[BIRADS 0 patient reclassification in a first-level of care unit]. / Reclasificación de pacientes BIRADS 0 en una unidad de primer nivel de atención.

Background: In Mexico and the world, breast cancer is the cancer type with the highest incidence and mortality for women. Its incidence has increased due to a higher life expectancy and a higher exposure to risk factors. Screening is done by mammography using the BIRADS (Breast Imaging Reporting and Data System) system, the standard for mammography screening report which classifies lesions assigning recommendations for patient follow-up. The system goes from 0 (not conclusive) to 6 (demonstrated malignancy), being of interest for this study the BIRADS 0 category. Objective: To describe patients classified as BIRADS 0 by mammography and their reclassification in a first-level hospital during 2021. Material and methods: Retrospective, descriptive, cross-sectional, observational study. Women over 40 years with a BIRADS 0 result were studied. The following databases were used: Institutional Cancer Registry, Family Medicine Information System, Electronic Clinical File, and the mammography and patient list from preventive medicine. Results: Reclassification by ultrasound (US) was achieved in 100% of patients, in all of the BIRADS US categories. In 3.8% of BIRADS 0 patients, ductal adenocarcinoma was found and confirmed by histological testing. Conclusion: All of the reassessed lesions with US were adequately reclassified.

Introducción: en México y el mundo, el cáncer de mama causa la mayor mortalidad por cáncer en mujeres. Su incidencia ha incrementado por una mayor esperanza de vida y exposición a factores de riesgo. El tamizaje de esta enfermedad se hace mediante mastografía, y para la estratificación de las lesiones se utiliza el sistema BIRADS (Breast Imaging Reporting and Data System), que estandariza el informe, categoriza las lesiones según el grado de sospecha y asigna recomendaciones a seguir. Dicho sistema va desde 0 (no concluyente) hasta 6 (lesión con malignidad demostrada) y es de interés para este estudio la categoría 0. Objetivo: describir la reclasificación de pacientes con reporte BIRADS 0 por mastografía durante 2021 en una unidad de primer nivel de atención. Material y métodos: estudio retrospectivo, descriptivo, transversal, observacional. Se estudiaron mujeres mayores de 40 años con resultado BIRADS 0. Se utilizaron las siguientes bases de datos: Registro Institucional de Cáncer, Sistema de Información de Medicina Familiar, Expediente Clínico Electrónico y lista nominal de mastografías y censo de pacientes sospechosos de medicina preventiva. Resultados: la reclasificación con ultrasonido (US) se logró en el 100% de pacientes, en todas las categorías de BIRADS US. En el 3.8% se confirmó carcinoma ductal por histología en las pacientes inicialmente categorizadas como BIRADS 0. Conclusiones: la totalidad de lesiones reevaluadas con US fueron reclasificadas satisfactoriamente.

Diving into the metabolic interactions of titanium dioxide nanoparticles in "Sparus aurata" and "Ruditapes philippinarum".

The biological response to nanomaterials exposure depends on their properties, route of exposure, or model organism. Titanium dioxide nanoparticles (TiO2 NPs) are among the most used nanomaterials; however, concerns related to oxidative stress and metabolic effects resulting from their ingestion are rising. Therefore, in the present work, we addressed the metabolic effects of citrate-coated 45 nm TiO2 NPs combining bioaccumulation, tissue ultrastructure, and proteomics approaches on gilthead seabream, Sparus aurata and Japanese carpet shell, Ruditapes philippinarum. Sparus aurata was exposed through artificially contaminated feeds, while R. philippinarum was exposed using TiO2 NPs-doped microalgae solutions. The accumulation of titanium and TiO2 NPs in fish liver is associated with alterations in hepatic tissue structure, and alteration to the expression of proteins related to lipid and fatty acid metabolism, lipid breakdown for energy, lipid transport, and homeostasis. While cellular structure alterations and the expression of proteins were less affected than in gilthead seabream, atypical gill cilia and microvilli and alterations in metabolic-related proteins were also observed in the bivalve. Overall, the effects of TiO2 NPs exposure through feeding appear to stem from various interactions with cells, involving alterations in key metabolic proteins, and changes in cell membranes, their structures, and organelles. The possible appearance of metabolic disorders and the environmental risks to aquatic organisms posed by TiO2 NPs deserve further study.

