The current situation of tutoring in specialised training in otorhinolaryngology-head and neck surgery in Spain. Where are we? Where do we want to go?

BACKGROUND AND OBJECTIVE: There is great heterogeneity in the methodology and evaluation in specialized health training (SHT) in otorhinolaryngology in our country. The figure of the resident tutor is the cornerstone on which the ESF system is based and the regulation and recognition of this figure varies. This article aims to take a snapshot of the current situation of the ESF in Spain and to describe the activity of tutors. MATERIALS AND METHODS: During the month of September 2023, a survey was sent in a Google Forms® format through the Spanish Society of Otolaryngology and Head and Neck Surgery. The survey consisted of 8 multiple-choice questions and 4 questions in which they were asked to rank a series of 5 weaknesses, threats, opportunities and strengths selected by the authors, in order to perform a SWOT analysis. RESULTS: A total of 103 responses were obtained, of which 81 corresponded to accredited tutors. 63% of the tutors indicated that they did not have enough time to carry out their teaching work and 48% did not carry out a regular assessment of their residents. 64% of the tutors believe that the quality of otorhinolaryngology training in Spain is good and 61% are satisfied with their job as tutors. The main weakness was the short duration of the training programme, and the pressure of care was found to be the main threat. An experienced training system was considered the main strength and the creation of a national network of tutors was seen as an opportunity for improvement. CONCLUSIONS: The creation of a common and transversal otorhinolaryngology training pathway for all accredited centres and the creation of a network of mentors and residents are necessary to address the problems of SHT. The role of the tutor must be recognised and reinforced to improve specialist training.

Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models.

Patient-derived xenograft (PDX) models are widely used in cancer research. To investigate the genomic fidelity of non-small cell lung cancer PDX models, we established 48 PDX models from 22 patients enrolled in the TRACERx study. Multi-region tumor sampling increased successful PDX engraftment and most models were histologically similar to their parent tumor. Whole-exome sequencing enabled comparison of tumors and PDX models and we provide an adapted mouse reference genome for improved removal of NOD scid gamma (NSG) mouse-derived reads from sequencing data. PDX model establishment caused a genomic bottleneck, with models often representing a single tumor subclone. While distinct tumor subclones were represented in independent models from the same tumor, individual PDX models did not fully recapitulate intratumor heterogeneity. On-going genomic evolution in mice contributed modestly to the genomic distance between tumors and PDX models. Our study highlights the importance of considering primary tumor heterogeneity when using PDX models and emphasizes the benefit of comprehensive tumor sampling.

Scaling-Up Microwave-Assisted Synthesis of Highly Defective Pd@UiO-66-NH2 Catalysts for Selective Olefin Hydrogenation under Ambient Conditions.

The need to develop green and cost-effective industrial catalytic processes has led to growing interest in preparing more robust, efficient, and selective heterogeneous catalysts at a large scale. In this regard, microwave-assisted synthesis is a fast method for fabricating heterogeneous catalysts (including metal oxides, zeolites, metal-organic frameworks, and supported metal nanoparticles) with enhanced catalytic properties, enabling synthesis scale-up. Herein, the synthesis of nanosized UiO-66-NH2 was optimized via a microwave-assisted hydrothermal method to obtain defective matrices essential for the stabilization of metal nanoparticles, promoting catalytically active sites for hydrogenation reactions (760 kg·m-3·day-1 space time yield, STY). Then, this protocol was scaled up in a multimodal microwave reactor, reaching 86% yield (ca. 1 g, 1450 kg·m-3·day-1 STY) in only 30 min. Afterward, Pd nanoparticles were formed in situ decorating the nanoMOF by an effective and fast microwave-assisted hydrothermal method, resulting in the formation of Pd@UiO-66-NH2 composites. Both the localization and oxidation states of Pd nanoparticles (NPs) in the MOF were achieved using high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) and X-ray photoelectron spectroscopy (XPS), respectively. The optimal composite, loaded with 1.7 wt % Pd, exhibited an extraordinary catalytic activity (>95% yield, 100% selectivity) under mild conditions (1 bar H2, 25 °C, 1 h reaction time), not only in the selective hydrogenation of a variety of single alkenes (1-hexene, 1-octene, 1-tridecene, cyclohexene, and tetraphenyl ethylene) but also in the conversion of a complex mixture of alkenes (i.e., 1-hexene, 1-tridecene, and anethole). The results showed a powerful interaction and synergy between the active phase (Pd NPs) and the catalytic porous scaffold (UiO-66-NH2), which are essential for the selectivity and recyclability.

