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Cyanogenic glycosides are α-hydroxynitrile glucosides present in approximately 3000 different plant species. Upon tissue disruption, cyanogenic glycosides are hydrolyzed to release toxic hydrogen cyanide as a means of chemical defense. Over 100 different cyanogenic glycosides have been reported, with structural diversity dependent on the precursor amino acid, and subsequent modifications. Cyanogenic glycosides represent a prime example of sporadic metabolite evolution, with the metabolic trait arising multiple times throughout the plant lineage as evidenced by recruitment of different enzyme families for biosynthesis. Here, we review the latest developments within cyanogenic glycoside biosynthesis, and argue possible factors driving sporadic evolution including shared intermediates and crossovers with other metabolic pathways crossovers, and metabolite multifunctionality beyond chemical defense.
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Machine learning (ML) systems can model quantitative structure-property relationships (QSPR) using existing experimental data and make property predictions for new molecules. With the advent of modalities such as targeted protein degraders (TPD), the applicability of QSPR models is questioned and ML usage in TPD-centric projects remains limited. Herein, ML models are developed and evaluated for TPDs' property predictions, including passive permeability, metabolic clearance, cytochrome P450 inhibition, plasma protein binding, and lipophilicity. Interestingly, performance on TPDs is comparable to that of other modalities. Predictions for glues and heterobifunctionals often yield lower and higher errors, respectively. For permeability, CYP3A4 inhibition, and human and rat microsomal clearance, misclassification errors into high and low risk categories are lower than 4% for glues and 15% for heterobifunctionals. For all modalities, misclassification errors range from 0.8% to 8.1%. Investigated transfer learning strategies improve predictions for heterobifunctionals. This is the first comprehensive evaluation of ML for the prediction of absorption, distribution, metabolism, and excretion (ADME) and physicochemical properties of TPD molecules, including heterobifunctional and molecular glue sub-modalities. Taken together, our investigations show that ML-based QSPR models are applicable to TPDs and support ML usage for TPDs' design, to potentially accelerate drug discovery.
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Aprendizaje Automático , Humanos , Ratas , Animales , Relación Estructura-Actividad Cuantitativa , Proteolisis , Citocromo P-450 CYP3A/metabolismo , Citocromo P-450 CYP3A/química , Unión Proteica , PermeabilidadRESUMEN
Introduction: Proteomic analysis of injured human peripheral nerves, particularly focusing on events occurring in the proximal and distal nerve ends, remains relatively underexplored. This study aimed to investigate the molecular patterns underlying a digital nerve injury, focusing on differences in protein expression between the proximal and distal nerve ends. Methods: A total of 26 human injured digital nerve samples (24 men; 2 women; median age 47 [30-66] years), harvested during primary nerve repair within 48 h post-injury from proximal and distal nerve ends, were analyzed using mass spectrometry. Results: A total of 3,914 proteins were identified, with 127 proteins showing significant differences in abundance between the proximal and the distal nerve ends. The downregulation of proteins in the distal nerve end was associated with synaptic transmission, autophagy, neurotransmitter regulation, cell adhesion and migration. Conversely, proteins upregulated in the distal nerve end were implicated in cellular stress response, neuromuscular junction stability and muscle contraction, neuronal excitability and neurotransmitter release, synaptic vesicle recycling and axon guidance and angiogenesis. Discussion: Investigation of proteins, with functional annotations analysis, in proximal and the distal ends of human injured digital nerves, revealed dynamic cellular responses aimed at promoting tissue degeneration and restoration, while suppressing non-essential processes.
