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Abstract Background Lawsonia intracellularis is the causative agent of Porcine Proliferative Enteropathy (PPE), one of the most prevalent pig enteric diseases worldwide, but with sparse information about early infections in suckling piglets in the epidemiology of PPE. With that aim, this study evaluates the prevalence of L. intracellularis in 3-week-old piglets by analysing ileal digesta content and mucosal scrapings from 383 pigs from 16 farms (aprox., 25 pigs/batch) by real-time qPCR and droplet digital PCR (ddPCR). Results Forty-nine samples yielded a qPCR positive result. Eleven samples from eight farms were confirmed as positive with concentrations of L. intracellularis from 3.5 log10 to 4.5 log10 bacteria/g of sample. Another 16 samples, eight farms, were classified as low positive (2.07–2.38 log10 bacteria/g) and 22 provided an uncertain result. Finally, 334 samples tested negative for L. intracellularis. At batch level, half of the farms included in the study had at least one positive sample and in 10 farms (62.5%) there was at least one low positive sample. The ddPCR was run in 50 of the 383 samples based on their PCR output (including low positive, uncertain and negative samples). Correlation analyses revealed a strong association between qPCR and the ddPCR results (ρ = 0.75; p

Mexico City emits several thousands of tons of particle matter from transportation and other economic sectors. We collected PM2.5 samples from January to March 2015. The chemical analyses showed that PM2.5 is made up of 39% organic carbon, 12% elemental carbon, 23% metals (Al, Si, S, P, and K), and 5% heavy metals (Pb, Cr, Mn, Zn, and Hg). Ca and Fe were also present in trace concentrations, probably due to the resuspension of soils. Nitrate, sulfate, and ammonium suggest that the southwest of Mexico City, specifically the sampling site, receives more oxidated pollutants from vehicle emissions than other emissions. The chemical analyses show no significant changes in the composition or concentration of particle matter compared to previous studies.

Human Papillomavirus (HPV) related Multiphenotypic Sinonasal Carcinoma (HMSC) is a rare tumor with features of both atypical squamous cell and adenoid cystic carcinoma, making diagnosis challenging. Approximately 80% of HMSC cases carries HPV type 33 followed by type 35. We present a patient with HMSC. Pathological classification was aided by immunohistochemistry (IHC). The presence of HPV-DNA was tested using PCR and HPV E6/E7 expression by RNA in situ hybridization (RNA ISH). Whole exome sequencing (WES) was used to identify somatic gene mutations and copy number alterations. A 55-year-old male presented with an HMSC in the right nostril. Histological examination showed a solid basaloid subtype with mucinous spaces and ductal structures. IHC showed positive staining for SOX-10, SMA, p40, p63, PanCK, CK8 and MYB. Diffuse positive staining for p16 was observed and PCR and RNA ISH indicated the presence of HPV type 35. The patient was treated with endoscopic surgery and radiotherapy and is currently alive and recurrence-free after 16 months of follow-up. WES revealed 38 somatic sequence variants and several chromosomal regions with copy number alterations, including a copy number gain at 6q23 where MYB is located. EP300, ZNF22, ZNF609 and LRIG3 are some of the genes whose mutations were indicated as probably pathogenic. We did not find mutations predictive for drug response according to the ESMO Scale for Clinical Actionability of Molecular Targets database. This is the first report of WES analysis of an HMSC, in this case associated with HPV type 35. The detected mutation in EP300 and the overexpression of MYB may serve as molecular targets for personalized therapy.

