Epidermal growth factor receptor (EGFR) is overexpressed in up to 90% of head and neck squamous cell carcinoma (HNSCC) tumors. Cetuximab is the first targeted (anti-EGFR) therapy approved for the ...treatment of HNSCC patients. However, its efficacy is limited due to primary and secondary resistance, and there is no predict biomarkers of response. New generation of EGFR inhibitors with pan HER targeting and irreversible action, such as afatinib and allitinib, represents a significant therapeutic promise. In this study, we intend to compare the potential cytotoxicity of two anti-EGFR inhibitors (afatinib and allitinib) with cetuximab and to identify potential predictive biomarkers of response in a panel of HNSCC cell lines. The mutational analysis in the eight HNSCC cell lines revealed an
mutation (p.H773Y) and gene amplification in the HN13 cells. According to the growth inhibition score (GI), allitinib was the most cytotoxic drug, followed by afatinib and finally cetuximab. The higher AKT phosphorylation level was associated with resistance to anti-EGFR agents. Therefore, we further performed drug combinations with anti-AKT agent (MK2206) and
gene editing, which demonstrated afatinib and allitinib sensitivity restored. Additionally,
analysis of TCGA database showed that AKT1 overexpression was present in 14.7% (41/279) of HNSCC cases, and was associated with perineural invasion in advanced stage. In conclusion, allitinib presented a greater cytotoxic profile when compared to afatinib and cetuximab. AKT pathway constitutes a predictive marker of allitinib response and combination with AKT inhibitors could restore response and increase treatment success.
Abstract Aim Anthropogenic‐driven biodiversity loss can impact ecosystem stability. However, most studies have only evaluated the diversity–stability relationship at the local scale and we do not ...fully understand which factors stabilize animal populations and communities across scales. Here, we investigate the role of species dispersal ability, climate, spatial distance and different facets of biodiversity on the stability of butterfly populations and communities across multiple spatial scales. Location Primarily Western Europe. Time Period 2005–2016. Major Taxa Studied Butterflies (Rhopalocera) of Europe. Methods We assembled a continent‐wide database of European butterflies' abundance and used Structural Equation Modelling to evaluate the direct and indirect effects of multiple stabilizing mechanisms. In parallel, we tested the effect of dispersal ability on the stability at multiple spatial scales, using a butterfly mobility index as an indicator of dispersal capacity. Results Regional stability strongly reflected local stability, which in turn was driven by both taxonomic and functional α‐diversity. Spatial asynchrony was also important for regional stability and it was driven by both functional β‐diversity and metapopulation asynchrony, which in turn increased with spatial distance among communities. We observed a positive effect of temperature on functional α‐diversity and on local stability, whereas precipitation negatively influenced local diversity. Finally, spatial asynchrony contributed more to the regional stability of less mobile species compared to highly mobile ones, indicating that both extrinsic and intrinsic determinants of connectivity impact regional stability indirectly. Main Conclusions Our results demonstrate the importance of local and regional processes for regional stability. However, the relative contribution of spatial asynchrony and metapopulation asynchrony increases with connectivity loss, especially for less mobile species, indicating that landscape management should be tailored depending on the dispersal capacity of organisms. Both local biodiversity loss and regional biotic homogenization destabilize metacommunities, with potential implications for the reliable provision of ecosystem functions.
Antigen-detecting rapid diagnostic tests (Ag-RDTs) for SARS-CoV-2 are important diagnostic tools. We assessed clinical performance and ease-of-use of seven Ag-RDTs in a prospective, ...manufacturer-independent, multi-centre cross-sectional diagnostic accuracy study to inform global decision makers.
Unvaccinated participants suspected of a first SARS-CoV-2 infection were recruited at six sites (Germany, Brazil). Ag-RDTs were evaluated sequentially, with collection of paired swabs for routine reverse transcription polymerase chain reaction (RT-PCR) testing and Ag-RDT testing. Performance was compared to RT-PCR overall and in sub-group analyses (viral load, symptoms, symptoms duration). To understandusability a System Usability Scale (SUS) questionnaire and ease-of-use (EoU) assessment were performed.
7471 participants were included in the analysis. Sensitivities across Ag-RDTs ranged from 70·4%-90·1%, specificities were above 97·2% for all Ag-RDTs but one (93·1%).Ag-RDTs, Mologic, Bionote, Standard Q, showed diagnostic accuracy in line with WHO targets (> 80% sensitivity, > 97% specificity). All tests showed high sensitivity in the first three days after symptom onset (≥87·1%) and in individuals with viral loads≥ 6 log10SARS-CoV2 RNA copies/mL (≥ 88·7%). Usability varied, with Rapigen, Bionote and Standard Q reaching very good scores; 90, 88 and 84/100, respectively.