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INTRODUCTION: Pediatric ovarian torsion (OT) is an emergency condition that remains challenging to diagnose because of its overall unspecific clinical presentation. The aim of this study was to determine the diagnostic value of clinical, ultrasound, and inflammatory laboratory markers in pediatric OT. METHODS: We performed a retrospective multicentric case-control study in patients with clinical and ultrasound suspicion of OT, in whom surgical examination was performed between 2016-2022 in seven pediatric hospitals. Patients were divided into two groups according to intraoperative findings: OT group (ovarian torsion), defined as torsion of the ovarian axis at least 360°, and non-OT group (no torsion). Demographics, clinical, ultrasound, and laboratory features at admission were analyzed. The diagnostic yield analysis was performed using logistic regression models, and the results were represented by ROC curves. RESULTS: We included a total of 110 patients (75 in OT group; 35 in non-OT group), with no demographic or clinical differences between them. OT-group patients had shorter time from symptom onset (8 vs. 12 h; p = 0.023), higher ultrasound median ovarian volume (63 vs. 51 mL; p = 0.013), and a significant increase in inflammatory markers (leukocytes, neutrophils, neutrophil-to-lymphocyte ratio, C-reactive protein) when compared to the non-OT group. In the ROC curve analysis, the neutrophil-to-lymphocyte ratio (NLR) presented the highest AUC (0.918), with maximum sensitivity (92.4%) and specificity (90.1%) at the cut-off point NLR = 2.57. CONCLUSIONS: NLR can be considered as a useful predictor of pediatric OT in cases with clinical and ultrasound suspicion. Values above 2.57 may help to anticipate urgent surgical treatment in these patients.
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Three genera of viruses of the family Totiviridae establish endosymbiotic associations with flagellated protozoa responsible for parasitic diseases of great impact in the context of One Health. Giardiavirus, Trichomonasvirus, and Leishmaniavirus infect the protozoa Giardia sp., Trichomonas vaginalis, and Leishmania sp., respectively. In the present work, we review the characteristics of the endosymbiotic relationships established, the advantages, and the consequences caused in mammalian hosts. Among the common characteristics of these double-stranded RNA viruses are that they do not integrate into the host genome, do not follow a lytic cycle, and do not cause cytopathic effects. However, in cases of endosymbiosis between Leishmaniavirus and Leishmania species from the Americas, and between Trichomonasvirus and Trichomonas vaginalis, it seems that it can alter their virulence (degree of pathogenicity). In a mammalian host, due to TLR3 activation of immune cells upon the recognition of viral RNA, uncontrolled inflammatory signaling responses are triggered, increasing pathological damage and the risk of failure of conventional standard treatment. Endosymbiosis with Giardiavirus can cause the loss of intestinal adherence of the protozoan, resulting in a benign disease. The current knowledge about viruses infecting flagellated protozoans is still fragmentary, and more research is required to unravel the intricacies of this three-way relationship. We need to develop early and effective diagnostic methods for further development in the field of translational medicine. Taking advantage of promising biotechnological advances, the aim is to develop ad hoc therapeutic strategies that focus not only on the disease-causing protozoan but also on the virus.
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Diabetes mellitus (DM) is a risk factor for the development of ulnar nerve entrapment (UNE). Differences in surgical outcomes for UNE between patients with and without DM have been reported, but studies on presurgical management are scarce. This study aimed to evaluate the presurgical management of UNE in patients with (DM diagnosis < 2 years of UNE diagnosis) and without DM regarding the level of care for diagnosis and the proportion that proceeds to surgery. Data from 6600 patients with UNE between 2004 and 2019 were included from the Skåne Health Care Register (SHR) and cross-linked with data from the Swedish National Diabetes Register (NDR). The group with UNE and DM was compared to the group with UNE without DM and prevalence ratios were calculated using Cox regression analysis. Patients with DM more often got their first UNE diagnosis in secondary care than in primary care (643/667, 96% vs. 5361/5786; 93%). Patients with and without DM, regardless of the type of DM, presence of retinopathy, or HbA1c levels, were surgically treated for UNE to the same extent (258/667, 39% of patients with DM vs. 2131/5786, 37% of patients without DM). The proportion of surgically treated was significantly lower among patients diagnosed with UNE in primary care compared to secondary care (59/449, 13% vs. 2330/5786, 38%). Men were more often surgically treated than women (1228/3191, 38% vs.1161/3262 36%). Patients with UNE and DM are surgically treated to the same extent as patients with UNE but without DM and are more likely to be diagnosed in specialized care.
