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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.
The mammalian target of rapamycin and the integrated stress response are central cellular hubs regulating translation upon stress. The precise proteins and pathway specificity of translation targets of these pathways remained largely unclear. We recently described a new method for quantitative translation proteomics and found that both pathways control translation of the same sets of proteins.
Minimal residual disease (MRD) is the strongest predictor of relapse in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In BLAST study (NCT01207388), adults with BCP-ALL in remission with MRD after chemotherapy received blinatumomab, a CD19 BiTE® immuno-oncotherapy, 15 µg/m2/day for up to four 6-week cycles (4 weeks continuous infusion, 2 weeks off). Survival was evaluated for 110 patients, including 74 who received HSCT in continuous complete remission. With a median follow-up of 59·8 months, median survival (months) was 36·5 (95% CI: 22.0–not reached [NR]). Median survival was NR (29.5–NR) for complete MRD responders (n = 84) and 14.4 (3.8–32.3) for MRD non-responders (n = 23; p = 0.002); after blinatumomab and HSCT, median survival was NR (25.7–NR) (n = 61) and 16.5 (1.1–NR) (n = 10; p = 0.065), respectively. This final analysis suggests complete MRD response during blinatumomab treatment is curative. Post-hoc analysis of study data suggests while post blinatumomab HSCT may be beneficial in appropriate patients, long-term survival without HSCT is also possible.
Introduction: Dravet syndrome (DS), a prototypic developmental and genetic epileptic encephalopathy (DEE), is characterized by an early onset of treatment-refractory seizures, together with impairments in motor control, behavior, and cognition. Even with multiple conventional anti-epileptic drugs, seizures remain poorly controlled, and there has been a considerable unmet need for effective and tolerable treatments. Areas covered: This targeted literature review aims to highlight recent changes to the therapeutic landscape for DS by summarizing the most up-to-date, evidence-based research, including pivotal data from the clinical development of stiripentol, cannabidiol, and fenfluramine, which are important milestones for DS treatment, together with the latest findings of other pharmacotherapies in development. In phase III, double-blind, placebo-controlled randomized controlled trials stiripentol, cannabidiol, and fenfluramine have shown clinically relevant reductions in convulsive seizure frequency, and are generally well tolerated. Stiripentol was associated with responder rates (greater than 50% reduction in convulsive seizure frequency) of 67%-71%, when added to valproic acid and clobazam; cannabidiol was associated with responder rates of 43%-49% (48%-63% in conjunction with clobazam), and fenfluramine of 54%-68% across studies. Therapies in development include soticlestat, ataluren, verapamil, and clemizole, with strategies to treat the underlying cause of DS, including gene therapy and antisense oligonucleotides beginning to emerge from preclinical studies. Expert opinion: Despite the challenges of drug development in rare diseases, this is an exciting time for the treatment of DS, with the promise of new efficacious and well-tolerated therapies, which may pave the way for treatment advances in other DEEs.
Background: Misconceptions about ADHD stigmatize affected people, reduce credibility of providers, and prevent/delay treatment. To challenge misconceptions, we curated findings with strong evidence base. Methods: We reviewed studies with more than 2000 participants or meta-analyses from five or more studies or 2000 or more participants. We excluded meta-analyses that did not assess publication bias, except for meta-analyses of prevalence. For network meta-analyses we required comparison adjusted funnel plots. We excluded treatment studies with waiting-list or treatment as usual controls. From this literature, we extracted evidence-based assertions about the disorder. Results: We generated 208 empirically supported statements about ADHD. The status of the included statements as empirically supported is approved by 80 authors from 27 countries and 6 continents. The contents of the manuscript are endorsed by 366 people who have read this document and agree with its contents. Conclusions: Many findings in ADHD are supported by meta-analysis. These allow for firm statements about the nature, course, outcome causes, and treatments for disorders that are useful for reducing misconceptions and stigma.
Background: Guselkumab is an interleukin (IL)-23 pathway blocker with proven efficacy in patients with moderate-to-severe plaque psoriasis. Early intervention with guselkumab may result in changes to the clinical disease course versus later intervention. Methods: and analysis Here we present the rationale and design of a phase 3b, randomised, double-blind, multicentre study (GUIDE), comparing treatment effects of guselkumab in patients with short (≤2 years) or longer (>2 years) duration of plaque-type psoriasis, measured from first appearance of psoriatic plaques. Participants achieving skin clearance (Psoriasis Area and Severity Index (PASI)=0) by week 20 and maintaining complete clearance at week 28 visit (‘super-responders’ (SRe)) will be randomised to continue approved maintenance dosing every 8 weeks (q8w) versus an investigational maintenance dosing interval of 16 weeks (q16w) until week 68. Primary endpoint: proportion of participants in the q8w vs q16w arms with absolute PASI <3 at week 68. Participants with PASI <3 at week 68 will be withdrawn from guselkumab treatment for up to 48 weeks. Participants not achieving SRe criteria (non-SRe) will remain in the study with q8w guselkumab dosing through week 68. Additional to serum samples obtained from all patients, skin biopsies and whole-blood samples will be taken from SRe and non-SRe participants at various time points in optional substudies. Analyses include: genetics; immunophenotyping (fluorescence-activated cell sorting); gene and protein expression profiling; immunohistology. By merging clinical endpoints with mechanistic findings, this study aims to elucidate how IL-23 blockade with guselkumab can modify the disease course by altering molecular and cellular drivers that cause relapse after treatment withdrawal, particularly among SRe. Ethics and dissemination: Approval obtained from ethics committee Medical Council Hamburg, Germany (PVN5925). GUIDE is compliant with the Declaration of Helsinki. Trial registration number: Registered at ClinicalTrials.gov (NCT03818035). All primary endpoint results (prespecified analyses) will be submitted to peer-reviewed, international journals within 18 months after primary completion date.
Circulating P2X7 receptor signaling components as diagnostic biomarkers for temporal lobe epilepsy
(2021)
Circulating molecules have potential as biomarkers to support the diagnosis of epilepsy and to assist with differential diagnosis, for example, in conditions resembling epilepsy, such as in psychogenic non-epileptic seizures (PNES). The P2X7 receptor (P2X7R) is an important regulator of inflammation and mounting evidence supports its activation in the brain during epilepsy. Whether the P2X7R or P2X7R-dependent signaling molecules can be used as biomarkers of epilepsy has not been reported. P2X7R levels were analyzed by quantitative ELISA using plasma samples from controls and patients with temporal lobe epilepsy (TLE) or PNES. Moreover, blood cell P2X7R expression and P2X7R-dependent cytokine signature was measured following status epilepticus in P2X7R-EGFP reporter, wildtype, and P2X7R-knockout mice. P2X7R plasma levels were higher in TLE patients when compared with controls and patients with PNES. Plasma levels of the broad inflammatory marker protein C-Reactive protein (CRP) were similar between the three groups. Using P2X7R-EGFP reporter mice, we identified monocytes as the main blood cell type expressing P2X7R after experimentally evoked seizures. Finally, cytokine array analysis in P2X7R-deficient mice identified KC/GRO as a potential P2X7R-dependent plasma biomarker following status epilepticus and during epilepsy. Our data suggest that P2X7R signaling components may be a promising subclass of circulating biomarkers to support the diagnosis of epilepsy.
Objective: The NADPH oxidase Nox4 is an important source of H2O2. Nox4-derived H2O2 limits vascular inflammation and promotes smooth muscle differentiation. On this basis, the role of Nox4 for restenosis development was determined in the mouse carotid artery injury model. Methods and results: Genetic deletion of Nox4 by a tamoxifen-activated Cre-Lox-system did not impact on neointima formation in the carotid artery wire injury model. To understand this unexpected finding, time-resolved single-cell RNA-sequencing (scRNAseq) from injured carotid arteries of control mice and massive-analysis-of-cDNA-ends (MACE)-RNAseq from the neointima harvested by laser capture microdissection of control and Nox4 knockout mice was performed. This revealed that resting smooth muscle cells (SMCs) and fibroblasts exhibit high Nox4 expression, but that the proliferating de-differentiated SMCs, which give rise to the neointima, have low Nox4 expression. In line with this, the first weeks after injury, gene expression was unchanged between the carotid artery neointimas of control and Nox4 knockout mice. Conclusion: Upon vascular injury, Nox4 expression is transiently lost in the cells which comprise the neointima. NADPH oxidase 4 therefore does not interfere with restenosis development after wire-induced vascular injury.
