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The Cantabrian capercaillie ( Tetrao urogallus cantabricus ) is one of the most severely threatened subspecies of capercaillie. Its current population range is restricted to a small area of the Cantabrian Mountains (northwestern Spain), with only around 200 individuals remaining. As part of the national strategy for the conservation of the subspecies, the Cantabrian capercaillie Captive Breeding Center of Sobrescobio opened in 2009. Here, we use the information provided by the necropsies performed in this facility on 29 individuals (11 males, 13 females and 5 undetermined; 16 chicks and 13 adults) in order to describe the main mortality causes of captive-bred Cantabrian capercaillies. After necropsy, tissue samples were taken for evaluation using standard methods in histology and microbiology. The majority of the captive animals (18/29, 62.07%) died due to infectious diseases, mainly due to Escherichia coli , Clostridium perfringens , or Aspergillus fumigatus infection. The remaining 11 animals died due to stress-related processes (i.e., rupture of the heart apex and cardiomyopathy or neurogenic shock) (8/29, 27.59%), duodenal obstruction and coelomitis (1/29, 3.45%), perforation of the proventriculus and heart with a briar branch (1/29, 3.45%) or euthanasia due to a valgus leg deformity that prevented proper animal welfare (1/29, 3.45%). Young animals (i.e., younger than 2 months) died mainly due to infectious diseases (14/16, 87.5%), while stress-related causes were responsible for most adult deaths (7/13, 53.85%). We additionally report that two free-ranging adult males died due to exertional myopathy. This study provides relevant information for reducing mortality in captive capercaillies and improving both living conditions in captivity and the adaptation of these animals to the wild.

Dunaliella tertiolecta RCC6 was cultivated indoors in glass bubble column photobioreactors operated under batch and semi-continuous regimens and using two different conditions of light and temperature. Biomass was harvested by centrifugation, frozen, and then lyophilized. The soluble material was obtained by sequential extraction of the lyophilized biomass with solvents with a gradient of polarity (hexane, ethyl acetate, and methanol) and its metabolic composition was investigated through nuclear magnetic resonance (NMR) spectroscopy. The effect of light on chlorophyll biosynthesis was clearly shown through the relative intensities of the 1 H NMR signals due to pheophytins. The highest signal intensity was observed for the biomasses obtained at lower light intensity, resulting in a lower light availability per cell. Under high temperature and light conditions, the 1 H NMR spectra of the hexane extracts showed an incipient accumulation of triacylglycerols. In these conditions and under semi-continuous regimen, an enhancement of β-carotene and sterols production was observed. The antibacterial and antibiofilm activities of the extracts were also tested. Antibacterial activity was not detected, regardless of culture conditions. In contrast, the minimal biofilm inhibitory concentrations (MBICs) against Escherichia coli for the hexane extract obtained under semi-continuous regimen using high temperature and irradiance conditions was promising., (© 2023 Phycological Society of America.)

The number of patients with post-COVID-19 syndrome continues to increase considerably, having serious healthcare, social and economic repercussions. The objective of this study is to describe the effectiveness of telerehabilitation to alleviate the symptoms of post-COVID-19 syndrome. A systematic review was conducted using the information available on four databases (PubMed, Medline, Scielo and PEDRo) on these patients until November 2022. The MeSH search terms were: Post-COVID syndrome, Post-COVID-19, Long COVID, Telerehabilitation, Physiotherapy, Rehabilitation, Virtual, Home care. Six articles were included which provided information on 140 patients, detailing their symptomatology, assessment, treatment and monitoring. The variables measured were dyspnea, fatigue, physical performance and quality of life. All studies included aerobic and anaerobic exercises. Most notable among the techniques used were rib cage expansion exercises, respiratory control and thoracic cage stretching, patient education, Mindfulness and virtual reality games to address physical, mental and relaxation aspects. The use of telerehabilitation could be an effective tool for the treatment of persistent symptoms after suffering from COVID-19. It has been shown in these studies that patients improve both their physical performance and their quality of life.

Red cell distribution width (RDW) could be of interest by its potential use in the assessment of celiac disorder (CD). The main objective of this study was to evaluate the case positive rate of CD and the utility of red cell distribution width (RDW) in the CD diagnosis. This prospective study included 9.066 middle adult (≥45 years old) and elderly patients (≥60 years old) from 2012 to 2021. CD diagnosis was performed by CD antibody tests (serology and Human Leucocyte Antigen genotype (HLA)) and biopsy. Gastrointestinal and extra-intestinal manifestations as well as hematological and biochemical parameters were analyzed. CD diagnoses were confirmed in 101 patients (median (IQR) age = 62 (52.3−73); 68.32% women) by serologic tests (100%) and intestinal biopsy (88.12%), showing mainly marked or complete atrophy (76.24%, MARSH 3a−c). Anemia was the most commonly presenting extra-intestinal manifestation (28.57%). Among 8975 individuals without CD, 168 age and sex matched were included. By comparison of CD and no CD individuals, we observed that high >14.3% RDW was exhibited by 58.40% and 35.2% individuals with CD and without CD, respectively. Furthermore, high RDW is associated with CD and grade III atrophy. We suggest that RDW could be used as a CD screening criterion.

The emergence and spread of multidrug-resistant bacteria are a global concern. The lack of new antibiotics in the pipeline points to the need for developing new strategies. In this sense, gold(III) complexes (G3Cs) could be a promising alternative due to their recently described antibacterial activity. The aim of this study was to evaluate the antimicrobial activity of G3Cs alone and in combination with colistin against pathogenic bacteria from veterinary sources. Minimal inhibitory concentration (MIC) values were determined by broth microdilution and compared with clinically relevant antibiotics. Antibiofilm activity was determined by crystal violet staining. Combinations of selected G3Cs with colistin and cytotoxicity in commercial human cell lines were evaluated. Four and seven G3Cs showed antibacterial effect against Gram-negative and Gram-positive strains, respectively, with this activity being higher among Gram-positive strains. The G3Cs showed antibiofilm activity against Gram-negative species at concentrations similar or one to four folds higher than the corresponding MICs. Combination of G3Cs with colistin showed a potential synergistic antibacterial effect reducing concentrations and toxicity of both agents. The antimicrobial and antibiofilm activity, the synergistic effect when combined with colistin and the in vitro toxicity suggest that G3Cs would provide a new therapeutic alternative against multidrug-resistant bacteria from veterinary origin.

Background: The invasion of Ukraine by Russia in February 2022 has resulted in destruction of healthcare infrastructure and triggered the largest wave of internally displaced populations and refugees since World War Two. Conflicts in transitioned countries such as Ukraine create new non-communicable disease (NCD) challenges, especially for cancer care for refugees and humanitarian assistance in host countries. In the early days, rapid attempts were made to model possible impacts., Methods: By evaluating open source intelligence used in the first three months of the conflict through snowball search methods, we aimed to address: (i) burden of cancer in Ukrainian population, specifically considering translating to the refugees population, and its cancer care capacity; ii) baseline capacity/strengths of cancer systems in initial host countries. Moreover, using a baseline scenario based on crude cancer incidence in Ukraine, and considering data from UNHCR, we estimated how cancer cases would be distributed across host countries. Finally, a surveillance assessment instrument was created, intersecting health system's capacity and influx of internally displaced populations and refugees., Findings and Conclusions: The total new cancer patients per month in pre-conflict Ukraine was estimated as 13,106, of which < 1 % are paediatric cases. The estimated cancer cases in the refugee population (combining prevalent and incident), assuming 7.5 million refugees by July 2022 and a female:male ratio of 9:1, was 33,121 individuals (Poland: 19284; Hungary: 3484; Moldova: 2651; Slovakia: 2421; Romania: 5281). According to our assessments, Poland is the only neighbouring country classified as green/yellow for cancer capacity, i.e. sufficient ablility to absorb additional burden into national health system; Slovakia we graded as yellow, Hungary and Romania as yellow/red and Moldova as red., Competing Interests: Conflicts of interest None to be declared., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The incidence of tuberculosis in Aragon, Spain, is around ten cases per 100,000 inhabitants. Since 2004, a molecular surveillance protocol has been carried out; therefore, all M. tuberculosis strains are genotyped. Recently, whole-genome sequencing has been implemented for relevant isolates. The aim of this work is to characterise at the molecular level the causative strains of the 26 largest outbreaks of the community (including ten or more cases), genotyped by IS6110-RFLP and causing 26% of tuberculosis cases. To achieve this objective, two or three isolates of each IS6110-cluster belonging to different years were selected for sequencing. We found that strains of lineages L4.8, L4.3 and L4.1.2 were the most frequent. The threshold of 12 SNPs as the maximum distance for confirming the belonging to an outbreak was met for 18 of the 26 IS6110-clusters. Four pairs of isolates with more than 90 SNPs were identified as not belonging to the same strain, and four other pairs were kept in doubt as the number of SNPs was close to 12, between 14 and 35. The study of Regions of Difference revealed that they are lineage conserved. Moreover, we could analyse the IS6110 locations for all genome-sequenced isolates, finding some frequent locations in isolates belonging to the same lineage and certain IS6110 movements between the paired isolates. In the vast majority, these movements were not captured by the IS6110-RFLP pattern. After classifying the genes containing SNP by their functional category, we could confirm that the number of SNPs detected in genes considered as virulence factors and the number of cases the strain produced were not related, suggesting that a particular SNP is more relevant than the number. The characteristics found in the most successful strains in our community could be useful for other researchers in epidemiology, virulence and pathogenesis., (© 2022. The Author(s).)

