Efficacy and Safety of an Inactivated Phase I Coxiella burnetii Vaccine to Control Q Fever in Ruminants: A Systematic Review.

Q fever is a disease caused by Coxiella burnetii that affects many animal species and humans. In ruminants, the disease is responsible for several reproductive disorders (such as abortions, stillbirths, premature births, weak offspring, retained foetal membranes and infertility). An inactivated vaccine based on a phase I antigen of C. burnetii is available for cattle, goats and sheep. This review aims to summarise the scientific literature regarding the efficacy and safety of this vaccine to control the infection in these three domestic ruminant species. Forty-five publications and one experimental veterinary thesis reporting on experimental studies, case reports, mathematical modelling and intervention studies were selected according to the PRISMA guidelines. Although some studies lack control groups or statistical analyses, for all three species, published data show that vaccination often results in a reduction in abortions and an improvement in reproductive performance in comparison with absence of vaccination. There is also evidence, including in infected herds and animals, that vaccination is associated with a reduction in bacterial shedding, both in intensity and duration in comparison with absence of vaccination. For these reasons, in case of human outbreaks, vaccination is one of the pillars of control measures. Vaccination is generally well tolerated, despite the rare occurrence of mild, transient side-effects, such as hyperthermia and reduction in milk yield.

Biochemical and molecular characterization of Campylobacter fetus isolates from bulls subjected to bovine genital campylobacteriosis diagnosis in Spain.

BACKGROUND: Bovine genital campylobacteriosis (BGC) is caused by Campylobacter fetus subsp. venerealis (Cfv) including its biovar intermedius (Cfvi). This sexually transmitted disease induces early reproductive failure causing considerable economic losses in the cattle industry. Using a collection of well-characterized isolates (n = 13), C. fetus field isolates (n = 64) and saprophytic isolates resembling Campylobacter (n = 75) obtained from smegma samples of breeding bulls, this study evaluated the concordance of the most used phenotypic (H2S production in cysteine medium and 1% glycine tolerance) and molecular (PCR) methods for the diagnosis of BGC and assessed possible cross-reactions in the molecular diagnostic methods. RESULTS: Characterization at the subspecies level (fetus vs. venerealis) of C. fetus isolated from bull preputial samples using phenotypic and molecular (PCR targeting nahE and ISCfe1) methods showed moderate concordance (κ = 0.462; CI: 0.256-0.669). No cross-reactions were observed with other saprophytic microaerophilic species or with other Campylobacter species that can be present in preputial samples. Whole genome sequencing (WGS) of discrepant isolates showed 100% agreement with PCR identification. For the differentiation of Cfv biovars, comparison of the H2S test (at 72 h and 5 days of incubation) and a PCR targeting the L-cysteine transporter genes showed higher concordance when H2S production was assessed after 5 days (72 h; κ = 0.553, 0.329-0.778 CI vs. 5 days; κ = 0.881, 0.631-1 CI), evidencing the efficacy of a longer incubation time. CONCLUSIONS: This study confirmed the limitations of biochemical tests to correctly identify C. fetus subspecies and biovars. However, in the case of biovars, when extended incubation times for the H2S test (5 days) were used, phenotypic identification results were significantly improved, although PCR-based methods produced more accurate results. Perfect agreement of WGS with the PCR results and absence of cross-reactions with non-C. fetus saprophytic bacteria from the smegma demonstrated the usefulness of these methods. Nevertheless, the identification of new C. fetus subspecies-specific genes would help to improve BGC diagnosis.

Comparative pangenomic analysis of Campylobacter fetus isolated from Spanish bulls and other mammalian species.

