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Abstract Background Recently, there has been a surge of literature utilizing the human amniotic membrane (hAM) to manage cases of macular holes. In this scoping review, we aimed to systematically narrate the literature to identify cases of macular holes that are managed using hAM and explore the visual and anatomical outcomes to inform future research questions. Methods This scoping review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A detailed database search strategy (Scopus, Embase, Medline, and Cochrane Central) was developed to identify English-language published articles that reported using hAM to manage macular holes. All human clinical studies were included for a narrative data synthesis divided across study types. Results The database search identified 82 articles, of which 34 were eligible for full-text review (0 randomized controlled trials (RCTs), 12 non-RCTs, 10 retrospective reviews, ten published case reports, and two clinical trial registries). The non-RCTs included patients with macular holes related to a wide range of retinal diseases, including retinal detachment, recurrent holes, and high myopia. Only two non-RCTs reported comparative data with a control group, but the study characteristics differed, and quantitative synthesis was impossible. Most retrospective interventional series and individual case reports reported a success rate of 93 -100% in hole closure and improvement in best-corrected visual acuity. None of the studies reported adverse effects after a hAM transplantation. Conclusion The hAM effectively seals macular holes without any safety concerns, improving anatomical and visual outcomes in all macular holes.

Abstract Background Recently, magnetic and inertial measurement units (MIMU) based systems have been applied in the spine mobility assessment; this evaluation is essential in the clinical practice for diagnosis and treatment evaluation. The available systems are limited in the number of sensors, and neither develops a methodology for the correct placement of the sensors, seeking the relevant mobility information of the spine. Methods This work presents a methodology for analyzing a system consisting of sixteen MIMUs to reduce the amount of information and obtain an optimal configuration that allows distinguishing between different body postures in a movement. Four machine learning algorithms were trained and assessed using data from the range of motion in three movements (Mov.1—Anterior hip flexion; Mov.2—Lateral trunk flexion; Mov.3—Axial trunk rotation) obtained from 12 patients with Ankylosing Spondylitis. Results The methodology identified the optimal minimal configuration for different movements. The configuration showed good accuracy in discriminating between different body postures. Specifically, it had an accuracy of 0.963 ± 0.021 for detecting when the subject is upright or bending in Mov.1, 0.944 ± 0.038 for identifying when the subject is flexed to the left or right in Mov.2, and 0.852 ± 0.097 for recognizing when the subject is rotated to the right or left in Mov.3. Conclusions Our results indicate that the methodology developed results in a feasible configuration for practical clinical studies and paves the way for designing specific IMU-based assessment instruments. Trial registration: Study approved by the Local Ethics Committee of the General Hospital of Mexico “Dr. Eduardo Liceaga” (protocol code DI/03/17/471).

Abstract Vitamin D (vitD) deficiency is frequently observed in patients with pulmonary arterial hypertension (PAH) and, in these patients, low levels of vitD correlate with worse prognosis. The aim of this study was to examine the expression and the antiproliferative role of vitD receptor (VDR) and its signalling pathway in the human pulmonary vasculature. VDR presence and expression was analyzed in lungs, pulmonary artery smooth muscle cells (PASMC) and endothelial cells (PAEC) from controls and PAH-patients. VDR expression and VDR-target genes were examined in PASMC treated with calcitriol. The antiproliferative effect of 48 h-calcitriol was studied in PASMC by MTT and BrdU assays. VDR is expressed in PASMC. It is downregulated in lungs and in PASMC, but not in PAEC, from PAH-patients compared to non-hypertensive controls. Calcitriol strongly upregulated VDR expression in PASMC and the VDR target genes KCNK3 (encoding TASK1), BIRC5 (encoding survivin) and BMP4. Calcitriol produced an antiproliferative effect which was diminished by silencing or by pharmacological inhibition of survivin or BMPR2, but not of TASK1. In conclusion, the expression of VDR is low in PAH-patients and can be rescued by calcitriol. VDR exerts an antiproliferative effect in PASMC by modulating survivin and the BMP signalling pathway.

Abstract Background Escherichia coli JU15 is a metabolically engineered strain capable to metabolize C5 and C6 sugars with a high yield of d-lactic acid production at its optimal growth temperature (37 °C). The simultaneous saccharification and fermentation process allow to use lignocellulosic biomass as a cost-effective and high-yield strategy. However, this process requires microorganisms capable of growth at a temperature close to 50 °C, at which the activity of cellulolytic enzymes works efficiently. Results The thermotolerant strain GT48 was generated by adaptive laboratory evolution in batch and chemostat cultures under temperature increments until 48 °C. The strain GT48 was able to grow and ferment glucose to d-lactate at 47 °C. It was found that a pH of 6.3 conciliated with GT48 growth and cellulase activity of a commercial cocktail. Hence, this pH was used for the SSF of a diluted acid-pretreated corn stover (DAPCS) at a solid load of 15% (w/w), 15 FPU/g-DAPCS, and 47 °C. Under such conditions, the strain GT48 exhibited remarkable performance, producing d-lactate at a level of 1.41, 1.42, and 1.48-fold higher in titer, productivity, and yield, respectively, compared to parental strain at 45 °C. Conclusions In general, our results show for the first time that a thermal-adapted strain of E. coli is capable of being used in the simultaneous saccharification and fermentation process without pre-saccharification stage at high temperatures.

We report a case of Burkholderia mallei causing glanders in a 73-year-old patient from the Northeast Region of Brazil. The patient was hospitalized with severe pneumonia. PCR and genomic sequencing confirmed B. mallei in pleural drainage. Genotyping revealed a novel genotype, emphasizing the need for genetic surveillance in zoonotic infections.

Highlights Urban trees in urban environments are commonly exposed to stresses, contributing to their health decline; Ectomycorrhizal fungi improve the vigour and resilience of Tilia seedlings, but their performance is dependent on soil pH. Inoculation promotes growth in height, biomass production, mycorrhization status, nutrient uptake, and proline accumulation, and these effects dependent on fungi species and soil pH; Inoculation with EcM can be a strategy to produce healthier saplings that when transplanted to the urban environment will have a better performance.

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 Meta-analyses show an overall decrease in soil N2O emissions after biochar (BC) amendment. Nonetheless, N2O mitigation with BC cannot be extrapolated to every BC-soil combination, inasmuch as an increase in soil N2O release has been occasionally reported. We hypothesized that BC characteristics are key, and performed two microcosm experiments to advance in the understanding of the properties associated. We first investigated how 22 well-characterized BCs affect N2O emissions in a calcareous soil under denitrification conditions. Whereas most BCs decreased N2O emissions, some substantially increased N2O emissions. In a second experiment, we selected and further characterized eight of the 22 previous BCs. We applied the 15N-gas-flux method to study how these BCs affect denitrification products (N2O and N2) in the same soil. Results indicate that the interaction between BC and the denitrification process depends on the temperature of pyrolysis. Whereas BCs produced at 400 °C tended to increase total denitrification (N2O+N2) by an average of 28%, BCs produced at 600 °C significantly reduced total denitrification by 53%. Nevertheless, this decline in overall denitrification did not result in a decrease of N2O emissions, as there was a strong shift in the N2O/(N2+N2O) ratio favoring N2O. A redundancy analysis revealed a direct correlation between carboxylic groups on BCs surface and N2O emissions. This research enhances our understanding of the interaction of BC with denitrification, particularly concerning the relevance of the temperature of pyrolysis, and opens up new paths for investigation, crucial for optimizing the application of BCs in different soil environments. Graphical Abstract

Abstract Increasing water stress is emerging as a global phenomenon, and is anticipated to have a marked impact on forest function. The role of tree functional strategies is pivotal in regulating forest fitness and their ability to cope with water stress. However, how the functional strategies found at the tree or species level scale up to characterise forest communities and their variation across regions is not yet well-established. By combining eight water-stress-related functional traits with forest inventory data from the USA and Europe, we investigated the community-level trait coordination and the biogeographic patterns of trait associations for woody plants, and analysed the relationships between the trait associations and climate factors. We find that the trait associations at the community level are consistent with those found at the species level. Traits associated with acquisitive-conservative strategies forms one dimension of variation, while leaf turgor loss point, associated with stomatal water regulation strategy, loads along a second dimension. Surprisingly, spatial patterns of community-level trait association are better explained by temperature than by aridity, suggesting a temperature-driven adaptation. These findings provide a basis to build predictions of forest response under water stress, with particular potential to improve simulations of tree mortality and forest biomass accumulation in a changing climate.

