Adherence to Supervised and Unsupervised Exercise Programmes in Ageing Population with Intermittent Claudication: A Randomized Controlled Trial.

Background: Intermittent Claudication symptomatic peripheral arterial disease (ICSPAD) is associated with reduced mobility, functional capacity, and quality of life. Physical exercise is an effective non-pharmacological intervention for the management of ICSPAD. Adherence to exercise programs is challenging, due to the nature of the disease and the complex comorbidities associated with it. This study aimed to determine adherence to three supervised physical exercise programs (a walking intervention, strength intervention, and concurrent intervention) and an unsupervised exercise program (standard advice) in individuals with ICSPAD. Methods: In this clinical trial, 122 patients were divided into four groups based on the type of exercise program they followed: standard advice, walking intervention, strength intervention, and concurrent intervention. Results: The results revealed that while the demographic characteristics were similar, the strength intervention group had a younger mean age, and the walking group had a higher prevalence of hypertension and increased usage of anti-hypertensive drugs. Adherence to physical exercise and pedometer wearing was highest in the standard advice group. Logistic regression analysis showed lower odds of adherence to exercise and pedometer wearing in the intervention groups compared to the standard advice group. Adherence did not significantly vary across ankle-brachial index categories. Furthermore, there was no significant difference in adherence between the severity levels of intermittent claudication, though mild cases tended to exhibit higher adherence. Conclusions: The results show that the standard advice from healthcare professionals positively influences treatment adherence.

Human papillomavirus-associated head and neck squamous cell carcinoma cells lose viability during triggered myocyte lineage differentiation.

Head and neck squamous cell carcinoma (HNSCC) is a highly malignant disease, and death rates have remained at approximately 50% for decades. New tumor-targeting strategies are desperately needed, and a previous report indicated the triggered differentiation of HPV-negative HNSCC cells to confer therapeutic benefits. Using patient-derived tumor cells, we created a similar HNSCC differentiation model of HPV+ tumor cells from two patients. We observed a loss of malignant characteristics in differentiating cell culture conditions, including irregularly enlarged cell morphology, cell cycle arrest with downregulation of Ki67, and reduced cell viability. RNA-Seq showed myocyte-like differentiation with upregulation of markers of myofibril assembly. Immunofluorescence staining of differentiated and undifferentiated primary HPV+ HNSCC cells confirmed an upregulation of these markers and the formation of parallel actin fibers reminiscent of myoblast-lineage cells. Moreover, immunofluorescence of HPV+ tumor tissue revealed areas of cells co-expressing the identified markers of myofibril assembly, HPV surrogate marker p16, and stress-associated basal keratinocyte marker KRT17, indicating that the observed myocyte-like in vitro differentiation occurs in human tissue. We are the first to report that carcinoma cells can undergo a triggered myocyte-like differentiation, and our study suggests that the targeted differentiation of HPV+ HNSCCs might be therapeutically valuable.

Time from injury to hip-fracture surgery in low-income and middle-income regions: a secondary analysis of data from the International Orthopaedic Multicentre Study in Fracture Care (INORMUS).

