaluated digital radiographs of 144 legs from 36 children and adolescents with pathological valgus alignment before a temporary hemiepiphysiodesis and before implant removal. Parameters included Mechanical Femorotibial Angle (MFA), Mechanical Axis Deviation (MAD), mechanical Lateral Distal Femoral Angle (mLDFA), mechanical Medial Proximal Tibial Angle (mMPTA), mechanical Lateral Proximal Femoral Angle (mLPFA), mechanical Lateral Distal Tibial Angle (mLDTA), Joint Line Convergence Angle (JLCA), femur length, tibial length. Intra- and interobserver reliability (ICC2,1), SEM95% and proportional errors were calculated.
Results: The intra- and interobserver reliability for almost all measurements was found to be good to excellent (Intra-ICC2,1: 0.849–0.999; Inter-ICC2,1: 0.864–0.996). The SEM95% of both observers was found to be ± 1.39° (MFA), ± 3.31 mm (MAD), ± 1.06° (mLDFA) and ± 1.29° (mMPTA). The proportional error of MAD and MFA is comparable (47.29% vs. 46.33%). The relevant knee joint surface angles show a lower proportional error for mLDFA (42.40%) than for mMPTA (51.60%). JLCA has a proportional error of 138%. Furthermore, the SEM95% for the absolute values of the femoral and tibial length was 4.53 mm for the femur and 3.12 mm for the tibia.
Conclusions: In conclusion, a precise malalignment measurement and the knowledge about SEM95% of the respective parameters are crucial for correct surgical or nonsurgical treatment. The susceptibility to error must be considered when interpreting malalignment analysis and must be considered when planning a surgical intervention. The results of the present study elucidate that MAD and MFA are equally susceptible to observer-dependent errors. This study shows good to excellent intra- and interobserver ICCs for all leg alignment parameters and joint surface angles, except for JLCA.
Trial registration: This study was registered with DRKS (German Clinical Trials Register) under the number DRKS00015053.
Level of evidence
I, Diagnostic Study.
Background: Lennox–Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy characterized by drug-resistant epilepsy with multiple seizure types starting in childhood, a typical slow spike-wave pattern on electroencephalogram, and cognitive dysfunction.
Methods: We performed a systematic literature review according to the PRISMA guidelines to identify, synthesize and appraise the burden of illness in LGS (including “probable” LGS). Studies were identified by searching MEDLINE, Embase and APA PsychInfo, Cochrane’s database of systematic reviews, and Epistemonikos. The outcomes were epidemiology (incidence, prevalence or mortality), direct and indirect costs, healthcare resource utilization, and patient and caregiver health-related quality of life (HRQoL).
Results: The search identified 22 publications evaluating the epidemiology (n = 10), direct costs and resource (n = 10) and/or HRQoL (n = 5). No studies reporting on indirect costs were identified. With no specific ICD code for LGS in many regions, several studies had to rely upon indirect methods to identify their patient populations (e.g., algorithms to search insurance claims databases to identify “probable” LGS). There was heterogeneity between studies in how LGS was defined, the size of the populations, ages of the patients and length of the follow-up period. The prevalence varied from 4.2 to 60.8 per 100,000 people across studies for probable LGS and 2.9–28 per 100,000 for a confirmed/narrow definition of LGS. LGS was associated with high mortality rates compared to the general population and epilepsy population. Healthcare resource utilization and direct costs were substantial across all studies. Mean annual direct costs per person varied from $24,048 to $80,545 across studies, and home-based care and inpatient care were significant cost drivers. Studies showed that the HRQoL of patients and caregivers was adversely affected, although only a few studies were identified. In addition, studies suggested that seizure events were associated with higher costs and worse HRQoL. The risk of bias was low or moderate in most studies.
Conclusions: LGS is associated with a significant burden of illness featuring resistant seizures associated with higher costs and worse HRQoL. More research is needed, especially in evaluating indirect costs and caregiver burden, where there is a notable lack of studies.
Rationale: Attention deficit/hyperactivity disorder (ADHD) is common in alcohol use disorder (AUD). Continuous performance tests (CPTs) allow to measure ADHD related deficits in a laboratory setting. Most studies on this topic focused on CPTs measuring inattention or impulsivity, disregarding hyperactivity as one of the core symptoms of ADHD.
Methods: We examined N = 47 in three groups (ADHD N = 19; AUD N = 16; ADHD + AUD N = 12) with questionnaires on ADHD core symptoms, executive functioning (EF), mind wandering, and quality of life (QoL). N = 46 (ADHD N = 16; AUD N = 16; ADHD + AUD N = 14) were examined with a CPT (QbTest®) that also measures motor activity objectively.
Results: Inattention and impulsivity were significantly increased in AUD vs. ADHD and in AUD vs. ADHD + AUD. Hyperactivity was significantly higher in ADHD + AUD vs. ADHD and ADHD + AUD vs. AUD, but not in ADHD vs. AUD. EF was lower in both ADHD groups vs. AUD. Mind wandering was increased in both ADHD groups vs. AUD. QoL was significantly lower in ADHD + AUD compared to AUD. In contrast, results of the QbTest were not significantly different between groups.
Conclusion: Questionnaires are more useful in assessing ADHD core symptoms than the QbTest®. Hyperactivity appears to be a relevant symptom in ADHD + AUD, suggesting a possible pathway from ADHD to AUD. The lower QoL in ADHD + AUD emphasizes the need for routine screening, diagnostic procedures and treatment strategies for this patient group.
Ferroptosis is a regulated form of cell death which is considered an oxidative iron-dependent process. The lipid hydroperoxidase glutathione peroxidase 4 prevents the iron (Fe2+)-dependent formation of toxic lipid reactive oxygen species. While emerging evidence indicates that inhibition of glutathione peroxidase 4 as a hallmark of ferroptosis in many cancer cell lines, the involvement of this biochemical pathway in neuronal death remains largely unclear. Here, we investigate, first whether the ferroptosis key players are involved in the neuronal cell death induced by erastin. The second objective was to examine whether there is a cross talk between ferroptosis and autophagy. The third main was to address neuron response to erastin, with a special focus on ferritin and nuclear receptor coactivator 4-mediated ferritinophagy. To test this in neurons, erastin (0.5–8 µM) was applied to hippocampal HT22 neurons for 16 hours. In addition, cells were cultured with the autophagy inhibitor, 3-methyladenin (10 mM) and/or ferroptosis inhibitors, ferrostatin 1 (10–20 µM) or deferoxamine (10–200 µM) before exposure to erastin. In this study, we demonstrated by immunofluorescence and western blot analysis, that erastin downregulates dramatically the expression of glutathione peroxidase 4, the sodium-independent cystine-glutamate antiporter and nuclear receptor coactivator 4. The protein levels of ferritin and mitochondrial ferritin in HT22 hippocampal neurons did not remarkably change following erastin treatment. In addition, we demonstrated that not only the ferroptosis inhibitor, ferrostatin1/deferoxamine abrogated the ferroptotic cell death induced by erastin in hippocampal HT22 neurons, but also the potent autophagy inhibitor, 3-methyladenin. We conclude that (1) erastin-induced ferroptosis in hippocampal HT22 neurons, despite reduced nuclear receptor coactivator 4 levels, (2) that either nuclear receptor coactivator 4-mediated ferritinophagy does not occur or is of secondary importance in this model, (3) that ferroptosis seems to share some features of the autophagic cell death process.
In the basal, proliferative layer of healthy skin, the mTOR complex 1 (mTORC1) is activated, thus regulating proliferation while preventing differentiation. When cells leave the proliferative, basal compartment, mTORC1 signaling is turned off, which allows differentiation. Under inflammatory conditions, this switch is hijacked by cytokines and prevents proper differentiation. It is currently unknown how mTORC1 is regulated to mediate these effects on keratinocyte differentiation. In other tissues, mTORC1 activity is controlled through various pathways via the tuberous sclerosis complex (TSC). Thus, we investigated whether the TS complex is regulated by proinflammatory cytokines and contributes to the pathogenesis of psoriasis. TNF-α as well as IL-1β induced the phosphorylation of TSC2, especially on S939 via the PI3-K/AKT and MAPK pathway. Surprisingly, increased TSC2 phosphorylation could not be detected in psoriasis patients. Instead, TSC2 was strongly downregulated in lesional psoriatic skin compared to non-lesional skin of the same patients or healthy skin. In vitro inflammatory cytokines induced dissociation of TSC2 from the lysosome, followed by destabilization of the TS complex and degradation. Thus, we assume that in psoriasis, inflammatory cytokines induce strong TSC2 phosphorylation, which in turn leads to its degradation. Consequently, chronic mTORC1 activity impairs ordered keratinocyte differentiation and contributes to the phenotypical changes seen in the psoriatic epidermis.
The culture of primary intestinal epithelia cells is not possible in a normal culture system. In 2009 a three-dimensional culture system of intestinal stem cells was established that shows many of the physiological features of the small intestine, such as crypt-villus structure, stem cell niche and all types of differentiated intestinal epithelial cells. These enteroids can be used to analyze biology of intestinal stem cells, gut homeostasis and the development of diseases. They also give the possibility to reduce animal numbers, as enteroids can be cryo-conserved and cultivated for many passages. To investigate the influence of genes such as NADPH oxidases on the gut homeostasis, transgenic approached are the method of choice. The generation of enteroids from knockout mice allows real-time observations of knockout effects. Often conditional knockout or overexpression strategies using inducible Cre recombinase are applied to avoid effects of adaption to the knockout. However, the Cre recombinase has many known caveats from unspecific binding and its endonuclease activity. In this study, we show that although NADPH oxidases are important for in vivo differentiation and proliferation of the intestine, their expression is drastically reduced in the organoid system. Activation of Cre recombinase by 4-hydroxy tamoxifen in freshly isolated enteroids, independently of floxed genes, leads to decreased diameter of organoids. This effect is concentration-dependent and is caused by reduced cell proliferation and induction of apoptosis and DNA damage. In contrast, constitutive expression of Cre has no impact on the enteroids. Therefore, reduction of tamoxifen concentration and treatment duration should be carefully titrated, and appropriate controls are necessary.
Purpose
To assess the diagnostic value of different imaging modalities in distinguishing systemic vasculitis from other internal and immunological diseases.
Methods
This retrospective study included 134 patients with suspected vasculitis who underwent ultrasound, magnetic resonance imaging (MRI), or 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) between 01/2010 and 01/2019, finally consisting of 70 individuals with vasculitis. The main study parameter was the confirmation of the diagnosis using one of the three different imaging modalities, with the adjudicated clinical and histopathological diagnosis as the gold standard. A secondary parameter was the morphological appearance of the vessel affected by vasculitis.
Results
Patients with systemic vasculitis had myriad clinical manifestations with joint pain as the most common symptom. We found significant correlations between different imaging findings suggestive of vasculitis and the final adjudicated clinical diagnosis. In this context, on MRI, vessel wall thickening, edema, and diameter differed significantly between vasculitis and non-vasculitis groups (p < 0.05). Ultrasound revealed different findings that may serve as red flags in identifying patients with vasculitis, such as vascular occlusion or halo sign (p = 0.02 vs. non-vasculitis group). Interestingly, comparing maximal standardized uptake values from PET/CT examinations with vessel wall thickening or vessel diameter did not result in significant differences (p > 0.05).
Conclusions
We observed significant correlations between different imaging findings suggestive of vasculitis on ultrasound or MRI and the final adjudicated diagnosis. While ultrasound and MRI were considered suitable imaging methods for detecting and discriminating typical vascular changes, 18F-FDG PET/CT requires careful timing and patient selection given its moderate diagnostic accuracy.
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.
Congenital diaphragmatic hernia (CDH) is a relatively common and life-threatening birth defect, characterized by an abnormal opening in the primordial diaphragm that interferes with normal lung development. As a result, CDH is accompanied by immature and hypoplastic lungs, being the leading cause of morbidity and mortality in patients with this condition. In recent decades, various animal models have contributed novel insights into the pathogenic mechanisms underlying CDH and associated pulmonary hypoplasia. In particular, the generation of genetically modified mouse models, which show both diaphragm and lung abnormalities, has resulted in the discovery of multiple genes and signaling pathways involved in the pathogenesis of CDH. This article aims to offer an up-to-date overview on CDH-implicated transcription factors, molecules regulating cell migration and signal transduction as well as components contributing to the formation of extracellular matrix, whilst also discussing the significance of these genetic models for studying altered lung development with regard to the human situation.
The long-term effect of protection by two doses of SARS-CoV-2 vaccination in patients receiving chronic intermittent hemodialysis (CIHD) is an urging question. We investigated the humoral and cellular immune response of 42 CIHD patients who had received two doses of SARS-CoV-2 vaccine, and again after a booster vaccine with mRNA-1273 six months later. We measured antibody levels and SARS-CoV-2-specific surrogate neutralizing antibodies (SNA). Functional T cell immune response to vaccination was assessed by quantifying interferon-γ (IFN-γ) and IL-2 secreting T cells specific for SARS-CoV-2 using an ELISpot assay. Our data reveal a moderate immune response after the second dose of vaccination, with significantly decreasing SARS-CoV-2-specific antibody levels and less than half of the study group showed neutralizing antibodies six months afterwards. Booster vaccines increased the humoral response dramatically and led to a response rate of 89.2% for antibody levels and a response rate of 94.6% for SNA. Measurement in a no response/low response (NR/LR) subgroup of our cohort, which differed from the whole group in age and rate of immunosuppressive drugs, indicated failure of a corresponding T cell response after the booster vaccine. We strongly argue in favor of a regular testing of surrogate neutralizing antibodies and consecutive booster vaccinations for CIHD patients to provide a stronger and persistent immunity.
Purpose: To assess the diagnostic precision of three different workstations for measuring thoracic aortic aneurysms (TAAs) in vivo and ex vivo using either pre-interventional computed tomography angiography scans (CTA) or a specifically designed phantom model.
Methods: This retrospective study included 23 patients with confirmed TAA on routinely performed CTAs. In addition to phantom tube diameters, one experienced blinded radiologist evaluated the dimensions of TAAs on three different workstations in two separate rounds. Precision was assessed by calculating measurement errors. In addition, correlation analysis was performed using Pearson correlation.
Results: Measurements acquired at the Siemens workstation deviated by 3.54% (range, 2.78–4.03%; p = 0.14) from the true size, those at General Electric by 4.05% (range, 1.46–7.09%; p < 0.0001), and at TeraRecon by 4.86% (range, 3.22–6.45%; p < 0.0001). Accordingly, Siemens provided the most precise workstation at simultaneously most fluctuating values (scattering of 4.46%). TeraRecon had the smallest fluctuation (scattering of 2.83%), but the largest deviation from the true size of the phantom. The workstation from General Electric showed a scattering of 2.94%. The highest overall correlation between the 1st and 2nd rounds was observed with measurements from Siemens (r = 0.898), followed by TeraRecon (r = 0.799), and General Electric (r = 0.703). Repetition of measurements reduced processing times by 40% when using General Electric, by 20% with Siemens, and by 18% with TeraRecon.
