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Introduction and objectiveThermal injuries associated with Holmium laser lithotripsy of the urinary tract are an underestimated problem in stone therapy. Surgical precision relies exclusively on visual target identification when applying laser energy for stone disintegration. This study evaluates a laser system that enables target identification automatically during bladder stone lithotripsy, URS, and PCNL in a porcine animal model.MethodsHolmium laser lithotripsy was performed on two domestic pigs by an experienced endourology surgeon in vivo. Human stone fragments (4–6 mm) were inserted in both ureters, renal pelvises, and bladders. Ho:YAG laser lithotripsy was conducted as a two-arm comparison study, evaluating the target identification system against common lithotripsy. We assessed the ureters’ lesions according to PULS and the other locations descriptively. Post-mortem nephroureterectomy and cystectomy specimens were examined by a pathologist.ResultsThe sufficient disintegration of stone samples was achieved in both setups. Endoscopic examination revealed numerous lesions in the urinary tract after the commercial Holmium laser system. The extent of lesions with the feedback system was semi-quantitatively and qualitatively lower. The energy applied was significantly less, with a mean reduction of more than 30% (URS 27.1%, PCNL 52.2%, bladder stone lithotripsy 17.1%). Pathology examination revealed only superficial lesions in both animals. There was no evidence of organ perforation in either study arm.ConclusionsOur study provides proof-of-concept for a laser system enabling automatic real-time target identification during lithotripsy on human urinary stones. Further studies in humans are necessary, and to objectively quantify this new system’s advantages, investigations involving a large number of cases are mandatory.

Background We evaluated the influence of comorbidity inferred risks for lymph node metastasis (pN1) and positive surgical margins (R1) after radical prostatectomy in order to optimize pretherapeutic risk classification. We analyzed 454 patients after radical prostatectomy (RP) between 2009 and 2014. Comorbidities were defined by patients’ medication from our electronic patient chart and stratified according to the ATC WHO code. Endpoints were lymph node metastasis (pN1) and positive surgical margins (R1). Results Rates for pN1 and R1 were 21.4% (97/454) and 29.3% (133/454), respectively. In addition to CAPRA and Gleason score, we identified diabetes as a significant medication inferred risk factor for pN1 (OR 2.9, p  = 0.004/OR 3.2, p  = 0.001/OR 3.5, p  = 0.001) and beta-blockers for R1 (OR 1.9, p  = 0.020/OR 2.9, p  = 0.004). Patients with diabetes showed no statistically significant difference in Gleason score, CAPRA Score, PSA, and age compared to non-diabetic patients. Conclusions We identified diabetes and beta1 adrenergic blockage as significant risk factors for lymph node metastasis and positive surgical margins in prostate cancer (PCa). Patients at risk will need intensive pretherapeutic staging for optimal therapeutic stratification.

Background Chimeric antigen receptor (CAR)-based T cell therapy is in early clinical trials to target the neuroectodermal tumor, neuroblastoma. No preclinical or clinical efficacy data are available for retinoblastoma to date. Whereas unilateral intraocular retinoblastoma is cured by enucleation of the eye, infiltration of the optic nerve indicates potential diffuse scattering and tumor spread leading to a major therapeutic challenge. CAR-T cell therapy could improve the currently limited therapeutic strategies for metastasized retinoblastoma by simultaneously killing both primary tumor and metastasizing malignant cells and by reducing chemotherapy-related late effects. Methods CD171 and GD2 expression was flow cytometrically analyzed in 11 retinoblastoma cell lines. CD171 expression and T cell infiltration (CD3 + ) was immunohistochemically assessed in retrospectively collected primary retinoblastomas. The efficacy of CAR-T cells targeting the CD171 and GD2 tumor-associated antigens was preclinically tested against three antigen-expressing retinoblastoma cell lines. CAR-T cell activation and exhaustion were assessed by cytokine release assays and flow cytometric detection of cell surface markers, and killing ability was assessed in cytotoxic assays. CAR constructs harboring different extracellular spacer lengths (short/long) and intracellular co-stimulatory domains (CD28/4-1BB) were compared to select the most potent constructs. Results All retinoblastoma cell lines investigated expressed CD171 and GD2. CD171 was expressed in 15/30 primary retinoblastomas. Retinoblastoma cell encounter strongly activated both CD171-specific and GD2-specific CAR-T cells. Targeting either CD171 or GD2 effectively killed all retinoblastoma cell lines examined. Similar activation and killing ability for either target was achieved by all CAR constructs irrespective of the length of the extracellular spacers and the co-stimulatory domain. Cell lines differentially lost tumor antigen expression upon CAR-T cell encounter, with CD171 being completely lost by all tested cell lines and GD2 further down-regulated in cell lines expressing low GD2 levels before CAR-T cell challenge. Alternating the CAR-T cell target in sequential challenges enhanced retinoblastoma cell killing. Conclusion Both CD171 and GD2 are effective targets on human retinoblastoma cell lines, and CAR-T cell therapy is highly effective against retinoblastoma in vitro. Targeting of two different antigens by sequential CAR-T cell applications enhanced tumor cell killing and preempted tumor antigen loss in preclinical testing.