IntroductionPatients with coronary artery disease (CAD) have a higher risk of developing cognitive impairment and mental health disorders compared to the general population. Physical exercise might improve their brain health. The overall goal of the HEART-BRAIN randomized controlled trial (RCT) is to investigate the effects of different types of exercise on brain health outcomes in patients with CAD, and the underlying mechanisms.MethodsThis three-arm, single-blinded RCT will include 90 patients with CAD (50–75 years). Participants will be randomized into: (1) control group—usual care (n = 30), (2) aerobic high-intensity interval training (HIIT) (n = 30), or (3) HIIT combined with resistance exercise training (n = 30). The 12-week intervention includes 3 supervised sessions (45-min each) per week for the exercise groups. Outcomes will be assessed at baseline and post-intervention. The primary outcome is to determine changes in cerebral blood flow assessed by magnetic resonance imaging. Secondary outcomes include changes in brain vascularization, cognitive measures (i.e., general cognition, executive function and episodic memory), and cardiorespiratory fitness. Additional health-related outcomes, and several potential mediators and moderators will be investigated (i.e., brain structure and function, cardiovascular and brain-based biomarkers, hemodynamics, physical function, body composition, mental health, and lifestyle behavior).ConclusionThe HEART-BRAIN RCT will provide novel insights on how exercise can impact brain health in patients with CAD and the potential mechanisms explaining the heart-brain connection, such as changes in cerebral blood flow. The results may have important clinical implications by increasing the evidence on the effectiveness of exercise-based strategies to delay cognitive decline in this high-risk population.Clinical trial registrationClinicalTrials.gov, identifier [NCT06214624].

Mercury (Hg) has been extensively studied due to its impact on the environment and health, but its effects on wild mammal populations are still poorly known. Therefore, the use of biomonitors has gained importance. Our objective was to report and compare, for the first time, the amount of mercury in small mammals belonging to three trophic guilds and to provide an initial toxicology perspective in the Mezquital Valley, a critically polluted area of Central Mexico. We quantified total Hg from the hair and liver of a nectarivorous bat (Leptonycteris yerbabuenae), an insectivorous bat (Corynorhinus townsendii) and a granivorous mouse (Peromyscus melanophrys) using atomic absorption spectrometry during the dry and rainy seasons. We compared the mercury concentrations between seasons, species and matrices. In all species, the average mercury content was higher in hair than liver, and there was no correlation between matrices. There was no difference in mercury content among species. Hg concentrations in the livers of P. melanophrys and C. townsendii were lower during the dry season than the rainy season, suggesting a seasonal decline in mercury availability. All of the values detected were below the neurotoxicity threshold reported in small mammals (10 ppm); however, we propose constant monitoring of Hg in their environment and confirm the utility of these species as biomonitors.

Resumen: Introducción: A raíz de la pandemia de SARS-CoV-2 en marzo del 2020 los laboratorios de función pulmonar (LFP) sufrieron una transformación, con la reducción del número de pruebas o cierre en algunos casos. El objetivo de este trabajo fue conocer la actividad de los LFP en España y la modificación de esta debido a la pandemia. Material y métodos: Se realizó una encuesta protocolizada a los miembros de los LFP a través de la Sociedad Española de Neumología y Cirugía Torácica (SEPAR). Resultados: Contestaron 39 hospitales del territorio nacional. Las pruebas de función pulmonar que más se realizaban en los LFP fueron: espirometría forzada con prueba broncodilatadora (100%), pletismografía corporal (97,4%), capacidad de transferencia CO (97,4%), fuerza de los músculos respiratorios medidos en boca (97,4%), prueba de la marcha de 6 min (94,7%), medición de fracción exhalada de óxido nítrico (92,3%) y prueba de esfuerzo incremental (71,8%).La pandemia produjo un descenso significativo en el número de pruebas (35,4%) durante el 2020 con posterior recuperación en el 2021, sin llegar a valores prepandemia.Los cambios más importantes fueron: incremento en los tiempos de exploración, el trabajo con equipos de protección individual y la ventilación de los espacios. La realización del frotis nasofaríngeo para estudio de SARS-CoV-2 previo a las pruebas no fue homogénea en los LFP. Conclusiones: La mayoría de los hospitales disponen del equipamiento suficiente para la realización de las pruebas de función pulmonar más frecuentes. La pandemia supuso una pérdida de actividad en todos los hospitales. Abstract: Introduction: Following the SARS-CoV-2 pandemic in March 2020, pulmonary function testing (PFT) laboratories underwent a transformation, with a reduction in the number of tests or closure in some cases. The aim of this work was to know the activity of PFT in Spain and the modification of this activity due to the pandemic. Material and methods: A protocolised survey was carried out to members of the PFT laboratories through the Spanish Society of Pneumology and Thoracic Surgery (SEPAR). Results: Thirty-nine hospitals in Spain responded. The pulmonary function tests most frequently performed in the PFT laboratories were forced spirometry with bronchodilator test (100%), body plethysmography (97.4%), CO transfer capacity (97.4%), respiratory muscle strength measured in the mouth (97.4%), 6-minute walking test (94.7%), measurement of exhaled fraction of nitric oxide (92.3%) and incremental exercise test (71.8%).The pandemic led to a significant decrease in the number of tests (35.4%) during 2020 with subsequent recovery in 2021, without reaching pre-pandemic values.The most important changes were increased examination times, working with personal protective equipment and ventilation of the rooms. The performance of the nasopharyngeal swab for SARS-CoV2 testing prior to the tests was not homogeneous in the PFT laboratories. Conclusions: Most hospitals are sufficiently equipped to perform the most common pulmonary function tests. The pandemic resulted in a loss of activity in all hospitals.