Impact of coordination mechanisms based on information and communication technologies on cross-level clinical coordination: A scoping review.

Background: Coordination mechanisms based on information and communication technologies (ICTs) are gaining attention, especially since the pandemic, due to their potential to improve communication between health professionals. However, their impact on cross-level clinical coordination remains unclear. The aim is to synthesize the evidence on the impact of ICT-based coordination mechanisms on clinical coordination between primary care and secondary care (SC) doctors and to identify knowledge gaps. Methods: A scoping review was conducted by searching for original articles in six electronic databases and a manual search, with no restrictions regarding time, area, or methodology. Titles and abstracts were screened. Full texts of the selected articles were reviewed and analysed to assess the impact of each mechanism, according to the cross-level clinical coordination conceptual framework. Results: Of the 6555 articles identified, 30 met the inclusion criteria. All had been conducted in high-income countries, most (n = 26) evaluated the impact of a single mechanism - asynchronous electronic consultations via electronic health records (EHR) - and were limited in terms of design and types and dimensions of cross-level clinical coordination analysed. The evaluation of electronic consultations showed positive impacts on the appropriateness of referrals and accessibility to SC, yet the qualitative studies also highlighted potential risks. Studies on other mechanisms were scarce (shared EHR, email consultations) or non-existent (videoconferencing, mobile applications). Conclusions: Evidence of the impact of ICT-based mechanisms on clinical coordination between levels is limited. Rigorous evaluations are needed to inform policies and strategies for improving coordination between healthcare levels, thus contributing to high-quality, efficient healthcare.

Has cross-level clinical coordination changed in the context of the pandemic? The case of the Catalan health system.

BACKGROUND: The COVID-19 pandemic triggered numerous changes in health services organisation, whose effects on clinical coordination are unknown. The aim is to analyse changes in the experience and perception of cross-level clinical coordination and related factors of primary (PC) and secondary care (SC) doctors in the Catalan health system between 2017 and 2022. METHODS: Comparison of two cross-sectional studies based on online surveys by means of the self-administration of the COORDENA-CAT (2017) and COORDENA-TICs (2022) questionnaires to PC and SC doctors. Final sample n = 3308 in 2017 and n = 2277 in 2022. OUTCOME VARIABLES: experience of cross-level information and clinical management coordination and perception of cross-level clinical coordination in the healthcare area and related factors. Stratification variables: level of care and year. Adjusting variables: sex, years of experience, type of specialty, type of hospital, type of management of PC/SC. Descriptive bivariate and multivariate analysis using Poisson regressions models to detect changes between years in total and by levels of care. RESULTS: Compared with 2017, while cross-level clinical information coordination remained relatively high, with a slight improvement, doctors of both care levels reported a worse experience of cross-level clinical management coordination, particularly of care consistency (repetition of test) and accessibility to PC and, of general perception, which was worse in SC doctors. There was also a worsening in organisational (institutional support, set objectives, time available for coordination), attitudinal (job satisfaction) and interactional factors (knowledge between doctors). The use of ICT-based coordination mechanisms such as shared electronic medical records and electronic consultations between PC and SC increased, while the participation in virtual joint clinical conferences was limited. CONCLUSIONS: Results show a slight improvement in clinical information but also less expected setbacks in some dimensions of clinical management coordination and in the perception of clinical coordination, suggesting that the increased use of some ICT-based coordination mechanisms did not counteract the effect of the worsened organisational, interactional, and attitudinal factors during the pandemic. Strategies are needed to facilitate direct communication, to improve conditions for the effective use of mechanisms and policies to protect healthcare professionals and services in order to better cope with new crises.

Tumor-Suppressive Cross-Linking of Anti-T. cruzi Antibodies in Acute Lymphoblastic Leukemia.

Parasites have been associated with possible anticancer activity, including Trypanosoma cruzi, which has been linked to inhibiting the growth of solid tumors. To better understand this antitumor effect, we investigated the association of anti-T. cruzi antibodies with B cells of the acute lymphoblastic leukemia (ALL) SUPB15 cell line. The antibodies were generated in rabbits. IgGs were purified by affinity chromatography. Two procedures (flow cytometry (CF) and Western blot(WB)) were employed to recognize anti-T. cruzi antibodies on SUPB15 cells. We also used CF to determine whether the anti-T. cruzi antibodies could suppress SUPB15 cells. The anti-T. cruzi antibodies recognized 35.5% of the surface antigens of SUPB15. The complement-dependent cytotoxicity (CDC) results demonstrate the cross-suppression of anti-T. cruzi antibodies on up to 8.4% of SUPB15 cells. For the WB analysis, a band at 100 kDa with high intensity was sequenced using mass spectrometry, identifying the protein as nucleolin. This protein may play a role in the antitumor effect on T. cruzi. The anti-T. cruzi antibodies represent promising polyclonal antibodies that have the effect of tumor-suppressive cross-linking on cancer cells, which should be further investigated.

