Low tumor interleukin-1ß expression predicts a limited effect of adjuvant platinum-based chemotherapy for patients with completely resected lung adenocarcinoma: An identification and validation study.

INTRODUCTION AND OBJECTIVES: Adjuvant platinum-based chemotherapy for completely resected non-small cell lung cancer is associated with modest improvement in survival; nevertheless, no validated biomarker exists for predicting the benefit or harm of adjuvant platinum-based chemotherapy. MATERIALS AND METHODS: We simultaneously measured 27 cytokines in operative tumor specimens from a discovery cohort (n = 97) by multiplex immunoassay; half of the patients received adjuvant platinum-based chemotherapy, and the other half were observed. We tested possible prognostic and predictive factors in multivariate Cox models for overall survival (OS) and relapse-free survival (RFS), and a tree-based method was applied to detect predictive factors with respect to RFS. The results were validated in an independent validation cohort (n = 93). RESULTS: Fifty-two of 97 (54 %) patients in the discovery cohort and 50 of 93 (54 %) in the validation cohort received adjuvant chemotherapy; forty-four (85 %) patients in the discovery cohort and 37 (74 %) in the validation cohort received four cycles as planned. In patients with low IL-1ß-expressing tumors, RFS and OS were worse after adjuvant chemotherapy than after observation. The limited effect of adjuvant chemotherapy for patients with low IL-1ß-expressing tumors was confirmed in the validation cohort. Additionally, RFS and OS were prolonged by adjuvant chemotherapy only in patients with high IL-1ß-expressing tumors in the validation cohort. CONCLUSIONS: This study identified and validated low tumor IL-1ß expression as a potential biomarker of a limited response to adjuvant platinum-based chemotherapy after complete resection of pulmonary adenocarcinoma. This finding has the potential to inform adjuvant treatment decisions.

Mesh vs. non-mesh repair of type I hiatal hernias: a propensity-score matching analysis of 6533 patients from the Herniamed registry.

INTRODUCTION: Surgical treatment of type I hiatal sliding hernias aims to control the gastroesophageal reflux symptoms and prevention of hernia recurrence. Usually, a cruroplasty is performed to narrow the hiatal orifice. Here, it remains controversial if a mesh reinforcement of the cruroplasty should be performed, since benefits as well as mesh-associated complications have been described. METHODS: We performed a propensity-score matching analysis with data derived from the Herniamed registry comparing patients undergoing laparoscopic type I hiatal hernia repair with and without synthetic mesh. We analyzed perioperative, intraoperative, and postoperative data including data derived from the 1-year follow-up in the registry. RESULTS: 6.533 patients with an axial, type I hiatal hernia and gastroesophageal reflux are included in this analysis. Mesh augmentation of the hiatoplasty was performed in n = 1.252/6.533 (19.2%) of patients. The defect size in the subgroup of patients with mesh augmentation was with mean 16.3 cm2 [14.5; 18.2] significantly larger as in the subgroups without mesh augmentation with 10.8 cm2 [8.7; 12.9]; (p < 0.001). In patients with mesh hiatoplasty n = 479 (38.3%) Nissen and n = 773 (61.7%) Toupet fundoplications are performed. 1.207 matched pairs could be analyzed. The mean defect size after matching was with 15.9 cm2 comparable in both groups. A significant association was seen regarding recurrence (4.72% mesh vs. 7.29% non-mesh hiatoplasty, p = 0.012). The same relation can be seen for pain on exertion (8.78% vs 12.10%; p = 0.014) and pain requiring treatment (6.13% vs 9.11%; p = 0.010). All other outcome parameter showed no significant correlation. CONCLUSIONS: Our data demonstrate that mesh-reinforced laparoscopic type I hiatal hernia repair in larger defects is associated with significantly lower rates for recurrence, pain on exertion and pain requiring treatment.

A five-gene qPCR signature can classify type 2 asthma comparably to microscopy of induced sputum from severe asthma patients.

