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Introduction: Peripheral neurofilament light chain (NfL) reflect neuronal and axonal damage. Most studies have been focused on NfL cerebrospinal fluid measures since peripheral levels were difficult to detect. However, with recent advent of single molecule array (SIMOA) technology, NfL is now detectable peripherally at small concentrations (pg/ml). In neurodegenerative disorders, NfL peripheral levels have been found significantly elevated compared against psychiatric disorders. However, there is still controversy of whether NfL peripheral levels might be altered in psychiatric disorders like major depressive disorder (MDD) when compared against a normal population., Methods: We have measured NfL plasma levels by using single molecule array (SIMOA) technology in a Spanish small cohort of MDD patients (n = 15) and a HC group (n = 15). We have used subjective scales to estimate depression severity (HDRS), anhedonia (SAAS), the general cognitive state (MMSE) and episodic memory (FCSRT) in MDD patients., Results: We have not detected a significant alteration in NfL plasma levels in MDD patients when compared against the HC subjects (U = 97, p-value = 0.532). Moreover, we have not detected any significant correlation between NfL plasma levels with any subjective scales. The only parameter that significantly and positively correlated with NfL plasma levels was age in both MDD and HC., Discussion: Significant alteration in NfL plasma levels in MDD patients might reflect neurobiological changes behind the predisposition to develop future neurodegenerative disorders such as Alzheimer's or Parkinson's diseases for which depression represents a risk factor. However, whether there is an increase in NfL due to MDD regardless of the ageing process is still a matter of debate., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fernández-Pereira, Fernández-Ceballos, Olivares, Prieto-González and Agís-Balboa.)

The study aimed to identify precompetitive anxiety profiles and analyze the impact of those profiles in their reasons to adhere to running. A sample of 473 Spanish Amateur Athletes participated in the study. Results revealed the emergence of three profiles: (a) a high precompetitive anxiety profile characterized by high cognitive and somatic anxiety and low self-confidence; (b) a precompetitive medium-low anxiety profile characterized by medium-low scores in cognitive and somatic anxiety and medium self-confidence; (c) a precompetitive low anxiety profile characterized by low scores in cognitive and somatic anxiety and medium self-confidence. Results showed that most of the working runners, who participate in ten-kilometer races, who practice three days a week, and most experienced runners, belonged to the extremely low anxiety profile. In conclusion, the precompetitive low anxiety profile reported the most suited outcomes which mean that is a more adaptive profile.

Recent advances in multiple sclerosis (MS) management have shifted perspectives on treatment strategies, advocating for the early initiation of high-efficacy disease-modifying therapies (heDMTs). This perspective review discusses the rationale, benefits, and challenges associated with early heDMT initiation, reflecting on the obsolescence of the traditional "first-line" and "second-line" treatment classifications. The article emerges from the last update of the consensus document of the Spanish Society of Neurology on the treatment of MS. During its development, there was a recognized need to further discuss the concept of treatment lines and the early use of heDMTs. Evidence from randomized controlled trials and real-world studies suggests that early heDMT initiation leads to improved clinical outcomes, including reduced relapse rates, slowed disease progression, and decreased radiological activity, especially in younger patients or those in early disease stages. Despite the historical belief that heDMTs involve more risks and adverse events compared to moderate-efficacy DMTs (meDMTs), some studies have reported comparable safety profiles between early heDMTs and meDMTs, though long-term safety data are still lacking. The review also addresses the need for a personalized approach based on patient characteristics, prognostic factors, and preferences, explores the importance of therapeutic inertia, and highlights the evolving landscape of international and national guidelines that increasingly advocate for early intensive treatment approaches. The article also addresses the challenges of ensuring access to these therapies and the importance of further research to establish long-term safety and effectiveness of DMTs in MS., (© The Author(s), 2024.)

Background: People with secondary progressive multiple sclerosis (pwSPMS) experience increasing disability, which impacts negatively on their health-related quality of life (HRQoL). Our aims were to assess the impact of secondary progressive multiple sclerosis (SPMS) on functional status and HRQoL and describe the clinical profile in this population., Methods: DISCOVER is an observational, cross-sectional, multicenter study with retrospective data collection in real-world clinical practice in Spain. Sociodemographic and clinical variables, functional and cognitive scales, patient-reported outcomes (PROs), and direct healthcare, and non-healthcare and indirect costs were collected., Results: A total of 297 evaluable pwSPMS with a EDSS score between 3-6.5 participated: 62.3 % were female and 18.9 % had active SPMS. At the study visit, 77 % of them presented an Expanded Disability Scale Score (EDSS) of 6-6.5. Nearly 40 % did not receive any disease-modifying treatment. Regarding the working situation, 61.6 % were inactive due to disability. PROs: 99.3 % showed mobility impairment in EuroQoL-5 Dimensions-5 Levels, and about 60 % reported physical impact on the Multiple Sclerosis Impact Scale-29. Fatigue was present in 76.1 %, and almost 40 % reported anxiety or depression. The Symbol Digit Modalities Test was used to assess cognitive impairment; 80 % of the patients were below the mean score. Participants who presented relapses two years before and had high EDSS scores had a more negative impact on HRQoL. PwSPMS with a negative impact on HRQoL presented a higher cost burden, primarily due to indirect costs., Conclusions: PwSPMS experience a negative impact on their HRQoL, with a high physical impact, fatigue, cognitive impairment, and a high burden of indirect costs., Competing Interests: Declaration of competing interest None, (Copyright © 2024. Published by Elsevier B.V.)