Abstract The ongoing increase in wild boar populations across Europe has fostered human–wildlife conflicts, including the transmission of emerging pathogens with zoonotic importance. Blastocystis is a ubiquitous, faecal-oral transmitted protist that can cause gastrointestinal illnesses and is observed in humans and animals worldwide. The role of wildlife in the epidemiology of Blastocystis is insufficiently understood. Thus, we investigated the occurrence and subtype diversity of Blastocystis in free-ranging wild boars from the Iberian Peninsula using conventional PCR and next-generation amplicon sequencing of a fragment of the ssu RNA gene. A total of 459 wild boar faecal samples were collected across Spain (n = 360) and Portugal (n = 99) between 2014 and 2021. Blastocystis was present in 15.3% (70/459; 95% CI 12.1–18.9) of the wild boars analysed, and its occurrence was significantly higher in Portugal (34.3%, 34/99; 95% CI 25.1–44.6) than in Spain (10.0%, 36/360; 95% CI 7.1–13.6). Seven Blastocystis subtypes (ST5, ST10b, ST13–ST15, ST24b, and ST43) were detected among the surveyed wild boar populations, with greater variability detected in Portuguese samples. ST5 was identified in all the Blastocystis-positive animals, whereas 14.3% of them harboured ST mixed colonisations. Our results demonstrate that Blastocystis ST5 is particularly adapted to infect wild boars. The additional identification of zoonotic STs reinforces the role of wild boars as spreaders of zoonotic infections with public health significance.

Abstract Polycystic ovary syndrome (PCOS) is a heterogeneous condition, defined by oligo-/anovulation, hyper-androgenism and/or polycystic ovaries. Metabolic complications are common in patients suffering PCOS, including obesity, insulin resistance and type-2 diabetes, which severely compromise the clinical course of affected women. Yet, therapeutic options remain mostly symptomatic and of limited efficacy for the metabolic and reproductive alterations of PCOS. We report here the hormonal, metabolic and gonadal responses to the glucagon-like peptide-1 (GLP1)-based multi-agonists, GLP1/Estrogen (GLP1/E), GLP1/gastric inhibitory peptide (GLP1/GIP) and GLP1/GIP/Glucagon, in two mouse PCOS models, with variable penetrance of metabolic and reproductive traits, and their comparison with metformin. Our data illustrate the superior efficacy of GLP1/E vs. other multi-agonists and metformin in the management of metabolic complications of PCOS; GLP1/E ameliorates also ovarian cyclicity in an ovulatory model of PCOS, without direct estrogenic uterotrophic effects. In keeping with GLP1-mediated brain targeting, quantitative proteomics reveals changes in common and distinct hypothalamic pathways in response to GLP1/E between the two PCOS models, as basis for differential efficiency. Altogether, our data set the basis for the use of GLP1-based multi-agonists, and particularly GLP1/E, in the personalized management of PCOS.

Abstract Introduction Pain and disability management are crucial for a speedy recovery. Combining analgesics with different mechanisms of action provides greater pain relief with lower doses, promoting efficient multimodal analgesia. This study evaluated the efficacy and safety between two fixed-dose combinations (FDC): etoricoxib/tramadol compared to paracetamol/tramadol for the management of acute low back pain (LBP) in a 7-day treatment. Methods We conducted a phase IIIb, prospective, randomized, and multicenter study in patients with acute LBP treated with etoricoxib 90 mg/tramadol 50 mg (one packet of granules diluted in 100 ml of water, once a day [QD], for 7 days) or paracetamol 975 mg/tramadol 112.5 mg (one tablet of 325 mg/37.5 mg, three times a day [TID], for 7 days) to assess the efficacy (in terms of pain and disability improvement) and safety. Results One hundred and twenty-four patients were randomized to receive either etoricoxib/tramadol QD (n = 61) or paracetamol/tramadol TID (n = 63). From the magnitude of change in pain evaluations, differences were observed between the treatment groups at 3 [p = 0.054, CI 95% − 0.648 (− 0.010 to 1.306)] and 5 days (p = 0.041). The proportion of patients with a 30% reduction in Visual Analogue Scale (VAS) score was statistically significant when comparing the treatment groups on the third day of follow-up [p = 0.008, CI 95% 0.241 (0.061–0.421)]. An improvement in LBP’s disability to perform activities of daily routine (Oswestry and Roland–Morris questionnaires) was observed in both treatment groups. A total of 79 adverse events (AEs) (38 [48.1%] with etoricoxib/tramadol and 41 [51.9%] with paracetamol/tramadol) were reported. The most frequent AEs were nausea (17.7%) and dizziness (16.4%). Conclusions The results show the clinical benefits of etoricoxib/tramadol FDC, such as the sparing effect of tramadol dose per day, early therapeutic response rate compared with paracetamol/tramadol; which translates into faster pain relief, better adherence, less tramadol drug dependency, and a reduction of related AEs incidence. Trial registration ClinicalTrials.gov identifier, NCT04968158.

Abstract Background Suicide is a major public health problem, especially among individuals over 50 years old. Despite the suitability of this life stage for prevention, research on the efficacy of psychological interventions is scarce and methodologically limited, affecting their clinical utility and efficacy. Brief, flexible interventions that can be applied both in-person and remotely are needed. This study aims to evaluate the efficacy of a brief problem-solving-based suicide prevention program applied through various modalities to individuals over 50 years old. Methods A randomized controlled trial will be conducted. A sample of 212 adults aged 50 or older with suicidal ideation will be randomly assigned to a problem-solving-based psychological intervention administered face-to-face (PSPI-P; n = 53), by telephone multiconference (PSPI-M; n = 53), via a smartphone app (PSPI-A; n = 53), or to a usual care control group (UCCG; n = 53). The intervention will be delivered in 7 sessions or modules of 90 min each. Blind trained evaluators will conduct assessments at pre-intervention, post-intervention, and follow-ups at 3, 6, and 12 months. The primary outcome will be suicidal ideation evaluated using the Suicidal Ideation Scale (SSI) and the Columbia Suicide Severity Rating Scale (C-SSRS). Secondary outcomes will include hopelessness, anxiety and depression symptoms, reasons for living, impulsivity, problem-solving skills, social support, anger syndrome, gratitude, personality, dropouts, treatment adherence, and satisfaction with the intervention. Discussion This study will provide evidence of the efficacy of a brief problem-solving-based intervention for suicide prevention in individuals over 50 years old, administered face-to-face, by telephone multiconference, and via a smartphone app. If results are favorable, it will indicate that an effective, accessible, clinically and socially useful suicide prevention intervention has been developed for affected individuals, families, and communities. Trial registration ClinicalTrials.gov NCT06338904. Registered April 1, 2024.

Abstract The challenge of transforming organized DNA structures into their metallized counterparts persists in the scientific field. In this context, utilizing DNA molecules modified with 7-deazapurine, provides a transformative solution. In this study, we present the solution structure of a DNA duplex that can be transformed into its metallized equivalent while retaining the natural base pairing arrangement through the creation of silver-modified Watson-Crick base pairs. Unlike previously documented X-ray structures, our research demonstrates the feasibility of preserving the intrinsic DNA self-assembly while incorporating AgI into the double helix, illustrating that the binding of silver does not disrupt the canonical base-pairing organization. Moreover, in our case, the uninterrupted AgI chain deviates from forming conventional straight linear chains; instead, it adheres to a helical arrangement dictated by the underlying DNA structure. This research challenges conventional assumptions and opens the door to precisely design structures based on the organization of highly stable Ag-DNA assemblies.