Kisspeptins centrally modulate food intake and locomotor activity in mice independently of gonadal steroids in a sexually dimorphic manner.

Kisspeptins are essential regulators of the reproductive axis, with capacity to potently activate gonadotropin-releasing hormone neurons, acting also as central conduits for the metabolic regulation of fertility. Recent evidence suggests that kisspeptins per se may also modulate several metabolic parameters, including body weight, food intake or energy expenditure, but their actual roles and site(s) of action remain unclear. We present herein a series of studies addressing the metabolic effects of central and peripheral administration of kisspeptin-10 (Kp-10; 1 nmol and 3 nmol daily, respectively) for 11 days in mice of both sexes. To assess direct metabolic actions of Kp-10 versus those derived indirectly from its capacity to modulate gonadal hormone secretion, kisspeptin effects were tested in adult male and female mice gonadectomized and supplemented with fixed, physiological doses of testosterone or 17ß-estradiol, respectively. Central administration of Kp-10 decreased food intake in male mice, especially during the dark phase (~50%), which was accompanied by a reduction in total and nocturnal energy expenditure (~16%) and locomotor activity (~70%). In contrast, opposite patterns were detected in female mice, with an increase in total and nocturnal locomotor activity (>65%), despite no changes in food intake or energy expenditure. These changes were independent of body weight, as no differences were detected in mice of both sexes at the end of Kp-10 treatments. Peripheral administration of Kp-10 failed to alter any of the metabolic parameters analyzed, except for a decrease in locomotor activity in male mice and a subtle increase in 24 h food intake in female mice, denoting a predominant central role of kisspeptins in the control of energy metabolism. Finally, glucose tolerance and insulin sensitivity were not significantly affected by central or peripheral treatment with Kp-10. In conclusion, our data reveal a potential role of kisspeptins in the control of key metabolic parameters, including food intake, energy expenditure and locomotor activity, with a preferential action at central level, which is sex steroid-independent but sexually dimorphic.

Comparative Brain Proteomic Analysis between Sham and Cerebral Ischemia Experimental Groups.

Sham control groups are essential in experimental animal studies to reduce the influence of surgical intervention. The intraluminal filament procedure is one of the most common models of middle cerebral artery occlusion (MCAO) used in the study of brain ischemia. However, a sham group is usually not included in the experimental design of these studies. In this study, we aimed to evaluate the relevance of the sham group by analyzing and comparing the brain protein profiles of the sham and MCAO groups. In the sham group, 98 dysregulated proteins were detected, compared to 171 in the ischemic group. Moreover, a comparative study of protein profiles revealed the existence of a pool of 57 proteins that appeared to be dysregulated in both sham and ischemic animals. These results indicated that the surgical procedure required for the intraluminal occlusion of the middle cerebral artery (MCA) induces changes in brain protein expression that are not associated with ischemic lesions. This study highlights the importance of including sham control groups in the experimental design, to ensure that surgical intervention does not affect the therapeutic target under study.

Placental pathology lesions: International Society for Ultrasound in Obstetrics and Gynecology vs Society for Maternal-Fetal Medicine fetal growth restriction definitions.