BACKGROUND: Globally, fall-related injuries are a substantial problem, and 80% of fatal falls occur in low-income and middle-income countries. We aimed to measure time from injury to hip-fracture surgery in people aged 50 years or older living in low-income and middle-income regions, as well as to measure the proportion of patients with surgical stabilisation of their hip fracture within 72 h of admission to hospital and to identify risk factors associated with surgical delay. METHODS: For this secondary analysis, we analysed data collected from Africa, Latin America, China, India, and Asia (excluding China and India) for the International Orthopaedic Multicentre Study in Fracture Care (INORMUS) between March 29, 2014, and June 15, 2022. Patients from INORMUS were included in this analysis if they were aged 50 years or older and had an isolated, primary hip fracture sustained from a ground-level fall. Staff at participating hospitals identified patients with musculoskeletal injury and referred them for assessment of eligibility. We report time from injury to surgery as three distinct time periods: time from injury to hospital admission, time from admission to surgery, and a total time from injury to surgery. Date and time of injury were self-reported by patients at the time of study recruitment. If time to hospital admission after injury exceeded 24 h, patients reported the primary reason for delayed admission. Reasons for surgery, no surgery, and surgical delay were reported by the treating team. For patients undergoing surgery, multivariable regression analyses were used to identify risk factors for surgical delay. FINDINGS: 4486 adults aged 50 years or older with an isolated, primary hip fracture were enrolled in INORMUS from 55 hospitals in 24 countries. Countries were grouped into five regions: Africa (418 [9·3%] of 4486), Latin America (558 [12·4%]), China (1680 [37·4%]), India (1059 [23·6%]) and Asia (excluding China and India; 771 [17·2%]). Of 4486 patients, 3805 (84·8%) received surgery. The rate of surgery was similar in all regions except in Africa, where only 193 (46·3%) of 418 patients had surgery. Overall, 2791 (62·2%) of 4486 patients were admitted to hospital within 24 h of injury. However, 1019 (22·7%) of 4486 patients had delayed hospital admission of 72 h or more from injury. The two most common reasons for delayed admission of more than 24 h were transfer from another hospital (522 [36·2%] of 1441) and delayed care-seeking because patients thought the injury would heal on its own (480 [33·3%]). Once admitted to hospital, 1451 (38·1%) of 3805 patients who received surgery did so within 72 h (median 4·0 days [IQR 1·7-6·0]). Regional variation was seen in the proportion of patients receiving surgery within 72 h of hospital admission (92 [17·9%] of 514 in Latin America, 53 [27·5%] of 193 in Africa, 454 [30·9%] of 1471 in China, 318 [44·4%] of 716 in Asia [excluding China and India], and 534 [58·6%] of 911 in India). Of all 3805 patients who received operative treatment, 2353 (61·8%) waited 72 h or more from hospital admission. From time of injury, the proportion of patients who were surgically stabilised within 72 h was 889 (23·4%) of 3805 (50 [9·7%] of 517 in Latin America, 31 [16·1%] of 193 in Africa, 277 [18·8%] of 1471 in China, 189 [26·4%] of 716 in Asia [excluding China and India], and 342 [37·5%] of 911 in India). INTERPRETATION: Access to surgery within 72 h of hospital admission was poor, with factors that affected time to surgery varying by region. Data are necessary to understand existing pathways of hip-fracture care to inform the local development of quality-improvement initiatives. FUNDING: The National Health and Medical Research Council of Australia, the Canadian Institutes of Health Research, McMaster Surgical Associates, Hamilton Health Sciences, and the US National Institutes of Health.

Digital morphology network for effective teaching of cytology, histology and histopathology for medical and biology curriculum. VM3.0 Erasmus+ project.

INTRODUCTION: Digital microscopy transformation, the basis for the virtual microscopy applications, is a challenge but also a requirement in modern Medical Education. This paper presents the scope, background, methods, and results of the project "Digital Transformation of Histology and Histopathology by Virtual Microscopy (VM) for an Innovative Medical School Curriculum", VM3.0, funded by the European Union under the Erasmus+ framework (ref.no.2022-1-RO01-KA220-HED-000089017). The project was initiated at Grigore T. Popa University of Medicine and Pharmacy, Iași, Romania, with the support of Euroed Foundation, Iași, and cooperation of University partners from Gdansk (Poland), Plovdiv (Bulgaria), Alicante (Spain), and Patras (Greece) aimed to implement digital histology and histopathology teaching in a common network. MATERIALS AND METHODS: The backbone of the project was the development of a Digital Slide Platform based on the scans of histological slides collected from all the partners of the participating universities and the creation of a simple and fast digital/internet communication tool that could be used to improve histology and histopathology teaching of medical and natural sciences students. The construction of a Virtual Microscopy Library (VML) has been based on the acquisition of whole scans of high-quality histological slides stained by hematoxylin and eosin (H&E) and other classical staining methods and description of the details in English as well as respective languages of the project's partners. The VML can be used for different approches, both for students' instruction in classes as well as for individual students' work and self-testing. Universities from other countries could use the modal structure of the developed VML system on the condition that more slides are provided and the implementation of national language(s) is implemented. CONCLUSIONS: The combined efforts of all university partners allowed to establish the dynamic low-cost virtual microscopy educational system. The VM system could help unify the standards of cytology, histology, and histopathology teaching in a quest for the digital transformation of the European educational system.

Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling.

The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies.

Prevalence of obstructive sleep apnea in obese patients candidates for bariatric surgery and predictive questionnaires.

INTRODUCTION AND OBJECTIVES: Obstructive sleep apnea (OSA) is a prevalent condition among electable to bariatric surgery obese patients, often remaining underdiagnosed, thereby increasing surgical risk. The main purpose was to determine prevalence of OSA among candidates for bariatric surgery and to assess the rate of underdiagnosis of this condition. Additionally, the study aimed to evaluate the specific performance of three sleep questionnaires and scales (Excessive Daytime Sleepiness Scale (EDSS), Epworth Sleepiness Scale (ESS), and STOP-Bang) in these patients. METHODS: A longitudinal, prospective, single-cohort study, with consecutive sampling including patients aged 18-65 years with obesity grade II (body mass index (BMI) ≥ 35 kg/m2) and hypertension, type 2 diabetes, metabolic syndrome or OSA or obesity grade III or IV (BMI ≥ 40 kg/m2) elective for bariatric surgery. Patients were evaluated at the Otorhinolaryngology department with an anamnesis regarding OSA including the administration of three sleep questionnaires (EDSS, ESS, and STOP-Bang), followed by cardiorespiratory polygraphy (CRP) for sleep evaluation. RESULTS: 124 patients were included in this study. While 74.2% of the sample exhibited OSA on CRP, only 28.2% had a prior diagnosis. The STOP-Bang questionnaire demonstrated the highest sensitivity (93.3%) for detecting moderate to severe OSA, although with low specificity (33.8%). EDSS and ESS did not show a significant association with the presence of OSA. CONCLUSIONS: OSA screening is crucial in candidates for bariatric surgery due to its high prevalence and low diagnosis rate. The STOP-Bang questionnaire may serve as a useful tool for identifying patients at risk of moderate to severe OSA and optimizing sleep assessments. However, further research is necessary to validate its utility in this specific population.

Association of TLR8 Variants in Sex-Based Clinical Differences in Patients with COVID-19.

The host immune response might confer differential vulnerability to SARS-CoV-2 infection. The Toll-like receptor 8 (TLR8), could participated for severe COVID-19 outcomes. To investigated the relationship of TLR8 rs3764879-C/G, rs3764880-A/G, and rs3761624-A/G with COVID-19 outcomes and with biochemical parameters. A cross-sectional study of 830 laboratory-confirmed COVID-19 patients was performed, and classified into mild, severe, critical, and deceased outcomes. The TLR8 rs3764879-C/G, rs3764880-A/G, and rs3761624-A/G polymorphisms were genotyped. A logistic regression analysis was performed to determinate the association with COVID-19. A stratified analysis was by alleles was done with clinical and metabolic markets. In all outcomes, men presented the highest ferritin levels compared to women (P < 0.001). LDH levels were significantly different between sex in mild (P = 0.003), severe (P < 0.001) and deceased (P = 0.01) COVID-19 outcomes. The GGG haplotype showed an Odds Ratio of 1.55 (Interval Confidence 95% 1.05-2.32; P = 0.03) in men. Among patients with severe outcome, we observed that the carriers of the GGG haplotype had lower Ferritin, C-reactive protein and LDH levels than the CAA carriers (P < 0.01). After further stratified by sex, these associations were also seen in the male patients, except for D-dimer. Interestingly, among men patients, we could observe associations between TLR8 haplotypes and Ferritin (P < 0.001), D-dimer (P = 0.04), C-reactive protein, and Lactate dehydrogenase in mild (P = 0.04) group. Our results suggest that even though TLR8 haplotypes show a significant association with COVID-19 outcomes, they are associated with clinical markers in COVID-19 severity.

