An integrated analysis of the Passifloraceae virome using public-domain data.

Passifloraceae is a plant family that includes several species of interest in the food, medicinal, and ornamental industries. The most relevant species are the purple and yellow varieties of P. edulis, which are among the most highly prized tropical fruits in the international markets. Unfortunately, the rapid expansion of this crop worldwide has resulted in the emergence of several viral diseases that endangered the productivity of this crop. In this work, we performed an integrated analysis of the Passifloraceae virome using public data. We investigated Pubmed and Genbank records and analyzed all the transcriptome data available for members of this plant family. This analysis resulted in the identification of six novel virus associations and six putative new viral species. We also used RNAseq to inspect virus accumulation levels and mixed infections. Using network analysis, we also examined the global distribution of Passiflora viruses and their associations with alternative hosts, which is valuable information in implementing viral disease management strategies. Our data suggest that a large diversity of viruses remains to be discovered. Finally, we used the information gathered in this work to estimate the cross-transmission risk of viruses in Colombian Passiflora fields.

Adaptation of turnip mosaic virus to Arabidopsis thaliana involves rewiring of VPg-host proteome interactions.

The outcome of a viral infection depends on a complex interplay between the host physiology and the virus, mediated through numerous protein-protein interactions. In a previous study, we used high-throughput yeast two-hybrid (HT-Y2H) to identify proteins in Arabidopsis thaliana that bind to the proteins encoded by the turnip mosaic virus (TuMV) genome. Furthermore, after experimental evolution of TuMV lineages in plants with mutations in defense-related or proviral genes, most mutations observed in the evolved viruses affected the VPg cistron. Among these mutations, D113G was a convergent mutation selected in many lineages across different plant genotypes, including cpr5-2 with constitutive expression of systemic acquired resistance. In contrast, mutation R118H specifically emerged in the jin1 mutant with affected jasmonate signaling. Using the HT-Y2H system, we analyzed the impact of these two mutations on VPg's interaction with plant proteins. Interestingly, both mutations severely compromised the interaction of VPg with the translation initiation factor eIF(iso)4E, a crucial interactor for potyvirus infection. Moreover, mutation D113G, but not R118H, adversely affected the interaction with RHD1, a zinc-finger homeodomain transcription factor involved in regulating DNA demethylation. Our results suggest that RHD1 enhances plant tolerance to TuMV infection. We also discuss our findings in a broad virus evolution context.

Morbidity and mortality of emergency surgery in octogenarian patient.

OBJECTIVE: To evaluate the health outcomes (postoperative morbidity and mortality) and the functional status at discharge of elderly patients older than 80 years who underwent emergency surgery. METHOD: Patients > 80 years of age who underwent emergency surgery during one year at the Marqués de Valdecilla University Hospital, Santander, Spain. Preoperative data (age, sex, type of surgery, comorbidity) and postoperative data (complications) were evaluated, as well as in-hospital mortality, at 30 days and 6 months after surgery. RESULTS: Five-hundred-sixty-eight patients underwent emergency surgery between 2018 and 2019. After the review, 407 patients were included in the study. Average age: 86.9 years. Women 61.7%. Mean hospital stay: 10.4 days. Traumatic interventions 41.3%, vascular surgery 19.7%, general-digestive surgery 25.3%. Medium ASA risk: 2.88. Functional status at discharge: 3.15. Postoperative complications: Clavien-Dindo I 40.8%, II 40.3%, IIIA 3.4%, IIIB 2.5%, IVA 3.9%, IVB 2.0% and V 7.1%. Hospital mortality 7.1%, 30-day mortality 10.3%, mortality at 6 months 24.6%. CONCLUSIONS: Patients > 80 years of age undergoing urgent surgery have high preoperative comorbidity, postoperative complications, and high mortality at 30 days and 6 months after surgery. This mortality is more significant in those ASA IV, nonagenarians and those undergoing high-risk surgery.