Conclusions: In conclusion, all three workstations facilitated precise assessment of dimensions in the majority of cases at simultaneously high reproducibility, ensuring accurate pre-interventional planning of thoracic endovascular aortic repair.
Background: Opsoclonus-myoclonus syndrome (OMS) is a rare, immune-mediated neurological disorder. In adults, the pathogenesis can be idiopathic, post-infectious or paraneoplastic, the latter etiology belonging to the ever-expanding group of defined paraneoplastic neurological syndromes (PNS). In contrast to other phenotypes of PNS, OMS cannot be ascribed to a single pathogenic autoantibody. Here, we report the first detailed case of paraneoplastic, antibody-negative OMS occurring in association with a pancreatic neuroendocrine tumor (pNET).
Case presentation: A 33-year-old female presented with a two-week history of severe ataxia of stance and gait, dysarthria, head tremor, myoclonus of the extremities and opsoclonus. Her past medical history was notable for a metastatic pancreatic neuroendocrine tumor, and she was subsequently diagnosed with paraneoplastic opsoclonus-myoclonus syndrome. Further workup did not reveal a paraneoplastic autoantibody. She responded well to plasmapheresis, as she was refractory to the first-line therapy with corticosteroids.
Conclusions: This case expands current knowledge on tumors associated with paraneoplastic opsoclonus-myoclonus syndrome and the age group in which it can occur. It further adds evidence to the effectiveness of plasmapheresis in severe cases of opsoclonus-myoclonus syndrome with a lack of response to first-line therapy.
Structured management programs have been developed for single diseases but rarely for patients with multiple medications. We conducted a qualitative study to investigate the views of stakeholders on the development and implementation of a polypharmacy management program in Germany. Overall, we interviewed ten experts in the fields of health policy and clinical practice. Using content analysis, we identified inclusion criteria for the selection of suitable patients, the individual elements that should make up such a program, healthcare providers and stakeholders that should be involved, and factors that may support or hinder the program’s implementation. All stakeholders were well aware of polypharmacy-related risks and challenges, as well as the urgent need for change. Intervention strategies should address all levels of care and include all concerned patients, caregivers, healthcare providers and stakeholders, and involved parties should agree on a joint approach.
Zielsetzung: Ziel der Studie ist die Frage, ob es möglich ist, einen Kommunikationskurs für ca. 400 Studierende erfolgreich in ein Blended Learning-Format (asynchrone Theorievermittlung/digitaler synchroner Praxisteil) umzustellen. Hauptfokus war dabei die Beurteilung des subjektiven Lernzuwachses und die Frage, inwiefern die Bedeutung des Themas Kommunikation und Gesprächsführung online abgebildet werden kann. Die Betrachtung erfolgt auf Basis von Evaluationsergebnissen der Studierenden und Dozierenden dieses Kurses.
Methodik: Die Studierenden des vierten vorklinischen Semesters aus dem Jahr 2020 wurden durch einen Selbsteinschätzungsbogen zu Beginn sowie durch eine Evaluation nach Abschluss des Kurses befragt. Zusätzlich wurden die Rückmeldungen der Dozierenden zum Kurs ausgewertet. Um die Ergebnisse vergleichen und mögliche Unterschiede feststellen zu können, wurden die entsprechenden Selbsteinschätzungs- und Evaluationsergebnisse der vorangegangenen zehn Jahre (in Form von Präsenzkursen) herangezogen.
Ergebnisse: Im Onlineformat wurde ein deutlicher subjektiver Lernzuwachs angegeben, der höher ausfiel als in den Vorjahren in Präsenz. Die Eignung des Onlineformats wurde von Studierenden sowie Dozierenden eher kritisch bewertet, während die Kursatmosphäre positiv gesehen wurde. Die Relevanz ärztlicher Gesprächsführung wurde im Onlineformat insgesamt besonders gut bewertet.
Schlussfolgerung: Aufgrund der Evaluationsergebnisse werden die Erfahrungen mit dem Blended Learning-Format auch in Zukunft in das Kommunikations-Curriculum des Medizinstudiums der Goethe-Universität Frankfurt einfließen. Die Ergebnisse haben gezeigt, dass das Erlernen ärztlicher Gesprächsführung online gut möglich ist. Daher kann dieses Format für zukünftige neue Konzepte empfohlen werden.
Objectives: To assess the impact of noise-optimised virtual monoenergetic imaging (VMI+) on image quality and diagnostic evaluation in abdominal dual-energy CT scans with impaired portal-venous contrast.
Methods: We screened 11,746 patients who underwent portal-venous abdominal dual-energy CT for cancer staging between 08/2014 and 11/2019 and identified those with poor portal-venous contrast.
Standard linearly-blended image series and VMI+ image series at 40, 50, and 60 keV were reconstructed. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of abdominal organs and vascular structures were calculated. Image noise, image contrast and overall image quality were rated by three radiologists using 5-point Likert scale.
Results: 452 of 11,746 (4%) exams were poorly opacified. We excluded 190 cases due to incomplete datasets or multiple exams of the same patient with a final study group of 262. Highest CNR values in all abdominal organs (liver, 6.4 ± 3.0; kidney, 17.4 ± 7.5; spleen, 8.0 ± 3.5) and vascular structures (aorta, 16.0 ± 7.3; intrahepatic vein, 11.3 ± 4.7; portal vein, 15.5 ± 6.7) were measured at 40 keV VMI+ with significantly superior values compared to all other series. In subjective analysis, highest image contrast was seen at 40 keV VMI+ (4.8 ± 0.4), whereas overall image quality peaked at 50 keV VMI+ (4.2 ± 0.5) with significantly superior results compared to all other series (p < 0.001).
Conclusions: Image reconstruction using VMI+ algorithm at 50 keV significantly improves image contrast and image quality of originally poorly opacified abdominal CT scans and reduces the number of non-diagnostic scans.
Advances in knowledge: We validated the impact of VMI+ reconstructions in poorly attenuated DECT studies of the abdomen in a big data cohort.
The effect of race/ethnicity on cancer-specific mortality after salvage radical prostatectomy
(2022)
Background: To test the effect of race/ethnicity on cancer-specific mortality (CSM) after salvage radical prostatectomy (SRP).
Material and methods: We relied on the Surveillance, Epidemiology and End Results database (SEER, 2004–2016) to identify SRP patients of all race/ethnicity background. Univariate and multivariate Cox regression models addressed CSM according to race/ethnicity.
Results: Of 426 assessable SRP patients, Caucasians accounted for 299 (69.9%) vs. 68 (15.9%) African-Americans vs. 39 (9.1%) Hispanics vs. 20 (4.7%) Asians. At diagnosis, African-Americans (64 years) were younger than Caucasians (66 years), but not younger than Hispanics (66 years) and Asians (67 years). PSA at diagnosis was significantly higher in African-Americans (13.2 ng/ml), Hispanics (13.0 ng/ml), and Asians (12.2 ng/ml) than in Caucasians (7.8 ng/ml, p = 0.01). Moreover, the distribution of African-Americans (10.3%–36.6%) and Hispanics (0%–15.8%) varied according to SEER region. The 10-year CSM was 46.5% in African-Americans vs. 22.4% in Caucasians vs. 15.4% in Hispanics vs. 15.0% in Asians. After multivariate adjustment (for age, clinical T stage, lymph node dissection status), African-American race/ethnicity was an independent predictor of higher CSM (HR: 2.2, p < 0.01), but not Hispanic or Asian race/ethnicity. The independent effect of African-American race/ethnicity did not persist after further adjustment for PSA.
Conclusion: African-Americans treated with SRP are at higher risk of CSM than other racial/ethnic groups and also exhibited the highest baseline PSA. The independent effect of African-American race/ethnicity on higher CSM no longer applies after PSA adjustment since higher PSA represents a distinguishing feature in African-American patients.
Background: Prostate cancer is a major health concern in aging men. Paralleling an aging society, prostate cancer prevalence increases emphasizing the need for efcient diagnostic algorithms.
Methods: Retrospectively, 106 prostate tissue samples from 48 patients (mean age,
66 ± 6.6 years) were included in the study. Patients sufered from prostate cancer (n = 38) or benign prostatic hyperplasia (n = 10) and were treated with radical prostatectomy or Holmium laser enucleation of the prostate, respectively. We constructed tissue microarrays (TMAs) comprising representative malignant (n = 38) and benign (n = 68) tissue cores. TMAs were processed to histological slides, stained, digitized and assessed for the applicability of machine learning strategies and open–source tools in diagnosis of prostate cancer. We applied the software QuPath to extract features for shape, stain intensity, and texture of TMA cores for three stainings, H&E, ERG, and PIN-4. Three machine learning algorithms, neural network (NN), support vector machines (SVM), and random forest (RF), were trained and cross-validated with 100 Monte Carlo random splits into 70% training set and 30% test set. We determined AUC values for single color channels, with and without optimization of hyperparameters by exhaustive grid search. We applied recursive feature elimination to feature sets of multiple color transforms.
Results: Mean AUC was above 0.80. PIN-4 stainings yielded higher AUC than H&E and
ERG. For PIN-4 with the color transform saturation, NN, RF, and SVM revealed AUC of 0.93 ± 0.04, 0.91 ± 0.06, and 0.92 ± 0.05, respectively. Optimization of hyperparameters improved the AUC only slightly by 0.01. For H&E, feature selection resulted in no increase of AUC but to an increase of 0.02–0.06 for ERG and PIN-4.
Conclusions: Automated pipelines may be able to discriminate with high accuracy between malignant and benign tissue. We found PIN-4 staining best suited for classifcation. Further bioinformatic analysis of larger data sets would be crucial to evaluate the reliability of automated classifcation methods for clinical practice and to evaluate potential discrimination of aggressiveness of cancer to pave the way to automatic precision medicine.
This prospective study sought to evaluate potential savings of radiation dose to medical staff using real-time dosimetry coupled with visual radiation dose feedback during angiographic interventions. For this purpose, we analyzed a total of 214 angiographic examinations that consisted of chemoembolizations and several other types of therapeutic interventions. The Unfors RaySafe i2 dosimeter was worn by the interventionalist at chest height over the lead protection. A total of 110 interventions were performed with real-time radiation dosimetry allowing the interventionalist to react upon higher x-ray exposure and 104 examinations served as the comparative group without real-time radiation monitoring. By using the real-time display during interventions, the overall mean operator radiation dose decreased from 3.67 (IQR, 0.95–23.01) to 2.36 μSv (IQR, 0.52–12.66) (−36%; p = 0.032) at simultaneously reduced operator exposure time by 4.5 min (p = 0.071). Dividing interventions into chemoembolizations and other types of therapeutic interventions, radiation dose decreased from 1.31 (IQR, 0.46-3.62) to 0.95 μSv (IQR, 0.53-3.11) and from 24.39 (IQR, 12.14-63.0) to 10.37 μSv (IQR, 0.85-36.84), respectively, using live-screen dosimetry (p ≤ 0.005). Radiation dose reductions were also observed for the participating assistants, indicating that they could also benefit from real-time visual feedback dosimetry during interventions (−30%; p = 0.039). Integration of real-time dosimetry into clinical processes might be useful in reducing occupational radiation exposure time during angiographic interventions. The real-time visual feedback raised the awareness of interventionalists and their assistants to the potential danger of prolonged radiation exposure leading to the adoption of radiation-sparing practices. Therefore, it might create a safer environment for the medical staff by keeping the applied radiation exposure as low as possible.
The combination of histological and biomolecular analyses provides deep understanding of different biological processes and is of high interest for basic and applied research. However, the available analytical methods are still limited, especially when considering bone samples. This study compared different fixation media to identify a sufficient analytical method for the combination of histological, immuno-histological and biomolecular analyses of the same fixed, processed and paraffin embedded bone sample. Bone core biopsies of rats’ femurs were fixed in different media (RNAlater + formaldehyde (R + FFPE), methacarn (MFPE) or formaldehyde (FFPE)) for 1 week prior to decalcification by EDTA and further histological processing and paraffin embedding. Snap freezing (unfixed frozen tissue, UFT) and incubation in RNAlater were used as additional controls. After gaining the paraffin sections for histological and immunohistological analysis, the samples were deparaffined and RNA was isolated by a modified TRIZOL protocol. Subsequently, gene expression was evaluated using RT-qPCR. Comparable histo-morphological and immuno-histological results were evident in all paraffin embedded samples of MFPE, FFPE and R + FFPE. The isolated RNA in the group of MFPE showed a high concentration and high purity, which was comparable to the UFT and RNAlater groups. However, in the groups of FFPE and R + FFPE, the RNA quality and quantity were statistically significantly lower when compared to MFPE, UFT and RNAlater. RT-qPCR results showed a comparable outcome in the group of MFPE and UFT, whereas the groups of FFPE and R + FFPE did not result in a correctly amplified gene product. Sample fixation by means of methacarn is of high interest for clinical samples to allow a combination of histological, immunohistological and biomolecular analysis. The implementation of such evaluation method in clinical research may allow a deeper understanding of the processes of bone formation and regeneration.
Background: Survival data regarding cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC) patients according to the type and extent of tumor-associated vascular thrombus are scarce.
Objective: To test for survival differences in mRCC patients treated with CN according to the type and extent of tumor-associated vascular thrombus.
Design, setting, and participants: Within Surveillance, Epidemiology, and End Results Research Plus (2004–2017), we identified CN mRCC patients with renal vein (pT3a-TT) versus infradiaphragmatic inferior vena cava (IVC; pT3b) versus supradiaphragmatic IVC tumor thrombus/IVC invasion (pT3c).
Outcome measurements and statistical analysis: Overall survival (OS) was addressed in Kaplan-Meier and Cox regression analyses, in addition to 3-mo landmark analyses.
Results and limitations: Of 2170 mRCC patients, 1880 (87%), 204 (9%), and 86 (4%) harbored pT3a-TT, pT3b, and pT3c, respectively. The respective median OS periods were 21, 23, and 12 mo (p < 0.001). In multivariable Cox regression models, pT3c stage, but not pT3b stage, was an independent predictor of higher overall mortality (hazard ratio [HR]: 1.37; 95% confidence interval [CI]: 1.09–1.73; p = 0.007), as well as in 6-mo landmark analyses (HR: 1.36; 95% CI: 1.02–1.80; p = 0.04). In the sensitivity analysis, relying on all pT3a patients, the predictor status of pT3c stage remained unchanged (HR: 1.37; 95% CI: 1.09–1.71; p = 0.007). Limitations have to be addressed regarding the sample size and the retrospective design of the current study.
Conclusions: Although overall mortality is significantly higher in pT3c mRCC patients than in their pT3b and pT3a-TT counterparts, these individuals may still expect 12-mo or better OS after CN versus virtually 2-yr OS in their pT3a and pT3b counterparts.