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Síndromes de Compresión del Nervio Cubital , Humanos , Masculino , Femenino , Persona de Mediana Edad , Síndromes de Compresión del Nervio Cubital/cirugía , Síndromes de Compresión del Nervio Cubital/etiología , Anciano , Suecia/epidemiología , Diabetes Mellitus/cirugía , Adulto , Sistema de Registros , Nervio Cubital/cirugía , Factores de RiesgoRESUMEN
Hepatic bile acid regulation is a multifaceted process modulated by several hepatic transporters and enzymes. Drug-induced cholestasis (DIC), a main type of drug-induced liver injury (DILI), denotes any drug-mediated condition in which hepatic bile flow is impaired. Our ability in translating preclinical toxicological findings to human DIC risk is currently very limited, mainly due to important interspecies differences. Accordingly, the anticipation of clinical DIC with available in vitro or in silico models is also challenging, due to the complexity of the bile acid homeostasis. Herein, we assessed the in vitro inhibition potential of 47 marketed drugs with various degrees of reported DILI severity towards all metabolic and transport mechanisms currently known to be involved in the hepatic regulation of bile acids. The reported DILI concern and/or cholestatic annotation correlated with the number of investigated processes being inhibited. Furthermore, we employed univariate and multivariate statistical methods to determine the important processes for DILI discrimination. We identified time-dependent inhibition (TDI) of cytochrome P450 (CYP) 3A4 and reversible inhibition of the organic anion transporting polypeptide (OATP) 1B1 as the major risk factors for DIC among the tested mechanisms related to bile acid transport and metabolism. These results were consistent across multiple statistical methods and DILI classification systems applied in our dataset. We anticipate that our assessment of the two most important processes in the development of cholestasis will enable a risk assessment for DIC to be efficiently integrated into the preclinical development process.
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Introduction: Sexual satisfaction has been shown to have a strong association with many aspects of sexual health and wellbeing. It is further considered a robust indicator of an individual's health status and general wellbeing, revealing that a person can enjoy pleasurable and healthy sexual experiences, beyond the mere absence of sexual and reproductive health issues. Objectives: This study aimed to analyze the relationship between sexual satisfaction, sexual behaviors, sexual self-efficacy, and the importance personally attributed to maintaining an active and satisfying sexual life among young and middle-aged women aged 18-50. Design: A descriptive correlational study with a cross-sectional design was conducted. Methods: Participants (N = 1,076 women) completed self-reports on sexual self-efficacy beliefs, frequency of sexual behaviors, the importance attributed to active and healthy sexuality, and multidimensional sexual satisfaction. Results: The supported mediation model indicated that sexual self-efficacy was related to sexual satisfaction directly and indirectly through sexual behavior and a serial path through sexual behavior and the perceived importance of healthy sexuality. The total effect was significant, and the full model explained 7.3% of the global sexual satisfaction variance (F = 17.218, p = 0.000), with the mediated effect accounting for 44.3%. Conclusion: This study confirms a partial serial mediation model by which sexual self-efficacy significantly predicts sexual satisfaction through sexual behaviors and the importance attributed to a healthy sexuality. Due to its significant contribution, the perceived importance of sexuality should be considered when studying correlates of sexual satisfaction. These findings have interesting implications for the development of strategies aimed at sexual health promotion and sexual education among women in early and middle adulthood.
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Background: Type 2 diabetes (T2D) is a major risk factor for carpal tunnel syndrome (CTS) and trigger finger (TF), but less is known regarding the risk of developing T2D after being diagnosed with CTS or TF. CTS and TF could be early signs of preclinical T2D, and early detection of T2D is crucial to prevent complications and morbidity. Therefore, we investigate the association between CTS/TF and T2D in an adult population without previous T2D using big data registers in Sweden. Methods: Data were collected by crosslinking five nationwide Swedish registers. Individuals aged 40-85 years on December 31, 2010, without prior overt diabetes, were included (nâ =â 3,948,517) and followed up from baseline (ie, a diagnosis of CTS or TF) or January 1, 2011, for controls, until a diagnosis of T2D, prescription of oral antidiabetics or insulin, or end of follow-up four years after baseline. Multivariate Cox regression models were created to calculate hazard ratios for T2D. Results: In total, 37,346 (0.95%) patients were diagnosed with CTS, whereof 1329 (3.46%) developed T2D. There were 17,432 (0.44%) patients who developed TF, whereof 639 (3.67%) developed T2D. Among the controls, 2.73% developed T2D. Compared with controls, there was an increased risk of developing T2D after being diagnosed with either CTS (HR 1.35; 95% confidence interval 1.28-1.43) or TF (HR 1.21; 95% confidence interval 1.12-1.31). Conclusion: Compared with controls, a diagnosis of CTS or TF was associated with 35% and 21% higher risk for later T2D, respectively, which might indicate the existence of undetected T2D in this population.
