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Abstract Aims The initial bundle of cares strongly affects haemodynamics and outcomes in acute decompensated heart failure cardiogenic shock (ADHF‐CS). We sought to characterize whether 24 h haemodynamic profiling provides superior prognostic information as compared with admission assessment and which haemodynamic parameters best predict in‐hospital death. Methods and results All patients with ADHF‐CS and with available admission and 24 h invasive haemodynamic assessment from two academic institutions were considered for this study. The primary endpoint was in‐hospital death. Regression analyses were run to identify relevant predictors of study outcome. We included 127 ADHF‐CS patients [65 (inter‐quartile range 52–72) years, 25.2% female]. Overall, in‐hospital mortality occurred in 26.8%. Non‐survivors were older, with greater CS severity. Among admission variables, age [odds ratio (OR) = 1.06; 95% confidence interval (CI): 1.02–1.11; Padj = 0.005] and CPIRAP (OR = 0.62 for 0.1 increment; 95% CI: 0.39–0.95; Padj = 0.034) were found significantly associated with in‐hospital death. Among 24 h haemodynamic univariate predictors of in‐hospital death, pulmonary elastance (PaE) was the strongest (area under the curve of 0.77; 95% CI: 0.68–0.86). PaE (OR = 5.98; 95% CI: 2.29–17.48; Padj

Background: Distinguishing between Charcot Neuroarthropathy (CN), osteomyelitis (OM), and CN complicated with superimposed OM in diabetic patients is crucial for the treatment choice. Given that current diagnostic methods lack specificity, advanced techniques, e.g., magnetic resonance imaging (MRI) and 99mTc-HMPAO–WBC Single Photon Emission Computed Tomography (SPECT/CT), are needed. This study addresses the challenges in distinguishing OM and CN. Methods: We included diabetic patients with CN and soft tissue ulceration. MRI and 99mTc-HMPAO–WBC SPECT/CT were used for the diagnosis. The patients were classified into three probability levels for OM (i.e., Definite, Probable, and Unlikely) according to the Consensus Criteria for Diabetic Foot Osteomyelitis (CC-DFO). Results: Eight patients met the eligibility criteria. MRI, supported by SPECT-CT and CC-DFO, showed consistency with the OM diagnosis in three cases. The key diagnostic features included the location of signal abnormalities and secondary features such as skin ulcers, sinus tracts, and abscesses. Notably, cases with inconclusive MRI were clarified by SPECT/CT, emphasizing its efficacy in challenging scenarios. Conclusions: The primary objective of this study was to compare the results of MRI and 99mTc-HMPAO–WBC SPECT/CT with the CC-DFO score in the diabetic foot with CN and suspected OM. Advanced imaging offers a complementary approach to distinguish between CN and OM. This can help delineate the limits of the disease for presurgical planning. While MRI is valuable, 99mTc-HMPAO–WBC SPECT/CT provides additional clarity, especially in challenging cases or when metallic implants affect MRI accuracy.

ABSTRACT Introduction: All forms of access to the peritoneal cavity in laparoscopy could damage intra-abdominal structures. Currently, ultrasound (USG) is being used in several procedures to guide needles: breast biopsy, central venous access puncture, anesthetic nerve blocks, etc. Therefore, this research seeks to verify the feasibility and viability of performing pneumoperitoneum using USG-guided puncture in a pilot study using a porcine model. Methods: The cross-sectional study was carried out with a sample of 10 anesthetized sows in the IRCAD-América Latina Barretos Unit laboratory. The experiment consisted of an abdominal puncture guided by USG with a linear transducer to create the pneumoperitoneum. After the puncture, the drop test was performed, and CO2 was insufflated into the cavity. Subsequently, a 10mm trocar was introduced to insert the optic. The parameters from the USG were the thickness of the abdominal wall layers, intraperitoneal needle measurement, drop test, and the presence of complications. Results: The average measurement of the layers was 0.45 centimeters of subcutaneous tissue, 0.67 centimeters of muscle, and 0.15 centimeters of peritoneum. The mean measurement of the intraperitoneal needle was 1.17cm. Furthermore, the drop test was positive in 100% of cases, and there was no bleeding or lesions on any attempt. Conclusion: Ultrasound-guided pneumoperitoneum is feasible and safe in the porcine model. The subcutaneous, muscular, and peritoneum layers are identifiable and measurable in this model. Subsequent studies are necessary to verify the importance of this new procedure.

