Resistance to carbapenems in the urban soil isolate Cupriavidus taiwanensis S2-1-W is associated with OXA-1206, a newly discovered carbapenemase.

AIMS: Cupriavidus isolates are found in environmental and clinical samples and are often resistant to carbapenems, which are last-resort antibiotics. However, their carbapenem-resistance molecular mechanisms remain unknown. This study aimed to (i) characterize and sequence the carbapenem-resistant soil isolate Cupriavidus taiwanensis S2-1-W to uncover its antibiotic resistance determinants; and (ii) clone and characterize a putative novel carbapenemase gene identified in this isolate. METHODS AND RESULTS: Antibiotic susceptibility testing of C. taiwanensis S2-1-W revealed that it was resistant to most carbapenems, other ß-lactams, and aminoglycosides tested. Genome sequencing of this isolate revealed a complex chromosomal resistome that included multidrug efflux pump genes, one aminoglycoside transferase gene, and three ß-lactamase genes. Among them, we identified a novel putative class D ß-lactamase gene (blaOXA-1206) that is highly conserved among other sequenced C. taiwanensis isolates. Cloning and characterization of blaOXA-1206 confirmed that it encodes for a newly discovered carbapenemase (OXA-1206) that confers resistance to carbapenems and other ß-lactams. CONCLUSION: Carbapenem-resistance in C. taiwanensis S2-1-W is associated with a newly discovered carbapenemase, OXA-1206.

BST2 induces vascular smooth muscle cell plasticity and phenotype switching during cancer progression.

Background: Smooth muscle cell (SMC) plasticity and phenotypic switching play prominent roles in the pathogenesis of multiple diseases, but their role in tumorigenesis is unknown. We investigated whether and how SMC diversity and plasticity plays a role in tumor angiogenesis and the tumor microenvironment. Methods and Results: We use SMC-specific lineage-tracing mouse models and single cell RNA sequencing to observe the phenotypic diversity of SMCs participating in tumor vascularization. We find that a significant proportion of SMCs adopt a phenotype traditionally associated with macrophage-like cells. These cells are transcriptionally similar to 'resolution phase' M2b macrophages, which have been described to have a role in inflammation resolution. Computationally predicted by the ligand-receptor algorithm CellChat, signaling from BST2 on the surface of tumor cells to PIRA2 on SMCs promote this phenotypic transition; in vitro SMC assays demonstrate upregulation of macrophage transcriptional programs, and increased proliferation, migration, and phagocytic ability when exposed to BST2. Knockdown of BST2 in the tumor significantly decreases the transition towards a macrophage-like phenotype, and cells that do transition have a comparatively higher inflammatory signal typically associated with anti-tumor effect. Conclusion: As BST2 is known to be a poor prognostic marker in multiple cancers where it is associated with an M2 macrophage-skewed TME, these studies suggest that phenotypically switched SMCs may have a previously unidentified role in this immunosuppressive milieu. Further translational work is needed to understand how this phenotypic switch could influence the response to anti-cancer agents and if targeted inhibition of SMC plasticity would be therapeutically beneficial.

Pro-efferocytic nanotherapies reduce vascular inflammation without inducing anemia in a large animal model of atherosclerosis.

Atherosclerosis is an inflammatory disorder responsible for cardiovascular disease. Reactivation of efferocytosis, the phagocytic removal of cells by macrophages, has emerged as a translational target for atherosclerosis. Systemic blockade of the key 'don't-eat-me' molecule, CD47, triggers the engulfment of apoptotic vascular tissue and potently reduces plaque burden. However, it also induces red blood cell clearance, leading to anemia. To overcome this, we previously developed a macrophage-specific nanotherapy loaded with a chemical inhibitor that promotes efferocytosis. Because it was found to be safe and effective in murine studies, we aimed to advance our nanoparticle into a porcine model of atherosclerosis. Here, we demonstrate that production can be scaled without impairing nanoparticle function. At an early stage of disease, we find our nanotherapy reduces apoptotic cell accumulation and inflammation in the atherosclerotic lesion. Notably, this therapy does not induce anemia, highlighting the translational potential of targeted macrophage checkpoint inhibitors.

Tobacco Taxation in Spain: A tax laggard with a brighter possible future.

