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Competing Interests: Declaration of competing interest None.

In the past several years there has been rapid adoption of artificial intelligence (AI) and machine learning (ML) tools for drug discovery. In this Microperspective, we comment on recent AI/ML applications to the discovery of allosteric modulators, focusing on breakthroughs with AlphaFold, structure-based drug discovery (SBDD), and medicinal chemistry applications. We discuss how these technologies are facilitating drug discovery and the remaining challenges to identify allosteric binding sites and ligands., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

Approaches to rapidly collecting global biodiversity data are increasingly important, but biodiversity blind spots persist. We organized a three-day Datathon event to improve the openness of local biodiversity data and facilitate data reuse by local researchers. The first Datathon, organized among microbial ecologists in Uruguay and Argentina assembled the largest microbiome dataset in the region to date and formed collaborative consortia for microbiome data synthesis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The prevalence of cardiovascular diseases (CVDs) is a growing global health concern. Recent advances have demonstrated significant reductions in acute cardiovascular events through the management of modifiable cardiovascular risk factors. However, these factors are responsible for about 50% of the global cardiovascular disease burden. Considering that CVDs are one of the top mortality causes worldwide, the concept of residual cardiovascular risk is an important emerging area of study. Different factors have been proposed as sources of residual risk markers, including non-HDL particles characterization, as well as inflammation measured by serum and imaging technics. Among these, metabolic-associated steatotic liver disease (MASLD) remains controversial. Two opposing viewpoints contend: one positing that fatty liver disease merely reflects classical risk factors and thus adds no additional risk and another asserting that fatty liver disease independently impacts cardiovascular disease incidence. To address this dilemma, one hypothetical approach is to identify specific hepatic energy-yielding mechanisms and assess their impact on the cardiovascular system. Ketogenesis, a metabolic intermediate process particularly linked to energy homeostasis during fasting, might help to link these concepts. Ketogenic metabolism has been shown to vary through MASLD progression. Additionally, newer evidence supports the significance of circulating ketone bodies in cardiovascular risk prediction. Furthermore, ketogenic metabolism modification seems to have a therapeutic impact on cardiovascular and endothelial damage. Describing the relationship, if any, between steatotic liver disease and cardiovascular disease development through ketogenesis impairment might help to clarify MASLD's role in cardiovascular risk. Furthermore, this evidence might help to solve the controversy surrounding liver steatosis impact in CVD and might lead to a more accurate risk assessment and therapeutic targets in the pursuit of precision medicine.

Soil water deficit and salinity represent a major factor impacting plant survival and agricultural production. The frequency and severity of both abiotic stresses are expected to increase in a context of climate change, especially in arid and semi-arid regions. This work studied the growth pattern, biomass and mineral distribution and the seasonal pattern of water status, photosynthetic rate and stomatal conductance in plant of Pistacia lentiscus grown under different levels of water deficit and salinity. P. lentiscus plants growing under greenhouse conditions were subjected to four irrigation treatments during 11 months: control (C, 1 dS m -1 ), moderate water deficit (MW, 1dS m -1 , 60% of the control), severe water deficit (SW, 1 dS m -1 , 40% of the control) and saline (S, 4dS m -1 ). The results show that Pistacia lentiscus plants were more affected by deficit irrigation than salinity. Deficit irrigation and salinity inhibited plant height, with reductions of 20%, 22% and 35% for S, MW and SW, respectively. Total leaf area was not modified by effect of the treatments, with the result that plant compactness increased in MW. The salt stressed plants only showed lower relative growth rate at the end of the experiment. Plants responded to saline or drought stress by increasing their osmotic adjustment, which was more pronounced under salinity. Saline plants had the highest values in Na + and Cl - ions and the lowest values for K + /Na + and Ca 2+ /Na + ratios in leaves and stems, which is correlated with a decrease in growth, stomatal conductance, photosynthesis and stem water potential, and can be used as a diagnostic tool to assess plant tolerance to salinity stress. As a measure of plant hydration, relative water content was more sensitive to deficit irrigation than salinity, being a good indicator of water stress. P. lentiscus plants subjected to both deficit irrigation treatments exhibited an increase in their intrinsic water use efficiency, which is an important adaptation for plants growing in environments with water scarcity., 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 © 2023 Álvarez, Acosta-Motos and Sánchez-Blanco.)