TENAYA and LUCERNE: Two-Year Results from the Phase 3 Neovascular Age-Related Macular Degeneration Trials of Faricimab with Treat-and-Extend Dosing in Year 2.

PURPOSE: To evaluate 2-year efficacy, durability, and safety of the bispecific antibody faricimab, which inhibits both angiopoietin-2 and VEGF-A. DESIGN: TENAYA (ClinicalTrials.gov identifier, NCT03823287) and LUCERNE (ClinicalTrials.gov identifier, NCT03823300) were identically designed, randomized, double-masked, active comparator-controlled phase 3 noninferiority trials. PARTICIPANTS: Treatment-naive patients with neovascular age-related macular degeneration (nAMD) 50 years of age or older. METHODS: Patients were randomized (1:1) to intravitreal faricimab 6.0 mg up to every 16 weeks (Q16W) or aflibercept 2.0 mg every 8 weeks (Q8W). Faricimab fixed dosing based on protocol-defined disease activity at weeks 20 and 24 up to week 60, followed up to week 108 by a treat-and-extend personalized treatment interval regimen. MAIN OUTCOME MEASURES: Efficacy analyses included change in best-corrected visual acuity (BCVA) from baseline at 2 years (averaged over weeks 104, 108, and 112) and proportion of patients receiving Q16W, every 12 weeks (Q12W), and Q8W dosing at week 112 in the intention-to-treat population. Safety analyses included ocular adverse events (AEs) in the study eye through study end at week 112. RESULTS: Of 1326 patients treated across TENAYA/LUCERNE, 1113 (83.9%) completed treatment (n = 555 faricimab; n = 558 aflibercept). The BCVA change from baseline at 2 years was comparable between faricimab and aflibercept groups in TENAYA (adjusted mean change, +3.7 letters [95% confidence interval (CI), +2.1 to +5.4] and +3.3 letters [95% CI, +1.7 to +4.9], respectively; mean difference, +0.4 letters [95% CI, -1.9 to +2.8]) and LUCERNE (adjusted mean change, +5.0 letters [95% CI, +3.4 to +6.6] and +5.2 letters [95% CI, +3.6 to +6.8], respectively; mean difference, -0.2 letters [95% CI, -2.4 to +2.1]). At week 112 in TENAYA and LUCERNE, 59.0% and 66.9%, respectively, achieved Q16W faricimab dosing, increasing from year 1, and 74.1% and 81.2%, achieved Q12W or longer dosing. Ocular AEs in the study eye were comparable between faricimab and aflibercept groups in TENAYA (55.0% and 56.5% of patients, respectively) and LUCERNE (52.9% and 47.5% of patients, respectively) through week 112. CONCLUSIONS: Treat-and-extend faricimab treatment based on nAMD disease activity maintained vision gains through year 2, with most patients achieving extended dosing intervals. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Heterogeneity in disease activity, frequency of treatments, and visual outcomes among patients with retinal vein occlusion: relationship between injection need and vision with as-needed ranibizumab.

BACKGROUND/AIMS: We characterised the relationships between monitoring frequency, ranibizumab injection need and vision in patients receiving as-needed (pro re nata; PRN) ranibizumab for macular oedema due to branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO) in this post-hoc analysis of SHORE and HORIZON. METHODS: Patients aged 18 years and older with macular oedema due to BRVO/CRVO were included in this analysis. Injection frequency and best-corrected visual acuity (BCVA) were evaluated by PRN injection frequency in the PRN dosing phase (months (M) 7-15) of SHORE and through 12 months of HORIZON. Prespecified PRN re-treatment criteria for each trial were based on protocol-prespecified BCVA and optical coherence tomography outcomes. RESULTS: After the initial 7 monthly ranibizumab injections, patients in SHORE gained a mean of 18.3 letters from baseline. Patients randomised to PRN, on average, maintained these gains. However, some patients experienced additional mean gains, whereas others suffered losses (range 4.0 (95% CI 0.7 to 7.3) to -4.6 (95% CI -11.8 to 2.6) letters in patients who received 0 and 6-7 PRN injections, respectively). In BRAVO and CRUISE (lead-in trials), patients experienced mean gains from baseline to M6 (monthly dosing) of 19.3 and 15.0 letters, respectively, with gains maintained with PRN from M6 to M12. However, mean BCVA changes from baseline to M12 varied in HORIZON (range -0.4 (95% CI -2.5 to 1.6) to -3.6 (95% CI -6.2 to -1.0) letters in patients who received zero and six injections, respectively, during the preceding PRN phase of BRAVO and CRUISE). CONCLUSION: The BRVO/CRVO population is heterogenous with a varied response to ranibizumab treatment.