Background: To identify variables predicting outcome in neuroblastoma patients assigned to the high-risk group solely by the presence of MYCN oncogene amplification (MNA). Methods: Clinical characteristics, genomic information, and outcome of 190 patients solely assigned to high-risk neuroblastoma by MNA were analyzed and compared to 205 patients with stage 4 neuroblastoma aged ≥18 months with MNA (control group). Results: Event-free survival (EFS) and overall survival (OS) at 10 years were 47% (95%-CI 39–54%) and 56% (95%-CI 49–63%), respectively, which was significantly better than EFS and OS of the control group (EFS 25%, 95%-CI 18–31%, p < 0.001; OS 32% 95%-CI 25–39%, p < 0.001). The presence of RAS-/p53-pathway gene alterations was associated with impaired 10-year EFS and OS (19% vs. 55%, and 19% vs. 67%, respectively; both p < 0.001). In time-dependent multivariable analyses, alterations of RAS-/p53-pathway genes and the extent of the best primary tumor resection were the only independent prognostic variables for OS (p < 0.001 and p = 0.011, respectively). Conclusions: Neuroblastoma patients attributed to high risk solely by MYCN amplification have generally a more favorable outcome. Mutations of genes of the RAS and/or p53 pathways and incomplete resection are the main risk factors predicting poor outcome.
Background: Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries. Methods: Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun’s electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries). Results: This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p < 0.01. Conclusion: A large change in solar insolation, both between winter and summer and between the minimum and maximum monthly values, may increase the risk of suicide attempts in bipolar I disorder. With frequent circadian rhythm dysfunction and suicidal behavior in bipolar disorder, greater understanding of the optimal roles of daylight and electric lighting in circadian entrainment is needed.
Introduction: The newest intravenous (IV) iron products show an improved safety profile over predecessors, allowing for the rapid administration of relatively high doses. Ferric derisomaltose (FDI; also known as iron isomaltoside), ferric carboxymaltose (FCM), and ferumoxytol (FER), are successful treatments for iron deficiency (Europe; FDI and FCM) and iron deficiency anemia (US; FDI, FCM, and FER). Areas covered: This review focusses on the chemistry and structure of FDI, FCM, and FER, and on three key aspects of IV iron safety: (1) hypersensitivity; (2) hypophosphatemia and sequelae; (3) cardiovascular safety. Expert opinion: Although the safety of modern IV iron has improved, immediate infusion reactions and the development of hypophosphatemia must be appreciated and recognized by those who prescribe and administer IV iron. Immediate infusion reactions can occur with any IV iron and are usually mild; severe reactions – particularly anaphylaxis – are extremely rare. The recognition and appropriate management of infusion reactions is an important consideration to the successful administration of IV iron. Severe, persistent, hypophosphatemia is a specific side effect of FCM. No cardiovascular safety signal has been identified for IV iron. Ongoing trials in heart failure will provide additional long-term efficacy and safety data.
Introduction: Prognosis of survivors from cardiac arrest is generally poor. Acute kidney injury (AKI) is a common finding in these patients. In general, AKI is well characterized as a marker of adverse outcome. In-hospital cardiac arrest (IHCA) represents a special subset of cardiac arrest scenarios with differential predisposing factors and courses after the event, compared to out-of-hospital resuscitations. Data about AKI in survivors after in-hospital cardiac arrest are scarce. Methods: In this study, we retrospectively analyzed patients after IHCA for incidence and risk factors of AKI and its prognostic impact on mortality. For inclusion in the analysis, patients had to survive at least 48 h after IHCA. Results: A total of 238 IHCA events with successful resuscitation and survival beyond 48 h after the initial event were recorded. Of those, 89.9% were patients of internal medicine, and 10.1% of patients from surgery, neurology or other departments. In 120/238 patients (50.4%), AKI was diagnosed. In 28 patients (23.3%), transient or permanent renal replacement therapy had to be initiated. Male gender, preexisting chronic kidney disease and a non-shockable first ECG rhythm during resuscitation were significantly associated with a higher incidence of AKI in IHCA-survivors. In-hospital mortality in survivors from IHCA without AKI was 29.7%, and 60.8% in patients after IHCA who developed AKI (p < 0.01 between groups). By multivariate analysis, AKI after IHCA persisted as an independent predictor of in-hospital mortality (HR 3.7 (95% CI 2.14–6.33, p ≤ 0.01)). Conclusion: In this cohort of survivors from IHCA, AKI is a frequent finding, with adverse impact on outcome. Therefore, therapeutic strategies to prevent AKI in post-IHCA patients are warranted.
Tuberous sclerosis complex (TSC) is a rare genetic disorder caused by mutations in the TSC1 or TSC2 genes, which encode proteins that antagonise the mammalian isoform of the target of rapamycin complex 1 (mTORC1) – a key mediator of cell growth and metabolism. TSC is characterised by the development of benign tumours in multiple organs, together with neurological manifestations including epilepsy and TSC-associated neuropsychiatric disorders (TAND). Epilepsy occurs frequently and is associated with significant morbidity and mortality; however, the management is challenging due to the intractable nature of the seizures. Preventative epilepsy treatment is a key aim, especially as patients with epilepsy may be at a higher risk of developing severe cognitive and behavioural impairment. Vigabatrin given preventatively reduces the risk and severity of epilepsy although the benefits for TAND are inconclusive. These promising results could pave the way for evaluating other treatments in a preventative capacity, especially those that may address the underlying pathophysiology of TSC, including everolimus, cannabidiol and the ketogenic diet (KD). Everolimus is an mTOR inhibitor approved for the adjunctive treatment of refractory TSC-associated seizures that has demonstrated significant reductions in seizure frequency compared with placebo, improvements that were sustained after 2 years of treatment. Highly purified cannabidiol, recently approved in the US as Epidiolex® for TSC-associated seizures in patients ⩾1 years of age, and the KD, may also participate in the regulation of the mTOR pathway. This review focusses on the pivotal clinical evidence surrounding these potential targeted therapies that may form the foundation of precision medicine for TSC-associated epilepsy, as well as other current treatments including anti-seizure drugs, vagus nerve stimulation and surgery. New future therapies are also discussed, together with the potential for preventative treatment with targeted therapies. Due to advances in understanding the molecular genetics and pathophysiology, TSC represents a prototypic clinical syndrome for studying epileptogenesis and the impact of precision medicine.
Background: The aim of this study was to evaluate the longer-term results of bicuspid aortic valve (BAV) repair with or without aortic root replacement. Methods: From 1999 to 2017, 142 patients with or without aortic root dilatation who underwent repair of a regurgitant BAV were included in the study. Ninety-four patients underwent isolated BAV repair (Group 1; median age 43 years) and 48 patients underwent valve-sparing aortic root replacement plus BAV repair (aortic valve reimplantation—Group 2; median age 48 years). Median clinical follow-up time was 5.9 years (range 0.5–15) in Group 1 and 3 years (range 0.5–16) in Group 2, respectively. Results: In-hospital mortality was 1% in Group 1, and 2% in Group 2 (p = .6). The 5- and 10-year survival was 93 ± 2.9% and 81 ± 5.8% in Group 1 and 96 ± 3.1% and 96 ± 3.1% in Group 2, respectively (p = .31). Eleven patients of Group 1 (1.7%/patient-year) and five patients of Group 2 (2.2%/patient-year) underwent reoperation of the aortic valve (p = .5). The 5- and 10-year freedom from reoperation were 93.0 ± 2.1% and 77.1 ± 7.1% in Group 1 and 93.0 ± 5.0% and 76.7 ± 9.6% in Group 2 (p = .83), respectively. At the latest follow-up, only two patients of Group 1 and 1 patient of Group 2 had AV regurgitation = 2° (p = .7). The cumulative linearized incidence of all valve-related complications (bleeding, stroke, endocarditis, and reoperation) was 2.9%/patient-year in Group 1% and 4%/patient-year in Group 2, respectively (p = .6). Conclusions: Isolated BAV repair and combined aortic valve reimplantation plus BAV repair provide good clinical longer-term outcomes with relatively low reoperation rate and durable valve function.