Piper is widely distributed in subtropical regions and species of this genus are known for their potent pharmacological activities. Piper arboreum Aubl. is a traditional medicinal plant popularly known as "pau-de-angola", "jaborandi", and chili pepper, demonstrating antifungal, trypanocidal, antibacterial, and antioxidant activities. The leaves of P. arboreum were extracted using Soxhlet and dichloromethane to obtain the extract, which was then fractionated using solvents of different polarities. Samples were analyzed using ultra-high-performance liquid chromatography coupled with mass spectrometry equipped with an electrospray ionization source. Antifungal microdilution assays were performed, and scanning and transmission electron microscopy were used to assess the invasion of the pretreated nail. The minimum inhibitory concentration (MIC) values of the extract and a dichloromethane fraction were, respectively, 62.5 μg/ml and 16.0 μg/ml against Trichophyton rubrum, and 125 μg/ml and 62.5 μg/ml, and 500 μg/ml and 500 μg/ml against T. mentagrophytes, and Microsporum gypseum, respectively. No growth was observed on nail fragments exposed to the extract (at concentrations > 64 µg/ml and then inoculated with spore suspension. Transmission electron microscopy revealed strong inhibition of hyphal growth and an irregular growth pattern following treatment with the extract and the dichloromethane fraction. Results demonstrated the antifungal properties of the P. arboreum extract and its dichloromethane fraction against dermatophytes, with the identification of three different alkaloid compounds. The cytotoxicity was specific towards the fungal cells, and morphological and ultrastructural analyses indicated damage to the cell wall and cytoplasmic membrane as the potential mechanism of action. The leaf material used to generate the extract can be taken from the plant without any detrimental effect thus enabling strategies to be implemented for the exploitation of this species.

Abstract The classic ketogenic diet is an effective treatment option for drug-resistant epilepsy, but its high fat content challenges patient compliance. Optimizing liver ketone production guided by a method comparing substrates for their ketogenic potential may help to reduce the fat content of the diet without loss in ketosis induction. Here, we present a liver cell assay measuring the β-hydroxybutyrate (βHB) yield from fatty acid substrates. Even chain albumin-conjugated fatty acids comprising between 4 and 18 carbon atoms showed a sigmoidal concentration-βHB response curve (CRC) whereas acetate and omega-3 PUFAs produced no CRC. While CRCs were not distinguished by their half-maximal effective concentration (EC50), they differed by maximum response, which related inversely to the carbon chain length and was highest for butyrate. The assay also suitably assessed the βHB yield from fatty acid blends detecting shifts in maximum response from exchanging medium chain fatty acids for long chain fatty acids. The assay further detected a dual role for butyrate and hexanoic acid as ketogenic substrate at high concentration and ketogenic enhancer at low concentration, augmenting the βHB yield from oleic acid and a fatty acid blend. The assay also found propionate to inhibit ketogenesis from oleic acid and a fatty acid blend at low physiological concentration. Although the in vitro assay shows promise as a tool to optimize the ketogenic yield of a fat blend, its predictive value requires human validation.

Abstract Background The mesenchymal subtype of colorectal cancer (CRC), associated with poor prognosis, is characterized by abundant expression of the cellular prion protein PrPC, which represents a candidate therapeutic target. How PrPC is induced in CRC remains elusive. This study aims to elucidate the signaling pathways governing PrPC expression and to shed light on the gene regulatory networks linked to PrPC. Methods We performed in silico analyses on diverse datasets of in vitro, ex vivo and in vivo models of mouse CRC and patient cohorts. We mined ChIPseq studies and performed promoter analysis. CRC cell lines were manipulated through genetic and pharmacological approaches. We created mice combining conditional inactivation of Apc in intestinal epithelial cells and overexpression of the human prion protein gene PRNP. Bio-informatic analyses were carried out in two randomized control trials totalizing over 3000 CRC patients. Results In silico analyses combined with cell-based assays identified the Wnt-β-catenin and glucocorticoid pathways as upstream regulators of PRNP expression, with subtle differences between mouse and human. We uncover multiple feedback loops between PrPC and these two pathways, which translate into an aggravation of CRC pathogenesis in mouse. In stage III CRC patients, the signature defined by PRNP-CTNNB1-NR3C1, encoding PrPC, β-catenin and the glucocorticoid receptor respectively, is overrepresented in the poor-prognosis, mesenchymal subtype and associates with reduced time to recurrence. Conclusions An unleashed PrPC-dependent vicious circle is pathognomonic of poor prognosis, mesenchymal CRC. Patients from this aggressive subtype of CRC may benefit from therapies targeting the PRNP-CTNNB1-NR3C1 axis.