The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance.

In this study, the impact of the apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3B expression in EGFR mutant (EGFRmut) non-small-cell lung cancer (NSCLC) mouse models constrained tumorigenesis, while A3B expression in tumors treated with EGFR-targeted cancer therapy was associated with treatment resistance. Analyses of human NSCLC models treated with EGFR-targeted therapy showed upregulation of A3B and revealed therapy-induced activation of nuclear factor kappa B (NF-κB) as an inducer of A3B expression. Significantly reduced viability was observed with A3B deficiency, and A3B was required for the enrichment of APOBEC mutation signatures, in targeted therapy-treated human NSCLC preclinical models. Upregulation of A3B was confirmed in patients with NSCLC treated with EGFR-targeted therapy. This study uncovers the multifaceted roles of A3B in NSCLC and identifies A3B as a potential target for more durable responses to targeted cancer therapy.

Incidence of Small Intestinal Bacterial Overgrowth and Symptoms After 7 Days of Proton Pump Inhibitor Use: A Study on Healthy Volunteers.

INTRODUCTION: Proton pump inhibitors (PPIs) are commonly prescribed drugs. Chronic PPI use has recently been associated with the risk for developing small intestinal bacterial overgrowth (SIBO). It is not known whether the short-term prescription of a PPI can trigger SIBO. Therefore, the aim of the present study was to evaluate the incidence of SIBO and gastrointestinal symptoms after 7 days of PPI use. MATERIALS AND METHODS: A prospective, pilot, open-label study was conducted on asymptomatic healthy volunteers. The incidence of SIBO was evaluated at the baseline and after administration of 40 mg of pantoprazole once a day for 7 days, through a glucose breath test. In addition, the presence of gastrointestinal symptoms, the number of bowel movements, and the consistency of stools, according to the Bristol scale, were assessed. RESULTS: Thirty-eight healthy subjects (71.1% women, mean age 25.18 ± 6.5 years) were analyzed. The incidence of SIBO after 7 days of PPI administration was 7.8% (95% CI 1.6-21.3%). The patients that developed SIBO had a greater prevalence of bloating (p = 0.0002) and flatulence (p = 0.004) after 7 days of treatment. CONCLUSIONS: Our study showed that a short-term 7-day PPI course produced SIBO in 7.8% of healthy subjects. Although, inappropriate use of PPIs should be discouraged, but since more than 90% of subjects who received PPIs for one week did not develop SIBO, the advantages of PPI administration seem to outweigh the disadvantages.

Spread of local anesthetic injected in the paravertebral space, intertransverse processes space, and erector spinae plane: a cadaveric model.

INTRODUCTION: Paraspinal fascial plane blocks have become popular and include the erector spinae plane (ESP) and intertransverse process (ITP) blocks. Controversy exists regarding the exact mechanism(s) of these blocks. We aimed to evaluate the spread of local anesthetic (LA) following ESP and ITP blocks as compared with paravertebral (PV) blocks in a cadaveric model. METHOD: Single-injection ultrasound guided ESP (n=5), ITP (n=5), and PV (n=5) blocks were performed in 15 fresh cadaver hemithoraces. The extent of LA spread within the erector spinae fascial plane, involvement of the dorsal ramus, and distribution within the PV space, were qualitatively described. RESULTS: The spread of LA following ESP block extended eight vertebral levels in a cranio-caudal direction, involving the dorsal ramus at each level, but without LA spread into the PV space nor to the ventral rami. LA spread following ITP block extended 1-2 vertebral levels within the PV space and 7 vertebral levels within the erector spinae fascial plane. The spread of LA following PV blocks extended 2-4 vertebral levels, involving the ventral and dorsal ramus at each level, but without LA spread into the ESP. CONCLUSION: Based on the results of this cadaveric experimental model of paraspinal fascial plane blocks, LA spread following ITP blocks extends into both the PV space and the erector spine fascial plane, and thus may offer a more favorable analgesic profile than ESP blocks.

Enzyme kinetics of deoxyuridine triphosphatase from Western corn rootworm.