Background: Few studies have investigated the long-term effects of COVID-19 on cancer patients. Materials & methods: The authors conducted a telephone survey on the long-term symptoms of cancer patients from Guy's Cancer Centre. They compared patients whose symptoms occurred/got worse over 4 weeks after COVID-19 diagnosis (classified as long COVID) with patients who did not develop symptoms or whose symptoms occurred/got worse in the first 4 weeks after diagnosis. Results: The authors analyzed responses from 80 patients with a previous COVID-19 diagnosis; 51.3% (n = 41) developed long COVID. The most common symptoms were fatigue, breathlessness and cognitive impairment. Conclusion: Findings suggest that over half of the cancer population will experience long-term effects after their initial COVID-19 diagnosis. Further studies are required to validate the findings of this study.

Chlorosphaerolactylate B, a newly discovered antimicrobial halometabolite from the cyanobacterium Sphaerospermopsis sp. LEGE 00249 has been synthesized in three steps by using 12-bromododecanoic acid as starting material. A total of 0.5 g was produced for in vitro and in vivo antimicrobial efficacy testing. In vitro , the minimal inhibitory concentration (MIC) was estimated to be 256 mg/L for Staphylococcus aureus , while the minimal biofilm inhibitory concentration (MBIC) was estimated to be 74 mg/L. The in vivo study utilized a porcine model of implant-associated osteomyelitis. In total, 12 female pigs were allocated into 3 groups based on inoculum ( n = 4 in each group). An implant cavity (IC) was drilled in the right tibia and followed by inoculation and insertion of a steel implant. All pigs were inoculated with 10 μL containing either: 11.79 mg synthetic Chlorosphaerolactylate B + 10 4 CFU of S. aureus (Group A), 10 4 CFU of S. aureus (Group B), or pure saline (Group C), respectively. Pigs were euthanized five days after inoculation. All Group B animals showed macroscopic and microscopic signs of bone infection and both tissue and implant harbored S. aureus bacteria (mean CFU on implants = 1.9 × 10 5 ). In contrast, S. aureus could not be isolated from animals inoculated with saline. In Group A, two animals had a low number of S. aureus (CFU = 6.7 × 10 1 and 3.8 × 10 1 , respectively) on the implants, otherwise all Group A animals were similar to Group C animals. In conclusion, synthetic Chlorosphaerolactylate B holds potential to be a novel antimicrobial and antibiofilm compound., 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 © 2022 Jensen, Jensen, Aalbaek, Blirup-Plum, Soto, Cepas, López, Gabasa, Gutiérrez-del-Río, Villar, Lombó, Iglesias, Soengas, López Ortiz and Jensen.)

Increasing evidence has linked the humoral immune response with the development of various cancers. Therefore, there is growing interest in investigating the predictive value of antibodies to assess overall and tissue site-specific cancer risk. Given the large amount of antibody types and the broad scope of the search (i.e. cancer risk), the primary aim of this systematic review was to present an overview of the most researched antibodies (i.e. immunoglobulin (Ig) isotypes (IgG, IgM, IgA, and IgE), tumour and self-antigen-reactive antibodies, infection-related antibodies) in relation to overall and site-specific cancer risk. We identified various antibody types that have been associated with the risk of cancer. While no significant associations were found for IgM serum levels, studies found an inconsistent association among IgE, IgA, and IgG serum levels in relation to cancer risk. When evaluating antibodies against infectious agents, most studies reported a positive link with specific cancers known to be associated with the specific agent recognized by serum antibodies (i.e. helicobacter pylori and gastric cancer, hepatitis B virus and hepatocellular carcinoma, and human papillomavirus and cervical cancer). Several reports identified autoantibodies, as single biomarkers (e.g. anti-p53, anti-MUC1, and anti-CA125) but especially in panels of multiple autoantibodies, to have potential as diagnostic biomarkers for specific cancer types. Overall, there is emerging evidence associating certain antibodies to cancer risk, especially immunoglobulin isotypes, tumour-associated antigen-specific, and self-reactive antibodies. Further experimental studies are necessary to assess the efficacy of specific antibodies as markers for the early diagnosis of cancer., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Immunology.)

Aim: To evaluate the impact of the pandemic on the well-being of cancer staff and determine the uptake of opt-in mitigation strategies. Materials & methods: Staff at Guy's Cancer Centre (London, UK) participated in an anonymized survey between May and August 2021. Results: Of 1182 staff, 257 (21.7%) participated. Ethnicity (p = 0.020) and comorbidity burden (p = 0.022) were associated with SARS-CoV-2 infection status. Of 199 respondents, seven (3.6%) were vaccine-hesitant, which was associated with low flu vaccine uptake (p < 0.001). Greater stress was associated with younger age (p = 0.030) and redeployment (p = 0.012). Lack of time and skepticism were barriers to using mental well-being resources. Conclusion: Albeit cautious, numerous trends the authors observed echo those in the published literature. Improved accessibility, awareness and utility of mental well-being resources are required.

Since 2004, a tuberculosis surveillance protocol has been carried out in Aragon, thereby managing to detect all tuberculosis outbreaks that take place in the community. The largest outbreak was caused by a strain named Mycobacterium tuberculosis Zaragoza (MtZ), causing 242 cases as of 2020. The main objective of this work was to analyze this outbreak and the molecular characteristics of this successful strain that could be related to its greater transmission. To do this, we first applied whole-genome sequencing to 57 of the isolates. This revealed two principal transmission clusters and six subclusters arising from them. The MtZ strain belongs to L4.8 and had eight specific single nucleotide polymorphisms (SNPs) in genes considered to be virulence factors [ ptpA , mc3D , mc3F , VapB41 , pks15 (two SNPs), virS , and VapC50 ]. Second, a transcriptomic study was carried out to better understand the multiple IS 6110 copies present in its genome. This allowed us to observe three effects of IS 6110 : the disruption of the gene in which the IS 6110 is inserted ( desA3 ), the overexpression of a gene ( ppe38 ), and the absence of transcription of genes ( cut1:Rv1765c ) due to the recombination of two IS 6110 copies. Finally, because of the disruption of ppe38 and ppe71 genes by an IS 6110 , a study of PE&#95;PGRS secretion was carried out, showing that MtZ secretes these factors in higher amounts than the reference strain, thereby differing from the hypervirulent phenotype described for the Beijing strains. In conclusion, MtZ consists of several SNPs in genes related to virulence, pathogenesis, and survival, as well as other genomic polymorphisms, which may be implicated in its success among our population., 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 © 2022 Comín, Madacki, Rabanaque, Zúñiga-Antón, Ibarz, Cebollada, Viñuelas, Torres, Sahagún, Klopp, Gonzalo-Asensio, Brosch, Iglesias and Samper.)

