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Students' metacognitive skills and perceptions are considered important variables for high-quality learning. In this study, students' perceptions were used to identify histological threshold concepts (integrative, irreversible, transformative, and troublesome) in three health sciences curricula. A specific questionnaire was developed and validated to characterize students' perceptions of histological threshold concepts. A sample of 410 undergraduate students enrolled in the dentistry, medicine, and pharmacy degree programs participated in the study. Concepts assessed in the study were clustered to ten categories (factors) by exploratory and confirmatory factor analysis. Concepts linked to tissue organization and tissue functional states received the highest scores from students in all degree programs, suggesting that the process of learning histology requires the integration of both static concepts related to the constituent elements of tissues and dynamic concepts such as stem cells as a tissue renewal substrate, or the euplasic, proplasic and retroplasic states of tissues. The complexity of integrating static and dynamic concepts may pose a challenging barrier to the comprehension of histology. In addition, several differences were detected among the students in different degree programs. Dentistry students more often perceived morphostructural concepts as threshold concepts, whereas medical students highlighted concepts related to two-dimensional microscopic identification. Lastly, pharmacy students identified concepts related to tissue general activity as critical for the comprehension and learning of histology. The identification of threshold concepts through students' perceptions is potentially useful to improve the teaching and learning process in health sciences curricula.

This article aims to question the widely accepted idea that female university students in Spain have, in the past, tended to opt for degrees in the field of humanities. Based on an analysis of the official statistics that are currently available, the paper demonstrates that Spanish female university students showed a clear preference for scientific studies, first medicine and later pharmacy. This pattern was not affected by Franco's regime and remained stable until the great transformation of Spanish universities during the 1960s. Finally, the paper argues that the basic reasons for this preference for the scientific field were equal access to the prestigious male baccalaureate curriculum, which was a characteristic of the Spanish model for incorporating women into secondary education, and the uneven prestige of the professions to which the degrees provided access. The conclusion drawn is that, historically, pharmacy was the most common professional career pursued by female university graduates in Spain.

The COVID-19 pandemic had adverse health outcomes on individuals and communities. In this cross-sectional study we evaluated the admission rates in a tertiary-level hospital during the first wave of the pandemic (March 22, 2020 to August 31, 2020).

Abstract Although there has been an increase in bench test evaluation of mechanical ventilators in recent years, a publication gap remains in assessing Pressure Control Continuous Mandatory Ventilation Modes with a set point targeting scheme PC-CMVs. This study evaluates the operational variability in PC-CMVs of eleven transport and emergency ventilators used in ICU units in Brazil during the COVID-19 pandemic. The assessment involved a comprehensive set of test scenarios derived from existing literature and the NBR ISO 80601-2-12:2014 standard. Nine parameters were computed for five consecutive breaths, offering a comprehensive characterization of pressure and flow waveforms. Most ventilators had Inspiratory pressure and PEEP values that fell outside of the tolerance ranges. Notably, three mechanical ventilators failed to reach the target pressures within the specified inspiratory times during test scenarios with a higher time constant (τ). We observed significant differences among emergency and transport ventilators in all assessed parameters, indicating a performance difference in PC-CMVs modes. The current results might help clinicians determine which ventilator models are suitable for specific clinical situations, particularly when unfavorable circumstances compel doctors to use ventilators that may not provide adequate support for patients in intensive care units.

Abstract The assessment of ctDNA has emerged as a minimally invasive avenue for molecular diagnosis and real-time tracking of tumor progression in NSCLC. However, the evaluation of ctDNA by amplicon-based NGS has been not endorsed by all the healthcare systems and remains to be fully integrated into clinical routine practice. To compare tissue single-gene with plasma multiplexed testing, we retrospectively evaluated 120 plasma samples from 12 consecutive patients with advanced non-squamous NSCLC who were part of a prospective study enrolling treatment-naïve patients and in which tissue samples were evaluated using a single-gene testing approach. While the plasma ctDNA detection of EGFR and BRAF mutations had an acceptable level of concordance with the archival tissue (85%), discordance was seen in all the patients in whom ALK alterations were only detected in tissue samples. Among six responders and six non-responders, early ctDNA mutant allelic frequency (MAF) reduction seemed to predict radiologic responses and longer survival, whereas increasing MAF values with the emergence of co-mutations like BRAFV600E, KRASG12V or TP53M237I seemed to be an early indicator of molecular and radiologic progression. This report using an amplicon-based NGS assay on ctDNA underscores the real-life need for plasma and tissue genotyping as complementary tools in the diagnostic and therapeutic decision-making process.

Abstract Two-dimensional transition metal dichalcogenides, particularly MoS2, are interesting materials for many applications in aerospace research, radiation therapy and bioscience more in general. Since in many of these applications MoS2-based nanomaterials can be placed in an aqueous environment while exposed to ionizing radiation, both experimental and theoretical studies of their behaviour under these conditions is particularly interesting. Here, we study the effects of tiny imparted doses of 511 keV photons to MoS2 nanoflakes in water solution. To the best of our knowledge, this is the first study in which ionizing radiation on 2D-MoS2 occurs in water. Interestingly, we find that, in addition to the direct interaction between high-energy photons and nanoflakes, reactive chemical species, generated by γ-photons induced radiolysis of water, come into play a relevant role. A radiation transport Monte Carlo simulation allowed determining the elements driving the morphological and spectroscopical changes of 2D-MoS2, experimentally monitored by SEM microscopy, DLS, Raman and UV–vis spectroscopy, AFM, and X-ray photoelectron techniques. Our study demonstrates that radiolysis products affect the Molybdenum oxidation state, which is massively changed from the stable + 4 and + 6 states into the rarer and more unstable + 5. These findings will be relevant for radiation-based therapies and diagnostics in patients that are assuming drugs or contrast agents containing 2D-MoS2 and for aerospace biomedical applications of 2DMs investigating their actions into living organisms on space station or satellites.

Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) is common in individuals with obesity. Sexual dimorphism is present in MASLD. A noninvasive test to diagnose the severity of the disease, in particular the presence of Metabolic dysfunction-associated steatohepatitis (MASH), is lacking. This European multicenter prospective study uses a blood test based on mid-infrared (MIR) metabolic fingerprinting of individuals with severe or morbid obesity to diagnose MASH. Three hundred eighty-two individuals with severe or morbid obesity undergoing bariatric surgery were enrolled prospectively. Liver biopsies were obtained during surgery and assessed centrally. An algorithm was defined to calculate a score from the recorded MIR spectrum and to establish a diagnostic threshold to classify patients with MASH. Among the women (n = 217), MASH was diagnosed in 14.3% of cases. For women, the performance in terms of AUC were 0.83 and 0.82 in the calibration and validation groups, respectively. For a threshold of 0.1817, sensitivities were 86% and 70%, specificities were 81% and 75%, PPV were 43% and 32%, NPV were 97% and 94% and ACC were 82% and 74% for the calibration and validation groups, respectively. For men (n = 78; MASH: 33.3%), the performance of the spectral model was poor. The metabolic fingerprint obtained by MIR spectroscopy can rule out MASH in women with severe or morbid obesity. Its value in men needs new studies. Trial registration: ClinicalTrials.gov identifier: ClinicalTrials.gov identifier: NCT03978247 (04/06/2019)

Limited data exist on mortality rates after tuberculosis (TB) treatment in the United States. We analyzed mortality rates for all adults in Georgia, USA, who had a TB diagnosis and finished treatment during January 1, 2008–December 31, 2019. We obtained posttreatment mortality rate data from the National Death Index and calculated standardized mortality ratios (SMRs) for TB treatment survivors and the general Georgia population. Among 3,182 TB treatment survivors, 233 (7.3%) had died as of December 31, 2019. The overall TB cohort age- and sex-adjusted SMR was 0.89 (95% CI 0.73–1.05). The SMR among US-born TB treatment survivors was 1.56 (95% CI 1.36–1.77). In the TB cohort, US-born status, HIV co-infection, excess alcohol use, diabetes mellitus, and end-stage renal disease were associated with increased risk for death after TB treatment. TB treatment survivors could benefit from improved linkage to primary and HIV comprehensive care to prevent posttreatment death.