BACKGROUND: Research on the definition of fetal growth restriction (FGR) has focused on predicting adverse perinatal outcomes. A significant limitation of this approach is that the individual outcomes of interest could be related to the condition and the treatment. Evaluation of outcomes that reflect the pathophysiology of FGR may overcome this limitation. OBJECTIVE: To compare the diagnostic performance of the FGR definitions established by the International Society for Ultrasound in Obstetrics and Gynecology (ISUOG) and the Society for Maternal-Fetal Medicine (SMFM) to predict placental histopathological findings associated with placental insufficiency and a composite adverse neonatal outcome (ANeO). STUDY DESIGN: In this retrospective cohort study of singleton pregnancies, the ISUOG and the SMFM guidelines were used to identify pregnancies with FGR and a corresponding control group. The primary outcome was the prediction of placental histopathological findings associated with placental insufficiency, defined as lesions associated with maternal vascular malperfusion (MVM). A composite ANeO (ie, umbilical artery pH≤7.1, Apgar score at 5 minutes ≤4, neonatal intensive care unit admission, hypoglycemia, respiratory distress syndrome requiring mechanical ventilation, intrapartum fetal distress requiring expedited delivery, and perinatal death) was investigated as a secondary outcome. Sensitivity, specificity, positive and negative predictive values, and the areas under the receiver-operating-characteristics curves were determined for each FGR definition. Logistic regression models were used to assess the association between each definition and the studied outcomes. A subgroup analysis of the diagnostic performance of both definitions stratifying the population in early and late FGR was also performed. RESULTS: Both societies' definitions showed a similar diagnostic performance as well as a significant association with the primary (ISUOG adjusted odds ratio 3.01 [95% confidence interval 2.42, 3.75]; SMFM adjusted odds ratio 2.85 [95% confidence interval 2.31, 3.51]) and secondary outcomes (ISUOG adjusted odds ratio 1.95 [95% confidence interval 1.56, 2.43]; SMFM adjusted odds ratio 2.12 [95% confidence interval 1.70, 2.65]). Furthermore, both FGR definitions had a limited discriminatory capacity for placental histopathological findings of MVM and the composite ANeO (area under the receiver-operating-characteristics curve ISUOG 0.63 [95% confidence interval 0.61, 0.65], 0.59 [95% confidence interval 0.56, 0.61]; area under the receiver-operating-characteristics SMFM 0.63 [95% confidence interval 0.61, 0.66], 0.60 [95% confidence interval 0.57, 0.62]). CONCLUSION: The ISUOG and the SMFM FGR definitions have limited discriminatory capacity for placental histopathological findings associated with placental insufficiency and a composite ANeO.

Clinical and treatment profiles of arterial hypertension in Mexico during the COVID-19 pandemic: a cross-sectional survey endorsed by the "Collaborative Group on Arterial Hypertension".

Background: Arterial hypertension is highly prevalent in Mexico; nevertheless, there are limited insights regarding its management during the COVID-19 pandemic. Here, we estimate the prevalence of clinical and treatment profiles of arterial hypertension and explore associated factors for undiagnosed and uncontrolled hypertension using a cross-sectional survey endorsed by the Collaborative Group on Arterial Hypertension from the Mexican Institute of Social Security. Methods: Our survey was conducted from May to November 2021 using the May-Measurement Month 2021 protocols of the International Society of Hypertension. Arterial hypertension (defined as: blood pressure [BP] ≥140/90 mmHg, previous diagnosis, or taking antihypertensives) and its clinical and treatment profiles were classified according to the World Hypertension League Expert Committee. Mixed-effects logistic regression models were used to explore associated factors for undiagnosed and uncontrolled hypertension. Results: Among 77,145 screened participants (women: 62.4%; median age: 46 [IQR: 32-59] years), the prevalence of arterial hypertension was 35.7% (95% CI: 35.3-36.0, n = 27,540). Among participants with arterial hypertension, 30.9% (95% CI: 30.4-31.5, n = 8,533) were undiagnosed, 6.6% (95% CI: 6.3%-6.9%, n = 1,806) were diagnosed but untreated, 43.4% (95% CI: 42.9-44.0, n = 11,965) had uncontrolled hypertension, and only 19% (95% CI: 18.6%-19.5%, n = 5,236) achieved hypertension control (BP < 130/80 mmHg). Explored associated factors for undiagnosed and uncontrolled hypertension include being men, living in the central and southern regions, lower educational attainments, higher use of pharmacological agents, and previous COVID-19 infection. Conclusion: Our findings suggest that adverse arterial hypertension profiles, mainly undiagnosed and uncontrolled hypertension, were highly prevalent during the context of the COVID-19 pandemic in Mexico.

Protective Efficacy of the Epitope-Conjugated Antigen N-Tc52/TSkb20 in Mitigating Trypanosoma cruzi Infection through CD8+ T-Cells and IFNγ Responses.

