Optical Kinetic Theory of Nonlinear Multimode Photonic Networks.

Recent experimental developments in multimode nonlinear photonic circuits (MMNPCs), have motivated the development of an optical thermodynamic theory that describes the equilibrium properties of an initial beam excitation. However, a nonequilibrium transport theory for these systems, when they are in contact with thermal reservoirs, is still terra incognita. Here, by combining Landauer and kinematics formalisms we develop a universal one-parameter scaling theory that describes the whole transport behavior from the ballistic to the diffusive regime, including both positive and negative optical temperature scenarios. We also derive a photonic version of the Wiedemann-Franz law that connects the thermal and power conductivities. Our work paves the way toward a fundamental understanding of the transport properties of MMNPCs and may be useful for the design of all-optical cooling protocols.

Quality of information about urologic pathology in English and Spanish from ChatGPT, BARD, and Copilot.

INTRODUCTION AND OBJECTIVE: Generative artificial intelligence makes it possible to ask about medical pathologies in dialog boxes. Our objective was to analyze the quality of information about the most common urological pathologies provided by ChatGPT (OpenIA), BARD (Google), and Copilot (Microsoft). METHODS: We analyzed information on the following pathologies and their treatments as provided by AI: prostate cancer, kidney cancer, bladder cancer, urinary lithiasis, and benign prostatic hypertrophy (BPH). Questions in English and Spanish were posed in dialog boxes; the answers were collected and analyzed with DISCERN questionnaires and the overall appropriateness of the response. Surgical procedures were performed with an informed consent questionnaire. RESULTS: The responses from the three chatbots explained the pathology, detailed risk factors, and described treatments. The difference is that BARD and Copilot provide external information citations, which ChatGPT does not. The highest DISCERN scores, in absolute numbers, were obtained in Copilot; however, on the appropriacy scale it was noted that their responses were not the most appropriate. The best surgical treatment scores were obtained by BARD, followed by ChatGPT, and finally Copilot. CONCLUSIONS: The answers obtained from generative AI on urological diseases depended on the formulation of the question. The information provided had significant biases, depending on pathology, language, and above all, the dialog box consulted.

Medical deserts in Spain-Insights from an international project.

INTRODUCTION: Medical deserts are a growing phenomenon across many European countries. They are usually defined as (i) rural areas, (ii) underserved areas or (iii) by applying a measure of distance/time to a facility or a combination of the three characteristics. The objective was to define medical deserts in Spain as well as map their driving factors and approaches to mitigate them. METHODS: A mixed methods approach was applied following the project "A Roadmap out of medical deserts into supportive health workforce initiatives and policies" work plan. It included the following elements: (i) a scoping literature review; (ii) a questionnaire survey; (iii) national stakeholders' workshop; (iv) a descriptive case study on medical deserts in Spain. RESULTS: Medical deserts in Spain exist in the form of mostly rural areas with limited access to health care. The main challenge in their identification and monitoring is local data availability. Diversity of both factors contributing to medical deserts and solutions applied to eliminate or mitigate them can be identified in Spain. They can be related to demand for or supply of health care services. More national data, analyses and/or initiatives seem to be focused on the health care supply dimension. CONCLUSIONS: Addressing medical deserts in Spain requires a comprehensive and multidimensional approach. Effective policies are needed to address both the medical staff education and planning system, working conditions, as well as more intersectoral approach to the population health management.

ChatGPT and most frequent urological diseases: analysing the quality of information and potential risks for patients.

PURPOSE: Artificial intelligence (AI) is a set of systems or combinations of algorithms, which mimic human intelligence. ChatGPT is software with artificial intelligence which was recently developed by OpenAI. One of its potential uses could be to consult the information about pathologies and treatments. Our objective was to assess the quality of the information provided by AI like ChatGPT and establish if it is a secure source of information for patients. METHODS: Questions about bladder cancer, prostate cancer, renal cancer, benign prostatic hypertrophy (BPH), and urinary stones were queried through ChatGPT 4.0. Two urologists analysed the responses provided by ChatGPT using DISCERN questionary and a brief instrument for evaluating the quality of informed consent documents. RESULTS: The overall information provided in all pathologies was well-balanced. In each pathology was explained its anatomical location, affected population and a description of the symptoms. It concluded with the established risk factors and possible treatment. All treatment answers had a moderate quality score with DISCERN (3 of 5 points). The answers about surgical options contain the recovery time, type of anaesthesia, and potential complications. After analysing all the responses related to each disease, all pathologies except BPH achieved a DISCERN score of 4. CONCLUSIONS: ChatGPT information should be used with caution since the chatbot does not disclose the sources of information and may contain bias even with simple questions related to the basics of urologic diseases.