Objective: Evaluation of survival of teeth with class III furcation involvement (FI) ≥5 years after active periodontal treatment (APT) and identification of prognostic factors. Methods: All charts of patients who completed APT at the Department of Periodontology of Goethe-University Frankfurt, Germany, beginning October 2004 were screened for teeth with class III FI. APT had to be accomplished for ≥5 years. Charts were analysed for data of class III FI teeth at baseline (T0), at accomplishment of APT (T1), and at the last supportive periodontal care (T2). Baseline radiographic bone loss (RBL) and treatment were assessed. Results: One-hundred and sixty patients (age: 54.4 ± 9.8 years; 82 females; 39 active smokers; 9 diabetics, 85 stage III, 75 stage IV, 59 grade B, 101 grade C) presented 265 teeth with class III FI. Ninety-eight teeth (37%) were lost during 110, 78/137 (median, lower/upper quartile) months. Logistic mixed-model regression and mixed Cox proportional hazard model associated adjunctive systemic antibiotics with fewer tooth loss (26% vs. 42%; p = .019/.004) and RBL (p = .014/.024) and mean probing pocket depth (PPD) at T1 (p < .001) with more tooth loss. Conclusions: Subgingival instrumentation with adjunctive systemic antibiotics favours retention of class III furcation-involved teeth. Baseline RBL and PPD at T1 deteriorate long-term prognosis.
Objective: This study was undertaken to evaluate the long-term efficacy, retention, and tolerability of add-on brivaracetam (BRV) in clinical practice. Methods: A multicenter, retrospective cohort study recruited all patients who initiated BRV between February and November 2016, with observation until February 2021. Results: Long-term data for 262 patients (mean age = 40 years, range = 5–81 years, 129 men) were analyzed, including 227 (87%) diagnosed with focal epilepsy, 19 (7%) with genetic generalized epilepsy, and 16 (6%) with other or unclassified epilepsy syndromes. Only 26 (10%) patients had never received levetiracetam (LEV), whereas 133 (50.8%) were switched from LEV. The length of BRV exposure ranged from 1 day to 5 years, with a median retention time of 1.6 years, resulting in a total BRV exposure time of 6829 months (569 years). The retention rate was 61.1% at 12 months, with a reported efficacy of 33.1% (79/239; 50% responder rate, 23 patients lost-to-follow-up), including 10.9% reported as seizure-free. The retention rate for the entire study period was 50.8%, and at last follow-up, 133 patients were receiving BRV at a mean dose of 222 ± 104 mg (median = 200, range = 25–400), including 52 (39.1%) who exceeded the recommended upper dose of 200 mg. Fewer concomitant antiseizure medications and switching from LEV to BRV correlated with better short-term responses, but no investigated parameters correlated with positive long-term outcomes. BRV was discontinued in 63 (24%) patients due to insufficient efficacy, in 29 (11%) for psychobehavioral adverse events, in 25 (10%) for other adverse events, and in 24 (9%) for other reasons. Significance: BRV showed a clinically useful 50% responder rate of 33% at 12 months and overall retention of >50%, despite 90% of included patients having previous LEV exposure. BRV was well tolerated; however, psychobehavioral adverse events occurred in one out of 10 patients. Although we identified short-term response and retention predictors, we could not identify significant predictors for long-term outcomes. Key Points Long-term postmarketing data for brivaracetam in 262 patients showed an overall retention rate of 50.8%; At 12 months, the 50% responder rate for brivaracetam was 33.1%, with 10.9% reporting seizure freedom; Previous treatment with levetiracetam (90%) did not impact brivaracetam retention or efficacy; Levetiracetam treatment failure should not preclude brivaracetam introduction; No long-term efficacy predictors could be identified.
Substantial evidence shows that physical activity and fitness play a protective role in the development of stress related disorders. However, the beneficial effects of fitness for resilience to modern life stress are not fully understood. Potentially protective effects may be attributed to enhanced resilience via underlying psychosocial mechanisms such as self-efficacy expectations. This study investigated whether physical activity and fitness contribute to prospectively measured resilience and examined the mediating effect of general self-efficacy. 431 initially healthy adults participated in fitness assessments as part of a longitudinal-prospective study, designed to identify mechanisms of resilience. Self-efficacy and habitual activity were assessed in parallel to cardiorespiratory and muscular fitness, which were determined by a submaximal step-test, hand strength and standing long jump test. Resilience was indexed by stressor reactivity: mental health problems in relation to reported life events and daily hassles, monitored quarterly for nine months. Hierarchical linear regression models and bootstrapped mediation analyses were applied. We could show that muscular and self-perceived fitness were positively associated with stress resilience. Extending this finding, the muscular fitness–resilience relationship was partly mediated by self-efficacy expectations. In this context, self-efficacy expectations may act as one underlying psychological mechanism, with complementary benefits for the promotion of mental health. While physical activity and cardiorespiratory fitness did not predict resilience prospectively, we found muscular and self-perceived fitness to be significant prognostic parameters for stress resilience. Although there is still more need to identify specific fitness parameters in light of stress resilience, our study underscores the general relevance of fitness for stress-related disorders prevention.
Purpose: Amblyopia with eccentric fixation, especially when not diagnosed early, is a therapeutic challenge, as visual outcome is known to be poorer than in amblyopia with central fixation. Consequently, treatment after late diagnosis is often denied. Electronic monitoring of occlusion provides us the chance to gain first focussed insight into age-dependent dose response and treatment efficiency, as well as the shift of fixation in this rare group of paediatric patients. Methods: In our prospective pilot study, we examined amblyopes with eccentric fixation during 12 months of occlusion treatment. We evaluated their visual acuity, recorded patching duration using a TheraMon®-microsensor, and determined their fixation with a direct ophthalmoscope. Dose-response relationship and treatment efficiency were calculated. Results: The study included 12 participants with strabismic and combined amblyopia aged 2.9–12.4 years (mean 6.5). Median prescription of occlusion was 7.7 h/day (range 6.6–9.9) and median daily received occlusion was 5.2 h/day (range 0.7–9.7). At study end, median acuity gain was 0.6 log units (range 0–1.6) and residual interocular visual acuity difference (IOVAD) 0.3 log units (range 0–1.8). There was neither significant acuity gain nor reduction in IOVAD after the 6th month of treatment. Children younger than 4 years showed best response with lowest residual IOVAD at study end. Efficiency calculation showed an acuity gain of approximately one line from 100 h of patching in the first 2 months and half a line after 6 months. There was a significant decline of treatment efficiency with age (p = 0.01). Foveolar fixation was achieved after median 3 months (range 1–6). Three patients (> 6 years) did not gain central fixation. Conclusion: Eccentric fixation is a challenge to therapy success. Based on electronic monitoring, our study quantified for the first time the reduction of treatment efficiency with increasing age in amblyopes with eccentric fixation. Despite some improvement in patients up to 8 years, older patients showed significantly lower treatment efficiency. In younger patients with good adherence, despite poor initial acuity, central fixation and low residual IOVAD could be attained after median 3 months. Hence, the necessity of early diagnosis and intensive occlusion should be emphasized.
Musculoskeletal disorders of the trunk and neck are common among cleaners. Vacuum cleaning is a demanding activity. The aim of this study was to present the movement profile of the trunk and neck during habitual vacuuming. The data were collected from 31 subjects (21f./10 m) using a 3D motion analysis system (Xsens). 10 cycles were analysed in vacuuming PVC and carpet floors with 8 vacuum cleaners. The joint angles and velocities were represented statistically descriptive. When vacuuming, the trunk is held in a forwardly inclined position by a flexion in the hip and rotated from this position. In the joint angles and velocities of the spine, the rotation proved to be dominant. A relatively large amount of movement took place in the cervical spine and also in the lumbar spine. The shown movement profile is rather a comfort area of vacuuming which may serve as a reference for ergonomics in vacuuming.