IntroductionWhile autonomic failure is a well-known prognostic factor for more aggressive disease progression in Parkinson's disease (PD), with a three- to sevenfold higher risk of dementia and death within 10 years after the diagnosis, the individual impact of cardiovascular, gastrointestinal, urogenital, thermoregulatory, and pupillomotor autonomic domains on PD clinical outcomes remains unclear.ObjectivesWe sought to determine the 5-year risk of developing dementia, falls, postural instability, dysarthria, and dysphagia in PD patients with and without autonomic impairment at baseline and to assess the joint and individual association of each autonomic domain on these key functional outcomes. In addition, we aimed to determine the impact of each autonomic domain on activities of daily living (ADLs) and health-related quality of life (HRQoL).MethodsWe enrolled 65 consecutive PD patients in a 5-year cohort study involving standardized evaluations of autonomic symptoms, orthostatic hypotension, and motor and non-motor features, including cognitive function. Associations were estimated as odds ratio and adjusted for PD duration, age, and baseline motor impairment.ResultsCardiovascular dysautonomia was associated with a sevenfold higher risk of developing dementia (95%CI: 1.154-50.436; p = 0.035) and a fivefold higher risk of falls (95%CI: 1.099-18.949; p = 0.039), as well as significantly higher impairment in ADLs (p = 0.042) and HRQoL (p = 0.031). No relevant associations were found between the other autonomic domains and these outcomes.ConclusionsCardiovascular dysautonomia, but not other domains, showed an association with worse 5-year clinical outcomes in PD. Our data suggest a specific role for cardiovascular autonomic dysregulation in the pathogenic mechanisms of PD progression.

Abstract Epilepsy is a chronic and heterogenous disease characterized by recurrent unprovoked seizures, that are commonly resistant to antiseizure medications. This study applies a transcriptome network-based approach across epilepsies aiming to improve understanding of molecular disease pathobiology, recognize affected biological mechanisms and apply causal reasoning to identify therapeutic hypotheses. This study included the most common drug-resistant epilepsies (DREs), such as temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), and mTOR pathway-related malformations of cortical development (mTORopathies). This systematic comparison characterized the global molecular signature of epilepsies, elucidating the key underlying mechanisms of disease pathology including neurotransmission and synaptic plasticity, brain extracellular matrix and energy metabolism. In addition, specific dysregulations in neuroinflammation and oligodendrocyte function were observed in TLE-HS and mTORopathies, respectively. The aforementioned mechanisms are proposed as molecular hallmarks of DRE with the identified upstream regulators offering opportunities for drug-target discovery and development.

Background/Objectives: Endometriosis (END) is a painful gynecological condition. Clinical examination, imaging, and laparoscopy can provide a definitive diagnosis of END. Nonetheless, non-invasive biomarkers could help enhance and streamline the diagnostic process. Micro-RNAs (miRNAs), a family of small non-coding RNAs, could serve as useful non-invasive biomarkers for END. The aim of this study was to perform serum miRNA profiling in a retrospective cohort of women to identify miRNAs that are differentially expressed in END compared to control patients. Methods: RNA was isolated from serum samples of 67 END patients and 60 control women. The expression profile of a 754-miRNA panel was studied with RT-qPCR performed on a QuantStudio 12K Flex with the TaqMan OpenArray miRNA panel. A Censored Regression Model was used for miRNA differential expression analysis. Several gene-enrichment algorithms were employed to identify pathways related to the target genes of differentially expressed miRNAs. Results: One hundred and thirty miRNAs were detected in at least 75% of samples from either the END or the control group. Sixteen miRNAs were significantly modulated between the END and control groups. Enrichment analysis identified targets significantly overrepresented in numerous pathways involved in biological processes related to END, including inflammation, angiogenesis, cellular invasion, cell-cycle/cell proliferation, and estrogen and progesterone hormonal signaling. Conclusions: Our study indicates that differentially expressed miRNAs between END patients and controls can be identified through liquid biopsy. Our findings also suggest a potential role for serum miRNAs in the pathophysiology of END, warranting further investigations for their use as non-invasive biomarkers.