Sawfly species of the genus Monophadnus are specialised on Ranunculaceae plants from which the larvae can sequester furostanol saponins into the haemolymph, mainly (25 R )-26-[(α-L-rhamnopyranosyl)oxy]-22α-methoxyfurost-5-en-3β-yl- O -β-D-glucopyranosyl-(1→3)- O -[6-acetyl-β-D-glucopyranosyl-(1→3)]- O -β-D-glucopyranoside (compound 1 ). In this work, TLC, GC-MS, and HPLC-DAD-ESI/MS analyses together with feeding, repeated simulated attacks, and ant deterrence bioassays were conducted to extend the chemoecological knowledge about two sawfly species specialised on H. foetidus L. ( Monophadnus species A) and H. viridis L. ( Monophadnus species B). Larvae of Monophadnus species B were mostly feeding on the squares treated with the n -butanol fraction from H. foetidus , compound 1 being its primary non-nutritional stimulant. In contrast, all H. viridis fractions stimulated feeding, with n -hexane marginally more active. β-sitosterol within n -hexane was determined as the nutritional stimulant. Quantitative analyses demonstrated that leaves of H. viridis but not H. foetidus contain the ecdysteroids 20-hydroxyecdysone and polypodine B. Moreover, the haemolymph of Monophadnus species B larvae reared on H. viridis contained the glycosides of polypodine B and 20-hydroxyecdysone at a concentration of 2.5 to 6.8 µmol/g fresh weight of haemolymph. This concentration is several thousand times higher than the concentration range of the aglycones in their host plant (3.63 × 10 -4 to 2.23 × 10 -4 µmol total ecdysteroids/g fresh weight of leaves), suggesting bioaccumulation. The larvae of both species fed on H. foetidus do not show any traces of ecdysteroids in their haemolymph, indicating a facultative role of these compounds in their defence as well as their inability to endogenously synthesise these compounds. The haemolymph containing ecdysteroids was a significant feeding deterrent against Myrmica rubra L. ant workers (one of their natural predators) at 0.8 mg/mL. The larvae kept effective deterrent levels of glycosylated ecdysteroids (≅175 mM) between simulated attacks on days 1 and 2, but the levels clearly decreased on day 3 (≅75 mM). Most larvae (89%) survived a first attack but only 23% a consecutive second one. As a conclusion, we report for the first time that two Monophadnus species feeding on H. viridis sequester phytoecdysteroids into the larval haemolymph in the form of glycosides. In addition, compound 1 possesses defensive and phagostimulant activities, and we present evidence for a combined effect of furostanol saponins and ecdysteroids as repellents against ants.

Multiple sclerosis (MS) is a multifaceted neurological condition characterized by challenges in timely diagnosis and personalized patient management. The application of Artificial Intelligence (AI) to MS holds promises for early detection, accurate diagnosis, and predictive modeling. The objectives of this study are: 1) to propose new MS trajectory descriptors that could be employed in Machine Learning (ML) regressors and classifiers to predict patient evolution; 2) to explore the contribution of ML models in discerning MS trajectory descriptors using only baseline Magnetic Resonance Imaging (MRI) studies. This study involved 446 MS patients who had a baseline MRI, at least two measurements of Expanded Disability Status Scale (EDSS), and a 1-year follow-up. Patients were divided into two groups: 1) for model development and 2) for evaluation. Three descriptors: β1, β2, and EDSS(t), were related to baseline MRI parameters using regression and classification XGBoost models. Shapley Additive Explanations (SHAP) analysis enhanced model transparency by identifying influential features. The results of this study demonstrate the potential of AI in predicting MS progression using the proposed patient trajectories and baseline MRI scans, outperforming classic Multiple Linear Regression (MLR) methods. In conclusion, MS trajectory descriptors are crucial; incorporating AI analysis into MRI assessments presents promising opportunities to advance predictive capabilities. SHAP analysis enhances model interpretation, revealing feature importance for clinical decisions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Campanioni et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Hyperthyroidism is the most common feline endocrinopathy. In hyperthyroid humans, untargeted metabolomic analysis identified persistent metabolic derangements despite achieving a euthyroid state. Therefore, we sought to define the metabolome of hyperthyroid cats and identify ongoing metabolic changes after treatment. We prospectively compared privately-owned hyperthyroid cats (n = 7) admitted for radioactive iodine (I-131) treatment and euthyroid privately-owned control (CON) cats (n = 12). Serum samples were collected before (T0), 1-month (T1), and three months after (T3) I-131 therapy for untargeted metabolomic analysis by MS/MS. Hyperthyroid cats (T0) had a distinct metabolic signature with 277 significantly different metabolites than controls (70 increased, 207 decreased). After treatment, 66 (T1 vs. CON) and 64 (T3 vs. CON) metabolite differences persisted. Clustering and data reduction analysis revealed separate clustering of hyperthyroid (T0) and CON cats with intermediate phenotypes after treatment (T1 & T3). Mevalonate/mevalonolactone and creatine phosphate were candidate biomarkers with excellent discrimination between hyperthyroid and healthy cats. We found several metabolic derangements (e.g., decreased carnitine and α-tocopherol) do not entirely resolve after achieving a euthyroid state after treating hyperthyroid cats with I-131. Further investigation is warranted to determine diagnostic and therapeutic implications for candidate biomarkers and persistent metabolic abnormalities., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Bechtold et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Recent meta-analyses and randomized studies have shown that among patients with acute ischemic stroke undergoing endovascular thrombectomy, general anesthesia with mechanical ventilation is associated with better functional status compared to local anesthesia and sedation, and they recommend its use. But once the procedure is completed, when is the optimal moment for extubation? Currently, there are no guidelines recommending the optimal moment for extubation. Prolonged mechanical ventilation time could potentially be linked to increased complications such as pneumonia or disturbances in cerebral blood flow due to the vasodilatation produced by most anesthetic drugs. However, premature extubation in a patient who has suffered a stroke could led to complications such as agitation, disorientation, abolished reflexes, sudden fluctuations in blood pressure, alterations in cerebral blood flow, respiratory distress, bronchial aspiration, and the need for reintubation. We therefore designed a randomized study hypothesizing that early compared with delayed extubation is associated with a better functional outcome 3 months after endovascular thrombectomy treatment under general anesthesia for acute ischemic stroke., Methods: This investigator-initiated, single-center, prospective, parallel, evaluated blinded, superiority, randomized controlled trial will include 178 patients with a proximal occlusion of the anterior circulation treated with successful endovascular thrombectomy (TICI 2b-3) under general anesthesia. Patients will be randomly allocated to receive early (< 6 h) or delayed (6-12 h) extubation after the procedure. The primary outcome measure is functional independence (mRS of 0-2) at 90 days, measured with the modified Rankin Score (mRS), ranging from 0 (no symptoms) to 6 (death)., Discussion: This will be the first trial to compare the effect of mechanical ventilation duration (early vs delayed extubation) after satisfactory endovascular thrombectomy for acute ischemic stroke under general anesthesia., Trial Registration: The study protocol was approved April 11, 2023, by the by the Santiago-Lugo Research Ethics Committee (CEI-SL), number 2023/127, and was registered into the clinicaltrials.gov clinical trials registry with No. NCT05847309. Informed consent is required. Participant recruitment begins on April 18, 2023. The results will be submitted for publication in a peer-reviewed journal and presented at one or more scientific conferences., (© 2024. The Author(s).)