Patient summary: In this study, we looked at the survival outcomes of metastatic renal cell carcinoma patients who presented with tumor thrombus at cytoreductive nephrectomy. Even though these patients with most advanced tumor thrombus stage demonstrated lower survival rates, the median overall survival was still 1 yr.
Middle-aged persons with multimorbidity have to take their illnesses into account in their daily work, family and leisure activities. The MuMiA project aims to identify early preventive measures that make it easier for those between 30 and 60 years of age with multiple chronic diseases to manage their illnesses in their everyday lives. An interdisciplinary workshop and interviews with multimorbid middle-aged adults and their principal healthcare providers will be used to collect information on the management of care in the contexts of patients’ daily work, family and leisure activities. Data obtained in the interviews will be coded inductively and analysed using content analysis. Workshop outputs will be transcribed and evaluated by the authors. This study has received ethical approval from the Faculty of Medicine Ethics Committee of Goethe University (2021-47). The project will generate prevention recommendations that reflect the experiences of middle-aged persons living with multimorbidity and the views of their principal healthcare providers. The findings will be disseminated via conferences and peer-reviewed publications.
Development of a multidimensional pain questionnaire in professional dance (MPQDA): a pilot study
(2022)
Background: Pain is part of the everyday life of professional dancers. It can indicate health risks and impair the ability to work. Suitable screening tools can be used to identify pain and its risk potential. A comprehensive, multidimensional, differentiated assessment tool for pain in professional dance does not currently exist.
Methods: An initial questionnaire was developed in German and English and was assessed in a qualitative pretest. In a field study with a cross-sectional design including n = 72 dancers from Germany (n = 36 responses each in the English and German language versions), the questionnaire was optimized by item analysis, its psychometric properties (dimensionality, construct validity, reliability) were examined and the ability of the pain dimensions to classify the subjective ability to work in training was analyzed (ROC analysis).
Results: The developed Multidimensional Pain Questionnaire in Professional Dance (MPQDA) was reduced and optimized in its psychometric properties. Following questions were reduced in their items or answer categories: pain localizations (from 20 to 15 regions), accompanying symptoms (from 6 to 3 items), sensory and affective pain quality (from 20 to 10 items), pain frequency (from 4 to 3 answer categories), and the motives of working with pain (from 14 to 12 items). Regarding the subjective ability to work in training, the variables of the ability to work in rehearsals and in performances, as well as the accompanying symptoms of tension and mobility restrictions, showed a relatively good classification ability (Area under the Curve (AUC) ≥ 0.7 in the 95% confidence interval) and significant, moderate to strong correlations (Somers' D > 0.25, p < 0.05). The classification ability of the other pain dimensions was largely absent or poor.
Conclusion: The MPQDA differentiates various pain dimensions in professional dancers and is available in a compatible manner in German and English. The clinical relevance needs to be explored further in the future.
Up to the present, there has been a lack of studies on the skin health of professional and recreational dancers. Dancers are at risk of skin diseases due to contact with allergenic or irritating substances and working in humid environments. The aim of the present study was, therefore, to examine skin health in two different dance styles and training periods. Methods: Physical dermatological examination of professional dancers (PD; n = 35) and Latin American formation dancers (LD; n = 79) after a 4-week period of recovery (T0) and a period of high training or work load (T1). Results: PD are significantly more frequently affected by skin dermatoses than LD (T0, p = 0.004) (frontal traction alopecia, hair loss, facial seborrhoea, xerosis cutis of the trunk and extremities, and facial folliculitis). The following significant differences between the sexes were observed in the LD: more folliculitis of the trunk in male subjects (T0 and T1, p = 0.009), more frequent xerosis cutis of the extremities (p < 0.001) and perioral dermatitis in female subjects (T1, p = 0.043). Subjects with skin lesions trained more frequently, performed more times per year, and had longer dance experience. Discussion: Based on the findings, preventive measures for skin protection (especially informing dancers about skin health) are necessary. At the same time, further studies on this topic are important.
The deep fascia is intimately linked to skeletal muscle and may be involved in delayed onset muscle soreness (DOMS). The present study therefore explored the effect of eccentric exercise on fascia stiffness and its relation with DOMS. Healthy active male adults (n = 19, 27 ± 4 years) performed 6 x 10 maximal eccentric knee flexions using an isokinetic dynamometer. Before (baseline) as well as immediately (T0), 1 hour (T1), and each day up to 72 hours (T24 to T72) afterwards, shear wave elastography was used to measure the mechanical stiffness of the biceps femoris muscle and the overlying fascia. As a surrogate of DOMS, pain upon palpation was captured by means of a 100mm visual analogue scale. While muscle stiffness remained unchanged (p > 0.05), deep fascia stiffness increased from baseline to T24 (median: 18 kPa to 21.12 kPa, p = 0.017) and T72 (median: 18 kPa to 21.3 kPa, p = 0.001) post-exercise. Linear regression showed an association of stiffness changes at T24 and pressure pain at T72 (r2 = 0.22, p < 0.05). Maximal eccentric exercise leads to a stiffening of the fascia, which, in turn, is related to the magnitude of future DOMS. Upcoming research should therefore gauge the effectiveness of interventions modifying the mechanical properties of the connective tissue in order to accelerate recovery.
Background: Primary viral myocarditis associated with severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) infection is a rare diagnosis.
Case presentation: We report the case of an unvaccinated, healthy patient with cardiogenic shock in the context of a COVID-19-associated myocarditis and therapy with simultaneous veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and percutaneous left ventricular decompression therapy with an Impella. The aim of this review is to provide an overview of therapeutic options for patients with COVID-19-associated myocarditis.
Conclusions: The majority of patients required a combination of two assist devices to achieve sufficient cardiac output until recovery of left ventricular ejection fraction. Due to the rapid onset of this fulminant cardiogenic shock immediate invasive bridging therapy in a specialized center was lifesaving.
Introduction: Studies of vocational ballet students are sparce. In particular, there is a lack of gender comparisons. The aim of the present study, therefore, was to give a musculoskeletal and sociodemographic description of the typical vocational ballet student in gender comparison. Methods: In this study, n = 414 female and n = 192 male students of the John Cranko School (JCS), aged between 5 and 22 years (Mean ± SD: 13.9 ± 3.5), were examined by an experienced orthopedist and dance physician. Results: Males started ballet (5.8/8.2 years, p < 0.001) and training at later age than females (13.5/14.6 years, p < 0.05). There was a high prevalence of low body weight among both sexes; however, particularly among female participants (58.4/16.2%, p < 0.001). Both sexes showed a large external rotation of the hip (f/m: 59/62°, p < 0.001), a large turnout (f/m: 82/86°, p < 0.01), high values for plantarflexion of the ankle joint (f/m: 72/68°, p < 0.001) and dorsiflexion of the metatarsophalangeal joint of the big toe (f/m: 90/87°, p < 0.001). Discussion: Differences in ballet-specific characteristics between genders (f/m) are converging and are smaller than described in the past. The particularly high prevalence of low body weight among students in the vocational training sector, particularly among females, highlights the need for deeper diagnostic investigation.
Structural brain morphometry as classifier and predictor of ADHD and reward-related comorbidities
(2022)
Attention deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, and around two-thirds of affected children report persisting problems in adulthood. This negative trajectory is associated with high comorbidity with disorders like obesity, depression, or substance use disorder (SUD). Decreases in cortical volume and thickness have also been reported in depression, SUD, and obesity, but it is unclear whether structural brain alterations represent unique disorder-specific profiles. A transdiagnostic exploration of ADHD and typical comorbid disorders could help to understand whether specific morphometric brain changes are due to ADHD or, alternatively, to the comorbid disorders. In the current study, we studied the brain morphometry of 136 subjects with ADHD with and without comorbid depression, SUD, and obesity to test whether there are unique or common brain alterations. We employed a machine-learning-algorithm trained to classify subjects with ADHD in the large ENIGMA-ADHD dataset and used it to predict the diagnostic status of subjects with ADHD and/or comorbidities. The parcellation analysis demonstrated decreased cortical thickness in medial prefrontal areas that was associated with presence of any comorbidity. However, these results did not survive correction for multiple comparisons. Similarly, the machine learning analysis indicated that the predictive algorithm grouped most of our ADHD participants as belonging to the ADHD-group, but no systematic differences between comorbidity status came up. In sum, neither a classical comparison of segmented structural brain metrics nor an ML model based on the ADHD ENIGMA data differentiate between ADHD with and without comorbidities. As the ML model is based in part on adolescent brains, this might indicate that comorbid disorders and their brain changes are not captured by the ML model because it represents a different developmental brain trajectory.
Objectives: The range of motion (ROM) of the cervical spine and postural stability are important for an economical and motorically adequate adaptation of the body to any situation. Therefore, this study aims to analyze whether these two components of postural and movement control can be influenced by means of a splint in a centric position compared to habitual occlusion.
Methods: 38 recreational male athletes volunteered. Cervical spine ROM was recorded using an ultrasound system and the a pressure measuring plate for postural stability (length of center of pressure (CoP) movement, area of CoP). The two dental occlusion conditions employed were the habitual occlusion and wearing a splint in an idealized, condylar position close to the centric position. Level of significance was set at ρ ≤ 0.05.
Results: The cervical spine mobility increased significantly by wearing the splint regarding rotation to the left (+3.9%) and right (+2.7%) and lateral flexion to the left (+4.4%) and right (+6.7%). Wearing the splint reduced the area of sway deflections by about 31.5% in the bipedal stance and by about 2.4% (left) and 28.2% (right) in the unipedal stance. The CoP trace was reduced in the sagittal plane by approximately 8.2% in the right single-leg stance.
Conclusions: The major findings seem to demonstrate that wearing a splint that keeps the jaw close to the centric relation may increase the cervical ROM and may improve balance stability in male recreational athletes. Changing the jaw relation in athletes can possibly aid the release of performance potentials by improving coordination skills.
Background: In order to determine possible pathological deviations in body weight distribution and body sway, it is helpful to have reference values for comparison: gender and age are two main influencing factors. For this reason, it was the aim of the present study to present reference values for women between 51 and 60 years of age.
Methods: For this study, 101 subjectively healthy female Germans aged between 51 and 60 years (55.16 ± 2.89 years) volunteered and were required to stand in a habitual posture on a pressure measuring platform.
Results: The average BMI of this age group was 25.02 ± 4.55 kg/m². The left and right foot showed an almost evenly balanced load distribution with a median load of 52.33% on the left foot [tolerance interval (TR) 38.00%/68.03%; confidence interval (CI) 51.00%/53.33%] and 47.67% on the right foot [TR 31.97%/62.00%; CI 46.67%/49.00%]. The measured median load of the forefoot was 33.33% [TR 21.37%/54.60%; CI 30.67%/36.00%] and that of the rear foot was 66.67% [TR 45.50%/78.63%; CI 64.00%/69.33%]. The median body sway in the frontal plane was 11 mm [TR 5.70 mm/26.30 mm; CI 10.00 mm/11.67 mm] and that of the sagittal plane was 16 mm [TR 7.37 mm/34.32 mm; CI 14.67 mm/18.67 mm]. The median ellipse area was 1.17 cm² [TR 0.29 cm²/4.96 cm²; CI 0.98 cm²/1.35 cm²], the median ellipse width was 0.91 cm [TR 0.42 cm/1.9 cm; CI 0.84 cm/1.02 cm] and its height was 0.40 cm [TR 0.22 cm/0.89 cm; CI 0.38 cm/0.43 cm].
Conclusions: The left-to-right ratio is almost balanced. The load distribution of the forefoot to the rear foot is approximately 1:2. The median body sway values for the frontal and sagittal planes (11 and 16 mm, respectively) agree with other values. The values for the height, body weight and the BMI are comparable to the values of average German women at this age; therefore, the measured values show a presentable cross section of women in the 51–60 age group in Germany. The present data can be used as a basis for women aged 51–60 years and can support the detection of possible dysfunctions as well as injury prevention in the parameters of postural control.
Background: In the COVID-19 pandemic, numerous researchers postponed their patient and public involvement (PPI) activities. This was mainly due to assumptions on patients’ willingness and skills to participate digitally. In fact, digital PPI workshops differ from in-person meetings as some forms of non-verbal cues and body language may be missing and technical barriers may exist. Within our project HYPERION-TransCare we adapted our PPI workshop series for intervention development to a digital format and assessed whether these digital workshops were feasible for patients, health care professionals and researchers.
Methods: We used a digital meeting tool that included communication via audio, video and chat. Discussions were documented simultaneously on a digital white board. Technical support was provided via phone and chat during the workshops and with a technical introduction workshop in advance. The workshop evaluation encompassed observation protocols, participants’ feedback via chat after each workshop on their chance to speak and the usability of the digital tools, and telephone interviews on patients’ and health professionals’ experiences after the end of the workshop series.
Results: Observation protocols showed an active role of moderators in verbally encouraging every participant to get involved. Technical challenges occurred, but were in most cases immediately addressed and solved. Participants median rating of their chance to speak and the usability of the digital tool was “very good”. In the evaluation interviews participants reported a change of perspective and mutual understanding as a main benefit from the PPI workshops and described the atmosphere as inclusive and on equal footing. Benefits of the digital format such as overcoming geographical distance, saving time and combining workshop participation with professional or childcare obligations were reported. Technical support was stressed as a pre-condition for getting actively involved in digital PPI.
Conclusions: Digital formats using different didactic and documentation techniques, accompanied by technical support, can foster active patient and public involvement. The advantages of digital PPI formats such as geographical flexibility and saving time for participants as well as the opportunity to prepare and hold workshops in geographically stretched research teams persists beyond the pandemic and may in some cases outweigh the advantages of in-person communication.
Although exercise guidelines now recommend exercise for patients with MCI, the long-term effects of exercise in patients with MCI has not been reviewed systematically. The aim was to assess (1) the effectiveness of exercise and physical activity (EXPA) interventions in improving long-term patient-relevant cognitive and non-cognitive outcomes in people with mild cognitive impairment, (2) how well the included trials reported details of the intervention, and (3) the extent to which reported endpoints were in line with patient preferences that were assessed in patient workshops. Following PRISMA guidelines, we performed a systematic review and meta-analysis including randomized controlled trials. A total of ten studies were included after searching in six electronic sources from 1995 onwards. There is a trend that 6 + -month EXPA interventions improve global cognition 12 months after initiation. Evidence on long-term effects of EXPA interventions on non-cognitive health outcomes could not be meaningfully pooled and the individual studies reported mixed results. Workshop participants considered freedom from pain and stress, mood, motivation and self-efficacy to be important, but these outcomes were rarely addressed. Too little information is available on intervention details for EXPA programs to be replicated and confidently recommended for patients with MCI. PROSPERO registration in December, 2021 (CRD42021287166).