TRP14 is the rate-limiting enzyme for intracellular cystine reduction and regulates proteome cysteinylation.

It has remained unknown how cells reduce cystine taken up from the extracellular space, which is a required step for further utilization of cysteine in key processes such as protein or glutathione synthesis. Here, we show that the thioredoxin-related protein of 14 kDa (TRP14, encoded by TXNDC17) is the rate-limiting enzyme for intracellular cystine reduction. When TRP14 is genetically knocked out, cysteine synthesis through the transsulfuration pathway becomes the major source of cysteine in human cells, and knockout of both pathways becomes lethal in C. elegans subjected to proteotoxic stress. TRP14 can also reduce cysteinyl moieties on proteins, rescuing their activities as here shown with cysteinylated peroxiredoxin 2. Txndc17 knockout mice were, surprisingly, protected in an acute pancreatitis model, concomitant with activation of Nrf2-driven antioxidant pathways and upregulation of transsulfuration. We conclude that TRP14 is the evolutionarily conserved enzyme principally responsible for intracellular cystine reduction in C. elegans, mice, and humans.

Modulation of Serotonin-Related Genes by Extracellular Vesicles of the Probiotic Escherichia coli Nissle 1917 in the Interleukin-1ß-Induced Inflammation Model of Intestinal Epithelial Cells.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition involving dysregulated immune responses and imbalances in the gut microbiota in genetically susceptible individuals. Current therapies for IBD often have significant side-effects and limited success, prompting the search for novel therapeutic strategies. Microbiome-based approaches aim to restore the gut microbiota balance towards anti-inflammatory and mucosa-healing profiles. Extracellular vesicles (EVs) from beneficial gut microbes are emerging as potential postbiotics. Serotonin plays a crucial role in intestinal homeostasis, and its dysregulation is associated with IBD severity. Our study investigated the impact of EVs from the probiotic Nissle 1917 (EcN) and commensal E. coli on intestinal serotonin metabolism under inflammatory conditions using an IL-1ß-induced inflammation model in Caco-2 cells. We found strain-specific effects. Specifically, EcN EVs reduced free serotonin levels by upregulating SERT expression through the downregulation of miR-24, miR-200a, TLR4, and NOD1. Additionally, EcN EVs mitigated IL-1ß-induced changes in tight junction proteins and oxidative stress markers. These findings underscore the potential of postbiotic interventions as a therapeutic approach for IBD and related pathologies, with EcN EVs exhibiting promise in modulating serotonin metabolism and preserving intestinal barrier integrity. This study is the first to demonstrate the regulation of miR-24 and miR-200a by probiotic-derived EVs.

Self-propelled enzyme-controlled IR-mesoporous silica Janus nanomotor for smart delivery.

Here, we report the preparation of a novel Janus nanoparticle with opposite Ir and mesoporous silica nanoparticles through a partial surface masking with toposelective modification method. This nanomaterial was employed to construct an enzyme-powered nanomachine with self-propulsion properties for on-command delivery. The cargo-loaded nanoparticle was provided with a pH-sensitive gate and unit control at the mesoporous face by first attaching boronic acid residues and further immobilization of glucose oxidase through reversible boronic acid esters with the carbohydrate residues of the glycoenzyme. Addition of glucose leads to the enzymatic production of H2O2 and gluconic acid, being the first compound catalytically decomposed at the Ir nanoparticle face producing O2 and causing the nanomachine propulsion. Gluconic acid leads to a pH reduction at the nanomachine microenvironment causing the disruption of the gating mechanism with the subsequent cargo release. This work demonstrates that enzyme-mediated self-propulsion improved release efficiency being this nanomotor successfully employed for the smart release of Doxorubicin in HeLa cancer cells.