Vascular tissue banking has been carried out in Brussels for over 30 years in compliance with EU and Swiss tissue banking regulations. A total of 2.765 vascular tissue donations were performed in Belgian, French, Netherlands and Suisse transplant centres: 547(20%), 1.013(37%) and 1.205(43%) during the first, second and third periods, respectively. 85% and 18% increase in donations during the second and third decades compared to previous one, were remarkable. Of the 7.066 evaluated vascular tissues, 2.407(227, 921 and 1.259) were discarded (34.1%), whereas 4.659(523, 1.861 and 2.275) accepted (65.9%) during the respective period. Of the 92 donated veins, 44(47.8%) were discarded and 48(52.2%) accepted. Allografts available for clinical application were stored in vapours of liquid nitrogen. A total of 4.636 allografts were delivered and transplanted for cases of infection (58%), critical limb ischaemia (16%) and congenital cardiac surgery (15%). Thirty veins were implanted. The progressive increases in donations of 20%, 37% and 43% and in transplantations of 20.8%, 34.6% and 45% during the first, second and third periods, respectively, were remarkable. Complications were reported after transplantation and these included acute rejection of two femoral arteries one month after transplantation. We conclude that the donation and transplantation of cryopreserved vascular allografts was stable with a progressive increase over time. Allografts were used predominantly for the treatment of infection, limb salvage for critical ischaemia and for neonates and infants with congenital cardiac malformation. Immune related rejection was observed. This should be a subject of future investigation., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

A 66-year-old woman was admitted to the emergency department with diarrhea, nausea, and vomiting as well as low-grade fever. She was initially treated with ciprofloxacin and metronidazole with symptomatic improvement and was discharged. One week later, she returned to the emergency department for gait instability, dizziness, and vomiting and had a witnessed generalized tonic-clonic seizure in the hospital. During both admissions, the presence of ionic alterations such as severe hypomagnesemia, hypophosphatemia, and hypokalemia stood out, while sodium levels remained normal. Among her antecedents, she had a hiatal hernia and had been receiving treatment with omeprazole for years., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Romero Calvo et al.)

A 41-year-old man was admitted to the Emergency Department with bilateral numbness in lower extremities and left femoral palsy. He also reported constitutional symptoms, vomiting and non-bloody diarrhoea for the last several months. He had a previous history of eosinophilic asthma with erratic follow-up. During admission, eosinophil count was 66% of white blood cells. Sural nerve biopsy revealed vasculitis with eosinophilic infiltration. Further evaluations consisted of colonoscopy and nasal endoscopy that confirmed eosinophil infiltrates on colonic ulcers and nasal polypi. The patient was started on systemic corticosteroids and cyclophosphamide. Among his personal records, he had been taking nandrolone decanoate without medical prescription, and had withdrawn a few years before the first asthma exacerbation., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Garcia-Blanco et al.)

Introduction: The consensus on recovery from alcohol use disorder (AUD) has shifted toward encompassing psychological wellbeing and quality of life dimensions. However, few studies have explored the long-term recovery process and its dimensions, timing, styles, and modes. The aim of this study was to investigate the extent, timing, and process of psychological wellbeing and quality of life recovery in alcohol use disorder (AUD) patients, as well as the relationship with classic dimensions of AUD recovery., Method: A cross-sectional study has been carried out with 348 participants with AUD, in different abstinence periods (1 month-28 years), and 171 control subjects. Participants underwent a psychological evaluation, which included self-informed measures of psychological wellbeing, quality of life, negative emotionality, and coping strategies related to alcohol consumption avoidance. Statistical analysis included linear and non-linear regression models between psychological dimensions and maintenance of abstinence, as well as matching the scores of the sample with AUD to those of controls. Scatter plots were used to explore inflection points. In addition, mean comparison tests were performed between participants with AUD and controls and by gender., Results: In general, according to the regression models, there were pronounced increases in indices of wellbeing and coping strategies (and pronounced decreases in negative emotionality) during the first 5 years of abstinence, followed by less pronounced improvements. The matching of AUD subjects in wellbeing and negative emotionality indices with controls occurs at different times: (a) 1 year or less: physical health; (b) 1-4 years: psychological health; (c) 4-10 years: social relationships, wellbeing, and negative emotionality; and (d) more than 10 years: autonomy and self-acceptance. There are statistically significant differences by gender for the negative emotionality and physical health variables., Conclusion: Recovery from AUD is a long process that involves improvements in wellbeing and quality of life. Four stages can be described in this process, with the most pronounced changes occurring during the first 5 years of abstinence. However, AUD patients take more time to obtain similar scores to controls in several psychological dimensions., 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 © 2023 Rubio, Esteban Rodríguez, Sion, Ramis Vidal, Blanco, Zamora-Bayon, Caba-Moreno, Macias-Molina, Pérez-Sánchez, Rubio-Escobar, Ruiz-Diez, Marin, Arias, Lora and Jurado-Barba.)