Campylobacter fetus comprises two closely related mammal-associated subspecies: Campylobacter fetus subsp. fetus (Cff) and Campylobacter fetus subsp. venerealis (Cfv). The latter causes bovine genital campylobacteriosis, a sexually-transmitted disease endemic in Spain that results in significant economic losses in the cattle industry. Here, 33 C. fetus Spanish isolates were whole-genome sequenced and compared with 62 publicly available C. fetus genomes from other countries. Genome-based taxonomic identification revealed high concordance with in silico PCR, confirming Spanish isolates as Cff (n = 4), Cfv (n = 9) and Cfv biovar intermedius (Cfvi, n = 20). MLST analysis assigned the Spanish isolates to 6 STs, including three novel: ST-76 and ST-77 for Cfv and ST-78 for Cff. Core genome SNP phylogenetic analysis of the 95 genomes identified multiple clusters, revealing associations at subspecies and biovar level between genomes with the same ST and separating the Cfvi genomes from Spain and other countries. A genome-wide association study identified pqqL as a Cfv-specific gene and a potential candidate for more accurate identification methods. Functionality analysis revealed variations in the accessory genome of C. fetus subspecies and biovars that deserve further studies. These results provide valuable information about the regional variants of C. fetus present in Spain and the genetic diversity and predicted functionality of the different subspecies.

Coxiella burnetii infection persistence in a goat herd during seven kidding seasons after an outbreak of abortions: the effect of vaccination.

Coxiella burnetii infection was monitored during seven kidding seasons (2017-2023) in a dairy goat herd that after an outbreak of Q fever abortions was vaccinated with an inactivated phase I vaccine. Due to the high infection rate just after the outbreak, only the replacement stock was vaccinated during the first three kidding seasons, and when the average herd immunity had decreased (fourth kidding season onwards), the whole herd was vaccinated. Vaginal swabs, feces, and milk were analyzed by PCR to monitor infection, and dust and aerosols were analyzed to measure C. burnetii environmental contamination. One year after the onset of the outbreak, a significant reduction in C. burnetii shedding loads was observed, but the percentage of shedding animals remained high until the third kidding season. By the seventh kidding season, no shedders were detected. The bacterial load excreted was significantly lower in vaccinated compared with unvaccinated animals, and in yearlings compared with multiparous. C. burnetii was detected by PCR in aerosols collected inside the animal premises throughout the study period except in the last season; whereas, aerosols collected outdoors tested negative in the last three kidding seasons. Viable C. burnetii was detectable in environmental dust collected inside the barn until the third kidding season following the outbreak. These results indicate that after an outbreak of Q fever, the risk of infection for humans and susceptible animals can remain high for at least three kidding seasons when the number of C. burnetii animal shedders is still high, even when bacterial excretion is low. IMPORTANCE: Q fever is a zoonosis distributed worldwide. Ruminants are the main reservoir, and infection can cause high rates of abortion. After entering a farm, Coxiella burnetii infection can persist in the animal population over several lambing/kidding periods. Once infection is established in a herd, vaccination with the inactivated Phase I vaccine significantly reduces bacterial shedding, but although at low levels, excretion may continue to occur for several lambing/kidding seasons. The time that C. burnetii remains viable in the farm environment after an outbreak of Q fever determines the period when risk of infection is high for the people in close contact. This work showed that this period extends at least three kidding seasons after the outbreak. These results provided valuable information on the epidemiology of C. burnetii infection in goat herds and may help to develop guidelines for controlling the disease and reducing infection risk for susceptible people and animals.

Whole-genome long-read sequencing to unveil Enterococcus antimicrobial resistance in dairy cattle farms exposed a widespread occurrence of Enterococcus lactis.

