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This commentary explores the potential cardiovascular (CV) benefits of combining methotrexate (MTX) and Janus kinase inhibitors (JAKis) in the treatment of rheumatoid arthritis (RA). While European guidelines recommend MTX as first-line treatment, concerns about the CV risks associated with JAKis have emerged. This article reviews the existing literature to assess the role of concomitant MTX in reducing CV risk when used with JAKis. Clinical trials confirm the efficacy of JAKis in combination with MTX in terms of treatment outcomes in RA. However, the number of major adverse cardiovascular events (MACEs) reported is too low to draw conclusions on adverse CV outcomes. Indirect evidence does, however, suggest potential protective effects of MTX on CV outcomes, as several mechanisms may contribute to MTX’s cardioprotective effects, including reduced inflammation, adenosine monophosphate-activated protein kinase (AMPK) activation, increased cholesterol efflux, and adenosine accumulation. These mechanisms and the available data may support the case for CV benefits of concomitant MTX when JAKis are used in the treatment of patients with RA, although further research is needed. In particular, the lipid paradox associated with RA highlights the complex relationship between RA treatments (MTX, JAKis, tumor necrosis factor (TNF) inhibitors, and interleukin (IL)-6 receptor inhibitors), inflammation, different lipid profiles, and CV risk. In the absence of contraindications and when MTX is tolerated, this commentary suggests the concomitant use of MTX and JAKis as a preferred option for optimizing CV protection in patients with RA.

Dendritic cells (DCs) have a role in the development and activation of self-reactive pathogenic T cells1,2. Genetic variants that are associated with the function of DCs have been linked to autoimmune disorders3,4, and DCs are therefore attractive therapeutic targets for such diseases. However, developing DC-targeted therapies for autoimmunity requires identification of the mechanisms that regulate DC function. Here, using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies, we identify a regulatory loop of negative feedback that operates in DCs to limit immunopathology. Specifically, we find that lactate, produced by activated DCs and other immune cells, boosts the expression of NDUFA4L2 through a mechanism mediated by hypoxia-inducible factor 1α (HIF-1α). NDUFA4L2 limits the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules in DCs that are involved in the control of pathogenic autoimmune T cells. We also engineer a probiotic that produces lactate and suppresses T cell autoimmunity through the activation of HIF-1α–NDUFA4L2 signalling in DCs. In summary, we identify an immunometabolic pathway that regulates DC function, and develop a synthetic probiotic for its therapeutic activation.

Some rheumatoid arthritis treatments cause patients to gain weight or are less effective in patients with obesity than in patients without obesity. Also, obesity can make rheumatoid arthritis worse. Filgotinib is a rheumatoid arthritis treatment that was evaluated in seven randomized clinical studies (FINCH 1–4 and DARWIN 1–3). We investigated whether filgotinib causes changes in weight and whether body mass index (BMI) affects the efficacy or safety of filgotinib. We analyzed how the BMI of patients who participated in FINCH 1, 2, or 3 changed over time. Most patients had a small increase in BMI (around 1–2 kg/m2) after 24 weeks of filgotinib treatment. This change in BMI was not affected by patients’ BMI at baseline. Baseline BMI did not impact the efficacy of filgotinib, which was assessed using standard measures of disease activity. Filgotinib was more effective than other rheumatoid arthritis treatments and placebo in all patients, regardless of BMI subgroup. Using safety data from all seven clinical studies (FINCH 1–4 and DARWIN 1–3), we found that some adverse events occurred more often in patients with obesity (a BMI of ≥ 30 kg/m2) than in those without obesity. The increased adverse events included venous thrombotic and embolic events and major adverse cardiovascular events, for which obesity is a known risk factor. These results show that filgotinib did not substantially change BMI (which increased by around 1–2 kg/m2in most patients), and that baseline BMI did not affect the efficacy of filgotinib.