The generation of multiple bonds in one reaction step has attracted massive interest in drug discovery and development. Multicomponent reactions (MCRs) offer the advantage of combining three or more reagents in a one-pot fashion to effectively yield a synthetic product. This approach significantly accelerates the synthesis of relevant compounds for biological testing. However, there is a perception that this methodology will only produce simple chemical scaffolds with limited use in medicinal chemistry. In this Microperspective, we want to highlight the value of MCRs toward the synthesis of complex molecules characterized by the presence of quaternary and chiral centers. This paper will cover specific examples showing the impact of this technology toward the discovery of clinical compounds and recent breakthroughs to expand the scope of the reactions toward topologically rich molecular chemotypes., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

Breast cancer is the most incidental and deadly neoplasm worldwide; in Mexico, very few epidemiologic reports have analyzed the pathological features and its impact on their clinical outcome. Here, we studied the relation between pathological features and the clinical presentation at diagnosis and their impact on the overall and progression-free survival of patients with breast cancer. For this purpose, we collected 199 clinical records of female patients, aged at least 18 years old (y/o), with breast cancer diagnosis confirmed by biopsy. We excluded patients with incomplete or conflicting clinical records. Afterward, we performed an analysis of overall and progression-free survival and associated risks. Our results showed an average age at diagnosis of 52 y/o (24-85), the most common features were: upper outer quadrant tumor (32%), invasive ductal carcinoma (76.8%), moderately differentiated (44.3%), early clinical stages (40.8%), asymptomatic patients (47.8%), luminal A subtype (47.8%). Median overall survival was not reached, but median progression-free survival was 32.2 months (29.75-34.64, CI 95%) associated risk were: clinical stage (p < 0.0001) symptomatic presentation (p = 0.009) and histologic grade (p = 0.02). Therefore, we concluded that symptom presence at diagnosis impacts progression-free survival, and palpable symptoms are related to an increased risk for mortality.

Insomnia is a modifiable cardiovascular risk factor. Previous studies suggested that attending a cardiac rehabilitation program may improve sleep quality in cardiac patients and pointed out the association between heart failure and poor sleep quality. The primary aim of this study was to evaluate sleep quality in patients attending a Multidisciplinary Cardiac Rehabilitation Program (MRCP), and to compare sleep quality between patients with and without heart failure. A prospective observational study was carried out on a consecutive sample of 240 patients attending an 8-week MRCP; 50 patients (20.8%) were included due to heart failure (NYHA stages I-III) and the rest of them after having undergone any revascularization procedure or valvular surgery. Before and after the completion of the MRCP, the quality of sleep was assessed by the Pittsburgh Sleep Quality Index (PSQI) score. Post-intervention global PSQI scores were statistically significantly lower than those of pre-intervention ( p = 0.008), but only 60 patients (25%) registered a clinically significant improvement. When comparing patients with heart failure with those without, no differences in sleep quality were found. This suggests that only a small percentage of patients can achieve clinically significant improvements in sleep quality attending conventional MCRP. Suggestions for future research are given.

The use of reclaimed water is considered an efficient tool for agricultural irrigation; however, the high salinity associated to this water could compromise plant quality and yields. Balm and spearmint plants were submitted for 15 days to three irrigation treatments in a controlled chamber: control with EC: 1.2 dS m -1 (control), reclaimed water from secondary effluent (EC: 1.6 dS m -1 ) (S) and water from secondary effluent with brine (EC: 4.4 dS m -1 ) (SB). The plant water status, stomatal and hormonal regulation, nutritional response, concentration of amino acids and plant oxidative stress-based markers, as well as growth were evaluated. Both species irrigated with saline reclaimed water reduced leaf water potential and gas exchange in comparison with control plants, following 2 days of exposure to irrigation treatments. Nevertheless, spearmint plants recovered photosynthetic activity from the seventh day onwards, maintaining growth. This was attributed to hormonal changes and a greater accumulation of some amino acids and some plant oxylipins (phytoprostanes) in comparison to balm plants, which contributed to the improvement in the organoleptic and health-promoting properties of spearmint. A longer irrigation period with saline reclaimed water would be necessary to assess whether the quality of both species, especially spearmint, could further improve without compromising their growth.