Background: Safe provision of systemic anti-cancer treatment (SACT) during the COVID-19 pandemic remains an ongoing concern amongst clinicians., Methods: Retrospective analysis on uro-oncology patients who continued or started SACT between 1st March and 31st May 2020 during the pandemic (with 2019 as a comparator)., Results: 441 patients received SACT in 2020 (292 prostate, 101 renal, 38 urothelial, 10 testicular) compared to 518 patients in 2019 (340 prostate, 121 renal, 42 urothelial, 15 testicular). In 2020, there were 75.00% fewer patients with stage 3 cancers receiving SACT (p < 0.0001) and 94.44% fewer patients receiving radical treatment (p = 0.00194). The number of patients started on a new line of SACT was similar between both years (118 in 2019 vs 102 in 2020; p = 0.898) but with 53.45% fewer patients started on chemotherapy in 2020 (p < 0.001). Overall, 5 patients tested positive for COVID-19 (one asymptomatic, one mild, two moderate, one severe resulting in death). Compared to 2019, 30-day mortality was similar (1.69% in 2019 vs 0.98% in 2020; p = 0.649) whereas 6-month mortality was lower (9.32% in 2019 vs 1.96% in 2020; p = 0.0209) in 2020., Conclusion: This study suggests that delivery of SACT to uro-oncology patients during COVID-19 pandemic may be safe in high-incidence areas with appropriate risk-reduction strategies., (© 2022. The Author(s).)

We explored the ability of ADP-glucose pyrophosphorylase (ADP-Glc PPase) from different bacteria to use glucosamine (GlcN) metabolites as a substrate or allosteric effectors. The enzyme from the actinobacteria Kocuria rhizophila exhibited marked and distinctive sensitivity to allosteric activation by GlcN-6P when producing ADP-Glc from glucose-1-phosphate (Glc-1P) and ATP. This behavior is also seen in the enzyme from Rhodococcus spp., the only one known so far to portray this activation. GlcN-6P had a more modest effect on the enzyme from other Actinobacteria ( Streptomyces coelicolor ), Firmicutes ( Ruminococcus albus ), and Proteobacteria ( Agrobacterium tumefaciens ) groups. In addition, we studied the catalytic capacity of ADP-Glc PPases from the different sources using GlcN-1P as a substrate when assayed in the presence of their respective allosteric activators. In all cases, the catalytic efficiency of Glc-1P was 1-2 orders of magnitude higher than GlcN-1P, except for the unregulated heterotetrameric protein (GlgC/GgD) from Geobacillus stearothermophilus . The Glc-1P substrate preference is explained using a model of ADP-Glc PPase from A. tumefaciens based on the crystallographic structure of the enzyme from potato tuber. The substrate-binding domain localizes near the N-terminal of an α-helix, which has a partial positive charge, thus favoring the interaction with a hydroxyl rather than a charged primary amine group. Results support the scenario where the ability of ADP-Glc PPases to use GlcN-1P as an alternative occurred during evolution despite the enzyme being selected to use Glc-1P and ATP for α-glucans synthesis. As an associated consequence in such a process, certain bacteria could have improved their ability to metabolize GlcN. The work also provides insights in designing molecular tools for producing oligo and polysaccharides with amino moieties., 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 © 2022 Bhayani, Iglesias, Minen, Cereijo, Ballicora, Iglesias and Asencion Diez.)

A State of the Art lecture titled "Proteomics in Thrombosis Research" was presented at the ISTH Congress in 2021. In clinical practice, there is a need for improved plasma biomarker-based tools for diagnosis and risk prediction of venous thromboembolism (VTE). Analysis of blood, to identify plasma proteins with potential utility for such tools, could enable an individualized approach to treatment and prevention. Technological advances to study the plasma proteome on a large scale allows broad screening for the identification of novel plasma biomarkers, both by targeted and nontargeted proteomics methods. However, assay limitations need to be considered when interpreting results, with orthogonal validation required before conclusions are drawn. Here, we review and provide perspectives on the application of affinity- and mass spectrometry-based methods for the identification and analysis of plasma protein biomarkers, with potential application in the field of VTE. We also provide a future perspective on discovery strategies and emerging technologies for targeted proteomics in thrombosis research. Finally, we summarize relevant new data on this topic, presented during the 2021 ISTH Congress., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Background: The diagnosis of celiac disease (CD) has been substantially improved with the availability of highly sensitive CD-specific IgA-TG2, Ig-GDP, and IgA-EMA. The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) published (2012) and updated (2020) diagnostic criteria for CD in order to simplify CD diagnosis and to avoid biopsies in selected patients., Methods: A prospective study including 5641 pediatric patients (0-16 years old) from January 2012 to January 2019 was performed. CD diagnosis was made according to the ESPGHAN algorithm. The objective of this study was to evaluate the utility of biomarkers and the relationship between TGA-IgA and EMA titers., Results: CD diagnoses were confirmed in 113 patients, 110 were IgA-TG2-positive and 3 (2.7%) had IgA deficiency. The diagnosis was made by serologic tests in 95 (84.1%) patients. Only 18 (15.9%) patients underwent intestinal biopsy. We obtained 100% concordance between IgA-EMA and positive results for IgA-TG2 ≥ 10 ULN with IgA-EMA antibody titer ≥ 1:80., Conclusions: This study provides evidence of a positive correlation between IgA-TG2 antibody serum levels and IgA-EMA. The diagnosis could be guaranteed with strict application of IgA-TG2 values ≥ 10 ULN (confirmed by subsequent testing) plus the serological response to the gluten-free diet (GFD).

The worldwide emergence and spread of infections caused by multidrug-resistant bacteria endangers the efficacy of current antibiotics in the clinical setting. The lack of new antibiotics in the pipeline points to the need of developing new strategies. Recently, gold-based drugs are being repurposed for antibacterial applications. Among them, gold(III) complexes have received increasing attention as metal-based anticancer agents. However, reports on their antibacterial activity are scarce due to stability issues. The present work demonstrates the antibacterial activity of the gold(III) complex 2 stabilized as C ∧ S-cycloaurated containing a diphenylphosphinothioic amide moiety, showing minimum inhibitory concentration (MIC) values that ranged from 4 to 8 and from 16 to 32 mg/L among Gram-positive and Gram-negative multidrug-resistant (MDR) pathogens, respectively. Complex 2 has a biofilm inhibitory activity of only two to four times than its MIC. We also describe for the first time a potent antibacterial synergistic effect of a gold(III) complex combined with colistin, showing a bactericidal effect in less than 2 h; confirming the role of the outer membrane as a permeability barrier. Complex 2 shows a low rate of internalization in Staphylococcus aureus and Acinetobacter baumannii ; it does not interact with replication enzymes or efflux pumps, causes ultrastructural damages in both membrane and cytoplasmic levels, and permeabilizes the bacterial membrane. Unlike control antibiotics, complex 2 did not generate resistant mutants in 30-day sequential cultures. We detected lower cytotoxicity in a non-tumoral THLE-2 cell line (IC 50 = 25.5 μM) and no acute toxicity signs in vivo after an i.v. 1-mg/kg dose. The characterization presented here reassures the potential of complex 2 as a new chemical class of antimicrobial agents., 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 © 2022 Ratia, Cepas, Soengas, Navarro, Velasco-de Andrés, Iglesias, Lozano, López-Ortiz and Soto.)

Background: The COVID-19 pandemic has been highly disruptive for cancer care. Here, we examined the effect COVID-19 had on performance of the 62-day Cancer Waiting Time (CWT) target set by the National Health Service (NHS) in England., Methods: Data were retrospectively obtained on COVID-19 hospitalisations and CWT for NHS hospitals in England (n = 121). We produced a 'COVID-19 burden' to describe the proportion of each provider's beds occupied with COVID-19 patients. COVID-19 burden was examined against CWT performance for 1st April - 30th May 2020 (Wave 1), and 1st October - 30th November 2020 (Wave 2). Two-tailed Spearman correlations were used to identify relationships between COVID-19 burden and CWT performance amongst different referral (i.e., 2-week-wait (2 W W) and internal specialist) and tumour types. Significantly correlated variables were further examined using linear regression models., Results: COVID-19 burden was negatively associated with the percentage of 2 W W pathway referrals that met the CWT target in Wave 1 (r= -0.30, p = 0.001) and Wave 2 (r= -0.21, p = 0.02). These associations were supported by the results from our linear regression models (B for wave 1: -0.71; 95 %CI: -1.03 to -0.40; B for wave 2: -0.38; 95 %CI: -0.68 to -0.07). No associations were found between COVID-19 burden and internal specialist referrals or tumour type., Conclusion: Increased COVID-19 burden was associated with lower compliance with CWT targets amongst urgent referrals from primary care in England. This will likely be an ongoing issue due to the backlog of patients awaiting investigations and treatment., Policy Summary: As the number of cancer referrals improve, we highlight the need for changes to primary and secondary care to manage the backlog within cancer diagnostic services to alleviate the impact of COVID-19., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