We report acute Oropouche virus infections in 2 previously healthy women from a nonendemic region of Brazil outside the Amazon Basin. Infections rapidly progressed to hemorrhagic manifestations and fatal outcomes in 4–5 days. These cases highlight the critical need for enhanced surveillance to clarify epidemiology of this neglected disease.

Inroduction: Schwannomas are the most common tumors of the peripheral nervous system. Surgical eradication with excision or enucleation is the treatment for symptomatic and large schwannomas. Aim: Few studies have investigated the clinical outcomes related to the surgical approach to schwannomas. Our study aims to evaluate the clinical and functional results of surgery for the treatment of upper limb schwannomas. Materials and methods: Twenty-two cases of upper limb schwannomas were surgically treated in our institution between January 2016 and December 2023. All cases underwent preoperative and 6-month postoperative MRI. For each case, we recorded the diagnostic interval (symptom-diagnosis), symptoms (stenosis or sensory deficits, pain, and Tinel test), and both pre-and postoperative functional status (with DASH and MSTS scores). We also recorded complications and local recurrences. Results: On average, the diagnosis was made 16.7 months after the onset of the first symptom. The mean preoperative MSTS, DASH, and MRC values were 27.9, 5.7, and 4.8, respectively. We had no intra-operative complications. After a mean follow-up of 43.1 months, MSTS, DASH were 29.7/30 and 0.7, respectively. No case developed local recurrences. No case recorded stenosis deficits at the last follow-up. Only one patient developed local paresthesia (9%), while two reported modest dysesthesias. Conclusions: An adequate surgical approach, possibly preceded by a rapid diagnosis, can significantly improve the symptoms caused by schwannoma, restoring the functionality of the upper limb.

Abstract The impact of environmental pollutants has been a focus of investigation in recent years. Studies assessing the effects of these pollutants are essential for understanding the challenges faced by non-target species. Among the many substances used for agricultural purposes, the herbicide glyphosate is one of the most widely marketed in recent years. This broad-spectrum herbicide is commonly used to protect a variety of crops. In this study, we evaluated the effects of chronic glyphosate exposure on a native amphibian species, Physalaemus gracilis. Amphibians, which develop in aquatic environments, are highly sensitive to pesticides. Because of this, we investigated morphological, physiological, behavioral, and biochemical parameters in the early stages of development. The animals were exposed to environmentally relevant concentrations of a glyphosate-based herbicide (0, 100, 350, and 700 µg L⁻¹) during their first seven days of life. As a result, we observed impairments in anti-predatory behavior, reduced body mass index, and scaled mass index, malformations of the mouth and intestine, increased acetylcholinesterase activity, cardiotoxicity, and oxidative stress. These findings underscore the importance of studying native non-target species and highlight the need to evaluate the effects of environmentally relevant concentrations, as well as to review legislation regarding permissible levels of glyphosate in surface water and public water supplies.

Abstract Biochar is an effective material for enhancing soil ecosystem services. However, the specific impacts of biochar on microbial indicators, particularly in degraded soils, remain poorly understood. This study aimed to evaluate the effects of biochar produced from cashew residues and sewage sludge, in a highly degraded soil, on microbial indicators. We analyzed soil chemical composition and microbial biomass C and N, enzyme activity, and stoichiometry. Cashew biochar increased soil respiration, indicating a higher availability of C to microorganisms compared to sewage sludge biochar and a better adaptation of soil microbial communities to C-rich organic material obtained from a native plant. Although the biochar differentially impacted microbial biomass C, both significantly increased N in the microbial biomass. Arylsulphatase activity did not respond to biochar application, while β-glucosidase, urease, and phosphatases showed significant changes with biochar treatments. Importantly, stoichiometry and vector analysis revealed that both types of biochar increased P limitation for soil microbes. Conversely, both biochar alleviated C and N limitations for the soil microbes. Thus, biochar applications in highly degraded soils should be supplemented with external P sources to maintain soil functions, mainly for cashew residues. Our results provide evidence that biochar can restore soil biological properties and enhance the availability of C and N to microorganisms. These findings have significant implications for restoration practices in degraded lands of semiarid regions.

Abstract High mobility group (HMG) proteins are intrinsically disordered nuclear non-histone chromosomal proteins that play an essential role in many biological processes by regulating the expression of numerous genes in eukaryote cells. HMGA proteins contain three DNA binding motifs, the “AT-hooks”, that bind preferentially to AT-rich sequences in the minor groove of B-form DNA. Understanding the interactions of AT-hook domains with DNA is very relevant from a medical point of view because HMGA proteins are involved in different conditions including cancer and parasitic diseases. We present here the first crystal structure (1.40 Å resolution) of the HMGA AT-hook 1 domain, bound to the minor groove of AT-rich DNA. In contrast to AT-hook 3 which bends DNA and shows a larger minor groove widening, AT-hook 1 binds neighbouring DNA molecules and displays moderate widening of DNA upon binding. The binding affinity and thermodynamics of binding were studied in solution with surface plasmon resonance (SPR)-biosensor and isothermal titration calorimetry (ITC) experiments. AT-hook 1 forms an entropy-driven 2:1 complex with (TTAA)2-containing DNA with relatively slow kinetics of association/dissociation. We show that N-phenylbenzamide-derived antikinetoplastid compounds (1–3) bind strongly and specifically to the minor groove of AT-DNA and compete with AT-hook 1 for binding. The central core of the molecule is the basis for the observed sequence selectivity of these compounds. These findings provide clues regarding a possible mode of action of DNA minor groove binding compounds that are relevant to major neglected tropical diseases such as leishmaniasis and trypanosomiasis.

Abstract Background and aim Migraine is a common disabling conditions which, globally, affects 15.2% of the population. It is the second cause of health loss in terms of years lived with disability, the first among women. Despite being so common, it is poorly recognised and too often undertreated. Specialty centres and neurologists with specific expertise on headache disorders have the knowledge to provide specific care: however, those who do not regularly treat patients with migraine will benefit from a synopsis on the most relevant and updated information about this condition. This paper presents a comprehensive view on the hallmarks of migraine, from genetics and diagnostic markers, up to treatments and societal impact, and reports the elements that identify migraine specific features. Main results The most relevant hallmark of migraine is that it has common and individual features together. Besides the known clinical manifestations, migraine presentation is heterogeneous with regard to frequency of attacks, presence of aura, response to therapy, associated comorbidities or other symptoms, which likely reflect migraine heterogeneous genetic and molecular basis. The amount of therapies for acute and for prophylactic treatment is really wide, and one of the difficulties is with finding the best treatment for the single patient. In addition to this, patients carry out different daily life activities, and might show lifestyle habits which are not entirely adequate to manage migraine day by day. Education will be more and more important as a strategy of brain health promotion, because this will enable reducing the amount of subjects needing specialty care, thus leaving it to those who require it in reason of refractory condition or presence of comorbidities. Conclusions Recognizing the hallmarks of migraine and the features of single patients enables prescribing specific pharmacological and non-pharmacological treatments. Medical research on headaches today particularly suffers from the syndrome of single-disease approach, but it is important to have a cross-sectional and joint vision with other close specialties, in order to treat our patients with a comprehensive approach that a heterogeneous condition like migraine requires.