Pancreatic cancer (PC) still remains a major cause of cancer-related death worldwide and alternative treatments are urgently required. A common problem of PC is the development of resistance against apoptosis that limits therapeutic success. Here we demonstrate that the prototypical Smac mimetic BV6 cooperates with the stimulator of interferon (IFN) genes (STING) ligand 2′,3′-cyclic guanosine monophosphate–adenosine monophosphate (2′3′-cGAMP) to trigger necroptosis in apoptosis-deficient PC cells. Pharmacological inhibition of key components of necroptosis signaling, such as receptor-interacting protein 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL), significantly rescues PC cells from 2′3′-cGAMP/BV6/zVAD.fmk-mediated cell death, suggesting the induction of necroptosis. Consistently, 2′3′-cGAMP/BV6 co-treatment promotes phosphorylation of MLKL. Furthermore, we show that 2′3′-cGAMP stimulates the production of type I IFNs, which cooperate with BV6 to trigger necroptosis in apoptosis-deficient settings. STING silencing via siRNA or CRISPR/Cas9-mediated gene knockout protects PC cells from 2′3′-cGAMP/BV6/zVAD.fmk-mediated cell death. Interestingly, we demonstrate that nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNFα), and IFN-regulatory factor 1 (IRF1) signaling are involved in triggering 2′3′-cGAMP/BV6/zVAD.fmk-induced necroptosis. In conclusion, we show that activated STING and BV6 act together to exert antitumor effects on PC cells with important implications for the design of new PC treatment concepts.
Körpergrößenschätzung und Geschlechtsdiskrimination anhand von metrischen Schädeldachparametern
(2021)
1. Körpergrößenschätzung und Geschlechtsdiskrimination; Messung des maximalen Längs- und Querdurchmessers des Schädels
Knöcherne Schädel sind häufig die einzigen Skelettüberreste, die für forensisch-osteologische Untersuchungen zur Verfügung stehen. Am Schädel lassen sich gute Hinweise für Geschlechtsdiskriminierung, Lebensalter und Herkunft erlangen. Es sollte überprüft werden, ob mithilfe der an der frischen Sägefläche des Hirnschädels gemessenen maximalen Schädellänge und -breite eine Schätzung der Körpergröße oder eine Geschlechtsdiskrimination möglich ist.
In die Untersuchung gingen die Autopsieberichte von 959 Verstorbenen ein, die das 21. Lebensjahr vollendet hatten und in den Jahren 2004 bis 2008 am Institut für Rechtsmedizin der Universität Gießen obduziert worden waren. Um den Einfluss der Herkunft der Individuen auf die untersuchten Maße abzuschätzen, wurde eine getrennte Betrachtung der in Deutschland (n=760) und außerhalb von Deutschland geborenen Individuen (n=199) durchgeführt. Trotz signifikanter Korrelationen der maximalen Schädellänge mit der Körpergröße konnte aufgrund der hohen Standardfehler keine sinnvolle einsetzbare Regressionsformel berechnet werden. Die maximale Schädelbreite zeigte keine nennenswerte Korrelation zur Körperlänge. Bezüglich der Geschlechtsdiskrimination konnte für kaukasoide Individuen folgende Aussage getroffen werden: Schädellängen kleiner 15,5 cm sprechen für weibliche und größer 19 cm für männliche Individuen. Bei der Schädelbreite weisen Werte kleiner 12,5 cm auf eine Frau und größer 15,5 cm auf einen Mann hin.
2. Über die Korrelation von Schädelnahtlängen und Körperhöhe bei Mitteleuropäern
An den Stellen des Schädeldachs, an denen 2 benachbarte Knochenanlagen aneinanderstoßen, bildet das Bindegewebe Knochennähte, Suturae (Sutura sagitalis, Sutura coronalis, Sutura lambdoidea) aus (Schiebler et al. 2002).
Ein vielversprechender Ansatz hinsichtlich der Verwendung der Schädelnähte zur Körperhöhenschätzung wurde von Rao et al. (2009) publiziert. Sie konnten in ihrer Studie an 87 Schädeln südindischer männlicher Individuen eine Korrelation sowohl zwischen Sagittal- als auch Coronarnaht und Körperhöhe nachweisen und für deren Berechnung eine Regressionsformel ableiten. In der vorliegenden prospektiven Studie sollte überprüft werden, ob sich die Ergebnisse von Rao et al. auf eine mitteleuropäische Population übertragen lassen, und ob sich anhand von Sektionsfällen eine Korrelation zwischen Schädelnahtlängen (Sagittal- und Coronarnaht) einerseits und Körperlänge andererseits nachweisen lässt.
Am Gießener Institut für Rechtsmedizin wurden in den Jahren 2009 und 2010 bei 117 Verstorbenen prospektiv die Längen der Sagittal- und Coronarnaht sowie die Körperhöhen gemessenen. Das Alter der Verstorbenen lag zwischen 15 und 96 Jahren (Mittelwert 52,8 Jahre, Median 51 Jahre); 82 Personen waren männlich und 35 weiblich. Die Länge der Sagittalnaht in Bezug auf die Körperhöhe ergab in der Regressionsanalyse einen Korrelationskoeffizienten von lediglich r = 0,045 (p = 0,617). Ähnliche Ergebnisse wurden für die Coronarnaht ermittelt; hierbei betrug der Korrelationskoeffizient r = 0,015. Bei Annahme einer maximal zulässigen Fehlerwahrscheinlichkeit von α = 0,05 erwies sich keine der durchgeführten Regressionsanalysen als statistisch signifikant. Nach den erhobenen Befunden ist weder die Länge der Sagittal- noch die Länge der Coronarnaht geeignet, bei Mitteleuropäern die Körperhöhe zu schätzen.
Die Therapie des critical size defects stellt eine große Herausforderung der Medizin dar. Die Knochendefekte können beispielsweise in Folge von Tumorresektionen, Knochenheilungsstörungen oder nach Frakturen entstehen. Den aktuellen Goldstandard in der Therapie großer Knochendefekte stellt die Transplantation von autologem Knochenmaterial dar. Die Entnahme des Materials aus dem Beckenkamm ist allerdings mit Nachteilen wie der Entnahmemorbididät verbunden. Alternativ können Tissue-Engineering Techniken eingesetzt werden, bei denen Zellen mit regenerativem Potential mit Knochenersatzmaterialien und Wachstumsfaktoren kombiniert werden, um eine Defektheilung zu erzielen. Der Einsatz von bone marrow mononuclear cells (BMC) mit einem osteokonduktiven Gerüst wie b-TCP hat sich als geeignetes Therapiekonzept bewiesen. Einen weiteren Ansatz stellt die Verwendung von autologen Blutkonzentraten wie beispielsweise des platelet rich fibrin (PRF) dar. Das PRF kann innerhalb weniger Minuten aus patienteneigenem Blut mittels Zentrifugation hergestellt und direkt angewandt werden. Durch seine charakteristische dreidimensionale Fibrinmatrix dient das PRF als Reservoir für Wachstums- und Regenerationsfaktoren.
Die Kombination von BMC mit PRF könnte also durch die gesteigerte Konzentration an Zytokinen und Wachstumsfaktoren wie VEGF und TGF-b zu einer Unterstützung der regenerativen Wirkung der BMC führen. Ziel dieser Arbeit war es daher, den Effekt von PRF auf BMC in vitro zu analysieren.
In Anlehnung an das low speed centrifugation concept wurden zwei verschiedene PRF-Matrices hergestellt. Diese wurden entweder mit mittlerer relativer Zentrifugalbeschleunigung (RCF) (208g) oder mit geringer RCF (60g) zentrifugiert. Um eine geeignete Konzentration des PRF zur Kombination mit den BMC zu finden, wurde im Vorfeld eine Dosisfindungskurve erstellt. Zu diesem Zweck wurde der Einfluss ansteigender PRF-Konzentrationen auf die metabolische Aktivität der BMC nach 7 Tagen Inkubation analysiert. Wir konnten einen Trend zu erhöhten Werten bei einer Konzentration von 10% des PRF beobachten. Die metabolische Aktivität der BMC wurde durch höhere PRF-Konzentrationen nicht weiter gesteigert.
Aufgrund dieser Ergebnisse wurde für die nachfolgenden Experimente eine Konzentration von 10% der PRF-Aufbereitungen und der Serum-Kontrolle eingesetzt.