Abstract Resistant starch from plantain (Macho Musa paradisiaca L.) and banana (Roatan Musa sapientum L.) varieties was chemically modified by crosslinking using epichlorohydrin (EPI). These modified starches were subjected to in vitro digestibility studies using the Englyst method to determine the content of rapidly digestible starch (RDS), slowly digestible starch (SDS) and resistant starch (RS). The thermal stability of these crosslinked starches was evaluated by gelatinization and retrogradation analyses, and their enthalpies were determined using differential scanning calorimetry (DSC). Additionally, their functional properties were evaluated. Chemical modification with EPI significantly increased the RS content in both starch varieties compared to that in native starch. The enthalpy and gelatinization temperature decreased in the EPI-modified starches of both varieties, indicating lower thermal stability during the gelatinization process compared to that of native starch. In general, both varieties of crosslinked plantain starch had lower viscosity (0.43 Pa*s) than did native starch (0.58 Pa*s). The results indicates that this starch crosslinked with EPI constitutes an alternative for use in food for people with health problems such as high cholesterol levels or postprandial insulin concentrations. Graphical Abstract

Abstract The diagnostic odysseys for rare disease patients are getting shorter as next-generation sequencing becomes more widespread. However, the complex genetic diversity and factors influencing expressivity continue to challenge accurate diagnosis, leaving more than 50% of genetic variants categorized as variants of uncertain significance. Genomic expression intricately hinges on localized interactions among its products. Conventional variant prioritization, biased towards known disease genes and the structure-function paradigm, overlooks the potential impact of variants shaping the composition, location, size, and properties of biomolecular condensates, genuine membraneless organelles swiftly sensing and responding to environmental changes, and modulating expressivity. To address this complexity, we propose to focus on the nexus of genetic variants within biomolecular condensates determinants. Scrutinizing variant effects in these membraneless organelles could refine prioritization, enhance diagnostics, and unveil the molecular underpinnings of rare diseases. Integrating comprehensive genome sequencing, transcriptomics, and computational models can unravel variant pathogenicity and disease mechanisms, enabling precision medicine. This paper presents the rationale driving our proposal and describes a protocol to implement this approach. By fusing state-of-the-art knowledge and methodologies into the clinical practice, we aim to redefine rare diseases diagnosis, leveraging the power of scientific advancement for more informed medical decisions.

The current literature lacks comprehensive research on the processing limits of the Friction Stir Channeling process (FSC) for creating the smallest continuous and integral channels, using tools with threaded probes 2 mm in diameter or smaller. This study pioneers the exploration of the extreme limits of the microscale FSC process, with potential applications in the development of ultra-compact heat exchangers, seeking to enhance the efficiency and sustainability of these systems. Customized tools were designed and manufactured, with predefined dimensions and geometries to establish a set of parameters that consistently produce continuous microchannels, maximizing the hydraulic diameter within the constraints of each tool's specifications and geometry. Comprehensive evaluations—including continuity, watertightness, micro-computed tomography, neutron computed tomography, microhardness testing, and thermal measurements—were conducted to ensure the channels' structural integrity and suitability for super-compact heating and cooling applications. Internal channels were successfully created using tools with threaded probes measuring 2.0, 1.0, and 0.5 mm in diameter, and corresponding shoulder diameters of 5, 4, and 3.5 mm, within 5 mm thick AW1050-H111 aluminum alloy plates. The smallest channel achieved a hydraulic diameter of 191 μm, using a 0.5 mm diameter threaded probe, thus qualifying it as a microchannel. The thermal performance of a compact heat exchanger model was also tested, demonstrating that despite the high cost associated with tool production, particularly due to the specialized manufacturing processes required, the FSC process remains viable, reliable, and repeatable for the production of mini- and micro-channels.

Background and objective: The depth of the prostate-specific antigen (PSA) decline after androgen receptor pathway inhibitor (ARPI) treatment combined with androgen deprivation therapy for patients with metastatic hormone-sensitive prostate cancer (mHSPC) may affect prognosis. The primary objective in our study was the correlation between the PSA response at 3 mo and radiologic progression-free survival (rPFS) at 24 mo. Three groups were defined according to the PSA decline: complete response (PSA ≤0.02 ng/ml), partial response (PSA >0.02 and ≤0.2 ng/ml), and incomplete response (PSA >0.2 ng/ml). Secondary objectives were correlation between the PSA response at 3 mo and overall survival, and the development of a model predicting complete PSA response. Methods: We conducted a retrospective multicenter study of patients with mHSPC treated with apalutamide from May 2018 to September 2023 registered in the Real-World Evidence APA registry across 20 centers. Key findings and limitations: We included 633 patients with mHSPC. The median age at diagnosis was 68 yr (interquartile range [IQR] 63–75) and median PSA was 16 ng/ml (IQR 7.5–64). Some 63% of the short had low-volume disease, 51% had de novo disease, 48% had recurrent disease. At 3 mo, 27% had a complete response, 42% a partial response, and 31% an incomplete response, with corresponding rRFS rates at 24 mo of 92%, 86%, and 63%. According to the predictive model, a complete PSA response at 3 mo was associated with the use of next-generation imaging and PSA

Abstract Macular holes (MHs), including atraumatic idiopathic and refractory MHs, affect central vision acuity due to full-thickness defects in the retinal tissue. The existing controversy regarding the pathophysiology and management of MHs has significantly improved with the implementation of internal limiting membrane (ILM) surgical techniques and improved MH closure rates. Thus, to determine the effect of ILM techniques on large idiopathic and refractory MH management, the present study systematically reviewed 5910 original research articles extracted from online literature databases, including PubMed, Cochrane, Google Scholar, and Embase, following the PRISMA guidelines. The primary outcome measures were MH closure rate and postoperative visual acuity. A total of 23 randomized controlled trials (RCTs) with adequate patient information and information on the effect of ILM peeling, inverted ILM flaps, autologous retinal transplantation (ART), and ILM insertion techniques on large idiopathic and refractory MH patients were retrieved and analyzed using RevMan software (version 5.3) provided by the Cochrane Collaboration. Statistical risk of bias analysis was also conducted on the selected sources using RoB2, which showed a low risk of bias in the included studies. A meta-analysis indicated that the inverted ILM flap technique had a significantly greater MH closure rate for primary MH than the other treatment methods (OR = 3. 22, 95% CI 1.34–7.43; p = 0.01). Furthermore, the findings showed that the inverted ILM flap group had significantly better postoperative visual acuity than did the other treatment options for patients with idiopathic MH (WMD = − 0.13; 95% CI = 0.22–0.09; p = 0.0002). The ILM peeling technique had the second highest statistical significance for MH closure rates in patients with idiopathic MH (OR = 2. 72, 95% CI: 1.26–6.32; p = 0.016). In refractory MHs, autologous retinal transplant (ART) and multilayer ILM plug (MIP) techniques improve the closure rate and visual function; human amniotic membrane grafting (hAMG) provides a high degree of anatomical outcomes but disappointing visual results. This study demonstrated the reliability and effectiveness of ILM techniques in improving the functional and anatomical outcomes of large idiopathic and refractory MH surgery. These findings will help clinicians choose the appropriate treatment technique for patients with idiopathic and refractory MH.