Abstract Introduction The 2023 nomenclature defined criteria for steatotic liver disease (SLD), including metabolic dysfunction-associated SLD (MASLD), alcohol-associated liver disease (ALD), and the overlapping MASLD/ALD (MetALD). We aimed to assess racial and ethnic disparities in the SLD prevalence among United States (US) adults based on this new nomenclature. Methods We undertook a cross-sectional study employing the 2017–2018 National Health and Nutrition Examination Survey (NHANES) database. We identified SLD according to a controlled attenuation parameter ≥288 dB/m, liver stiffness ≥7.2 kPa, or elevated aminotransferase levels. Alcohol use thresholds were established according to the updated SLD definition. We estimated prevalences using the complex design of the NHANES survey. Multivariable logistic regressions with complex design weights were employed. Results A total of 5532 individuals are included. The mean age is 45.4 years, and 50.9% are women. The adjusted estimated prevalence of MASLD is 42.4% (95% CI: 41.1–43.8%), MetALD 1.7% (95% CI: 1.3–2.0%), and ALD 0.6% (95% CI: 0.3–0.8%). Hispanics exhibit a higher prevalence of SLD, but there are no significant differences in advanced fibrosis prevalence due to SLD among racial/ethnic groups. In MASLD, men, individuals aged 40–64 and ≥65 years, Hispanics, those with health insurance, higher BMI, diabetes, hypertension, hypertriglyceridemia, and low high-density lipoprotein (HDL) cholesterol or use of lipid-lowering agents are independently associated with a higher risk, while Blacks have the lowest risk. In MetALD, men and higher BMI are independently associated with a higher risk of MetALD in adjusted multivariable analysis. In ALD, the adjusted multivariable analysis shows that only health insurance is independently associated with a lower ALD risk. Conclusions MASLD prevalence is high in the US, especially in men, older individuals, and Hispanics. MetALD and ALD prevalence was substantial but could be underestimated.

Abstract Artificial Intelligence (AI) is transforming systematic reviews (SRs) in health research by automating processes such as study screening, data extraction, and quality assessment. This perspective highlights recent advancements in AI tools that enhance efficiency and accuracy in SRs. It discusses the benefits, challenges, and future directions of AI integration, emphasising the need for human oversight to ensure the reliability of AI outputs in evidence synthesis and decision-making in healthcare.

Abstract Despite the increase in research of hamstring stiffness through the use of ultrasound-based shear wave elastography, the active stiffness of biceps femoris long head (BFlh) and semitendinosus (ST) muscles under fatigue conditions at various contraction intensities has not been sufficiently explored. This study aimed to compare the effects of knee flexor’s isometric contraction until exhaustion performed at 20% vs. 40% of maximal voluntary isometric contraction (MVIC), on the active stiffness responses of BFlh and ST. Eighteen recreationally active males performed two experimental sessions. The knee flexors’ MVIC was assessed before the fatiguing task, which involved a submaximal isometric contraction until failure at 20% or 40% of MVIC. Active muscle stiffness of the BFlh and ST was assessed using shear wave elastography. BFlh active stiffness remained relatively unaltered at 20% of MVIC, while ST active stiffness decreased from ≅ 91% contraction time (55.79 to 44.52 kPa; p 0.05) or ST (63.62 to 53.54 kPa; p > 0.05) at 40% of MVIC session. Intermuscular active stiffness at 20% of MVIC differed until 64% contraction time (p 0.05), but a steeper increase in BFlh/ST ratio was found for 20% (0.004 ± 0.003 ratio/%) compared to 40% (0.001 ± 0.003 ratio/%) of MVIC (p = 0.003). These results suggest that contraction duration could play a major role in inducing changes in hamstrings’ mechanical properties during fatigue tasks compared to contraction intensity.

Abstract As the internet is becoming more and more accessible and prevalent, there has been growing interest in determining the effect of internet use on human cognition, particularly memory. However, much less is known about how internet use frequency is related to episodic memory, which refers to the memory of past events as opposed to facts (i.e., semantic memory). Episodic memory is very relevant to the internet because of the notion that the internet is a form of transactive memory, which requires people to retrieve how information was accessed (i.e., episodic memory) rather than the information itself (i.e., semantic memory). By analyzing data from 36, 542 participants with 44.06% females and a mean age of 46.63 years old from the Understanding Society using multivariate and univariate analysis of variances (ANOVA), the current study found that the frequency of internet use is positively related to episodic memory (assessed using the immediate recall and delayed word recall tasks). These results provide support to the notion that the internet is a form of transactive memory and the “use it, or lose it” theory.

Abstract The share of solar power in Brazil’s electrical grid has rapidly increased, relieving GHG emissions and diversifying energy sources for greater energy security. Besides that, solar resource is susceptible to climate change, adding uncertainty to electrical grid resilience. This study uses satellite and reanalysis data to evaluate the performance of CMIP6 models in replicating and predicting surface solar irradiance (SSR) in Brazil. The results from the most reliable models indicate an increase in SSR by 2% to 8% in most regions, with a decrease of around 3% in the South. These findings highlight the potential for increased photovoltaic (PV) yield if backed by supportive public policies while underlining the importance of uncertainty assessment of climate models.

Abstract The availability of a number of bDMARDs with different mechanism of action increases potential treatment pathways in psoriatic arthritis (PsA). In clinical practice, following the failure of one bDMARD, it is normal to consider which options are the best for switching strategy. In most cases this choice involves IL17i and TNFi. The main aim of this study was to compare the effectiveness of cycling (from TNFi to another TNFi) and swapping (from TNFi to IL17i or vice versa) strategies. In this monocentric retrospective observational study, all PsA patients treated with TNFi or IL17i between January 2016 and January 2022 were enrolled. The prescriptions were clustered in one cycling group (CG), and two swap groups: from TNFi to IL17i (SG1) and from IL17i to TNFi (SG2). The Kaplan–Meier method and Cox regression models were applied to compare the drug retention rates and to identify factors affecting treatment persistence. A total of 122 patients were enrolled. The CG, SG1 and SG2 2-years retention rates were 51%, 58% and 34% (p = 0.1), respectively. SG1 strategy (HR 0.53; CI 0.31–0.89; p = 0.02), age (HR 0.98; CI 0.96–0.99; p = 0.003), Disease Activity PsA (HR 1.11; CI 1.08–1.13; p