Chagas disease, caused by the protozoan Trypanosoma cruzi, remains a major public health challenge affecting millions in Latin America and worldwide. Although significant progress has been made in vector control, no vaccine exists to prevent infection or mitigate disease pathogenesis. We developed a rationally designed chimeric protein vaccine, N-Tc52/TSkb20, incorporating immunodominant epitopes from two T. cruzi antigens, the amino-terminal portion of Tc52 and the TSkb20 epitope derived from trans-sialidase. The objectives of this study were to construct and characterize the antigen and evaluate its protective potential in an immunoprophylactic murine model of T. cruzi infection. The N-Tc52/TSkb20 protein was recombinantly expressed in E. coli and its identity was confirmed using mass spectrometry and Western blotting. Immunization with the chimeric protein significantly controlled parasitemia and reduced the heart, colon, and skeletal muscle parasite burdens compared to non-vaccinated mice. Protection was superior to vaccination with the individual parental antigen components. Mechanistically, the vaccine induced potent CD8+ T-cell and IFNγ responses against the incorporated epitopes and a protective IgG antibody profile. A relatively low IL-10 response favored early parasite control. These results validate the promising multi-epitope approach and support the continued development of this type of rational vaccine design strategy against Chagas disease.

A Phase II Trial of Stereotactic Body Radiation Therapy and Androgen Deprivation for Oligometastases in Prostate Cancer (SBRT-SG 05).

PURPOSE: SBRT-Spanish Group-05 (ClinicalTrials.gov.Identifier: NCT02192788) is a collaborative (SBRT-SG, Grupo de Investigación Clínica en Oncología Radioterápica, and Sociedad Española de Oncología Radioterápica) prospective multicenter phase II trial testing stereotactic body radiation therapy (SBRT) and androgen deprivation therapy (ADT) in patients with oligorecurrent prostate cancer. METHODS AND MATERIALS: Two cohorts of patients with prostate cancer in an oligorecurrent stage (hormone-sensitive in the principal cohort and castration-resistant in the exploratory cohort) were assigned to receive ADT and SBRT for at least 24 months from the time of the enrollment. Concomitant treatment with chemotherapy, abiraterone, or enzalutamide was not allowed. Oncologic outcomes were assessed in both cohorts. Toxicity was prospectively analyzed. RESULTS: From 2014 to 2019, 81 patients with a total of 126 lesions from 14 centers met the inclusion criteria, 14 of whom were castration-resistant. With a median follow-up of 40 months (12-58 months), 3-year local recurrence-free survival was 92.5% (95% CI, 79.9%-96.3%) and 85.7% (95% CI, 48.2%-95.6%) in the principal and exploratory cohorts, respectively. In the principal cohort, biochemical relapse-free survival and metastasis progression-free survival at 1, 2, and 3 years were 91% (95% CI, 81%-95.8%), 73.7% (95% CI, 61.1%-82.8%), 50.6% (95% CI, 36.2%-63.3%), and 92% (95% CI, 83%-97%), 81% (95% CI, 70%-89%), and 67% (95% CI, 53%-77%), respectively. In the exploratory cohort, metastasis progression-free survival at 1, 2, and 3 years was 64% (95% CI, 34%-83%), 43% (95% CI, 18%-66%), and 26% (95% CI, 7%-51%), respectively. None of the patients developed grade III or higher toxicity or symptoms related to local progression, and only 2 (2.4%) patients developed grade II toxicity. CONCLUSIONS: The combination of SBRT and ADT is safe and shows favorable clinical outcomes in patients with hormone-sensitive and castration-resistant prostate cancer. Validation studies are needed in patients with castration-resistant prostate cancer.

Mediterranean Diet Information on TikTok and Implications for Digital Health Promotion Research: Social Media Content Analysis.