Abstract Several studies published so far used highly selective image datasets from unclear sources to train computer vision models and that may lead to overestimated results, while those studies conducted in real-life remain scarce. To avoid image selection bias, we stacked convolutional and recurrent neural networks (CNN-RNN) to analyze complete optical coherence tomography (OCT) cubes in a row and predict diabetic macular edema (DME), in a real-world diabetic retinopathy screening program. A retrospective cohort study was carried out. Throughout 4-years, 5314 OCT cubes from 4408 subjects who attended to the diabetic retinopathy (DR) screening program were included. We arranged twenty-two (22) pre-trained CNNs in parallel with a bidirectional RNN layer stacked at the bottom, allowing the model to make a prediction for the whole OCT cube. The staff of retina experts built a ground truth of DME later used to train a set of these CNN-RNN models with different configurations. For each trained CNN-RNN model, we performed threshold tuning to find the optimal cut-off point for binary classification of DME. Finally, the best models were selected according to sensitivity, specificity, and area under the receiver operating characteristics curve (AUROC) with their 95% confidence intervals (95%CI). An ensemble of the best models was also explored. 5188 cubes were non-DME and 126 were DME. Three models achieved an AUROC of 0.94. Among these, sensitivity, and specificity (95%CI) ranged from 84.1–90.5 and 89.7–93.3, respectively, at threshold 1, from 89.7–92.1 and 80–83.1 at threshold 2, and from 80.2–81 and 93.8–97, at threshold 3. The ensemble model improved these results, and lower specificity was observed among subjects with sight-threatening DR. Analysis by age, gender, or grade of DME did not vary the performance of the models. CNN-RNN models showed high diagnostic accuracy for detecting DME in a real-world setting. This engine allowed us to detect extra-foveal DMEs commonly overlooked in other studies, and showed potential for application as the first filter of non-referable patients in an outpatient center within a population-based DR screening program, otherwise ended up in specialized care.

Abstract Background To our knowledge, only one study has examined the association between glucose variability (GV) and mortality in the elderly population with diabetes. GV was assessed by HbA1c, and a J-shaped curve was observed in the relationship between HbA1c thresholds and mortality. No study of GV was conducted during the COVID-19 pandemic and its lockdown. This study aims to evaluate whether GV is an independent predictor of all-cause mortality in patients aged 75 years or older with and without COVID-19 who were followed during the first year of the COVID-19 pandemic and its lockdown measures. Methods This was a retrospective cohort study of 407,492 patients from the AGED-MADRID dataset aged 83.5 (SD 5.8) years; 63.2% were women, and 29.3% had diabetes. GV was measured by the coefficient of variation of fasting plasma glucose (CV-FPG) over 6 years of follow-up (2015–2020). The outcome measure was all-cause mortality in 2020. Four models of logistic regression were performed, from simple (age, sex) to fully adjusted, to assess the effect of CV-FPG on all-cause mortality. Results During follow-up, 34,925 patients died (14,999 women and 19,926 men), with an all-cause mortality rate of 822.3 per 10,000 person-years (95% confidence interval (CI), 813.7 to 822.3) (739 per 10,000; 95% CI 728.7 to 739.0 in women and 967.1 per 10,000; 95% CI 951.7 to 967.2 in men). The highest quartile of CV-FPG was significantly more common in the deceased group (40.1% vs. 23.6%; p

Abstract Objective Duchenne and Becker muscular dystrophies (DMD and BMD) are dystrophinopathies caused by variants in DMD gene, resulting in reduced or absent dystrophin. These conditions, characterized by muscle weakness, also manifest central nervous system (CNS) comorbidities due to dystrophin expression in the CNS. Prior studies have indicated a higher prevalence of epilepsy in individuals with dystrophinopathy compared to the general population. Our research aimed to investigate epilepsy prevalence in dystrophinopathies and characterize associated electroencephalograms (EEGs) and seizures. Methods We reviewed 416 individuals with dystrophinopathy, followed up at three centers between 2010 and 2023, to investigate the lifetime epilepsy prevalence and characterize EEGs and seizures in those individuals diagnosed with epilepsy. Associations between epilepsy and type of dystrophinopathy, genotype, and cognitive involvement were studied. Results Our study revealed a higher epilepsy prevalence than the general population (1.4%; 95% confidence interval: 0.7–3.2%), but notably lower than previously reported in smaller dystrophinopathy cohorts. No significant differences were found in epilepsy prevalence between DMD and BMD or based on underlying genotypes. Cognitive impairment was not found to be linked to higher epilepsy rates. The most prevalent epilepsy types in dystrophinopathies resembled those observed in the broader pediatric population, with most individuals effectively controlled through monotherapy. Interpretation The actual epilepsy prevalence in dystrophinopathies may be markedly lower than previously estimated, possibly half or even less. Our study provides valuable insights into the epilepsy landscape in individuals with dystrophinopathy, impacting medical care, especially for those with concurrent epilepsy.

Postoperative pain management is challenging. We used mice with a transverse laparotomy to study tactile allodynia measured by the von Frey test, pain at rest measured by facial pain expressions detected by an artificial intelligence algorithm, and movement-induced pain measured by reductions in exploratory activity. The standard analgesics morphine and ibuprofen induced distinct patterns of outcome-dependent effects. Whereas morphine was more effective in reversing pain at rest compared to tactile allodynia, it was unable to alter movement-induced pain. Ibuprofen showed comparable effects across the three outcomes. Administered together, the compounds induced synergistic effects in the three aspects of postoperative pain, mirroring the known advantages of multimodal analgesia used in clinical practice. We explored the impact of neuroimmune interactions using a neutrophil depletion strategy. This reversed pain at rest and movement-induced pain, but did not alter cutaneous sensitivity. Non-peptidergic (IB4+) and peptidergic (CGRP+) nociceptors are segregated neuronal populations in the mouse. We tested the effects of gefapixant, an antitussive drug targeting non-peptidergic nociceptors through P2X3 antagonism, and olcegepant, an antimigraine drug acting as a CGRP antagonist. Both compounds reversed tactile allodynia, while only gefapixant reversed pain at rest, and none of them reversed movement-induced pain. In conclusion, tactile allodynia, pain at rest, and movement-induced pain after surgery have different pharmacological profiles, and none of the three aspects of postoperative pain can predict the effects of a given intervention on the other two. Combining these measures provides a more realistic view of postoperative pain and has the potential to benefit analgesic development.

IntroductionDementia comprise a broad spectrum of cognitive declines affecting 47 million people worldwide, with numbers projected to reach 131 million by 2050. Predominantly associated with older adults, dementia can also impact younger individuals, having a significant impact on daily functioning of the affected patients, relatives, caregivers and the socioeconomic system. Recent research underscores the utility of social media, particularly X (previously designed as Twitter), in understanding public perceptions and sentiments related to neurological disorders. Despite some initial studies have explored social perceptions of dementia in X, broader and deeper analysis of this condition is still warranted.Materials and methodsIn this retrospective study, we collected and examined all tweets posted in English or Spanish from 2007 to 2023 that mentioned dementia and compare the information with other highly representative neurological disorders like migraines, epilepsy, multiple sclerosis, spinal cord injury, or Parkinson's disease. We developed a codebook to analyze tweets, classifying them by themes such as trivialization, treatment perceptions, and etiopathogenesis. Manually categorized tweets trained machine learning models, BERTWEET for English and BETO for Spanish, which then classified larger datasets with high accuracy. Statistical analysis, including ANOVA, Kruskal-Wallis, and chi-square tests, was conducted to explore linguistic and cultural differences in perceptions of neurological disorders, with results visualized.ResultsOur study reveals that dementia is by far the most frequently discussed neurological disorder on X. Likewise, this condition appears to be the most trivialized neurological disorder in Spanish tweets and the second most trivialized in English tweets, with notable differences in geolocation data. Additionally, we found significant differences in perceptions of dementia treatment and associated sentiments between Spanish and English tweets. Furthermore, our study identified varying perceptions of medical content (etiology) and non-medical content (positive/negative experiences and aid requests) related to dementia and other neurological disorders, unveiling a complex landscape of these topics on X.ConclusionsThis study explores the importance of X as a social platform for addressing various critical issues related to dementia, comparing it with other neurological disorders in English and Spanish tweets. Future research could further investigate the valuable role of social media in understanding public perceptions and needs regarding dementia and neurological disorders among X users.