Abstract Myelofibrosis (MF) is a complex myeloproliferative neoplasm characterized by abnormal hematopoietic stem cell proliferation and subsequent bone marrow (BM) fibrosis. First documented in the late 19th century, MF has since been extensively studied to unravel its pathophysiology, clinical phenotypes, and therapeutic interventions. MF can be classified into primary and secondary forms, both driven by mutations in genes such as JAK2, CALR, and MPL, which activate the JAK-STAT signaling pathway. These driver mutations are frequently accompanied by additional non-driver mutations in genes like TET2, SRSF2, and TP53, contributing to disease complexity. The BM microenvironment, consisting of stromal cells, extracellular matrix, and cytokines such as TGF-β and TNF-α, plays a critical role in fibrosis and aberrant hematopoiesis. Clinically, MF manifests with symptoms ranging from anemia, splenomegaly, and fatigue to severe complications such as leukemic transformation. Splenomegaly, caused by extramedullary hematopoiesis, leads to abdominal discomfort and early satiety. Current therapeutic strategies include JAK inhibitors like Ruxolitinib, which target the JAK-STAT pathway, alongside supportive treatments such as blood transfusions, erythropoiesis-stimulating agents and developing combinatorial approaches. Allogeneic hematopoietic stem cell transplantation remains the only curative option, though it is limited to younger, high-risk patients. Recently approved JAK inhibitors, including Fedratinib, Pacritinib, and Momelotinib, have expanded the therapeutic landscape. Spatially Resolved Transcriptomics (SRT) has revolutionized the study of gene expression within the spatial context of tissues, providing unprecedented insights into cellular heterogeneity, spatial gene regulation, and microenvironmental interactions, including stromal-hematopoietic dynamics. SRT enables high-resolution mapping of gene expression in the BM and spleen, revealing molecular signatures, spatial heterogeneity, and pathological niches that drive disease progression. These technologies elucidate the role of the spleen in MF, highlighting its transformation into a site of abnormal hematopoietic activity, fibrotic changes, and immune cell infiltration, functioning as a “tumor surrogate.” By profiling diverse cell populations and molecular alterations within the BM and spleen, SRT facilitates a deeper understanding of MF pathophysiology, helping identify novel therapeutic targets and biomarkers. Ultimately, integrating spatial transcriptomics into MF research promises to enhance diagnostic precision and therapeutic innovation, addressing the multifaceted challenges of this disease.

Abstract Torque teno virus (TTV) viral load (VL), a component of the human virome, increases during immune suppression or dysregulation. This study aimed to explore TTV VL in youths living with vertically acquired HIV (YWVH) and its potential as an immunovirological marker. We performed an observational, retrospective study involving YWVH under antiretroviral treatment (ART) from the Spanish Cohort of HIV-infected children, adolescents, and vertically HIV-infected patients transferred to Adult Units (CoRISpe-FARO), compared to HIV-negative healthy donors (HD). Plasma TTV VL was assessed by qPCR. T-cell phenotype was analysed on cryopreserved peripheral blood mononuclear cells by flow cytometry. Correlations with baseline CD4 and CD8 and long-term virological evolution were examined. A total of 57 YWVH were compared with 23 HD. YWVH had a median CD4 T-cells of 736 cells/mm3 [IQR: 574–906], a median of 17 years [IQR: 14–20.5] since ART initiation, and 65 months [IQR: 39–116] under HIV-RNA virological control. TTV VL was higher among YWVH and in males compared with females (p

Abstract Maternal smoking during pregnancy (MSDP), driven by nicotine crossing the placenta, causes lifelong decreases in offspring pulmonary function and vitamin C supplementation during pregnancy prevents some of those changes. We have also shown in animal models of prenatal nicotine exposure that vitamin C supplementation during pregnancy improves placental function. In this study we examined whether vitamin C supplementation mitigates the effects of MSDP on placental structure, function, and gene expression in pregnant human smokers. Doppler ultrasound was performed in a subset of 55 pregnant smokers participating in the “Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function” (VCSIP) randomized clinical trial (NCT01723696) and in 33 pregnant nonsmokers. Doppler ultrasound measurements showed decreased umbilical vein Doppler velocity (Vmax) in placebo-treated smokers that was significantly improved in smokers randomized to vitamin C, restoring to levels comparable to nonsmokers. RNA-sequencing demonstrated that vitamin C supplementation to pregnant smokers was associated with changes in mRNA expression in genes highly relevant to vascular and cardiac development, suggesting a potential mechanism for vitamin C supplementation in pregnant smokers to improve some aspects of offspring health.

Abstract This study investigates the fabrication and characterization of electrospun poly (ε-caprolactone)/poly (vinyl pyrrolidone) (PCL/PVP) fibers integrated with a nanocomposite of chitosan, silver nanocrystals, and graphene oxide (ChAgG), aimed at developing advanced wound dressing materials. The ChAgG nanocomposite, recognized for its antimicrobial and biocompatible properties, was incorporated into PCL/PVP fibers through electrospinning techniques. We assessed the resultant fibers’ morphological, physicochemical, and mechanical properties, which exhibited significant enhancements in mechanical strength and demonstrated effective antimicrobial activity against common bacterial pathogens. The findings suggest that the PCL/PVP-ChAgG fibers maintain biocompatibility and facilitate controlled therapeutic delivery, positioning them as a promising solution for managing chronic and burn-related wounds. This study underscores the potential of these advanced materials to improve healing outcomes cost-effectively, particularly in settings plagued by high incidences of burn injuries. Further clinical investigations are recommended to explore these innovative fibers’ full potential and real-world applicability.

Abstract Background Medical education has undergone significant changes over the last decades. Scientific and technological progress alongside contemporary society’s changing requirements have driven demand for highly trained, competent doctors. In response to this need, university faculties of medicine have sought innovative forms of teaching and evaluating the students on their degree courses. The aim of this study was to quantify the characteristics and extent of academic training in teaching methods, of participation in innovative teaching initiatives, and training in simulation and debriefing among the teaching personnel on the degree course in medicine at the University of Granada (Spain). Methods This transversal descriptive study was conducted among a population of 121 educators teaching on the medical degree course at the University of Granada, Spain. All responded to a specially designed CoRe-Content Representation questionnaire. This consisted of various parts: (a) demographic data; (b) teaching experience and qualifications; (c) specific information about training in teaching skills received. The Fisher test was applied whenever the dependent variable had two values (dichotomous) and the Chi-square test when it had more than two values (polytomic). Statistical significance was established with an alpha error of 5%. Results The results showed that 87.60% of the educators had received no training in debriefing. There was a notable gender gap, whereby women held fewer management posts, fewer were engaged in clinical activity, and fewer had undergone training in clinical simulation. Teachers with degrees in medicine had undergone less regulated training than educators with other degree qualifications. Conclusion The main areas of medical training that require improvement (and so present challenges to be met in the years to come) are as follows: a definitive solution to the existing gender gap, general implementation of new educational models and methods (especially learning based on clinical problem-solving and simulation), closing generation gaps, and improved training processes for educators with clinical attachment.