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Carpal tunnel syndrome (CTS) occurs more often among individuals with diabetes. The aim of this retrospective observational registry study was to examine whether individuals with diabetes and CTS are treated surgically to the same extent as individuals with CTS but without diabetes. Data on CTS diagnosis and surgery were collected from the Skåne Healthcare Register (SHR). A total of 35,105 individuals (age ≥ 18 years) diagnosed with CTS from 2004-2019 were included. Data were matched to the Swedish National Diabetes Register (NDR. Cox regression models were used to calculate the risk of the use of surgical treatment. Of the 35,105 included individuals with a CTS diagnosis, 17,662 (50%) were treated surgically, and 4,966 (14%) had diabetes. A higher number of individuals with diabetes were treated surgically (2,935/4,966, 59%) than individuals without diabetes (14,727/30,139, 49%). In the Cox regression model, diabetes remained a significant risk factor for surgical treatment (PR 1.14 (95% CI 1.11-1.17)). Individuals with type 1 diabetes were more frequently treated surgically (490/757, 65%) than individuals with type 2 diabetes (2,445/4,209, 58%). There was no difference between the sexes and their treatment. The duration of diabetes was also a risk factor for surgical treatment in diabetes type 2, but high HbA1c levels were not. Individuals with diabetes are more likely to be treated surgically for CTS than individuals without diabetes. Individuals with type 1 diabetes are more likely to be treated surgically for CTS than individuals with type 2 diabetes.
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Síndrome del Túnel Carpiano , Humanos , Síndrome del Túnel Carpiano/cirugía , Síndrome del Túnel Carpiano/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Adulto , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/cirugía , Suecia/epidemiología , Sistema de Registros , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/cirugía , Factores de Riesgo , Modelos de Riesgos ProporcionalesRESUMEN
High-risk pregnancies elevate maternal stress, impacting offspring neurodevelopment and behavior. This study, involving 112 participants, aimed to compare perceived stress, neurodevelopment, and behavior in high-risk and low-risk pregnancies. Two groups, high-risk and low-risk, were assessed during pregnancy for stress using hair cortisol and psychological analysis. At 24 months post-birth, their children's neurodevelopment and behavior were evaluated. Results revealed higher perceived stress and pregnancy-related concerns in high-risk pregnancies, contrasting with low-risk pregnancies. Offspring from high-risk pregnancies displayed elevated internalizing behavior scores, while low-risk pregnancies showed higher externalizing behavior scores. Additionally, women in low-risk pregnancies exhibited increased cortisol concentrations 24 months post-delivery. These findings underscore the necessity for early stress detection and prevention programs during pregnancy, particularly in high-risk cases, to enhance maternal and infant health.
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Peripheral nerve injuries in the upper limb can lead to substantial disability and pain. We aimed to assess how socioeconomic factors affect outcomes after repaired or reconstructed digital or major nerve trunk injuries in the upper limb. We identified 670 individuals, who underwent surgical nerve repair or reconstruction using sensory nerve autografts, in the Swedish National Quality Registry for Hand Surgery 2010-2018. Socioeconomic factors, including education, cohabitation, type of work, sick leave, immigrant status and income, were gathered from the Swedish statistical agency ( www.scb.se ) and National Diabetes Register (NDR). We calculated prevalence ratios (PR) to assess the relationship between socioeconomic factors and surgical outcomes for the nerve injuries. Individuals with a major nerve trunk injury had higher QuickDASH scores and lower income compared to those with digital nerve injury. Individuals with immigration background (adjusted PR = 2.0, 95% CI 1.2-3.2), history of > 4 weeks of sick leave the year before surgery (adjusted PR = 1.8, 95% CI 1.1-3.1), or education level below tertiary (adjusted PR = 2.8, 95% CI 1.7-4.7) had significantly higher QuickDASH scores. Recognizing impact of non-biological factors, including immigration, prior sick leave, and education level, on outcome after nerve surgery is crucial for improving prognosis in socioeconomically deprived individuals.