Introducción: Las úlceras genitales constituyen un reto diagnóstico por sus múltiples etiologías. Uno de los casos a tener en cuenta en la población femenina son las úlceras de Lipschu?tz. El objetivo es presentar dos casos que se diagnosticaron en el año 2022 en una institución de tercer nivel en Boyacá, Colombia. Caso clínico 1: Paciente de 16 años. Ingresa por cuadro de 5 días con fiebre y aparición de lesiones ulceradas en el área genital. Se tomaron laboratorios para infecciones de transmisión sexual, negativos, con virus Epstein Barr IgG positiva. Se hospitalizó para tratamiento analgésico y antibiótico, y ante la sospecha de infecciones asociadas se tomó la decisión de llevar a desbridamiento y toma de biopsia. Ante la notable mejoría, se dio egreso días después. Caso clínico 2: Paciente de 19 años con discapacidad auditiva y visual, perteneciente a comunidad indígena. Acude por presencia de lesión genital de evolución desconocida. Se solicitaron laboratorios para descartar infecciones de transmisión sexual, Epstein Barr y Leishmania. Se tomó biopsia para descartar malignidad, con resultados negativos. Dermatología considera que se trata de úlcera de Lipschu?tz, se ajusta manejo ambulatorio y se le da egreso. Conclusiones: La identificación temprana de las lesiones en la región genital en las pacientes menores de edad mejora la sintomatología, tranquiliza a las jóvenes y sus familiares, descarta la asociación con enfermedades de transmisión sexual y disminuye procedimientos e ingresos hospitalarios en ocasiones innecesarios.

The objective conditions of people's lives have historically played a greater role than subjective perceptions. However, this trend is shifting, accompanied by an ongoing debate about life satisfaction and urbanization. This research has two objectives, the first is to test the hypothesis of the urban paradox. The second is to analyze the differences in the determinants of life satisfaction by urbanization levels. In order to determine the degrees of urbanization, a geographic grid was used to distinguish between rural, intermediate, and urban areas. In addition, a multi-group analysis in structural equation models with partial least squares was conducted to analyze the determinants of life satisfaction. The model has been developed using three general determinants: economic situation, health, and social relations, which has been applied to a case study of the Region of Murcia. The database used for this study includes 2462 samples. The population living in rural areas showed less life satisfaction. Regarding the determinants, it was found that health acts as a partial mediator of social relations. Differences were also observed in the intensity of the determinants according to the degree of urbanization. Thus, the degree of urbanization acts as a moderator of life satisfaction. This research is noteworthy because it provides valuable insights for guiding regional public policies.

When analyzing occupational safety factors, a human factor is associated with 80–90% of incidents and accidents that occur. Controlling this factor is essential when it comes to creating healthy and safe organizations. Personality traits have shown great relevance when understanding the behavior of safety or self-protection in the workplace, affecting the motivation of subjects and, therefore, their behavior. The objective of this study is to analyze the influence of the extraversion trait on compliance with safety rules and behaviors, while evaluating the mediating effect of motivation for safety in health professionals. The sample is composed of 183 nurses and wardens of a hospital in Spain. The obtained results confirm the hypotheses raised, validating the negative influences of extraversion on motivation for security and compliance with norms, behaviors, and security, while verifying the effect of the total mediation of motivation for security in the influence of extraversion on security compliance. This confirms the effect of this personality trait on employees’ safety behaviors, and the possibility of reducing this influence by controlling personal motivations with interventions from the organization.

Abstract Background Sepsis can lead to coagulopathy and microvascular thrombosis. Prior studies, including ours, reported an increased level of extracellular vimentin in blood derived from septic patients. Moreover, we identified the contribution of extracellular vimentin to fibrin formation and to the fibrin clot structure ex vivo in plasma from septic patients. Here, we tested the status of plasma vimentin and its impact on fibrin clots using our recently described swine model of methicillin-resistant Staphylococcus aureus (MRSA) sepsis-induced coagulopathy. Results We employed ELISA, size-exclusion chromatography, vimentin antibodies, confocal microscopy, and turbidity assays on piglet plasma obtained at pre- and post-MRSA inoculation. Plasma vimentin level at 70 h post-MRSA inoculation was on average twofold higher compared to pre-infection (0 h) level in the same animal. Anti-vimentin antibody effectively reduced fibrin formation ex vivo and increased porosity in the fibrin clot structure generated from septic piglet plasma. In contrast to plasma at 0 h, the size-exclusion chromatography revealed that phosphorylated vimentin was in-complex with fibrinogen in septic piglet plasma. Conclusions Thus, our swine model of sepsis-induced coagulopathy, reproduced increased extracellular circulating vimentin and subsequent potentiation of fibrin formation, often observed in septic patient. These outcomes validate the use of large animal models to investigate the dysregulated host immune response to infection leading to coagulopathy, and to develop new therapies for sepsis-induced disseminated microvascular thrombosis.

Abstract Skin inflammation with the potential sequel of moist epitheliolysis and edema constitute the most frequent breast radiotherapy (RT) acute side effects. The aim of this study was to compare the predictive value of tissue-derived radiomics features to the total breast volume (TBV) for the moist cells epitheliolysis as a surrogate for skin inflammation, and edema. Radiomics features were extracted from computed tomography (CT) scans of 252 breast cancer patients from two volumes of interest: TBV and glandular tissue (GT). Machine learning classifiers were trained on radiomics and clinical features, which were evaluated for both side effects. The best radiomics model was a least absolute shrinkage and selection operator (LASSO) classifier, using TBV features, predicting moist cells epitheliolysis, achieving an area under the receiver operating characteristic (AUROC) of 0.74. This was comparable to TBV breast volume (AUROC of 0.75). Combined models of radiomics and clinical features did not improve performance. Exclusion of volume-correlated features slightly reduced the predictive performance (AUROC 0.71). We could demonstrate the general propensity of planning CT-based radiomics models to predict breast RT-dependent side effects. Mammary tissue was more predictive than glandular tissue. The radiomics features performance was influenced by their high correlation to TBV volume.

Abstract Background Health disparities have been highlighted among patient with prostate adenocarcinoma (PRAD) due to ethnicity. Mexican men present a more aggressive disease than other patients resulting in less favorable treatment outcome. We aimed to identify the mutational landscape which could help to reduce the health disparities among minority groups and generate the first genomics exploratory study of PRAD in Mexican patients. Methods Paraffin-embedded formalin-fixed tumoral tissue from 20 Mexican patients with early-stage PRAD treated at The Instituto Nacional de Cancerología, Mexico City from 2017 to 2019 were analyzed. Tumoral DNA was prepared for whole exome sequencing, the resulting files were mapped against h19 using BWA-MEM. Strelka2 and Lancet packages were used to identify single nucleotide variants (SNV) and insertions or deletions. FACETS was used to determine somatic copy number alterations (SCNA). Cancer Genome Interpreter web interface was used to determine the clinical relevance of variants. Results Patients were in an early clinical stage and had a mean age of 59.55 years (standard deviation [SD]: 7.1 years) with 90% of them having a Gleason Score of 7. Follow-up time was 48.50 months (SD: 32.77) with recurrences and progression in 30% and 15% of the patients, respectively. NUP98 (20%), CSMD3 (15%) and FAT1 (15%) were the genes most frequently affected by SNV; ARAF (75%) and ZNF419 (70%) were the most frequently affected by losses and gains SNCA’s. One quarter of the patients had mutations useful as biomarkers for the use of PARP inhibitors, they comprise mutations in BRCA, RAD54L and ATM. SBS05, DBS03 and ID08 were the most common mutational signatures present in this cohort. No associations with recurrence or progression were identified. Conclusions This pilot study reveals the mutational landscape of early-stage prostate adenocarcinoma in Mexican men, providing a first approach to understand the mutational patterns and actionable mutations in early prostate cancer can inform personalized treatment approaches and reduce the underrepresentation in genomic cancer studies.