Asthma is a heterogenous disease characterized by airway inflammation and variable expiratory airflow limitation resulting in variable respiratory symptoms. Characterization of airway inflammation is important to choose the optimal treatment for severe asthma patients eligible for biological treatment. However, counting cells in induced sputum samples are a time-consuming process, highly dependent on personal skills. Replacing eosinophil and neutrophil cell counting with qPCR for transcripts of selected mast cell, and basophil genes may provide more reproducible results. Aims: The objective of this study was to compare qPCR with microscopy in asthma endotyping. Methods: A qPCR method measuring five mast cell/basophil genes was applied on induced sputum samples from 30 severe asthma patients and compared with microscopy. Target gene Ct-values (CPA3, GATA2, HDC, MS4A2, TPSAB1/TPSB2) were referenced to household ß-actin Ct values as a measure of relative mRNA abundance of the target in each sample. Target/ß-actin-ratios in eosinophilic and non-eosinophilic groups determined by microscopy with an eosinophil threshold of 3% in 400 cells were compared using Mann-Whitney U Test. Spearman´s correlations were used to test for correlation between targets vs. FENO and targets vs. blood eosinophil counts. Results: The study demonstrated a statistical difference in relative mRNA abundance for four mast cell/basophil specific genes. CPA3, GATA2, HDC and MS4A2 were elevated in eosinophilic asthma versus non-eosinophilic asthma patients. The study found that GATA2, CPA3, MS4A2 and TPSAB1/TPSB2 transcripts are positively correlated with FENO. Neither the five mast cell genes nor the five-gene signature correlated with blood eosinophils. The five-gene signature with a target/ß-actin-ratio cut-off ≥2 generated sensitivity = 87%, specificity = 94%, NPV = 88% and PPV = 92% compared to microscopy. Conclusion: This study confirms the contribution of mast cells in the pathogenesis of EA and suggests that mast cell mRNA markers could be one of the biomarkers used to identify EA.

Flow-based basophil activation test in immediate drug hypersensitivity. An EAACI task force position paper.

Diagnosing immediate drug hypersensitivity reactions (IDHRs) can pose a significant challenge and there is an urgent need for safe and reliable tests. Evidence has emerged that the basophil activation test (BAT), an in vitro assay that mirrors the in vivo response, can be a complementary test for many drugs. In this position paper, members of Task Force (TF) "Basophil activation test in the evaluation of Drug Hypersensitivity Reactions" from the European Academy of Allergy and Clinical Immunology (EAACI) present the data from a survey about the use and utility of BAT in IDHRs in Europe. The survey results indicate that there is a great interest for using BAT especially for diagnosing IDHRs. However, there are still main needs, mainly in the standardization of the protocols. Subsequently consensus-based recommendations were formulated for: (i) Technical aspects of BAT in IDHRs including type of sample, management of drugs, flow cytometry protocols, interpretation of the results; and (ii) Drug-specific aspects that should be taken into account when performing BAT in relation to betalactams, neuromuscular blocking agents, fluoroquinolones, chlorhexidine, opioids, radio contrast media, chemotherapeutics, biological agents, nonsteroidal anti-inflammatory drugs, COVID vaccine, and excipients. Moreover, aspects in the evaluation of pediatric population have also been considered. All this indicates that BAT offers the clinician and laboratory a complementary tool for a safe diagnostic for IDHRs, although its place in the diagnostic algorithm depends on the drug class and patient population (phenotype, geography, and age). The standardization of BAT is important for generalizing this method beyond the individual laboratory.

EUFOREA summit in Brussels 2023: inspiring the future of allergy & respiratory care.

In March 2023, the European Forum for Research and Education in Allergy and Airways diseases (EUFOREA) organized its bi-annual Summit in Brussels with expert panel members of EUFOREA, representatives of the EUFOREA patient advisory board, and the EUFOREA board and management teams. Its aim was to define the research, educational and advocacy initiatives to be developed by EUFOREA over the next 2 years until the 10th anniversary in 2025. EUFOREA is an international non-for-profit organization forming an alliance of all stakeholders dedicated to reducing the prevalence and burden of chronic allergic and respiratory diseases via research, education, and advocacy. Based on its medical scientific core competency, EUFOREA offers an evidence-supported platform to introduce innovation and education in healthcare leading to optimal patient care, bridging the gap between latest scientific evidence and daily practice. Aligned with the mission of improving health care, the expert panels of asthma, allergic rhinitis (AR), chronic rhinosinusitis (CRS) & European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS), allergen immunotherapy (AIT) and paediatrics have proposed and elaborated a variety of activities that correspond to major unmet needs in the allergy and respiratory field. The current report provides a concise overview of the achievements, ambitions, and action plan of EUFOREA for the future, allowing all stakeholders in the allergy and respiratory field to be up-dated and inspired to join forces in Europe and beyond.

Pan-sarbecovirus prophylaxis with human anti-ACE2 monoclonal antibodies.