Características clínicas de la mortalidad neonatal en un hospital de tercer nivel del Paraguay: un estudio observacional retrospectivo

Introducción: La mortalidad neonatal sigue siendo un importante problema de salud pública en todo el mundo, especialmente en países en desarrollo. La mayoría de las muertes neonatales son atribuibles a complicaciones prevenibles, como la prematuridad, la sepsis neonatal y la asfixia al nacer. Objetivo: Determinar las características clínicas de la mortalidad neonatal en un hospital de tercer nivel del Paraguay mediante un estudio observacional retrospectivo. Metodología: El presente estudio es de diseño observacional, descriptivo y retrospectivo, se realizó en el Hospital de Clínicas de Paraguay. Este diseño permitió obtener información de los registros médicos de los recién nacidos atendidos en el hospital durante un período de cinco años. Resultados: En el periodo comprendido entre el 2018 y el 2022, se registraron un total de 131 casos de mortalidad neonatal en el Hospital de Clínicas del Paraguay. El peso medio al nacer de 2009,5 ± 991,4 kilogramos y una edad gestacional media de 32,87 ± 4,5 semanas. Los diagnósticos de óbito más frecuentes en los neonatos fueron sepsis (37 casos), afectación cardiaca (61 casos) y síndrome genético (39 casos). Discusión: Los datos obtenidos del estudio sugieren que existen factores de riesgo maternos y neonatales que están vinculados con la mortalidad neonatal en el Hospital de Clínicas del Paraguay. Se necesitan estudios posteriores que permitan profundizar en el análisis de estos factores y que permitan el desarrollo de estrategias preventivas para disminuir la tasa de mortalidad neonatal en el país.

Introduction: Neonatal mortality remains a major public health problem worldwide, particularly in developing countries. Most neonatal deaths are attributable to preventable complications, such as premature birth, neonatal sepsis, and birth asphyxia. Objective: To determine the clinical characteristics of neonatal mortality in a tertiary-level hospital in Paraguay through a retrospective observational study. Methods: This observational, descriptive, and retrospective study was conducted at the Hospital de Clínicas in Paraguay. This design allowed information to be obtained from the medical records of newborns who attended the hospital over a period of five years. Results: Between 2018 and 2022, 121 cases of neonatal mortality were recorded at the Hospital de Clínicas del Paraguay. The mean birth weight was 2013.51 ± 1021 kg and mean gestational age was 32.87 ± 4.6 weeks. The most frequent diagnoses of neonatal death were sepsis (37 cases), cardiac involvement (61 cases), and genetic syndromes (39 cases). Discussion: The data obtained from this study suggest that maternal and neonatal risk factors are associated with neonatal mortality in the Hospital de Clínicas of Paraguay. Further studies are needed to analyze these factors and develop preventive strategies to reduce the neonatal mortality rate in the country.

Structural basis for the inactivation of cytosolic DNA sensing by the vaccinia virus.

Detection of cytosolic DNA is a central element of the innate immunity system against viral infection. The Ku heterodimer, a component of the NHEJ pathway of DNA repair in the nucleus, functions as DNA sensor that detects dsDNA of viruses that replicate in the cytoplasm. Vaccinia virus expresses two proteins, C4 and C16, that inactivate DNA sensing and enhance virulence. The structural basis for this is unknown. Here we determine the structure of the C16 - Ku complex using cryoEM. Ku binds dsDNA by a preformed ring but C16 sterically blocks this access route, abrogating binding to a dsDNA end and its insertion into DNA-PK, thereby averting signalling into the downstream innate immunity system. C4 replicates these activities using a domain with 54% identity to C16. Our results reveal how vaccinia virus subverts the capacity of Ku to recognize viral DNA.

Anti-drug antibodies in the current management of cancer.

Monoclonal antibodies (mAbs) have become one of the main therapeutic weapons in modern oncology, mainly as targeted therapies, and immune checkpoint inhibitors. The generation of anti-drug antibodies (ADAs) after their administration can alter their pharmacokinetic, pharmacodynamic, efficacy and safety profile causing infusion-related reactions. Several risk factors have been associated with ADAs development, notably host genetics and immune status, comorbidity, concomitant medications, mAbs molecular structure, dose and route of administration. ADAs are not usually tested on daily clinical practice, being their analysis generally placed in early stages of drug development. ELISA-type assay the most common method. ADAs detection can involve important implications for treatment strategies of cancer patients, guiding therapeutic adjustment. In oncology, some studies about ADAs synthesis related to targeted therapies and immune checkpoint inhibitors have been recently published. Several strategies are proposed to reduce mAbs immunogenicity, such as different schedules, routes of administration or even the use of immunosuppressants. Another question that arises in relation to ADAs generation is the need to measure the concentration levels of active drug to guide the administration schedule. In this review, we will discuss all the aspects that are currently under discussion in relation with ADAs in oncology.