Abstract Background Reproducibility is a major concern in biomedical studies, and existing publication guidelines do not solve the problem. Batch effects and quality imbalances between groups of biological samples are major factors hampering reproducibility. Yet, the latter is rarely considered in the scientific literature. Results Our analysis uses 40 clinically relevant RNA-seq datasets to quantify the impact of quality imbalance between groups of samples on the reproducibility of gene expression studies. High-quality imbalance is frequent (14 datasets; 35%), and hundreds of quality markers are present in more than 50% of the datasets. Enrichment analysis suggests common stress-driven effects among the low-quality samples and highlights a complementary role of transcription factors and miRNAs to regulate stress response. Preliminary ChIP-seq results show similar trends. Quality imbalance has an impact on the number of differential genes derived by comparing control to disease samples (the higher the imbalance, the higher the number of genes), on the proportion of quality markers in top differential genes (the higher the imbalance, the higher the proportion; up to 22%) and on the proportion of known disease genes in top differential genes (the higher the imbalance, the lower the proportion). We show that removing outliers based on their quality score improves the resulting downstream analysis. Conclusions Thanks to a stringent selection of well-designed datasets, we demonstrate that quality imbalance between groups of samples can significantly reduce the relevance of differential genes, consequently reducing reproducibility between studies. Appropriate experimental design and analysis methods can substantially reduce the problem.

Abstract Analyzing changes in gene expression within specific brain regions of individuals with Type 2 Diabetes (T2DM) who do not exhibit significant cognitive deficits can yield valuable insights into the mechanisms underlying the progression towards a more severe phenotype. In this study, transcriptomic analysis of the cortex and hippocampus of mice with long-term T2DM revealed alterations in the expression of 28 genes in the cerebral cortex and 15 genes in the hippocampus. Among these genes, six displayed consistent changes in both the cortex and hippocampus: Interferon regulatory factor 7 (Irf7), Hypoxia-inducible factor 3 alpha (Hif-3α), period circadian clock 2 (Per2), xanthine dehydrogenase (Xdh), and Transforming growth factor β-stimulated clone 22/TSC22 (Tsc22d3) were upregulated, while Claudin-5 (Cldn5) was downregulated. Confirmation of these changes was achieved through RT-qPCR. At the protein level, CLDN5 and IRF7 exhibited similar alterations, with CLDN5 being downregulated and IRF7 being upregulated. In addition, the hippocampus and cortex of the T2DM mice showed decreased levels of IκBα, implying the involvement of NF-κB pathways as well. Taken together, these results suggest that the weakening of the blood-brain barrier and an abnormal inflammatory response via the Interferon 1 and NF-κB pathways underlie cognitive impairment in individuals with long-standing T2DM

Anthropogenic pressures on marine ecosystems are increasing worldwide, causing loss of biodiversity and ecosystem functioning, and driving species towards risk of extinction. To protect vulnerable species and habitats, Marine Protected Areas (MPAs) are increasingly established worldwide as conservation measures. Seahorses act as flagship species for coastal ecosystem conservation due to their charismatic appearance and high vulnerability to habitat degradation. Here, the habitat suitability of the two European seahorse species, Hippocampus hippocampus and Hippocampus guttulatus, was assessed along the western Iberian Peninsula, using an ensemble species distribution modelling approach. Furthermore, the coverage of their core habitat (relative habitat suitability (HS) ≥ 0.5) with MPAs was estimated. The results show that the main drivers for habitat suitability were distance to the coast, aspect of the seafloor, tidal amplitude, and temperature. However, the importance differed between the two species. The suitable habitat of H. hippocampus extended to higher distances to the coast, while H. guttulatus were mostly restricted to areas in the vicinity of the coast and facing away from the open sea (i.e., the westerly aspect of the seafloor). Furthermore, temperature contributes more to the variation in habitat suitability in H. hippocampus than in H. guttulatus. The areas with the highest habitat suitability are estuarine or inlet waters and sheltered coasts in northwestern Spain, central and south of Portugal. Both species’ core habitats are covered by about 19–20 % with implemented protected areas in Portugal. In comparison, there is less coverage for both species in Spain, with 12 % for H. guttulatus and 6 % for H. hippocampus. Besides, zones of full protection cover less than 0.5 % of the core habitat while the rest of the protected areas provide only moderate to low restrictions and do not specifically address the protection of seahorses in their management plans. The results provide useful information on the distribution and the different habitat preferences of the two species, indications for further monitoring of populations, and recommendations for efficient spatial conservation areas that can protect the species and other associated vulnerable species and habitats.

La diversidad de metodologías existentes para definir y analizar la dinámica de las superficies de agua muestra la dificultad que genera investigar su comportamiento, aunado a que existen variables que dificultan su delimitación tales como la precipitación o la evapotranspiración. Este trabajo tuvo como objetivo analizar la dinámica espaciotemporal de humedales de alto impacto socioambiental en la Cuenca Baja del Rio Grijalva para el periodo de 1986 a 2018. Para el análisis se integró una base de datos satelital con 169 imágenes de Landsat 5 y Landsat 8. Se calcularon índices espectrales (MNDWI y MBWI) y se identificaron los umbrales que caracterizan las superficies de agua en el área en estudio. Los resultados mostraron que el MBWI fue superior en la estimación de superficies de agua. Finalmente, se generaron los mapas de probabilidades de la dinámica espaciotemporal en los humedales de mayor importancia ecológica y económica de la CBRG. Estos mapas revelaron los periodos de retorno de los procesos de expansión y retroceso longitudinal en los humedales y que en periodos de la Niña la formación de los humedales temporales podría estar asociado a la saturación del manto freático y no a los aportes superficiales.

Abstract The pan-immune-inflammation value (PIV), calculated as (neutrophil × platelet × monocyte)/lymphocyte count, may be useful for estimating survival in breast cancer patients. To determine the prognostic value of PIV for overall survival in breast cancer patients in Lima, Peru. A retrospective cohort study was conducted. 97 breast cancer patients diagnosed between January 2010 and December 2016 had their medical records analyzed. The primary dependent variable was overall survival, and the key independent variable was the PIV, divided into high (≥ 310) and low (

Abstract Emergency medical services (EMSs) face critical situations that require patient risk classification based on analytical and vital signs. We aimed to establish clustering-derived phenotypes based on prehospital analytical and vital signs that allow risk stratification. This was a prospective, multicenter, EMS-delivered, ambulance-based cohort study considering six advanced life support units, 38 basic life support units, and four tertiary hospitals in Spain. Adults with unselected acute diseases managed by the EMS and evacuated with discharge priority to emergency departments were considered between January 1, 2020, and June 30, 2023. Prehospital point-of-care testing and on-scene vital signs were used for the unsupervised machine learning method (clustering) to determine the phenotypes. Then phenotypes were compared with the primary outcome (cumulative mortality (all-cause) at 2, 7, and 30 days). A total of 7909 patients were included. The median (IQR) age was 64 (51–80) years, 41% were women, and 26% were living in rural areas. Three clusters were identified: alpha 16.2% (1281 patients), beta 28.8% (2279), and gamma 55% (4349). The mortality rates for alpha, beta and gamma at 2 days were 18.6%, 4.1%, and 0.8%, respectively; at 7 days, were 24.7%, 6.2%, and 1.7%; and at 30 days, were 33%, 10.2%, and 3.2%, respectively. Based on standard vital signs and blood test biomarkers in the prehospital scenario, three clusters were identified: alpha (high-risk), beta and gamma (medium- and low-risk, respectively). This permits the EMS system to quickly identify patients who are potentially compromised and to proactively implement the necessary interventions.