Abstract Background Facioscapulohumeral dystrophy (FSHD) is a myopathy characterized by the loss of repressive epigenetic features affecting the D4Z4 locus (4q35). The assessment of DNA methylation at two regions (DUX4-PAS and DR1) of D4Z4 locus proved to be an effective method to detect epigenetic signatures compatible with FSHD. The present study aims at validating the employment of this method into clinical practice and improving the protocol by refining the classification thresholds of 4qA/4qA patients. To this purpose, 218 subjects with clinical suspicion of FSHD collected in 2022–2023 were analyzed. Each participant underwent in parallel the traditional FSHD molecular testing (D4Z4 sizing) and the proposed methylation assay. The results provided by both analyses were compared to evaluate the concordance and calculate the performance metrics of the methylation test. Results Among the 218 subjects, the 4q variant type distribution was 54% 4qA/4qA, 43% 4qA/4qB and 3% 4qB/4qB. The methylation analysis was performed only on carriers of at least one 4qA allele. After refining the classification threshold, the test reached the following performance metrics: sensitivity = 0.90, specificity = 1.00 and accuracy = 0.93. These results confirmed the effectiveness of the methylation assay in identifying patients with genetic signature compatible with FSHD1 and FSHD2 based on their DUX4-PAS and DR1 profile, respectively. The methylation data were also evaluated with respect to the clinical information. Conclusions The study confirmed the ability of the method to accurately identify methylation profiles compatible with FSHD genetic signatures considering the 4q genotype. Moreover, the test allows the detection of hypomethylated profiles in asymptomatic patients, suggesting its potential application in identifying preclinical conditions in patients with positive family history and FSHD genetic signatures. Furthermore, the present work emphasizes the importance of interpreting methylation profiles considering the patients’ clinical data.

Introducción: La hernia inguinal, un desafío global de salud, afecta significativamente a la población. Este estudio comparativo entre las técnicas de Lichtenstein y laparoscópica TAPP en el Hospital General del Estado de Sonora buscó analizar resultados postoperatorios. Objetivo: Comparar los resultados post quirúrgicos entre pacientes intervenidos de hernioplastia técnica Lichstenstein con abordaje TAPP. Material y Métodos: Observacional y transversal, 78 pacientes (49 Lichtenstein, 29 TAPP). Datos recolectados de enero de 2020 a diciembre de 2022. Análisis estadístico con pruebas U-Mann Whitney y Fisher-Freeman-Halton. Resultados: Sin diferencia significativa en tiempo quirúrgico. Mayor dolor en Lichtenstein (p=0,0344). Estancia hospitalaria promedio de 1,7 días. Recurrencia del 3,8%, más en Lichtenstein (4,1% vs. 3,4%). Complicaciones no difirieron significativamente, pero su distribución sí se asoció con la técnica utilizada (p=0,025). Conclusión: Ambas técnicas son efectivas, pero la elección podría afectar el perfil de complicaciones y el dolor postoperatorio específico. Estos resultados ofrecen información relevante para la toma de decisiones en la reparación de hernias inguinales, destacando la importancia de considerar el tipo de hernia al seleccionar la técnica quirúrgica.

Abstract In recent years, research has progressively increased the importance of considering sex differences in stress and fear memory studies. Many studies have traditionally focused on male subjects, potentially overlooking critical differences with females. Emerging evidence suggests that males and females can exhibit distinct behavioral and neurophysiological responses to stress and fear conditioning. These differences may be attributable to variations in hormone levels, brain structure, and neural circuitry, particularly in regions such as the prefrontal cortex (PFC). In the present study, we explored sex differences in prelimbic cortex (PL) calcium activity in animals submitted to immobilization stress (IMO), fear conditioning (FC), and fear extinction (FE). While no significant sex differences were found in behavioral responses, we did observe differences in several PL calcium activity parameters. To determine whether these results were related to behaviors beyond stress and fear memory, we conducted correlation studies between the movement of the animals and PL activity during IMO and freezing behavior during FC and FE. Our findings revealed a clear correlation between PL calcium activity with movement during stress exposure and freezing behavior, with no sex differences observed in these correlations. These results suggest a significant role for the PL in movement and locomotion, in addition to its involvement in fear-related processes. The inclusion of both female and male subjects is crucial for studies like this to fully understand the role of the PFC and other brain areas in stress and fear responses. Recognizing sex differences enhances our comprehension of brain function and can lead to more personalized and effective approaches in the study and treatment of stress and fear-related conditions.

Abstract The objective of this study is to ascertain whether subvalvular papillary muscle repair in conjunction with restrictive mitral valve annuloplasty represents the most efficacious treatment for patients presenting with secondary ischemic mitral regurgitation, as compared to restrictive mitral valve annuloplasty alone and to mitral valve replacement. A network meta-analysis was conducted to investigate outcomes of randomized controlled trials, propensity-matched studies, and observational studies, comparing various treatments for secondary ischemic mitral regurgitation. The average follow-up duration for late mortality was 4.4 years. Coronary artery bypass grafting (CABG) without mitral valve surgery had a late mortality incidence of 3.7%. Restrictive mitral annuloplasty demonstrated a rate of 6.5%, while restrictive mitral annuloplasty + CABG resulted in a rate of 4.1%. Subvalvular papillary muscle repair plus restrictive mitral annuloplasty ± CABG and mitral valve replacement + CABG had rates of 4.4% and 5.1%. SUCRA analysis showed that CABG was the most effective treatment for reducing late mortality (70.0%). This was followed by subvalvular papillary muscle repair plus restrictive mitral annuloplasty with or without CABG (62.4%). The top strategy for decreasing early death, reoperation, and readmission to the hospital for heart failure is subvalvular papillary muscle repair plus restrictive mitral annuloplasty with or without CABG, based on SUCRA probabilities (84.6%, 85.54%, and 86.3%, respectively). Subvalvular papillary muscle repair plus restrictive mitral annuloplasty ± CABG has potential to reduce the risks associated with early mortality, reoperation, and re-hospitalization for heart failure. However, further research is required to substantiate these findings.

Abstract The objective of the research is to develop a new methodology capable of quantifying the emissions of internal combustion engine cars based not only on their technology but also on the dynamic behavior of the individual vehicle. No complicated exhaust measurement apparatus is needed. Employing just a telematic device equipped with GNSS and an inertial measurement unit, which can be easily attached to the vehicle, we demonstrate how individualised, accurate climate-altering emissions result by using figures extracted from European test databases, appropriately combined with real travelled distances, speeds, and driving style of each individual car. Pollutant emissions are, in this paper, also assessed though in a more general manner, and this represents a starting point for a future complete vehicle-centric emissions evaluation. This research demonstrates that circulating car emissions have to be assessed considering not only the Euro class and type of fuel, but also how the vehicle is driven. In this work a new, implementation oriented methodology is proposed in order to properly merge average European standard emission data with car-based telematic measures to highlight a new paradigm for regulating in a more conscious way the transition of the internal combustion engine car park towards a large scale, sustainable mobility ecosystem. This approach would place greater responsibility on the driver, without leaving anyone behind and without compelling the car scrapping solely based on the Euro class of its engine. The key contribution is ultimately to establish an easy to handle methodology enabling targeted and behavior-based traffic management policies. In fact, through a massive telematics recent dataset, the proposed virtual emission sensing system reveals that an extensive and inefficient use of eco-friendly vehicles produces much more greenhouse gas emissions than older vehicles driven in an environmentally responsible way.