OBJECTIVE: The Western corn rootworm (WCR), Diabrotica virgifera virgifera, is a highly adaptable insect pest that has evolved resistance to a variety of control strategies, including insecticides. Therefore, it is interesting to examine how housekeeping proteins in WCR have been changed under WCR-controlling strategies. In this study, we focused on one of such proteins in WCR, a ubiquitous enzyme 5'-triphosphate nucleotidohydrolase (dUTPase). In the thymidine synthetic pathway, dUTPase hydrolyzes deoxyuridine triphosphate (dUTP) and supplies the substrate, deoxyuridine monophosphate, for the thymidylate synthase (TS). It decreases the cellular content of uracil, reducing uracil misincorporation into DNA. Suppressing the dUTPase activity, therefore, contributes to thymineless death. In this study, we investigated the enzymatic properties of dUTPase. RESULTS: The WCR dUTPase gene (DUT) was synthesized with the addition of His-tag corresponding DNA sequence and then cloned and expressed in Escherichia coli, and the protein product was purified. The product of WCR DUT hydrolyzed dUTP and was designated as dUTPase. WCR dUTPase did not hydrolyze dATP, dTTP, dCTP, or dGTP. WCR dUTPase was analyzed via size-exclusion chromatography and exhibited a molecular weight corresponding to that of trimer. The present format can be interpreted as nuclear trimer type. Possible isomers will be examined once transcriptome analyses are conducted.

First report of Aphrialatifrons (Diptera, Tachinidae, Leskiini) in the Canary Islands.

Background: The Canary Islands are an archipelago of volcanic origin, located off north-west Africa comprising eight islands. Fuerteventura and Lanzarote are the oldest (20 and 15 millon years old, respectively) and the easternmost islands. The order Diptera is one of the most relevant taxa in the Canary Islands as they constitute the second highest species richness. Within this order, the family Tachinidae is especially interesting as all species are endoparasitoids of arthropods and most species play a key role as pollinators. In the Canary Islands, the family comprises 52 species, with Fuerteventura and Lanzarote harbouring up to 20 species each. New information: Aphrialatifrons, a Palaearctic tachinid fly, is reported for the first time from the Canary Islands, where it was found on Fuerteventura and Lanzarote. Morphological examination was carried out and the first known barcode of the species is presented. Its potential distribution and source of origin are discussed.

Wellens pattern as the debut of acute pulmonary embolism: A case report.

The Wellens pattern is an electrocardiographic finding seen in patients with chest pain and atherosclerotic coronary artery disease and is described as a symmetrical T-wave inversion or biphasic T-wave inversion in precordial leads. The deep inversion of the precordial T wave is a sign associated with various etiologies, including left ventricular hypertrophy, vasospasm, and pulmonary embolism. We present the case of a patient who debuts with chest pain and electrocardiographic findings consistent with the Wellens and McGinn-White patterns, who was subsequently diagnosed with intermediate-risk pulmonary embolism after ruling out obstructive coronary artery disease. We discussed the differential diagnostic approach to T-wave inversion as a sign associated with high-risk conditions.

Prevalence, Knowledge and Perceptions of Smoking and Tobacco Products and Vape Among SEPAR Members.

Introduction: The professional dedicated to respiratory health has an exemplary role in tobacco control, promoting smoking cessation in their patients. However, multiple circumstances cause a low implementation. Therefore, the objective of the study is to identify the consumption, knowledge and perception of tobacco and its emerging products in a representative sample of professionals involved in the treatment of respiratory patients integrated into the Spanish Society of Pneumology and Thoracic Surgery (SEPAR). Methods: Descriptive analysis of a structured online interview addressed to 5340 SEPAR members. Results: In a sample of 802 respondents, more than 33% have smoked at some time and 6.6% continue to smoke. More than 66% consider smoking as a chronic disease. More than 90% consider their role model important and advise their patients to quit smoking, but less than half carry out a smoking intervention. Only 35% of them believe that the ban on smoking in health centers is always complied. More than 75% do not consider nicotine delivery devices an option for smoking cessation or harm reduction. 22% are unaware of water pipes and 29% of heated tobacco. Conclusions: Professionals specialized in respiratory diseases are highly sensitized to smoking. Despite this, there are still weak points such as the insufficient implementation of smoking cessation interventions or the scant training in smoking and in new emerging products.