Association of mortality and early tracheostomy in patients with COVID-19: a retrospective analysis
(2022)
COVID-19 adds to the complexity of optimal timing for tracheostomy. Over the course of this pandemic, and expanded knowledge of the disease, many centers have changed their operating procedures and performed an early tracheostomy. We studied the data on early and delayed tracheostomy regarding patient outcome such as mortality. We performed a retrospective analysis of all tracheostomies at our institution in patients diagnosed with COVID-19 from March 2020 to June 2021. Time from intubation to tracheostomy and mortality of early (≤ 10 days) vs. late (> 10 days) tracheostomy were the primary objectives of this study. We used mixed cox-regression models to calculate the effect of distinct variables on events. We studied 117 tracheostomies. Intubation to tracheostomy shortened significantly (Spearman’s correlation coefficient; rho = − 0.44, p ≤ 0.001) during the course of this pandemic. Early tracheostomy was associated with a significant increase in mortality in uni- and multivariate analysis (Hazard ratio 1.83, 95% CI 1.07–3.17, p = 0.029). The timing of tracheostomy in COVID-19 patients has a potentially critical impact on mortality. The timing of tracheostomy has changed during this pandemic tending to be performed earlier. Future prospective research is necessary to substantiate these results.
Compressive knee joint contact force during walking is thought to be related to initiation and progression of knee osteoarthritis. However, joint loading is often evaluated with surrogate measures, like the external knee adduction moment, due to the complexity of computing joint contact forces. Statistical models have shown promising correlations between medial knee joint contact forces and knee adduction moments in particularly in individuals with knee osteoarthritis or after total knee replacements (R2 = 0.44–0.60). The purpose of this study was to evaluate how accurately model-based predictions of peak medial and lateral knee joint contact forces during walking could be estimated by linear mixed-effects models including joint moments for children and adolescents with and without valgus malalignment. Peak knee joint moments were strongly correlated (R2 > 0.85, p < 0.001) with both peak medial and lateral knee joint contact forces. The knee flexion and adduction moments were significant covariates in the models, strengthening the understanding of the statistical relationship between both moments and medial and lateral knee joint contact forces. In the future, these models could be used to evaluate peak knee joint contact forces from musculoskeletal simulations using peak joint moments from motion capture software, obviating the need for time-consuming musculoskeletal simulations.
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.
Perceptual expectations influence perception, attention and the perceptual decision bias during visuospatial orienting, which is impaired in individuals with Autism Spectrum Disorder (ASD). In this study, we investigated whether during visuospatial orienting, perceptual expectations in ASD differentially influence perception, attention and the perceptual decision bias relative to neurotypical controls (NT). Twenty-three children and adolescents with ASD and 23 NT completed a visuospatial orienting task, which compared the effect of a valid relative to an invalid perceptual expectation on target detection (cue validity effect). Group differences were calculated regarding the cue validity effect on neural correlates of processing gain (N1a amplitude) and attention (N1pc amplitude), the perceptual decision bias and mean reaction time (RT). In ASD relative to NT, findings showed a reduced processing gain for validly relative to invalidly cued targets and increased attentional response following invalidly relative to validly cued targets. Increased attention correlated with faster performance across groups. Increased processing correlated with a higher perceptual decision bias and faster mean RT in NT, but not in ASD. Results suggest that during visuospatial orienting, perceptual expectations in ASD may drive changes in sensory processing and stimulus-driven attention, which may differentially guide behavioural responses.
A recent in-vivo experiment has shown that force can be transmitted between the gastrocnemius and the hamstring muscles due to a direct tissue continuity. However, it remains unclear if this mechanical interaction is affected by the stiffness of the structural connection. This study therefore aimed to investigate the impact of the knee angle on myofascial force transmission across the dorsal knee. A randomized, cross-over study was performed, including n = 56 healthy participants (25.36 ± 3.9 years, 25 females). On two separate days, they adopted a prone position on an isokinetic dynamometer (knee extended or 60° flexed). In each condition, the device moved the ankle three times from maximal plantarflexion to maximal dorsal extension. Muscle inactivity was ensured using EMG. High-resolution ultrasound videos of the semimembranosus (SM) and the gastrocnemius medialis (GM) soft tissue were recorded. Maximal horizontal tissue displacement, obtained using cross-correlation, was examined as a surrogate of force transmission. SM tissue displacement was higher at extended (4.83 ± 2.04 mm) than at flexed knees (3.81 ± 2.36 mm). Linear regression demonstrated significant associations between (1) SM and GM soft tissue displacement (extended: R2 = 0.18, p = 0.001; flexed: R2 = 0.17, p = 0.002) as well as (2) SM soft tissue displacement and ankle range of motion (extended: R2 = 0.103, p = 0.017; flexed: R2 = 0.095, p = 0.022). Our results further strengthen the evidence that local stretching induces a force transmission to neighboring muscles. Resulting remote exercise effects such as increased range of motion, seem to depend on the stiffness of the continuity.
Trial registration: DRKS (Deutsches Register Klinischer Studien), registration number DRKS00024420, first registered 08/02/2021, https://drks.de/search/de/trial/DRKS00024420.
Macrophages are plastic and heterogeneous immune cells that adapt pro- or anti-inflammatory phenotypes upon exposure to different stimuli. Even though there has been evidence supporting a crosstalk between coagulation and innate immunity, the way in which protein components of the hemostasis pathway influence macrophages remains unclear. We investigated the effect of thrombin on macrophage polarization. On the basis of gene expression and cytokine secretion, our results suggest that polarization with thrombin induces an anti-inflammatory, M2-like phenotype. In functional studies, thrombin polarization promoted oxLDL phagocytosis by macrophages, and conditioned medium from the same cells increased endothelial cell proliferation. There were, however, clear differences between the classical M2a polarization and the effects of thrombin on gene expression. Finally, the deletion and inactivation of secreted modular Ca2+-binding protein 1 (SMOC1) attenuated phagocytosis by thrombin-stimulated macrophages, a phenomenon revered by the addition of recombinant SMOC1. Manipulation of SMOC1 levels also had a pronounced impact on the expression of TGF-β-signaling-related genes. Taken together, our results show that thrombin induces an anti-inflammatory macrophage phenotype with similarities as well as differences to the classical alternatively activated M2 polarization states, highlighting the importance of tissue levels of SMOC1 in modifying thrombin-induced macrophage polarization.
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.
Diagnostic value of dynamic magnetic resonance imaging of temporomandibular joint dysfunction
(2021)
Background: To estimate the diagnostic value of dynamic magnetic resonance imaging (MRI) for the assessment of the temporomandibular joint (TMJ) compared to standard static MRI sequences in patients with TMJ dysfunction (TMD).
Methods and materials: This retrospective study included 71 patients with clinical diagnose of TMD. We acquired 5 static T1- and T2-weighted sequences in parasagittal and paracoronal views and one dynamic sequence (trueFISP) in parasagittal view for each TMJ. Image analysis included evaluation of morphology and function of intra-articular structures and rating of the dynamic images as more, equally, or less informative compared to static MRI sequences.
Results: Mean age was 35.0 ± 14.7 years and 50/71 (70.4%) were female. 127/142 (89.4%) TMJs were of diagnostic quality. 42/127 (33.1%) TMJs showed no disc displacement (DD), 56 (44.1%) had DD with disc reduction (DDwR), and 29 (22.8%) had DD without disc reduction (DDwoR). In 38/127 (29.9%) TMJs, dynamic images were rated “more informative”, in 84/127 (66.2%) “equally informative”, and in 5/127 (3.9%) “less informative” compared to solely static images. Overall, 27/71 (38.0%) patients benefited from additional dynamic sequences compared to solely static images. Dynamic images were “more informative” in TMJs with DDwR (23/56 [41.1%], p < 0.001) and in TMJs with DDwoR (13/29 [44.8%], p = 0.007), while it had no beneficial value for TMJ without DD. For evaluation of joint effusion, static T2-weighted images were rated better in 102/127 (80.3%) TMJs compared to dynamic images (<0.001).
Conclusion: Dynamic MRI sequences are beneficial for the evaluation of morphology and function of the TMJ compared to static sequences, especially in patients with temporomandibular disc displacement.
Rationale and objectives: To provide a detailed analysis of injury patterns of the spine following blunt trauma and establish the role of supplementary MRI by evaluating discrepancies in the detection rates of damaged structures in CT and MRI.
Method: 216 patients with blunt trauma to the spine who underwent CT followed by supplementary MRI were included in this study. Two board-certified radiologists blinded to clinical symptoms and injury mechanisms independently interpreted all acquired CT and MRI images. The interpretation was performed using a dedicated catalogue of typical findings associated with spinal trauma and assessed for spinal stability using the AO classification systems.
Results: Lesions to structures associated with spinal instability were present in 31.0% in the cervical spine, 12.3% in the thoracic spine, and 29.9% in the lumbar spine. In all spinal segments, MRI provided additional information regarding potentially unstable injuries. Novel information derived from supplementary MRI changed clinical management in 3.6% of patients with injury to the cervical spine. No change in clinical management resulted from novel information on the thoracolumbar spine. Patients with injuries to the vertebral body, intervertebral disc, or spinous process were significantly more likely to benefit from supplementary MRI.
Conclusion: In patients that sustained blunt spinal trauma, supplementary MRI of the cervical spine should routinely be performed to detect injuries that require surgical treatment, whereas CT is the superior imaging modality for the detection of unstable injuries in the thoracolumbar spine.
Background: The categorization of individuals as normosmic, hyposmic, or anosmic from test results of odor threshold, discrimination, and identification may provide a limited view of the sense of smell. The purpose of this study was to expand the clinical diagnostic repertoire by including additional tests. Methods: A random cohort of n = 135 individuals (83 women and 52 men, aged 21 to 94 years) was tested for odor threshold, discrimination, and identification, plus a distance test, in which the odor of peanut butter is perceived, a sorting task of odor dilutions for phenylethyl alcohol and eugenol, a discrimination test for odorant enantiomers, a lateralization test with eucalyptol, a threshold assessment after 10 min of exposure to phenylethyl alcohol, and a questionnaire on the importance of olfaction. Unsupervised methods were used to detect structure in the olfaction-related data, followed by supervised feature selection methods from statistics and machine learning to identify relevant variables. Results: The structure in the olfaction-related data divided the cohort into two distinct clusters with n = 80 and 55 subjects. Odor threshold, discrimination, and identification did not play a relevant role for cluster assignment, which, on the other hand, depended on performance in the two odor dilution sorting tasks, from which cluster assignment was possible with a median 100-fold cross-validated balanced accuracy of 77–88%. Conclusions: The addition of an odor sorting task with the two proposed odor dilutions to the odor test battery expands the phenotype of olfaction and fits seamlessly into the sensory focus of standard test batteries.
Selecting the k best features is a common task in machine learning. Typically, a few features have high importance, but many have low importance (right-skewed distribution). This report proposes a numerically precise method to address this skewed feature importance distribution in order to reduce a feature set to the informative minimum of items. Computed ABC analysis (cABC) is an item categorization method that aims to identify the most important items by partitioning a set of non-negative numerical items into subsets "A", "B", and "C" such that subset "A" contains the "few important" items based on specific properties of ABC curves defined by their relationship to Lorenz curves. In its recursive form, the cABC analysis can be applied again to subset "A". A generic image dataset and three biomedical datasets (lipidomics and two genomics datasets) with a large number of variables were used to perform the experiments. The experimental results show that the recursive cABC analysis limits the dimensions of the data projection to a minimum where the relevant information is still preserved and directs the feature selection in machine learning to the most important class-relevant information, including filtering feature sets for nonsense variables. Feature sets were reduced to 10% or less of the original variables and still provided accurate classification in data not used for feature selection. cABC analysis, in its recursive variant, provides a computationally precise means of reducing information to a minimum. The minimum is the result of a computation of the number of k most relevant items, rather than a decision to select the k best items from a list. In addition, there are precise criteria for stopping the reduction process. The reduction to the most important features can improve the human understanding of the properties of the data set. The cABC method is implemented in the Python package "cABCanalysis" available at https://pypi.org/project/cABCanalysis/.
Comparative values are essential for the classification of orthopedic abnormalities and the assessment of a necessary therapy. At present, reference values for the upper body posture for healthy, male adults exist for the age groups of 18–35, 31–40 and 41–50 years. However, corresponding data on the decade of 51 to 60 year-old healthy men are still lacking. 23 parameters of the upper body posture were analyzed in 102 healthy male participants aged 51–60 (55.36 ± 2.78) years. The average height was 180.76 ± 7.81 cm with a weight of 88.22 ± 14.57 kg. The calculated BMI was 26.96 ± 3.92 kg/m2. In the habitual, upright position, the bare upper body was scanned three-dimensionally using video raster stereography. Mean or median values, confidence intervals, tolerance ranges and group comparisons, as well as correlations of BMI and physical activity, were calculated for all parameters. The spinal column parameters exhibited a good exploration of the frontal plane in the habitual standing position. In the sagittal plane, a slight, ventral inclination of the trunk with an increased kyphosis angle of the thoracic spine and increased thoracic bending angle was observed. The parameters of the pelvis showed a pronounced symmetry with deviations from the 0° axis within the measurement error margin of 1 mm/1°. The scapula height together with the scapula angles of the right and left side described a slightly elevated position of the left shoulder compared to the right side. The upper body posture is influenced by parameters of age, height, weight and BMI. Primarily there are significant correlations to measurements of trunk lengths D (age: p ≤ 0.02, rho = -0.23; height: p ≤ 0.001, rho = 0.58; weight: p ≤ 0.001, rho = 0.33), trunk lengths S (age: p ≤ 0.01, rho = -0.27; height: p ≤ 0.001, rho = 0.58; weight: p ≤ 0.001, rho = 0.32), pelvic distance (height: p ≤ 0.01, rho = 0.26; weight: p ≤ 0.001, rho = 0.32; BMI: p ≤ 0.03, rho = 0.22) and scapula distance (weight: p ≤ 0.001, rho = .32; BMI: p ≤ 0.01, rho = 0.27), but also to sagittal parameters of trunk decline (weight: p ≤ 0.001, rho = -0.29; BMI: p ≤ 0.01, rho = -0.24), thoracic bending angle (height: p ≤ 0.01, rho = 0.27) and kyphosis angle (BMI: p ≤ 0.03, rho = 0.21). The upper body posture of healthy men between the ages of 51 and 60 years was axially almost aligned and balanced. With the findings of this investigation and the reference values obtained, suitable comparative values for use in clinical practice and for further scientific studies with the same experimental set-up have been established.
Background: Diet and physical activity (PA) have a major impact on physical and mental health. However, there is a lack of effective strategies for sustaining these health-protective behaviors. A shift to a microtemporal, within-person approach is needed to capture dynamic processes underlying eating behavior and PA, as they change rapidly across minutes or hours and differ among individuals. However, a tool that captures these microtemporal, within-person processes in daily life is currently not present.
Objective: The APPetite-mobile-app is developed for the ecological momentary assessment of microtemporal, within-person processes of complex dietary intake, objectively recorded PA, and related factors. This study aims to evaluate the feasibility and usability of the APPetite-mobile-app and the validity of the incorporated APPetite-food record.