Rheumatoid arthritis (RA) is an autoimmune disease characterised by persistent inflammation of the synovial joints as well as other tissues and organs. Left untreated, it can lead to joint damage, disability and even increased mortality. The disease is driven by inflammatory cytokines that contribute to the chronic inflammation seen in RA. Interleukin-6 (IL-6) is a key pathological cytokine and a target for treatments aiming to alleviate local and systemic inflammation. Despite advances in understanding RA and the introduction of new treatments, achieving sustained remission remains challenging. This review explores the role of IL-6 in RA pathogenesis, its potential as a treatment target and the significance of personalised medicine in RA management. IL-6 has a dual signalling mechanism, classical and trans-signalling, which influences various intracellular pathways. While several targeted therapies have emerged, no single mechanism-based therapy is universally effective due to the diversity and complexity of the disease. Different approaches to targeting IL-6 have been tested, including biologic blockade of receptors or ligands, and inhibition of IL-6 signalling. IL-6 receptor inhibitors have been validated as RA therapeutics, either alone or in combination with other treatments. Tocilizumab, the first approved IL-6 inhibitor, blocks both soluble and membrane-bound IL-6 receptors, reducing the inflammatory cascade. Clinical trials confirm the efficacy and safety of tocilizumab and its role as a treatment option for patients unresponsive to conventional therapies. The benefits of IL-6 inhibition extend beyond reduced joint inflammation to the amelioration of comorbidities like anaemia, cardiovascular disease, depression and osteoporosis. Tailoring treatment to patients’ profiles and comorbidities is essential for optimal outcomes. A ‘treat-to-profile’ approach, focusing on a holistic view of the patient, could improve personalised medicine strategies. Biosimilars – lower-cost alternatives to biologics – further enhance the accessibility and cost-effectiveness of treatment. IL-6 inhibitors present a valuable treatment option for RA management, particularly for patients with specific comorbidities.

En los últimos años, hemos asistido a un incremento en el diagnóstico de las patologías importadas, debido al aumento mantenido de los viajes y los desplazamientos internacionales a zonas tropicales y subtropicales. Esto supone un reto para la medicina del viajero. Las parasitosis importadas, encabezadas por la malaria por Plasmodium falciparum,suponen uno de los principales problemas de salud durante el viaje. La complejidad del diagnóstico de parasitosis importadas en nuestro medio, así como sus posibles complicaciones, hacen necesario minimizar los riesgos de infección durante el viaje, para lo que es necesario consultar con un profesional especializado antes de la partida, con el fin de actuar en la parte inicial del proceso: la prevención.

Las parasitosis que afectan al sistema nervioso central se asocian con una alta mortalidad y morbilidad, especialmente en países con escasez de recursos, a pesar de lo cual siguen siendo enfermedades desatendidas. Estas infecciones son cada vez más frecuentes en nuestro medio, debido a los movimientos migratorios, los viajes internacionales o los tratamientos inmunosupresores. La parasitosis con afectación neurológica más frecuente es la cisticercosis. Pueden producir crisis comiciales, deterioro cognitivo, déficits sensoriales o alteraciones de la movilidad y, en ocasiones, importantes secuelas de por vida. Las características propias de cada parásito, con sus ciclos de vida y su localización geográfica específica, así como las manifestaciones clínicas, inespecíficas y superponibles en muchos casos, dificultan en gran medida el diagnóstico de estas entidades. A continuación, se revisan las principales parasitosis producidas por cestodos, trematodos, nematodos y protozoos que causan manifestaciones neurológicas, y se propone un algoritmo simplificado para su diagnóstico y tratamiento.

Las lesiones cutáneas son una causa común en los viajeros que regresan de zonas tropicales y subtropicales y buscan una evaluación médica. Entre los viajeros enfermos evaluados al regresar, las patologías dermatológicas ocupan el tercer problema más frecuente (después de la fiebre y la diarrea aguda). Problemas dermatológicos crónicos como la dermatitis crónica pueden empeorar en un clima tropical. El diagnóstico diferencial de las lesiones cutáneas que ocurren durante o después del viaje es amplio, e incluye tanto causas infecciosas (virus, bacterias, hongos, helmintos, protozoos) como no infecciosas (quemaduras, reacciones alérgicas, traumáticas). La distribución, las características clínicas de la lesión y la sintomatología asociada, su localización (zonas expuestas o no expuestas), el estado inmunitario del paciente, el antecedente de ciertas actividades de riesgo, así como el tiempo transcurrido desde el regreso, la duración del viaje y el destino nos pueden ayudar a orientar el diagnóstico de sospecha. El propósito de esta actualización es identificar las dermatosis parasitarias más comunes relacionadas con los viajes y describir los aspectos epidemiológicos y geográficos, así como las características clínicas, la prevención, el diagnóstico y el tratamiento.