Abstract Colorectal cancer (CRC) ranks among the most prevalent malignancies worldwide, driving a quest for comprehensive characterization methods. We report a characterization of the ex vivo autofluorescence lifetime fingerprint of colorectal tissues obtained from 73 patients that underwent surgical resection. We specifically target the autofluorescence characteristics of collagens, reduced nicotine adenine (phosphate) dinucleotide (NAD(P)H), and flavins employing a fiber-based dual excitation (375 nm and 445 nm) optical imaging system. Autofluorescence-derived parameters obtained from normal tissues, adenomatous lesions, and adenocarcinomas were analyzed considering the underlying clinicopathological features. Our results indicate that differences between tissues are primarily driven by collagen and flavins autofluorescence parameters. We also report changes in the autofluorescence parameters associated with NAD(P)H that we tentatively attribute to intratumoral heterogeneity, potentially associated to the presence of distinct metabolic subpopulations. Changes in autofluorescence signatures of malignant tumors were also observed with lymphatic and venous invasion, differentiation grade, and microsatellite instability. Finally, we characterized the impact of radiative treatment in the autofluorescence fingerprints of rectal tissues and observed a generalized increase in the mean lifetime of radiated adenocarcinomas, which is suggestive of altered metabolism and structural remodeling. Overall, our preliminary findings indicate that multiparametric autofluorescence lifetime measurements have the potential to significantly enhance clinical decision-making in CRC, spanning from initial diagnosis to ongoing management. We believe that our results will provide a foundational framework for future investigations to further understand and combat CRC exploiting autofluorescence measurements.

Abstract The KATITA-25 (Kidney AlloTransplant Immunosuppressive Therapy Adherence) Questionnaire is a multidimensional self-administered scale developed in Brazilian Portuguese that measures the predisposition for non-adherence to immunosuppressive medication in candidate patients for kidney transplantation, in the pre-transplant setting. The aim of this study was the cross-cultural validation of the Spanish version of the KATITA-25 scale. The translation/back-translation method was used, followed by cognitive interviews and a pre-test. The Spanish version of KATITA-25 was administered to 163 candidate patients for kidney transplantation from 2 kidney transplant centres and 2 dialysis centres in Catalonia, Spain. The scale was re-administered to the first 79 patients included into the study, after a 2 to 4 weeks interval. Internal consistency was assessed using Cronbach’s alpha, test–retest reliability with the intraclass correlation coefficient (ICC); construct validity with goodness of fit indices after confirmatory factor analysis using structural equation modelling. The Cronbach’s alpha of the Spanish version was 0.83, the ICC was 0.86. Confirmatory factor analysis showed adequate fit of the structural model. Overall, the analytical results closely resembled those obtained in the validation of the original scale. In conclusion, this cross-cultural validation study showed adequate reliability and construct validity of the Spanish version of the KATITA-25 questionnaire.

Abstract Background Although neuroimaging investigations have consistently demonstrated that “hyperresponsive” and “hyperconnected” visual cortices may represent the functional substrate of cortical spreading depolarization in patients with migraine with aura, the mechanisms which underpin the brain “tendency” to ignite the cortical spreading depolarization and, consequently, aura phenomenon are still matter of debate. Considering that triggers able to induce aura phenomenon constrain brain to increase global (such as physical activity, stressors and sleep abnormalities) or local (such as bright light visual stimulations) energy demand, a vascular supply unable to satisfy the increased energy requirement could be hypothesized in these patients. Methods Twenty-three patients with migraine with aura, 25 patients with migraine without aura and 20 healthy controls underwent a 3-Tesla MRI study. Cerebral blood flow and local functional connectivity (regional homogeneity) maps were obtained and registered to the MNI space where 100 cortical regions were derived using a functional local-global normative parcellation. A surrogate estimate of the regional neurovascular coupling for each subject was obtained at each parcel from the correlation coefficient between the z-scored ReHo map and the z-scored cerebral blood flow maps. Results A significantly higher regional cerebral blood flow across the visual cortex of both hemispheres (i.e. fusiform and lingual gyri) was detected in migraine with aura patients when compared to patients with migraine without aura (p

Abstract Background Recent studies have highlighted the importance of the cell-free DNA (cfDNA) methylation profile in detecting breast cancer (BC) and its different subtypes. We investigated whether plasma cfDNA methylation, using cell-free Methylated DNA Immunoprecipitation and High-Throughput Sequencing (cfMeDIP-seq), may be informative in characterizing breast cancer in patients with BRCA1/2 germline mutations for early cancer detection and response to therapy. Methods We enrolled 23 BC patients with germline mutation of BRCA1 and BRCA2 genes, 19 healthy controls without BRCA1/2 mutation, and two healthy individuals who carried BRCA1/2 mutations. Blood samples were collected for all study subjects at the diagnosis, and plasma was isolated by centrifugation. Cell-free DNA was extracted from 1 mL of plasma, and cfMeDIP-seq was performed for each sample. Shallow whole genome sequencing was performed on the immuno-precipitated samples. Then, the differentially methylated 300-bp regions (DMRs) between 25 BRCA germline mutation carriers and 19 non-carriers were identified. DMRs were compared with tumor-specific regions from public datasets to perform an unbiased analysis. Finally, two statistical classifiers were trained based on the GLMnet and random forest model to evaluate if the identified DMRs could discriminate BRCA-positive from healthy samples. Results We identified 7,095 hypermethylated and 212 hypomethylated regions in 25 BRCA germline mutation carriers compared to 19 controls. These regions discriminate tumors from healthy samples with high accuracy and sensitivity. We show that the circulating tumor DNA of BRCA1/2 mutant breast cancers is characterized by the hypomethylation of genes involved in DNA repair and cell cycle. We uncovered the TFs associated with these DRMs and identified that proteins of the Erythroblast Transformation Specific (ETS) family are particularly active in the hypermethylated regions. Finally, we assessed that these regions could discriminate between BRCA positives from healthy samples with an AUC of 0.95, a sensitivity of 88%, and a specificity of 94.74%. Conclusions Our study emphasizes the importance of tumor cell-derived DNA methylation in BC, reporting a different methylation profile between patients carrying mutations in BRCA1, BRCA2, and wild-type controls. Our minimally invasive approach could allow early cancer diagnosis, assessment of minimal residual disease, and monitoring of response to therapy.

Abstract Background Congenital diaphragmatic hernia (CDH) is a rare disease that affects the development of the diaphragm, leading to abnormal lung development. Unfortunately, there is no established therapy for CDH. Retinoic acid pathways are implicated in the ethology of CDH and macrophages are known to play a role in repairing organ damage. Methods We have analyzed the effect of several Toll like receptor (TLR) ligands in the nitrofen-induced CDH model in pregnant rats widely used to study this disease and in the G2-GATA4Cre;Wt1fl/fl CDH genetic mice model. Morphometric and histological studies were carried out. Immune cell infiltration was assayed by immunochemistry and immunofluorescence and retinoic pathway gene expression analyzed in vivo and in vitro in macrophages. Results We found that administering a single dose of atypical TLR2/4 ligands (CS1 or CS2), 3 days after nitrofen, cured diaphragmatic hernia in 73% of the fetuses and repaired the lesion with complete diaphragm closure being on the other hand nontoxic for the mothers or pups. Moreover, these immunomodulators also improved pulmonary hypoplasia and alveolar maturation and vessel hypertrophy, enhancing pulmonary maturity of fetuses. We also found that CS1 treatment rescued the CDH phenotype in the G2-GATA4Cre;Wt1fl/fl CDH genetic mice model. Only 1 out of 11 mutant embryos showed CDH after CS1 administration, whereas CDH prevalence was 70% in untreated mutant embryos. Mechanistically, CS1 stimulated the infiltration of repairing M2 macrophages (CD206+ and Arg1+) into the damaged diaphragm and reduced T cell infiltration. Additionally, those TLR ligands induced retinol pathway genes, including RBP1, RALDH2, RARα, and RARβ, in the affected lungs and the diaphragm and in macrophages in vitro. Conclusions Our research has shown that TLR ligand immunomodulators that influence anti-inflammatory macrophage activation can be effective in treating CDH, being nontoxic for the mothers or pups suggesting that those TLR ligands are a promising solution for CDH leading to orphan drug designation for CS1. The immune system of the fetus would be responsible for repairing the damage and closure of the hernia in the diaphragm and enhanced proper lung development after CS1 treatment.