Methods: The APPetite-mobile-app captures dietary intake event-contingently through a food record, captures PA continuously through accelerometers, and captures related factors (eg, stress) signal-contingently through 8 prompts per day. Empirical data on feasibility (n=157), usability (n=84), and validity (n=44) were collected within the Eat2beNICE-APPetite-study. Feasibility and usability were examined in healthy participants and psychiatric patients. The relative validity of the APPetite-food record was assessed with a subgroup of healthy participants by using a counterbalanced crossover design. The reference method was a 24-hour recall. In addition, the energy intake was compared with the total energy expenditure estimated from accelerometry.
Results: Good feasibility, with compliance rates above 80% for prompts and the accelerometer, as well as reasonable average response and recording durations (prompt: 2.04 min; food record per day: 17.66 min) and latencies (prompts: 3.16 min; food record: 58.35 min) were found. Usability was rated as moderate, with a score of 61.9 of 100 on the System Usability Scale. The evaluation of validity identified large differences in energy and macronutrient intake between the two methods at the group and individual levels. The APPetite-food record captured higher dietary intakes, indicating a lower level of underreporting, compared with the 24-hour recall. Energy intake was assessed fairly accurately by the APPetite-food record at the group level on 2 of 3 days when compared with total energy expenditure. The comparison with mean total energy expenditure (2417.8 kcal, SD 410) showed that the 24-hour recall (1909.2 kcal, SD 478.8) underestimated habitual energy intake to a larger degree than the APPetite-food record (2146.4 kcal, SD 574.5).
Conclusions: The APPetite-mobile-app is a promising tool for capturing microtemporal, within-person processes of diet, PA, and related factors in real time or near real time and is, to the best of our knowledge, the first of its kind. First evidence supports the good feasibility and moderate usability of the APPetite-mobile-app and the validity of the APPetite-food record. Future findings in this context will build the foundation for the development of personalized lifestyle modification interventions, such as just-in-time adaptive interventions.
Background: Acute bleeding requires fast and targeted therapy. Therefore, knowledge of the patient's potential to form a clot is crucial. Point-of-care testing (POCT) provides fast and reliable information on coagulation. Structural circumstances, such as person-bound sample transport, can prolong the reporting of the results. The aim of the present study was to investigate the diagnostic quality and accuracy between POCT INR diagnostics and standard laboratory analysis (SLA) as well as the time advantage between a pneumatic tube and a personal-based transport system. Methods: Two groups of haemorrhagic patients (EG: emergency department; OG: delivery room; each n = 12) were examined in the context of bleeding emergencies using POCT and SLA. Samples were transported via a pneumatic tube system or by a personal transport service. Results: INR results between POCT and SLA showed a high and significant correlation (EG: p < 0.001; OG: p < 0.001). POCT results were reported significantly more quickly (EG: 1.1 vs. 39.6 min; OG: 2.0 vs. 75.0 min; p < 0.001) and required less time for analysis (EG: 0.3 vs. 24.0 min; OG: 0.5 vs. 45.0 min; p < 0.001) compared to SLA. The time for transportation with the pneumatic tube was significantly shorter (8.0 vs. 18.5 min; p < 0.001) than with the personal-based transport system. Conclusion: The results of the present study suggest that POCT may be a suitable method for the emergency diagnosis and may be used as prognostic diagnostic elements in haemotherapy algorithms to initiate targeted haemotherapy at an early point in time.
Molecular surveillance of carbapenem-resistant gram-negative bacteria in liver transplant candidates
(2021)
Background: Carbapenem-resistant Gram-negative bacteria (CRGN) cause life-threatening infections due to limited antimicrobial treatment options. The occurrence of CRGN is often linked to hospitalization and antimicrobial treatment but remains incompletely understood. CRGN are common in patients with severe illness (e.g., liver transplantation patients). Using whole-genome sequencing (WGS), we aimed to elucidate the evolution of CRGN in this vulnerable cohort and to reconstruct potential transmission routes.
Methods: From 351 patients evaluated for liver transplantation, 18 CRGN isolates (from 17 patients) were analyzed. Using WGS and bioinformatic analysis, genotypes and phylogenetic relationships were explored. Potential epidemiological links were assessed by analysis of patient charts.
Results: Carbapenem-resistant (CR) Klebsiella pneumoniae (n=9) and CR Pseudomonas aeruginosa (n=7) were the predominating pathogens. In silico analysis revealed that 14/18 CRGN did not harbor carbapenemase-coding genes, whereas in 4/18 CRGN, carbapenemases (VIM-1, VIM-2, OXA-232, and OXA-72) were detected. Among all isolates, there was no evidence of plasmid transfer-mediated carbapenem resistance. A close phylogenetic relatedness was found for three K. pneumoniae isolates. Although no epidemiological context was comprehensible for the CRGN isolates, evidence was found that the isolates resulted of a transmission of a carbapenem-susceptible ancestor before individual radiation into CRGN.
Conclusion: The integrative epidemiological study reveals a high diversity of CRGN in liver cirrhosis patients. Mutation of carbapenem-susceptible ancestors appears to be the dominant way of CR acquisition rather than in-hospital transmission of CRGN or carbapenemase-encoding genetic elements. This study underlines the need to avoid transmission of carbapenem-susceptible ancestors in vulnerable patient cohorts.
Childbirth-related post-traumatic stress disorder (CB-PTSD) occurs in 3–7% of all pregnancies and about 35% of women after preterm birth (PTB) meet the criteria for acute stress reaction. Known risk factors are trait anxiety and pain intensity, whereas planned delivery mode, medical support, and positive childbirth experience are protective factors. It has not yet been investigated whether the effects of anxiety and delivery mode are mediated by other factors, and whether a PTB-risk alters these relationships. 284 women were investigated antepartum and six weeks postpartum (risk-group with preterm birth (RG-PB) N = 95, risk-group with term birth (RG-TB) N = 99, and control group (CG) N = 90). CB-PTSD symptoms and anxiety were measured using standardized psychological questionnaires. Pain intensity, medical support, and childbirth experience were assessed by single items. Delivery modes were subdivided into planned vs. unplanned delivery modes. Group differences were examined using MANOVA. To examine direct and indirect effects on CB-PTSD symptoms, a multi-sample path analysis was performed. Rates of PTS were highest in the RG-PB = 11.58% (RG-TB = 7.01%, CG = 1.1%). MANOVA revealed higher values of CB-PTSD symptoms and pain intensity in RG-PB compared to RG-TB and CG. Women with planned delivery mode reported a more positive birth experience. Path modeling revealed a good model fit. Explained variance was highest in RG-PB (R2 = 44.7%). Direct enhancing effects of trait anxiety and indirect reducing effects of planned delivery mode on CB-PTSD symptoms were observed in all groups. In both risk groups, CB-PTSD symptoms were indirectly reduced via support by medical staff and positive childbirth experience, while trait anxiety indirectly enhanced CB-PTSD symptoms via pain intensity in the CG. Especially in the RG-PB, a positive birth experience serves as protective factor against CB-PTSD symptoms. Therefore, our data highlights the importance of involving patients in the decision process even under stressful birth conditions and the need for psychological support antepartum, mainly in patients with PTB-risk and anxious traits.
Introduction: Cesarean section (CS) rates are increasing worldwide. One constant indication is the breech presentation at term. By offering external cephalic version (ECV) and vaginal breech delivery CS rates can be further reduced. Objective: This study aimed to analyze the ECV at 38 weeks of gestation with the associate uptake rate, predicting factors, success rate, and complications at a tertiary healthcare provider in Germany specializing in vaginal breech delivery. Methods: We conducted a prospective cohort study with retrospective data acquisition. All women with a singleton fetus in breech presentation presenting after 34 weeks of gestation for counseling between 2013 and 2017 were included. ECV impact factors were analyzed using logistic regression. Results: A total of 1,598 women presented for breech birth planning. ECV was performed on 353 patients. The overall success rate was 22.4%. A later week of gestation (odds ratio [OR] 1.69), an abundant amniotic fluid index (AFI score) (OR 5.74), fundal (OR 3.78) and anterior (OR 0.39) placental location, and an oblique lie (OR 9.08) were significantly associated with successful ECV in our population. No major complications were observed. The overall vaginal delivery rates could be increased to approximately 14% with ECV. Conclusion: The demand for alternative birth modes other than CS for breech birth is high in the area of Frankfurt, Germany. Our study offers evidence of the safety of ECV at 38 weeks. Centers with expertise in vaginal breech delivery and ECV can reduce CS-rates. To further establish vaginal breech delivery and ECV as alternate options, the required knowledge and skill should be implemented in the revised curricula.
Background: Pathogenesis of portal hypertension is multifactorial and includes pathologic intrahepatic angiogenesis, whereby TIPS insertion is an effective therapy of portal hypertension associated complications. While angiogenin is a potent contributor to angiogenesis in general, little is known about its impact on TIPS function over time. Methods: In a total of 118 samples from 47 patients, angiogenin concentrations were measured in portal and inferior caval vein plasma at TIPS insertion (each blood compartment n = 23) or angiographic intervention after TIPS (each blood compartment n = 36) and its relationship with patient outcome was investigated. Results: Angiogenin levels in the inferior caval vein were significantly higher compared to the portal vein (P = 0.048). Ten to 14 days after TIPS, inferior caval vein angiogenin level correlated inversely with the portal systemic pressure gradient (P<0.001), measured invasively during control angiography. Moreover, patients with TIPS revision during this angiography, showed significantly lower angiogenin level in the inferior caval vein compared to patients without TIPS dysfunction (P = 0.01). Conclusion: In cirrhosis patients with complications of severe portal hypertension, circulating levels of angiogenin are derived from the injured liver. Moreover, angiogenin levels in the inferior caval vein after TIPS may predict TIPS dysfunction.
Introduction: Clinically complex patients often require multiple medications. Polypharmacy is associated with inappropriate prescriptions, which may lead to negative outcomes. Few effective tools are available to help physicians optimise patient medication. This study assesses whether an electronic medication management support system (eMMa) reduces hospitalisation and mortality and improves prescription quality/safety in patients with polypharmacy. Methods and analysis: Planned design: pragmatic, parallel cluster-randomised controlled trial; general practices as randomisation unit; patients as analysis unit. As practice recruitment was poor, we included additional data to our primary endpoint analysis for practices and quarters from October 2017 to March 2021. Since randomisation was performed in waves, final study design corresponds to a stepped-wedge design with open cohort and step-length of one quarter. Scope: general practices, Westphalia-Lippe (Germany), caring for BARMER health fund-covered patients. Population: patients (≥18 years) with polypharmacy (≥5 prescriptions). Sample size: initially, 32 patients from each of 539 practices were required for each study arm (17 200 patients/arm), but only 688 practices were randomised after 2 years of recruitment. Design change ensures that 80% power is nonetheless achieved. Intervention: complex intervention eMMa. Follow-up: at least five quarters/cluster (practice). recruitment: practices recruited/randomised at different times; after follow-up, control group practices may access eMMa. Outcomes: primary endpoint is all-cause mortality and hospitalisation; secondary endpoints are number of potentially inappropriate medications, cause-specific hospitalisation preceded by high-risk prescribing and medication underuse. Statistical analysis: primary and secondary outcomes are measured quarterly at patient level. A generalised linear mixed-effect model and repeated patient measurements are used to consider patient clusters within practices. Time and intervention group are considered fixed factors; variation between practices and patients is fitted as random effects. Intention-to-treat principle is used to analyse primary and key secondary endpoints.
DNA methylation-based prediction of response to immune checkpoint inhibition in metastatic melanoma
(2021)
Background: Therapies based on targeting immune checkpoints have revolutionized the treatment of metastatic melanoma in recent years. Still, biomarkers predicting long-term therapy responses are lacking. Methods: A novel approach of reference-free deconvolution of large-scale DNA methylation data enabled us to develop a machine learning classifier based on CpG sites, specific for latent methylation components (LMC), that allowed for patient allocation to prognostic clusters. DNA methylation data were processed using reference-free analyses (MeDeCom) and reference-based computational tumor deconvolution (MethylCIBERSORT, LUMP). Results: We provide evidence that DNA methylation signatures of tumor tissue from cutaneous metastases are predictive for therapy response to immune checkpoint inhibition in patients with stage IV metastatic melanoma. Conclusions: These results demonstrate that LMC-based segregation of large-scale DNA methylation data is a promising tool for classifier development and treatment response estimation in cancer patients under targeted immunotherapy.
Cancer stem cells (CSCs) are nowadays one of the major focuses in tumor research since this subpopulation was revealed to be a great obstacle for successful treatment. The identification of CSCs in pediatric solid tumors harbors major challenges because of the immature character of these tumors. Here, we present CD34, CD90, OV-6 and cell-surface vimentin (csVimentin) as reliable markers to identify CSCs in hepatoblastoma cell lines. We were able to identify CSC characteristics for the subset of CD34+CD90+OV-6+csVimentin+-co-expressing cells, such as pluripotency, self-renewal, increased expression of EMT markers and migration. Treatment with Cisplatin as the standard chemotherapeutic drug in hepatoblastoma therapy further revealed the chemo-resistance of this subset, which is a main characteristic of CSCs. When we treated the cells with the Hsp90 inhibitor 17-AAG, we observed a significant reduction in the CSC subset. With our study, we identified CSCs of hepatoblastoma using CD34, CD90, OV-6 and csVimentin. This set of markers could be helpful to estimate the success of novel therapeutic approaches, as resistant CSCs are responsible for tumor relapses.
Rodent models of Parkinson’s disease are based on transgenic expression of mutant synuclein, deletion of PD genes, injections of MPTP or rotenone, or seeding of synuclein fibrils. The models show histopathologic features of PD such as Lewi bodies but mostly only subtle in vivo manifestations or systemic toxicity. The models only partly mimic a predominant loss of dopaminergic neurons in the substantia nigra. We therefore generated mice that express the transgenic diphtheria toxin receptor (DTR) specifically in DA neurons by crossing DAT-Cre mice with Rosa26 loxP-STOP-loxP DTR mice. After defining a well-tolerated DTx dose, DAT-DTR and DTR-flfl controls were subjected to non-toxic DTx treatment (5 × 100 pg/g) and subsequent histology and behavioral tests. DAT protein levels were reduced in the midbrain, and tyrosine hydroxylase-positive neurons were reduced in the substantia nigra, whereas the pan-neuronal marker NeuN was not affected. Despite the promising histologic results, there was no difference in motor function tests or open field behavior. These are tests in which double mutant Pink1−/−SNCAA53T Parkinson mice show behavioral abnormalities. Higher doses of DTx were toxic in both groups. The data suggest that DTx treatment in mice with Cre/loxP-driven DAT-DTR expression leads to partial ablation of DA-neurons but without PD-reminiscent behavioral correlates.