OBJETIVO: Evaluar los resultados en salud (morbilidad y mortalidad posoperatorias) y el estado funcional al alta de los pacientes mayores de 80 años sometidos a cirugía de urgencia. MÉTODO: Pacientes de edad > 80 años sometidos a cirugía de urgencia durante 1 año en el Hospital Universitario Marqués de Valdecilla, Santander, España. Se evaluaron datos preoperatorios (edad, sexo, tipo de cirugía, comorbilidad) y posoperatorios (complicaciones), así como mortalidad hospitalaria, a los 30 días y a los 6 meses de la cirugía. RESULTADOS: En 2018-2019 fueron operados de urgencia 568 pacientes, de los cuales 407 fueron incluidos en el estudio. Edad media: 86.9 años. El 61.7% fueron mujeres. Estancia media hospitalaria: 10.4 días. El 41.3% fueron intervenciones traumatológicas, el 19.7% cirugía vascular, el 25.3% cirugía general-digestiva. Riesgo ASA medio: 2.88. Estado funcional al alta: 3.15. Complicaciones posoperatorias: Clavien-Dindo I 40.8%, II 40.3%, IIIA 3.4%, IIIB 2.5%, IVA 3.9%, IVB 2.0% y V 7.1%. Mortalidad: hospitalaria 7.1%, a los 30 días 10.3% y a los 6 meses 24.6%. CONCLUSIONES: Los pacientes > 80 años sometidos a cirugía urgente presentan elevada comorbilidad preoperatoria, complicaciones posoperatorias y elevada mortalidad a 30 días y 6 meses de la cirugía. Esta mortalidad es más significativa en los ASA IV, nonagenarios y sometidos a cirugía de alto riesgo.

Correction: Del Valle-Moreno et al. Model-Informed Precision Dosing Software Tools for Dosage Regimen Individualization: A Scoping Review. Pharmaceutics 2023, 15, 1859.

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Metabolism-driven in vitro/in vivo disconnect of an oral ERɑ VHL-PROTAC.

Targeting the estrogen receptor alpha (ERα) pathway is validated in the clinic as an effective means to treat ER+ breast cancers. Here we present the development of a VHL-targeting and orally bioavailable proteolysis-targeting chimera (PROTAC) degrader of ERα. In vitro studies with this PROTAC demonstrate excellent ERα degradation and ER antagonism in ER+ breast cancer cell lines. However, upon dosing the compound in vivo we observe an in vitro-in vivo disconnect. ERα degradation is lower in vivo than expected based on the in vitro data. Investigation into potential causes for the reduced maximal degradation reveals that metabolic instability of the PROTAC linker generates metabolites that compete for binding to ERα with the full PROTAC, limiting degradation. This observation highlights the requirement for metabolically stable PROTACs to ensure maximal efficacy and thus optimisation of the linker should be a key consideration when designing PROTACs.

Electronic Medication Reconciliation Tools Aimed at Healthcare Professionals to Support Medication Reconciliation: a Systematic Review.

The development of health information technology available and accessible to professionals is increasing in the last few years. However, a low number of electronic health tools included some kind of information about medication reconciliation. To identify all the electronic medication reconciliation tools aimed at healthcare professionals and summarize their main features, availability, and clinical impact on patient safety. A systematic review of studies that included a description of an electronic medication reconciliation tool (web-based or mobile app) aimed at healthcare professionals was conducted. The review protocol was registered with PROSPERO: registration number CRD42022366662, and followed PRISMA guidelines. The literature search was performed using four healthcare databases: PubMed, EMBASE, Cochrane Library, and Scopus with no language or publication date restrictions. We identified a total of 1227 articles, of which only 12 met the inclusion criteria.Through these articles,12 electronic tools were detected. Viewing and comparing different medication lists and grouping medications into multiple categories were some of the more recurring features of the tools. With respect to the clinical impact on patient safety, a reduction in adverse drug events or medication discrepancies was detected in up to four tools, but no significant differences in emergency room visits or hospital readmissions were found. 12 e-MedRec tools aimed at health professionals have been developed to date but none was designed as a mobile app. The main features that healthcare professionals requested to be included in e-MedRec tools were interoperability, "user-friendly" information, and integration with the ordering process.

Combined or Sequential Treatment with Immune Checkpoint Inhibitors and Car-T Cell Therapies for the Management of Haematological Malignancies: A Systematic Review.