Determining SARS-CoV-2 immunity is critical to assess COVID-19 risk and the need for prevention and mitigation strategies. We measured SARS-CoV-2 Spike/Nucleocapsid seroprevalence and serum neutralizing activity against Wu01, BA.4/5 and BQ.1.1 in a convenience sample of 1,411 patients receiving medical treatment in the emergency departments of five university hospitals in North Rhine-Westphalia, Germany, in August/September 2022. 62% reported underlying medical conditions and 67.7% were vaccinated according to German COVID-19 vaccination recommendations (13.9% fully vaccinated, 54.3% one booster, 23.4% two boosters). We detected Spike-IgG in 95.6%, Nucleocapsid-IgG in 24.0%, and neutralization against Wu01, BA.4/5 and BQ.1.1 in 94.4%, 85.0%, and 73.8% of participants, respectively. Neutralization against BA.4/5 and BQ.1.1 was 5.6- and 23.4-fold lower compared to Wu01. Accuracy of S-IgG detection for determination of neutralizing activity against BQ.1.1 was reduced substantially. We explored previous vaccinations and infections as correlates of BQ.1.1 neutralization using multivariable and Bayesian network analyses. Given a rather moderate adherence to COVID-19 vaccination recommendations, this analysis highlights the need to improve vaccine-uptake to reduce the COVID-19 risk of immune evasive variants. The study was registered as clinical trial (DRKS00029414). Dewald et al. show a high Spike-IgG seroprevalence (95%) in a multicenter study with 1,411 participants. They determined a substantially reduced serum neutralization against the SARS-CoV-2 VOCs BA.4/5 and BQ.1.1. and explored predictive factors of neutralizing activity.

Background In order to reduce the health burden and the health care costs caused by the most common mental disorders, health care systems throughout Europe have tried to improve services and treatment choices. Recently, a collaborative and stepped care (CSC) model for patients with depressive, anxiety, somatoform or alcohol-related disorders and their comorbidities was developed and implemented under routine care conditions in Germany. The aim of this study was to determine the cost-effectiveness of this CSC model from a societal perspective with a 12-month follow-up. Methods This study was part of a cluster-randomized controlled trial to compare a CSC model with treatment as usual (TAU) in patients with depressive, anxiety, somatoform or alcohol-related disorders and their comorbidities in German routine care. The cost-effectiveness of the CSC model compared with TAU was analyzed based on the incremental cost-utility ratio (ICUR) with quality-adjusted life years (QALYs) based on the EQ-5D-5L index as measure of health effect. The uncertainty of the ICUR was assessed using cost-effectiveness acceptability curves based on net-benefit regressions. Results In total, n  = 307 patients in the CSC and n  = 308 patients in the TAU group were included, with a mean age of 38 and 43 years, respectively. There were no differences in mean QALYs and total costs between the CSC (0.86 QALY, 27,174€) and the TAU group (0.86 QALY, 26,441€). Only the adjusted mean costs for outpatient mental health services were higher in the CSC group (+685€; 95% CI 398€ to 972€; p  < 0.001). The probability of cost-effectiveness of the CSC model was 35% at a willingness-to-pay (WTP) of 0€ and 34% at a WTP of 50,000€ per additional QALY. Conclusion The evaluated CSC model was unlikely to be cost-effective compared with TAU from a societal perspective for patients with depressive, anxiety, somatoform or alcohol-related disorders and their comorbidities during the 12-month follow-up period. The higher mean costs for outpatient mental health services might indicate that general practitioners in the CSC group were able to refer patients to psychotherapists and psychiatrists more frequently through the network of health care providers. Trial registration ClinicalTrials.gov: NCT03226743. Registration date: 24/7/2017.

Cancers of the digestive system are major contributors to global cancer-associated morbidity and mortality, accounting for 35% of annual cases of cancer deaths. The etiologies, molecular features, and therapeutic management of these cancer entities are highly heterogeneous and complex. Over the last decade, genomic and functional studies have provided unprecedented insights into the biology of digestive cancers, identifying genetic drivers of tumor progression and key interaction points of tumor cells with the immune system. This knowledge is continuously translated into novel treatment concepts and targets, which are dynamically reshaping the therapeutic landscape of these tumors. In this review, we provide a concise overview of the etiology and molecular pathology of the six most common cancers of the digestive system, including esophageal, gastric, biliary tract, pancreatic, hepatocellular, and colorectal cancers. We comprehensively describe the current stage-dependent pharmacological management of these malignancies, including chemo-, targeted, and immunotherapy. For each cancer entity, we provide an overview of recent therapeutic advancements and research progress. Finally, we describe how novel insights into tumor heterogeneity and immune evasion deepen our understanding of therapy resistance and provide an outlook on innovative therapeutic strategies that will shape the future management of digestive cancers, including CAR-T cell therapy, novel antibody-drug conjugates and targeted therapies.