Brain diseases are a major cause of death and disability worldwide and contribute significantly to years of potential life lost. Although there have been considerable advances in biological mechanisms associated with brain disorders as well as drug discovery paradigms in recent years, these have not been sufficiently translated into effective treatments. This Special Article expands on Keystone Symposia's pre- and post-pandemic panel discussions on translational neuroscience research. In the article, we discuss how lessons learned from the COVID-19 pandemic can catalyze critical progress in translational research, with efficient collaboration bridging the gap between basic discovery and clinical application. To achieve this, we must place patients at the center of the research paradigm. Furthermore, we need commitment from all collaborators to jointly mitigate the risk associated with the research process. This will require support from investors, the public sector and pharmaceutical companies to translate disease mechanisms into world-class drugs. We also discuss the role of scientific publishing in supporting these models of open innovation. Open science journals can now function as hubs to accelerate progress from discovery to treatments, in neuroscience in particular, making this process less tortuous by bringing scientists together and enabling them to exchange data, tools and knowledge effectively. As stakeholders from a broad range of scientific professions, we feel an urgency to advance brain disease therapies and encourage readers to work together in tackling this challenge., Competing Interests: Competing interests M.-J.B., M.I.L. and K.M. were the organizers of the Keystone Symposia events discussed in this article. J.H. is Senior Editor at DMM but was not involved in any aspect of the editorial handling of the article. S.C. is Head of Research at The Michael J. Fox Foundation for Parkinson's Research and thus has extensive knowledge of this funder's priorities., (© 2022. Published by The Company of Biologists Ltd.)

Drug discovery and development has experienced an incredible paradigm shift in the past two decades. What once was considered a predominant R&D landscape of small molecules within a prescribed properties and mechanism space now includes an innovative wave of new chemical modalities. Scientists in the pharmaceutical industry can now strategize across a variety of modalities to find the best option to modulate a given target and provide treatment for a specific disease. We have witnessed a remarkable change not only in molecular design but also in creative approaches to drug delivery that have enabled advancement of novel modalities to clinical studies. In this Microperspective, we evaluate the critical differences between traditional small molecules and beyond rule of 5 compounds, peptides, oligonucleotides, and biologics for advancing into development, particularly their pharmacokinetic profiles and drug delivery strategies., Competing Interests: The authors declare the following competing financial interest(s): M.N.N. discloses that his research is funded by AbbVie. He is a consultant for Axonis and on the SAB of Sionna Therapeutics., (© 2022 American Chemical Society.)

N -Methyl-d-aspartate receptor (NMDAR) positive allosteric modulators (PAMs) have received increased interest as a powerful mechanism of action to provide relief as therapies for CNS disorders. Sage Therapeutics has previously published the discovery of endogenous neuroactive steroid 24( S )-hydroxycholesterol as an NMDAR PAM. In this article, we detail the discovery of development candidate SAGE-718 ( 5 ), a potent and high intrinsic activity NMDAR PAM with an optimized pharmacokinetic profile for oral dosing. Compound 5 has completed phase 1 single ascending dose and multiple ascending dose clinical trials and is currently undergoing phase 2 clinical trials for treatment of cognitive impairment in Huntington's disease.

Mycobacterium tuberculosis ( Mtb ), the etiological agent of tuberculosis, is one of the most devastating infectious agents in the world. Chemical-genetic characterization through in vitro evolution combined with whole genome sequencing analysis was used identify novel drug targets and drug resistance genes in Mtb associated with its intracellular growth in human macrophages. We performed a genome analysis of 53 Mtb mutants resistant to 15 different hit compounds. We found nonsynonymous mutations/indels in 30 genes that may be associated with drug resistance acquisitions. Beyond confirming previously identified drug resistance mechanisms such as rpoB and lead targets reported in novel anti-tuberculosis drug screenings such as mmpL3 , ethA , and mbtA , we have discovered several unrecognized candidate drug targets including prrB . The exploration of the Mtb chemical mutant genomes could help novel drug discovery and the structural biology of compounds and associated mechanisms of action relevant to tuberculosis treatment.