The aim of this paper was to review the available evidence on the efficacy and safety of combined or sequential use of PD-1/PD-L1 immune checkpoint inhibitors (ICI) and CAR-T cell therapies in relapsed/refractory (R/R) haematological malignancies. A systematic literature review was performed until 21 November 2022. Inclusion criteria: cohort studies/clinical trials aimed at evaluating the efficacy and/or safety of the combination of CAR-T cell therapy with PD-1/PD-L1 inhibitors in R/R haematological malignancies, which had reported results. Those focusing only on ICI or CAR-T separately or evaluating the combination in other non-hematological solid tumours were excluded. We used a specific checklist for quality assessment of the studies, and then we extracted data on efficacy or efficiency and safety. A total of 1867 articles were identified, and 9 articles were finally included (early phase studies, with small samples of patients and acceptable quality). The main pathologies were B-cell acute lymphoblastic leukaemia (B-ALL) and B-cell non-Hodgkin's lymphoma (B-NHL). The most studied combination was tisagenlecleucel with pembrolizumab. In terms of efficacy, there is great variability: the combination could be a promising option in B-ALL, with modest data, and in B-NHL, although hopeful responses were received, the combination does not appear better than CAR-T cell monotherapy. The safety profile could be considered comparable to that described for CAR-T cell monotherapy.

The Next-Generation Oral Selective Estrogen Receptor Degrader Camizestrant (AZD9833) Suppresses ER+ Breast Cancer Growth and Overcomes Endocrine and CDK4/6 Inhibitor Resistance.

Oral selective estrogen receptor degraders (SERD) could become the backbone of endocrine therapy (ET) for estrogen receptor-positive (ER+) breast cancer, as they achieve greater inhibition of ER-driven cancers than current ETs and overcome key resistance mechanisms. In this study, we evaluated the preclinical pharmacology and efficacy of the next-generation oral SERD camizestrant (AZD9833) and assessed ER-co-targeting strategies by combining camizestrant with CDK4/6 inhibitors (CDK4/6i) and PI3K/AKT/mTOR-targeted therapy in models of progression on CDK4/6i and/or ET. Camizestrant demonstrated robust and selective ER degradation, modulated ER-regulated gene expression, and induced complete ER antagonism and significant antiproliferation activity in ESR1 wild-type (ESR1wt) and mutant (ESR1m) breast cancer cell lines and patient-derived xenograft (PDX) models. Camizestrant also delivered strong antitumor activity in fulvestrant-resistant ESR1wt and ESR1m PDX models. Evaluation of camizestrant in combination with CDK4/6i (palbociclib or abemaciclib) in CDK4/6-naive and -resistant models, as well as in combination with PI3Kαi (alpelisib), mTORi (everolimus), or AKTi (capivasertib), indicated that camizestrant was active with CDK4/6i or PI3K/AKT/mTORi and that antitumor activity was further increased by the triple combination. The response was observed independently of PI3K pathway mutation status. Overall, camizestrant shows strong and broad antitumor activity in ER+ breast cancer as a monotherapy and when combined with CDK4/6i and PI3K/AKT/mTORi. SIGNIFICANCE: Camizestrant, a next-generation oral SERD, shows promise in preclinical models of ER+ breast cancer alone and in combination with CDK4/6 and PI3K/AKT/mTOR inhibitors to address endocrine resistance, a current barrier to treatment.

Model-Informed Precision Dosing Software Tools for Dosage Regimen Individualization: A Scoping Review.

BACKGROUND: Pharmacokinetic nomograms, equations, and software are considered the main tools available for Therapeutic Drug Monitoring (TDM). Model-informed precision dosing (MIPD) is an advanced discipline of TDM that allows dose individualization, and requires a software for knowledge integration and statistical calculations. Due to its precision and extensive applicability, the use of these software is widespread in clinical practice. However, the currently available evidence on these tools remains scarce. OBJECTIVES: To review and summarize the available evidence on MIPD software tools to facilitate its identification, evaluation, and selection by users. METHODS: An electronic literature search was conducted in MEDLINE, EMBASE, OpenAIRE, and BASE before July 2022. The PRISMA-ScR was applied. The main inclusion criteria were studies focused on developing software for use in clinical practice, research, or modelling. RESULTS: Twenty-eight software were classified as MIPD software. Ten are currently unavailable. The remaining 18 software were described in depth. It is noteworthy that all MIPD software used Bayesian statistical methods to estimate drug exposure and all provided a population model by default, except NONMEN. CONCLUSIONS: Pharmacokinetic software have become relevant tools for TDM. MIPD software have been compared, facilitating its selection for use in clinical practice. However, it would be interesting to standardize the quality and validate the software tools.