Variability in test performance is partially explained by variable viral loads in population evaluated over the course of the pandemic. All Ag-RDTs reach high sensitivity early in the disease and in individuals with high viral loads, supporting their role in identifying transmission relevant infections. For easy-to-use tests, performance shown will likely be maintained in routine implementation.
Ministry of Science, Research and Arts, State of Baden-Wuerttemberg, Germany, internal funds from Heidelberg University Hospital, University Hospital Charité − Universitätsmedizin Berlin, UK Department of International Development, WHO, Unitaid.
Atrial-oesophageal fistula is a serious complication related to ablation of atrial fibrillation. As its occurrence is rare, there is a great lack of information about their mechanisms, incidence, ...presentations, and treatment. The objective of this manuscript is to present a series of cases of atrial-oesophageal fistula in Brazil, focusing on incidence, clinical presentation, and follow-up.
This is a retrospective multicentre registry of atrial-oesophageal fistula cases that occurred in eight Brazilian centres from 2003 to 2015. Ten cases (0.113%) of atrial-oesophageal fistula were reported in 8863 ablation procedures in the period. Most of the subjects were male (70%) with age 59.6 ± 9.3 years. Eight centres were reference units in atrial fibrillation ablation with an experience over than 200 procedures at the time of fistula occurrence. Oesophageal temperature monitoring was performed in eight cases using coated sensors in six. The first atrial-oesophageal fistula clinical manifestation was typically fever (in six patients), with a median onset time of 16.5 (12–43) days after ablation. There was a delay of 7.8 ± 3.3 days between the first manifestation and the diagnosis in five patients. The treatment was surgical in six cases, clinical in three and stenting in one. Seven patients died (70%) and two developed permanent neurological sequelae.
Atrial-oesophageal fistula remains a serious complication following AF ablation despite the incorporation of protective measures and increased technical experience of the groups. The high morbidity and mortality despite the treatment indicates the need to develop adequate preventive strategies.
Brazilian Society of Cardiology - The Women's Letter Oliveira, Glaucia Maria Moraes de; Negri, Fátima Elizabeth Fonseca de Oliveira; Clausell, Nadine Oliveira ...
Arquivos brasileiros de cardiologia,
06/2019, Volume:
112, Issue:
6
Journal Article
We analyzed the association between HLA polymorphisms and susceptibility to SARS‐CoV‐2 infection and disease severity. Genotyping data from a total of 9373 COVID‐19‐positive cases from the Spanish ...Coalition to Unlock Research on Host Genetics on COVID‐19 (SCOURGE) consortium and 5943 population controls were included in the study. We found an association of the alleles HLA‐B*14:02 and HLA‐C*08:02 with a lower risk to COVID‐19 infection (p = 0.006, OR = 0.84, 95% CI = 0.75–0.95, p = 0.024, OR = 0.86, 95% CI = 0.78–0.95, respectively). We also found the alleles HLA‐A*11:01 and HLA‐C*04:01 associated with disease severity (p = 0.033, OR = 1.16, 95% CI = 1.04–1.31, p = 0.045, OR = 1.14, 95% CI = 1.05–1.25, respectively). These results suggest that an effective presentation of viral peptides by HLA class I alleles involve a faster infection clearance, decreasing the susceptibility and severity of COVID‐19.
Objectives We attempted to determine the prognostic value of coronary computed tomographic angiography (CTA) in patients with inconclusive functional stress tests. Background Patients with suspected ...coronary artery disease (CAD) and inconclusive noninvasive cardiac stress tests represent a frequent management challenge. Methods We examined 529 consecutive patients with suspected CAD and prior inconclusive functional stress tests. All patients underwent a coronary CTA scan using a 64-slice multidetector row scanner. CAD severity by coronary CTA was categorized as: 1) no evidence of CAD; 2) nonobstructive coronary plaques (<30%); 3) mild stenosis (30% to 49%); 4) moderate stenosis (50% to 69%); and 5) severe stenosis (≥70%). Patients were also categorized according to a modified Duke prognostic CAD index. Survival analyses were performed using Cox proportional hazards models adjusted for baseline risk factors and coronary artery calcium score. The primary outcome of the study was the combined endpoint of all-cause mortality and nonfatal myocardial infarction. Results Among patients with inconclusive stress tests, the large majority (69%) did not demonstrate significant CAD by coronary CTA. During a mean follow-up of 30.1 ± 11.1 months, there were 20 (3.8%) deaths and 17 (3.2%) nonfatal myocardial infarctions. Multivariable Cox regression analysis revealed that the presence of increasing degrees of obstructive CAD by CTA was an independent predictor of adverse events (hazard ratio HR: 1.66 95% confidence interval (CI): 1.23 to 2.23, p = 0.001). Indeed, the presence of ≥50% coronary stenosis was associated with an increased risk of events (HR: 3.15 95% CI: 1.26 to 7.89, p = 0.01). Likewise, the Duke prognostic CAD index was also found to be an independent predictor of events (HR: 1.54 95% CI: 1.20 to 1.97, p = 0.001). Conclusions Among patients with inconclusive functional stress tests, the noninvasive assessment of CAD severity by coronary CTA has been shown to provide incremental prognostic information beyond the evaluation of traditional risk factors and coronary artery calcium score.