Enterococcus faecalis (Efs) and Enterococcus faecium (Efm) are major causes of multiresistant healthcare-associated or nosocomial infections. Efm has been traditionally divided into clades A (healthcare associated) and B (community associated) but clade B has been recently reassigned to Enterococcus lactis (Elc). However, identification techniques do not routinely differentiate Elc from Efm. As part of a longitudinal study to investigate the antimicrobial resistance of Enterococcus in dairy cattle, isolates initially identified as Efm were confirmed as Elc after Oxford-Nanopore long-fragment whole-genome sequencing and genome comparisons. An Efm-specific PCR assay was developed and used to identify isolates recovered from animal feces on five farms, resulting in 44 Efs, 23 Efm, and 59 Elc. Resistance, determined by broth microdilution, was more frequent in Efs than in Efm and Elc but all isolates were susceptible to ampicillin, daptomycin, teicoplanin, tigecycline, and vancomycin. Genome sequencing analysis of 32 isolates identified 23 antimicrobial resistance genes (ARGs, mostly plasmid-located) and 2 single nucleotide polymorphisms associated with resistance to 10 antimicrobial classes, showing high concordance with phenotypic resistance. Notably, linezolid resistance in Efm was encoded by the optrA gene, located in plasmids downstream of the fexA gene. Although most Elc lacked virulence factors and genetic determinants of resistance, one isolate carried a plasmid with eight ARGs. This study showed that Elc is more prevalent than Efm in dairy cattle but carries fewer ARGs and virulence genes. However, Elc can carry multi-drug-resistant plasmids like those harbored by Efm and could act as a donor of ARGs for other pathogenic enterococcal species.IMPORTANCEEnterococcus species identification is crucial due to differences in pathogenicity and antibiotic resistance profiles. The failure of traditional methods or whole-genome sequencing-based taxonomic classifiers to distinguish Enterococcus lactis (Elc) from Enterococcus faecium (Efm) results in a biased interpretation of Efm epidemiology. The Efm species-specific real-time PCR assay developed here will help to properly identify Efm (only the formerly known clade A) in future studies. Here, we showed that Elc is prevalent in dairy cattle, and although this species carries fewer genetic determinants of resistance (GDRs) than Enterococcus faecalis (Efs) and Efm, it can carry multi-drug-resistant (MDR) plasmids and could act as a donor of resistance genes for other pathogenic enterococcal species. Although all isolates (Efs, Efm, and Elc) were susceptible to critically or highly important antibiotics like daptomycin, teicoplanin, tigecycline, and vancomycin, the presence of GDRs in MDR-plasmids is a concern since antimicrobials commonly used in livestock could co-select and confer resistance to critically important antimicrobials not used in food-producing animals.

An allosteric switch between the activation loop and a c-terminal palindromic phospho-motif controls c-Src function.

Autophosphorylation controls the transition between discrete functional and conformational states in protein kinases, yet the structural and molecular determinants underlying this fundamental process remain unclear. Here we show that c-terminal Tyr 530 is a de facto c-Src autophosphorylation site with slow time-resolution kinetics and a strong intermolecular component. On the contrary, activation-loop Tyr 419 undergoes faster kinetics and a cis-to-trans phosphorylation switch that controls c-terminal Tyr 530 autophosphorylation, enzyme specificity, and strikingly, c-Src non-catalytic function as a substrate. In line with this, we visualize by X-ray crystallography a snapshot of Tyr 530 intermolecular autophosphorylation. In an asymmetric arrangement of both catalytic domains, a c-terminal palindromic phospho-motif flanking Tyr 530 on the substrate molecule engages the G-loop of the active kinase adopting a position ready for entry into the catalytic cleft. Perturbation of the phospho-motif accounts for c-Src dysfunction as indicated by viral and colorectal cancer (CRC)-associated c-terminal deleted variants. We show that c-terminal residues 531 to 536 are required for c-Src Tyr 530 autophosphorylation, and such a detrimental effect is caused by the substrate molecule inhibiting allosterically the active kinase. Our work reveals a crosstalk between the activation and c-terminal segments that control the allosteric interplay between substrate- and enzyme-acting kinases during autophosphorylation.

Effects of imipramine on cancer patients over-expressing Fascin1; description of the HITCLIF clinical trial.