E3 ubiquitin ligases mediate the last step of the ubiquitination pathway in the ubiquitin-proteasome system (UPS). By targeting transcriptional regulators for their turnover, E3s play a crucial role in every aspect of plant biology. In plants, SKP1/CULLIN1/F-BOX PROTEIN (SCF)-type E3 ubiquitin ligases are essential for the perception and signaling of several key hormones including auxins and jasmonates (JAs). F-box proteins, TRANSPORT INHIBITOR RESPONSE 1 (TIR1) and CORONATINE INSENSITIVE 1 (COI1), bind directly transcriptional repressors AUXIN/INDOLE-3-ACETIC ACID (AUX/IAA) and JASMONATE ZIM-DOMAIN (JAZ) in auxin- and JAs-depending manner, respectively, which permits the perception of the hormones and transcriptional activation of signaling pathways. Redox modification of proteins mainly by S-nitrosation of cysteines (Cys) residues via nitric oxide (NO) has emerged as a valued regulatory mechanism in physiological processes requiring its rapid and versatile integration. Previously, we demonstrated that TIR1 and Arabidopsis thaliana SKP1 (ASK1) are targets of S-nitrosation, and these NO-dependent posttranslational modifications enhance protein-protein interactions and positively regulate SCF TIR1 complex assembly and expression of auxin response genes. In this work, we confirmed S-nitrosation of Cys140 in TIR1, which was associated in planta to auxin-dependent developmental and stress-associated responses. In addition, we provide evidence on the modulation of the SCF COI1 complex by different S-nitrosation events. We demonstrated that S-nitrosation of ASK1 Cys118 enhanced ASK1-COI1 protein-protein interaction. Overexpression of non-nitrosable ask1 mutant protein impaired the activation of JA-responsive genes mediated by SCF COI1 illustrating the functional relevance of this redox-mediated regulation in planta . In silico analysis positions COI1 as a promising S-nitrosation target, and demonstrated that plants treated with methyl JA (MeJA) or S-nitrosocysteine (NO-Cys, S-nitrosation agent) develop shared responses at a genome-wide level. The regulation of SCF components involved in hormonal perception by S-nitrosation may represent a key strategy to determine the precise time and site-dependent activation of each hormonal signaling pathway and highlights NO as a pivotal molecular player in these scenarios., Competing Interests: LIACV was employed by company KWS Gateway Research Center, LLC. The remaining 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 © 2022 Terrile, Tebez, Colman, Mateos, Morato-López, Sánchez-López, Izquierdo-Álvarez, Marina, Calderón Villalobos, Estelle, Martínez-Ruiz, Fiol, Casalongué and Iglesias.)

The COVID-19 pandemic and lockdown brought numerous teaching challenges requiring innovative approaches to teaching and learning, including novel modes of content delivery, virtual classrooms, and online assessment schemes. The aim of this study is to describe and assess the efficacy of the methods implemented at the University of León (Spain) to adapt to lockdowns in the context of the Cytology and Histology (CH) course for veterinary medicine undergraduate students. To evaluate the success of lockdown-adapted methodologies, we used inferential statistical analysis to compare the academic outcomes of two cohorts: 2018-2019 (traditional face-to-face-presential-learning and evaluation) and 2019-2020 (some face-to-face and some online lockdown-adapted learning and online lockdown-adapted evaluation). This analysis considered scores in both theoretical and practical exams and students' final subject score. We also evaluated the number of logs onto the Moodle platform throughout the 2019-2020 period, as well as performing a student satisfaction survey in both courses. The use of explanatory pre-recorded lectures, continuous online self-assessment tests, and virtual microscopy (VM) may have produced significant improvements in the acquisition of histology competencies among students in the lockdown cohort. However, we need to implement further strategies to improve the assessment of students' true level of knowledge acquisition. According to the student feedback, VM is a well-accepted resource that is perceived as a flexible and enjoyable tool to use. However, while students found that the resource enhances their ability to learn about microscopic structures, they felt that it should not completely replace optical microscopy.

Objective: To report on the outcomes of urological cancer patients undergoing radical surgery between March-September 2020 (compared with 2019) in the European Institute of Oncology (IEO) in Milan and the South East London Cancer Alliance (SELCA)., Materials and Methods: Since March 2020, both institutions implemented a COVID-19 minimal 'green' pathway, whereby patients were required to isolate for 14 days prior to admission and report a negative COVID-19 polymerase chain reaction (PCR) test within 3 days of surgery. COVID-19 positive patients had surgery deferred until a negative swab. Surgical outcomes assessed were: American Society of Anaesthesiologists (ASA) grade; surgery time; theatre time; intensive care unit (ICU) stay >24 h; pneumonia; length of stay (LOS); re-admission. Postoperative COVID-19 infection rates and associated mortality were also recorded., Results: At IEO, uro-oncological surgery increased by 4%, as compared with the same period in 2019 ( n  = 515 vs. 534). The main increase was observed for renal (16%, n  = 98 vs. 114), bladder (24%, n  = 45 vs. 56) and testicular (27%, n  = 26 vs. 33). Patient demographics were all comparable between 2019 and 2020. Only one bladder cancer patient developed COVID-19, reporting mild/moderate disease. There was no COVID-19 associated mortality. In the SELCA cohort, uro-oncological surgery declined by 23% ( n  = 403 vs. 312) compared with the previous year. The biggest decrease was seen for prostate (-42%, n  = 156 vs. 91), penile (-100%, n  = 4 vs. 0) and testicular cancers (-46%, n  = 35 vs. 24). Various patient demographic characteristics were notably different when comparing 2020 versus 2019. This likely reflects the clinical decision of deferring COVID-19 vulnerable patients. One patient developed COVID-19, with no COVID-19 related mortality., Conclusion: The COVID-19 minimal 'green' pathways that were put in place have shown to be safe for uro-oncological patients requiring radical surgery. There were limited complications, almost no peri-operative COVID-19 infection and no COVID-19-related mortality in either cohort., (© 2021 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

Introduction: Cystic fibrosis (CF) is an autosomal recessive disease that involves the cells that produce mucus and sweat, affecting many organs, especially the lungs. Positive expiratory pressure (PEP) devices generate a pressure opposite to that exerted by the airways during expiration, thus improving mucociliary clearance., Objectives: To evaluate the efficacy of PEP devices as a resource to facilitate the mucus removal and other outcomes in people with CF, as well as the possible adverse effects derived from their use., Material and Method: A systematic review and meta-analysis was conducted according to PRISMA standards. The descriptors were 'cystic fibrosis', 'PEP', and 'physiotherapy and/or physical therapy'. The search was performed in four databases: PubMed, PEDro, and Web of Science and Scopus, in July 2021. The inclusion criteria were randomized controlled trials (RCTs) over the last 10 years. The methodological quality of the studies was analyzed and meta-analysis was performed with Review Manager software., Results: Ten RCTs met the objectives and criteria, with a total of 274 participants. The trials score a moderate methodological quality on the PEDro scale. No clear results were obtained on whether PEP provides better lung function than other breathing techniques (such as airway clearance); but it does achieve a higher rate of lung clearance than physical exercise., Conclusions: PEP is more effective than usual care or no intervention, although there is not enough evidence to confirm that PEP achieves improvements in forced expiratory volume in the first second (FEV 1 ) compared with other techniques. It is a safe technique, without adverse effects.

Objective: Endothelial cell (EC) dysfunction is a well-established response to cardiovascular disease risk factors, such as smoking and obesity. Risk factor exposure can modify EC signaling and behavior, leading to arterial and venous disease development. Here, we aimed to identify biomarker panels for the assessment of EC dysfunction, which could be useful for risk stratification or to monitor treatment response. Approach and Results: We used affinity proteomics to identify EC proteins circulating in plasma that were associated with cardiovascular disease risk factor exposure. Two hundred sixteen proteins, which we previously predicted to be EC-enriched across vascular beds, were measured in plasma samples (N=1005) from the population-based SCAPIS (Swedish Cardiopulmonary Bioimage Study) pilot. Thirty-eight of these proteins were associated with body mass index, total cholesterol, low-density lipoprotein, smoking, hypertension, or diabetes. Sex-specific analysis revealed that associations predominantly observed in female- or male-only samples were most frequently with the risk factors body mass index, or total cholesterol and smoking, respectively. We show a relationship between individual cardiovascular disease risk, calculated with the Framingham risk score, and the corresponding biomarker profiles., Conclusions: EC proteins in plasma could reflect vascular health status.