Zur Charakterisierung der beiden PRF-Aufbereitungen wurde der Gehalt an Wachstumsfaktoren im Vergleich zu humanem Serum untersucht. Es zeigten sich signifikant gesteigerte Konzentrationen von Insulin-like Growth Factor-1 (IGF-1), soluble Intercellular Adhesion Molecule-1 (sICAM-1) und Transforming Growth Factor-b (TGF-b) in dem PRF. Bezüglich des Vascular Endothelial Growth Factor (VEGF)-Gehaltes ließ sich allerdings kein Unterschied zwischen humanem Serum und den PRF-Matrices darstellen.
Der Effekt des PRF low-RCF und PRF medium-RCF auf die Viabilität der BMC wurde anhand der metabolischen Aktivität nach 2, 7 und 14 Tagen Inkubation untersucht. Als Kontrollgruppe diente hierbei der Zusatz von humanem Serum. Die metabolische Aktivität der BMC zeigte sich an Tag 14 in allen Gruppen signifikant gesteigert.
Außerdem konnten wir zeigen, dass der Zusatz von PRF zu BMC zu einer statistisch signifikant erhöhten Genexpression der Matrix-Metalloproteasen (MMP) -2, -7 und - 9 im Vergleich zur Serum-Kontrollgruppe führt.
In unseren Versuchen konnte nachgewiesen werden, dass die apoptotische Aktivität der BMC durch Kombination mit PRF nicht negativ beeinflusst wird. Zusammenfassend lässt sich sagen, dass sich PRF-Matrices als geeignete allogene oder autologe Quelle von Wachstums- und Regenerationsfaktoren nutzen lassen. Sie besitzen damit die Kapazität, Zellen wie die BMC zu stimulieren und zu aktivieren. Unsere Studie zeigt, dass der Zusatz von PRF für BMC-gestützte Therapien förderlich sein könnte. Dies muss jedoch in geeigneten Tiermodellen überprüft werden.
Doping ist ein Thema, das den modernen Leistungssport – und nicht nur diesen – seit jeher begleitet. Immer wieder werden Sportler – oft noch nach Jahren – überführt, illegale Substanzen zur Leistungssteigerung eingenommen zu haben. Der Landessportbund Hessen e. V. hat im Sommer 2013 Professor Dr. Dr. Gerd Geißlinger zum Anti-Doping-Beauftragten berufen. Für den UniReport hat Dr. Beate Meichsner mit dem Direktor des Instituts für Klinische Pharmakologie am Klinikum der Goethe-Universität über die damit verbundenen Aufgaben, Ziele und
Möglichkeiten gesprochen.
Bei seiner Einschulung hatte Wolfgang Niedecken ein besonderes Erlebnis, als er im Alter von 6 Jahren bemerkte, dass es höchste Zeit war, ordentlich sprechen zu lernen. Im Elternhaus war ausschließlich Kölsch gesprochen worden. Hochdeutsch war seine erste Fremdsprache, die sie in letzter Konsequenz auch immer geblieben ist. Denken, empfinden und träumen tut Niedecken nach wie vor auf Kölsch, wie er selbst beteuert.
Im Sommer 1976 schreibt Wolfgang Niedecken seinen ersten Song auf Kölsch: "Helfe kann dir keiner". 1979 erscheint sein erstes Album mit dem Titel: "Wolfgang Niedecken’s BAP rockt andere kölsche Leeder".
Nie hat sich BAP auf seinen Tourneen vor den „Karren politischer Machthaber“ spannen lassen. Zu Zeiten zweier deutscher Staaten sorgten die offenen Worte von „Deshalv spill`mer he“ für einen Eklat. Das Lied sprach sich unmissverständlich nicht nur für die westdeutsche Friedensbewegung, sondern ebenfalls für die ostdeutschen Friedens- und Menschenrechtsinitiativen aus. Als die DDR-Kulturbehörden BAP verboten, den Song zu spielen, platzt am Vorabend des ersten Konzertes im Berliner Palast der Republik die über 14 Stationen geplante und längst ausverkaufte DDR-Tournee.
Am 9. November 1992 findet das „Arsch huh“-Konzert gegen Ausländerfeindlichkeit und Rassismus auf dem Kölner Chlodwigplatz vor über 100.000 Menschen statt. Danach ähnliche Konzerte in Frankfurt „Heute die, morgen Du“ und in Leipzig „Gewalt ätzt“ vor ähnlich großer Kulisse. Für sein gesellschaftspolitisches Engagement bekommt Niedecken 1998 das Bundesverdienstkreuz von Bundespräsident Roman Herzog überreicht. In der Laudatio heißt es: „Kölsch-Rock, BAP und Kölner Dialekt sind untrennbar mit ihm verbunden. Er ist einer der profiliertesten Rockmusiker Deutschlands. Als engagierter Künstler hat er sich nachhaltig für Frieden, Toleranz, Demokratie und gegen Fremdenfeindlichkeit eingesetzt.“
Zu Niedeckens 60. Geburtstag, den er am 30. März 2011 mit etwa 500 Gästen auf einem Rheinschiff feiert, sendet der WDR die „Niedecken-Nacht“. Zu seinem Geburtstag erscheint im Verlag Hoffmann und Campe auch das Buch „Für 'ne Moment. Autobiographie“. Auf über 500 Seiten erzählt der Musiker von seiner Familie, einer behüteten frühen Kindheit und der schwierigen Zeit als Heranwachsender im katholischen Internat, von seinem Kunststudium und Aufenthalten in der New Yorker Kunstszene, der ehe zufälligen Gründung von BAP, die zur erfolgreichsten Mundartgruppe Deutschlands wurde.
Und dann das: Am 2. November gegen 13 Uhr bemerkt Wolfgang Niedecken beim Lesen, „dass ich nichts mehr kapierte. Ich musste die Seiten immer wieder neu lesen. Dann wurde es nebelig vor den Augen, alles sah merkwürdig aus, mein ganzes Umfeld hatte amorphe Formen. Und dann begegnete ich Gott sei Dank meinem Schutzengel.“ Wolfgang Niedecken hatte einen Schlaganfall erlitten, obwohl er eigentlich kein typischer Schlaganfallpatient war. Es kann also jeden treffen! Dank des schnellen Reagierens seiner Frau Tina konnte das Schlimmste verhindert werden.
Gentechnik im Klassenzimmer
(2010)
Gerlach zum zweiten Mal in den Rat der Gesundheitsweisen berufen Foto: Institut für Allgemeinmedizin
(2010)
Für eine erfolgreiche Behandlung mit implantatprothetischen Therapiekonzepten ist eine stabile Implantat-Abutment-Verbindung entscheidend. Vor allem die Abutmentschraube als komplikationsanfälligste Komponente dieser Verbindung steht im Mittelpunkt zahlreicher wissenschaftlicher Untersuchungen. Implantate und Komponenten aus Zirkoniumdioxid sind schon seit einigen Jahren auf dem Markt erhältlich. Dennoch gibt es keine Studien, die sich mit der Vorspannkraft von Schrauben bei Implantaten und Abutments aus Zirkoniumdioxid beschäftigen. Ebenso wurden bisher noch keine Schrauben mit Feingewinde im Bereich der Implantologie untersucht. Die vorliegende Studie soll den beschriebenen Forschungsbedarf abdecken.
Um zu ermitteln, in wieweit die Schraubengeometrie Einfluss auf die Vorspannkraft bei Implantat-Abutment-Verbindungen aus Zirkoniumdioxid hat, wurden verschiedene Schrauben hergestellt. Mit einem Schraubenkopfwinkel von 90° wurden Schrauben mit Feingewinde (M1,4x0,2) und 2, 4 und 6 Gewindegängen produziert. Zur Variation des Schraubenkopfwinkels wurden Schrauben mit Feingewinde und 4 Gewindegängen sowie einem Schraubenkopfwinkel von 30° und 60° hergestellt. Es wurden Gewindehülsen als Implantat-Analog und Schraubenkopfauflagen aus Zirkoniumdioxid extern hergestellt und eingekauft (Firma Microceram, Meißen, Deutschland).
Um die Vorspannkraft der Verbindung messen zu können, wurden die Prüfkörper in eine zu diesem Zweck entwickelte Messeinheit integriert. Die Messeinheit besteht aus einem Gerüstzylinder, der als Rahmenkonstrukt dient. Im Inneren des Gerüstzylinders befindet sich die Gewindehülse als Implantat-Analog in einem Spannfutter, das in direkter Verbindung mit dem Messsensor steht. In einer Fassung über der Gewindehülse befindet sich die Schraubenkopfauflage als Abutment-Analog. Gewindehülse und Schraubenkopfauflage stehen dabei nicht in direktem Kontakt. Erst durch die Versuchsschrauben kommt diese Verbindung zustande. Die Zugkraft, die beim Anziehen der Schraubenverbindung entsteht, wird vom Sensor registriert. Er leitet daraus die Vorspannkraft der Verbindung ab.