Background: Tumor invasion and metastasis are responsible for the majority of cancer-related deaths. The identification of molecules involved in these processes is crucial to design effective treatments that can halt the progression of cancer. To spread and metastasize, tumor cells must restructure their cytoskeleton and emit protrusions. A key molecule in this process of creating these invading structures is Fascin1, the main protein involved in the formation of actin cytoskeleton bundles and a consistent marker of bad prognosis in several types of cancer. Recent studies have shown that imipramine, an FDA- and EMA-approved antidepressant, can block Fascin1and prevent the formation of actin bundles, making it a promising candidate for the treatment of Fascin1-expressing cancers. As a result, a clinical trial will be conducted to assess the efficacy of imipramine being the first experimental clinical study selecting patients based on Fascin1 expression. Methods: The HITCLIF trial is a multicenter, double-blind, placebo-controlled, randomized and non-commercial phase II clinical trial conducted in parallel groups to evaluate the effectiveness of the tricyclic antidepressant imipramine as anti-invasive agent in the treatment of localized colon, rectal and triple negative breast cancer patients with overexpression of Fascin1. Eligible patients will be randomly assigned, in a 1:1 ratio, to receive imipramine or placebo. Patients will be stratified into 2 groups according to whether administration of imipramine is concomitant with neoadjuvant chemotherapy regimen. Group A will receive imipramine alone without neoadjuvant chemotherapy, while Group B will receive imipramine treatment along with the standard neoadjuvant chemotherapy regimen. The primary endpoint of the trial is the grade of alteration in the prognostic histopathological features at invasive margins (tumor budding, cytoplasmic pseudo-fragments, tumor growth pattern, and peritumoral lymphocytic infiltration). Discussion: Fascin1 is an interesting therapeutical target as it plays a causative role in the invasion and metastasis of cancer cells. Moreover, its expression is virtually absent in normal epithelia but highly expressed in cancer with bad prognosis. In silico, in vitro and in vivo studies by our group have demonstrated that the antidepressant imipramine has Fascin1-dependant anti-invasive and anti-metastatic effects in colorectal cancer cells. Now we are recruiting patients in a clinical trial based on Fascin1 over-expression in which administration of imipramine will be carried out during the period between the diagnosis biopsy and surgical resection to explore the drug effects on tumor invasive front. Clinical trial registration: https:///www.clinicaltrialsregister.eu/ctr-search/trial/2021-001328-17/ES, identifier 2021-001328-17.

Monitoring within-farm transmission dynamics of antimicrobial-resistant Campylobacter in dairy cattle using broth microdilution and long-read whole genome sequencing.

Campylobacter jejuni and Campylobacter coli are important foodborne zoonotic pathogens and cause for concern due to the increasing trend in antimicrobial resistance. A long-run surveillance study was conducted in animals from different age groups in five dairy cattle farms to investigate the within-farm diversity and transmission dynamics of resistant Campylobacter throughout time. The resistance phenotype of the circulating isolates (170 C. jejuni and 37 C. coli) was determined by broth microdilution and a selection of 56 isolates were whole genome sequenced using the Oxford-Nanopore long-fragment sequencing technology resulting in completely resolved and circularized genomes (both chromosomes and plasmids). C. jejuni was isolated from all farms while C. coli was isolated from only two farms, but resistance rates were higher in C. coli than in C. jejuni and in calves than in adult animals. Some genotypes (e.g. ST-48, gyrA_T86I/tet(O)/blaOXA-61 in farm F1; ST-12000, aadE-Cc/tet(O)/blaOXA-489 in F4) persisted throughout the study while others were only sporadically detected. Acquisition of extracellular genes from other isolates and intracellular mutational events were identified as the processes that led to the emergence of the resistant genotypes that spread within the herds. Monitoring with Oxford Nanopore Technologies sequencing helped to decipher the complex molecular epidemiology underlying the within-farm dissemination of resistant Campylobacter.

EVC-EVC2 complex stability and ciliary targeting are regulated by modification with ubiquitin and SUMO.