BACKGROUND: The Mediterranean diet has been linked to reduced risk for several cardiometabolic diseases. The lack of a clear definition of the Mediterranean diet in the scientific literature and the documented proliferation of nutrition misinformation on the internet suggest the potential for confusion among consumers seeking web-based Mediterranean diet information. OBJECTIVE: We conducted a social media content analysis of information about the Mediterranean diet on the influential social media platform, TikTok, to examine public discourse about the diet and identify potential areas of misinformation. We then analyzed these findings in the context of health promotion to identify potential challenges and opportunities for the use of TikTok in promoting the Mediterranean diet for healthy living. METHODS: The first-appearing 202 TikTok posts that resulted from a search of the hashtag #mediterraneandiet were downloaded and qualitatively examined. Post features and characteristics, poster information, and engagement metrics were extracted and synthesized across posts. Posts were categorized as those created by health professionals and those created by nonhealth professionals based on poster-reported credentials. In addition to descriptive statistics of the entire sample, we compared posts created by professionals and nonprofessionals for content using chi-square tests. RESULTS: TikTok posts varied in content, but posts that were developed by health professionals versus nonprofessionals were more likely to offer a definition of the Mediterranean diet (16/106, 15.1% vs 2/96, 2.1%; P=.001), use scientific citations to support claims (26/106, 24.5% vs 0/96, 0%; P<.001), and discuss specific nutrients (33/106, 31.1% vs 6/96, 6.3%; P<.001) and diseases related to the diet (27/106, 25.5% vs 5/96, 5.2%; P<.001) compared to posts created by nonhealth professionals. CONCLUSIONS: Social media holds promise as a venue to promote the Mediterranean diet, but the variability in information found in this study highlights the need to create clear definitions about the diet and its components when developing Mediterranean diet interventions that use new media structures.

Simple electrochemical synthesis of cyclic hydroxamic acids by reduction of nitroarenes.

The electrochemical reduction of nitroarenes allows direct access to manifold nitrogen containing heterocycles. This work reports the simple and direct electro-organic synthesis of 18 different examples of 2H,4H-4-hydroxy-1,4-benzoxazin-3-ones in up to 81% yield. The scalability of the method was demonstrated on a gram-scale.

Dissemination of extensively drug-resistant NDM-producing Providencia stuartii in Europe linked to patients transferred from Ukraine, March 2022 to March 2023.

BackgroundThe war in Ukraine led to migration of Ukrainian people. Early 2022, several European national surveillance systems detected multidrug-resistant (MDR) bacteria related to Ukrainian patients.AimTo investigate the genomic epidemiology of New Delhi metallo-ß-lactamase (NDM)-producing Providencia stuartii from Ukrainian patients among European countries.MethodsWhole-genome sequencing of 66 isolates sampled in 2022-2023 in 10 European countries enabled whole-genome multilocus sequence typing (wgMLST), identification of resistance genes, replicons, and plasmid reconstructions. Five bla NDM-1-carrying-P. stuartii isolates underwent antimicrobial susceptibility testing (AST). Transferability to Escherichia coli of a bla NDM-1-carrying plasmid from a patient strain was assessed. Epidemiological characteristics of patients with NDM-producing P. stuartii were gathered by questionnaire.ResultswgMLST of the 66 isolates revealed two genetic clusters unrelated to Ukraine and three linked to Ukrainian patients. Of these three, two comprised bla NDM-1-carrying-P. stuartii and the third bla NDM-5-carrying-P. stuartii. The bla NDM-1 clusters (PstCluster-001, n = 22 isolates; PstCluster-002, n = 8 isolates) comprised strains from seven and four countries, respectively. The bla NDM-5 cluster (PstCluster-003) included 13 isolates from six countries. PstCluster-001 and PstCluster-002 isolates carried an MDR plasmid harbouring bla NDM-1, bla OXA-10, bla CMY-16, rmtC and armA, which was transferrable in vitro and, for some Ukrainian patients, shared by other Enterobacterales. AST revealed PstCluster-001 isolates to be extensively drug-resistant (XDR), but susceptible to cefiderocol and aztreonam-avibactam. Patients with data on age (n = 41) were 19-74 years old; of 49 with information on sex, 38 were male.ConclusionXDR P. stuartii were introduced into European countries, requiring increased awareness and precautions when treating patients from conflict-affected areas.

Haemoglobinopathies and other rare anemias in Spain: ten years of a nationwide registry (REHem-AR).