Los virus están cobrando cada vez más importancia como agentes etiológicos de la neumonía, en base, principalmente, a la mejoría de las técnicas de diagnóstico, suponiendo actualmente aproximadamente un tercio de los casos de neumonía adquirida en la comunidad. Suelen ocurrir en la edad infantil y en pacientes de edad avanzada, causando desde casos leves a casos graves que precisan intubación y cuidados intensivos. Entre los principales agentes responsables están: rinovirus, virus influenza A o B, meta-pneumovirus, virus respiratorio sincitial, parainfluenzae, coronavirus o adenovirus. La infección producida por SARS-CoV-2, causante de la actual pandemia de COVID-19 de consecuencias devastadoras, es muestra de la vital importancia de la neumonía vírica y representa el objeto principal de la presente actualización. Usando la abundante información disponible, en continua evolución desde el inicio de la pandemia, en esta actualización se revisarán las principales características del virus, su fisiopatología y las manifestaciones clínicas, así como los principales métodos de diagnóstico y tratamiento.

Aunque la fiebre y los síntomas respiratorios son la principal expresión clínica de la enfermedad de la COVID-19, pueden aparecer importantes complicaciones extrapulmonares que afectan a la mayoría de los órganos y sistemas. La participación multisistémica puede atribuirse principalmente a la localización generalizada en todo el organismo de los receptores de la ECA2, que actúan como el principal punto de entrada del virus. Las manifestaciones sistémicas pueden aparecer, en ocasiones, antes que la sintomatología típica, aunque en general son tardías o representan secuelas de la enfermedad. Las complicaciones tromboembólicas son preocupantes por su frecuencia y gravedad, y traducen un estado procoagulante con múltiples manifestaciones clínicas posibles. Pueden aparecer complicaciones cardíacas, neurológicas, digestivas, renales, endocrinometabólicas, cutáneas y oculares. Se comentan las manifestaciones y los aspectos terapéuticos específicos sobre la enfermedad de la COVID-19 en la mujer embarazada, y sobre las implicaciones de la enfermedad en los niños. En todo paciente con sospecha clínica de COVID-19, se realizarán las pruebas correspondientes para confirmar el diagnóstico de la infección. Las pruebas diagnósticas específicas indicativas de afectación de los distintos órganos irán dirigidas en función de la sospecha clínica. La realización de estas pruebas podrá ser individualizada, teniendo en cuenta las medidas de aislamiento requeridas y la gravedad de cada caso. Asimismo, se administrará el tratamiento correspondiente, siguiendo criterios generalmente superponibles a los de la población general.

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Objectives: Interstitial lung disease (ILD) occurs in up to 30% of patients with rheumatoid arthritis (RA), resulting in increased morbidity and death in the absence of proven therapies. The aim of this study is to estimate the number of incident ILD cases reported through development studies with baricitinib in patients with RA. Methods: Estimates were based on 3770 patients with RA from eight randomized clinical trials (four phase 3, three phase 2, one phase 1b) and one long-term extension study on baricitinib for which ILD was not an exclusion criterion with 12,358 patient-years of exposure (PYE). Results: Twenty-one non-infectious cases of ILD were reported with an exposure-adjusted incidence rate (EAIR) of 0.17 per 100 PYE. Of the 21 cases, six were reported as serious and 15 as non-serious resulting in an incidence rate of 0.05 per 100 PYE and 0.12 per 100 PYE, respectively. There were also 11 cases caused by an infectious agent: seven serious (IR: 0.06 per 100 PYE) and four non-serious cases (IR: 0.03 per 100 PYE). Conclusions: The findings of this analysis in patients with RA treated with baricitinib are consistent with a low risk to develop non-infectious ILD during baricitinib treatment, similar to that observed with other Janus kinase inhibitors.

The protein complexes of the mitochondrial electron transport chain exist in isolation and in higher order assemblies termed supercomplexes (SCs) or respirasomes (SC I+III2+IV). The association of complexes I, III and IV into the respirasome is regulated by unknown mechanisms. Here, we designed a nanoluciferase complementation reporter for complex III and IV proximity to determine in vivo respirasome levels. In a chemical screen, we found that inhibitors of the de novo pyrimidine synthesis enzyme dihydroorotate dehydrogenase (DHODH) potently increased respirasome assembly and activity. By-passing DHODH inhibition via uridine supplementation decreases SC assembly by altering mitochondrial phospholipid composition, specifically elevated peroxisomal-derived ether phospholipids. Cell growth rates upon DHODH inhibition depend on ether lipid synthesis and SC assembly. These data reveal that nucleotide pools signal to peroxisomes to modulate synthesis and transport of ether phospholipids to mitochondria for SC assembly, which are necessary for optimal cell growth in conditions of nucleotide limitation.

Difficult laparoscopic cholecystectomy (DLC) is a stressful condition for surgeon which is followed by greater risk for various injuries (biliary, vascular etc.) Preoperative factors that are related to DLC are landmarks for surgeon to assess the possibilities for overcoming difficulties and making early decision about conversion to an open surgery. In prospective cohort study we evaluated and defined the importance and impact of preoperative parameters on difficulties encountered during surgery, defined DLC, predictors of DLC and index of DLC.