Introduction: Bipolar disorder (BD) is a recurrent and disabling psychiatric disorder related to low-grade peripheral inflammation and altered levels of the members of the insulin-like growth factor (IGF) family. The aim of this study was to evaluate the plasma levels of IGF-2, insulin-like growth factor-binding protein 1 (IGFBP-1), IGFBP-3, IGFBP-5, IGFBP-7, and inflammatory markers such as tumor necrosis factor α (TNF-α), monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory protein 1β (MIP-1β). Methods: We used the Young Mania Rating Scale (YMRS) to determine the severity of the symptomatology, while proteins were measured by enzyme-linked immunosorbent assay (ELISA). We included 20 patients with BD who suffered a manic episode and 20 controls. Some BD patients ( n = 10) were evaluated after a period (17 ± 8 days) of pharmacological treatment. Results: No statistical difference was found in IGF-2, IGFBP-1, IGFBP-7, TNF-α, and MIP-1β levels. However, IGFBP-3 and IGFBP-5 levels were found to be statistically decreased in BD patients. Conversely, the MCP-1 level was significantly increased in BD patients, but their levels were normalized after treatment. Intriguingly, only IGFBP-1 levels were significantly decreased after treatment. No significant correlation was found between the YMRS and any of the proteins studied either before or after treatment or between IGF proteins and inflammatory markers. Discussion: To some extent, IGFBP-3 and IGFBP-5 might be further explored as potential indicators of treatment responsiveness or diagnosis biomarkers in BD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fernández-Pereira, Penedo, Alonso-Núñez, Rivera-Baltanás, Viéitez, Prieto-González, Vilariño-Vilariño, Olivares, Ortolano and Agís-Balboa.)

Introduction: The Spasticity-Plus Syndrome (SPS) in multiple sclerosis (MS) refers to a combination of spasticity and other signs/symptoms such as spasms, cramps, bladder dysfunction, tremor, sleep disorder, pain, and fatigue. The main purpose is to develop a user-friendly tool that could help neurologists to detect SPS in MS patients as soon as possible., Methods: A survey research based on a conjoint analysis approach was used. An orthogonal factorial design was employed to form 12 patient profiles combining, at random, the eight principal SPS signs/symptoms. Expert neurologists evaluated in a survey and a logistic regression model determined the weight of each SPS sign/symptom, classifying profiles as SPS or not., Results: 72 neurologists participated in the survey answering the conjoint exercise. Logistic regression results of the survey showed the relative contribution of each sign/symptom to the classification as SPS. Spasticity was the most influential sign, followed by spasms, tremor, cramps, and bladder dysfunction. The goodness of fit of the model was appropriate (AUC = 0.816). Concordance between the experts' evaluation vs. model estimation showed strong Pearson's ( r  = 0.936) and Spearman's ( r  = 0.893) correlation coefficients. The application of the algorithm provides with a probability of showing SPS and the following ranges are proposed to interpret the results: high (> 60%), moderate (30-60%), or low (< 30%) probability of SPS., Discussion: This study offers an algorithmic tool to help healthcare professionals to identify SPS in MS patients. The use of this tool could simplify the management of SPS, reducing side effects related with polypharmacotherapy., Competing Interests: ÓF has received honoraria in the past as consultant in advisory boards, and as chairmen or lecturer in meetings, and has also participated or participates at present in clinical trials and other research projects promoted by Biogen, Bayer, Merck-Serono, Teva, Novartis, Actelion, Almirall, Roche, Allergan, Horizon, and Ala Diagnostics. LC-F has served at scientific advisory boards, participated in meetings sponsored by and received speaking honoraria or travel funding or research grants from Biogen, Bristol-Myers Squibb, Janssen, Horizon, Merck-Serono, Novartis, Roche and Sanofi. MM has received honoraria as speaker, consultant in advisory boards, travel support or research grants from Merck, Biogen, Novartis, Sanofi-Genzyme, Almirall, Viatris, Horizon, Bristol-Myers Squibb, Roche, Sandoz and Janssen. PM has received compensation for consulting services and speaking fees from Allergan, Almirall, Biogen, Merz and Sanofi. JP has served as consultant, speaker and/or moderator for Bayer Pharmaceuticals, Biogen, Bristol-Myers Squibb, Daiichi Sankyo, Genzyme Corporation, Janssen, Merck Serono, Novartis, Sanofi, Sandoz, Teva, Roche Pharma, Almirall and Celgene. LR-T has received compensation for consulting services and speaking fees from Biogen, Novartis, Bayer, Merck, Sanofi, Genzyme, Roche, Bristol-Myers Squibb, Teva and Janssen. AM has received honoraria for scientific and commercial activities from Biogen, Teva, Merck, Sanofi, Novartis, Roche, Almirall, and Mylan. YA has received research grants, travel support and lecturing and consulting fees from Bayer, Biogen, Roche, Merck, Novartis, Almirall, Sanofi-Genzyme, Janssen and Bristol-Myers Squibb. AA has received honoraria as a speaker or advisor from Almirall, Biogen, Bristol-Myers Squibb, Janssen, Merck, Novartis, Roche and Sanofi. EÁ has received collaborations and fees for participation in advisories, scientific and educational activities from Almirall, Biogen, Janssen Cilag, Sanofi-Genzyme, Merck, Novartis, Roche and Teva. AL-F reports no disclosures relevant to the manuscript. LL has received collaborations and fees for participation in advisories, scientific and educational activities, from Almirall, Bayer, Biogen, Bristol-Myers Squibb, Sanofi-Genzyme, Merck, Novartis, UCB Pharma, Roche and Teva. EM has received honoraria as consultant in advisory boards, and or as chairperson or lecturer in meetings, attendance to congresses and has also participated in clinical trials and other research projects promoted by Almirall, Bayer, Biogen, Bristol Myers Squibb, Janssen, Merck, Teva, Novartis, Roche, Sandoz and Sanofi-Genzyme. PO-N has received collaborations and fees for participation in advisories, scientific and educational activities from Almirall, Biogen, Bristol-Myers Squibb, Sanofi-Genzyme, Merck, Novartis, UCB Pharma, Roche and Teva., (Copyright © 2024 Fernández Fernández, Costa-Frossard, Martínez Ginés, Montero Escribano, Prieto González, Ramió-Torrentà, Aladro, Alonso Torres, Álvarez Rodríguez, Labiano-Fontcuberta, Landete Pascual, Miralles Martínez, Moral Torres and Oliva-Nacarino.)

Metalloproteins play a fundamental role in molecular biology, contributing to various biological processes. However, the discovery of high-affinity ligands targeting metalloproteins has been delayed due, in part, to a lack of suitable tools and data. Molecular docking, a widely used technique for virtual screening of small-molecule ligand interactions with proteins, often faces challenges when applied to metalloproteins due to the particular nature of the ligand metal bond. To address these limitations associated with docking metalloproteins, we introduce a knowledge-driven docking approach known as "metalloprotein bias docking" (MBD), which extends the AutoDock Bias technique. We assembled a comprehensive data set of metalloprotein-ligand complexes from 15 different metalloprotein families, encompassing Ca, Co, Fe, Mg, Mn, and Zn metal ions. Subsequently, we conducted a performance analysis of our MBD method and compared it to the conventional docking (CD) program AutoDock4, applied to various metalloprotein targets within our data set. Our results demonstrate that MBD outperforms CD, significantly enhancing accuracy, selectivity, and precision in ligand pose prediction. Additionally, we observed a positive correlation between our predicted ligand free energies and the corresponding experimental values. These findings underscore the potential of MBD as a valuable tool for the effective exploration of metalloprotein-ligand interactions.