The involvement of androgens in the regulation of energy metabolism has been demonstrated. The main objective of the present research was to study the involvement of androgens in both the programming of energy metabolism and the regulatory peptides associated with feeding. For this purpose, androgen receptors and the main metabolic pathways of testosterone were inhibited during the first five days of postnatal life in male and female Wistar rats. Pups received a daily s.c. injection from the day of birth, postnatal day (P) 1, to P5 of Flutamide (a competitive inhibitor of androgen receptors), Letrozole (an aromatase inhibitor), Finasteride (a 5-alpha-reductase inhibitor) or vehicle. Body weight, food intake and fat pads were measured. Moreover, hypothalamic Agouti-related peptide (AgRP), neuropeptide Y (NPY), orexin, and proopiomelanocortin (POMC) were analyzed by quantitative real-time polymerase chain reaction assay. The inhibition of androgenic activity during the first five days of life produced a significant decrease in body weight in females at P90 but did not affect this parameter in males. Moreover, the inhibition of aromatase decreased hypothalamic AgRP mRNA levels in males while the inhibition of 5α-reductase decreased hypothalamic AgRP and orexin mRNA levels in female rats. Finally, food intake and visceral fat, but not subcutaneous fat, were affected in both males and females depending on which testosterone metabolic pathway was inhibited. Our results highlight the differential involvement of androgens in the programming of energy metabolism as well as the AgRP and orexin systems during development in male and female rats.

Nitric oxide (NO) is a small vasodilator playing a key role in the pathogenesis of portal hypertension. Here, we assessed the potential therapeutic effect of a NO donor targeted to the liver by poly(beta-amino ester) nanoparticles (pBAE NPs) in experimental cirrhosis. Retinol-functionalized NO donor pBAE NPs (Ret pBAE NPs) were synthetized with the aim of actively targeting the liver. Administration of Ret pBAE NPs resulted in uptake and transfection by the liver and spleen. NPs were not found in other organs or the systemic circulation. Treatment with NO donor Ret pBAE NPs (30 mg/ kg body weight) significantly decreased aspartate aminotransferase, lactate dehydrogenase and portal pressure (9.75 ± 0.64 mmHg) compared to control NPs (13.4 ± 0.53 mmHg) in cirrhotic rats. There were no effects on mean arterial pressure and cardiac output. Liver-targeted NO donor NPs reduced collagen fibers and steatosis, activation of hepatic stellate cells and mRNA expression of profibrogenic and proinflammatory genes. Finally, Ret pBAE NPs displayed efficient transfection in human liver slices. Overall, liver-specific NO donor NPs effectively target the liver and mitigated inflammation and portal hypertension in cirrhotic rats. The use of Ret pBAE may prove to be an effective therapeutic strategy to treat advanced liver disease.