Swirling Fluid Reduces the Bounce of Partially Filled Containers.

Certain spatial distributions of water inside partially filled containers can significantly reduce the bounce of the container. In experiments with containers filled to a volume fraction ϕ, we show that rotation offers control and high efficiency in setting such distributions and, consequently, in altering bounce markedly. High-speed imaging evidences the physics of the phenomenon and reveals a rich sequence of fluid-dynamics processes, which we translate into a model that captures our overall experimental findings.

Aging affects GABAergic function and calcium homeostasis in the mammalian central clock.

Introduction: Aging impairs the function of the central circadian clock in mammals, the suprachiasmatic nucleus (SCN), leading to a reduction in the output signal. The weaker timing signal from the SCN results in a decline in rhythm strength in many physiological functions, including sleep-wake patterns. Accumulating evidence suggests that the reduced amplitude of the SCN signal is caused by a decreased synchrony among the SCN neurons. The present study was aimed to investigate the hypothesis that the excitation/inhibition (E/I) balance plays a role in synchronization within the network. Methods: Using calcium (Ca2+) imaging, the polarity of Ca2+ transients in response to GABA stimulation in SCN slices of old mice (20-24 months) and young controls was studied. Results: We found that the amount of GABAergic excitation was increased, and that concordantly the E/I balance was higher in SCN slices of old mice when compared to young controls. Moreover, we showed an effect of aging on the baseline intracellular Ca2+ concentration, with higher Ca2+ levels in SCN neurons of old mice, indicating an alteration in Ca2+ homeostasis in the aged SCN. We conclude that the change in GABAergic function, and possibly the Ca2+ homeostasis, in SCN neurons may contribute to the altered synchrony within the aged SCN network.

Gender bias in clinical trials of biological agents for migraine: A systematic review.

Migraine is considered one of the most disabling diseases. Currently, there are few studies on clinical migraine treatment based on sex-related differences, despite the important role of sex in migraine. Our aim was to evaluate gender bias in published clinical trials on monoclonal antibodies (erenumab, galcanezumab, fremanezumab and eptinezumab). We performed a systematic review of controlled clinical trials of erenumab, galcanezumab, fremanezumab and eptinezumab, searching the PubMed/MEDLINE database for articles published before December 2021. The search identified 760 articles, 25 of which met the inclusion criteria. Of all the patients included in these trials, 85.1% were women. Only one study had female lead authors. Two of the 25 studies included a sex-based analysis of the primary endpoint. None of the articles discussed the results separately for men and for women. The proportion of men recruited in trials is scarce and more studies are needed to guarantee the safety and tolerability of monoclonal antibodies used in male migraine. As observed in our study, despite the high number of women recruited, only 2 studies analysed the results separately by sex. Thus, a potential risk of gender bias was found in these clinical trials.

Radiation Exposure in Endovascular Surgery According to Complexity: Protocol for a Prospective Observational Study.

In the past decades, we have witnessed tremendous developments in endovascular surgery. Nowadays, highly complex procedures are performed by minimally invasive means. A key point is equipment improvement. Modern C-arms provide advanced imaging capabilities, facilitating endovascular navigation with an adequate open surgical environment. Nevertheless, radiation exposure remains an issue of concern. This study aims to analyze radiation used during endovascular procedures according to complexity, comparing a mobile X-ray system with a hybrid room (fixed X-ray system). This is an observational and prospective study based on a cohort of non-randomized patients treated by endovascular procedures in a Vascular Surgery department using two imaging systems. The study is planned for a 3-year duration with a recruitment period of 30 months (beginning 20 July 2021) and a 1-month follow-up period for each patient. This is the first prospective study designed to describe the radiation dose according to the complexity of the procedure. Another strength of this study is that radiologic variables are obtained directly from the C-arm and no additional measurements are required for feasibility benefit. The results from this study will help us determine the level of radiation in different endovascular procedures, in view of their complexity.

Alectinib - induced acute renal failure.