Jede Prüfverbindung wurde mit vier aufeinander folgenden Anzugsdrehmomenten angezogen (15 Ncm, 20 Ncm, 25 Ncm und 30 Ncm). Nach jedem Anzugsvorgang erfolgte die Messung der Vorspannkraft. Die Messwerte sind somit in Abhängigkeit des Anzugsdrehmoments erhoben worden.
Die Ergebnisse zeigen, dass die Gewindegangzahl der Schrauben keinen Einfluss auf die erzielte Vorspannkraft der Verbindung hat. Die gemessenen Vorspannkräfte bei Schrauben mit 2, 4 und 6 Gewindegängen weisen einen nahezu linearen Einfluss des Anzugsdrehmoments auf die Vorspannkraft nach: Je höher das Anzugsdrehmoment, desto höher auch die ermittelte Vorspannkraft.
Der Schraubenkopfwinkel hingegen zeigte einen Einfluss auf die Vorspannkraft. Bei einem sehr steilen Schraubenkopfwinkel von 30° wurden die geringsten Werte für die Vorspannkraft ermittelt, bei einem Schraubenkopfwinkel von 90° die Höchsten.
Die Ergebnisse dieser Studie wurden mit Ergebnissen einer anderen Versuchsgruppe verglichen, die im selben Versuchsaufbau Schrauben mit gleicher Konfiguration, aber Regelgewinde (M1,6x0,35) statt Feingewinde und größerem Schraubendurchmesser untersuchten. Im Vergleich der Ergebnisse ergab sich kein Vorteil im Bezug auf die erzielte Vorspannkraft bei Schrauben mit Feingewinde.
Schrauben mit 2 Gewindegängen lieferten eine ähnliche Vorspannkraft wie Schrauben mit 4 oder 6 Gewindegängen. Dies legt die Möglichkeit nahe, kürzere Schrauben und somit kürzere Implantate zu entwickeln, um aufwendige Augmentationsmaßnahmen bei geringer Restknochenhöhe umgehen zu können. Vorher müssen jedoch weitere Untersuchungen folgen, um die Stabilität von Schrauben mit 2 Gewindegängen zu überprüfen.
Ziel der vorliegenden Arbeit war die Untersuchung der Kurzzeitdynamik zirkulierender Tumorzellen bei hepatozellulären Karzinompatienten, die erstmalig eine radiologische Intervention in Form einer transarteriellen Chemoembolisation oder einer Mikrowellenablation als Therapie erhielten. Dafür wurde in Vorversuchen eine neuartige Methode zur Isolation und Detektion von zirkulierenden Tumorzellen entwickelt.
Zugleich sollte ein potenzieller Einsatz dieser Methode als Screeningverfahren für hepatozelluläre Karzinompatienten mithilfe der Sensitivität und Spezifität überprüft werden. Darüber hinaus wurde eine mögliche Korrelation der Kurzzeitdynamik zirkulierender Tumorzellen sowohl mit der Kurzzeitdynamik des AFP-Wertes als anerkannten HCC-Tumormarker, als auch des IL-6-Wertes als aktuell diskutierten Tumormarker analysiert. Ferner wurde die Kurzzeitdynamik zirkulierender Tumorzellen mit dem klinischen Verlauf der Patienten verglichen.
Im Zeitraum von September 2017 bis Juni 2018 konnten Blutproben von 18 Patienten mit einem hepatozellulären Karzinom untersucht werden. Davon wurden zehn Patienten mittels Mikrowellenablation und acht Patienten mittels transarterieller Chemoembolisation behandelt. Daneben wurden Blutproben von 13 gesunden Probanden ausgewertet.
Methodisch wurden jeweils im Anschluss an die Gewinnung des Patientenblutes, vor und unmittelbar nach jeweiliger radiologischer Intervention, die zirkulierenden Tumorzellen aus dem Blut isoliert und die gewonnenen Zellen durch die Durchflusszytometrie nachgewiesen und quantifiziert. Als zirkulierende Tumorzellen wurden dabei jene Zellen betrachtet, die eine Negativität auf den Marker CD45 sowie eine Positivität auf die Marker ASGPR-1, CD146, CD274 und CD90 zeigten.
Durch den Vergleich der Proben vor und nach radiologischer Intervention konnte gezeigt werden, dass die Anzahlen zirkulierender Tumorzellen nach der radiologischen Intervention im Mittel niedriger sind als vor der Therapie. Die Anzahl zirkulierender Tumorzellen sank dabei im Schnitt bei den mit Mikrowellenablation behandelten Patienten stärker im Vergleich zu denen, die eine transarterielle Chemoembolisation erhielten. Dies bestätigte den klinischen Verlauf der Patientengruppen, da die Mortalität der Gruppe, die eine transarterielle Chemoembolisation erhielten deutlich höher war als bei den übrigen Patienten.
Als klinisch einsetzbare Screening-Methode im Sinne einer „Liquid Biopsy“ für das HCC müssen die Sensitivität und Spezifität weitergehend optimiert werden. Eine signifikante Korrelation zwischen der Kurzzeitdynamik der Anzahlen zirkulierender Tumorzellen und der Kurzzeitdynamik der AFP-Werte und der IL-6-Werte konnte nicht festgestellt werden. Entgegen des erwarteten Trends, legte die angewendete Methode, durch das Absinken der zirkulierenden Tumorzellen, die positive Wirkung der transarteriellen Chemoembolisation und der Mikrowellenablation in hepatozellulären Karzinompatienten dar.
Purpose: To compare Cancer-specific mortality (CSM) in patients with Squamous cell carcinoma (SCC) vs. non-SCC penile cancer, since survival outcomes may differ between histological subtypes. Methods: Within the Surveillance, Epidemiology and End Results database (2004–2016), penile cancer patients of all stages were identified. Temporal trend analyses, cumulative incidence and Kaplan–Meier plots, multivariable Cox regression and Fine and Gray competing-risks regression analyses tested for CSM differences between non-SCC vs. SCC penile cancer patients. Results: Of 4,120 eligible penile cancer patients, 123 (3%) harbored non-SCC vs. 4,027 (97%) SCC. Of all non-SCC patients, 51 (41%) harbored melanomas, 42 (34%) basal cell carcinomas, 10 (8%) adenocarcinomas, eight (6.5%) skin appendage malignancies, six (5%) epithelial cell neoplasms, two (1.5%) neuroendocrine tumors, two (1.5%) lymphomas, two (1.5%) sarcomas. Stage at presentation differed between non-SCC vs. SCC. In temporal trend analyses, non-SCC diagnoses neither decreased nor increased over time (p > 0.05). After stratification according to localized, locally advanced, and metastatic stage, no CSM differences were observed between non-SCC vs. SCC, with 5-year survival rates of 11 vs 11% (p = 0.9) for localized, 33 vs. 37% (p = 0.4) for locally advanced, and 1-year survival rates of 37 vs. 53% (p = 0.9) for metastatic penile cancer, respectively. After propensity score matching for patient and tumor characteristics and additional multivariable adjustment, no CSM differences between non-SCC vs. SCC were observed. Conclusion: Non-SCC penile cancer is rare. Although exceptions exist, on average, non-SCC penile cancer has comparable CSM as SCC penile cancer patients, after stratification for localized, locally invasive, and metastatic disease.