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.

Transcription factor Tox2 is required for metabolic adaptation and tissue residency of ILC3 in the gut.

Group 3 innate lymphoid cells (ILC3) are the major subset of gut-resident ILC with essential roles in infections and tissue repair, but how they adapt to the gut environment to maintain tissue residency is unclear. We report that Tox2 is critical for gut ILC3 maintenance and function. Gut ILC3 highly expressed Tox2, and depletion of Tox2 markedly decreased ILC3 in gut but not at central sites, resulting in defective control of Citrobacter rodentium infection. Single-cell transcriptional profiling revealed decreased expression of Hexokinase-2 in Tox2-deficient gut ILC3. Consistent with the requirement for hexokinases in glycolysis, Tox2-/- ILC3 displayed decreased ability to utilize glycolysis for protein translation. Ectopic expression of Hexokinase-2 rescued Tox2-/- gut ILC3 defects. Hypoxia and interleukin (IL)-17A each induced Tox2 expression in ILC3, suggesting a mechanism by which ILC3 adjusts to fluctuating environments by programming glycolytic metabolism. Our results reveal the requirement for Tox2 to support the metabolic adaptation of ILC3 within the gastrointestinal tract.

The role of ferroptosis as a regulator of oxidative stress in the pathogenesis of ischemic stroke.

Ferroptosis is a unique form of cell death that was first described in 2012 and plays a significant role in various diseases, including neurodegenerative conditions. It depends on a dysregulation of cellular iron metabolism, which increases free, redox-active, iron that can trigger Fenton reactions, generating hydroxyl radicals that damage cells through oxidative stress and lipid peroxidation. Lipid peroxides, resulting mainly from unsaturated fatty acids, damage cells by disrupting membrane integrity and propagating cell death signals. Moreover, lipid peroxide degradation products can further affect cellular components such as DNA, proteins, and amines. In ischemic stroke, where blood flow to the brain is restricted, there is increased iron absorption, oxidative stress, and compromised blood-brain barrier integrity. Imbalances in iron-transport and -storage proteins increase lipid oxidation and contribute to neuronal damage, thus pointing to the possibility of brain cells, especially neurons, dying from ferroptosis. Here, we review the evidence showing a role of ferroptosis in ischemic stroke, both in recent studies directly assessing this type of cell death, as well as in previous studies showing evidence that can now be revisited with our new knowledge on ferroptosis mechanisms. We also review the efforts made to target ferroptosis in ischemic stroke as a possible treatment to mitigate cellular damage and death.

The fatal contribution of serine protease-related genetic variants to COVID-19 outcomes.

Introduction: Serine proteases play a critical role during SARS-CoV-2 infection. Therefore, polymorphisms of transmembrane protease serine 2 (TMPRSS2) and serpine family E member 1 (SERPINE1) could help to elucidate the contribution of variability to COVID-19 outcomes. Methods: To evaluate the genetic variants of the genes previously associated with COVID-19 outcomes, we performed a cross-sectional study in which 1536 SARS-CoV-2-positive participants were enrolled. TMPRSS2 (rs2070788, rs75603675, rs12329760) and SERPINE1 (rs2227631, rs2227667, rs2070682, rs2227692) were genotyped using the Open Array Platform. The association of polymorphisms with disease outcomes was determined by logistic regression analysis adjusted for covariates (age, sex, hypertension, type 2 diabetes, and obesity). Results: According to our codominant model, the GA genotype of rs2227667 (OR=0.55; 95% CI = 0.36-0.84; p=0.006) and the AG genotype of rs2227667 (OR=0.59; 95% CI = 0.38-0.91; p=0.02) of SERPINE1 played a protective role against disease. However, the rs2227692 T allele and TT genotype SERPINE1 (OR=1.45; 95% CI = 1.11-1.91; p=0.006; OR=2.08; 95% CI = 1.22-3.57; p=0.007; respectively) were associated with a decreased risk of death. Similarly, the rs75603675 AA genotype TMPRSS2 had an OR of 1.97 (95% CI = 1.07-3.6; p=0.03) for deceased patients. Finally, the rs2227692 T allele SERPINE1 was associated with increased D-dimer levels (OR=1.24; 95% CI = 1.03-1.48; p=0.02). Discussion: Our data suggest that the rs75603675 TMPRSS2 and rs2227692 SERPINE1 polymorphisms are associated with a poor outcome. Additionally, rs2227692 SERPINE1 could participate in hypercoagulable conditions in critical COVID-19 patients, and this genetic variant could contribute to the identification of new pharmacological targets and treatment strategies to block the inhibition of TMPRSS2 entry into SARS-CoV-2.