ABSTRACTCryptococcus neoformans is an encapsulated yeast able to cause disease (mainly meningoencephalitis) among immunosuppressed patients, mostly HIV+. This yeast can form the so-called titan cells in vivo, which are cells of an abnormally larger size due to an increase in both the capsule and the cell body size (total size reaching between 50–70 μm). This phenomenon can be partially reproduced in vitro to obtain cells of an intermediate size (25–30 μm), which have been denominated titan-like cells. In this work, we have screened 1,520 compounds from the Prestwick Chemical Library and identified off-patent drugs that inhibited titan-like cell formation in vitro. We developed an automated fluorescence-based microscopy assay and identified 64 compounds as possible inhibitors of titan-like cells. We chose 10 of these compounds to perform dose-response curves and confirmed them as inhibitors of titan-like cell formation. Several of the compounds identified had antioxidant properties (i.e., retinoic acid), indicating a possible role of free radicals during titan cell formation. Using fluorescent probes, we found that there was an endogenous accumulation of reactive oxygen species (ROS) during cell growth, which was inhibited in the presence of retinoic acid. Furthermore, we found that during titanization, there were significant changes in the mitochondria, which is the main organelle where ROS are produced. We hypothesize that an intracellular increase of free radicals at the mitochondria might be a triggering signal to induce titanization.IMPORTANCECryptococcus neoformans is an excellent model to investigate fungal pathogenesis. This yeast can produce “titan cells,” which are cells of an abnormally larger size that contribute to the persistence of the yeast in the host. In this work, we have used a new approach to characterize them by identifying drugs that inhibit this process. We have used a repurposing off-patent drug library, combined with an automatic method to image and analyze fungal cell size. In this way, we have identified many compounds that inhibit this transition. Interestingly, several compounds were antioxidants, allowing us to confirm that endogenous ROS and mitochondrial changes are important for titan cell formation. This work provides new evidence of the mechanisms required for titanization. Furthermore, the future characterization of the inhibitory mechanisms of the identified compounds by the scientific community will contribute to better understand the role of titan cells in virulence.

The prevalence of cardiovascular diseases (CVDs) is a growing global health concern. Recent advances have demonstrated significant reductions in acute cardiovascular events through the management of modifiable cardiovascular risk factors. However, these factors are responsible for about 50% of the global cardiovascular disease burden. Considering that CVDs are one of the top mortality causes worldwide, the concept of residual cardiovascular risk is an important emerging area of study. Different factors have been proposed as sources of residual risk markers, including non-HDL particles characterization, as well as inflammation measured by serum and imaging technics. Among these, metabolic-associated steatotic liver disease (MASLD) remains controversial. Two opposing viewpoints contend: one positing that fatty liver disease merely reflects classical risk factors and thus adds no additional risk and another asserting that fatty liver disease independently impacts cardiovascular disease incidence. To address this dilemma, one hypothetical approach is to identify specific hepatic energy-yielding mechanisms and assess their impact on the cardiovascular system. Ketogenesis, a metabolic intermediate process particularly linked to energy homeostasis during fasting, might help to link these concepts. Ketogenic metabolism has been shown to vary through MASLD progression. Additionally, newer evidence supports the significance of circulating ketone bodies in cardiovascular risk prediction. Furthermore, ketogenic metabolism modification seems to have a therapeutic impact on cardiovascular and endothelial damage. Describing the relationship, if any, between steatotic liver disease and cardiovascular disease development through ketogenesis impairment might help to clarify MASLD’s role in cardiovascular risk. Furthermore, this evidence might help to solve the controversy surrounding liver steatosis impact in CVD and might lead to a more accurate risk assessment and therapeutic targets in the pursuit of precision medicine.

HER2-positive breast cancer is associated with aggressive behavior and reduced survival rates. Calcitriol restores the antiproliferative activity of antiestrogens in estrogen receptor (ER)-negative breast cancer cells by re-expressing ERα. Furthermore, calcitriol and its analog, EB1089, enhance responses to standard anti-cancer drugs. Therefore, we aimed to investigate EB1089 effects when added to the combined treatment of lapatinib and antiestrogens on the proliferation of HER2-positive breast cancer cells. BT-474 (ER-positive/HER2-positive) and SK-BR-3 (ER-negative/HER2-positive) cells were pre-treated with EB1089 to modulate ER expression. Then, cells were treated with EB1089 in the presence of lapatinib with or without the antiestrogens, and proliferation, phosphorylation array assays, and Western blot analysis were performed. The results showed that EB1089 restored the antiproliferative response to antiestrogens in SK-BR-3 cells and improved the inhibitory effects of the combination of lapatinib with antiestrogens in the two cell lines. Moreover, EB1089, alone or combined, modulated ERα protein expression and reduced Akt phosphorylation in HER2-positive cells. EB1089 significantly enhanced the cell growth inhibitory effect of lapatinib combined with antiestrogens in HER2-positive breast cancer cells by modulating ERα expression and Akt phosphorylation suppression. These results highlight the potential of this therapeutic approach as a promising strategy for managing HER2-positive breast cancer.