Introduction: There is limited literature on the optimal approach to treat adhesive small bowel obstruction (ASBO) in children. We sought to compare rates and outcomes of laparoscopic (LAP) and open (OPEN) surgery for pediatric ASBO., Methods: A California statewide database was used to identify children (<18 years old) with an index ASBO from 2007 to 2020. The primary outcome was the type of operative management: LAP or OPEN. Secondary outcomes were hospital characteristics, patient demographics, and postoperative complications. We excluded patients treated non-operatively., Results: Our study group had 545 patients. 381 (70%) underwent OPEN and 164 (30%) LAP during the index admission. Over the study period, there was increasing use of laparoscopic surgery, with higher use in older children (p < 0.001). LAP was associated with fewer overall complications (65.2% vs. 81.6%, p < 0.001), with a decreasing trend in complications over time (p < 0.001). The LAP group had significantly lower rates of bowel resection (4.9% vs. 17.1%, p < 0.001), length of stay (LOS) (17 vs. 23 days, p < 0.001), and TPN use (12.2% vs. 29.1%, p < 0.001). Mortality rates were equivalent. Although the LAP group had lower readmission rates (22.6% vs. 37.3%, p < 0.001), the length of time between discharge and readmission was similar (171 vs. 165 days, p = 0.190)., Discussion: The use of laparoscopic surgery for index ASBO increased over the study period. However, it was less commonly utilized in younger children. LAP had fewer overall complications as well as shorter LOS, decreased TPN use, and fewer readmissions. The benefits and risks of each approach must be weighed., Level of Evidence: III., Competing Interests: Conflict of interest None of the authors have a financial or other conflict of interest. Dr. Ignacio is a voluntary Associate Editor for the Journal of Surgical Research. There is no financial support or additional aid provided by the Journal of Surgical Research for this position, and he was excluded from the entire peer-review and editorial process for this manuscript. The views in this paper are those of the authors and do not reflect the official policy or position of the Department of the Navy, the Department of Defense, or the United States Government., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Bacterial P450 cytochromes (BacCYPs) are versatile heme-containing proteins responsible for oxidation reactions on a wide range of substrates, contributing to the production of valuable natural products with limitless biotechnological potential. While the sequencing of microbial genomes has provided a wealth of BacCYP sequences, functional characterization lags behind, hindering our understanding of their roles. This study employs a comprehensive approach to predict BacCYP substrate specificity, bridging the gap between sequence and function. We employed an integrated approach combining sequence and functional data analysis, genomic context exploration, 3D structural modeling with molecular docking, and phylogenetic clustering. The research begins with an in-depth analysis of BacCYP sequence diversity and structural characteristics, revealing conserved motifs and recurrent residues in the active site. Phylogenetic analysis identifies distinct groups within the BacCYP family based on sequence similarity. However, our study reveals that sequence alone does not consistently predict substrate specificity, necessitating additional perspectives. The study delves into the genetic context of BacCYPs, utilizing neighboring gene information to infer potential substrates, a method proven very effective in many cases. Molecular docking is employed to assess BacCYP-substrate interactions, confirming potential substrates and providing insights into selectivity. Finally, a comprehensive strategy is proposed for predicting BacCYP substrates, involving all the evaluated approaches. The effectiveness of this strategy is demonstrated with two case studies, highlighting its potential for substrate discovery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Schottlender, Prieto, Clemente, Schuster, Dumas, Fernández Do Porto and Martí.)

Cutaneous melanoma is an aggressive type of skin cancer with a complex genetic landscape caused by the malignant transformation of melanocytes. This study aimed at providing an in silico network model based on the systematic profiling of the melanoma-associated genes considering germline mutations, somatic mutations, and genome-wide association study signals accounting for a total of 232 unique melanoma risk genes. A protein-protein interaction network was constructed using the melanoma risk genes as seeds and evaluated to describe the functional landscape in which the melanoma genes operate within the cellular milieu. Not only were the majority of the melanoma risk genes able to interact with each other at the protein level within the core of the network, but this showed significant enrichment for genes whose expression is altered in human melanoma specimens. Functional annotation showed the melanoma risk network to be significantly associated with processes related to DNA metabolism and telomeres, DNA damage and repair, cellular ageing, and response to radiation. We further explored whether the melanoma risk network could be used as an in silico tool to predict the efficacy of anti-melanoma phytochemicals, that are considered active molecules with potentially less systemic toxicity than classical cytotoxic drugs. A significant portion of the melanoma risk network showed differential expression when SK-MEL-28 human melanoma cells were exposed to the phytochemicals harmine and berberine chloride. This reinforced our hypothesis that the network modeling approach not only provides an alternative way to identify molecular pathways relevant to disease but it may also represent an alternative screening approach to prioritize potentially active compounds., Competing Interests: Conflicts of interest The author(s) declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America.)

Quinoa (Chenopodium quinoa Willd.) leafy greens (QLGs) are plant-based foods of high nutritional value that have been scarcely studied. In this work, the nutritional and functional composition of three QLGs varieties was evaluated. A protein content higher than 35 g 100 g -1 dw with a well-balanced essential amino acid composition was found making them a good source of vegetable protein. In addition, elevated contents of dietary fibre and minerals, higher than those detected in quinoa seeds and other leafy vegetables, were found. The lipid profile showed higher contents of linoleic (C18:2, ω6) (20.2 %) and linolenic acids (C18:3, ω3) (52.8 %) with low ω6/ ω3 ratios (∼0.4/1). A total sugar content <1 g 100 g -1 dw was found for all varieties tested, lower than that obtained in seeds. The saponin content varied between 0.76 and 0.87 %. Also, high values of total phenolic compounds (969.8-1195.4 mg gallic acid 100 g -1 ), mainly hydroxycinnamic acids and flavonoids, and great antioxidant activities (7.64-8.90 g Trolox kg -1 ) were found. Multivariate analysis here used allowed us to classify the samples according to the quinoa variety evaluated, and the sequential stepwise multiple regression applied revealed that the PUFA and sucrose contents negatively influenced the protein content while the palmitic acid content affected positively this parameter. Overall, this study shows that QLGs are promising nutritious and functional plant-based foods supporting the necessity of promoting their cultivation, commercialization, and consumption., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Consumers demand food products that can impact positively health. Those made from quinoa or amaranth flours could meet these expectations. Thus, the main goal of this work was to evaluate the nutritional composition of easy-to-eat snacks combining red pepper, carrot, or zucchini with quinoa or amaranth flours, well-recognized superfoods. In addition, these were compared with snacks incorporating wheat flour, a widely used conventional cereal. The results showed higher protein content in quinoa or amaranth snacks. The snacks with quinoa showed lower saturated fatty acid contents and the highest contents of unsaturated fatty acids. Furthermore, the discriminant model obtained could be used as a powerful predictive model to classify the samples according to the vegetable and flours used. Besides, the canonical discriminant analysis showed that the most influential grouping variable was the flour rather than the vegetable., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