Lipids are one of the primary metabolites of microalgae and cyanobacteria, which enrich their utility in the pharmaceutical, feed, cosmetic, and chemistry sectors. This work describes the isolation, structural elucidation, and the antibiotic and antibiofilm activities of diverse lipids produced by different microalgae and cyanobacteria strains from two European collections (ACOI and LEGE-CC). Three microalgae strains and one cyanobacteria strain were selected for their antibacterial and/or antibiofilm activity after the screening of about 600 strains carried out under the NoMorFilm European project. The total organic extracts were firstly fractionated using solid phase extraction methods, and the minimum inhibitory concentration and minimal biofilm inhibitory concentration against an array of human pathogens were determined. The isolation was carried out by bioassay-guided HPLC-DAD purification, and the structure of the isolated molecules responsible for the observed activities was determined by HPLC-HRESIMS and NMR methods. Sulfoquinovosyldiacylglycerol, monogalactosylmonoacylglycerol, sulfoquinovosylmonoacylglycerol, α-linolenic acid, hexadeca-4,7,10,13-tetraenoic acid (HDTA), palmitoleic acid, and lysophosphatidylcholine were found among the different active sub-fractions selected. In conclusion, cyanobacteria and microalgae produce a great variety of lipids with antibiotic and antibiofilm activity against the most important pathogens causing severe infections in humans. The use of these lipids in clinical treatments alone or in combination with antibiotics may provide an alternative to the current treatments.

Bilirubin has strong antioxidant properties that have been hypothesized to be preventive against the development of cancer. Thus, we aimed to investigate the association between serum total bilirubin (STB) and risk of overall and site-specific cancers in the large Swedish Apolipoprotein Mortality Risk (AMORIS) cohort. We also performed a systematic review and meta-analysis for specific cancer types (colorectal, breast and lung). We found no association between high levels of STB and risk of overall cancer. Regarding site-specific cancer, there was an inverse association between increased STB and lung cancer (Hazard Ratio (HR) for the 4th quartile (Q4) vs. Q1: 0.50; 95%CI: 0.44-0.59) and gynecological cancer (HR for Q4 vs. Q1: 0.86; 95%CI: 0.76-0.99). A positive association was found with melanoma (HR for Q4 vs. Q1: 1.25; 95%CI: 1.06-1.47) and breast cancer (HR for Q4 vs. Q1: 1.13; 95%CI: 1.01-1.25) risk. The meta-analysis showed an inverse association between high levels of STB and risk of lung cancer (Relative risk (RR): 0.69; 95%CI: 0.55-0.86). No associations were seen for colorectal and breast cancer risk. Further studies are required to establish if bilirubin can be used as a biomarker for risk assessment and/or as a novel therapeutic target.

The herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) is widely used due to it selective action, and preferential control of dicotyledonous weeds affecting cereal crops. Physiological responses of sensitive dicotyledonous plants to 2,4-D include growth retardation, senescence, and cell death. Due to soil and water contamination by agricultural practices, 2,4-D constitutes a potential risk to non-target plant species. In this work, the potential advantage of using organic modified bentonite (Bent) to adsorb 2,4-D and therefore mitigate damage produced by this herbicide on sensitive not-target vegetable species was investigated. Dodecylamine (DDA) was used as an organic modifier to change the hydrophilic nature of Bent into an organophilic matrix. The adsorption performances of 2,4-D by Bent-DDA were analyzed. The maximum adsorptions of 2,4-D (22.1 mg/L) from aqueous solution containing 1.0 or 2.5 mg/mL Bent-DDA were 40 and 80 %, respectively. The physical interaction of Bent-DDA with 2,4-D was characterized by Wide Angle X-ray Scattering (WAXS) and thermogravimetric analysis (TGA). The biological functionality of Bent-DDA matrix as 2,4-D adsorbent was tested in a bioassay in the Arabidopsis thaliana plant model system. The primary root growth of Arabidopsis seedlings is strongly inhibited by low concentrations of 2,4-D. Arabidopsis seedlings submitted to Bent-DDA pre-treated herbicide aqueous solution showed similar root growth than 2,4-D non-treated seedlings. Finally, the ability of Bent-DDA to prevent 2,4-D phytotoxicity was exploratory investigated in lettuce plants. Lettuce plants pre-treated with 20 μg/mL Bent-DDA showed reduced sensitivity to 2,4-D including an increment on chlorophyll content and biomass compared with non-treated plants. Our findings revealed a promising scenario for the application of Bent-DDA as an effective adsorbent of 2,4-D at productive scale., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Using an updated dataset with more patients and extended follow-up, we further established cancer patient characteristics associated with COVID-19 death., Methods: Data on all cancer patients with a positive reverse transcription-polymerase chain reaction swab for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) at Guy's Cancer Centre and King's College Hospital between 29 February and 31 July 2020 was used. Cox proportional hazards regression was performed to identify which factors were associated with COVID-19 mortality., Results: Three hundred and six SARS-CoV-2-positive cancer patients were included. Seventy-one had mild/moderate and 29% had severe COVID-19. Seventy-two patients died of COVID-19 (24%), of whom 35 died <7 days. Male sex [hazard ratio (HR): 1.97 (95% confidence interval (CI): 1.15-3.38)], Asian ethnicity [3.42 (1. 59-7.35)], haematological cancer [2.03 (1.16-3.56)] and a cancer diagnosis for >2-5 years [2.81 (1.41-5.59)] or ≥5 years were associated with an increased mortality. Age >60 years and raised C-reactive protein (CRP) were also associated with COVID-19 death. Haematological cancer, a longer-established cancer diagnosis, dyspnoea at diagnosis and raised CRP were indicative of early COVID-19-related death in cancer patients (<7 days from diagnosis)., Conclusions: Findings further substantiate evidence for increased risk of COVID-19 mortality for male and Asian cancer patients, and those with haematological malignancies or a cancer diagnosis >2 years. These factors should be accounted for when making clinical decisions for cancer patients., (© 2021. The Author(s).)

A collection of 177 Francisella tularensis subsp. holarctica clinical isolates (29 from humans and 148 from animals, mainly hares and voles) was gathered from diverse tularemia outbreaks in the Castilla y León region (northwestern Spain) that occurred from the end of the 20th century to the 2020s. Along with four F. tularensis subsp. holarctica reference strains, all of these clinical isolates were tested using a broth microdilution method to determine their susceptibility to 22 antimicrobial agents, including β-lactams, aminoglycosides and one member each of the tetracycline, glycylcycline, quinolone and sulphonamide classes. Many multi-resistance profiles were found among the tested isolates, but especially among those of human origin (all but two isolates showed resistance to at least 13 of 18 antimicrobial agents). Even so, all human isolates were susceptible to gentamicin and tobramycin, while more than 96% of animal isolates were susceptible to these two aminoglycosides. Ciprofloxacin showed activity against more than 92% of animal and human isolates. However, almost 21% of human isolates were resistant to tetracycline, and more than 65% were resistant to tigecycline. Finally, a quite similar activity to other F. tularensis subsp. holarctica isolates collected 20 years earlier in Spain was observed.

Venous thromboembolism is the third common cardiovascular disease and is composed of two entities, deep vein thrombosis (DVT) and its potential fatal form, pulmonary embolism (PE). While PE is observed in ~ 40% of patients with documented DVT, there is limited biomarkers that can help identifying patients at high PE risk. To fill this need, we implemented a two hidden-layers artificial neural networks (ANN) on 376 antibodies and 19 biological traits measured in the plasma of 1388 DVT patients, with or without PE, of the MARTHA study. We used the LIME algorithm to obtain a linear approximate of the resulting ANN prediction model. As MARTHA patients were typed for genotyping DNA arrays, a genome wide association study (GWAS) was conducted on the LIME estimate. Detected single nucleotide polymorphisms (SNPs) were tested for association with PE risk in MARTHA. Main findings were replicated in the EOVT study composed of 143 PE patients and 196 DVT only patients. The derived ANN model for PE achieved an accuracy of 0.89 and 0.79 in our training and testing sets, respectively. A GWAS on the LIME approximate identified a strong statistical association peak (rs1424597: p = 5.3 × 10 -7 ) at the PLXNA4 locus. Homozygote carriers for the rs1424597-A allele were then more frequently observed in PE than in DVT patients from the MARTHA (2% vs. 0.4%, p = 0.005) and the EOVT (3% vs. 0%, p = 0.013) studies. In a sample of 112 COVID-19 patients known to have endotheliopathy leading to acute lung injury and an increased risk of PE, decreased PLXNA4 levels were associated (p = 0.025) with worsened respiratory function. Using an original integrated proteomics and genetics strategy, we identified PLXNA4 as a new susceptibility gene for PE whose exact role now needs to be further elucidated.