Ellis van Creveld syndrome and Weyers acrofacial dysostosis are two rare genetic diseases affecting skeletal development. They are both ciliopathies, as they are due to malfunction of primary cilia, microtubule-based plasma membrane protrusions that function as cellular antennae and are required for Hedgehog signaling, a key pathway during skeletal morphogenesis. These ciliopathies are caused by mutations affecting the EVC-EVC2 complex, a transmembrane protein heterodimer that regulates Hedgehog signaling from inside primary cilia. Despite the importance of this complex, the mechanisms underlying its stability, targeting and function are poorly understood. To address this, we characterized the endogenous EVC protein interactome in control and Evc-null cells. This proteomic screen confirmed EVC's main known interactors (EVC2, IQCE, EFCAB7), while revealing new ones, including USP7, a deubiquitinating enzyme involved in Hedgehog signaling. We therefore looked at EVC-EVC2 complex ubiquitination. Such ubiquitination exists but is independent of USP7 (and of USP48, also involved in Hh signaling). We did find, however, that monoubiquitination of EVC-EVC2 cytosolic tails greatly reduces their protein levels. On the other hand, modification of EVC-EVC2 cytosolic tails with the small ubiquitin-related modifier SUMO3 has a different effect, enhancing complex accumulation at the EvC zone, immediately distal to the ciliary transition zone, possibly via increased binding to the EFCAB7-IQCE complex. Lastly, we find that EvC zone targeting of EVC-EVC2 depends on two separate EFCAB7-binding motifs within EVC2's Weyers-deleted peptide. Only one of these motifs had been characterized previously, so we have mapped the second herein. Altogether, our data shed light on EVC-EVC2 complex regulatory mechanisms, with implications for ciliopathies.

A Q fever outbreak among visitors to a natural cave, Bizkaia, Spain, December 2020 to October 2021.

We describe a large Q fever outbreak reported in Spain, including 108 cases, 53 with pneumonia and 27 requiring hospitalisations. The first cases were detected in February 2021 among rock climbers visiting a cave in Bizkaia, and the last case was detected in October 2021. Most cases were notified after the Easter holiday (April-May 2021). More males (63.9%) than females (36.1%) were infected (median ages: 42 (1-68) and 39 years (6-61), respectively). We detected Coxiella burnetii by PCR in faecal, dust and/or aerosol samples taken inside the cave in March 2021, and in dust and aerosol samples collected between March 2021 and February 2023. Coxiella burnetii from dust samples were cultured on Vero cells, showing viability for 24 months. Based on serological and genotyping data, goats sheltering in the cave were the most likely source of infection. The cave was closed on 29 April 2021, movements of goats and sheep in the area were restricted (March-July 2021), and the animals were vaccinated in October 2021. Investigation of Q fever outbreaks requires a multidisciplinary One Health approach as these outbreaks can occur in unexpected places like natural sites where animals are present.

Long-Term In Vitro Adhesive Properties of Two Universal Adhesives to Dentin.

The composition of universal adhesives, as well as the adhesive strategy, may influence bonding effectiveness and durability. This study aimed to evaluate the microtensile bond strength (µTBS) and nanoleakage (NL), immediately and after 6-month aging, and in situ degree of conversion (DC), of two universal adhesives (Scotchbond Universal Adhesive, SBU; Xeno Select, XEN) applied with etch-and-rinse (ER) and self-etch (SE) strategies, in comparison with a two-step SE adhesive (Clearfil SE Bond, CSE). Dentin surfaces of fifty human third molars were randomly assigned to the following adhesives: two universal adhesives, SBU and XEN, applied in ER or SE mode and CSE, used as control. Teeth were sectioned into beams to be tested under µTBS, half of them after 24 h, and the rest after 6 months of water aging. Selected beams from each tooth were used for NL evaluation and in situ DC quantification. SBU and CSE showed significantly higher mean µTBS and lower nanoleakage than XEN, regardless of the evaluation time and adhesion strategy. XEN-SE yielded the lowest degree of conversion. Therefore, adhesive properties of universal adhesives to dentin are material dependent, regardless of the adhesion strategy, exhibiting XEN a significantly worse performance than SBU.

Structural and dynamic determinants for highly selective RET kinase inhibition reveal cryptic druggability.