Introduction: Alectinib is a potent and selective orally active tyrosine kinase inhibitor used for anaplastic lymphoma kinase-positive non-small cell lung cancer, which has a better safety profile than other inhibitors of anaplastic lymphoma kinase. We report a case of a mixed pattern of acute interstitial nephritis and acute tubular necrosis proven by renal biopsy upon starting alectinib therapy. Case report: A 68-year-old man with diabetes, hypertension, and dyslipidaemia, diagnosed with anaplastic lymphoma kinase-positive non-small cell lung cancer stage IV, had 27 days previously started alectinib 600 mg twice daily. He presented at the emergency room due to vomiting, nausea, and more dyspnoea than usual. A high creatinine level and metabolic imbalances were detected in laboratory tests. Management and outcomes: After a diagnosis of acute renal failure, the patient was admitted to hospital. Nephrotoxic drugs were suspended, and haemodialysis was required. After dismissing other causes, a probable diagnosis of acute interstitial nephritis due to alectinib was established. Corticotherapy was initiated and renal function returned to baseline levels. Renal biopsy showed a mixed pattern of acute interstitial nephritis and acute tubular necrosis. The patient was discharged, and alectinib therapy was modified to lorlatinib. No polymorphisms were found in a pharmacogenetic test. After 10 months with lorlatinib, renal function remains stable. Discussion: The relationship between acute renal failure and alectinib initiation is considered probable in this patient. Although it is an adverse effect reported in less than 1% of cases, it would be advisable to monitor renal function in this kind of patient.

An integrated modelling approach for targeted degradation: insights on optimization, data requirements and PKPD predictions from semi- or fully-mechanistic models and exact steady state solutions.

The value of an integrated mathematical modelling approach for protein degraders which combines the benefits of traditional turnover models and fully mechanistic models is presented. Firstly, we show how exact solutions of the mechanistic models of monovalent and bivalent degraders can provide insight on the role of each system parameter in driving the pharmacological response. We show how on/off binding rates and degradation rates are related to potency and maximal effect of monovalent degraders, and how such relationship can be used to suggest a compound optimization strategy. Even convoluted exact steady state solutions for bivalent degraders provide insight on the type of observations required to ensure the predictive capacity of a mechanistic approach. Specifically for PROTACs, the structure of the exact steady state solution suggests that the total remaining target at steady state, which is easily accessible experimentally, is insufficient to reconstruct the state of the whole system at equilibrium and observations on different species (such as binary/ternary complexes) are necessary. Secondly, global sensitivity analysis of fully mechanistic models for PROTACs suggests that both target and ligase baselines (actually, their ratio) are the major sources of variability in the response of non-cooperative systems, which speaks to the importance of characterizing their distribution in the target patient population. Finally, we propose a pragmatic modelling approach which incorporates the insights generated with fully mechanistic models into simpler turnover models to improve their predictive ability, hence enabling acceleration of drug discovery programs and increased probability of success in the clinic.

Discovery of Clinical Candidate AZD0095, a Selective Inhibitor of Monocarboxylate Transporter 4 (MCT4) for Oncology.

Due to increased reliance on glycolysis, which produces lactate, monocarboxylate transporters (MCTs) are often upregulated in cancer. MCT4 is associated with the export of lactic acid from cancer cells under hypoxia, so inhibition of MCT4 may lead to cytotoxic levels of intracellular lactate. In addition, tumor-derived lactate is known to be immunosuppressive, so MCT4 inhibition may be of interest for immuno-oncology. At the outset, no potent and selective MCT4 inhibitors had been reported, but a screen identified a triazolopyrimidine hit, with no close structural analogues. Minor modifications to the triazolopyrimidine were made, alongside design of a constrained linker and broad SAR exploration of the biaryl tail to improve potency, physical properties, PK, and hERG. The resulting clinical candidate 15 (AZD0095) has excellent potency (1.3 nM), MCT1 selectivity (>1000×), secondary pharmacology, clean mechanism of action, suitable properties for oral administration in the clinic, and good preclinical efficacy in combination with cediranib.

Stability of a tilted granular monolayer: How many spheres can we pick before the collapse?