Human monoclonal antibodies (mAbs) that target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein have been isolated from convalescent individuals and developed into therapeutics for SARS-CoV-2 infection. However, therapeutic mAbs for SARS-CoV-2 have been rendered obsolete by the emergence of mAb-resistant virus variants. Here we report the generation of a set of six human mAbs that bind the human angiotensin-converting enzyme-2 (hACE2) receptor, rather than the SARS-CoV-2 spike protein. We show that these antibodies block infection by all hACE2 binding sarbecoviruses tested, including SARS-CoV-2 ancestral, Delta and Omicron variants at concentrations of ~7-100 ng ml-1. These antibodies target an hACE2 epitope that binds to the SARS-CoV-2 spike, but they do not inhibit hACE2 enzymatic activity nor do they induce cell-surface depletion of hACE2. They have favourable pharmacology, protect hACE2 knock-in mice against SARS-CoV-2 infection and should present a high genetic barrier to the acquisition of resistance. These antibodies should be useful prophylactic and treatment agents against any current or future SARS-CoV-2 variants and might be useful to treat infection with any hACE2-binding sarbecoviruses that emerge in the future.

Gender differences in epigastric hernia repair: a propensity score matching analysis of 15,925 patients from the Herniamed registry.

INTRODUCTION: In recent surgical literature, gender-specific differences in the outcome of hernia surgery has been analyzed. We already know that female patients are at higher risk to develop chronic postoperative pain after inguinal, incisional, and umbilical hernia surgery. In this study, we evaluated the impact of gender on the outcome after epigastric hernia surgery. METHODS: A covariable-adjusted matched-paired analysis with data derived from the Herniamed registry was performed. In total of 15,925 patients with 1-year follow-up data were included in the study. Propensity score matching was performed for the 7786 female (48.9%) and 8139 male (51.1%) patients, creating 6350 pairs (81.6%). RESULTS: Matched-paired analysis revealed a significant disadvantage for female patients for pain on exertion (12.1% vs. 7.6%; p < 0.001) compared to male patients. The same effect was demonstrated for pain at rest (6.2% in female patients vs. 4.1% in male patients; p < 0.001) and pain requiring treatment (4.6% in female patients vs. 3.1% in male patients; p < 0.001). All other outcome parameters showed no significant differences between female and male patients. CONCLUSIONS: Female patients are at a higher risk for chronic pain after elective epigastric hernia repairs compared to the male patient population. These results complete findings of previous studies showing the same effect in inguinal, umbilical, and incisional hernia repair.

Organotypic human lung bud microarrays identify BMP-dependent SARS-CoV-2 infection in lung cells.

Although lung disease is the primary clinical outcome in COVID-19 patients, how SARS-CoV-2 induces lung pathology remains elusive. Here we describe a high-throughput platform to generate self-organizing and commensurate human lung buds derived from hESCs cultured on micropatterned substrates. Lung buds resemble human fetal lungs and display proximodistal patterning of alveolar and airway tissue directed by KGF. These lung buds are susceptible to infection by SARS-CoV-2 and endemic coronaviruses and can be used to track cell type-specific cytopathic effects in hundreds of lung buds in parallel. Transcriptomic comparisons of infected lung buds and postmortem tissue of COVID-19 patients identified an induction of BMP signaling pathway. BMP activity renders lung cells more susceptible to SARS-CoV-2 infection and its pharmacological inhibition impairs infection by this virus. These data highlight the rapid and scalable access to disease-relevant tissue using lung buds that recapitulate key features of human lung morphogenesis and viral infection biology.

[Inguinal hernia operations-Always outpatient?] / Leistenhernienoperationen ­ immer ambulant?

Inguinal hernia operations represent the most frequent operations overall with 300,000 interventions annually in Germany, Austria and Switzerland (DACH region). Despite the announced political willingness and the increasing pressure from the legislator to avoid costly inpatient treatment by carrying out as many outpatient operations as possible, outpatient treatment has so far played a subordinate role in the DACH region. The Boards of the specialist societies the German Hernia Society (DHG), the Surgical Working Group Hernia (CAH of the DHG), the Austrian Hernia Society (ÖHG) and the Swiss Working Group Hernia Surgery (SAHC) make inroads into this problem, describe the initial position and assess the current situation.

Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.

Common human genetic variants of APOE impact murine COVID-19 mortality.