Prostate (PC) and breast cancer (BC) are heterogeneous hormonal cancers. Treatment resistance and adverse effects are the main limitations of conventional chemotherapy treatment. The use of sensitizing agents could improve the effectiveness of chemotherapeutic drugs as well as obviate these limitations. This study analyzes the effect of single catechin (CAT), procyanidin B2 (ProB2) treatment as well as the co-adjuvant treatment of each of these compounds with docetaxel (DOCE). We used PC- and BC-derived cell lines (PC3, DU-145, T47D, MCF-7 and MDA-MB-231). The short and long-term pro-apoptotic, anti-proliferative and anti-migratory effects were analyzed. RT-qPCR was used to discover molecular bases of the therapeutic efficacy of these compounds. ProB2 treatment induced a two- to five-fold increase in anti-proliferative and pro-apoptotic effects compared to single DOCE treatment, and also had a more sensitizing effect than DOCE on DU145 cells. Regarding BC cells, ProB2- and CAT-mediated sensitization to DOCE anti-proliferative and pro-apoptotic effects was cell-independent and cell-dependent, respectively. Combined treatment led to high-efficacy effects on MCF-7 cells, which were associated to the up-regulation of CDKN1A, BAX, caspase 9 and E-cadherin mRNA under combined treatment compared to single DOCE treatment. CAT and ProB2 can enhance the efficacy of DOCE therapy on PC and BC cells by the sensitizing mechanism.

A set of 207 Streptococcus suis isolates were collected from ten autonomous communities from Spain in 2019 to 2020 from pigs with meningitis, pneumonic lungs, arthritic joints or other swollen viscera, to a lesser extent. Thirteen capsular types were detected being the most prevalent serotype 2 (21.7%), followed by serotypes 1 (21.3%), 9 (19.3%) and 3 (6.3%). Serotypes 2 and 9 were recovered mainly from the central nervous system (CNS), while serotype 1 was isolated mostly from swollen joints and serotype 3 from the lungs. Twenty-five isolates (12.1%) could not be typed. The most prevalent pathotype was epf + mrp + sly + luxS (49 isolates, 23.8%), and it was related mainly to serotypes 1 and 2. Serotypes 1-3 and 9 were significantly associated with anatomical sites of isolation and virulence factors, serotype 9 (CNS) and serotypes 3 and 9 (lungs) being associated with virulence profiles without the epf gene. S. suis isolates showed globally high antimicrobial resistances, but ampicillin followed by spectinomycin and tiamulin resulted in the highest activities, while the greatest resistances were detected for sulphadimethoxine, tetracyclines, neomycin, clindamycin and macrolides. A total of 87.4% isolates were positive to the tetO gene, 62.4% to the ermB gene and 25.2% to the fexA gene, while 14.6% were positive to all three genes simultaneously. A significative association between isolate resistances to tetracyclines and macrolides and the resistance genes tested was established, except for phenicol resistance and the fexA gene. A set of 14 multiresistance patterns were obtained according to the number of antimicrobials to which the isolates were resistant, the resistances to 12 or more agents being the most prevalent ones. A remarkable amount of multiresistance profiles could be seen among the S. suis serotype 9 isolates.

Pregnancy can affect the mother's oral health, increasing their susceptibility to oral diseases that have been associated with harmful effects on the newborn. Despite the severity of oral diseases during pregnancy, the demand for dental care during the gestational period is low, which may improve with the participation of midwives in promoting oral health activities. The objectives of this study were: (i) to determine the knowledge, attitudes, and practices of Spanish midwives and midwifery students regarding oral health in pregnant women; and (ii) to identify the barriers faced by these healthcare professionals in addressing oral health promotion during pregnancy. An observational cross-sectional descriptive study was conducted. A total of 128 midwives and/or midwifery students ≥ 18 years old and of both sexes were invited to self-complete a questionnaire between January and April 2020. A total of 85 people participated in the study. Participants had a regular level of knowledge about oral health during pregnancy (overall knowledge score: 6.53), and although they were interested in activities that promote oral healthcare, their oral healthcare practices during pregnancy were limited. As midwives play an important role in promoting health, their training in oral healthcare could help to improve pregnant women's oral health.

Very few studies investigating COVID-19 in cancer patients have included cancer patients as controls. We aimed to identify factors associated with the risk of testing positive for SARS CoV2 infection in a cohort of cancer patients. We analyzed data from all cancer patients swabbed for COVID-19 between 1 st March and 31 st July 2020 at Guy's Cancer Centre. We conducted logistic regression analyses to identify which factors were associated with a positive COVID-19 test. Results: Of the 2152 patients tested for COVID-19, 190 (9%) tested positive. Male sex, black ethnicity, and hematological cancer type were positively associated with risk of COVID-19 (OR = 1.85, 95%CI:1.37-2.51; OR = 1.93, 95%CI:1.31-2.84; OR = 2.29, 95%CI:1.45-3.62, respectively) as compared to females, white ethnicity, or solid cancer type, respectively. Male, Asian ethnicity, and hematological cancer type were associated with an increased risk of severe COVID-19 (OR = 3.12, 95%CI:1.58-6.14; OR = 2.97, 95%CI:1.00-8.93; OR = 2.43, 95%CI:1.00-5.90, respectively). This study is one of the first to compare the risk of COVID-19 incidence and severity in cancer patients when including cancer patients as controls. Results from this study have echoed those of previous reports, that patients who are male, of black or Asian ethnicity, or with a hematological malignancy are at an increased risk of COVID-19.

Purpose: Pancreas transplantation (PT) is one of the few ways to restore euglycemia within diabetic patients; however, the high morbidity caused by surgical complications and the need for immunosuppressive therapy has raised controversy about PT improving the health-related quality-of-life (HRQoL). The aim of this study is to assess the long-term (≥ 5 years after PT) HRQoL and to identify the factors affecting it., Methods: A single-center, cross-sectional study of 49 sequential PT was performed. All patients conducted a telephone interview to fulfill the modification of Medical Outcome Health Survey Short Form questionnaire (SF-36v2) and were compared to similar post-PT studies from the literature., Results: Patients with a history of replacement renal therapy (RRT) or neuropathy undergoing a PT were associated to a worse bodily pain (P = 0.03) and physical function (P = 0.04), respectively, whereas those with retinopathy showed an improved Role Emotional (P = 0.04). Multivariate analysis revealed the presence of RRT as the only independent prognostic factor for a worse bodily pain [relative risk = 3.9; 95% confidence interval (1.1-14.6)], (P = 0.04). Furthermore, nearly all PT recipients (91.8%) claimed an overall better health than prior to PT., Conclusion: Our study confirms that PT recipients' HRQoL improves after PT, showing similar HRQoL scores across different populations and suggests that patients in predialysis could benefit from an improved HRQoL if transplanted on the early stages of the disease.

Pancreatic cancer (PCa) is associated with a poor prognosis and high mortality rate. The causes of PCa are not fully elucidated yet, although certain exposome factors have been identified. The exposome is defined as the sum of all environmental factors influencing the occurrence of a disease during a life span. The development of an exposome approach for PCa has the potential to discover new disease-associated factors to better understand the carcinogenesis of PCa and help with early detection strategies. Our systematic review of the literature identified several exposome factors that have been associated with PCa alone and in combination with other exposures. A potential inflammatory signature has been observed among the interaction of several exposures (i.e., smoking, alcohol consumption, diabetes mellitus, obesity, and inflammatory markers) that further increases the incidence and progression of PCa. A large number of exposures have been identified such as genetic, hormonal, microorganism infections and immune responses that warrant further investigation. Future early detection strategies should utilize this information to assess individuals' risk for PCa.