Gaining detailed knowledge about sex-related immunoregulation remains a crucial prerequisite for the development of adequate disease models and therapeutic strategies enabling personalized medicine. Here, the key parameter of the production of cytokines mediating disease resolution was investigated. Among these cytokines, STAT3-activating interleukin (IL)-22 is principally associated with recovery from tissue injury. By investigating paradigmatic acetaminophen-induced liver injury, we demonstrated that IL-22 expression is enhanced in female mice. Increased female IL-22 was confirmed at a cellular level using murine splenocytes stimulated by lipopolysaccharide or αCD3/CD28 to model innate or adaptive immunoactivation. Interestingly, testosterone or dihydrotestosterone reduced IL-22 production by female but not by male splenocytes. Mechanistic studies on PMA/PHA-stimulated T-cell-lymphoma EL-4 cells verified the capability of testosterone/dihydrotestosterone to reduce IL-22 production. Moreover, we demonstrated by chromatin immunoprecipitation that testosterone impairs binding of the aryl hydrocarbon receptor to xenobiotic responsive elements within the murine IL-22 promoter. Overall, female mice undergoing acute liver injury and cultured female splenocytes upon inflammatory activation display increased IL-22. This observation is likely related to the immunosuppressive effects of androgens in males. The data presented concur with more pronounced immunological alertness demonstrable in females, which may relate to the sex-specific course of some immunological disorders.
A high incidence of thromboembolic events associated with high mortality has been reported in severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infections with respiratory failure. The present study characterized post-transcriptional gene regulation by global microRNA (miRNA) expression in relation to activated coagulation and inflammation in 21 critically ill SARS-CoV-2 patients. The cohort consisted of patients with moderate respiratory failure (n = 11) and severe respiratory failure (n = 10) at an acute stage (day 0–3) and in the later course of the disease (>7 days). All patients needed supplemental oxygen and severe patients were defined by the requirement of positive pressure ventilation (intubation). Levels of D-dimers, activated partial thromboplastin time (aPTT), C-reactive protein (CRP), and interleukin (IL)-6 were significantly higher in patients with severe compared with moderate respiratory failure. Concurrently, next generation sequencing (NGS) analysis demonstrated increased dysregulation of miRNA expression with progression of disease severity connected to extreme downregulation of miR-320a, miR-320b and miR-320c. Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed involvement in the Hippo signaling pathway, the transforming growth factor (TGF)-β signaling pathway and in the regulation of adherens junctions. The expression of all miR-320 family members was significantly correlated with CRP, IL-6, and D-dimer levels. In conclusion, our analysis underlines the importance of thromboembolic processes in patients with respiratory failure and emphasizes miRNA-320s as potential biomarkers for severe progressive SARS-CoV-2 infection.
Selfish genetic elements that act as post-segregation distorters cause lethality in non-carrier individuals after fertilization. Two post-segregation distorters have been previously identified in Caenorhabditis elegans, the peel-1/zeel-1 and the sup-35/pha-1 elements. These elements seem to act as modification-rescue systems, also called toxin/antidote pairs. Here we show that the maternal-effect toxin/zygotic antidote pair sup-35/pha-1 is required for proper expression of apical junction (AJ) components in epithelia and that sup-35 toxicity increases when pathways that establish and maintain basal epithelial characteristics, die-1, elt-1, lin-26, and vab-10, are compromised. We demonstrate that pha-1(e2123) embryos, which lack the antidote, are defective in epidermal morphogenesis and frequently fail to elongate. Moreover, seam cells are frequently misshaped and mispositioned and cell bond tension is reduced in pha-1(e2123) embryos, suggesting altered tissue material properties in the epidermis. Several aspects of this phenotype can also be induced in wild-type embryos by exerting mechanical stress through uniaxial loading. Seam cell shape, tissue mechanics, and elongation can be restored in pha-1(e2123) embryos if expression of the AJ molecule DLG-1/Discs large is reduced. Thus, our experiments suggest that maternal-effect toxicity disrupts proper development of the epidermis which involves distinct transcriptional regulators and AJ components.
Background: This study aims to test the effect of the 10 most common nonurological primary cancers (skin, rectal, colon, lymphoma, leukemia, pancreas, stomach, esophagus, liver, lung) on overall mortality (OM) after secondary prostate cancer (PCa). Material and Methods: Within the Surveillance, Epidemiology, and End Results (SEER) database, patients with 10 most common primary cancers and concomitant secondary PCa (diagnosed 2004–2016) were identified and were matched in 1:4 fashion (age, year at diagnosis, race/ethnicity, treatment type, TNM stage) with primary PCa controls. OM was compared between secondary and primary PCa patients and was stratified according to primary cancer type, as well as according to time interval between primary cancer vs. secondary PCa diagnoses. Results: We identified 24,848 secondary PCa patients (skin, n = 3,871; rectal, n = 798; colon, n = 3,665; lymphoma, n = 2,583; leukemia, n = 1,102; pancreatic, n = 118; stomach, n = 361; esophagus, n = 219; liver, n = 160; lung, n = 1,328) vs. 531,732 primary PCa patients. Secondary PCa characteristics were less favorable than those of primary PCa patients (PSA and grade), and smaller proportions of secondary PCa patients received active treatment. After 1:4 matching, all secondary PCa exhibited worse OM than primary PCa patients. Finally, subgroup analyses showed that the survival disadvantage of secondary PCa patients decreased with longer time interval since primary cancer diagnosis and subsequent secondary PCa. Conclusion: Patients with secondary PCa are diagnosed with less favorable PSA and grade. Even after matching for PCa characteristics, secondary PCa patients still exhibit worse survival. However, the survival disadvantage is attenuated, when secondary PCa diagnosis is made after longer time interval, since primary cancer diagnosis.
Preeclampsia (PE), a gestational hypertensive disease originating from the placenta, is characterized by an imbalance of various cellular processes. The cell cycle regulator p21Cip1/CDKN1A (p21) and its family members p27 and p57 regulate signaling pathways fundamental to placental development. The aim of the present study was to enlighten the individual roles of these cell cycle regulators in placental development and their molecular involvement in the pathogenesis of PE. The expression and localization of p21, phospho-p21 (Thr-145), p27, and p57 was immunohistochemically analyzed in placental tissues from patients with early-onset PE, early-onset PE complicated by the HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome as well as late-onset PE compared to their corresponding control tissues from well-matched women undergoing caesarean sections. The gene level was evaluated using real-time quantitative PCR. We demonstrate that the delivery mode strongly influenced placental gene expression, especially for CDKN1A (p21) and CDKN1B (p27), which were significantly upregulated in response to labor. Cell cycle regulators were highly expressed in first trimester placentas and impacted by hypoxic conditions. In support of these observations, p21 protein was abundant in trophoblast organoids and hypoxia reduced its gene expression. Microarray analysis of the trophoblastic BeWo cell line depleted of p21 revealed various interesting candidate genes and signaling pathways for the fusion process. The level of p21 was reduced in fusing cytotrophoblasts in early-onset PE placentas and depletion of p21 led to reduced expression of fusion-related genes such as syncytin-2 and human chorionic gonadotropin (β-hCG), which adversely affected the fusion capability of trophoblastic cells. These data highlight that cell cycle regulators are important for the development of the placenta. Interfering with p21 influences multiple pathways related to the pathogenesis of PE.
Although anti-cancer properties of the natural compound curcumin have been reported, low absorption and rapid metabolisation limit clinical use. The present study investigated whether irradiation with visible light may enhance the inhibitory effects of low-dosed curcumin on prostate cancer cell growth, proliferation, and metastasis in vitro. DU145 and PC3 cells were incubated with low-dosed curcumin (0.1–0.4 µg/mL) and subsequently irradiated with 1.65 J/cm2 visible light for 5 min. Controls remained untreated and/or non-irradiated. Cell growth, proliferation, apoptosis, adhesion, and chemotaxis were evaluated, as was cell cycle regulating protein expression (CDK, Cyclins), and integrins of the α- and β-family. Curcumin or light alone did not cause any significant effects on tumor growth, proliferation, or metastasis. However, curcumin combined with light irradiation significantly suppressed tumor growth, adhesion, and migration. Phosphorylation of CDK1 decreased and expression of the counter-receptors cyclin A and B was diminished. Integrin α and β subtypes were also reduced, compared to controls. Irradiation distinctly enhances the anti-tumor potential of curcumin in vitro and may hold promise in treating prostate cancer.
Background: Dentists (Ds) and dental assistants (DAs) have a high lifetime prevalence of musculoskeletal disorders (MSDs). In this context, it is assumed that they have an increased intake of substances such as pain medication. Currently, there exist no data on the use of medication among Ds and DAs with MSDs in Germany. Methods: The online questionnaire (i.e., the Nordic Questionnaire) analysed the medical therapies used by 389 Ds (240 f/149 m) and 406 DAs (401 f/5 m) to treat their MSDs. Results: Ds (28.3–11.5%) and DAs (29.4–10.3%) with MSDs took medication depending on the affected body region. A trend between the Ds and DAs in the intake of drug therapy and the frequency was found for the neck region (Ds: 21.1%, DAs: 28.7%). A single medication was taken most frequently (Ds: 60.0–33.3%, DAs: 71.4–27.3%). The frequency of use varied greatly for both occupational groups depending on the region affected. Conclusion: Ds and DAs perceived the need for medical therapies because of their MSDs. Painkillers such as ibuprofen and systemic diclofenac were the medications most frequently taken by both occupational groups. The intake of pain killers, most notably for the neck, should prevent sick leave.
The capacity of convalescent and vaccine-elicited sera and monoclonal antibodies (mAb) to neutralize SARS-CoV-2 variants is currently of high relevance to assess the protection against infections. We performed a cell culture-based neutralization assay focusing on authentic SARS-CoV-2 variants B.1.617.1 (Kappa), B.1.617.2 (Delta), B.1.427/B.1.429 (Epsilon), all harboring the spike substitution L452R. We found that authentic SARS-CoV-2 variants harboring L452R had reduced susceptibility to convalescent and vaccine-elicited sera and mAbs. Compared to B.1, Kappa and Delta showed a reduced neutralization by convalescent sera by a factor of 8.00 and 5.33, respectively, which constitutes a 2-fold greater reduction when compared to Epsilon. BNT2b2 and mRNA1273 vaccine-elicited sera were less effective against Kappa, Delta, and Epsilon compared to B.1. No difference was observed between Kappa and Delta towards vaccine-elicited sera, whereas convalescent sera were 1.51-fold less effective against Delta, respectively. Both B.1.617 variants Kappa (+E484Q) and Delta (+T478K) were less susceptible to either casirivimab or imdevimab. In conclusion, in contrast to the parallel circulating Kappa variant, the neutralization efficiency of convalescent and vaccine-elicited sera against Delta was moderately reduced. Delta was resistant to imdevimab, which, however, might be circumvented by combination therapy with casirivimab together.
Background: Inflammation is essential for the pathogenesis of multiple sclerosis (MS). While the immune system contribution to the development of neurological symptoms has been intensively studied, inflammatory biomarkers for mental symptoms such as depression are poorly understood in the context of MS. Here, we test if depression correlates with peripheral and central inflammation markers in MS patients as soon as the diagnosis is established. Methods: Forty-four patients were newly diagnosed with relapsing-remitting MS, primary progressive MS or clinically isolated syndrome. Age, gender, EDSS, C-reactive protein (CRP), albumin, white blood cells count in cerebrospinal fluid (CSF WBC), presence of gadolinium enhanced lesions (GE) on T1-weighted images and total number of typical MS lesion locations were included in linear regression models to predict Beck Depression Inventory (BDI) score and the depression dimension of the Symptoms Checklist 90-Revised (SCL90RD). Results: CRP elevation and GE predicted significantly BDI (CRP: p = 0.007; GE: p = 0.019) and SCL90RD (CRP: p = 0.004; GE: p = 0.049). The combination of both factors resulted in more pronounced depressive symptoms (p = 0.04). CSF WBC and EDSS as well as the other variables were not correlated with depressive symptoms. Conclusions: CRP elevation and GE are associated with depressive symptoms in newly diagnosed MS patients. These markers can be used to identify MS patients exhibiting a high risk for the development of depressive symptoms in early phases of the disease.
Genes encoding endocannabinoid and sphingolipid metabolism pathways were suggested to contribute to the genetic risk towards attention deficit hyperactivity disorder (ADHD). The present pilot study assessed plasma concentrations of candidate endocannabinoids, sphingolipids and ceramides in individuals with adult ADHD in comparison with healthy controls and patients with affective disorders. Targeted lipid analyses of 23 different lipid species were performed in 71 mental disorder patients and 98 healthy controls (HC). The patients were diagnosed with adult ADHD (n = 12), affective disorder (major depression, MD n = 16 or bipolar disorder, BD n = 6) or adult ADHD with comorbid affective disorders (n = 37). Canonical discriminant analysis and CHAID analyses were used to identify major components that predicted the diagnostic group. ADHD patients had increased plasma concentrations of sphingosine-1-phosphate (S1P d18:1) and sphinganine-1-phosphate (S1P d18:0). In addition, the endocannabinoids, anandamide (AEA) and arachidonoylglycerol were increased. MD/BD patients had increased long chain ceramides, most prominently Cer22:0, but low endocannabinoids in contrast to ADHD patients. Patients with ADHD and comorbid affective disorders displayed increased S1P d18:1 and increased Cer22:0, but the individual lipid levels were lower than in the non-comorbid disorders. Sphingolipid profiles differ between patients suffering from ADHD and affective disorders, with overlapping patterns in comorbid patients. The S1P d18:1 to Cer22:0 ratio may constitute a diagnostic or prognostic tool.
Study design: Systematic review. Background and objectives: Preoperative neuromuscular function is predictive for knee function and return to sports (RTS) after reconstruction of the anterior cruciate ligament (ACL). The aim of this review was to examine the potential benefits of prehabilitation on pre-/postoperative objective, self-reported and RTS-specific outcomes. Methods: A systematic search was conducted within three databases. From the 1.071 studies screened, two randomized control trials (RCTs), two control trials (CTs) and two cohort studies (CS) met the inclusion criteria. Methodological quality rating adopted the PEDro- (RCT, CT) or Newcastle-Ottawa-Scale (CS). Results and conclusions: Methodological quality of the included studies was moderate (PEDro score: 6.5 ± 1.7; range 4 to 9). Two studies reported higher increases of the maximal quadriceps torque from baseline to pre-reconstruction: one study in the limb symmetry index (LSI), and one in both legs of the prehabilitation group compared to the controls. At 12-weeks post-reconstruction, one study (from two) indicated that the prehabilitation group had a lesser post-operative decline in the single-leg-hop for distance LSI (clinically meaningful). Similar findings were found in terms of quadriceps strength LSI (one study). At both pre-reconstruction (three studies) and two-year post-surgery (two studies), the prehabilitation groups reached significantly higher self-reported knee function (clinically meaningful) than the controls. RTS tended to be faster (one study). At two years post-surgery, RTS rates (one study) were higher in the prehabilitation groups. The results provide evidence for the relevance of prehabilitation prior to ACL-reconstruction to improve neuromuscular and self-reported knee function as well as RTS. More high quality confirmatory RCTs are warranted.