Context. One of the long-term goals of exoplanet science is the atmospheric characterization of dozens of small exoplanets in order to understand their diversity and search for habitable worlds and potential biosignatures. Achieving this goal requires a space mission of sufficient scale that can spatially separate the signals from exoplanets and their host stars and thus directly scrutinize the exoplanets and their atmospheres.Aims. We seek to quantify the exoplanet detection performance of a space-based mid-infrared (MIR) nulling interferometer that measures the thermal emission of exoplanets. We study the impact of various parameters and compare the performance with that of large single-aperture mission concepts that detect exoplanets in reflected light.Methods. We have developed an instrument simulator that considers all major astrophysical noise sources and coupled it with Monte Carlo simulations of a synthetic exoplanet population around main-sequence stars within 20 pc of the Sun. This allows us to quantify the number (and types) of exoplanets that our mission concept could detect. Considering single visits only, we discuss two different scenarios for distributing 2.5 yr of an initial search phase among the stellar targets. Different apertures sizes and wavelength ranges are investigated.Results. An interferometer consisting of four 2 m apertures working in the 4–18.5 μ.m wavelength range with a total instrument throughput of 5% could detect up to ≈550 exoplanets with radii between 0.5 and 6 R⊕ with an integrated S/N ≥ 7. At least ≈160 of the detected exoplanets have radii ≤1.5 R⊕. Depending on the observing scenario, ≈25–45 rocky exoplanets (objects with radii between 0.5 and 1.5 R⊕) orbiting within the empirical habitable zone (eHZ) of their host stars are among the detections. With four 3.5 m apertures, the total number of detections can increase to up to ≈770, including ≈60–80 rocky eHZ planets. With four times 1 m apertures, the maximum detection yield is ≈315 exoplanets, including ≤20 rocky eHZ planets. The vast majority of small, temperate exoplanets are detected around M dwarfs. The impact of changing the wavelength range to 3–20 μm or 6–17 μm on the detection yield is negligible.Conclusions. A large space-based MIR nulling interferometer will be able to directly detect hundreds of small, nearby exoplanets, tens of which would be habitable world candidates. This shows that such a mission can compete with large single-aperture reflected light missions. Further increasing the number of habitable world candidates, in particular around solar-type stars, appears possible via the implementation of a multi-visit strategy during the search phase. The high median S/N of most of the detected planets will allow for first estimates of their radii and effective temperatures and will help prioritize the targets for a second mission phase to obtain high-S/N thermal emission spectra, leveraging the superior diagnostic power of the MIR regime compared to shorter wavelengths.

Introdução: O diabetes mellitus tipo 2 (DM2) é uma das doenças crônicas mais prevalentes em todo o mundo, devido à maior frequência de estilos de vida pouco saudáveis. O ômega-3 (w-3) possui ação anti-inflamatória e podem ser eficazes na prevenção e tratamento do DM2, portanto, o objetivo do estudo foi analisar as evidências do efeito da suplementação de w-3 em indivíduos com DM2. Materiais e Métodos: Foi realizada uma revisão integrativa da literatura foi conduzida sobre o papel da suplementação de w-3 em indivíduos com DM2. Foram consultadas as bases de dados Pubmed e Bireme, utilizando os descritores “type 2, Diabetes Mellitus” e “acids, omega-3 fatty”. Foram incluídos no estudo ensaios clínicos randomizados disponíveis na íntegra, publicados nos últimos cinco anos, que abordaram os efeitos da suplementação oral de ômega-3 em indivíduos com DM2. Foram encontrados 100 artigos e oito artigos foram selecionados e analisados. Resultados: A suplementação de w-3 em indivíduos com DM2 resultou na diminuição de triglicerídeos séricos, índice aterogênico, IL-6, MCP-1, leptina, HOMA-IR, aumentou o a atividade do PPAR-γ e HDL-c. Os parâmetros de glicemia, hemoglobina glicada, insulina, LDL-c, status antioxidante foram controversos. Conclusão: A suplementação de w-3 em indivíduos com DM2, tem ação hipotrigliceridêmica, reduz o índice aterogênico e citocinas inflamatórias, melhorando a resistência insulínica, o perfil lipídico e inflamatório dos indivíduos, enquanto os efeitos na glicemia ainda são controversos.