REHem-AR was created in 2013. The progressive implementation of neonatal screening for haemoglobinopathies in Spanish autonomous communities where the registry had not been implemented, as well as the addition of new centres during this period, has considerably increased the sample of patients covered. In this study, we update our previous publication in this area, after a follow-up of more than 5 years. An observational, descriptive, multicentre and ambispective study of adult and paediatric patients with haemoglobinopathies and rare anaemias registered in REHem was performed. The data are from a cross-sectional analysis performed on 1 June, 2023. The study population comprised 1,756 patients, of whom 1,317 had SCD, 214 had thalassaemia and 224 were diagnosed with another condition. Slightly more than one third of SCD patients (37%) were diagnosed based on neonatal bloodspot screening, and the mean age at diagnosis was 2.5 years; 71% of thalassaemia patients were diagnosed based on the presence of anaemia. Vaso-occlusive crisis and acute chest syndrome continue to be the most frequent complications in SCD. HSCT was performed in 83 patients with SCD and in 50 patients with thalassaemia. Since the previous publication, REHem-AR has grown in size by more than 500 cases. SCD and TM are less frequent in Spain than in other European countries, although the data show that rare anaemias are frequent within rare diseases. REHem-AR constitutes an important structure for following the natural history of rare anaemias and enables us to calculate investment needs for current and future treatments.

Mitochondrial antiviral signaling protein enhances MASLD progression through the ERK/TNFα/NFκß pathway.

BACKGROUND AND AIMS: Mitochondrial antiviral signaling protein (MAVS) is a critical regulator that activates the host's innate immunity against RNA viruses, and its signaling pathway has been linked to the secretion of proinflammatory cytokines. However, the actions of MAVS on inflammatory pathways during the development of metabolic dysfunction-associated steatotic liver disease (MASLD) have been little studied. APPROACH AND RESULTS: Liver proteomic analysis of mice with genetically manipulated hepatic p63, a transcription factor that induces liver steatosis, revealed MAVS as a target downstream of p63. MAVS was thus further evaluated in liver samples from patients and in animal models with MASLD. Genetic inhibition of MAVS was performed in hepatocyte cell lines, primary hepatocytes, spheroids, and mice. MAVS expression is induced in the liver of both animal models and people with MASLD as compared with those without liver disease. Using genetic knockdown of MAVS in adult mice ameliorates diet-induced MASLD. In vitro, silencing MAVS blunts oleic and palmitic acid-induced lipid content, while its overexpression increases the lipid load in hepatocytes. Inhibiting hepatic MAVS reduces circulating levels of the proinflammatory cytokine TNFα and the hepatic expression of both TNFα and NFκß. Moreover, the inhibition of ERK abolished the activation of TNFα induced by MAVS. The posttranslational modification O -GlcNAcylation of MAVS is required to activate inflammation and to promote the high lipid content in hepatocytes. CONCLUSIONS: MAVS is involved in the development of steatosis, and its inhibition in previously damaged hepatocytes can ameliorate MASLD.

Inhibition of hepatic p63 ameliorates steatohepatitis with fibrosis in mice.

OBJECTIVE: p63 is a transcription factor involved in multiple biological functions. In the liver, the TAp63 isoform induces lipid accumulation in hepatocytes. However, the role of liver TAp63 in the progression of metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis is unknown. METHODS: We evaluated the hepatic p63 levels in different mouse models of steatohepatitis with fibrosis induced by diet. Next, we used virogenetic approaches to manipulate the expression of TAp63 in adult mice under diet-induced steatohepatitis with fibrosis and characterized the disease condition. Finally, we performed proteomics analysis in mice with overexpression and knockdown of hepatic TAp63. RESULTS: Levels of TAp63, but not of ΔN isoform, are increased in the liver of mice with diet-induced steatohepatitis with fibrosis. Both preventive and interventional strategies for the knockdown of hepatic TAp63 significantly ameliorated diet-induced steatohepatitis with fibrosis in mice fed a methionine- and choline-deficient diet (MCDD) and choline deficient and high fat diet (CDHFD). The overexpression of hepatic TAp63 in mice aggravated the liver condition in mice fed a CDHFD. Proteomic analysis in the liver of these mice revealed alteration in multiple proteins and pathways, such as oxidative phosphorylation, antioxidant activity, peroxisome function and LDL clearance. CONCLUSIONS: These results indicate that liver TAp63 plays a critical role in the progression of diet-induced steatohepatitis with fibrosis, and its inhibition ameliorates the disease.

Characterizing carbapenemase-producing Escherichia coli isolates from Spain: high genetic heterogeneity and wide geographical spread.