This study explores the perceived effects of a home-based end-of-life social care program in palliative care in Spain, from the perspective of caregivers. A qualitative study using semi-structured interviews with 75 caregivers from the INTecum project. Non-probability purposive sampling was used to recruit the study participants. The analytical process followed a thematic analysis. Caregivers expressed several factors that were influential in reducing stress and anxiety. Knowing that they can count on a case manager in a situation of need was highlighted as very positive. Another important factor that helped to create a positive sense of security was the speed of the project in offering its services. One of the problems that arose was the lack of support in situations where a transition between home and hospital care was required. Aspects such as listening and kindness, and affection, are highlighted in a very positive way. In addition to the final desires, caregivers also recognized that it was important for professionals to take their relative's wishes into account when making decisions. Incorporating a psychosocial component in palliative care for both patients and family caregivers is recognized and such actions are recommended, as well the strengthening of social and health care coordination.

Introduction: Teriflunomide is a once-daily oral immunomodulator approved for relapsing forms of multiple sclerosis (MS) or relapsing-remitting multiple sclerosis (RRMS; depending on the local label), based on extensive evidence from clinical trials and a real-world setting on efficacy, tolerability and patient-reported benefits. The TERICARE study assessed the impact of teriflunomide treatment over 2 years on health-related quality of life (HRQoL) and some of the most common and disabling symptoms of MS, such as fatigue and depression., Methods: This prospective observational study in Spain included RRMS patients treated with teriflunomide for ≤ 4 weeks. The following patient-reported outcomes (PROs) were collected at baseline and every 6 months for 2 years: the 29-item Multiple Sclerosis Impact Scale version 2 (MSIS-29), the 21-item Modified Fatigue Impact Scale (MFIS-21), the Beck Depression Inventory (BDI-II), the Short Form (SF)-Qualiveen and the Treatment Satisfaction Questionnaire for Medication v1.4 (TSQM). Annualised relapse rate (ARR), disability progression according to the Expanded Disability Status Scale (EDSS), and no evidence of disease activity (NEDA-3) were also assessed., Results: A total of 325 patients were analysed. Patients had a mean (SD) age of 43.2 years (10.4), a mean baseline EDSS score of 1.75 (1.5), a mean number of relapses in the past 2 years of 1.5 (0.7), and 64% had received prior disease-modifying therapy (DMT). Patients showed significant improvements in the psychological domain of MSIS-29 from 35.9 (26.6) at baseline to 29.4 (25.5) at 18 months (p = 0.004) and 29.0 (24.6) at 24 months (p = 0.002). Levels of fatigue and depression were also reduced. After 2 years of treatment with teriflunomide, ARR was reduced to 0.17 (95% CI 0.14-0.21) from the baseline of 0.42 (95% CI 0.38-0.48), representing a 60.1% reduction. Mean EDSS scores remained stable during the study, and 79.9% of patients showed no disability progression. 54.7% of patients achieved NEDA-3 in the first 12 months, which increased to 61.4% during months 12-24. Patients reported increased satisfaction with treatment over the course of the study, regardless of whether they were DMT naive or not., Conclusion: Teriflunomide improves psychological aspects of HRQoL and maintains low levels of fatigue and depression. Treatment with teriflunomide over 2 years is effective in reducing ARR and disability progression., (© 2023. The Author(s).)

Introduction: To examine practice patterns and surgical outcomes of nonoperative versus operative management (OPM) of children presenting with an index adhesive small bowel obstruction (ASBO)., Methods: A California statewide health discharge database was used to identify children (<18 y old) with an index ASBO from 2007 to 2020. The primary study outcome was evaluating initial management patterns (nonoperative versus OPM and early [≤3 d] versus late surgery [>3 d]) of ASBO. Secondary outcomes were hospital characteristics, patient demographics, and postoperative complications., Results: Of the 2297 patients identified, 1948 (85%) underwent OPM for ASBO during the index admission. Of these, 14.7% underwent early surgery within 3 d. Teaching hospitals had higher operative intervention than nonteaching centers (87.1% versus 83.7%, P = 0.034). OPM was the highest in 0-5-year-olds compared to other ages (89% versus 82%, P < 0.001). In comparison to early surgery, late surgery was associated with longer length of stay (early 7[interquartile range 5-10], late 9[interquartile range 6-17], P < 0.001), increased infectious complications (16.4% versus 9.8%, P = 0.004), and greater use of total parenteral nutrition (28.0% versus 14.3%, P = 0.001); there was no difference in bowel resection (21% versus 18%, P = 0.102) or mortality (P = 0.423)., Conclusions: Our pediatric study demonstrated a high rate of OPM for index ASBO, especially in newborns and toddlers. Although operative intervention, especially late surgery, was associated with increased length of stay, increased infectious complications, and increased total parenteral nutrition use, the rates of bowel resection and mortality did not differ by management strategy. These trends need to be further evaluated to optimize outcomes., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The EMCOVID project conducted a multi-centre cohort study to investigate the impact of COVID-19 on patients with Multiple Sclerosis (pwMS) receiving disease-modifying therapies (DMTs). The study aimed to evaluate the seroprevalence and persistence of SARS-CoV-2 antibodies in MS patients enrolled in the EMCOVID database. The DMTs were used to manage MS by reducing relapses, lesion accumulation, and disability progression. However, concerns arose regarding the susceptibility of pwMS to COVID-19 due to potential interactions between SARS-CoV-2 and the immune system, as well as the immunomodulatory effects of DMTs., Methods: This prospective observational study utilized data from a Multiple Sclerosis and COVID-19 (EMCOVID-19) study. Demographic characteristics, MS history, laboratory data, SARS-CoV-2 serology, and symptoms of COVID-19 were extracted for pwMS receiving any type of DMT. The relationship between demographics, MS phenotype, DMTs, and COVID-19 was evaluated. The evolution of SARS-CoV-2 antibodies over a 6-month period was also assessed., Results: The study included 709 pwMS, with 376 patients providing samples at the 6-month follow-up visit. The seroprevalence of SARS-CoV-2 antibodies was higher among pwMS than the general population, with Interferon treatment being significantly associated with greater seroprevalence (16.9% vs. 8.4%; p 0.003). However, no other specific DMT showed a significant association with antibody presence. A total of 32 patients (8.5%) tested positive for IgG, IgM, or IgA antibodies against SARS-CoV-2 at baseline, but then tested negative at 6 months. Most of the pwMS in the cohort were asymptomatic for COVID-19 and, even among symptomatic cases, the prognosis was generally favourable., Conclusion: pwMS undergoing DMTs exhibited a higher seroprevalence of COVID-19 than the general population. Interferon treatment was associated with a higher seroprevalence, suggesting a more robust humoral response. This study provides valuable insights into the seroprevalence and persistence of SARS-CoV-2 antibodies in pwMS and contributes to our understanding of the impact of COVID-19 amongst this population.