Abstract We present a flora and fauna dataset for the Mira-Mataje binational basins. This is an area shared between southwestern Colombia and northwestern Ecuador, where both the Chocó and Tropical Andes biodiversity hotspots converge. We systematized data from 120 sources in the Darwin Core Archive (DwC-A) standard and geospatial vector data format for geographic information systems (GIS) (shapefiles). Sources included natural history museums, published literature, and citizen science repositories across 13 countries. The resulting database has 33,460 records from 6,821 species, of which 540 have been recorded as endemic, and 612 as threatened. The diversity represented in the dataset is equivalent to 10% of the total plant species and 26% of the total terrestrial vertebrate species in both hotspots. The dataset can be used to estimate and compare biodiversity patterns with environmental parameters and provide value to ecosystems, ecoregions, and protected areas. The dataset is a baseline for future assessments of biodiversity in the face of environmental degradation, climate change, and accelerated extinction processes.

Abstract The agronomic use of compost and biochar as soil amendments may exhibit contrasting results in terms of soil fertility and plant nutrition. The effects of the biennial application of biochar, compost and a blend of compost:biochar (90:10; % dw:dw) on the agronomical performance of an organically managed and well established 25-year-old olive orchard was assessed 5 years after the initial application. The agronomical evaluation was based on the assessment of the soil physical, chemical, and biological characteristics, and the assessment of the soil fertility by both crop production and nutritional status of the orchard, and the bioassay with olive plantlets. Biochar mainly benefited the physical properties (bulk density, total porosity, aeration, water retention capacity) of soil, especially in the top 0–5 cm. Compost and its blend with biochar improved microbial activity, soil nutritional status (increasing the content of soluble organic C, N, and P) and favoured the formation of aggregates in soil. The bioassay conducted with young plantlets confirmed the enhanced soil fertility status in the three amended treatments, particularly in the case of biochar and its blend with compost. However, this effect was not significantly observed in the adult plants after 5 years of application, reflecting the slow response of adult olive trees to changes in fertilization. Based on these results, alongside the desirable long-residence time of biochar in soil and the ready availability of compost, the blend of biochar with compost assayed in this study is defined as a valid strategy for preparing high quality soil organic amendments.

Abstract In this study, we investigate deviations from the Planck- $$\Lambda $$ Λ CDM model in the late universe ( $$z \lesssim 2.5$$ z ≲ 2.5 ) using the Gaussian Processes method, with minimal assumptions. Our goal is to understand where exploring new physics in the late universe is most relevant. We analyze recent Cosmic Chronometers (CC), Type Ia Supernovae (SN), and Baryon Acoustic Oscillations (BAO) data. By examining reconstructions of the dimensionless parameter $$\delta (z)$$ δ ( z ) , which measures deviations of the Hubble parameter from the Planck- $$\Lambda $$ Λ CDM predictions, we identify intriguing features at low ( $$z \lesssim 0.5$$ z ≲ 0.5 ) and high ( $$z \gtrsim 2$$ z ≳ 2 ) redshifts. Deviations from the Planck- $$\Lambda $$ Λ CDM model were not significant between $$0.5\lesssim z \lesssim 2$$ 0.5 ≲ z ≲ 2 . Using the combined CC+SN+BAO dataset, we gain insights into dark energy (DE) dynamics, resembling characteristics of omnipotent DE, extending beyond quintessence and phantom models. DE exhibits n-quintessence traits for $$z\gtrsim 2$$ z ≳ 2 , transitioning with a singularity around $$z\sim 2$$ z ∼ 2 to usual phantom traits in $$1\lesssim z\lesssim 2$$ 1 ≲ z ≲ 2 . DE characteristics differ between scenarios ( $$H_0$$ H 0 -SH0ES and $$H_0$$ H 0 - $$\Lambda $$ Λ &CMB), with $$H_0$$ H 0 -SH0ES leaning towards phantom traits and $$H_0$$ H 0 - $$\Lambda $$ Λ &CMB towards quintessence. We suggest exploring new physics at $$z\lesssim 0.5$$ z ≲ 0.5 and $$1.5\lesssim z\lesssim 2.5$$ 1.5 ≲ z ≲ 2.5 , particularly around $$z = 2$$ z = 2 , to understand cosmological tensions such as $$H_0$$ H 0 and $$S_8$$ S 8 .

Abstract Water pollution and antimicrobial resistance (AMR) have become two global threats; 80% of diseases and 50% of child deaths are due to poor water quality. In this study, hydrothermal processing was employed to manufacture manganese oxide nanorods. Silver dopant was deposited on the surface of manganese oxide. XRD diffractogram confirmed the facile synthesis of Ag/Mn2O3 nanocomposite. XPS survey analysis demonstrated silver content of 9.43 atom %. Photocatalytic measurements demonstrated the outstanding efficiency of the Ag-Mn2O3 compared to virgin oxide particles under visible radiation. Degradation efficiencies Mn2O3 and Ag/Mn2O3 on methyl orange (MO) dye was found to be 53% and 85% under visible spectrum. Silver dopant was found to decrease the binding energy of valence electrons; this action could support electron–hole pair generation under visible spectrum and could promote catalytic performance. Ag/Mn2O3 NPs demonstrated most effective performance (95% removal efficiency) at pH 3; this could be ascribed to the electrostatic attraction between positively charged catalyst and the negatively charged MO. Ag/Mn2O3 demonstrated enhanced antibacterial activity against Gram-positive Staphylococcus aureus (S. aureus) (19 mm ZOI), and Gram-negative Escherichia coli (E. coli) (22 mm ZOI) respectively; the developed nanocomposite demonstrated advanced anti-film activity with inhibition percentage of 95.5% against E. coli followed by 89.5% against S. aureus.

Abstract Impaired ion channels regulating Golgi pH lead to structural alterations in the Golgi apparatus, such as fragmentation, which is found, along with cognitive impairment, in Alzheimer’s disease. However, the causal relationship between altered Golgi structure and cognitive impairment remains elusive due to the lack of understanding of ion channels in the Golgi apparatus of brain cells. Here, we identify that a transmembrane protein TMEM87A, renamed Golgi-pH-regulating cation channel (GolpHCat), expressed in astrocytes and neurons that contributes to hippocampus-dependent memory. We find that GolpHCat displays unique voltage-dependent currents, which is potently inhibited by gluconate. Additionally, we gain structural insights into the ion conduction through GolpHCat at the molecular level by determining three high-resolution cryogenic-electron microscopy structures of human GolpHCat. GolpHCat-knockout mice show fragmented Golgi morphology and altered protein glycosylation and functions in the hippocampus, leading to impaired spatial memory. These findings suggest a molecular target for Golgi-related diseases and cognitive impairment.

Abstract Purines and their derivatives control intracellular energy homeostasis and nucleotide synthesis, and act as signaling molecules. Here, we combine structural and sequence information to define a purine-binding motif that is present in sensor domains of thousands of bacterial receptors that modulate motility, gene expression, metabolism, and second-messenger turnover. Microcalorimetric titrations of selected sensor domains validate their ability to specifically bind purine derivatives, and evolutionary analyses indicate that purine sensors share a common ancestor with amino-acid receptors. Furthermore, we provide experimental evidence of physiological relevance of purine sensing in a second-messenger signaling system that modulates c-di-GMP levels.

Abstract Hereditary fructose intolerance (HFI) is a painful and potentially lethal genetic disease caused by a mutation in aldolase B resulting in accumulation of fructose-1-phosphate (F1P). No cure exists for HFI and treatment is limited to avoid exposure to fructose and sugar. Using aldolase B deficient mice, here we identify a yet unrecognized metabolic event activated in HFI and associated with the progression of the disease. Besides the accumulation of F1P, here we show that the activation of the purine degradation pathway is a common feature in aldolase B deficient mice exposed to fructose. The purine degradation pathway is a metabolic route initiated by adenosine monophosphate deaminase 2 (AMPD2) that regulates overall energy balance. We demonstrate that very low amounts of fructose are sufficient to activate AMPD2 in these mice via a phosphate trap. While blocking AMPD2 do not impact F1P accumulation and the risk of hypoglycemia, its deletion in hepatocytes markedly improves the metabolic dysregulation induced by fructose and corrects fat and glycogen storage while significantly increasing the voluntary tolerance of these mice to fructose. In summary, we provide evidence for a critical pathway activated in HFI that could be targeted to improve the metabolic consequences associated with fructose consumption.