Purpose: In patients with pyogenic spondylodiscitis, surgery is considered the treatment of choice to conduct proper debridement, stabilise the spine and avoid extended bed rest, which in turn is a risk factor for complications such as deep vein thrombosis and pulmonary embolism. Methods: We conducted a retrospective clinical study with analysis of a group of 99 patients who had undergone treatment for pyogenic discitis at our institution between June 2012 and August 2017. Included parameters were age, sex, disease pattern, the presence of deep vein thrombosis, resuscitation, in-hospital mortality, present anticoagulation, preexisting comorbidities, tobacco abuse, body mass index, microbiological germ detection and laboratory results. Results: Among the analysed cohort, 12% of the treated patients for pyogenic spondylodiscitis suffered from a radiologically confirmed pulmonary embolism. Coronary heart disease (p < 0.01), female sex (p < 0.01), anticoagulation at admission (p < 0.01) and non-O blood type (p < 0.001) were associated with development of pulmonary embolism. Pulmonary embolism was significantly associated with resuscitation (p < 0.005) and deep vein thrombosis (p < 0.001). Neurosurgery was not associated with increased risk for pulmonary embolism compared to conservative-treated patients (p > 0.05). Conclusion: Surgery for pyogenic spondylodiscitis was not associated with an elevated risk of pulmonary embolism in our analysis. However, we describe several risk factors for pulmonary embolism in this vulnerable cohort. Prospective studies are necessary to improve prevention and postoperative management in patients with pyogenic spondylodiscitis.
HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders
(2021)
Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10−3; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
TRIANNI mice carry an entire set of human immunoglobulin V region gene segments and are a powerful tool to rapidly isolate human monoclonal antibodies. After immunizing these mice with DNA encoding the spike protein of SARS-CoV-2 and boosting with spike protein, we identified 29 hybridoma antibodies that reacted with the SARS-CoV-2 spike protein. Nine antibodies neutralize SARS-CoV-2 infection at IC50 values in the subnanomolar range. ELISA-binding studies and DNA sequence analyses revealed one cluster of three clonally related neutralizing antibodies that target the receptor-binding domain and compete with the cellular receptor hACE2. A second cluster of six clonally related neutralizing antibodies bind to the N-terminal domain of the spike protein without competing with the binding of hACE2 or cluster 1 antibodies. SARS-CoV-2 mutants selected for resistance to an antibody from one cluster are still neutralized by an antibody from the other cluster. Antibodies from both clusters markedly reduced viral spread in mice transgenic for human ACE2 and protected the animals from SARS-CoV-2-induced weight loss. The two clusters of potent noncompeting SARS-CoV-2 neutralizing antibodies provide potential candidates for therapy and prophylaxis of COVID-19. The study further supports transgenic animals with a human immunoglobulin gene repertoire as a powerful platform in pandemic preparedness initiatives.
Purpose: Scientific and clinical achievements in radiation, medical, and surgical oncology are changing the landscape of interdisciplinary oncology. The German Society for Radiation Oncology (DEGRO) working group of young clinicians and scientists (yDEGRO) and the DEGRO representation of associate and full professors (AKRO) are aware of the essential role of radiation oncology in multidisciplinary treatment approaches. Together, yDEGRO and AKRO endorsed developing a German radiotherapy & radiation oncology vision 2030 to address future challenges in patient care, research, and education. The vision 2030 aims to identify priorities and goals for the next decade in the field of radiation oncology. Methods: The vision development comprised three phases. During the first phase, areas of interest, objectives, and the process of vision development were defined jointly by the yDEGRO, AKRO, and the DEGRO board. In the second phase, a one-day strategy retreat was held to develop AKRO and yDEGRO representatives’ final vision from medicine, biology, and physics. The third phase was dedicated to vision interpretation and program development by yDEGRO representatives. Results: The strategy retreat’s development process resulted in conception of the final vision “Innovative radiation oncology Together – Precise, Personalized, Human.” The first term “Innovative radiation oncology” comprises the promotion of preclinical research and clinical trials and highlights the development of a national committee for strategic development in radiation oncology research. The term “together” underpins collaborations within radiation oncology departments as well as with other partners in the clinical and scientific setting. “Precise” mainly covers technological precision in radiotherapy as well as targeted oncologic therapeutics. “Personalized” emphasizes biology-directed individualization of radiation treatment. Finally, “Human” underlines the patient-centered approach and points towards the need for individual longer-term career curricula for clinicians and researchers in the field. Conclusion: The vision 2030 balances the ambition of physical, technological, and biological innovation as well as a comprehensive, patient-centered, and collaborative approach towards radiotherapy & radiation oncology in Germany.
Background: Cases of immune complex vasculitis have been reported following COVID-19 infections; so far none in association with novel mRNA-based COVID-19 vaccination. This case report describes a cutaneous immune complex vasculitis after vaccination with BNT162b2. Case presentation: A 76-year old male with liver cirrhosis developed an immune complex vasculitis 12 days after the second injection of BNT162b2. On physical examination, the patient presented with pruritic purpuric macules on hands and feet, flexor and extensor parts of both legs and thighs and lower abdomen, and bloody diarrhoea. Laboratory testing showed elevated inflammatory markers. After short treatment with oral steroids all clinical manifestations and laboratory findings resolved. Conclusions: An increasing number of clinical manifestations have been attributed to COVID-19 infection and vaccination. This is the first written report of immune complex vasculitis after vaccination with BNT162b2. We present our case report and a discussion in the light of type three hypersensitivity reaction.
Rationale: Both attention deficit-/hyperactivity disorder (ADHD) and alcohol use disorder (AUD) are accompanied by deficits in response inhibition. Furthermore, the prevalence of comorbidity of ADHD and AUD is high. However, there is a lack of research on whether the same neuronal subprocesses of inhibition (i.e., interference inhibition, action withholding and action cancellation) exhibit deficits in both psychiatric disorders. Methods: We examined these three neural subprocesses of response inhibition in patient groups and healthy controls: non-medicated individuals with ADHD (ADHD; N = 16), recently detoxified and abstinent individuals with alcohol use disorder (AUD; N = 15), and healthy controls (HC; N = 15). A hybrid response inhibition task covering interference inhibition, action withholding, and action cancellation was applied using a 3T functional magnetic resonance imaging (fMRI). Results: Individuals with ADHD showed an overall stronger hypoactivation in attention related brain areas compared to AUD or HC during action withholding. Further, this hypoactivation was more accentuated during action cancellation. Individuals with AUD recruited a broader network, including the striatum, compared to HC during action withholding. During action cancellation, however, they showed hypoactivation in motor regions. Additionally, specific neural activation profiles regarding group and subprocess became apparent. Conclusions: Even though deficits in response inhibition are related to both ADHD and AUD, neural activation and recruited networks during response inhibition differ regarding both neuronal subprocesses and examined groups. While a replication of this study is needed in a larger sample, the results suggest that tasks have to be carefully selected when examining neural activation patterns of response inhibition either in research on various psychiatric disorders or transdiagnostic questions.
Patients with neuroendocrine tumors (NET) often go through a long phase between onset of symptoms and initial diagnosis. Assessment of time to diagnosis and pre-clinical pathway in patients with gastroenteropancreatic NET (GEP-NET) with regard to metastases and symptoms. Retrospective analysis of patients with GEP-NET at a tertiary referral center from 1984 to 2019; inclusion criteria: Patients ≥18 years, diagnosis of GEP-NET; statistical analysis using non-parametrical methods. Four hundred eighty-six patients with 488 tumors were identified; median age at first diagnosis (478/486, 8 unknown) was 59 years; 52.9% male patients. Pancreatic NET: 143/488 tumors; 29.3%; small intestinal NET: 145/488 tumors, 29.7%. 128/303 patients (42.2%) showed NET specific and 122/486 (25%) patients other tumor-specific symptoms. 222/279 patients had distant metastases at initial diagnosis (187/222 liver metastases). 154/488 (31.6%) of GEP-NET were incidental findings. Median time from tumor manifestation (e.g., symptoms related to NET) to initial diagnosis across all entities was 19.5 (95% CI: 12–28) days. No significant difference in patients with or without distant metastases (median 73 vs 105 days, P = .42). A large proportion of GEP-NET are incidental findings and only about half of all patients are symptomatic at the time of diagnosis. We did not find a significant influence of the presence of metastases on time to diagnosis, which shows a large variability with a median of <30 days.