Clinical outcomes of severe acute respiratory syndrome 2 (SARS-CoV-2) infection are highly heterogeneous, ranging from asymptomatic infection to lethal coronavirus disease 2019 (COVID-19). The factors underlying this heterogeneity remain insufficiently understood. Genetic association studies have suggested that genetic variants contribute to the heterogeneity of COVID-19 outcomes, but the underlying potential causal mechanisms are insufficiently understood. Here we show that common variants of the apolipoprotein E (APOE) gene, homozygous in approximately 3% of the world's population1 and associated with Alzheimer's disease, atherosclerosis and anti-tumour immunity2-5, affect COVID-19 outcome in a mouse model that recapitulates increased susceptibility conferred by male sex and advanced age. Mice bearing the APOE2 or APOE4 variant exhibited rapid disease progression and poor survival outcomes relative to mice bearing the most prevalent APOE3 allele. APOE2 and APOE4 mice exhibited increased viral loads as well as suppressed adaptive immune responses early after infection. In vitro assays demonstrated increased infection in the presence of APOE2 and APOE4 relative to APOE3, indicating that differential outcomes are mediated by differential effects of APOE variants on both viral infection and antiviral immunity. Consistent with these in vivo findings in mice, our results also show that APOE genotype is associated with survival in patients infected with SARS-CoV-2 in the UK Biobank (candidate variant analysis, P = 2.6 × 10-7). Our findings suggest APOE genotype to partially explain the heterogeneity of COVID-19 outcomes and warrant prospective studies to assess APOE genotyping as a means of identifying patients at high risk for adverse outcomes.

Perioperative outcome in groin hernia repair: what are the most important influencing factors?

INTRODUCTION: Using registry analyses, a large number of influencing factors on the perioperative outcome of groin hernia repair has been identified. The interactions between several influencing factors and differences in the influencing value have to date been inadequately investigated. METHODS: This retrospective analysis of prospectively collected data from the Herniamed Registry included all fully documented cases with minimum age of 16 years and groin hernia repair. Patients were assigned to the risk groups unilateral, bilateral, recurrent and emergency groin hernia repair. Multivariable analysis was performed to investigate the influence of confirmatory defined patient- and procedure-related characteristics on the outcome parameters intraoperative, postoperative general and postoperative surgical complications, complication-related reoperation and total perioperative complications. RESULTS: A highly significantly unfavorable association with the total perioperative complication rate was identified for emergency groin hernia repair, scrotal hernia, anticoagulant medication and coagulopathy. A significantly unfavorable relation with the total perioperative complication rate was found for recurrence procedure, bilateral repair, high age, ASA score III/IV, femoral hernia, antithrombotic medication, smoking, COPD and corticosteroid medication. A significantly favorable correlation with the total perioperative complication rate was observed for the laparo-endoscopic techniques, smaller defects, female gender, normal weight and medial hernia. CONCLUSION: Both the number of potential influencing factors and their influencing value on the perioperative outcome should be considered when estimating the individual risk of a patient with groin hernia repair.

What is the reality in outpatient vs inpatient groin hernia repair? An analysis from the Herniamed Registry.

INTRODUCTION: Groin hernia repair is performed increasingly more often as an outpatient procedure across the world. However, the rates are extremely different and vary between below 10% and above 90%. The outpatient procedure appears to negatively impact the proportion of laparo-endoscopic repairs. To date, only very few studies have compared inpatient vs outpatient groin hernia repair. METHODS: All outpatient and inpatient primary elective unilateral groin hernia repairs performed between 2010 and 2019 were identified in the Herniamed Registry and their treatment and outcomes compared. RESULTS: The 737 participating hospitals/surgeons performed a total of 342,072 primary elective unilateral groin hernia repairs from 2010 to 2019. The proportion of outpatient repairs was 20.2% in 2013 and 14.3% in 2019. Whereas the proportion of laparo-endoscopic repairs among the inpatient cases was 71.9% in 2019, the last year for which data are available, it was only 34.3%.for outpatient repairs. In outpatient groin hernia repairs, the rates of patients aged ≥ 60 years, with ASA score III and IV and risk factors were highly significantly lower. Given this rigorous patient selection for outpatient groin hernia repair, a more favorable perioperative outcome was achieved. At 1-year follow-up there were no significant differences in the pain and recurrence rates. CONCLUSION: With an appropriate patient selection, outpatient primary elective unilateral groin hernia repair can be performed with acceptable risks and good outcomes. Since to date no studies have compared inpatient vs outpatient groin hernia repair, the impact of a higher rate of outpatient groin hernia repair cannot currently be evaluated.

A CRISPR Activation Screen Identifies an Atypical Rho GTPase That Enhances Zika Viral Entry.