The SARS-CoV-2 (COVID-19) pandemic is having a large effect on the management of cancer patients. This study reports on the approach and outcomes of cancer patients receiving radical surgery with curative intent between March and September 2020 (in comparison to 2019) in the European Institute of Oncology, IRCCS (IEO) in Milan and the South East London Cancer Alliance (SELCA). Both institutions implemented a COVID-19 minimal pathway where patients were required to self-isolate prior to admission and were swabbed for COVID-19 within 72 h of surgery. Positive patients had surgery deferred until a negative swab. At IEO, radical surgeries declined by 6% as compared to the same period in 2019 ( n = 1477 vs. 1560, respectively). Readmissions were required for 3% ( n = 41), and <1% ( n = 9) developed COVID-19, of which only one had severe disease and died. At SELCA, radical surgeries declined by 34% ( n = 1553 vs. 2336). Readmissions were required for 11% ( n = 36), <1% ( n = 7) developed COVID-19, and none died from it. Whilst a decline in number of surgeries was observed in both centres, the implemented COVID-19 minimal pathways have shown to be safe for cancer patients requiring radical treatment, with limited complications and almost no COVID-19 infections.

Competing Interests: Declaration of Competing Interest We have no conflicts of interest to disclose and there has been no significant financial support for this work that could have influenced its outcome.

The synthesis of phosphinic amides containing one 4-amino-TEMPO substituent at the ortho position has been achieved through copper(i) catalyzed cross-coupling reactions of ortho-iodophosphinic amides with 4-amino-TEMPO. The method has been extended to the preparation of the first example of a P-stereogenic ortho-(4-amino-tempo)phosphinic amide radical 10. The reaction of 10 with Cu(hfac)2 afforded the P-stereogenic CuII complex 19. The crystal structure of both chiral compounds is reported. The molecular structure of 10 consists of a supramolecular zig-zag chain formed by intermolecular hydrogen bonds between the NH group of the phosphinic amide moiety and the nitroxide oxygen atom. In complex 19, the ligand acts as a bridge between two CuII ions coordinated to the oxygen atoms of the P[double bond, length as m-dash]O and N-O· groups leading to the formation of a polymeric helicate chain in which the metal ions exist in a distorted octahedral geometry. The magnetic behavior of ligand 10 is characterized by very weak intermolecular antiferromagnetic interactions, whereas ferro- and anti-ferromagnetic interactions are present in complex 19.

We investigated the association between metabolic syndrome (MetS) and its components and risk of prostate cancer (PCa) in a cohort of men enrolled in the UK Biobank. Our study cohort included 220 622 PCa-free men with baseline measurements of triglycerides (TGs), HDL-cholesterol (HDL), glycated hemoglobin (HbA1c), blood pressure (BP), and waist circumference (WC). Multivariable Cox proportional hazards regression was used to analyze associations with PCa for: individual metabolic components (TG, HDL, HbA1c, BP, WC), combinations of two and three components, and MetS overall (three or more components). We conducted mediation analyses to examine potential hormonal and inflammatory pathways (total testosterone [TT], C-reactive protein [CRP], insulin-like growth factor 1 [IGF-1]) through which MetS components may influence PCa risk. A total of 5409 men in the study developed PCa during a median follow-up of 6.9 years. We found no significant association between MetS and PCa risk (hazard ratio [HR] = 0.99, 95% confidence interval [CI] = 0.92-1.06). No associations were found with PCa risk and individual measurements of TG, HDL, BP, or WC. However, an inverse association was observed with elevated HbA1c (≥42 mmol/mol) (HR = 0.89, 95% CI = 0.79-0.98). Consistent inverse associations were observed between HbA1c and risk of PCa. Mediation analysis revealed TT, CRP, and IGF-1 as potential mediating factors for this association contributing 10.2%, 7.1%, and 7.9% to the total effect, respectively. Overall MetS had no association with PCa risk. However, a consistent inverse association with PCa risk was found for HbA1c. This association may be explained in part through hormonal and inflammatory pathways., (© 2020 Union for International Cancer Control.)

We describe the synthesis of 1,4-(disubstituted)-5-triazenyl-1,2,3-triazoles through a ligand-free domino copper(I)-catalyzed azide-alkyne-azide process of chelating aryl azides bearing N-P═O, P═O, and SO 3 H groups at the ortho position with a wide variety of acetylenes. DFT calculations reveal that Cu-chelation is a crucial factor in the interception of the CuAAC intermediate by the azide. The crystal structure of the catalytic species has been determined by X-ray diffraction.

Lineage 4/X-family of Mycobacterium tuberculosis is not very notorious, except for the CDC1551 strain. One strain of this family, named Ara50, caused one of the largest tuberculosis outbreaks of the Aragon region, Spain, during the 1990s and remained until 2018. These X-strains are characterised by high transmissibility and by carrying a low copy number of IS6110 in their genomes. Epidemiological data of the 61 patients consisted of inmates, HIV seropositives, intravenous drug users and the homeless. The application of whole-genome sequencing (WGS) to 36 out of 61 isolates, selected by IS6110-RFLP, allowed to confirm 32 as recent transmissions. We found 10 SNPs in genes considered as virulence factors, five of them specific of this strain. WGS identified three sub-clusters (CLSs). The largest one, sub-CLS 1, included 10 cases. Seven of them shared a SNP in the mce3C gene, considered a virulence factor gene. Sub-CLS 2 involved familiar cases, and no link was known for sub-CLS 3. Finally, the strain showed efficacy in latency as a confirmed epidemiological link was established between two cases, with 6 years of distance in their diagnosis. This outbreak study combined epidemiological and molecular analyses in order to elucidate tuberculosis transmission., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Systematic exploration of the dynamic human plasma proteome enables the discovery of novel protein biomarkers. Using state-of-the-art technologies holds the promise to facilitate a better diagnosis and risk prediction of diseases. Cardiovascular disease (CVD) pathophysiology is characterized for unbalancing of processes such as vascular inflammation, endothelial dysfunction, or lipid profiles among others. Such processes have a direct impact on the dynamic and complex composition of blood and hence the plasma proteome. Therefore, the study of the plasma proteome comprises an excellent exploratory source of biomarker research particularly for CVD. We describe the protocol for performing the discovery of protein biomarker candidates using the suspension bead array technology. The process does not require depletion steps to remove abundant proteins and consumes only a few microliters of sample from the body fluid of interest. The approach is scalable to measure many analytes as well as large numbers of samples. Moreover, we describe a bead-assisted antibody-labeling process that helps to develop quantitative assays for validation purposes and facilitate the translation of the identified candidates into clinical studies.

Protein biomarkers in biological fluids represent an important resource for improving the clinical management of diseases. Current proteomics technologies are capable of performing high-throughput and multiplex profiling in different types of fluids, often leading to the shortlisting of tens of candidate biomarkers per study. However, before reaching any clinical setting, these discoveries require thorough validation and an assay that would be suitable for routine analyses. In the path from biomarker discovery to validation, the performance of the assay implemented for the intended protein quantification is extremely critical toward achieving reliable and reproducible results. Development of robust sandwich immunoassays for individual candidates is challenging and labor and resource intensive, and multiplies when evaluating a panel of interesting candidates at the same time. Here we describe a versatile pipeline that facilitates the systematic and parallel development of multiple sandwich immunoassays using a bead-based technology.

Objective: To determine whether smart conversational agents can be used for detection of neuropsychiatric disorders. Therefore, we reviewed the technologies used, targeted mental disorders and validation procedures of relevant proposals in this field., Methods: We searched Scopus, PubMed, Pro-Quest, IEEE Xplore, Web of Science, CINAHL and the Cochrane Library using a predefined search strategy. Studies were included if they focused on neuropsychiatric disorders and involved conversational data for detection and diagnosis. They were assessed for eligibility by independent reviewers and ultimately included if a consensus was reached about their relevance., Results: 2356 references were initially retrieved. Eventually, 17 articles - referring 9 smart conversational agents - met the inclusion criteria. Out of the selected studies, 7 are targeted at neurocognitive disorders, 7 at depression and 3 at other conditions. They apply diverse technological solutions and analysis techniques (82.4% use Artificial Intelligence), and they usually rely on gold standard tests for criterion validity assessment. Acceptability, reliability and other aspects of validity were rarely addressed., Conclusion: The use of smart conversational agents for the detection of neuropsychiatric disorders is an emerging and promising field of research, with a broad coverage of mental disorders and extended use of AI. However, the few published studies did not undergo robust psychometric validation processes. Future research in this field would benefit from more rigorous validation mechanisms and standardized software and hardware platforms., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We aimed to assess the risk of cancer in patients with abdominal symptoms after a complete colonoscopy without colorectal cancer (CRC), according to the carcinoembryonic antigen (CEA) concentration, as well as its diagnostic accuracy. For this purpose, we performed a post-hoc analysis within a cohort of 1431 patients from the COLONPREDICT study, prospectively designed to assess the fecal immunochemical test accuracy in detecting CRC. Over 36.5 ± 8.4 months, cancer was detected in 115 (8%) patients. Patients with CEA values higher than 3 ng/mL revealed an increased risk of cancer (HR 2.0, 95% CI 1.3-3.1), CRC (HR 4.4, 95% CI 1.1-17.7) and non-gastrointestinal cancer (HR 1.7, 95% CI 1.0-2.8). A new malignancy was detected in 51 (3.6%) patients during the first year and three variables were independently associated: anemia (OR 2.8, 95% CI 1.3-5.8), rectal bleeding (OR 0.3, 95% CI 0.1-0.7) and CEA level >3 ng/mL (OR 3.4, 95% CI 1.7-7.1). However, CEA was increased only in 31.8% (95% CI, 16.4-52.7%) and 50% (95% CI, 25.4-74.6%) of patients with and without anemia, respectively, who would be diagnosed with cancer during the first year of follow-up. On the basis of this information, CEA should not be used to assist in the triage of patients presenting with lower bowel symptoms who have recently been ruled out a CRC.