Purpose: Early detection of adenocarcinomas in the esophagus is crucial for achieving curative endoscopic therapy. Targeted biopsies of suspicious lesions, as well as four-quadrant biopsies, represent the current diagnostic standard. However, this procedure is time-consuming, cost-intensive, and examiner-dependent. The aim of this study was to test whether impedance spectroscopy is capable of distinguishing between healthy, premalignant, and malignant lesions. An ex vivo measurement method was developed to examine esophageal lesions using impedance spectroscopy immediately after endoscopic resection. Methods: After endoscopic resection of suspicious lesions in the esophagus, impedance measurements were performed on resected cork-covered tissue using a measuring head that was developed, with eight gold electrodes, over 10 different measurement settings and with frequencies from 100 Hz to 1 MHz. Results: A total of 105 measurements were performed in 60 patients. A dataset of 400 per investigation and a total of more than 42,000 impedance measurements were therefore collected. Electrical impedance spectroscopy (EIS) was able to detect dysplastic esophageal mucosa with a sensitivity of 81% in Barrett’s esophagus. Conclusion: In summary, EIS was able to distinguish different tissue characteristics in the different esophageal tissues. EIS thus holds potential for further development of targeted biopsies during surveillance endoscopy.
Introduction: In an emergency department, the majority of pediatric trauma patients present because of minor injuries. The aim of this study was to evaluate temporal changes in age-related injury pattern, trauma mechanism, and surgeries in pediatric patients. Methods: This retrospective study included patients < 18 years of age following trauma from 01/2009 to 12/2018 at a level I trauma center. They were divided into two groups: group A (A: 01/2009 to 12/2013) and group B (B: 01/2014 to 12/2018). Injury mechanism, injury pattern, and surgeries were analyzed. As major injuries fractures, dislocations, and organ injuries and as minor injuries contusions and superficial wounds were defined. Results: 23,582 patients were included (58% male, median age 8.2 years). There was a slight increase in patients comparing A (n = 11,557) and B (n = 12,025) with no difference concerning demographic characteristics. Significant more patients (A: 1.9%; B: 2.4%) were admitted to resuscitation room, though the number of multiple injured patients was not significantly different. In A (25.5%), major injuries occurred significantly less frequently than in B (27.0%), minor injuries occurred equally. Extremity fractures were significantly more frequent in B (21.5%) than in A (20.2%), peaking at 8–12 years. Most trauma mechanisms of both groups were constant, with a rising of sport injuries at 8–12 years. Conclusion: Although number of patients increases only slightly over a decade, there was a clear increase in major injuries, particularly extremity fractures, peaking at 8–12 years. At this age also sport accidents significantly increased. At least, admittance to resuscitation room rose but without an increase of multiple injured patients.
Introduction: Improvements in both musculoskeletal and non-musculoskeletal manifestations are important treatment goals in psoriatic arthritis (PsA). Objective: These post hoc analyses determined whether additional benefits related to various PsA domains are observed in patients simultaneously achieving 50% improvement in American College of Rheumatology criteria (ACR50) and 100% improvement in Psoriasis Area Severity Index (PASI100), the primary endpoint of the SPIRIT-H2H study. Methods: Patients with active PsA and psoriasis in SPIRIT-H2H (N = 566) were categorised into two sets of four response groups irrespective of treatment allocation (approved dosages of ixekizumab or adalimumab): patients who simultaneously achieved ACR50 and PASI100 response, achieved ACR50 response only, achieved PASI100 response only, or did not achieve ACR50 or PASI100 response after 24 and 52 weeks of treatment. Patients achieving simultaneous ACR50 and PASI100 response were compared with the other patient response groups at the corresponding time point for efficacy and health-related quality of life (HRQoL) outcomes. Results: Patients simultaneously achieving ACR50 and PASI100 responses at week 24 or 52 showed higher rates of ACR70 response, minimal disease activity, Disease Activity in Psoriatic Arthritis ≤ 4, resolution of enthesitis and dactylitis, and HRQoL improvement at weeks 24 and 52, respectively, than the other corresponding response groups at both time points. Conclusion: High levels of disease control, such as those obtained with simultaneous achievement of ACR50 and PASI100 response, were linked to better outcomes across a wide range of endpoints that are important for patients with PsA. Patients meeting this combined endpoint showed more comprehensive and thus greater control of disease activity.
Purpose: To investigate short-term (3 months follow-up) changes in visual quality following Descemet membrane endothelial keratoplasty (DMEK) for Fuchs endothelial dystrophy (FED). Methods: In this prospective institutional case series, 51 patients that underwent DMEK for FED were included. Assessment included the Quality of Vision (QoV) questionnaire preoperatively, at 1 month, and 3 months after surgery. Secondary outcome measures were anterior segment parameters acquired by Scheimpflug imaging, corrected distance visual acuity (CDVA), and endothelial cell density (ECD). Results: Glare, hazy vision, blurred vision, and daily fluctuation in vision were the symptoms mostly reported preoperatively. All symptoms demonstrated a significant reduction of item scores for severity, frequency, and bothersome in the course after DMEK (P < 0.01). Glare and fluctuation in vision remained to some extent during the follow-up period (median score = 1). Preoperatively, corneal densitometry correlated moderately to weakly with severity of hazy vision (rs = 0.39; P = 0.03) and frequency (rs = 0.26; P = 0.02) as well as severity (rs = 0.27; P = 0.03) of blurry vision. CDVA and central corneal thickness (CCT) did not correlate with visual complains. Conclusions: Following DMEK for FED, patient-reported visual symptoms assessed by the QoV questionnaire represent a useful tool providing valuable information on the impact of DMEK on visual quality that cannot be directly estimated by morphological parameters and visual acuity only.
Background: Due to the coronavirus disease 2019 (COVID-19) pandemic, interventions in the upper airways are considered high-risk procedures for otolaryngologists and their colleagues. The purpose of this study was to evaluate limitations in hearing and communication when using a powered air-purifying respirator (PAPR) system to protect against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) transmission and to assess the benefit of a headset. Methods: Acoustic properties of the PAPR system were measured using a head and torso simulator. Audiological tests (tone audiometry, Freiburg speech test, Oldenburg sentence test (OLSA)) were performed in normal-hearing subjects (n = 10) to assess hearing with PAPR. The audiological test setup also included simulation of conditions in which the target speaker used either a PAPR, a filtering face piece (FFP) 3 respirator, or a surgical face mask. Results: Audiological measurements revealed that sound insulation by the PAPR headtop and noise, generated by the blower-assisted respiratory protection system, resulted in significantly deteriorated hearing thresholds (4.0 ± 7.2 dB hearing level (HL) vs. 49.2 ± 11.0
Objectives: To evaluate the predictive value of volumetric bone mineral density (BMD) assessment of the lumbar spine derived from phantomless dual-energy CT (DECT)-based volumetric material decomposition as an indicator for the 2-year occurrence risk of osteoporosis-associated fractures. Methods: L1 of 92 patients (46 men, 46 women; mean age, 64 years, range, 19–103 years) who had undergone third-generation dual-source DECT between 01/2016 and 12/2018 was retrospectively analyzed. For phantomless BMD assessment, dedicated DECT postprocessing software using material decomposition was applied. Digital files of all patients were sighted for 2 years following DECT to obtain the incidence of osteoporotic fractures. Receiver operating characteristic (ROC) analysis was used to calculate cut-off values and logistic regression models were used to determine associations of BMD, sex, and age with the occurrence of osteoporotic fractures. Results: A DECT-derived BMD cut-off of 93.70 mg/cm3 yielded 85.45% sensitivity and 89.19% specificity for the prediction to sustain one or more osteoporosis-associated fractures within 2 years after BMD measurement. DECT-derived BMD was significantly associated with the occurrence of new fractures (odds ratio of 0.8710, 95% CI, 0.091–0.9375, p < .001), indicating a protective effect of increased DECT-derived BMD values. Overall AUC was 0.9373 (CI, 0.867–0.977, p < .001) for the differentiation of patients who sustained osteoporosis-associated fractures within 2 years of BMD assessment. Conclusions: Retrospective DECT-based volumetric BMD assessment can accurately predict the 2-year risk to sustain an osteoporosis-associated fracture in at-risk patients without requiring a calibration phantom. Lower DECT-based BMD values are strongly associated with an increased risk to sustain fragility fractures.
Key Points: Dual-energy CT–derived assessment of bone mineral density can identify patients at risk to sustain osteoporosis-associated fractures with a sensitivity of 85.45% and a specificity of 89.19%. The DECT-derived BMD threshold for identification of at-risk patients lies above the American College of Radiology (ACR) QCT guidelines for the identification of osteoporosis (93.70 mg/cm 3 vs 80 mg/cm 3 ).