Background and Purpose: Uveal melanoma is the most common primary malignant intraocular tumour in the adult population, with a survival rate of 50% despite advances in treatment and knowledge of this disease. The presence of extraocular extension (EE) worsens the prognosis of these patients, so its proper identification can ensure its management and early intervention. Ophthalmological ultrasound is the technique of choice for the diagnosis and follow-up of these patients, both of the anterior EE using ultrasonic biomicroscopy (UBM), and the posterior EE using A and B ultrasound. The aim of this study is to describe the ultrasound characteristics of the BMU and the A and B ultrasound., Material and Methods: A descriptive and retrospective study is carried out on patients diagnosed with uveal melanoma (UM) and EE from 2003 to 2019. The ultrasound characteristics of the local disease and the follow-up after treatment were recorded completely and at each visit. In the case of anterior EE, photographs of the anterior segment and UBM were taken, while those involving the posterior segment were explored under A and B mode ultrasound. All enucleated eyes were sent for anatomopathological study., Results: Ten patients with an average age of 72.3 years were included. The largest proportion of them were medium-sized tumours, followed by large and small ones. The most frequent morphology of the primary tumour was cupuliform. All the EE presented lower internal reflectivity compared to the primary tumour. No trans-scleral connection bridges were found between the primary tumour and the EE in the ultrasound studies. 50% of patients underwent primary enucleation at the time of diagnosis of intraocular MU due to the presence of the EE, and the remaining 50% presented the EE after initial treatment of the primary tumour with I125 brachytherapy. Sixty percent of the patients presented with posterior EE, and were therefore diagnosed with ultrasound A and B. The most frequent histopathological pattern with 87.5% of patients was the epithelioid pattern., Discussion: Ultrasound scanning in patients with MU is mandatory for diagnosis and follow-up of EE. BMU and A and B ultrasound are the test of choice for anterior and posterior EE, respectively. EE have particular ultrasound characteristics such as low internal reflectivity, regularity of their contour and their location usually adjacent to the base of the primary intraocular tumor., (Copyright © 2021 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Venous thrombotic events (VTE) are frequent in COVID-19, and elevated plasma D-dimer (pDd) and dyspnea are common in both entities., Objective: To determine the admission pDd cut-off value associated with in-hospital VTE in patients with COVID-19., Methods: Multicenter, retrospective study analyzing the at-admission pDd cut-off value to predict VTE and anticoagulation intensity along hospitalization due to COVID-19., Results: Among 9386 patients, 2.2% had VTE: 1.6% pulmonary embolism (PE), 0.4% deep vein thrombosis (DVT), and 0.2% both. Those with VTE had a higher prevalence of tachypnea (42.9% vs. 31.1%; p = 0.0005), basal O2 saturation <93% (45.4% vs. 33.1%; p = 0.0003), higher at admission pDd (median [IQR]: 1.4 [0.6-5.5] vs. 0.6 [0.4-1.2] μg/ml; p < 0.0001) and platelet count (median [IQR]: 208 [158-289] vs. 189 [148-245] platelets × 10 9 /L; p = 0.0013). A pDd cut-off of 1.1 μg/ml showed specificity 72%, sensitivity 49%, positive predictive value (PPV) 4%, and negative predictive value (NPV) 99% for in-hospital VTE. A cut-off value of 4.7 μg/ml showed specificity of 95%, sensitivity of 27%, PPV of 9%, and NPV of 98%. Overall mortality was proportional to pDd value, with the lowest incidence for each pDd category depending on anticoagulation intensity: 26.3% for those with pDd >1.0 μg/ml treated with prophylactic dose (p < 0.0001), 28.8% for pDd for patients with pDd >2.0 μg/ml treated with intermediate dose (p = 0.0001), and 31.3% for those with pDd >3.0 μg/ml and full anticoagulation (p = 0.0183)., Conclusions: In hospitalized patients with COVID-19, a pDd value greater than 3.0 μg/ml can be considered to screen VTE and to consider full-dose anticoagulation., (© 2021. Society of General Internal Medicine.)