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Traumatismos de los Nervios Periféricos , Procedimientos de Cirugía Plástica , Humanos , Traumatismos de los Nervios Periféricos/cirugía , Extremidad Superior/cirugía , Extremidad Superior/lesiones , Pronóstico , Factores SocioeconómicosRESUMEN
Most drugs are mainly metabolized by cytochrome P450 (CYP450), which can lead to drug-drug interactions (DDI). Specifically, time-dependent inhibition (TDI) of CYP3A4 isoenzyme has been associated with clinically relevant DDI. To overcome potential DDI issues, high-throughput in vitro assays were established to assess the TDI of CYP3A4 during the discovery and lead optimization phases. However, in silico machine learning models would enable an earlier and larger-scale assessment of TDI potential liabilities. For CYP inhibition, most modeling efforts have focused on highly imbalanced and small data sets. Moreover, assay variability is rarely considered, which is key to understand the model's quality and suitability for decision-making. In this work, machine learning models were built for the prediction of TDI of CYP3A4, evaluated prospectively, and compared to the variability of the experimental assay. Different modeling strategies were investigated to assess their influence on the model's performance. Through multitask learning, additional data sets were leveraged for model building, coming from public databases, in-house CYP-related assays, or other pharmaceutical companies (federated learning). Apart from the numerical prediction of inactivation rates of CYP3A4 TDI, three-class predictions were carried out, giving a negative (inactivation rate kobs < 0.01 min-1), weak positive (0.01 ≤ kobs ≤ 0.025 min-1), or positive (kobs > 0.025 min-1) output. The final multitask graph neural network model achieved misclassification rates of 8 and 7% for positive and negative TDI, respectively. Importantly, the presented deep learning-based predictions had a similar precision to the reproducibility of in vitro experiments and thus offered great opportunities for drug design, early derisk of DDI potential, and selection of experiments. To facilitate CYP inhibition modeling efforts in the public domain, the developed model was used to annotate â¼16â¯000 publicly available structures, and a surrogate data set is shared as Supporting Information.
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Citocromo P-450 CYP3A , Aprendizaje Profundo , Citocromo P-450 CYP3A/metabolismo , Reproducibilidad de los Resultados , Sistema Enzimático del Citocromo P-450/metabolismo , Interacciones Farmacológicas , Modelos BiológicosRESUMEN
BACKGROUND: Calcitonin gene-related peptide has shown to play a central role in cluster headache (CH) pathophysiology. A clinical trial with galcanezumab was carried out in chronic cluster headache (CCH) but did not meet its primay endpoint. However, its off-label use in patients with CCH refractory to other therapies could be considered. We aimed to asses the efficacy and safety of galcanezumab as CCH preventive treatment in a real-life setting. METHODS: An observational study was conducted. Patients with CCH who received at least one dose of 240 mg of galcanezumab. RESULTS: Twenty-one patients who tried a mean of 6.3 ± 1.9 preventive therapies, including onabotulinumtoxinA in 90.5%. At baseline, the median of frequency was 60 (37.5-105) monthly attacks with 10 (8.3-10) points in pain intensity (Numerical Rating Scale). After one month, the frequency decreased to 31 (10.5-45) (p = 0.003) with 8.5 (8-9.5) intensity (p = 0.007); 10 (47.6%) patients were 50% responders of whom four (19%) were 75% responders. Of the 15 patients with 3 months of follow-up, seven (46.6%) reduced their frequency by 50% and four (26.6%) by 75%, with 40 (10-60) monthly attacks (p = 0.07) and pain intensity of 8 (5-10) (p = 0.026). Some 52% patients experienced adverse events, mostly mild. CONCLUSIONS: In our cohort of refractory CCH, galcanezumab was effective in almost 50% of patients. This finding supports individual off-label treatment attempts.