Optimal management of A3 and A4 cervical spine fractures, as defined by the AO Spine Subaxial Injury Classification System, remains controversial. The objectives of this study were to determine ...whether significant management variations exist with respect to 1) fracture location across the upper, middle, and lower subaxial cervical spine and 2) geographic region, experience, or specialty.
A survey was internationally distributed to 272 AO Spine members across six geographic regions (North America, South America, Europe, Africa, Asia, and the Middle East). Participants' management of A3 and A4 subaxial cervical fractures across cervical regions was assessed in four clinical scenarios. Key characteristics considered in the vignettes included degree of neurological deficit, pain severity, cervical spine stability, presence of comorbidities, and fitness for surgery. Respondents were also directly asked about their preferences for operative management and misalignment acceptance across the subaxial cervical spine.
In total, 155 (57.0%) participants completed the survey. Pooled analysis demonstrated that surgeons were more likely to offer operative intervention for both A3 (p < 0.001) and A4 (p < 0.001) fractures located at the cervicothoracic junction compared with fractures at the upper or middle subaxial cervical regions. There were no significant variations in management for junctional incomplete (p = 0.116) or complete (p = 0.342) burst fractures between geographic regions. Surgeons with more than 10 years of experience were more likely to operatively manage A3 (p < 0.001) and A4 (p < 0.001) fractures than their younger counterparts. Neurosurgeons were more likely to offer surgical stabilization of A3 (p < 0.001) and A4 (p < 0.001) fractures than their orthopedic colleagues. Clinicians from both specialties agreed regarding their preference for fixation of lower junctional A3 (p = 0.866) and A4 (p = 0.368) fractures. Overall, surgical fixation was recommended more often for A4 than A3 fractures in all four scenarios (p < 0.001).
The subaxial cervical spine should not be considered a single unified entity. Both A3 and A4 fracture subtypes were more likely to be surgically managed at the cervicothoracic junction than the upper or middle subaxial cervical regions. The authors also determined that treatment strategies for A3 and A4 subaxial cervical spine fractures varied significantly, with the latter demonstrating a greater likelihood of operative management. These findings should be reflected in future subaxial cervical spine trauma algorithms.
Background
Decades of researches aiming to unveil truths about human neuropsychology may have instead unveil facts appropriate to only a fraction of the world’s population: those living in western ...educated rich democratic nations (Muthukrishna et al., 2020 Psych Sci). So far, most studies were conducted as if education and cultural assumptions on which neuropsychology is based were universals and applied everywhere in the world. The importance given to sociological or cultural factors is thus still relatively ignored. With the growth of international clinical studies on dementia, we believe that documenting the potential inter‐cultural differences at stake in a common neuropsychological assessment is an essential topic. This study thus aimed to explore these potential variations in two classical tasks used in neuropsychology that are composing the mini‐SEA (Bertoux et al., 2012 JNNP), i.e. a reduced version of the well‐known Ekman faces (FER), where one has to recognize facial emotions, and a modified version of the Faux Pas test (mFP), where one has to detect and explain social faux.
Method
The data of 573 control participants were collected through the Social Cognition & FTLD Network, an international consortium investigating social cognitive changes in dementia covering 3 continents (18 research centres in 12 countries). Impact of demographic factors and the effect of countries on performance (mini‐SEA, FER, mFP) were explored through linear mixed‐effects models.
Result
Age, education and gender were found to significantly impact the performance of the mini‐SEA subtests. Significant and important variations across the countries were also retrieved, with England having the highest performance for all scores. When controlling for demographical factors, differences within countries explained between 14% (mFP) and 24% (FER) of the variance at the mini‐SEA. These variations were not explained by any economical or sociological metrics.
Conclusion
Important variations of performance were observed across the 12 countries of the consortium, showing how cultural differences may critically impact neuropsychological performance in international studies.
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