INTRODUCTION: The structural and dynamic determinants that confer highly selective RET kinase inhibition are poorly understood. OBJECTIVES: To explore the druggability landscape of the RET active site in order to uncover structural and dynamic vulnerabilities that can be therapeutically exploited. METHODS: We apply an integrated structural, computational and biochemical approach in order to explore the druggability landscape of the RET active site. RESULTS: We demonstrate that the that the druggability landscape of the RET active site is determined by the conformational setting of the ATP-binding (P-) loop and its coordination with the αC helix. Open and intermediate P-loop structures display additional druggable vulnerabilities within the active site that were not exploited by first generation RET inhibitors. We identify a cryptic pocket adjacent to the catalytic lysine formed by K758, L760, E768 and L772, that we name the post-lysine pocket, with higher druggability potential than the adenine-binding site and with important implications in the regulation of the phospho-tyrosine kinase activity. Crystal structure and simulation data show that the binding mode of highly-selective RET kinase inhibitors LOXO-292 and BLU-667 is controlled by a synchronous open P-loop and αC-in configuration that allows accessibility to the post-lysine pocket. Molecular dynamics simulations show that these inhibitors efficiently occupy the post-lysine pocket with high stability through the simulation time-scale (300 ns), with both inhibitors forming hydrophobic contacts further stabilized by pi-cation interactions with the catalytic K758. Engineered mutants targeting the post-lysine pocket impact on inhibitor binding and sensitivity, as well as RET tyrosine kinase activity. CONCLUSIONS: The identification of the post-lysine pocket as a new druggable vulnerability in the RET kinase and its exploitation by second generation RET inhibitors have important implications for future drug design and the development of personalized therapies for patients with RET-driven cancers.

Efficacy of Vaporized Hydrogen Peroxide Combined with Silver Ions against Multidrug-Resistant Gram-Negative and Gram-Positive Clinical Isolates.

Antimicrobial resistance (AMR) is a serious public health problem that results in high morbidity and mortality rates. In particular, multidrug-resistant (MDR) strains circulating in hospital settings pose a major threat as they are associated with serious nosocomial infections. Therefore, regular cleaning and disinfection procedures, usually using chemical disinfectants, must be implemented in these facilities. Hydrogen peroxide (HP)-based disinfectants have proven high microbicidal activity and several comparative advantages over conventional disinfectants. We assessed the in vitro biocidal activity of an 8% HP solution combined with 30 mg/L silver ions (HP + Ag) against MDR clinical isolates of Klebsiella pneumoniae (MDRKp) and Pseudomonas aeruginosa (MDRPa), and methicillin-resistant Staphylococcus aureus (MRSA). Accordingly, the in vitro antibacterial activity was determined using the macrodilution method, and the efficacy was determined for 30 min in terms of (1) activity on bacteria in suspension and (2) activity on surfaces using vaporized HP + Ag on a 20 cm2 stainless steel surface. A strong bactericidal effect of HP + Ag was observed against MDRKp, MDRPa, and MRSA strains, with minimum inhibitory concentrations and minimum bactericidal concentrations between 362.5 and 5800 mg/L. A strong effect was observed during the 30 min of HP + Ag exposure to the resistant clinical isolates, with over 4-Log10 reduction in CFUs. Regarding the efficacy of the disinfectant on surfaces, bacterial load reductions of >99% were observed. These results suggest that HP + Ag is potentially useful as an effective disinfectant for decontaminating surfaces in hospital settings suspected of contamination with MDR bacteria.

Cannabidiol pharmacotherapy for delta-9-tetrahidrocannabinol dependence / Cannabis de grado médico para el tratamiento de la dependencia a Δ-9-Tetrahidrocannabinol.

Addictions are one of the most important health problems worldwide. Within these disorders, cannabis is one of the psychoactive substances with more burden of morbidity and mortality worldwide. The actual knowledge about the effectiveness of treatments for cannabis use disorders is unsatisfactory. This review aims to explore the evidence on cannabidiol for the treatment of cannabis use disorder. There are several clinical pharmacotherapy trials researching cannabis use disorders with limited evidence. A smaller number of trials in animal models and humans on the use of cannabinoids, especially Cannabidiol and Tetrahydrocannabinol to treat cannabis dependence show evidence of reduction in days of use, withdrawal symptoms and craving. New trials are under development, and there is an urgent need for trials with larger numbers of patients and longer treatment periods to support possible indications in the near future.