Paraplegia Following Type B Acute Aortic Dissection Can Spare the Spinal Cord.

Ischemic lumbosacral plexopathy secondary to an acute aortic dissection is a rare condition that is usually unilateral and frequently accompanied by a simultaneous spinal cord infarction. The functional prognosis relies on the severity of the nervous system involvement being usually worse when the spinal cord is involved. We present a case of a 46-year-old man who suffered an acute type B aortic dissection presenting as acute paraplegia due to bilateral ischemic lumbosacral plexopathy treated with thoracic endovascular aortic repair. An up-to-date review of the literature on ischemic lumbosacral plexus injury is provided.

Guía clínica para el diagnóstico y seguimiento de la distrofia miotónica tipo 1, DM1 o enfermedad de Steinert / Clinical guide for the diagnosis and follow-up of myotonic dystrophy type 1, MD1 or Steinert's disease

Antecedentes y objetivos: La enfermedad de Steinert o distrofia miotónica tipo 1 (DM1), (OMIM 160900) es la miopatía más prevalente en el adulto. Es una enfermedad multisistémica con alteración de prácticamente todos los órganos y tejidos y una variabilidad fenotípica muy amplia, lo que implica que deba ser atendida por diferentes especialistas que dominen las alteraciones más importantes. En los últimos años se ha avanzado de manera exponencial en el conocimiento de la enfermedad y en su manejo. El objetivo de la guía es establecer recomendaciones para el diagnóstico, el pronóstico, el seguimiento y el tratamiento de las diferentes alteraciones de la DM1. Material y métodos: Esta guía de consenso se ha realizado de manera multidisciplinar. Se ha contado con neurólogos, neumólogos, cardiólogos, endocrinólogos, neuropediatras y genetistas que han realizado una revisión sistemática de la literatura. Recomendaciones: Se recomienda realizar un diagnóstico genético con cuantificación precisa de tripletes CTG. Los pacientes con DM1 deben seguir control cardiológico y neumológico de por vida. Antes de cualquier cirugía con anestesia general debe realizarse una evaluación respiratoria. Debe monitorizarse la presencia de síntomas de disfagia periódicamente. Debe ofrecerse consejo genético a los pacientes con DM1 y a sus familiares. Conclusión: La DM1 es una enfermedad multisistémica que requiere un seguimiento en unidades especializadas multidisciplinares

Background and objectives: Steinert's disease or myotonic dystrophy type 1 (MD1), (OMIM 160900), is the most prevalent myopathy in adults. It is a multisystemic disorder with dysfunction of virtually all organs and tissues and a great phenotypical variability, which implies that it has to be addressed by different specialities with experience in the disease. The knowledge of the disease and its management has changed dramatically in recent years. This guide tries to establish recommendations for the diagnosis, prognosis, follow-up and treatment of the complications of MD1. Material and methods: Consensus guide developed through a multidisciplinary approach with a systematic literature review. Neurologists, pulmonologists, cardiologists, endocrinologists, neuropaediatricians and geneticists have participated in the guide. Recommendations: The genetic diagnosis should quantify the number of CTG repetitions. MD1 patients need cardiac and respiratory lifetime follow-up. Before any surgery under general anaesthesia, a respiratory evaluation must be done. Dysphagia must be screened periodically. Genetic counselling must be offered to patients and relatives. Conclusion: MD1 is a multisystemic disease that requires specialised multidisciplinary follow-up

Clinical guide for the diagnosis and follow-up of myotonic dystrophy type 1, MD1 or Steinert's disease. / Guía clínica para el diagnóstico y seguimiento de la distrofia miotónica tipo 1, DM1 o enfermedad de Steinert.

BACKGROUND AND OBJECTIVES: Steinert's disease or myotonic dystrophy type 1 (MD1), (OMIM 160900), is the most prevalent myopathy in adults. It is a multisystemic disorder with dysfunction of virtually all organs and tissues and a great phenotypical variability, which implies that it has to be addressed by different specialities with experience in the disease. The knowledge of the disease and its management has changed dramatically in recent years. This guide tries to establish recommendations for the diagnosis, prognosis, follow-up and treatment of the complications of MD1. MATERIAL AND METHODS: Consensus guide developed through a multidisciplinary approach with a systematic literature review. Neurologists, pulmonologists, cardiologists, endocrinologists, neuropaediatricians and geneticists have participated in the guide. RECOMMENDATIONS: The genetic diagnosis should quantify the number of CTG repetitions. MD1 patients need cardiac and respiratory lifetime follow-up. Before any surgery under general anaesthesia, a respiratory evaluation must be done. Dysphagia must be screened periodically. Genetic counselling must be offered to patients and relatives. CONCLUSION: MD1 is a multisystemic disease that requires specialised multidisciplinary follow-up.