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Abstract Background Equitable health service utilization is key to health systems' optimal performance and universal health coverage. The evidence shows that men and women use health services differently. However, current analyses have failed to explore these differences in depth and investigate how such gender disparities vary by service type. This study examined the gender gap in the use of outpatient health services by Mexican adults with non-communicable diseases (NCDs) from 2006 to 2022. Methods A cross-sectional population-based analysis of data drawn from National Health and Nutrition Surveys of 2006, 2011–12, 2020, 2021, and 2022 was performed. Information was gathered from 300,878 Mexican adults aged 20 years and older who either had some form of public health insurance or were uninsured. We assessed the use of outpatient health services provided by qualified personnel for adults who reported having experienced an NCD and seeking outpatient care in the 2 weeks before the survey. Outpatient service utilization was disaggregated into four categories: non-use, use of public health services from providers not corresponding to the user’s health insurance, use of public health services from providers not corresponding to the user’s health insurance, and use of private services. This study reported the mean percentages (with 95% confidence intervals [95% CIs]) for each sociodemographic covariate associated with service utilization, disaggregated by gender. The percentages were reported for each survey year, the entire study period, the types of service use, and the reasons for non-use, according to the type of health problem. The gender gap in health service utilization was calculated using predictive margins by gender, type of disease, and survey year, and adjusted through a multinomial logistic regression model. Results Overall, we found that women were less likely to fall within the “non-use” category than men during the entire study period (21.8% vs. 27.8%, P

Abstract The prognosis of patients with advanced high-grade (G3) digestive neuroendocrine neoplasms (NENs) is rather poor. The addition of immune checkpoint inhibition to platinum-based chemotherapy may improve survival. NICE-NEC (NCT03980925) is a single-arm, phase II trial that recruited chemotherapy-naive, unresectable advanced or metastatic G3 NENs of gastroenteropancreatic (GEP) or unknown origin. Patients received nivolumab 360 mg intravenously (iv) on day 1, carboplatin AUC 5 iv on day 1, and etoposide 100 mg/m2/d iv on days 1–3, every 3 weeks for up to six cycles, followed by nivolumab 480 mg every 4 weeks for up to 24 months, disease progression, death or unacceptable toxicity. The primary endpoint was the 12-month overall survival (OS) rate (H0 50%, H1 72%, β 80%, α 5%). Secondary endpoints were objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and safety. From 2019 to 2021, 37 patients were enrolled. The most common primary sites were the pancreas (37.8%), stomach (16.2%) and colon (10.8%). Twenty-five patients (67.6%) were poorly differentiated carcinomas (NECs) and/or had a Ki67 index >55%. The ORR was 56.8%. Median PFS was 5.7 months (95%CI: 5.1-9) and median OS 13.9 months (95%CI: 8.3-Not reached), with a 12-month OS rate of 54.1% (95%CI: 40.2-72.8) that did not meet the primary endpoint. However, 37.6% of patients were long-term survivors (>2 years). The safety profile was consistent with previous reports. There was one treatment-related death. Nivolumab plus platinum-based chemotherapy was associated with prolonged survival in over one-third of chemonaïve patients with G3 GEP-NENs, with a manageable safety profile.