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Anticuerpos Monoclonales Humanizados , Cefalalgia Histamínica , Trastornos Migrañosos , Humanos , Cefalalgia Histamínica/tratamiento farmacológico , Cefalalgia Histamínica/inducido químicamente , Anticuerpos Monoclonales/uso terapéutico , Trastornos Migrañosos/tratamiento farmacológico , Estudios Prospectivos , Resultado del Tratamiento , Método Doble CiegoRESUMEN
It is common practice in drug discovery and development to predict in vivo hepatic clearance from in vitro incubations with liver microsomes or hepatocytes using the well-stirred model (WSM). When applying the WSM to a set of approximately 3000 Novartis research compounds, 73% of neutral and basic compounds (extended clearance classification system [ECCS] class 2) were well-predicted within 3-fold. In contrast, only 44% (ECCS class 1A) or 34% (ECCS class 1B) of acids were predicted within 3-fold. To explore the hypothesis whether the higher degree of plasma protein binding for acids contributes to the in vitro-in vivo correlation (IVIVC) disconnect, 68 proprietary compounds were incubated with rat liver microsomes in the presence and absence of 5% plasma. A minor impact of plasma on clearance IVIVC was found for moderately bound compounds (fraction unbound in plasma [fup] ≥1%). However, addition of plasma significantly improved the IVIVC for highly bound compounds (fup <1%) as indicated by an increase of the average fold error from 0.10 to 0.36. Correlating fup with the scaled unbound intrinsic clearance ratio in the presence or absence of plasma allowed the establishment of an empirical, nonlinear correction equation that depends on fup Taken together, estimation of the metabolic clearance of highly bound compounds was enhanced by the addition of plasma to microsomal incubations. For standard incubations in buffer only, application of an empirical correction provided improved clearance predictions. SIGNIFICANCE STATEMENT: Application of the well-stirred liver model for clearance in vitro-in vivo extrapolation (IVIVE) in rat generally underpredicts the clearance of acids and the strong protein binding of acids is suspected to be one responsible factor. Unbound intrinsic in vitro clearance (CLint,u) determinations using rat liver microsomes supplemented with 5% plasma resulted in an improved IVIVE. An empirical equation was derived that can be applied to correct CLint,u-values in dependance of fraction unbound in plasma (fup) and measured CLint in buffer.
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Microsomas Hepáticos , Modelos Biológicos , Animales , Ratas , Microsomas Hepáticos/metabolismo , Tasa de Depuración Metabólica , Hígado/metabolismo , Hepatocitos/metabolismo , Proteínas Sanguíneas/metabolismoRESUMEN
A key attribute of some long noncoding RNAs (lncRNAs) is their ability to regulate expression of neighbouring genes in cis. However, such 'cis-lncRNAs' are presently defined using ad hoc criteria that, we show, are prone to false-positive predictions. The resulting lack of cis-lncRNA catalogues hinders our understanding of their extent, characteristics and mechanisms. Here, we introduce TransCistor, a framework for defining and identifying cis-lncRNAs based on enrichment of targets amongst proximal genes. TransCistor's simple and conservative statistical models are compatible with functionally defined target gene maps generated by existing and future technologies. Using transcriptome-wide perturbation experiments for 268 human and 134 mouse lncRNAs, we provide the first large-scale survey of cis-lncRNAs. Known cis-lncRNAs are correctly identified, including XIST, LINC00240 and UMLILO, and predictions are consistent across analysis methods, perturbation types and independent experiments. We detect cis-activity in a minority of lncRNAs, primarily involving activators over repressors. Cis-lncRNAs are detected by both RNA interference and antisense oligonucleotide perturbations. Mechanistically, cis-lncRNA transcripts are observed to physically associate with their target genes and are weakly enriched with enhancer elements. In summary, TransCistor establishes a quantitative foundation for cis-lncRNAs, opening a path to elucidating their molecular mechanisms and biological significance.
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Biología Computacional , Técnicas Genéticas , ARN Largo no Codificante , Animales , Humanos , Ratones , ARN Largo no Codificante/genética , ARN Largo no Codificante/aislamiento & purificación , Factores de Transcripción/genética , Transcriptoma , Programas Informáticos/normas , Biología Computacional/métodosRESUMEN
Medicinal chemistry and drug design efforts can be assisted by machine learning (ML) models that relate the molecular structure to compound properties. Such quantitative structure-property relationship models are generally trained on large data sets that include diverse chemical series (global models). In the pharmaceutical industry, these ML global models are available across discovery projects as an "out-of-the-box" solution to assist in drug design, synthesis prioritization, and experiment selection. However, drug discovery projects typically focus on confined parts of the chemical space (e.g., chemical series), where global models might not be applicable. Local ML models are sometimes generated to focus on specific projects or series. Herein, ML-based global models, local models, and hybrid global-local strategies were benchmarked. Analyses were done for more than 300 drug discovery projects at Novartis and ten absorption, distribution, metabolism, and excretion (ADME) assays. In this work, hybrid global-local strategies based on transfer learning approaches were proposed to leverage both historical ADME data (global) and project-specific data (local) to adapt model predictions. Fine-tuning a pretrained global ML model (used for weights' initialization, WI) was the top-performing method. Average improvements of mean absolute errors across all assays were 16% and 27% compared with global and local models, respectively. Interestingly, when the effect of training set size was analyzed, WI fine-tuning was found to be successful even in low-data scenarios (e.g., â¼10 molecules per project). Taken together, this work highlights the potential of domain adaptation in the field of molecular property predictions to refine existing pretrained models on a new compound data distribution.