Ferruginol is a promising abietane-type antitumor diterpene able to induce apoptosis in SK-Mel-28 human malignant melanoma. We aim to increase this activity by testing the effect of a small library of ferruginol analogues. After a screening of their antiproliferative activity (SRB staining, 48 h) on SK-Mel-28 cells the analogue 18-aminoferruginol (GI50 ≈ 10 µM) was further selected for mechanistic studies including induction of apoptosis (DAPI staining, p < 0.001), changes in cell morphology associated with the treatment (cell shrinkage and membrane blebbing), induction of caspase-3/7 activity (2.5 at 48 h, 6.5 at 72 h; p < 0.0001), changes in the mitochondrial membrane potential (not significant) and in vitro effects on cell migration and cell invasion (Transwell assays, not significant). The results were compared to those of the parent molecule (ferruginol, GI50 ≈ 50 µM, depolarisation of mitochondrial membrane p < 0.01 at 72 h; no caspases 3/7 activation) and paclitaxel (GI50 ≈ 10 nM; caspases 3/7 activation p < 0.0001) as a reference drug. Computational studies of the antiproliferative activity of 18-aminoferruginol show a consistent improvement in the activity over ferruginol across a vast majority of cancer cells in the NCI60 panel. In conclusion, we demonstrate here that the derivatisation of ferruginol into 18-aminoferruginol increases its antiproliferative activity five times in SK-MEL-28 cells and changes the apoptotic mechanism of its parent molecule, ferruginol.

This paper reports the preparation and herbicidal evaluation of a small library of acylhydrazones based on the synthetic herbicide metribuzin. The hydrazone linkage easily obtained by reaction of metribuzin with aliphatic and aromatic aldehydes, masks efficiently the exocyclic amino group, thereby altering significantly H-bonding with the receptor and increasing the lipophilicity relative to the parent herbicide. The structures of all compounds, including key stereochemical issues on conformation and E/Z configuration around the C[bond, double bond]N bond were thoroughly elucidated by spectroscopic methods, and unambiguously corroborated by X-ray diffraction analysis. The herbicidal assays using an aliphatic and an aromatic acylhydrazone were performed on tomato and rapeseed plants grown in greenhouse. Our results demonstrate, regardless of rate application, that such acylhydrazone formulations do not alter the selectivity of metribuzin. Moreover, the herbicide activity was even higher in the alkyl derivative than that achieved by commercial metribuzin, thus suggesting that this substance can be applied with no need of combination with chemical coadjuvants, unlike most formulations of commercially available herbicides. Therefore, the study shows the promising effect of chemical derivatization of a common herbicide as metribuzin, to improve the herbicide activity without compromising selectivity, and allowing the farmers its use in crop protection safely and effectively., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)

The Insulin-like growth factor 2 (IGF-2) has been recently proven to alleviate depressive-like behaviors in both rats and mice models. However, its potential role as a peripheral biomarker has not been evaluated in depression. To do this, we measured plasma IGF-2 and other members of the IGF family such as Binding Proteins (IGFBP-1, IGFBP-3, IGFBP-5 and IGFBP-7) in a depressed group of patients (n = 51) and in a healthy control group (n = 48). In some of these patients (n = 15), we measured these proteins after a period (19 ± 6 days) of treatment with antidepressants. The Hamilton Depressive Rating Scale (HDRS) and the Self-Assessment Anhedonia Scale (SAAS) were used to measure depression severity and anhedonia, respectively. The general cognition state was assessed by the Mini-Mental State Examination (MMSE) test and memory with the Free and Cued Selective Reminding Test (FCSRT). The levels of both IGF-2 and IGFBP-7 were found to be significantly increased in the depressed group; however, only IGF-2 remained significantly elevated after correction by age and sex. On the other hand, the levels of IGF-2, IGFBP-3 and IGFBP-5 were significantly decreased after treatment, whereas only IGFBP-7 was significantly increased. Therefore, peripheral changes in the IGF family and their response to antidepressants might represent alterations at the brain level in depression.

HIV-associated neurocognitive disorders (HANDs) still persist despite improved life expectancy, reduced viral loads, and decreased infection severity. The number of patients affected by HANDs ranges from (30 to 50) % of HIV-infected individuals. The pathological mechanisms contributing to HANDs and the most serious manifestation of the disease, HIV-associated dementia (HAD), are not yet well understood. Evidence suggests that these mechanisms are likely multifactorial, producing neurocognitive complications involving disorders such as neurogenesis, autophagy, neuroinflammation, and mitochondrial dysfunction. Over the years, multiple pharmacological approaches with specific mechanisms of action acting upon distinct targets have been approved. Although these therapies are effective in reducing viral loading to undetectable levels, they also present some disadvantages such as common side effects, the need for administration with a very high frequency, and the possibility of drug resistance. Genetic studies on HANDs provide insights into the biological pathways and mechanisms that contribute to cognitive impairment in people living with HIV-1. Furthermore, they also help identify genetic variants that increase susceptibility to HANDs and can be used to tailor treatment approaches for HIV-1 patients. Identification of the genetic markers associated with disease progression can help clinicians predict which individuals require more aggressive management and by understanding the genetic basis of the disorder, it will be possible to develop targeted therapies to mitigate cognitive impairment. The main goal of this review is to provide details on the epidemiological data currently available and to summarise the genetic (specifically, the genetic makeup of the immune system), transcriptomic, and epigenetic studies available on HANDs to date. In addition, we address the potential pharmacological therapeutic strategies currently being investigated. This will provide valuable information that can guide clinical care, drug development, and our overall understanding of these diseases.