Objetivo. Describir la metodología de la búsqueda intencionada y reclasificación de muertes maternas (BIRMM), que permite identificar y corregir la clasificación errónea y el subregistro de defunciones maternas. Métodos. Se utiliza la metodología BIRMM, desarrollada inicialmente en México en el 2003 y difundida en otros países de América Latina a partir del 2012. La BIRMM consta de cuatro componentes clave: i) reclasificación de muertes maternas confirmadas; ii) identificación e investigación de casos sospechosos de muerte materna; iii) confronta con otras fuentes de información; y iv) publicación de resultados y análisis estadístico de la mortalidad materna. Resultados. La aplicación de la BIRMM permite identificar y analizar las muertes maternas en comités de mortalidad materna, lo que ha facilitado la implementación de planes de respuesta efectivos, contribuyendo a una reducción sostenida de la mortalidad materna en los países. Conclusiones. La metodología BIRMM es una herramienta efectiva para corregir el subregistro y la mala clasificación de muertes maternas, lo que permite una mejor vigilancia y respuesta a este problema. Su adopción y ejecución rutinaria son esenciales para mejorar la calidad de la información sobre mortalidad materna y reducir las muertes maternas en la Región de las Américas. La sostenibilidad de esta metodología depende del compromiso institucional y la voluntad política en los países.

Abstract A novel synthetic pathway for synthesizing isocyanate-free polyurethanes is reported here. β-Amino alcohols were efficiently synthesized from the aminolysis of the epoxide ring of (R)-(+)-limonene oxide with different primary amines as nucleophiles and hot water as catalysts. The regio- and diastereoselectivities of the reactions were investigated and supported by computational studies. DFT calculations were performed to understand the experimental results more deeply. It confirmed the crucial roles of water molecules and the nature of the nucleophile in forming the products. The formation of the product is entirely driven by the free energy of activation that affects the reaction rate. Cyclic carbamates were prepared from β-amino alcohols using the dialkyl carbonate (DAC) chemistry. An oligourethane was obtained from Anionic Ring-Opening Polymerization (AROP) of a cyclic carbamate derived from (R)-(+)-limonene-oxide. All the products were characterized by employing 1H and 13C NMR spectroscopies. The assignments of the signals in 1H and 13C NMR spectra were also supported by 2D NMR spectroscopy.

Abstract The development of accurate predictions for a new drug’s absorption, distribution, metabolism, and excretion profiles in the early stages of drug development is crucial due to high candidate failure rates. The absence of comprehensive, standardised, and updated pharmacokinetic (PK) repositories limits pre-clinical predictions and often requires searching through the scientific literature for PK parameter estimates from similar compounds. While text mining offers promising advancements in automatic PK parameter extraction, accurate Named Entity Recognition (NER) of PK terms remains a bottleneck due to limited resources. This work addresses this gap by introducing novel corpora and language models specifically designed for effective NER of PK parameters. Leveraging active learning approaches, we developed an annotated corpus containing over 4000 entity mentions found across the PK literature on PubMed. To identify the most effective model for PK NER, we fine-tuned and evaluated different NER architectures on our corpus. Fine-tuning BioBERT exhibited the best results, achieving a strict $$F_{1}$$ F 1 score of 90.37% in recognising PK parameter mentions, significantly outperforming heuristic approaches and models trained on existing corpora. To accelerate the development of end-to-end PK information extraction pipelines and improve pre-clinical PK predictions, the PK NER models and the labelled corpus were released open source at https://github.com/PKPDAI/PKNER .

Abstract The COVID-19 pandemic remains a significant global health threat, with uncertainties persisting regarding the factors determining whether individuals experience mild symptoms, severe conditions, or succumb to the disease. This study presents an NMR metabolomics-based approach, analysing 80 serum and urine samples from COVID-19 patients (34 intensive care patients and 46 hospitalized patients) and 32 from healthy controls. Our research identifies discriminant metabolites and clinical variables relevant to COVID-19 diagnosis and severity. These discriminant metabolites play a role in specific pathways, mainly “Phenylalanine, tyrosine and tryptophan biosynthesis”, “Phenylalanine metabolism”, “Glycerolipid metabolism” and “Arginine and proline metabolism”. We propose a three-metabolite diagnostic panel—comprising isoleucine, TMAO, and glucose—that effectively discriminates COVID-19 patients from healthy individuals, achieving high efficiency. Furthermore, we found an optimal biomarker panel capable of efficiently classify disease severity considering both clinical characteristics (obesity/overweight, dyslipidemia, and lymphocyte count) together with metabolites content (ethanol, TMAO, tyrosine and betaine).

Abstract Beyond its clinical diversity and severity, acute myeloid leukemia (AML) is known for its complex molecular background and for rewiring biological processes to aid disease onset and maintenance. FLT3 mutations are among the most recurring molecular entities that cooperatively drive AML, and their inhibition is a critical molecularly oriented therapeutic strategy. Despite being a promising avenue, it still faces challenges such as intrinsic and acquired drug resistance, which led us to investigate whether and how autophagy and inflammasome interact and whether this interaction could be leveraged to enhance FLT3 inhibition as a therapeutic strategy. We observed a strong and positive correlation between the expression of key genes associated with autophagy and the inflammasome. Gene set enrichment analysis of the FLT3-ITD samples and their ex vivo response to five different FLT3 inhibitors revealed a common molecular signature compatible with autophagy and inflammasome activation across all poor responders. Inflammasome activation was also shown to strongly increase the likelihood of a poor ex vivo response to the FLT3 inhibitors quizartinib and sorafenib. These findings reveal a distinct molecular pattern within FLT3-ITD AML samples that underscores the necessity for further exploration into how approaching these supportive parallel yet altered pathways could improve therapeutic strategies.

Abstract Neoadjuvant endocrine therapy (NET) for hormone receptor-positive (HR+) breast cancer might be as effective as chemotherapy, with a better toxicity profile. Blocking a crucial process such as angiogenesis with sunitinib may have a synergistic effect with NET. We aimed to assess the efficacy and safety of neoadjuvant sunitinib plus exemestane in early-stage HR+/HER2-negative breast cancer. In this phase I/II study, postmenopausal women with HR+/HER2− stage II-III breast cancer received neoadjuvant exemestane at conventional dose of 25mg plus sunitinib in a 3 + 3 design at 25mg (3/1weeks scheme) or 37.5mg continuous dose, for 6 months. Coprimary endpoints were the recommended dose of sunitinib combined with exemestane and objective response. Secondary endpoints included safety and biomarkers of early response. For 15 months, 18 patients were enrolled, 15 at sunitinib 25mg and 3 at 37.5mg. Median age was 73, 77% of patients had T2 tumors and 67% node-positive disease. The most common grade 2 toxicity was asthenia (44%), as was hypertension (22%) for grade 3. No grade 4–5 were reported. Twelve patients (66%) achieved an objective response. VEGFR-2 levels significantly decreased after one month of treatment. Differential gene expression analysis showed downregulation of ESR1, PGR and NAT1 in post-treatment samples and upregulation of EGFR, MYC, SFRP1, and FOXC1. PAM50 analysis on 83% of patients showed a prevalence of luminal A subtype, both in pre-treatment (63.6%) and post-treatment tumors (54.5%). Sunitinib plus exemestane was associated with substantial yet reversible toxicities, providing safety, efficacy and biological impact insights of combining an antiangiogenic drug with hormone therapy in early-stage breast cancer. Trial registration: Registered with ClinicalTrials.gov, NCT00931450. 02/07/2009