Introduction: Carbapenemase-Producing Escherichia coli (CP-Eco) isolates, though less prevalent than other CP-Enterobacterales, have the capacity to rapidly disseminate antibiotic resistance genes (ARGs) and cause serious difficult-to-treat infections. The aim of this study is phenotypically and genotypically characterizing CP-Eco isolates collected from Spain to better understand their resistance mechanisms and population structure. Methods: Ninety representative isolates received from 2015 to 2020 from 25 provinces and 59 hospitals Spanish hospitals were included. Antibiotic susceptibility was determined according to EUCAST guidelines and whole-genome sequencing was performed. Antibiotic resistance and virulence-associated genes, phylogeny and population structure, and carbapenemase genes-carrying plasmids were analyzed. Results and discussion: The 90 CP-Eco isolates were highly polyclonal, where the most prevalent was ST131, detected in 14 (15.6%) of the isolates. The carbapenemase genes detected were bla OXA-48 (45.6%), bla VIM-1 (23.3%), bla NDM-1 (7.8%), bla KPC-3 (6.7%), and bla NDM-5 (6.7%). Forty (44.4%) were resistant to 6 or more antibiotic groups and the most active antibiotics were colistin (98.9%), plazomicin (92.2%) and cefiderocol (92.2%). Four of the seven cefiderocol-resistant isolates belonged to ST167 and six harbored bla NDM. Five of the plazomicin-resistant isolates harbored rmt. IncL plasmids were the most frequent (45.7%) and eight of these harbored bla VIM-1. bla OXA-48 was found in IncF plasmids in eight isolates. Metallo-ß-lactamases were more frequent in isolates with resistance to six or more antibiotic groups, with their genes often present on the same plasmid/integron. ST131 isolates were associated with sat and pap virulence genes. This study highlights the genetic versatility of CP-Eco and its potential to disseminate ARGs and cause community and nosocomial infections.

The evolutionary conserved miR-137/325 tandem mediates obesity-induced hypogonadism and metabolic comorbidities by repressing hypothalamic kisspeptin.

BACKGROUND: Obesity-induced hypogonadism (OIH) is a prevalent, but often neglected condition in men, which aggravates the metabolic complications of overweight. While hypothalamic suppression of Kiss1-encoded kisspeptin has been suggested to contribute to OIH, the molecular mechanisms for such repression in obesity, and the therapeutic implications thereof, remain unknown. METHODS: A combination of bioinformatic, expression and functional analyses was implemented, assessing the role of the evolutionary-conserved miRNAs, miR-137 and miR-325, in mediating obesity-induced suppression of hypothalamic kisspeptin, as putative mechanism of central hypogonadism and metabolic comorbidities. The implications of such miR-137/325-kisspeptin interplay for therapeutic intervention in obesity were also explored using preclinical OIH models. RESULTS: MiR-137/325 repressed human KISS1 3'-UTR in-vitro and inhibited hypothalamic kisspeptin content in male rats, while miR-137/325 expression was up-regulated, and Kiss1/kisspeptin decreased, in the medio-basal hypothalamus of obese rats. Selective over-expression of miR-137 in Kiss1 neurons reduced Kiss1/ kisspeptin and partially replicated reproductive and metabolic alterations of OIH in lean mice. Conversely, interference of the repressive actions of miR-137/325 selectively on Kiss1 3'-UTR in vivo, using target-site blockers (TSB), enhanced kisspeptin content and reversed central hypogonadism in obese rats, together with improvement of glucose intolerance, insulin resistance and cardiovascular and inflammatory markers, despite persistent exposure to obesogenic diet. Reversal of OIH by TSB miR-137/325 was more effective than chronic kisspeptin or testosterone treatments in obese rats. CONCLUSIONS: Our data disclose that the miR-137/325-Kisspeptin repressive interaction is a major player in the pathogenesis of obesity-induced hypogonadism and a putative druggable target for improved management of this condition and its metabolic comorbidities in men suffering obesity. SIGNIFICANCE STATEMENT: Up to half of the men suffering obesity display also central hypogonadism, an often neglected complication of overweight that can aggravate the clinical course of obesity and its complications. The mechanisms for such obesity-induced hypogonadism remain poorly defined. We show here that the evolutionary conserved miR137/miR325 tandem centrally mediates obesity-induced hypogonadism via repression of the reproductive-stimulatory signal, kisspeptin; this may represent an amenable druggable target for improved management of hypogonadism and other metabolic complications of obesity.