Introducción: El profesional dedicado a la salud respiratoria tiene un papel ejemplar en el control del tabaquismo, promoviendo el abandono del hábito tabáquico en sus pacientes. Sin embargo, múltiples circunstancias provocan una baja implementación. Por tanto, el objetivo del estudio es identificar el consumo, el conocimiento y la percepción sobre el tabaco y sus productos emergentes en una muestra representativa de profesionales implicados en el tratamiento de pacientes respiratorios integrados en la Sociedad Española de Neumología y Cirugía Torácica (SEPAR). Métodos: Análisis descriptivo de una entrevista estructurada en línea dirigida a 5.340 miembros de la SEPAR. Resultados: En una muestra de 802 encuestados, más del 33% ha fumado alguna vez y el 6.6% sigue fumando. Más del 66% considera el tabaquismo como una enfermedad crónica. Más del 90% considera importante su modelo a seguir y aconseja a sus pacientes que dejen de fumar, pero menos de la mitad realiza una intervención para dejar de fumar. Solo el 35% de ellos cree que la prohibición de fumar en los centros de salud se cumple siempre. Más del 75% no considera que los dispositivos de suministro de nicotina sean una opción para dejar de fumar o reducir los daños. El 22% desconoce las pipas de agua y el 29% el tabaco calentado. Conclusiones: Los profesionales especialistas en enfermedades respiratorias están altamente sensibilizados al tabaquismo. A pesar de ello, aún existen puntos débiles como la insuficiente implantación de intervenciones para dejar de fumar o la escasa formación en tabaquismo y en nuevos productos emergentes.

Clinical Practice Guideline of Spanish Society of Pneumology and Thoracic Surgery (SEPAR) on Pharmacological Treatment of Tobacco Dependence 2023.

INTRODUCTION: There are multiple systematic reviews and meta-analyses on the efficacy and safety of pharmacological treatments against nicotine dependence. However, there are few guidelines to answer frequent questions asked by a clinician treating a smoker. Therefore, the aim of this paper is to facilitate the treatment of tobacco addiction. MATERIAL AND METHODS: 12 PICO questions are formulated from a GLOBAL PICO question: "Efficacy and safety of pharmacological treatment of tobacco dependence". A systematic review was carried out to answer each of the questions and recommendations were made. The GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system was used to grade the certainty of the estimated effects and the strength of the recommendations. RESULTS: Varenicline, nicotine replacement therapy (NRT), bupropion and cytisine are more effective than placebo. Varenicline and combined nicotine therapy are superior to the other therapies. In smokers with high dependence, a combination of drugs is recommended, being more effective those associations containing varenicline. Other optimization strategies with lower efficacy consist of increasing the doses, the duration, or retreat with varenicline. In specific populations varenicline or NRT is recommended. In hospitalized, the treatment of choice is NRT. In pregnancy it is indicated to prioritize behavioral treatment. The financing of smoking cessation treatments increases the number of smokers who quit smoking. There is no scientific evidence of the efficacy of pharmacological treatment of smoking cessation in adolescents. CONCLUSIONS: The answers to the 12 questions allow us to extract recommendations and algorithms for the pharmacological treatment of tobacco dependence.

The N-Terminal Region of the BcWCL1 Photoreceptor Is Necessary for Self-Dimerization and Transcriptional Activation upon Light Stimulation in Yeast.

The BcWCL1 protein is a blue-light photoreceptor from the fungus Botrytis cinerea. This protein has a central role in B. cinerea circadian regulation and is an ortholog to WC-1 from Neurospora crassa. The BcWCL1 and WC-1 proteins have similar protein domains, including a LOV (Light Oxygen Voltage) domain for light sensing, two PAS (Per Arnt Sim) domains for protein-protein interaction, and a DNA binding domain from the GATA family. Recently, the blue-light response of BcWCL1 was demonstrated in a version without PAS domains (BcWCL1PAS∆). Here, we demonstrated that BcWCL1PAS∆ is capable of self-dimerization through its N-terminal region upon blue-light stimulation. Interestingly, we observed that BcWCL1PAS∆ enables transcriptional activation as a single component in yeast. By using chimeric transcription factors and the luciferase reporter gene, we assessed the transcriptional activity of different fragments of the N-terminal and C-terminal regions of BcWCL1PAS∆, identifying a functional transcriptional activation domain (AD) in the N-terminal region that belongs to the 9aaTAD family. Finally, we determined that the transcriptional activation levels of BcWCL1PAS∆ AD are comparable to those obtained with commonly used ADs in eukaryotic cells (Gal4 and p65). In conclusion, the BcWCL1PAS∆ protein self-dimerized and activated transcription in a blue-light-dependent fashion, opening future applications of this photoreceptor in yeast optogenetics.