Abstract Epilepsy surgery may be a curative therapy for patients with drug‐resistant epilepsies when focal lesions or foci are identified. Genetic testing is not yet routinely included in many presurgical evaluation programs although recent evidence support that finding a germline genetic mutation could help to better delineate the patient candidacy to surgery and provide valuable information on the expected surgery outcome. In this study, we report nine patients presenting drug‐resistant focal epilepsy enrolled in presurgical evaluation. We show how the identification of genetic pathogenic variant in epilepsy known genes led to the interruption of the presurgical work‐up and ruled out surgery in 7 of them. We observed that the co‐existence of some recurrent clinical characteristics as early seizures' onset, frequent precipitating factors including fever, and developmental delay or intellectual disability may be useful markers for germline genetic pathogenic variants. In this group, genetic assessment should be mandatory during presurgical work up, mainly in patients with negative magnetic resonance imaging (MRI) or doubtful structural lesions. The integration of next generation targeted sequencing into the presurgical evaluation can improve the selection of candidates for resective surgery and fosters a personalized medicine approach with a better outcome. Plaine Language Abstract Genetic testing is not yet systematically included in the pre‐surgical assessment of patients with drug‐resistant focal epilepsies. In this study, through the description of nine patients, we underline how the integration of genomics into the presurgical work up can help in evaluating the patient candidacy to surgery and provide valuable information on expected surgery outcome.

Deliberate ignorance is the willful choice not to know the answer to a question of personal relevance. The question of whether a man is the biological father of his child is a sensitive issue in many cultures and can lead to litigation, divorce, and disinheritance. Thanks to DNA tests, men are easily able to resolve the uncertainty. Psychological theories that picture humans as informavores who are averse to ambiguity suggest men would do a DNA test, as does evolutionary theory, which considers investing in raising a rival’s offspring a mistake. We conducted two representative studies using computer-based face-to-face interviews in Germany (n = 969) and Spain (n = 1,002) to investigate whether men actually want to know and how women would react to this desire. As a base line, Germans (Spanish) estimated that 10% (20%) of fathers mistakenly believe that they are the biological father of their child. Nevertheless, in both countries, only 4% of fathers reported that they had performed a DNA paternity test, while 96% said they had not. In contrast, among men without children, 38% (33%) of Germans (Spanish) stated they would do a DNA test if they had children, mostly without telling their partners. Spanish women with children would more often disapprove of a paternity test or threaten their husbands with divorce (25%) than would German women (13%). We find that a simple test of risk aversion, measured also by the purchase of non-mandatory insurances, is correlated with not wanting to know.

The decline in Acropora palmata populations in Colombian reefs has been mainly attributed to diseases outbreaks. The population size structure and prevalence of white pox and white band disease were evaluated in six localities of the Colombian Caribbean. Here, we aimed to isolate enteric bacteria and Vibrios from healthy and diseased coral mucus to relate its presence to the health status of Acropora palmata. The isolated bacteria were identified using molecular analyses with the 16S rRNA gene. Larger colonies had the highest percentage of the prevalence of both diseases. The strains that were identified as Vibrio sp. and Bacillus sp. were common in the healthy and diseased mucus of the holobiont. The Exiguobacterium sp. and Cobetia sp. strains isolated from diseased mucus may indicate maintenance and resilience mechanisms in the coral. Enterococcus sp. and other bacteria of the Enterobacteriaceae family were isolated from some localities, suggesting that probably contamination due to poor treatment of domestic wastewater and contributions from river discharges can affect coral health. The spatial heterogeneity of Colombian coral reefs exhibited variability in the bacteria, wherein environmental alterations can trigger signs of disease.

Nerve agents are highly toxic chemical compounds that pose significant threats to human health and safety. Detecting and identifying these agents quickly is crucial for preventing their exposure and providing timely treatment. This study proposes the use of nanohybrids comprising crystalline octahedral molybdenum iodide cluster material supported on graphene (Mo6@Graphene) as a novel sensing material for the detection of dimethyl methylphosphonate (DMMP), a simulant of sarin nerve agent. The electrical sensing performance towards different concentrations of DMMP and at room temperature demonstrated fast and sensitive responses to DMMP, with almost full recovery of the sensor baseline in a few minutes. The calibration curve obtained showed a linear relationship between the sensor response and DMMP concentration, enabling the estimation of the limit of detection (LOD) of 270 ppb. The robustness of the Mo6@Graphene nanomaterial towards DMMP was assessed using various techniques, including Raman spectroscopy, X-ray diffraction and photoelectron spectroscopy. The binding energies (BEs) between DMMP and the supported Mo6 clusters determined by DFT calculations revealed H-bonding interactions involved in the sensing mechanism. The excellent sensing performance of the Mo6@Graphene film, combined with its low power consumption and high stability, makes it a promising candidate for the detection of nerve agents and their simulants.