Impact of COVID-19 Pandemic on Cutaneous Squamous Cell Carcinoma: A Single-Centre Study of Epidemiologic, Clinic and Histopathological Factors / Impacto de la pandemia de COVID-19 en el carcinoma de células escamosas cutáneo: un estudio unicéntrico de los factores epidemiológicos, clínicos e histopatológicos

Background: The COVID-19 pandemic may have adversely affected the early diagnosis of skin cancer. Objective To compare epidemiological, clinical and histopathological characteristics in patients undergoing cutaneous squamous cell carcinoma (SCC) surgery before and after the beginning of the pandemic. Material & methods: We conducted a cross-sectional study including two case series: (1) patients operated on for SCC in the year after the first state of alarm in Spain (15 March 2020), and (2) patients with SCC operated on in the previous year. Epidemiological, clinical and histopathological variables, tumour stage and risk grade were collected. Results: 248 patients were included (127 undergoing surgery before the pandemic and 121 after the pandemic). After the beginning of the pandemic, the percentage of high-risk SCC significantly increased from 35.3% to 46.2% (p=0.011). However, no significant differences were found in thickness, perineural invasion or metastases. Conclusions: Although there has not been a significant reduction in the number of SCC operated on after the pandemic, there has been a significant increase in high-risk SCC. All this could lead to an increase in skin cancer mortality in the future. (AU)

Antecedentes: La pandemia de COVID-19 ha podido afectar negativamente el diagnóstico precoz del cáncer de piel. Objetivo Comparar las características epidemiológicas, clínicas e histopatológicas en los pacientes intervenidos de carcinoma de células escamosas (CCE) cutáneo antes de la pandemia y después del inicio de la pandemia. Material y métodos: Se diseñó un estudio transversal que incluía 2 series de pacientes: 1) pacientes intervenidos de CCE el año posterior a la declaración del confinamiento general en España (15 de marzo de 2020), y 2) pacientes intervenidos de CCE el año previo. Se recogieron variables epidemiológicas, clínicas e histopatológicas, así como el estadio tumoral y el grado de riesgo. Resultados: Se incluyeron 248 pacientes (127 intervenidos antes de la pandemia y 121 intervenidos después de la pandemia). Tras el inicio de la pandemia, el porcentaje de CCE de alto riesgo aumentó significativamente de 32,3 a 45,5% (p=0,011). No obstante, no se encontraron diferencias significativas en el grosor tumoral, la invasión perineural o la presencia de metástasis. Conclusiones: Aunque no se produjo una reducción significativa en el número de CCE intervenidos después de la pandemia, ha habido un incremento significativo en los CCE de alto riesgo. Todo ello puede conllevar un incremento en la mortalidad por cáncer de piel en el futuro. (AU)

[Artículo traducido] Impacto de la pandemia COVID-19 en el carcinoma de células escamosas cutáneo: un estudio unicéntrico de los factores epidemiológicos, clínicos e histopatológicos / Impact of COVID-19 Pandemic on Cutaneous Squamous Cell Carcinoma: A Single-Centre Study of Epidemiologic, Clinic and Histopathological Factors