Class I and II histone deacetylases (HDAC) are considered important regulators of immunity and inflammation. Modulation of HDAC expression and activity is associated with altered inflammatory responses but reports are controversial and the specific impact of single HDACs is not clear. We examined class I and II HDACs in TLR-4 signaling pathways in murine macrophages with a focus on IκB kinase epsilon (IKKε) which has not been investigated in this context before. Therefore, we applied the pan-HDAC inhibitors (HDACi) trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) as well as HDAC-specific siRNA. Administration of HDACi reduced HDAC activity and decreased expression of IKKε although its acetylation was increased. Other pro-inflammatory genes (IL-1β, iNOS, TNFα) also decreased while COX-2 expression increased. HDAC 2, 3 and 4, respectively, might be involved in IKKε and iNOS downregulation with potential participation of NF-κB transcription factor inhibition. Suppression of HDAC 1–3, activation of NF-κB and RNA stabilization mechanisms might contribute to increased COX-2 expression. In conclusion, our results indicate that TSA and SAHA exert a number of histone- and HDAC-independent functions. Furthermore, the data show that different HDAC enzymes fulfill different functions in macrophages and might lead to both pro- and anti-inflammatory effects which have to be considered in therapeutic approaches.
Objectives: The ongoing coronavirus pandemic is challenging, especially in severely affected patients who require intubation and sedation. Although the potential benefits of sedation with volatile anesthetics in coronavirus disease 2019 patients are currently being discussed, the use of isoflurane in patients with coronavirus disease 2019–induced acute respiratory distress syndrome has not yet been reported. Design: We performed a retrospective analysis of critically ill patients with hypoxemic respiratory failure requiring mechanical ventilation. Setting: The study was conducted with patients admitted between April 4 and May 15, 2020 to our ICU. Patients: We included five patients who were previously diagnosed with severe acute respiratory syndrome coronavirus 2 infection. Intervention: Even with high doses of several IV sedatives, the targeted level of sedation could not be achieved. Therefore, the sedation regimen was switched to inhalational isoflurane. Clinical data were recorded using a patient data management system. We recorded demographical data, laboratory results, ventilation variables, sedative dosages, sedation level, prone positioning, duration of volatile sedation and outcomes. Measurements & Main Results: Mean age (four men, one women) was 53.0 (± 12.7) years. The mean duration of isoflurane sedation was 103.2 (± 66.2) hours. Our data demonstrate a substantial improvement in the oxygenation ratio when using isoflurane sedation. Deep sedation as assessed by the Richmond Agitation and Sedation Scale was rapidly and closely controlled in all patients, and the subsequent discontinuation of IV sedation was possible within the first 30 minutes. No adverse events were detected. Conclusions: Our findings demonstrate the feasibility of isoflurane sedation in five patients suffering from severe coronavirus disease 2019 infection. Volatile isoflurane was able to achieve the required deep sedation and reduced the need for IV sedation.
Introduction Disseminated infection due to non-tuberculous mycobacteria has been a major factor of mortality and comorbidity in HIV patients. Until 2018, U.S. American guidelines have recommended antimycobacterial prophylaxis in patients with low CD4 cell counts, a practice that has not been adopted in Europe. This study aimed at examining the impact of disseminated NTM disease on clinical outcome in German HIV patients with a severe immunodeficiency. Materials and methods In this retrospective case control study, HIV patients with disseminated NTM disease were identified by retrospective chart review and matched by their CD4 cell counts to HIV patients without NTM infection in a 1:1 alocation. Primary endpoints were mortality and time to first rehospitalisation. In addition, other opportunistic diseases, as well as antimycobacterial and antiretroviral treatments were examined. Results Between 2006 and 2016, we identified 37 HIV patients with disseminated NTM disease. Most of them were suffering from infections due to M. avium complex (n = 31, 77.5%). Time to event analysis showed a non-significant trend to higher mortality in patients with disseminated NTM disease (p = 0.24). Rehospitalisation took place significantly earlier in patients with disseminated NTM infections (median 40.5 days vs. 109 days, p<0.0001). Conclusion In this retrospective case control study, we could demonstrate that mortality is not significantly higher in HIV patients with disseminated NTM disease in the ART era, but that they require specialised medical attention in the first months following discharge.
Quantitative MRI allows to probe tissue properties by measuring relaxation times and may thus detect subtle changes in tissue composition. In this work we analyzed different relaxation times (T1, T2, T2* and T2′) and histological features in 321 samples that were acquired from 25 patients with newly diagnosed IDH wild-type glioma. Quantitative relaxation times before intravenous application of gadolinium-based contrast agent (GBCA), T1 relaxation time after GBCA as well as the relative difference between T1 relaxation times pre-to-post GBCA (T1rel) were compared with histopathologic features such as the presence of tumor cells, cell and vessel density, endogenous markers for hypoxia and cell proliferation. Image-guided stereotactic biopsy allowed for the attribution of each tissue specimen to its corresponding position in the respective relaxation time map. Compared to normal tissue, T1 and T2 relaxation times and T1rel were prolonged in samples containing tumor cells. The presence of vascular proliferates was associated with higher T1rel values. Immunopositivity for lactate dehydrogenase A (LDHA) involved slightly longer T1 relaxation times. However, low T2′ values, suggesting high amounts of deoxyhemoglobin, were found in samples with elevated vessel densities, but not in samples with increased immunopositivity for LDHA. Taken together, some of our observations were consistent with previous findings but the correlation of quantitative MRI and histologic parameters did not confirm all our pathophysiology-based assumptions.
Olfactory self-assessments have been analyzed with often negative but also positive conclusions about their usefulness as a surrogate for sensory olfactory testing. Patients with nasal polyposis have been highlighted as a well-predisposed group for reliable self-assessment. In a prospective cohort of n = 156 nasal polyposis patients, olfactory threshold, odor discrimination, and odor identification were tested using the “Sniffin’ Sticks” test battery, along with self-assessments of olfactory acuity on a numerical rating scale with seven named items or on a 10-point scale with only the extremes named. Apparent highly significant correlations in the complete cohort proved to reflect the group differences in olfactory diagnoses of anosmia (n = 65), hyposmia (n = 74), and normosmia (n = 17), more than the true correlations of self-ratings with olfactory test results, which were mostly very weak. The olfactory self-ratings correlated with a quality of life score, however, only weakly. By contrast, olfactory self-ratings proved as informative in assigning the categorical olfactory diagnosis. Using an olfactory diagnostic instrument, which consists of a mapping rule of two numerical rating scales of one’s olfactory function to the olfactory functional diagnosis based on the “Sniffin’ Sticks” clinical test battery, the diagnoses of anosmia, hyposmia, or normosmia could be derived from the self-ratings at a satisfactorily balanced accuracy of about 80%. It remains to be seen whether this approach of translating self-assessments into olfactory diagnoses of anosmia, hyposmia, and normosmia can be generalized to other clinical cohorts in which olfaction plays a role.
Throughout life, macrophages are located in every tissue of the body, where their main roles are to phagocytose cellular debris and recycle aging red blood cells. In the tissue niche, they promote homeostasis through trophic, regulatory, and repair functions by responding to internal and external stimuli. This in turn polarizes macrophages into a broad spectrum of functional activation states, also reflected in their iron-regulated gene profile. The fast adaptation to the environment in which they are located helps to maintain tissue homeostasis under physiological conditions.
In humans, alterations of circadian rhythms and autophagy are linked to metabolic, cardiovascular and neurological dysfunction. Autophagy constitutes a specific form of cell recycling in many eukaryotic cells. Aging is the principal risk factor for the development of neurodegenerative diseases. Thus, we assume that both the circadian clock and autophagy are indispensable to counteract aging. We have previously shown that the hippocampus of Per1−/−-mice exhibits a reduced autophagy and higher neuronal susceptibility to ischemic insults compared to wild type (WT). Therefore, we chose to study the link between aging and loss of clock gene Per1−/−-mice. Young and aged C3H- and Per1−/−-mice were used as models to analyze the hippocampal distribution of Aβ42, lipofuscin, presenilin, microglia, synaptophysin and doublecortin. We detected several changes in the hippocampus of aged Per1−/−-mice compared to their wild type littermates. Our results show significant alterations of microglia morphology, an increase in Aβ42 deposition, overexpression of presenilin, decrease in synaptophysin levels and massive accumulation of lipofuscin in the hippocampus of 24-month-old Per1−/−-mice, without alteration of adult neurogenesis. We suggest that the marked lipofuscin accumulation, Aβ42 deposition, and overexpression of presenilin-2 observed in our experiments may be some of the consequences of the slowed autophagy in the hippocampus of aged Per1−/−-mice. This may lead during aging to excessive accumulation of misfolded proteins which may, consequently, result in higher neuronal vulnerability.
The group of proton-sensing G-protein coupled receptors (GPCRs) consists of the four receptors GPR4, TDAG8 (GPR65), OGR1 (GPR68), and G2A (GPR132). These receptors are cellular sensors of acidification, a property that has been attributed to the presence of crucial histidine residues. However, the pH detection varies considerably among the group of proton-sensing GPCRs and ranges from pH of 5.5 to 7.8. While the proton-sensing GPCRs were initially considered to detect acidic cellular environments in the context of inflammation, recent observations have expanded our knowledge about their physiological and pathophysiological functions and many additional individual and unique features have been discovered that suggest a more differentiated role of these receptors in health and disease. It is known that all four receptors contribute to different aspects of tumor biology, cardiovascular physiology, and asthma. However, apart from their overlapping functions, they seem to have individual properties, and recent publications identify potential roles of individual GPCRs in mechanosensation, intestinal inflammation, oncoimmunological interactions, hematopoiesis, as well as inflammatory and neuropathic pain. Here, we put together the knowledge about the biological functions and structural features of the four proton-sensing GPCRs and discuss the biological role of each of the four receptors individually. We explore all currently known pharmacological modulators of the four receptors and highlight potential use. Finally, we point out knowledge gaps in the biological and pharmacological context of proton-sensing GPCRs that should be addressed by future studies.
Exogenous adenosine and its metabolite inosine exert anti-inflammatory effects in synoviocytes of osteoarthritis (OA) and rheumatoid arthritis (RA) patients. We analyzed whether these cells are able to synthesize adenosine/inosine and which adenosine receptors (ARs) contribute to anti-inflammatory effects. The functionality of synthesizing enzymes and ARs was tested using agonists/antagonists. Both OA and RA cells expressed CD39 (converts ATP to AMP), CD73 (converts AMP to adenosine), ADA (converts adenosine to inosine), ENT1/2 (adenosine transporters), all AR subtypes (A1, A2A, A2B and A3) and synthesized predominantly adenosine. The CD73 inhibitor AMPCP significantly increased IL-6 and decreased IL-10 in both cell types, while TNF only increased in RA cells. The ADA inhibitor DAA significantly reduced IL-6 and induced IL-10 in both OA and RA cells. The A2AAR agonist CGS 21680 significantly inhibited IL-6 and induced TNF and IL-10 only in RA, while the A2BAR agonist BAY 60-6583 had the same effect in both OA and RA. Taken together, OA and RA synoviocytes express the complete enzymatic machinery to synthesize adenosine/inosine; however, mainly adenosine is responsible for the anti- (IL-6 and IL-10) or pro-inflammatory (TNF) effects mediated by A2A- and A2BAR. Stimulating CD39/CD73 with simultaneous ADA blockage in addition to TNF inhibition might represent a promising therapeutic strategy.
The purpose of the study was to investigate the bacterial viability of the initial biofilm on the surface of experimental modified dental resin composites. Twenty-five healthy individuals with good oral hygiene were included in this study. In a split-mouth design, they received acrylic splints with five experimental composite resin specimens. Four of them were modified with either a novel polymeric hollow-bead delivery system or methacrylated polymerizable Irgasan (Antibacterial B), while one specimen served as an unmodified control (ST). A delivery system based on Poly-Pore® was loaded with one of the active agents: Tego® Protect 5000 (Antiadhesive A), Dimethicone (Antiadhesive B), or Irgasan (Antibacterial A). All study subjects refrained from toothbrushing during the study period. Specimens were detached from the splints after 8 h and given a live/dead staining before fluorescence microscopy. A Friedman test and a post hoc Nemenyi test were applied with a significance level at p < 0.05. In summary, all materials but Antibacterial B showed a significant antibacterial effect compared to ST. The results suggested the role of the materials’ chemistry in the dominance of cell adhesion. In conclusion, dental resin composites with Poly-Pore-loaded active agents showed antibacterial effectiveness in situ.
Sulforaphane (SFN) is a natural glucosinolate found in cruciferous vegetables that acts as a chemopreventive agent, but its mechanism of action is not clear. Due to antioxidative mechanisms being thought central in preventing cancer progression, SFN could play a role in oxidative processes. Since redox imbalance with increased levels of reactive oxygen species (ROS) is involved in the initiation and progression of bladder cancer, this mechanism might be involved when chemoresistance occurs. This review summarizes current understanding regarding the influence of SFN on ROS and ROS-related pathways and appraises a possible role of SFN in bladder cancer treatment.
Multinucleated giant cells (MNGCs) are frequently observed in the implantation areas of different biomaterials. The main aim of the present study was to analyze the long-term polarization pattern of the pro- and anti-inflammatory phenotypes of macrophages and MNGCs for 180 days to better understand their role in the success or failure of biomaterials. For this purpose, silk fibroin (SF) was implanted in a subcutaneous implantation model of Wistar rats as a model for biomaterial-induced MNGCs. A sham operation was used as a control for physiological wound healing. The expression of different inflammatory markers (proinflammatory M1: CCR-7, iNos; anti-inflammatory M2: CD-206, CD-163) and tartrate-resistant acid phosphatase (TRAP) and CD-68 were identified using immunohistochemical staining. The results showed significantly higher numbers of macrophages and MNGCs within the implantation bed of SF-expressed M1 markers, compared to M2 markers. Interestingly, the expression of proinflammatory markers was sustained over the long observation period of 180 days. By contrast, the control group showed a peak of M1 macrophages only on day 3. Thereafter, the inflammatory pattern shifted to M2 macrophages. No MNGCs were observed in the control group. To the best of our knowledge, this is study is the first to outline the persistence of pro-inflammatory MNGCs within the implantation bed of SF and to describe their long-term kinetics over 180 days. Clinically, these results are highly relevant to understand the role of biomaterial-induced MNGCs in the long term. These findings suggest that tailored physicochemical properties may be a key to avoiding extensive inflammatory reactions and achieving clinical success. Therefore, further research is needed to elucidate the correlation between proinflammatory MNGCs and the physicochemical characteristics of the implanted biomaterial.