La infección de las prótesis vasculares es una complicación temible por su alta morbimortalidad, en la que el diagnóstico precoz es imprescindible. Evaluamos la utilidad de la gammagrafía con leucocitos marcados con 99mTc-HMPAO y SPECT/TC (GLM-SPECT/TC) en el diagnóstico de esta patología.

Little information is available on the official postgraduate and subspecialty training programs in movement disorders (MD) in Europe and North Africa. To survey the accessible MD clinical training in these regions. We designed a survey on clinical training in MD in different medical fields, at postgraduate and specialized levels. We assessed the characteristics of the participants and the facilities for MD care in their respective countries. We examined whether there are structured, or even accredited postgraduate, or subspecialty MD training programs in neurology, neurosurgery, internal medicine, geriatrics, neuroradiology, neuropediatrics, and general practice. Participants also shared their suggestions and needs. The survey was completed in 31/49 countries. Structured postgraduate MD programs in neurology exist in 20 countries; structured neurology subspecialty training exists in 14 countries and is being developed in two additional countries. Certified neurology subspecialty training was reported to exist in 7 countries. Recommended reading lists, printed books, and other materials are the most popular educational tools, while courses, lectures, webinars, and case presentations are the most popular learning formats. Mandatory activities and skills to be certified were not defined in 15/31 countries. Most participants expressed their need for a mandatory postgraduate MD program and for certified MD sub-specialization programs in neurology. Certified postgraduate and subspecialty training exists only in a minority of European countries and was not found in the surveyed Egypt and Tunisia. MD training should be improved in many countries.

Exudative pleural diseases are a common cause of respiratory distress and systemic illness in dogs and cats. This article covers the pathophysiology, development, and classification of exudative pleural effusions. The most current diagnostic strategies, causes, imaging findings, and medical or surgical treatment options for select diseases are reviewed in detail.

The fire resistance of composite slabs with steel decking, in Europe, is usually defined using simple calculation models provided by the Eurocode EN 1994-1-2. For assessing the methodology of these simple calculation methods, a new advanced calculation method is presented, using the software ANSYS. The numerical model is first validated with experimental data reported on bibliography and then a parametric analysis is conducted to better understand the effect of the load level on the composite structure under fire. The validation of the simulations consisted of three different models: the first model considers perfect contact between the steel deck and the concrete topping, and the two following models consider the existence of an air gap between these materials, acting as a thermal resistance on the temperature field through the thickness of the slab. The numerical results show good approximation to the experimental results, mainly when using the non-perfect contact model, reaching 3.88% and 16.91% of difference with respect to the insulation and load-bearing criteria, respectively. Based on the validation models, a parametric study is presented, modifying the load level from 10% up to 75%. New simple calculation models are presented to define the fire resistance of composite slabs, considering the load level, and the debonding effect between the concrete and the steel deck.

Abstract: Treat-to-target (T2T) and dose tapering after obtaining the therapeutic objective (called “treat-to-budget”-T2B-in this Commentary) are the two most commonly used therapeutic strategies in rheumatoid arthritis. In theory, both strategies could add value to the healthcare system, although they are focused on different objectives: T2T strategy improves outcomes but increases short-term costs, while the cost savings obtained through T2B are associated with higher relapse rates. The systematic implementation of both strategies must be founded on solid evidence of their effectiveness and efficiency. However, the level of evidence between guidelines and individual studies is inconsistent for both strategies and the number and the quality of cost-effectiveness analyses is scarce. Raising the level of evidence requires a move from generalization to individualization by conducting randomized clinical trials that assess each of the many strategies that fall under the umbrella of the overall T2T and T2B concepts. In addition, such studies should consider the therapeutic goals and impact of the disease from the perspective of individual patients, which is only possible by promoting shared decision-making. Funding: Lilly Spain.