Antecedentes: La pandemia de COVID-19ha podido afectar negativamente el diagnóstico precoz del cáncer de piel. Objetivo Comparar las características epidemiológicas, clínicas e histopatológicas en los pacientes intervenidos de carcinoma de células escamosas (CCE) cutáneo antes de la pandemia y después del inicio de la pandemia. Material y métodos: Se diseñó un estudio transversal que incluía 2 series de pacientes: 1) pacientes intervenidos de CCE el año posterior a la declaración del confinamiento general en España (15 de marzo de 2020), y 2) pacientes intervenidos de CCE el año previo. Se recogieron variables epidemiológicas, clínicas e histopatológicas, así como el estadio tumoral y el grado de riesgo. Resultados: Se incluyeron 248 pacientes (127 intervenidos antes de la pandemia y 121 intervenidos después de la pandemia). Tras el inicio de la pandemia, el porcentaje de CCE de alto riesgo aumentó significativamente de 32,3 a 45,5% (p=0,011). No obstante, no se encontraron diferencias significativas en el grosor tumoral, la invasión perineural o la presencia de metástasis. Conclusiones: Aunque no se produjo una reducción significativa en el número de CCE intervenidos después de la pandemia, ha habido un incremento significativo en los CCE de alto riesgo. Todo ello puede conllevar un incremento en la mortalidad por cáncer de piel en el futuro. (AU)

Background: The COVID-19 pandemic may have adversely affected the early diagnosis of skin cancer. Objective To compare epidemiological, clinical and histopathological characteristics in patients undergoing cutaneous squamous cell carcinoma (SCC) surgery before and after the beginning of the pandemic. Material & methods: We conducted a cross-sectional study including two case series: (1) patients operated on for SCC in the year after the first state of alarm in Spain (15 March 2020), and (2) patients with SCC operated on in the previous year. Epidemiological, clinical and histopathological variables, tumour stage and risk grade were collected. Results: 248 patients were included (127 undergoing surgery before the pandemic and 121 after the pandemic). After the beginning of the pandemic, the percentage of high-risk SCC significantly increased from 35.3% to 46.2% (p=0.011). However, no significant differences were found in thickness, perineural invasion or metastases. Conclusions: Although there has not been a significant reduction in the number of SCC operated on after the pandemic, there has been a significant increase in high-risk SCC. All this could lead to an increase in skin cancer mortality in the future. (AU)

Indicación, realización y resultado del cateterismo de venas adrenales en pacientes con hiperaldosteronismo primario / Indication, performance and outcomes of adrenal vein sampling in patients with primary hyperaldosteronism

El hiperaldosteronismo primario (HAP) es una causa importante de hipertensión arterial (HTA) secundaria. El estudio del mismo precisa de una alta sospecha clínica, además de un estudio hormonal que confirme la hipersecreción hormonal. Es importante iniciar el tratamiento adecuado una vez se confirma el diagnóstico, y para ello es preciso demostrar si la hipersecreción hormonal es unilateral (pacientes que podrían ser tributarios a tratamiento quirúrgico) o bilateral (pacientes que son tributarios a tratamiento únicamente farmacológico). En el Hospital del Mar desde el año 2016 existe un equipo de trabajo multidisciplinar en el que participan nefrólogos, endocrinólogos, radiólogos y cirujanos para evaluar los casos con sospecha de hiperaldosteronismo y consensuar el mejor abordaje diagnóstico-terapéutico de estos pacientes, incluyendo la necesidad de cateterismo venoso adrenal, que es una técnica que en los últimos años se ha erigido como gold standard para el estudio del HAP. En el presente estudio recogemos la experiencia de nuestro centro en la realización de cateterismo venoso adrenal y en la utilidad de este para el manejo de tales pacientes (AU)