Background & Aims: Non-invasive scoring systems (NSS) are used to identify patients with non-alcoholic fatty liver disease (NAFLD) who are at risk of advanced fibrosis, but their reliability in predicting long-term outcomes for hepatic/extrahepatic complications or death and their concordance in cross-sectional and longitudinal risk stratification remain uncertain., Methods: The most common NSS (NFS, FIB-4, BARD, APRI) and the Hepamet fibrosis score (HFS) were assessed in 1,173 European patients with NAFLD from tertiary centres. Performance for fibrosis risk stratification and for the prediction of long-term hepatic/extrahepatic events, hepatocarcinoma (HCC) and overall mortality were evaluated in terms of AUC and Harrell's c-index. For longitudinal data, NSS-based Cox proportional hazard models were trained on the whole cohort with repeated 5-fold cross-validation, sampling for testing from the 607 patients with all NSS available., Results: Cross-sectional analysis revealed HFS as the best performer for the identification of significant (F0-1 vs. F2-4, AUC = 0.758) and advanced (F0-2 vs. F3-4, AUC = 0.805) fibrosis, while NFS and FIB-4 showed the best performance for detecting histological cirrhosis (range AUCs 0.85-0.88). Considering longitudinal data (follow-up between 62 and 110 months), NFS and FIB-4 were the best at predicting liver-related events (c-indices>0.7), NFS for HCC (c-index = 0.9 on average), and FIB-4 and HFS for overall mortality (c-indices >0.8). All NSS showed limited performance (c-indices <0.7) for extrahepatic events., Conclusions: Overall, NFS, HFS and FIB-4 outperformed APRI and BARD for both cross-sectional identification of fibrosis and prediction of long-term outcomes, confirming that they are useful tools for the clinical management of patients with NAFLD at increased risk of fibrosis and liver-related complications or death., Lay Summary: Non-invasive scoring systems are increasingly being used in patients with non-alcoholic fatty liver disease to identify those at risk of advanced fibrosis and hence clinical complications. Herein, we compared various non-invasive scoring systems and identified those that were best at identifying risk, as well as those that were best for the prediction of long-term outcomes, such as liver-related events, liver cancer and death., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: COVID-19 related in-hospital venous thromboembolism (VTE) incidence is high but data reported vary significantly. Some studies show that up to half of the events are diagnosed early after admission., Objectives: To study symptomatic VTE incidence in acute COVID-19 hospitalized patients and to describe timing of VTE diagnosis., Methods: Multicenter cohort of 5966 patients hospitalized with acute COVID-19. Multicenter Registry of 844 hospitalized patients with acute COVID-19 and associated acute VTE., Results: By the time of cohort data collection, 68 patients (1.14%) were still hospitalized, 19.8% had died, and 5.4% required ICU. During a median follow-up of 6 days (IQR, 4-12), 183 patients (3.07%; 95% CI, 2.64-3.55) presented a symptomatic VTE event. The cumulative incidences of VTE at 7, 14 and 21 days in wards [2.3% (95% CI, 1.9-2.7), 3.6% (95% CI, 3.0-4.3), and 4.3% (95% CI, 3.5-5.1)] were similar to the ones reported in ICU [2.2% (95% CI, 1.0-4.4), 2.9% (95% CI, 1.5-5.3), and 4.1% (95% CI, 2.2-6.8)], but at 30 and 60 days were higher in ICU [6.9% (95% CI, 4.2-10.5), and 12.8% (95% CI, 8.1-18.5)] than in wards. Eighty-eight VTE events (48%) were diagnosed early, within 48 h of admission. VTE was not associated with death (HR, 0.79; 95% CI, 0.55-1.12)., Conclusions: Incidence of symptomatic VTE in our COVID-19 cohort is consistent with that of other real-life studies recently published. Early VTE events are, along with COVID-19, the reason for admission rather than an in-hospital complication., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Our main aim was to describe the effect on the severity of ACEI (angiotensin-converting enzyme inhibitor) and ARB (angiotensin II receptor blocker) during COVID-19 hospitalization. A retrospective, observational, multicenter study evaluating hospitalized patients with COVID-19 treated with ACEI/ARB. The primary endpoint was the incidence of the composite outcome of prognosis (IMV (invasive mechanical ventilation), NIMV (non-invasive mechanical ventilation), ICU admission (intensive care unit), and/or all-cause mortality). We evaluated both outcomes in patients whose treatment with ACEI/ARB was continued or withdrawn. Between February and June 2020, 11,205 patients were included, mean age 67 years (SD = 16.3) and 43.1% female; 2162 patients received ACEI/ARB treatment. ACEI/ARB treatment showed lower all-cause mortality ( p < 0.0001). Hypertensive patients in the ACEI/ARB group had better results in IMV, ICU admission, and the composite outcome of prognosis ( p < 0.0001 for all). No differences were found in the incidence of major adverse cardiovascular events. Patients previously treated with ACEI/ARB continuing treatment during hospitalization had a lower incidence of the composite outcome of prognosis than those whose treatment was withdrawn (RR 0.67, 95%CI 0.63-0.76). ARB was associated with better survival than ACEI (HR 0.77, 95%CI 0.62-0.96). ACEI/ARB treatment during COVID-19 hospitalization was associated with protection on mortality. The benefits were greater in hypertensive, those who continued treatment, and those taking ARB.

Cistus species can form ectomycorrhizae and arbuscular mycorrhizal fungus that can bring benefits when plants are under water stress conditions. However, the application of some ectomycorrhizae on the water uptake under drought through physiological traits and hormonal regulation is less known. The experiment was performed during three months in a growth chamber with Cistus albidus plants in which the combined effect of the ectomycorrhiza Pisolithus tinctorious inoculation and two irrigation treatments (control and water-stressed plants) were applied. Irrigation absence caused significant decrease in aerial growth and tended to decrease soil water potential at the root surface, leading to a decrease in leaf water potential. Under these conditions, the abscisic acid and salicylic acid content increased while the precursor of ethylene decreased. Although the mycorrhization percentages were not high, the inoculation of P. tinctorious improved the water status and slightly cushioned the rise in leaf temperature of water-stressed plants. The ectomycorrhiza decreased the scopoletin values in leaves of plants subjected to deficit irrigation, indicating that inoculated plants had been able to synthesize defense mechanisms. Therefore, Pisolithus tinctorious alleviated some of the harmful effects of water scarcity in Cistus plants, being its use a sustainable option in gardening or restoration projects.