INTRODUCTION: In recent years tobacco taxation in Spain has regressed, with its Tobacconomics tax scorecard falling from 3.9 points (out of 5) in 2014, to only 2.625 in 2020. The objective of this research is to provide a detailed analysis of the causes behind this deterioration and identify possible ways forward for reversing this trend. METHODS: A retrospective 2014-2022 analysis of manufactured cigarettes (FM) and roll-your-own tobacco (RYO) markets including tax structure/rates, affordability, retail price gaps across products, and price differentials with bordering countries. A market level simulation model to 2028 studied the impact of various tax policy scenarios on smoking prevalence, premature deaths averted, smoking intensity, product substitution, government revenue, sales, and industry profit. RESULTS: A lack of tax increases in a context of inflation and income growth during the past 8 years means FM and RYO have become 13% more affordable, with a constant differential of €2 between 20 FM and RYO sticks, and the price gap between Spain and neighbouring France increased. Modelling of two realistic reform scenarios that reduce/eliminate the price gap between FM and RYO suggest substantial increases in government revenues and up to 700,000 fewer smokers and 210,000 fewer premature deaths. CONCLUSIONS: Current European Union legislation on tobacco taxes leaves ample room for much needed tobacco tax reform. For the sake of both public health and the economy, Spain should increase its Minimum Excise Tax. This would not only save lives, but also bring much needed revenue for the government. IMPLICATIONS: The stance of Spain on tobacco taxes has deteriorated recently. This study argues that the failure of successive governments to raise minimum taxes in an inflationary context has made tobacco products more affordable, and quantifies the improvements in smoking prevalence and excise revenue that would accrue if the authorities act urgently increasing rates within realistic limits.Spain is representative of European countries where government inaction has rendered minimum tobacco taxes obsolete. Given the postponement of the revision of the European Union Tobacco Tax Directive, this study highlights the need to act unilaterally within the existing legal framework.

Outcomes of Descemet Stripping Only Without Postoperative Use of Topical Rho-Associated Protein Kinase Inhibitors.

PURPOSE: Descemet stripping only (DSO) is a promising surgical option for select patients with Fuchs endothelial dystrophy (FED). There is growing support for the use of topical Rho-associated protein kinase inhibitors (ROCKi) to optimize DSO outcomes. However, in many settings, ROCKi are either unavailable or not approved to treat corneal diseases. This study sought to characterize patient outcomes after DSO in the absence of ROCKi and potentially broaden the settings where DSO can be offered to patients. METHODS: Single-center retrospective case series of 15 eyes/11 patients (66 years; 52-74) that underwent DSO, alone or combined with cataract surgery, by one surgeon between August 2020 and January 2023. Patients included in analyses had FED with central guttae, no clinical evidence of corneal edema, and a clinically healthy peripheral corneal endothelium. RESULTS: Mean follow-up time was 14 months (2-34). Fourteen of 15 eyes achieved corneal clearance (93.3%). Mean time to clearance was 8.5 weeks (3-23). Eleven eyes (73%) achieved corrected distance visual acuity of ≤0.2 with a significant postoperative improvement at 4 to 8 months ( P < 0.05) and sustained improvements at >12 months. No significant astigmatism was introduced by the procedure. Two eyes developed cystoid macular edema postoperatively. A trend toward earlier clearance was observed in the <65 years old group. CONCLUSIONS: Despite a longer time to corneal clearance in this cohort compared with the few studies using ROCKi, the overall success rate and visual outcomes for the patients in our cohort supports the use of DSO in settings where ROCKi are not readily available.

Exploring calcium-free alternatives in endochondral bone repair tested on In vivo trials - A review.

Bone repair via endochondral ossification is a complex process for the critical size reparation of bone defects. Tissue engineering strategies are being developed as alternative treatments to autografts or allografts. Most approaches to bone regeneration involve the use of calcium composites. However, exploring calcium-free alternatives in endochondral bone repair has emerged as a promising way to contribute to bone healing. By analyzing researches from the last ten years, this review identifies the potential benefits of such alternatives compared to traditional calcium-based approaches. Understanding the impact of calcium-free alternatives on endochondral bone repair can have profound implications for orthopedic and regenerative medicine. This review evaluates the efficacy of calcium-free alternatives in endochondral bone repair through in vivo trials. The findings may guide future research to develop innovative strategies to improve endochondral bone repair without relying on calcium. Exploring alternative approaches may lead to the discovery of novel therapies that improve bone healing outcomes.

Small intestinal bacterial overgrowth in obese patients with biopsy-confirmed metabolic dysfunction-associated steatotic liver disease: a cross-sectional study.

Background/aims: The metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity are frequent comorbidities with a high prevalence worldwide. Their pathogenesis are multifactorial, including intestinal dysbiosis. The role of small intestinal bacterial overgrowth (SIBO) in MASLD progression in obese patients remains unknown. We aimed to determine the association between SIBO and the severity of MASLD in obese patients. Methods: An observational and cross-sectional study was conducted in obese patients, diagnosed with or without MASLD by liver biopsy. Metabolic dysfunction-associated steatotic liver (MASL), metabolic dysfunction-associated steatohepatitis without fibrosis (MASH-NF), MASH with fibrosis (MASH-F), or without MASLD (control subjects, CS) were identified by presence of steatosis, portal and lobular inflammation, and fibrosis. SIBO was determined by standardized lactulose breath tests. Results: A total of 59 patients with MASLD, 16 with MASL, 20 with MASH-NF, 23 with MASH-F, and 14 CS were recruited. Higher percentages of SIBO were observed in MASLD patients (44.2%) compared to CS (14.2%; p = 0.0363). Interestingly, MASH-F showed higher percentages of SIBO (65.2%) in comparison to non-fibrotic MASLD (33.3%; p = 0.0165). The presence of SIBO was not correlated with the level of hepatic steatosis in MASLD patients. Conclusions: A positive correlation between MASLD and SIBO in obese patients was principally explained by the presence of liver fibrosis. Our findings suggest a pathogenic role of intestinal dysbiosis in the progression of MASLD. Future research will elucidate the underlying mechanisms of SIBO in MASLD advancement.