Las adicciones son uno de los problemas de salud más importantes a nivel mundial. Dentro de estos trastornos, el cannabis es una de las sustancias psicoactivas que provoca mayor morbimortalidad a nivel mundial. La efectividad documentada de los tratamientos para los trastornos por uso de cannabis no es satisfactoria. Esta revisión tiene por objetivo explorar las evidencias sobre la implementación de tratamientos con cannabinoides para el abordaje de estos trastornos. La bibliografía actual cuenta con muchos ensayos sobre el uso de neuropsicofármacos en los trastornos por uso de cannabis con limitada evidencia a favor; mientras que un número más reducido de ensayos en modelos animales y en pacientes sobre el uso de cannabinoides, en especial Cannabidiol y Tetrahidrocannabinol para tratar dicha dependencia muestran evidencias de reducción en días de consumo, síntomas de abstinencia y craving. Se encuentran en desarrollo nuevos ensayos clínicos, estos son una necesidad imperiosa para proveer mayor número de pacientes y con períodos de tratamiento más prolongados y así poder explorar más a fondo su posible indicación en un futuro cercano.

Within-farm dynamics of ESBL-producing Escherichia coli in dairy cattle: Resistance profiles and molecular characterization by long-read whole-genome sequencing.

A longitudinal study was designed in five dairy cattle farms to assess the within-farm dynamics of ESBL-/AmpC-/carbapenemase-producing E. coli and their resistance profiles, along with the genes conferring the resistance phenotypes. Twelve samplings were performed over a period of 16 months, collecting rectal feces from apparently healthy animals in three age groups (calves, heifers, and lactating cows) that were subjected to selective isolation in cefotaxime-containing media. Minimum inhibitory concentrations were determined by broth microdilution for 197 cefotaxime-resistant E. coli (1-3 isolates per age group and sampling date), and 41 of them were selected for long-read whole-genome sequencing. Cefotaxime-resistant E. coli were detected in the five farms, but isolation frequency and resistance profiles varied among farms and age groups. The genetic profiling of a selection of isolates recovered in two of the farms was described in full detail, showing the predominance of a few genomic subtypes of E. coli in one farm (F1) and great variability of strains in another one (F4). Two predominant distinct strains carrying the bla CTX-M-1 gene in IncX1 plasmids successively spread and persisted in F1 over a prolonged period. In F4, 13 different MLST types carrying a high diversity of ESBL-encoding genes in 6 different plasmid types were observed, probably as the result of multiple source contamination events. In both farms, the presence of certain plasmid types with the same repertoire of ARGs in different E. coli STs strongly suggested the occurrence of horizontal transfer of such plasmids among strains circulating within the farms. Considering the public health importance of ESBL-producing E. coli both as pathogens and as vectors for resistance mechanisms, the presence of ß-lactamase- and other AMR-encoding genes in plasmids that can be readily transferred between bacteria is a concern that highlights the need for One Health surveillance.

FunAndes - A functional trait database of Andean plants.

We introduce the FunAndes database, a compilation of functional trait data for the Andean flora spanning six countries. FunAndes contains data on 24 traits across 2,694 taxa, for a total of 105,466 entries. The database features plant-morphological attributes including growth form, and leaf, stem, and wood traits measured at the species or individual level, together with geographic metadata (i.e., coordinates and elevation). FunAndes follows the field names, trait descriptions and units of measurement of the TRY database. It is currently available in open access in the FIGSHARE data repository, and will be part of TRY's next release. Open access trait data from Andean plants will contribute to ecological research in the region, the most species rich terrestrial biodiversity hotspot.

Antitumoral Effects of Tricyclic Antidepressants: Beyond Neuropathic Pain Treatment.

Growing evidence shows that nerves play an active role in cancer development and progression by altering crucial molecular pathways and cell functions. Conversely, the use of neurotropic drugs, such as tricyclic antidepressants (TCAs), may modulate these molecular signals with a therapeutic purpose based on a direct antitumoral effect and beyond the TCA use to treat neuropathic pain in oncology patients. In this review, we discuss the TCAs' safety and their central effects against neuropathic pain in cancer, and the antitumoral effects of TCAs in in vitro and preclinical studies, as well as in the clinical setting. The current evidence points out that TCAs are safe and beneficial to treat neuropathic pain associated with cancer and chemotherapy, and they block different molecular pathways used by cancer cells from different locations for tumor growth and promotion. Likewise, ongoing clinical trials evaluating the antineoplastic effects of TCAs are discussed. TCAs are very biologically active compounds, and their repurposing as antitumoral drugs is a promising and straightforward approach to treat specific cancer subtypes and to further define their molecular targets, as well as an interesting starting point to design analogues with increased antitumoral activity.