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Aprendizaje Profundo , Descubrimiento de Drogas/métodos , Diseño de Fármacos , Aprendizaje Automático , Relación Estructura-Actividad CuantitativaRESUMEN
BACKGROUND: Peripheral intravenous cannulation is a common procedure in the emergency department. Nevertheless, failure rates during the first attempt are as high as 40% in adults and 65% in children. Evidence suggests that physician performed ultrasound-guided peripheral intravenous cannulation (USG-PIVC) is an effective alternative to the traditional method; however, there is insufficient data on the efficacy of the technique performed by nurses. OBJECTIVE: To examine the efficacy of the USG-PIVC technique performed by emergency department nurses. METHODS: A literature review with meta-analysis was performed. The databases used were PubMed, Scopus and CINAHL. The search was conducted in March 2023. Two meta-analysis one of clinical trials about the effectiveness and one about the succession rate were performed. RESULTS: 20 studies were selected and analysed. The studies showed that USGPIVC performed by emergency nurses increased the probability of both the overall success and a successful first attempt compared to the standard technique. In addition, patients showed high satisfaction and lower complication rates. However, the procedure had no significant effect on the time or number of attempts required. A lower probability of success was obtained as regards peripheral intravenous cannulation when the standard technique was used, OR = 0.42 (95 %CI 0.25-0.70p < 0,05). CONCLUSIONS: Ultrasound-guided peripheral intravenous cannulation performed by emergency nurses is a safe and effective technique.
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Cateterismo Periférico , Enfermería de Urgencia , Ultrasonografía Intervencional , Humanos , Cateterismo Periférico/métodos , Servicio de Urgencia en Hospital , Ultrasonografía Intervencional/métodosRESUMEN
The aim of this study was to investigate the efficacy of physical exercise in chronic kidney disease, describing its impact on the Klotho-FGF23 axis. PubMed, Web of Science and Scopus databases, updated to January 2023, were searched. The present study employed mean difference and a 95% confidence interval (CI) to examine the efficacy of the intervention. Heterogeneity was assessed through inconsistency statistics (I2). Out of the 299 studies identified, a total of 4 randomized controlled trials (RCTs), comprising 272 participants, met the eligibility criteria. Compared with the control group, physical exercise significantly decreased the concentrations of FGF23 (MD: -102.07 Pg/mL, 95% CI: -176.23.47, -27.91 I2= 97%, p = 0.001), and a significantly increased the concentrations of Klotho protein: (MD: 158.82 Pg/mL, 95% CI: 123.33, -194.31, I2 = 0%, p = 0.001). The results of our study indicated that the exercise has a direct relationship with Klotho-FGF23 axis. We can conclude that physical exercise in patients with CKD produces beneficial effects on the pathophysiological components related to this disease, including cardiorespiratory fitness and vascular functions. As observed, both endurance and aerobic physical exercise increase Klotho production and decrease FGF23 levels. Evidence indicates that exercise attenuates the progression of CKD, improves uremic parameters and down-regulates inflammation-related markers.
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Glucuronidasa , Insuficiencia Renal Crónica , Humanos , Ejercicio Físico , Factores de Crecimiento de Fibroblastos , Riñón , Insuficiencia Renal Crónica/terapiaRESUMEN
Rectal perforations due to topical treatments (enemas or foams) are unusual complications and they have been mostly reported in the use of barium enemas or in elderly patients with constipation. Very little has been reported about perforations secondary to topical treatment in patients with ulcerative colitis. We present the case of a patient with ulcerative colitis who suffered a rectal perforation complicated with a superinfected collection after the application of topical mesalazine foam.