Honeybees and wild bees are among the most important pollinators of both wild and cultivated landscapes. In recent years, however, a significant decline in these pollinators has been recorded. This decrease can have many causes including the heavy use of biocidal plant protection products in agriculture. The most frequent residues in bee products originate from fungicides, while neonicotinoids and, to a lesser extent, pyrethroids are among the most popular insecticides detected in bee products. There is abundant evidence of toxic side effects on honeybees and wild bees produced by neonicotinoids, but only few studies have investigated side effects of fungicides, because they are generally regarded as not being harmful for bees. In the field, a variety of substances are taken up by bees including mixtures of insecticides and fungicides, and their combinations can be lethal for these pollinators, depending on the specific group of insecticide or fungicide. This review discusses the different combinations of major insecticide and fungicide classes and their effects on honeybees and wild bees. Fungicides inhibiting the sterol biosynthesis pathway can strongly increase the toxicity of neonicotinoids and pyrethroids. Other fungicides, in contrast, do not appear to enhance toxicity when combined with neonicotinoid or pyrethroid insecticides. But the knowledge on possible interactions of fungicides not inhibiting the sterol biosynthesis pathway and insecticides is poor, particularly in wild bees, emphasizing the need for further studies on possible effects of insecticide-fungicide interactions in bees.

Automated detection of lesions using artificial intelligence creates new standards in medical imaging. For people with epilepsy, automated detection of focal cortical dysplasias (FCDs) is widely used because subtle FCDs often escape conventional neuroradiological diagnosis. Accurate recognition of FCDs, however, is of outstanding importance for affected people, as surgical resection of the dysplastic cortex is associated with a high chance of postsurgical seizure freedom. Here, we make publicly available a dataset of 85 people affected by epilepsy due to FCD type II and 85 healthy control persons. We publish 3D-T1 and 3D-FLAIR, manually labeled regions of interest, and carefully selected clinical features. The open presurgery MRI dataset may be used to validate existing automated algorithms of FCD detection as well as to create new approaches. Most importantly, it will enable comparability of already existing approaches and support a more widespread use of automated lesion detection tools.

Background The SARS-CoV-2 pandemic is currently leading to increasing numbers of COVID-19 patients all over the world. Clinical presentations range from asymptomatic, mild respiratory tract infection, to severe cases with acute respiratory distress syndrome, respiratory failure, and death. Reports on a dysregulated immune system in the severe cases call for a better characterization and understanding of the changes in the immune system. Methods In order to dissect COVID-19-driven immune host responses, we performed RNA-seq of whole blood cell transcriptomes and granulocyte preparations from mild and severe COVID-19 patients and analyzed the data using a combination of conventional and data-driven co-expression analysis. Additionally, publicly available data was used to show the distinction from COVID-19 to other diseases. Reverse drug target prediction was used to identify known or novel drug candidates based on finding from data-driven findings. Results Here, we profiled whole blood transcriptomes of 39 COVID-19 patients and 10 control donors enabling a data-driven stratification based on molecular phenotype. Neutrophil activation-associated signatures were prominently enriched in severe patient groups, which was corroborated in whole blood transcriptomes from an independent second cohort of 30 as well as in granulocyte samples from a third cohort of 16 COVID-19 patients (44 samples). Comparison of COVID-19 blood transcriptomes with those of a collection of over 3100 samples derived from 12 different viral infections, inflammatory diseases, and independent control samples revealed highly specific transcriptome signatures for COVID-19. Further, stratified transcriptomes predicted patient subgroup-specific drug candidates targeting the dysregulated systemic immune response of the host. Conclusions Our study provides novel insights in the distinct molecular subgroups or phenotypes that are not simply explained by clinical parameters. We show that whole blood transcriptomes are extremely informative for COVID-19 since they capture granulocytes which are major drivers of disease severity.

In October 2016, the German REACH Congress was held at the German Federal Institute for Risk Assessment (BfR) in Berlin. Here, the associated improvement made in the fields of consumer protection and the progress in and experiences gained from the implementation of the authorisation procedure were discussed. Several speakers from EU institutions, German authorities, industry, and civil society organisations were invited to present their views. There was a shared consensus that REACH contributes to the advancement of consumer protection against chemical risks, mainly because more and higher quality information on substance-related hazards and potential exposures becomes available. In addition, risk management measures, particularly regarding restrictions on uses, scale down consumer exposures to chemicals. Opportunities for improvements identified at the congress include the quality of registration dossiers and the management of and communication on substances of very high concern (SVHC) that may be present in consumer articles. Although regarded as being in an early implementation phase, the authorisation process was generally found to be operational and progressing well. Criticism was expressed with regard to the consistency of authorisation decisions and the costs and uncertainties related to authorisation applications. Consumer protection legislation consists of several legal provisions which are interlinked. The congress participants agreed that REACH is an important element of this legal framework as it enhances and complements other legal provisions.