[Improved cognitive performance and post-injury plasticity during intensive outpatient treatment for substance use disorder. A case report]. / Mejoramiento del rendimiento cognitivo y plasticidad post lesional durante el tratamiento ambulatorio intensivo por trastorno por uso de sustancias. Reporte de caso.

There are different degrees of cognitive functional decline and modifiable risk factors related to their evolution. Mild cognitive impairment is a state of cognitive function between that seen in normal aging and dementia and is related to an increased risk of developing dementia. Among its potentially modifiable risk factors, substance use disorders have been described. In particular, techniques with predictive value have been developed to identify this impairment during neuropsychological assessment. We present a clinical case of a young patient with mild cognitive deficit and multiple drug abuse who after 24 months of an intensive outpatient treatment showed improvement in cognitive screening scores and neuroimaging. Together with other modifiable lifestyle factors, early cognitive screening in patients with substance use disorder could be a tool to detect other dimensions affected and contribute with specific therapies that promote post-injury plasticity and overall patient improvement.

Mechanical life support algorithm developed by simulation for inpatient emergency management of recipients of implantable left ventricular assist devices.

Background: Published guidance concerning emergency management of left ventricular assist device (LVAD) recipients is both limited and lacking in consensus which increases the risk of delayed and/or inappropriate actions. Methods: In our specialist tertiary referral centre we developed, by iteration, a novel in-hospital resuscitation algorithm for LVAD emergencies which we validated through simulation and assessment of our multi-disciplinary team. A Mechanical Life Support course was established to provide theoretical and practical education combined with simulation to consolidate knowledge and confidence in algorithm use. We assessed these measures using confidence scoring, a key performance indicator (the time taken to restart LVAD function) and a multiple-choice question (MCQ) examination. Results: The mean baseline staff confidence score in management of LVAD emergencies was 2.4 ± 1.2 out of a maximum of 5 (n = 29). After training with simulation, mean confidence score increased to 3.5 ± 0.8 (n = 13).Clinical personnel who were provided with the novel resuscitation algorithm were able to reduce time taken to restart LVAD function from a mean value of 49 ± 8.2 seconds (pre-training) to 20.4 ± 5 seconds (post-training) (n = 42, p < 0.0001).The Mechanical Life Support course increased mean confidence from 2.5 ± 1.2 to 4 ± 0.6 (n = 44, p < 0.0001) and mean MCQ score from 18.7 ± 3.4 to 22.8 ± 2.6, out of a maximum of 28 (n = 44, p < 0.0001). Conclusion: We present a simplified LVAD Advanced Life Support algorithm to aid the crucial first minutes of resuscitation where basic interventions are likely to be critical in assuring good patient outcomes.

A European-wide dataset to uncover adaptive traits of Listeria monocytogenes to diverse ecological niches.

Listeria monocytogenes (Lm) is a ubiquitous bacterium that causes listeriosis, a serious foodborne illness. In the nature-to-human transmission route, Lm can prosper in various ecological niches. Soil and decaying organic matter are its primary reservoirs. Certain clonal complexes (CCs) are over-represented in food production and represent a challenge to food safety. To gain new understanding of Lm adaptation mechanisms in food, the genetic background of strains found in animals and environment should be investigated in comparison to that of food strains. Twenty-one partners, including food, environment, veterinary and public health laboratories, constructed a dataset of 1484 genomes originating from Lm strains collected in 19 European countries. This dataset encompasses a large number of CCs occurring worldwide, covers many diverse habitats and is balanced between ecological compartments and geographic regions. The dataset presented here will contribute to improve our understanding of Lm ecology and should aid in the surveillance of Lm. This dataset provides a basis for the discovery of the genetic traits underlying Lm adaptation to different ecological niches.