Background and Aims. Systemic treatment with sorafenib has been the standard of care (SOC) in patients with advanced Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC) for more than a decade. TACE has been reported to allow better local tumor control in selected patients with BCLC stage C HCC. Methods. A retrospective analysis of patients with BCLC stage C HCC that were treated with sorafenib and TACE was conducted; they were compared to BCLC stage C patients treated either with TACE or sorafenib in the same period of time outside a clinical trial. Results. A total of 201 patients with BCLC stage C were identified, who were treated with either sorafenib and TACE (group A; n = 54), sorafenib (group B; n = 82) or TACE (group C; n = 65). No significant difference in baseline characteristics was observed. Time to progression was 7.0 months (95% CI: 4.3–9.7), 4.1 months (95% CI: 3.6–4.7) and 5.0 months (95% CI: 2.9–7.1) in groups A, B and C, respectively, and overall survival was 16.5 months (95% CI: 15.0–18.1), 8.4 months (95% CI: 6.0–10.8) and 10.5 months (95% CI: 7.5–13.6), respectively (group A vs. group B: p < 0.001; group A vs. group C: p = 0.0023). Adverse events of grade 3/4 occurred in 34% of patients in group A. Conclusions. Although sorafenib is a SOC in patients with BCLC stage C HCC, TACE is frequently used as an additional locoregional treatment in selected patients. This combined approach resulted in a significant overall survival benefit in selected patients, although randomized trials have not yet proven this benefit.
Introduction: Gastroesophageal reflux disease (GERD) is associated with accelerated decline in lung health in children with cystic fibrosis (CF). Thus, antireflux surgery (ARS) is offered to a selected CF cohort with refractory GERD, but outcomes remain poorly investigated. This study aimed to determine the incidence of GERD in children with CF and to evaluate complications and outcomes of ARS. Materials and Methods: A systematic literature-based search was conducted using various online databases according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The number of GERD cases in pediatric CF cohorts who underwent diagnostic investigation(s) was recorded. Data on postoperative complications and outcomes (including symptoms, lung function, and nutritional status) following ARS were analyzed. Results: Ten articles (n = 289 patients) met the defined inclusion criteria (51% male; age range, 0.5 month–36 years). The overall incidence of GERD was 46% (range, 19–81%), derived from seven studies (n = 212 patients). Four publications (n = 82 patients) reported on ARS due to uncontrolled GERD. All ARSs were Nissen fundoplication (majority with gastrostomy placement). Major postoperative complications occurred in 15 (18%) patients, two required redo-ARS. Median follow-up time was 2 years (range, 3 months–6 years); 59% showed symptom improvement, and pulmonary exacerbations and decline in lung function were reduced. Nutritional status mainly improved in milder CF cases. There were no deaths related to ARS. Conclusion: Approximately half of pediatric CF patients have GERD. Published data for children with CF are limited and heterogeneous in terms of GERD diagnosis and outcomes following ARS. However, ARS has shown to slow the deterioration of lung function in CF.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the acute respiratory disease COVID-19, which has become a global concern due to its rapid spread. The common methods to monitor and quantitate SARS-CoV-2 infectivity in cell culture are so far time-consuming and labor-intensive. Using the Sleeping Beauty transposase system, we generated a robust and versatile cellular infection model that allows SARS-CoV-2 infection experiments compatible for high-throughput and live cell imaging. The model is based on lung derived A549 cells, which show a profound interferon response and convenient cell culture characteristics. ACE2 and TMPRSS2 were introduced for constitutive expression (A549-AT). Subclones with varying levels of ACE2/TMPRSS2 were screened for optimal SARS-CoV-2 susceptibility. Furthermore, extensive evaluation demonstrated that SARS-CoV-2 infected A549-AT cells were distinguishable from mock-infected cells and already showed approximately 12 h post infection a clear signal to noise ratio in terms of cell roughness, fluorescence and a profound visible cytopathic effect. Moreover, due to the high transfection efficiency and proliferation capacity, Sleeping Beauty transposase-based overexpression cell lines with a second inducible fluorescence reporter cassette (eGFP) can be generated in a very short time, enabling the investigation of host and restriction factors in a doxycycline-inducible manner. Thus, the novel model cell line allows rapid and sensitive monitoring of SARS-CoV-2 infection and the screening for host factors essential for viral replication. HIGHLIGHTS: Sleeping Beauty transposon-based cellular system was used to generate a highly susceptible cell line for monitoring SARS-CoV-2 infection; The versatile model cell line A549-AT is suitable for rapid and sensitive high-throughput assays; Additional gene specific expression cassettes allow the screening for compounds and cellular factors limiting SARS-CoV-2 replication.
Background: dental professionals suffer frequently from musculoskeletal disorders (MSD). Dentists and dental assistants work closely with each other in a mutually dependent relationship. To date, MSD in dental assistants have only been marginally investigated and compared to their occurrence in dentists. Therefore, the aim of this study was to compare the prevalence of MSD between dentists and dental assistants by considering occupational factors, physical activity and gender. Methods: This was a cross-sectional observational study. A Germany-wide survey, using a modified version of the Nordic Questionnaire and work-related questions, was applied. In total, 2548 participants took part, of which 389 dentists (240 females and 149 males) and 322 dental assistants (320 females and 2 males) were included in the analysis. Data were collected between May 2018 and May 2019. Differences between the dentists and dental assistants were determined by using the Chi2 test for nominal and the Wilcoxon–Mann–Whitney U test for both ordinal and non-normally distributed metric data. Results: A greater number of dental assistants reported complaints than dentists in all queried body regions. Significant differences in the most affected body regions (neck, shoulders, wrist/hands, upper back, lower back and feet/ankles) were found for the lifetime prevalence, annual prevalence and weekly prevalence. Data from the occupational factors, physical activity and gender analyses revealed significant differences between dentists and dental assistants. Conclusions: Dental assistants appear to be particularly affected by MSD when compared to dentists. This circumstance can be explained only to a limited extent by differences in gender distribution and occupational habits between the occupations.
Clinical data on antifungal combination therapy are limited, in particular in the pediatric setting. We analyzed real-life data collected in two major pediatric cancer centers over a period of 4 years. Patients were identified in an observational study on children with acute leukemia and lymphoma or undergoing hematopoietic cell transplantation. Out of 438 patients, 19 patients received 21 episodes of antifungal combination therapy. Therapy was mostly started for sepsis (n = 5) or clinical deterioration with pulmonary infiltrates (n = 10), and less often for periorbital swelling with suspected mold infection (n = 2), clinical deterioration and new skin lesions, secondary antifungal prophylaxis, a persistently elevated galactomannan index, or as pre-emptive treatment (n = 1 each). Diagnostics revealed proven, probable, and possible invasive fungal disease in two, seven and four episodes, respectively. Most regimens included caspofungin (n = 19), and treatment was initiated as first line therapy in 10 episodes. The median duration was 13 days (4–46 days). Nine of the 13 patients with proven, probable, or possible invasive fungal disease survived, which was comparable to patients receiving antifungal monotherapy. Our analysis demonstrates that combination therapy has mainly been prescribed in selected immunocompromised patients with clinical deterioration due to suspected invasive fungal disease or those with sepsis, and is well tolerated. Future studies need to better characterize clinical settings in which patients may benefit from antifungal combination therapy.
Endothelial cells can acquire a mesenchymal phenotype through a process called Endothelial-to-Mesenchymal transition (EndMT). This event is found in embryonic development, but also in pathological conditions. Blood vessels lose their ability to maintain vascular homeostasis and ultimately develop atherosclerosis, pulmonary hypertension, or fibrosis. An increase in inflammatory signals causes an upregulation of EndMT transcription factors, mesenchymal markers, and a decrease in endothelial markers. In our study, we show that the induction of EndMT results in an increase in long non-coding RNA AERRIE expression. JMJD2B, a known EndMT regulator, induces AERRIE and subsequently SULF1. Silencing of AERRIE shows a partial regulation of SULF1 but showed no effect on the endothelial and mesenchymal markers. Additionally, the overexpression of AERRIE results in no significant changes in EndMT markers, suggesting that AERRIE is marginally regulating mesenchymal markers and transcription factors. This study identifies AERRIE as a novel factor in EndMT, but its mechanism of action still needs to be elucidated.
Diabetes is associated with platelet hyper-reactivity and enhanced risk of thrombosis development. Here we compared protein expression in platelets from healthy donors and diabetic patients to identify differentially expressed proteins and their possible function in platelet activation. Mass spectrometry analyses identified cyclin Y (CCNY) in platelets and its reduced expression in platelets from diabetic patients, a phenomenon that could be attributed to the increased activity of calpains. To determine the role of CCNY in platelets, mice globally lacking the protein were studied. CCNY-/- mice demonstrated lower numbers of circulating platelets but platelet responsiveness to thrombin and a thromboxane A2 analogue were comparable with that of wild-type mice, as was agonist-induced α and dense granule secretion. CCNY-deficient platelets demonstrated enhanced adhesion to fibronectin and collagen as well as an attenuated spreading and clot retraction, indicating an alteration in “outside in” integrin signalling. This phenotype was accompanied by a significant reduction in the agonist-induced tyrosine phosphorylation of β3 integrin. Taken together we have shown that CCNY is present in anucleated platelets where it is involved in the regulation of integrin-mediated outside in signalling associated with thrombin stimulation.
Background: Current literature is inconsistent regarding the risk of severe side effects using accelerated induction protocols in Hymenoptera venom immunotherapy (VIT). In addition, several data indicate the influence of purity grade of venom preparation on tolerability. We evaluated the safety and tolerability of ultra-rush and rush build-up protocols using purified and non-purified venom preparations. Methods: Retrospective single-center study of 581 VIT inductions (325 ultra-rush and 256 rush protocols) from 2005 to 2018 in 559 patients with bee and vespid venom allergy using aqueous purified (ALK SQ®) for ultra-rush protocol and aqueous non-purified (ALK Reless®) venom preparations for rush protocol. Results: Urticaria (8% vs. 3.1%, p = 0,013) and dose reductions (4.3% vs. 1.2%, p = 0,026) were significantly more frequent in the ultra-rush group. Overall rate of moderate-to-severe side effects (anaphylaxis ≥grade 2 according to Ring and Meβmer) was low and did not differ significantly between protocols (p = 0.105). Severe events (grade 4 anaphylaxis) were not reported. Discontinuation rate was very low in both cohorts (0.6% vs 1.2%). The higher purity grade of venom preparations in the ultra-rush cohort did not improve tolerability. The bee venom group showed a non-significant trend towards higher incidence of mild reactions (urticaria), resulting in more frequent dose reductions and antiallergic therapy. Conclusion: Rush and ultra-rush protocols show an excellent safety profile with only infrequent and mild anaphylactic reactions in bee and vespid venom allergy. Ultra-rush immunotherapy reduces the duration of the inpatient build-up phase setting and thus is viewed by the authors as preferred treatment in Hymenoptera venom allergic patients.
Background: Dental professionals are subjected to higher risks for musculoskeletal disorders (MSDs) than other professional groups, especially the hand region. This study aims to investigate the prevalence of hand complaints among dentists (Ds) and dental assistants (DAs) and examines applied therapies. Methods: For this purpose, an online questionnaire analysed 389 Ds (240female/149male) and 406 DAs (401female/5male) working in Germany. The self-reported data of the two occupational groups were compared with regard to the topics examined. The questionnaire was based on the Nordic Questionnaire (self-reported lifetime, 12-month and 7-day MSDs prevalence of the hand, the conducted therapy and its success), additional occupational and sociodemographic questions as well as questions about specific medical conditions. Results: 30.8% of Ds affirmed MSDs in the hand at any time in their lives, 20.3% in the last twelve months and 9.5% in the last seven days. Among DAs, 42.6% reported a prevalence of MSDs in the hand at any time in their lives, 31.8% in the last 12 months and 15.3% in the last seven days. 37.5% of the Ds and 28.3% of the DAs stated that they had certain treatments. For both, Ds and DAs, physiotherapy was the most frequently chosen form of therapy. 89.7% of Ds and 63.3% of DAs who received therapy reported an improvement of MSDs. Conclusion: Although the prevalence of MSDs on the hand is higher among DAs than among Ds, the use of therapeutic options and the success of therapy is lower for DAs compared to Ds.
This study deals with 3D laser investigation on the border between the human lymph node T-zone and germinal centre. Only a few T-cells specific for antigen selected B-cells are allowed to enter germinal centres. This selection process is guided by sinus structures, chemokine gradients and inherent motility of the lymphoid cells. We measured gaps and wall-like structures manually, using IMARIS, a 3D image software for analysis and interpretation of microscopy datasets. In this paper, we describe alpha-actin positive and semipermeable walls and wall-like structures that may hinder T-cells and other cell types from entering germinal centres. Some clearly defined holes or gaps probably regulate lymphoid traffic between T- and B-cell areas. In lymphadenitis, the morphology of this border structure is clearly defined. However, in case of malignant lymphoma, the wall-like structure is disrupted. This has been demonstrated exemplarily in case of angioimmunoblastic T-cell lymphoma. We revealed significant differences of lengths of the wall-like structures in angioimmunoblastic T-cell lymphoma in comparison with wall-like structures in reactive tissue slices. The alterations of morphological structures lead to abnormal and less controlled T- and B-cell distributions probably preventing the immune defence against tumour cells and infectious agents by dysregulating immune homeostasis.
Background: The intraoperative blood loss is estimated daily in the operating room and is mainly done by visual techniques. Due to local standards, the surgical sponge colours can vary (e.g. white in US, green in Germany). The influence of sponge colour on accuracy of estimation has not been in the focus of research yet. Material and methods: A blood loss simulation study containing four “bleeding” scenarios each per sponge colour were created by using expired whole blood donation samples. The blood donations were applied to white and green surgical sponges after dilution with full electrolyte solution. Study participants had to estimate the absorbed blood loss in sponges in all scenarios. The difference to the reference blood loss was analysed. Multivariate linear regression analysis was performed to investigate other influence factors such as staff experience and sponge colour. Results: A total of 53 anaesthesists participated in the study. Visual estimation correlated moderately with reference blood loss in white (Spearman's rho: 0.521; p = 3.748*10−16) and green sponges (Spearman's rho: 0.452; p = 4.683*10−12). The median visually estimated blood loss was higher in white sponges (250ml IRQ 150–412.5ml) than in green sponges (150ml IQR 100-300ml), compared to reference blood loss (103ml IQR 86–162.8). For both colour types of sponges, major under- and overestimation was observed. The multivariate statistics demonstrates that fabric colours have a significant influence on estimation (p = 3.04*10−10), as well as clinician’s qualification level (p = 2.20*10−10, p = 1.54*10−08) and amount of RBL to be estimated (p < 2*10−16). Conclusion: The deviation of correct blood loss estimation was smaller with white surgical sponges compared to green sponges. In general, deviations were so severe for both types of sponges, that it appears to be advisable to refrain from visually estimating blood loss whenever possible and instead to use other techniques such as e.g. colorimetric estimation.