Chronically activated microglia and the resulting cascade of neuroinflammatory mechanisms have been postulated to play a critical role in neurodegenerative disorders. Microglia are the main component of the brain's innate immune system and become activated by infection, injury, misfolded proteins or a multitude of other stimuli. Activated microglia release pro-inflammatory and cytotoxic factors that can damage neurons and transform astrocytes to become toxic to neurons as well. Therapeutic approaches aiming to modulate microglia activation may be beneficial to mitigate the progression of inflammatory-mediated neurodegenerative diseases. In this literature review, we provide an overview of recent progress on key microglia targets and discovery of small molecule compounds advancing in clinical trials to minimize neuroinflammation., Competing Interests: There is no conflict of interest to declare., (This journal is © The Royal Society of Chemistry.)

Organic residues (compost) can be used as growth medium but may contain phytotoxic ions that, combined with a water deficit may alter the behavior of plants. The experiment was carried out in a growth chamber with Cistus albidus in a commercial substrate, C (sphagnum peat, coconut fiber and perlite, 8:7:1) and a mixture of compost substrates, Cp (slurry compost, coconut fiber and perlite, 3:6:1). Plants were grown in pots under well-watered, maintaining values of Ψ l around -0.9 MPa (WW) and water-stressed (WS) conditions, where the irrigation was removed until reached values of Ψ l around -3.0 MPa (water stress period), after then, water was re-established in all plants (recovery period). Although, the well-watered plants had a leaf water potential (Ψ l ) around -0.9 MPa, stomatal conductance (g s ) was 125 mmol m -2 s -1 in the commercial substrate and 30 mmol m -2 s-1 in compost. The time taken to reach the threshold value at which water stress occurs was 13 days in the commercial substrate and 53 days in compost. Water-stressed plants in the commercial substrate had significantly lower values of Ψ l and g s than well-watered. Plants in compost maintained values of g s similar in both irrigation treatments (WW and WS) and accumulated less biomass than those that grown in commercial. The water stress in compost led an increase in the adaxial epidermis, parenchyma and mesophyll, whereas water stress in commercial the proportions of the different tissues decreased. Higher lipid peroxidation values were found in plants grown in both substrates under water stress. The recovery time of the plants, until manage Ψ l values around -0.9 MPa, depended on the type of substrate. The restoration of irrigation in commercial substrate act as a new stress, as reflected in the photochemical mechanisms., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

This study investigates the impact of dual ionic and covalent cross-links (ion-XrL and cov-XrL) on the properties of chitosan-based (CTS) hydrogels as eco-friendly drug delivery systems (DDS) for the model drug diclofenac sodium (DCNa). Citric acid and a diiodo-trehalose derivative (ITrh) were the chosen ionic and covalent cross-linker, respectively. The novel hydrogels completely disintegrated within 96 h by means of a hydrolysis process mediated by the enzyme trehalase. As far as the authors are aware, this is the first time that a trehalose derivative has been used as a covalent cross-linker in the formation of biodegradable hydrogels. The impact of CTS concentration and degree of cov-XrL on rheological parameters were examined by means of an experimental model design and marked differences were found between the materials. Hydrogels with maximum elastic properties were achieved at high CTS concentrations and high degrees of cov-XrL. DCNa-loaded formulations displayed well-controlled drug-release profiles strongly dependent on formulation composition (from 17% to 40% in 72 h). Surprisingly, higher degrees of covalent cross-linking led to a boost in drug release. The formulations presented herein provides a simple and straightforward pathway to design fully biodegradable, tailor-made controlled drug delivery systems with improved rheological properties., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aims: The influence of the COVID-19 pandemic on attendance to out-of-hospital cardiac arrest (OHCA) has only been described in city or regional settings. The impact of COVID-19 across an entire country with a high infection rate is yet to be explored., Methods: The study uses data from 8629 cases recorded in two time-series (2017/2018 and 2020) of the Spanish national registry. Data from a non-COVID-19 period and the COVID-19 period (February 1st-April 30th 2020) were compared. During the COVID-19 period, data a further analysis comparing non-pandemic and pandemic weeks (defined according to the WHO declaration on March 11th, 2020) was conducted. The chi-squared analysis examined differences in OHCA attendance and other patient and resuscitation characteristics. Multivariate logistic regression examined survival likelihood to hospital admission and discharge. The multilevel analysis examined the differential effects of regional COVID-19 incidence on these same outcomes., Results: During the COVID-19 period, the incidence of resuscitation attempts declined and survival to hospital admission (OR = 1.72; 95%CI = 1.46-2.04; p < 0.001) and discharge (OR = 1.38; 95%CI = 1.07-1.78; p = 0.013) fell compared to the non-COVID period. This pattern was also observed when comparing non-pandemic weeks and pandemic weeks. COVID-19 incidence impinged significantly upon outcomes regardless of regional variation, with low, medium, and high incidence regions equally affected., Conclusions: The pandemic, irrespective of its incidence, seems to have particularly impeded the pre-hospital phase of OHCA care. Present findings call for the need to adapt out-of-hospital care for periods of serious infection risk., Study Registration Number: ISRCTN10437835., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Cross-coupling reactions have played a critical role enabling the rapid expansion of structure-activity relationships (SAR) during the drug discovery phase to identify a clinical candidate and facilitate subsequent drug development processes. The reliability and flexibility of this methodology have attracted great interest in the pharmaceutical industry, becoming one of the most used approaches from Lead Generation to Lead Optimization. In this mini-review, we present an overview of cross-coupling reaction applications to medicinal chemistry efforts, in particular the Suzuki-Miyaura and Buchwald-Hartwig cross-coupling reactions as a remarkable resource for the generation of carbon-carbon and carbon-heteroatom bonds. To further appreciate the impact of this methodology, the authors discuss some recent examples of clinical candidates that utilize key cross-coupling reactions in their large-scale synthetic process. Looking into future opportunities, the authors highlight the versatility of the cross-coupling reactions towards new chemical modalities like DNA-encoded libraries (DELs), new generation of peptides and cyclopeptides, allosteric modulators, and proteolysis targeting chimera (PROTAC) approaches.