Zika virus (ZIKV) is a re-emerging flavivirus that has caused large-scale epidemics. Infection during pregnancy can lead to neurologic developmental abnormalities in children. There is no approved vaccine or therapy for ZIKV. To uncover cellular pathways required for ZIKV that can be therapeutically targeted, we transcriptionally upregulated all known human coding genes with an engineered CRISPR-Cas9 activation complex in human fibroblasts deficient in interferon (IFN) signaling. We identified Ras homolog family member V (RhoV) and WW domain-containing transcription regulator 1 (WWTR1) as proviral factors, and found them to play important roles during early ZIKV infection in A549 cells. We then focused on RhoV, a Rho GTPase with atypical terminal sequences and membrane association, and validated its proviral effects on ZIKV infection and virion production in SNB-19 cells. We found that RhoV promotes infection of some flaviviruses and acts at the step of viral entry. Furthermore, RhoV proviral effects depend on the complete GTPase cycle. By depleting Rho GTPases and related proteins, we identified RhoB and Pak1 as additional proviral factors. Taken together, these results highlight the positive role of RhoV in ZIKV infection and confirm CRISPR activation as a relevant method to identify novel host-pathogen interactions.

Replication and single-cycle delivery of SARS-CoV-2 replicons.

Molecular virology tools are critical for basic studies of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and for developing new therapeutics. Experimental systems that do not rely on viruses capable of spread are needed for potential use in lower-containment settings. In this work, we use a yeast-based reverse genetics system to develop spike-deleted SARS-CoV-2 self-replicating RNAs. These noninfectious self-replicating RNAs, or replicons, can be trans-complemented with viral glycoproteins to generate replicon delivery particles for single-cycle delivery into a range of cell types. This SARS-CoV-2 replicon system represents a convenient and versatile platform for antiviral drug screening, neutralization assays, host factor validation, and viral variant characterization.

Comparison of outcomes in rectus abdominis diastasis repair-which data do we need in a hernia registry?

INTRODUCTION: Rectus abdominis diastasis (RAD) ± concomitant hernia is a complex hernia entity of growing significance in everyday clinical practice. Due to a multitude of described surgical techniques, a so far missing universally accepted classification and hardly existing comparative studies, there are no clear recommendations in guidelines. Therefore, "RAD ± concomitant hernia" will be documented as a separate hernia entity in the Herniamed Registry in the future. For this purpose, an appropriate case report form will be developed on the basis of the existing literature. METHODS: A systematic search of the available literature was performed in March 2021 using Medline, PubMed, Google Scholar, Scopus, Embase, Springer Link, and the Cochrane Library. 93 publications were identified as relevant for this topic. RESULTS: In total 45 different surgical techniques for the repair of RAD ± concomitant hernia were identified in the surgical literature. RAD ± concomitant hernia is predominantly repaired by plastic but also by general surgeons. Classification of RAD ± concomitant hernia is based on a proposal of the German Hernia Society and the International Endohernia Society. Surgical techniques are summarized as groups subject to certain aspects: Techniques with abdominoplasty, open techniques, mini-less-open and endoscopic sublay techniques, mini-less-open and endoscopic subcutaneous/preaponeurotic techniques and laparoscopic techniques. Additional data impacting the outcome are also recorded as is the case for other hernia entities. Despite the complexity of this topic, documentation of RAD ± concomitant hernia has not proved to be any more cumbersome than for any of the other hernia entities when using this classification. CONCLUSION: Using the case report form described here, the complex hernia entity RAD ± concomitant hernia can be recorded in a registry for proper analysis of comparative treatment options.

[Small Cell Lung Cancer]. / Kleinzelliges Lungenkarzinom.

Small cell lung cancer is an aggressive cancer entity and characterized by rapid progression, early distant metastasis and poor prognosis. Only the minority of patients presents with a non-metastatic stage disease where chemo-radiotherapy or - in very selected cases - even surgical resection may be discussed. For most patients, the efficacy of systemic therapy is crucial. However, although most patients respond to platinum doublet chemotherapy, virtually all patients with metastatic disease eventually develop tumor progression for which there are limited treatment options. Recently and for the first time since decades, the systemic approaches have been enriched by the implementation of immunotherapy. Moreover, novel therapeutic approaches such as new cytotoxic agents or further immune modulatory strategies are being tested in clinical studies that might broaden our treatment options in the future even further.

Creating leadership collectives for sustainability transformations.

Enduring sustainability challenges requires a new model of collective leadership that embraces critical reflection, inclusivity and care. Leadership collectives can support a move in academia from metrics to merits, from a focus on career to care, and enact a shift from disciplinary to inter- and trans-disciplinary research. Academic organisations need to reorient their training programs, work ethics and reward systems to encourage collective excellence and to allow space for future leaders to develop and enact a radically re-imagined vision of how to lead as a collective with care for people and the planet. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11625-021-00909-y.