Primary hyperaldosteronism (PAH) is an important cause of secondary hypertension (HTN). The study of the same requires a high clinical suspicion in addition to a hormonal study that confirms hormonal hypersecretion. It is important to start the appropriate treatment once the diagnosis is confirmed, and for this is necessary to demonstrate whether the hormonal hypersecretion is unilateral (patients who could be candidates for surgical treatment) or bilateral (patients who are candidates for pharmacological treatment only). At the Hospital del Mar since 2016 there has been a multidisciplinary work team in which Nephrologists, Endocrinologists, Radiologists and Surgeons participate to evaluate cases with suspected hyperaldosteronism and agree on the best diagnostic-therapeutic approach for these patients, including the need for adrenal vein sampling, which is a technique that in recent years has become the gold standard for the study of PAH. In the present study we collect the experience of our center in performing adrenal vein catheterization and its usefulness for the management of these patients (AU)

Inhibition of ALK3-mediated signalling pathway protects against acetaminophen-induced liver injury.

Acetaminophen (APAP)-induced liver injury is one of the most prevalent causes of acute liver failure (ALF). We assessed the role of the bone morphogenetic protein (BMP) type I receptors ALK2 and ALK3 in APAP-induced hepatotoxicity. The molecular mechanisms that regulate the balance between cell death and survival and the response to oxidative stress induced by APAP was assessed in cultured human hepatocyte-derived (Huh7) cells treated with pharmacological inhibitors of ALK receptors and with modulated expression of ALK2 or ALK3 by lentiviral infection, and in a mouse model of APAP-induced hepatotoxicity. Inhibition of ALK3 signalling with the pharmacological inhibitor DMH2, or by silencing of ALK3, showed a decreased cell death both by necrosis and apoptosis after APAP treatment. Also, upon APAP challenge, ROS generation was ameliorated and, thus, ROS-mediated JNK and P38 MAPK phosphorylation was reduced in ALK3-inhibited cells compared to control cells. These results were also observed in an experimental model of APAP-induced ALF in which post-treatment with DMH2 after APAP administration significantly reduced liver tissue damage, apoptosis and oxidative stress. This study shows the protective effect of ALK3 receptor inhibition against APAP-induced hepatotoxicity. Furthermore, findings obtained from the animal model suggest that BMP signalling might be a new pharmacological target for the treatment of ALF.

Maintenance of different life stages of old-growth forest trees in deforested tropical landscapes.

Tropical tree species are increasingly being pushed to inhabit deforested landscapes. The habitat amount hypothesis posits that, in remaining forest patches, species diversity in equal-sized samples decreases with decreasing forest cover in the surrounding landscape. We tested this prediction by taking into account three important factors that can affect species responses to forest loss. First, forest loss effects can be linear (proportional) or nonlinear, as there can be threshold values of forest loss beyond which species extirpation may be accelerated. Second, such effects are usually scale dependent and may go unnoticed if assessed at suboptimal scales. Finally, species extirpation may take decades to become evident, so the effects of forest loss can be undetected when assessing long-lived organisms, like adult old-growth forest trees. Here, we evaluated the linear and nonlinear effects of landscape forest loss across different spatial scales on site-scale abundance and diversity of old-growth forest trees, separately for four plant-life stages (seeds, saplings, juveniles, and adults) in two rainforest regions with different levels of deforestation. We expected stronger (and negative) forest loss effects on early plant-life stages, especially in the region with the highest deforestation. Surprisingly, in 13 of 16 study cases (2 responses × 4 life stages × 2 regions), null models showed higher empirical support than linear and nonlinear models at any scale. Therefore, the species richness and abundance of local tree assemblages seem to be weakly affected by landscape-scale forest loss independently of the spatial scale, life stage, and region. Yet, as expected, the predictive power of forest cover was relatively lower in the least deforested region. Our findings suggest that landscape-scale forest loss is poorly related to site-scale processes, such as seed dispersal and seedling recruitment, or, at least, such effects are too small to shape the abundance and diversity of tree assemblages within forest patches. Therefore, our findings do not support the most important prediction of the habitat amount hypothesis but imply that, on a per-area basis, a unit of habitat (forest) in a highly deforested landscape has a conservation value similar to that of a more forested one, particularly in moderately deforested rainforests.