Background: Cats commonly develop thyroid disease but little is known about the long-term biological variability of serum thyroid hormone and thyrotropin (thyroid-stimulating hormone; TSH) concentrations., Objectives: We aimed to determine the long-term biological variation of thyroid hormones and TSH in clinically healthy cats., Methods: A prospective, observational study was carried out. Serum samples for analysis of total thyroxine (T 4, by radioimmunoassay [RIA] and homogenous enzyme immunoassay [EIA]), triiodothyronine (T 3 ), free T 4 (by dialysis), and TSH were obtained every 8 weeks for 1 year from 15 healthy cats, then frozen until single-batch analysis. Coefficients of variation (CV) within individual cats ( CV I ) and among individual cats ( CV G ), as well as the variation between duplicates (ie, analytical variation [ CV A ]) were determined with restricted maximum likelihood estimation. The indices of individuality (IoI) and reference change values (RCVs) for each hormone were calculated., Results: Some thyroid hormones showed similar (total T 4 by EIA) or greater (TSH) interindividual relative to intraindividual variation resulting in intermediate to high IoI, consistent with previous studies evaluating the biological variation of these hormones weekly for 5-6 weeks. By contrast, total T 4 (by RIA) and free T 4 had a low IoI. Total T 3 had a high ratio of CV A to CV I ; therefore, interindividual variation could not be distinguished from analytical variation. No seasonal variability in the hormones could be demonstrated., Conclusions: Clinicians might improve the diagnosis of feline thyroid disease by establishing baseline concentrations for analytes with intermediate-high IoI (total T 4, TSH) for individual cats and applying RCVs to subsequent measurements., (© 2023 American Society for Veterinary Clinical Pathology.)

Family planning is essential for establishing Multiple Sclerosis (MS) prognosis, treatment decision, and disease monitoring. We aimed to generate an expert consensus addressing recommendations for family planning in MS patients of childbearing age. Initially, a committee comprising seven neurologists, experts in the MS field, identified the topics to be addressed. Then, the committee elaborated on different evidence-based preliminary statements. Next, using the Delphi methodology, a panel of neurologists manifested their level of agreement on the different statements using a Likert-type scale. Consensus was reached when ⩾70% of respondents expressed an agreement or disagreement using a five-point scale. Consensus was achieved on 47 out of 63 recommendations after three rounds of evaluations. The panel considered it essential to address family planning in all patients of childbearing age. There was also consensus that treatment should not be delayed due to the patient's desire for pregnancy. Additionally, in highly active patients, planning the pregnancy in the medium to long term using depletory drugs such as cladribine or alemtuzumab might represent a useful strategy. However, risks of adverse effects on the fetus due to drug-associated secondary autoimmunity should be addressed when alemtuzumab is considered. Moreover, the maintenance of natalizumab during pregnancy in very active patients reached expert consensus. Also, the panel supported the use of certain disease-modifying treatment (DMT) during lactation in selected cases. Our results identified specific areas of pregnancy planning in MS patients, where different treatment strategies might be considered to facilitate a safe and successful pregnancy while maintaining clinical and radiological stability., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2023, Oreja-Guevara et al.)

Badgers ( Meles meles ) are a major tuberculosis (TB) reservoir in Europe, with the potential to transmit infection to cattle. Here we assessed whether a recently described oral tuberculosis vaccine based on heat-inactivated Mycobacterium bovis (HIMB) , delivered as edible baits, can protect badgers from infection. Eight badgers were given individually five baits, each one consisting of a ball of peanut butter, natural peanut and oat flakes including a dose of the vaccine containing 5 × 10 7  colony-forming units. In parallel, a control group of seven badgers did not receive the vaccine. One month and a half later a second dose of the vaccine was offered to the vaccinated group. Ninety-four days after the second dose, all badgers were challenged with M. bovis (10 3  colony-forming units per animal) delivered endobronchially to the right middle lung lobe. Clinical, immunological, pathological and bacteriological variables were measured throughout the whole study to assess the efficacy of the vaccine. Two vaccinated animals showed high bacterial load of M. bovis and worsening of pathological lesions of TB. Conversely, the other six vaccinated animals showed slight improvement in bacterial load and pathology with respect to the control group. These results suggest that delivering the TB vaccine via food bait can partially protect wild badger populations, although vaccination can lead to either protection or tolerization, likely depending on the animal's immune status and general condition at the time of vaccination. Further optimization of the vaccination trial/strategy is needed to reduce the rate of tolerization, such as altering vaccine dose, number of doses, type of bait, use of adjuvants or route of administration., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

"Yerba mate" (YM), an aqueous extract of Ilex paraguariensis, has antioxidant, diuretic, cardio-protective and hypoglycaemic properties. Since its effect on the pancreatic islets remains unclear, we evaluated insulin sensitivity and glucose-stimulated insulin secretion (GSIS) in rats consuming YM or tap water (C) for 21 days. Glucose tolerance, glycemia, triglyceridemia, insulinemia, TBARS and FRAP serum levels were evaluated. GSIS and mRNA levels of insulin signaling pathway and inflammatory markers were measured in isolated pancreatic islets from both groups. In C rats, islets were incubated with YM extract or its phenolic components to measure GSIS. YM improved glucose tolerance, enhanced GSIS, increased FRAP plasma levels and islet mRNA levels of IRS-1 and PI3K (p110), and decreased TBARS plasma levels and islet gene expression of TNF-α and PAI-1. Islets from C rats incubated with 100 µg/mL dry YM extract, 1 µM chlorogenic acid, 0.1 and 1 µM rutin, 1 µM caffeic acid or 1 µM quercetin showed an increase in GSIS. Our results suggest that YM enhances glucose tolerance because of its positive effects on GSIS, oxidative stress rate and insulin sensitivity in rat islets, suggesting that long-term dietary supplementation with YM may improve glucose homeostasis in pre-diabetes or type 2 diabetes.

This study aims to evaluate the in vitro cytotoxic and anti-migratory effects of Marantodes pumilum Blume Kuntze plant extracts on prostate cancer cells, identify the active compound/s, and characterize their mechanism of action. The crude methanolic extract was partitioned into n -hexane (MPh), chloroform (MPc), and aqueous (MPa) extracts. Antiproliferative fractions (IC50 < 30 μg/mL based on SRB staining of LNCaP and PC3 cell lines) were further fractionated. Active compound/s were identified using spectroscopic methods. In vitro mechanistic studies on PC3 cells included: annexin V-FITC staining, mitochondrial membrane potential (MMP) depolarization measurements, the activity of caspases 3 and 7, nuclear DNA fragmentation, cell cycle analysis, modulation of Bax, Bcl-2, Smac/Diablo, Alox-5, VEGF-A, CXCR4, and CXCL12 mRNA gene expression via RT-PCR, 2D migration (scratch assay), and 3D invasion (Boyden chamber). MPc extract was the most active, inducing cell death ( p < 0.05) via apoptosis, as evidenced by nuclear DNA fragmentation and an increase in MMP depolarization ( p < 0.05) as well as the activation of caspases 3/7 (MPc p < 0.01) in both PC3 and LNCaP cell lines. In addition, MPc upregulated Bax and Smac/DIABLO, downregulated Bcl-2 ( p < 0.05), and inhibited ALOX-5 mRNA gene expression ( p < 0.001). MPc was not cytotoxic against normal human fibroblast cells (HDFa) at the tested concentrations. Moreover, MPc inhibited migration and invasion of PC3 cells ( p < 0.01). These effects were accompanied by the downregulation of both VEGF-A and CXCL-12 gene expressions ( p < 0.001). A monounsaturated 5-alkyl resorcinol was isolated as the active compound in the MPc extract and identified as 5-henicosene-1-yl-resorcinol.