Structural Insight into the Core of CAD, the Multifunctional Protein Leading De Novo Pyrimidine Biosynthesis.

CAD, the multifunctional protein initiating and controlling de novo biosynthesis of pyrimidines in animals, self-assembles into ∼1.5 MDa hexamers. The structures of the dihydroorotase (DHO) and aspartate transcarbamoylase (ATC) domains of human CAD have been previously determined, but we lack information on how these domains associate and interact with the rest of CAD forming a multienzymatic unit. Here, we prove that a construct covering human DHO and ATC oligomerizes as a dimer of trimers and that this arrangement is conserved in CAD-like from fungi, which holds an inactive DHO-like domain. The crystal structures of the ATC trimer and DHO-like dimer from the fungus Chaetomium thermophilum confirm the similarity with the human CAD homologs. These results demonstrate that, despite being inactive, the fungal DHO-like domain has a conserved structural function. We propose a model that sets the DHO and ATC complex as the central element in the architecture of CAD.

Structure and Functional Characterization of Human Aspartate Transcarbamoylase, the Target of the Anti-tumoral Drug PALA.

CAD, the multienzymatic protein that initiates and controls de novo synthesis of pyrimidines in animals, associates through its aspartate transcarbamoylase (ATCase) domain into particles of 1.5 MDa. Despite numerous structures of prokaryotic ATCases, we lack structural information on the ATCase domain of CAD. Here, we report the structure and functional characterization of human ATCase, confirming the overall similarity with bacterial homologs. Unexpectedly, human ATCase exhibits cooperativity effects that reduce the affinity for the anti-tumoral drug PALA. Combining structural, mutagenic, and biochemical analysis, we identified key elements for the necessary regulation and transmission of conformational changes leading to cooperativity between subunits. Mutation of one of these elements, R2024, was recently found to cause the first non-lethal CAD deficit. We reproduced this mutation in human ATCase and measured its effect, demonstrating that this arginine is part of a molecular switch that regulates the equilibrium between low- and high-affinity states for the ligands.

Cortactin autoantibodies in myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness, fatigability, and autoantibodies against protein antigens of the muscle endplate. Antibodies against acetylcholine receptor (AChR), and less frequently against muscle-Specific Kinase (MuSK) or lipoprotein related protein 4 (LRP4) occur in patients with seropositive MG (SPMG). However, about 10% of patients do not have detectable autoantibodies despite evidence suggesting that the disorder is immune mediated; this disorder is known as seronegative MG (SNMG). Using a protein array approach we identified cortactin (a protein that acts downstream from agrin/MuSK promoting AChR clustering) as potential new target antigen in SNMG. We set up an ELISA assay and screened sera from patients with SPMG, SNMG, other autoimmune diseases and controls. Results were validated by immunoblot. We found that 19.7% of patients with SNMG had antibodies against cortactin whereas only 4.8% of patients with SPMG were positive. Cortactin antibodies were also found in 12.5% of patients with other autoimmune disorders but only in 5.2% of healthy controls. We conclude that the finding of cortactin antibodies in patients with SNMG, suggests an underlying autoimmune mechanism, supporting the use of immune therapy.

Expression, purification, crystallization and preliminary X-ray diffraction analysis of the aspartate transcarbamoylase domain of human CAD.

Aspartate transcarbamoylase (ATCase) catalyzes the synthesis of N-carbamoyl-L-aspartate from carbamoyl phosphate and aspartate in the second step of the de novo biosynthesis of pyrimidines. In prokaryotes, the first three activities of the pathway, namely carbamoyl phosphate synthetase (CPSase), ATCase and dihydroorotase (DHOase), are encoded as distinct proteins that function independently or in noncovalent association. In animals, CPSase, ATCase and DHOase are part of a 243 kDa multifunctional polypeptide named CAD. Up-regulation of CAD is essential for normal and tumour cell proliferation. Although the structures of numerous prokaryotic ATCases have been determined, there is no structural information about any eukaryotic ATCase. In fact, the only detailed structural information about CAD is that it self-assembles into hexamers and trimers through interactions of the ATCase domains. Here, the expression, purification and crystallization of the ATCase domain of human CAD is reported. The recombinant protein, which was expressed in bacteria and purified with good yield, formed homotrimers in solution. Crystallization experiments both in the absence and in the presence of the inhibitor PALA yielded small crystals that diffracted X-rays to 2.1 Å resolution using synchrotron radiation. The crystals appeared to belong to the hexagonal space group P6(3)22, and Matthews coefficient calculation indicated the presence of one ATCase subunit per asymmetric unit, with a solvent content of 48%. However, analysis of the intensity statistics suggests a special case of the P21 lattice with pseudo-symmetry and possibly twinning.