Objectives To evaluate the efficacy of mandibular advancement devices (MADs) in improving apnea-hypopnea index (AHI) in positional obstructive sleep apnea (POSA), compared with a control group of nonpositional OSA (NPOSA) patients, from mild to very severe degree, in order to to find the main variables characterizing the examined group as potential predictors of treatment success.

In high-metallicity environments the mass that black holes (BHs) can reach just after core collapse widely depends on how much mass their progenitor stars lose via winds. On one hand, new theoretical and observational insights suggest that early-stage winds should be weaker than what many canonical models prescribe. On the other hand, the proximity to the Eddington limit should affect the formation of optically thick envelopes already during the earliest stages of stars with initial masses M _ZAMS ≳ 100 M _⊙ , hence resulting in higher mass-loss rates during the main sequence. We use the evolutionary codes MESA and Genec to calculate a suite of tracks for massive stars at solar metallicity Z _⊙ = 0.014, which incorporate these changes in our wind-mass-loss prescription. In our calculations we employ moderate rotation, high overshooting, and magnetic angular momentum transport. We find a maximum BH mass ${M}_{\mathrm{BH},\max }=28.3$ M _⊙ at Z _⊙ . The most massive BHs are predicted to form from stars with M _ZAMS ≳ 250 M _⊙ , with the BH mass directly proportional to its progenitor’s M _ZAMS . We also find in our models that at Z _⊙ almost any BH progenitor naturally evolves into a Wolf–Rayet star due to the combined effect of internal mixing and wind mass loss. These results are considerably different from most recent studies regarding the final mass of stars before their collapse into BHs. While we acknowledge the inherent uncertainties in stellar evolution modeling, our study underscores the importance of employing the most up-to-date physics in BH mass predictions.

The study of temporal changes in riparian vegetation is essential for understanding the paths taken by the ecosystem during ecological succession. In order to evaluate the changes in floristic composition, structure, and dynamics of the arboreal vegetation in an area of Semideciduous Seasonal Alluvial Forest, we aim to understand the secondary succession that occurs in the Paraná River floodplain. Based on a study conducted 20 years ago, in the municipality of Batayporã, Mato Grosso do Sul, a re-sampling was carried out in the same area, using the same methodology. Phytosociological and ecological parameters between the two temporal samplings were collected and compared using Student's ‘t’ test, where it was possible to find statistically significant variations (p

Background & Aims: Axin1 is a negative regulator of wingless-type MMTV integration site family, member 1 (Wnt)/β-catenin signaling with tumor-suppressor function. The Wnt pathway has a critical role in the intestine, both during homeostasis and cancer, but the role of Axin1 remains elusive. Methods: We assessed the role of Axin1 in normal intestinal homeostasis, with control, epithelial-specific, Axin1-knockout mice (Axin1ΔIEC) and Axin2-knockout mice. We evaluated the tumor-suppressor function of Axin1 during chemically induced colorectal tumorigenesis and dextran sulfate sodium–induced colitis, and performed comparative gene expression profiling by whole-genome RNA sequencing. The clinical relevance of the Axin1-dependent gene expression signature then was tested in a database of 2239 clinical colorectal cancer (CRC) samples. Results: We found that Axin1 was dispensable for normal intestinal homeostasis and redundant with Axin2 for Wnt pathway down-regulation. Axin1 deficiency in intestinal epithelial cells rendered mice more susceptible to chemically induced colon carcinogenesis, but reduced dextran sulfate sodium–induced colitis by attenuating the induction of a proinflammatory program. RNA-seq analyses identified an interferon γ/T-helper1 immune program controlled by Axin1 that enhances the inflammatory response and protects against CRC. The Axin1-dependent gene expression signature was applied to human CRC samples and identified a group of patients with potential vulnerability to immune checkpoint blockade therapies. Conclusions: Our study establishes, in vivo, that Axin1 has redundant function with Axin2 for Wnt down-regulation and infers a new role for Axin1. Physiologically, Axin1 stimulates gut inflammation via an interferon γ/Th1 program that prevents tumor growth. Linked to its T-cell–mediated effect, the colonic Axin1 signature offers therapeutic perspectives for CRC.