Between September and November 2020, four pregnant women under 35 years of age were diagnosed with pneumonia and severe preeclampsia. The patients required admission to the intensive care unit (ICU), mechanical ventilation, and extracorporeal membrane oxygenation. Paraclinical tests showed increased C-reactive protein and lactate dehydrogenase, lymphopenia, and a reduced neutrophil/lymphocyte ratio. One newborn was positive for SARS-CoV-2. Three mothers and one newborn died. Preeclampsia has been associated with COVID-19 in pregnant women. The high mortality found and the vertical transmission in one case are noteworthy. In conclusion, the development of severe preeclampsia in all cases may have been an additional factor contributing to the fatal outcome in 3 of them. It is suggested that lymphopenia and the reduced neutrophil/lymphocyte ratio may be useful as prognostic factors. Future studies will help elucidate the consequences of COVID-19 in pregnancy.

Abstract Objective We developed an in-house bioinformatics pipeline to improve the detection of respiratory pathogens in metagenomic sequencing data. This pipeline addresses the need for short-time analysis, high accuracy, scalability, and reproducibility in a high-performance computing environment. Results We evaluated our pipeline using ninety synthetic metagenomes designed to simulate nasopharyngeal swab samples. The pipeline successfully identified 177 out of 204 respiratory pathogens present in the compositions, with an average processing time of approximately 4 min per sample (processing 1 million paired-end reads of 150 base pairs). For the estimation of all the 470 taxa included in the compositions, the pipeline demonstrated high accuracy, identifying 420 and achieving a correlation of 0.9 between their actual and predicted relative abundances. Among the identified taxa, 27 were significantly underestimated or overestimated, including only three clinically relevant pathogens. We also validated the pipeline by applying it to a clinical dataset from a study on metagenomic pathogen characterization in patients with acute respiratory infections and successfully identified all pathogens responsible for the diagnosed infections. These findings underscore the pipeline’s effectiveness in pathogen detection and highlight its potential utility in respiratory pathogen surveillance.

Abstract Male breast cancer (MBC) is a rare condition with unique characteristics compared to female breast cancer (FBC). Despite its scarceness, there is growing evidence that MBC should not be studied and treated as FBC due to factors like later diagnosis stage and distinct genetic makeup. Retrospective observational study in the EpiChron Cohort, selecting all the prevalent patients with breast cancer between 2010 and 2019. Logistic models were used to determine associated comorbidities. Between 2010 and 2019, 105 MBC and 11,657 FBC patients were found in the EpiChron Cohort. MBC patients had a high mean age at diagnosis and number of comorbidities. Paying attention to comorbidity prevalences in breast cancer patients, it was clear that MBC patients tended to be prone to cardio-metabolic coexisting diseases, while FBC patients were more prone to hormone-, bone- and mental diseases. There were nine chronic conditions associated to MBC patients, but after a year-by-birth matching only four associations remained. Two of them were associated previously [odds ratio (95% confidence interval)]: “Disorder of lipid metabolism” [1.65 (1.03–2.64)] and “Genitourinary symptoms and ill-defined conditions” [2.03 (1.07–3.87)]; and the other two were new, “Anxiety disorders” [2.05 (1.09–3.87)] and “Osteoporosis” [3.58 (1.26–10.14)]. After comparing associated comorbidities in FBC with those in MBC, it seems MBC patients share some of them, but they have their own particular set of coexisting diseases. In fact, once a year-by-birth matching was performed in MBC patient cohort, it was more obvious MBC comorbidities behave more similar to none-Breast-Cancer male population than to FBC patients. These findings highlight the distinct characteristics of the MBC patient population and the need for a tailored approach of managing MBC.

Craniosacral rhythm is a manual therapy technique that focuses on the subtle, rhythmic movement of cerebrospinal fluid as it flows through the central nervous system and musculoskeletal system. Through light and delicate manipulation of the cranial bones, membranes and soft tissues of the head and neck, it promotes rebalancing and release from tension in the body, improving the circulation of the cerebrospinal fluid and the individual’s health. In the field of prosthetic dentistry, in rare cases, such as a full arch or removable partial denture, the patient perceives a sensation of constriction even though all procedures have been used correctly. In this work, a new design fora removable partial denture is proposed that does not interfere with the primary respiratory mechanism, reducing the sensation of constriction in the patient. The materials used are the same as those used for a normal removable partial denture, and the technique used is the “lost wax” one: the novelty is that the prosthesis is made in two separate parts that are joined by a central connection; the result is a removable partial denture with a small central thickening in the main joint represented by the connection of the two pieces. Craniosacral breathing movements are favored with this prosthesis as the metal structure is hyperstatic towards intrusion movements, more or less virtual in the opposite direction, i.e., extrusion towards the vestibule.

El propósito del estudio fue describir las características clínicas, anatomopatológicas, tratamiento y supervivencia de los pacientes con cáncer de tiroides diferenciado. Se realizó un estudio de cohorte retrospectiva con datos de 150 pacientes de un hospital peruano entre los años 2010 al 2020. Se describieron las características y supervivencia (método de Kaplan-Meier). La media de edad fue 48,3 años, 130 (86,7%) fueron mujeres y el tipo histológico más frecuente fue el papilar 94,6%. El 74,2% tenían estadio TNM I, 70,7% tiroidectomía total y 68,7% recibió yodo radiactivo. La supervivencia global a los 5 años fue 89,3%, siendo menor en aquellos con estadio TNM IV y mayor en los que usaron yodo radiactivo. En conclusión, en un hospital de Cusco, el cáncer diferenciado de tiroides fue más frecuente en mujeres y la supervivencia fue menor en comparación con reportes de otros países.

Abstract The cellular prion protein (PrPC) plays many roles in the developing and adult brain. In addition, PrPC binds to several amyloids in oligomeric and prefibrillar forms and may act as a putative receptor of abnormal misfolded protein species. The role of PrPC in tau seeding and spreading is not known. In the present study, we have inoculated well-characterized sarkosyl-insoluble fractions of sporadic Alzheimer’s disease (sAD) into the brain of adult wild-type mice (Prnp +/+), Prnp 0/0 (ZH3 strain) mice, and mice over-expressing the secreted form of PrPC lacking their GPI anchor (Tg44 strain). Phospho-tau (ptau) seeding and spreading involving neurons and oligodendrocytes were observed three and six months after inoculation. 3Rtau and 4Rtau deposits from the host tau, as revealed by inoculating Mapt 0/0 mice and by using specific anti-mouse and anti-human tau antibodies suggest modulation of exon 10 splicing of the host mouse Mapt gene elicited by exogenous sAD-tau. However, no tau seeding and spreading differences were observed among Prnp genotypes. Our results show that PrPC does not affect tau seeding and spreading in vivo.