Background: Biological variation helps determine whether population-based or subject-based reference intervals are more appropriate to assess changes in serial analytical values. Previous studies have investigated the biological variation of biochemical analytes weekly or with variable frequency over 5-14 weeks in cats, but none have considered biological variation at less frequent intervals over 1 year., Objectives: We aimed to evaluate the long-term biological variation of 19 biochemical analytes in clinically healthy cats., Methods: A prospective, observational study in which 15 clinically healthy, client-owned cats were sampled for serum biochemical analyses every 8 weeks for 1 year. Frozen serum samples were single-batch analyzed. Restricted maximum likelihood estimation was used to determine the coefficients of variation (CV), describing variation within each cat, between cats, and the analytical variation. These CVs were used to determine the indices of individuality and reference change values (RCVs)., Results: Albumin, alkaline phosphatase, creatine kinase, and globulin had high indices of individuality, indicating that they are best evaluated by RCVs. Phosphorus, potassium, chloride, sodium, symmetric dimethylarginine, and total CO 2 had low indices of individuality, indicating that population-based reference intervals are appropriate. Alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, calcium, cholesterol, creatinine, glucose, total bilirubin, and total protein had intermediate indices of individuality, indicating that RCVs may provide additional insight into the interpretation of analyte measurements beyond the population-based reference intervals., Conclusions: For many analytes, the biological variation detected was similar to that reported in prior studies. Clinicians should consider the biological variation of analytes to best interpret clinically relevant changes in serial analyte measurements., (© 2022 American Society for Veterinary Clinical Pathology.)

Prostate cancer (PCa) remains both a global health burden and a scientific challenge. We present a review of the molecular targets driving current drug discovery to fight this disease. Moreover, the preventable nature of most PCa cases represents an opportunity for phytochemicals as chemopreventive when adequately integrated into nutritional interventions. With a renovated interest in natural remedies as a commodity and their essential role in cancer drug discovery, Malaysia is looking towards capitalizing on its mega biodiversity, which includes the oldest rainforest in the world and an estimated 1200 medicinal plants. We here explore whether the list of top Malay plants prioritized by the Malaysian government may fulfill the potential of becoming newer, sustainable sources of prostate cancer chemotherapy. These include Andrographis paniculate, Centella asiatica, Clinacanthus nutans, Eurycoma longifolia, Ficus deltoidea, Hibiscus sabdariffa, Marantodes pumilum ( syn . Labisia pumila), Morinda citrifolia, Orthosiphon aristatus, and Phyllanthus niruri . Our review highlights the importance of resistance factors such as Smac/DIABLO in cancer progression, the role of the CXCL12/CXCR4 axis in cancer metastasis, and the regulation of PCa cells by some promising terpenes (andrographolide, Asiatic acid, rosmarinic acid), flavonoids (isovitexin, gossypin, sinensetin), and alkylresorcinols (labisiaquinones) among others.

Introduction and Objectives: Recently, neurologists have begun to perform focused cardiac ultrasound for the detection of a cardiac source of embolism in stroke patients, requiring them to undergo a prior accredited training process. We designed a prospective study to analyze the incidence of heart disease detected by a focused cardiac ultrasound program within a stroke care network with cardiac imaging units and to identify the outcomes of detected structural heart disease at 1 year of follow-up., Methods: We included patients admitted to a university hospital for ischemic stroke or a transient ischemic attack between 2017 and 2021 who were evaluated by focused cardiac ultrasound. We studied the presence of structural heart disease and cardioembolic sources. We analyzed cardiovascular events (CVE) during the first year of follow-up., Results: Focused cardiac ultrasound was performed in 706 patients. Structural heart disease was detected in 52.1% and a cardioembolic source in 31.9%. Adverse CVE occurred in 5.49% of the patients in the first year of follow-up. The presence of de novo structural heart disease was independently associated with a higher probability of adverse CVE (HR, 1.72; 95%CI, 1.01- 2.91; P=.046)., Conclusions: Focused cardiac ultrasound within a stroke care network with cardiac imaging units is an accessible technique with high diagnostic yield. Its use allows clinical and therapeutic actions in the prevention of stroke recurrences and other CVEs in this group of patients., (Copyright © 2022 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction: We analyzed the impact of treating center designation and case volume of penetrating trauma on outcomes after pediatric penetrating thoracic injuries (PTI)., Methods: PTI patients <18 years were identified from the National Trauma Data Bank (2013-2016). Centers were categorized by type (Pediatric or Adult) and designation status (Level I, Level II, and other). Performance was calculated as the difference between observed and expected mortality and standardized using the total penetrating trauma volume per center. Expected mortality was calculated using the Trauma Mortality Prediction Model. Pearson correlation and linear mixed-effects models evaluated the association between variables and performance., Results: We identified 4,134 PTI patients treated at 596 trauma centers: 879 (21%) at Adult Level I, 608 (15%) at Adult Level II, 531 (13%) at Pediatric Level I, 320 (8%) at Pediatric Level II, and 1,796 (43%) at other centers. Primary injury mechanisms were firearm-related (58%) and cut/piercing (42%). Overall mortality was 16% and median predicted mortality was 3.6% (IQR: 1.5% - 11.2%). Among patients with thoracic firearm-related injuries, centers with lower penetrating case volume and total trauma care demonstrated significantly worse outcomes. Multivariable analysis revealed Adult Level I centers had superior outcomes compared with all other non-Level I centers. There was no difference in mortality between Pediatric and Adult Level I centers., Discussion: Adult Level I trauma center designation and annual case volume of penetrating thoracic trauma are associated with improved mortality after pediatric firearm-related thoracic injuries. Further study is needed to identify factors in higher volume centers that improve outcomes., Level of Evidence: Level III., Competing Interests: Declaration of Competing Interest The authors report no conflict of interest. The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article., (Copyright © 2022 Elsevier Inc. All rights reserved.)