The triggering of avalanches is investigated using discrete element simulations for a process of random extraction of spheres. A monolayer, formed by identical spheres in a hexagonal configuration, is placed on a tilted plane surrounded by a small fence that sustains the spheres, mimicking the disposal of fruits in the market. Then, a random continuous extraction process of spheres is imposed until the collapse. For this simple numerical experiment, a phase diagram was obtained to visualize the occurrence of avalanches triggered by vacancies as a function of the tilting angle, system size, and friction coefficient. More importantly, a subzone was found where we can predict the critical number of extractions until the avalanche takes place. The prediction is made from an evolution model of the average coordination number based on statistical considerations. The theoretical prediction also gives a constant critical void fraction of spheres, which implies the system collapses at a critical packing fraction.

Checking Different Video Game Mechanics to Assess Cognitive Abilities in Groups with and without Emotional Problems.

This study assesses cognitive abilities through video games for entertainment (Blek, Edge, and Unpossible) that were programmed from scratch to record players' behavior and the levels achieved in a sample without emotional problems and in one with emotional problems. The non-emotional-problem sample was recruited from three universities and two bachelor's degree programs. The emotional-problem sample was recruited from two outpatient centers. The participants in the emotional-problem sample completed reduced versions of the ability tests and video games, as required by their emotional problems. Three subtests of the Differential Aptitude Test that assessed abstract reasoning, visuospatial reasoning, and perceptual speed were selected as ability tests. All participants were required to complete a mental health questionnaire (PROMIS) and a brief questionnaire on their gaming habits and previous experience with the video games used. The results that were obtained showed good convergent validity of the video games as measures of cognitive abilities, and they showed that the behavior of players in the sample without emotional problems while playing predicted the level achieved in the Blek and Unpossible game fragments, but this was only true for Unpossible in the emotional-problem sample; finally, shorter versions of the Blek and Edge game fragments can be used because they maintain their good psychometric properties.

Prevalencia de virus de ARN en tubérculos-semilla certificados de Solanum tuberosum cv. Diacol Capiro de la sabana Cundiboyacense

La papa (Solanum tuberosum) Diacol Capiro es uno de los cultivares con mayor producción y consumo interno en Colombia, siendo los departamentos de Cundinamarca y Boyacá, los principales productores. Este cultivo, se ve afectado por un complejo de virus, que disminuye la calidad de los tubérculos y los rendimientos. En este trabajo, se evaluó la prevalencia de los virus de ARN: PLRV, PVY, PVX, PVS, PVV, PYVV, PMTV y PVB, en brotes de tubérculos-semilla certificados, provenientes de la sabana Cundiboyacense, mediante RT-qPCR. Los resultados revelan la ocurrencia de siete de los ochos virus en las muestras, con niveles de infección de 100 % (PVS, PVX y PYVV), 75 % (PLRV), 50 % (PVY), 37,5 % (PMTV) y 12,5 % (PVB). Adicionalmente, con el fin de obtener información de los genomas de los virus detectados, se utilizó secuenciación de alto rendimiento (HTS), de una muestra compuesta (bulk) de brotes, siendo posible obtener el genoma completo del PLRV y el genoma parcial del PVY. Los análisis filogenéticos realizados con dichas secuencias ubicaron a los virus PLRV y PVY en clados, conformados por aislamientos colombianos, con niveles de identidad superiores al 97 %. Estos hallazgos evidencian la necesidad de fortalecer los programas de certificación de tubérculos-semilla de papa en el país, mediante la utilización de pruebas moleculares de detección viral.

Diacol-Capiro is one of the most important potato (Solanum tuberosum) cultivars in Colombia with most production concentrated in the provinces of Cundinamarca and Boyacá. Unfortunately, this crop is seriously affected by several viruses that compromise the quality of tubers and yields. In this work, it was evaluated the prevalence of the RNA viruses: PLRV, PVY, PVX, PVS, PVV, PYVV, PMTV, and PVB in certified tuber-seed sprouts produced in the highlands of Cundinamarca and Boyacá by RT-qPCR. Results revealed a prevalence of 100 % for PVS, PVX, and PYVV; 75 % for PLRV, 50 % for PVY, 37.5 % for PMTV, and 12.5 % for PVB. Additionally, high-throughput sequencing from a sprout´s bulk sample was used to gather genomic information of infecting viruses, which resulted in a partial PVY sequence, and a complete PLRV genome. Phylogenetic analysis revealed that both assemblies cluster within clades comprising other Colombian isolates with more than 97 % nucleotide sequence identity. These findings highlight the need to update potato seed-tuber certification programs in Colombia with the implementation of more sensitive molecular tests.