The aim of our study was to investigate the influence of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and body mass index (BMI) on circulating drug levels and clinical response to tumour necrosis factor inhibitor (TNFi) therapy in axial spondyloarthritis (axSpA) patients. Prospective observational study during 1 year with 2 cohorts (Madrid and Amsterdam) including 180 axSpA patients treated with standard doses of infliximab or adalimumab. Patients were stratified by BMI, being 78 (43%) normal weight (18.5–24.9 kg/m2) and 102 (57%) overweight/obese (≥ 25.0 kg/m2). After the first year of treatment, TNFi trough levels were measured by capture ELISA. Clinical response to TNFi was defined as ∆BASDAI ≥ 2 and clinical remission as BASDAI < 2 and CRP ≤ 5 mg/L. Logistic regression models were employed to analyse the association between concomitant csDMARDs and BMI with drug levels and clinical response. Seventy-nine patients (44%) received concomitant csDMARDs. The administration of concomitant csDMARDs (OR 3.82; 95% CI 1.06–13.84) and being normal weight (OR 18.38; 95% CI 2.24–150.63) were independently associated with serum TNFi drug persistence. Additionally, the use of concomitant csDMARDs contributed positively to achieve clinical response (OR 7.86; 95% CI 2.39–25.78) and remission (OR 4.84; 95% CI 1.09–21.36) in overweight/obese patients, but no association was found for normal-weight patients (OR 1.10; 0.33–3.58). The use of concomitant csDMARDs with TNFi may increase the probability of achieving clinical response in overweight/obese axSpA patients. Further research studies including larger cohorts of patients need to be done to confirm it.

La Organización Mundial de la Salud recomienda la educación interprofesional cuando estudiantes de 2 o más profesiones sanitarias aprenden juntos, para favorecer el desarrollo de las competencias interprofesionales que les van a permitir trabajar en equipo proporcionando la mejor asistencia sanitaria. En la Universidad Europea de Madrid existe un programa de educación interprofesional que trabaja las competencias de clarificación de roles, comunicación y autoridad, con estudiantes de diferentes titulaciones. Una de sus actividades es la de atención domiciliaria, en la que participan estudiantes de último curso de Medicina y de Enfermería. El objetivo de este estudio es analizar la percepción de los estudiantes que han participado en la actividad de atención domiciliaria durante el curso 2016-2017 en relación con las 3 competencias interprofesionales.

Significant advances in veterinary minimally invasive surgeries and procedures have occurred in the past 10 years. These advances have been allowed due to continual research into optimizing working space through one-lung ventilation techniques and carbon dioxide insufflation. Additionally, minimally invasive surgery enthusiasts have joined forces with interventionalists and in many cases physicians to push the boundaries, minimize pain, suffering and time away from owners with advances in a variety of procedures. Several larger multi-institutional retrospective studies on various disease processes allow veterinarians and owners to understand that minimally invasive approaches allow for outcomes comparable to traditional open surgery and in some cases may now be considered the standard of care in canine and feline patients.

Sentinel lymph node biopsy is the standard of care for axillary staging in early, clinically node-negative breast cancer. The lymphatic pathways could be altered after receiving axillary treatments such as radiation and/or axillary lymph node dissection. We report a case of inguinal and contralateral axilla SLNs in breast cancer recurrence.

Background: Previous studies have shown that Souvenaid (medical food) can have benefits on memory, cognition, and function in early Alzheimer’s disease (AD) and mild cognitive impairment (MCI).Objective: Demonstrate that Souvenaid could improve or maintain cognition and has an effect on neurodegeneration biomarkers.Methods: This cohort study was carried out from June 2015 through December 2016 in the Neurology Department, Infanta Cristina Hospital, Madrid, Spain. MCI-HR-AD were recruited using Petersen criteria, neuropsychology (NPS), and 18F-FDG PET scans to confirm the high risk of progression to dementia with one year of follow-up. Age, sex, vascular risk factors (VRF), and NPS values (Barcelona brief version) were analyzed. 18F-FDG PET scans were analyzed as a visual procedure. The study was approved by the Research Committee of ICH. Statistical analysis was made with SPSS 22.0 version.Results: Subjects included 43 MCI patients (58.5% women; mean age 69.78±7.89): 17 receiving Souvenaid®treatment (ST), 24 receiving no treatment (WT) and 2 who withdrew. No differences were seen in VRF, only hypercholesterolemia, and were less prevalent in the ST group (p?=?0.002). The rate of progression to dementia was 48.8% (no differences between groups, p?=?0.654). A second round of 18F-FDG PET scans showed a significance worsening of glucose metabolism in WT (p?=?0.001) versus ST, in which it was low (p?=?0.050). For NPS testing, there was a significant worsening in memory performance in the WT group (p?=?0.011) and a stabilization in ST (p?=?0.083), as well as in executive functions and attention (worsening in WT, p?=?0.014). For the Subjective Changing Scale (SCS), caregivers indicated a stabilization/improvement in ST (p?=?0.017).Conclusion: Souvenaid had a significant effect on several cognitive domains, and on SCS in patients with MCI-HR-AD. Its intervention had an impact on preservation on 18F-FDG PET scans.