Molecular epidemiology of circulating clinical isolates is crucial to improve prevention strategies. The Spanish Working Group on multidrug resistant tuberculosis (MDR-TB) is a network that monitors the MDR-TB isolates in Spain since 1998. The aim of this study was to present the study of the MDR-TB and extensively drug-resistant tuberculosis (XDR-TB) patterns in Spain using the different recommended genotyping methods over time by a national coordinated system. Based on the proposed genotyping methods in the European Union until 2018, the preservation of one method, MIRU-VNTR, applied to selected clustered strains permitted to maintain our study open for 20 years. The distribution of demographic, clinical and epidemiological characteristics of clustered and non-clustered cases of MDR/XDR tuberculosis with proportion differences as assessed by Pearson's chi-squared or Fisher's exact test was compared. The differences in the quantitative variables using the Student's-t test and the Mann-Whitney U test were evaluated. The results obtained showed a total of 48.4% of the cases grouped in 77 clusters. Younger age groups, having a known TB case contact (10.2% vs 4.7%) and XDR-TB (16.5% vs 1.8%) were significantly associated with clustering. The largest cluster corresponded to a Mycobacterium bovis strain mainly spread during the nineties. A total of 68.4% of the clusters detected were distributed among the different Spanish regions and six clusters involving 104 cases were grouped in 17 and 18 years. Comparison of the genotypes obtained with those European genotypes included in The European Surveillance System (TESSy) showed that 87 cases had become part of 20 European clusters. The continuity of MDR strain genotyping in time has offered a widespread picture of the situation that allows better management of this public health problem. It also shows the advantage of maintaining one genotyping method over time, which allowed the comparison between ancient, present and future samples.

A series of tri- and tetrasubstituted spiro-oxaphosphetanes stabilized by ortho -benzamide ( o BA) and N -methyl ortho -benzamide (M o BA) ligands have been synthesized by the reaction of C α ,C ortho -dilithiated phosphazenes with aldehydes and ketones. They include enantiopure products and the first example of an isolated oxaphosphetane having a phenyl substituent at C3 of the ring. Kinetic studies of their thermal decomposition showed that the process takes place irreversibly through a polar transition state (ρ = -0.22) under the influence of electronic, [1,2], [1,3] steric, and solvent effects, with C3/P-[1,2] interactions as the largest contribution to Δ G ⧧ of olefination. Inversion of the phosphorus configuration through stereomutation has been observed in a number of cases. DFT calculations showed that o BA derivatives olefinated through the isolated (N, O)(Ph, C 6 H 4 , C) oxaphosphetanes (Channel A), whereas M o BA compounds decomposed faster via the isomer (C 6 H 4 , O)(C, N, Ph) formed by P-stereomutation involving a M B2 permutational mechanism (Channel B). The energy barrier of P-isomerization is lower than that of olefination. Fragmentation takes place in a concerted asynchronous reaction. The thermal stability of oxaphosphetanes is determined by strong C3/P-[1,2] interactions destabilizing the transition state of olefination. The effect of charge distribution and C3/C4-[1,2] and C4/P-[1,3] steric and solvent interactions on Δ G ⧧ was also evaluated.

Background: p53 protein is essential for the regulation of cell proliferation. Aberrant accumulation of it usually occurs in cutaneous malignancies. Mutant p53 is detected by immunohistochemistry because it is more stable than the wild-type p53. However, post-translational modifications of p53 in response to ultraviolet radiation are important mechanisms of wild-type p53 stabilization, leading to positive staining in the absence of mutation. The aims were: 1) to analyze the immunohistochemical expression of p53 and phospho-p53 Serine 392 in canine skin endothelial tumours; and 2) to determine if any relationship exists between p53 and phospho-p53 Serine 392 overexpression and cell proliferation., Results: p53 and phospho-p53 Serine 392 immunolabeling was examined in 40 canine cutaneous endothelial tumours (13 hemangiomas and 27 hemangiosarcomas). Their expression was associated with tumour size, hemangiosarcoma stage (dermal versus hypodermal), histological diagnosis and proliferative activity (mitotic count and Ki-67 index). Statistical analysis revealed a significant increase of p53 immunoreactivity in hemangiosarcomas (median, 74.61%; interquartile range [IQR], 66.97-82.98%) versus hemangiomas (median, 0%; IQR, 0-20.91%) (p < .001) and in well-differentiated hemangiosarcomas (median, 82.40%; IQR, 66.49-83.17%) versus hemangiomas (p = .002). Phospho-p53 Serine 392 immunoreactivity was significantly higher in hemangiosarcomas (median, 53.80%; IQR, 0-69.50%) than in hemangiomas (median, 0%; IQR, 0.0%) (p < .001). Positive correlation of the overexpression of p53 and phospho-p53 Serine 392 with mitotic count and Ki-67 index was found in the cutaneous vascular tumours (p < .001). The Ki-67 index of the hemangiomas (median, 0.50%; IQR, 0-2.80%) was significantly lower than that of the hemangiosarcomas (median, 34.85%; IQR, 23.88-42.33%) (p < .001), and that specifically of well-differentiated hemangiosarcomas (median, 24.60%; IQR, 15.45-39.35%) (p = .001). Immunolabeling of 18 visceral hemangiosarcomas showed that the p53 (median, 41.59%; IQR, 26.89-64.87%) and phospho-p53 Serine392 (median, 0%; IQR, 0-22.53%) indexes were significantly lower than those of skin (p = .001; p = .006, respectively)., Conclusions: The p53 and phospho-p53 Serine 392 overexpression together with high proliferative activity in hemangiosarcomas versus hemangiomas indicated that p53 might play a role in the acquisition of malignant phenotypes in cutaneous endothelial neoplasms in dogs. The Ki-67 index may be useful in distinguishing canine well-differentiated hemangiosarcomas from hemangiomas.

Sarcoptic mange is caused by the mite Sarcoptes scabiei and has been described in several species of domestic and wild mammals. Macroscopic lesions are predominantly hyperkeratotic (type I hypersensitivity) in fox, chamois and deer, but alopecic (type IV hypersensitivity) in wolf and some fox populations. To begin to understand the immune processes underlying these species differences in lesions, we examined skin biopsies from wolves ( Canis lupus ), foxes ( Vulpes vulpes ), chamois ( Rupicapra rupicapra ) and red deer ( Cervus elaphus ) naturally infested with S. scabiei . Twenty skin samples from five animals per species were used. Sections were immuno-stained with primary antibodies against Iba1 to detect macrophages, lambda chain to detect plasma cells, CD3 to detect T lymphocytes and CD20 to detect B lymphocytes. Skin lesions contained significantly more inflammatory cells in the fox than in the wolf and chamois. Macrophages were the most abundant inflammatory cells in the lesions of all the species studied, suggesting a predominantly innate, non-specific immune response. Lesions from the wolf contained higher proportions of macrophages than the other species, which may reflect a more effective response, leading to alopecic lesions. In red deer, macrophages were significantly more abundant than plasma cells, T lymphocytes and B lymphocytes, which were similarly abundant. The fox proportion of plasma cells was significantly higher than those of T and B lymphocytes. In chamois, T lymphocytes were more abundant than B lymphocytes and plasma cells, although the differences were significant only in the case of macrophages. These results suggest that all the species examined mount a predominantly innate immune response against S. scabiei infestation, while fox and chamois may also mount substantial humoral and cellular immune responses, respectively, with apparently scarce effectiveness that lead to hyperkeratotic lesions.