Aims: To analyse the profile of patients suffering from falls in the hospital environment., Method: Longitudinal study, prospective follow-up of a cohort of patients recruited from May 2014 to March 2016. Medical, surgical and intensive care units of 5 acute hospitals of the Community of Andalusia participated. Patients older than 16 years were included. The variables of characterization were: age, sex, unit, stay, preventive measures, and those of result: level of consciousness, sensory deficits, mobility, number of falls, circumstances and consequences, medications, previous falls., Results: 1,247 patients were recruited, of whom 977 completed the study. The incidence of falls was 2.35%. The average age of the faller was 73.6 years (P=.015). The event occurred mostly in women (56.5%) and in medical units (79%). The falls caused minor damage. Rearrangement of the furniture proved to be the only protective measure (OR= 3.95, 95% CI 1.46-10.68, P=.015). The predictors of the event were: having been admitted to the hospital after a fall (HR= 5.88, 95% CI 3.23-10.67, P<.001), followed by visual problems, frequent visits to the bathroom and having suffered previous falls., Conclusions: The profile of the patient suffering falls in the hospital is presented as aged over 70 years old, female, admitted to a medical unit, during the night shift, being in bed and alone, without impaired level of consciousness and with a history of falls., (Copyright © 2019 Elsevier España, S.L.U. All rights reserved.)

Mentoring is an essential opportunity to be embraced by medicinal chemists seeking a gratifying career. In this Viewpoint, we highlight the importance of developing an intentional mindset about mentoring to achieve professional goals. The impact of mentoring is even more critical for underrepresented minorities in drug discovery and in particular for women aspiring to achieve leadership positions in the field., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Recent years have seen an unprecedented level of innovation in allosteric drug discovery and development, with multiple drug candidates advancing into clinical studies. From early examples of allosteric drugs like GABA A receptor modulators (benzodiazepines) in the 1960s to more recent GPCR negative allosteric modulators of CCR5 (maraviroc) approved in 2007, the opportunities for interrogating allosteric sites in drug discovery have expanded to other target classes such as protein-protein interactions, kinases, and nuclear hormone receptors. In this Innovation Letter, the authors highlight the latest advances of allosteric drug discovery from different target classes and novel emerging chemical modalities beyond small molecules., Competing Interests: The authors declare no competing financial interest.

The classical toolbox for drug discovery is continuously expanding beyond traditional small molecules. New chemical modalities including RNA therapeutics, protein degraders, cyclopeptides, antibody drug conjugates, and gene therapy have matured, demonstrating clinical success and are now considered early in target appraisal. In this Viewpoint, we highlight recent progress in the field., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Objective: The aim of this study was to investigate the association between rhegmatogenous retinal detachment (RRD) and solar radiation in northwestern Spain., Methods: All RRD cases in Pontevedra from 2008 and 2014 were retrospectively analyzed. Climatological data from 4 weather stations in the area were collected. The association between RRD incidence and solar radiation was investigated., Results: A total of 256 RRD cases were identified. There was a seasonal variation in the incidence of RRD with a maximum number of incident cases observed in June and July and a minimum number of cases observed in January and December. An association was found between RRD incidence and solar radiation both monthly (p = 0.004) and bimonthly (p = 0.057). The right eye was more frequently affected than the left eye (p = 0.035). RD cases other than rhegmatogenous showed neither seasonality nor association with radiation., Conclusions: Solar radiation may play a role in RRD genesis in our area. Laterality could be related to the amount of radiation reaching each eye., (© 2019 S. Karger AG, Basel.)