Abstract Teratoma, due to its remarkable ability to differentiate into multiple cell lineages, is a valuable model for studying human embryonic development. The similarity of the gene expression and chromatin accessibility patterns in these cells to those observed in vivo further underscores its potential as a research tool. Notably, teratomas derived from human naïve (pre-implantation epiblast-like) pluripotent stem cells (PSCs) have larger embryonic cell diversity and contain extraembryonic lineages, making them more suitable to study developmental processes. However, the cell type-specific epigenetic profiles of naïve PSC teratomas have not been yet characterized. Using single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq), we analyzed 66,384 cell profiles from five teratomas derived from human naïve PSCs and their post-implantation epiblast-like (primed) counterparts. We observed 17 distinct cell types from both embryonic and extraembryonic lineages, resembling the corresponding cell types in human fetal tissues. Additionally, we identified key transcription factors specific to different cell types. Our dataset provides a resource for investigating gene regulatory programs in a relevant model of human embryonic development.

Abstract Background Abiotic factors play a significant role in the evolution of Leishmania infantum infection due to its vectorial nature. This study aims to assess the evolution in the detection of new L. infantum infection cases in Valdeorras (Ourense, Northwestern Spain) over a 20-year period and how different climatic variables and preventive measures may have affected it. Methods Indirect immunofluorescence antibody tests (IFAT) were performed on serum samples collected from dogs attending the ‘Servicios Veterinarios de Sil’ veterinary clinic (Valdeorras, Northwestern Spain) between May 2003 and April 2023 to detect L. infantum exposure. The percentage of new cases of L. infantum infection was calculated from May of one year to April of the following year. Climatic conditions in the region, global sales of ectoparasiticides and the number of vaccines against L. infantum delivered in the veterinary clinic from 2003 to 2022 were recorded. Statistical analyses were conducted to determine the associations between these factors and the percentage of new cases of L. infantum infection. Results A total of 2909 dogs were assessed, and 3785 IFAT tests were performed between May 2003 and April 2023. The mean percentage of new seropositive cases over the 20-year period studied was 21.65 ± 10.8%, with a decline from the beginning to the end of the period studied. The percentage was significantly higher between May 2003 and April 2008 compared with the other periods (May 2008 to April 2013, May 2013 to April 2018 and May 2018 to April 2023). There was a positive correlation between the percentage of new cases of L. infantum infection and the maximum relative humidity in winter. Conversely, there was a negative correlation between the percentage of new cases and sales of ectoparasiticides and vaccination against L. infantum. Conclusions This study is one of the longest evaluations of the evolution of L. infantum infection in a fixed location and its association with external factors including climatic conditions and preventive measures. The results confirm that Valdeorras is a high-risk area for L. infantum infection. The use of ectoparasiticides and vaccines against L. infantum has been shown to play a significant role in preventing L. infantum infection, highlighting the crucial role of veterinarians in the fight against this disease. Graphical Abstract

Abstract Background Inherited retinal dystrophies (IRD) are one of the main causes of incurable blindness worldwide. IRD are caused by mutations in genes that encode essential proteins for the retina, leading to photoreceptor degeneration and loss of visual function. IRD generates an enormous global financial burden due to the lack of understanding of a significant part of its pathophysiology, molecular diagnosis, and the near absence of non-palliative treatment options. Patient-derived induced pluripotent stem cells (iPSC) for IRD seem to be an excellent option for addressing these questions, serving as exceptional tools for in-depth studies of IRD pathophysiology and testing new therapeutic approaches. Methods From a cohort of 8 patients with PROM1-related IRD, we identified 3 patients carrying the same variant (c.1354dupT) but expressing three different IRD phenotypes: Cone and rod dystrophy (CORD), Retinitis pigmentosa (RP), and Stargardt disease type 4 (STGD4). These three target patients, along with one healthy relative from each, underwent comprehensive ophthalmic examinations and their genetic panel study was expanded through clinical exome sequencing (CES). Subsequently, non-integrative patient-derived iPSC were generated and fully characterized. Correction of the c.1354dupT mutation was performed using CRISPR/Cas9, and the genetic restoration of the PROM1 gene was confirmed through flow cytometry and western blotting in the patient-derived iPSC lines. Results CES revealed that 2 target patients with the c.1354dupT mutation presented monoallelic variants in genes associated with the complement system or photoreceptor differentiation and peroxisome biogenesis disorders, respectively. The pluripotency and functionality of the patient-derived iPSC lines were confirmed, and the correction of the target mutation fully restored the capability of encoding Prominin-1 (CD133) in the genetically repaired patient-derived iPSC lines. Conclusions The c.1354dupT mutation in the PROM1 gene is associated to three distinct AR phenotypes of IRD. This pleotropic effect might be related to the influence of monoallelic variants in other genes associated with retinal dystrophies. However, further evidence needs to be provided. Future experiments should include gene-edited patient-derived iPSC due to its potential as disease modelling tools to elucidate this matter in question. Graphical Abstract

ABSTRACT: Cheese is a food in which toxic concentrations of biogenic amines (BA) may be reached, mainly as a consequence of the decarboxylation of determined amino acids by certain lactic acid bacteria (LAB). To maintain the food safety of cheese, environmentally friendly strategies are needed that specifically prevent the growth of BA-producing LAB and the accumulation of BA. The bacteriocins produced by LAB are natural compounds with great potential as food biopreservatives. This work examines the antimicrobial potential of 7 bacteriocin-containing, cell-free supernatants (CFS: coagulin A-CFS, enterocin A-CFS, enterocin P-CFS, lacticin 481-CFS, nisin A-CFS, nisin Z-CFS and plantaricin A-CFS) produced by LAB against 48 strains of the LAB species largely responsible for the accumulation of the most important BA in cheese, that is, histamine, tyramine, and putrescine. Susceptibility to the different CFS was strain-dependent. The histamine-producing species with the broadest sensitivity spectrum were Lentilactobacillus parabuchneri (the species mainly responsible for the accumulation of histamine in cheese) and Pediococcus parvulus. The tyramine-producing species with the broadest sensitivity spectrum was Enterococcus faecium, and Enterococcus faecalis and Enterococcus hirae were among the most sensitive putrescine producers. Nisin A-CFS was active against 31 of the 48 BA-producing strains (the broadest antimicrobial spectrum recorded). Moreover, commercial nisin A prevented biofilm formation by 67% of the BA-producing, biofilm-forming LAB strains. These findings underscore the potential of bacteriocins in the control of BA-producing LAB and support the use of nisin A as a food-grade biopreservative for keeping BA-producing LAB in check and reducing BA accumulation in cheese.

Background: The bipolar disorder (BD) is a severe, disabling mental disorder characterized by phases of mania, hypomania, or depression. The present quasi-experimental study of 21 BD patients (Mage = 44 years, SD = 11.45, 6% women) compared the efficacy of a mutual aid group (MAG) with a MAG that followed a mindfulness-based intervention (MAG+M) over 6 weeks. Method: Both groups were evaluated pre-test and post-test with the following variables: depression, mania, anxiety, mindfulness, and psychological acceptance. Results: Pretest and post-test intragroup analyses showed that MAG+M improved significantly in measures of depression (z = -2.31, p = .02) and trait anxiety (z = -2.43, p = .01), while MAG did not improve in any of the measures. There were no statistically significant differences between groups in the post-test. Conclusions: Our findings suggest that mindfulness meditation may improve symptoms of depression and anxiety in a MAG for BD patients.