The Millennia-Long Development of Drugs Associated with the 80-Year-Old Artificial Intelligence Story: The Therapeutic Big Bang?

The journey of drug discovery (DD) has evolved from ancient practices to modern technology-driven approaches, with Artificial Intelligence (AI) emerging as a pivotal force in streamlining and accelerating the process. Despite the vital importance of DD, it faces challenges such as high costs and lengthy timelines. This review examines the historical progression and current market of DD alongside the development and integration of AI technologies. We analyse the challenges encountered in applying AI to DD, focusing on drug design and protein-protein interactions. The discussion is enriched by presenting models that put forward the application of AI in DD. Three case studies are highlighted to demonstrate the successful application of AI in DD, including the discovery of a novel class of antibiotics and a small-molecule inhibitor that has progressed to phase II clinical trials. These cases underscore the potential of AI to identify new drug candidates and optimise the development process. The convergence of DD and AI embodies a transformative shift in the field, offering a path to overcome traditional obstacles. By leveraging AI, the future of DD promises enhanced efficiency and novel breakthroughs, heralding a new era of medical innovation even though there is still a long way to go.

Drivers of business model innovation in family firms: A dataset analysis.

In recent years, both in the world of research and consulting, the concept of innovation in the business model has been gaining a lot of interest. As a result, an incipient number of scientific and popular publications are being generated, which try to delimit and explain this term, as well as work methodologies for its application in the business world. The family business field can benefit from the application of this approach. But, at the same time, it can also serve as an object of study since its special idiosyncrasy will allow to deepen the analysis of successful business models. To illustrate innovation in business models, data from 112 family firms representative of the regional economy are presented. The companies are also associated with the Murcian Association of Family Businesses (Amefmur). The collaboration with this organization has made it possible to obtain very valuable and representative information thanks to the support provided. The collection of information was carried out through an electronic survey. These data could be especially useful for establishing business recommendations for this type of companies and for analyzing other possible interrelationships of the variables available in the database.

Clinical use of polygenic risk scores for detection of peripheral artery disease and cardiovascular events.

We have previously shown that polygenic risk scores (PRS) can improve risk stratification of peripheral artery disease (PAD) in a large, retrospective cohort. Here, we evaluate the potential of PRS in improving the detection of PAD and prediction of major adverse cardiovascular and cerebrovascular events (MACCE) and adverse events (AE) in an institutional patient cohort. We created a cohort of 278 patients (52 cases and 226 controls) and fit a PAD-specific PRS based on the weighted sum of risk alleles. We built traditional clinical risk models and machine learning (ML) models using clinical and genetic variables to detect PAD, MACCE, and AE. The models' performances were measured using the area under the curve (AUC), net reclassification index (NRI), integrated discrimination improvement (IDI), and Brier score. We also evaluated the clinical utility of our PAD model using decision curve analysis (DCA). We found a modest, but not statistically significant improvement in the PAD detection model's performance with the inclusion of PRS from 0.902 (95% CI: 0.846-0.957) (clinical variables only) to 0.909 (95% CI: 0.856-0.961) (clinical variables with PRS). The PRS inclusion significantly improved risk re-classification of PAD with an NRI of 0.07 (95% CI: 0.002-0.137), p = 0.04. For our ML model predicting MACCE, the addition of PRS did not significantly improve the AUC, however, NRI analysis demonstrated significant improvement in risk re-classification (p = 2e-05). Decision curve analysis showed higher net benefit of our combined PRS-clinical model across all thresholds of PAD detection. Including PRS to a clinical PAD-risk model was associated with improvement in risk stratification and clinical utility, although we did not see a significant change in AUC. This result underscores the potential clinical utility of incorporating PRS data into clinical risk models for prevalent PAD and the need for use of evaluation metrics that can discern the clinical impact of using new biomarkers in smaller populations.

Digitalisation of information and management optimisation in Multiple Victim Incidents. Analytical study.

INTRODUCTION: Triage is a crucial tool for managing a Multiple Victim Incident (MVI). One particularly problematic issue is the communication of results to the chain of command and control. Favourable data exists to suggest that digital triage can improve some features of analogue triage. Within this context we have witnessed the emergence of the Valkyries Project, which is working to develop strategies to respond to MVIs, and especially cross-border incidents. To that end, an IT platform called "SIGRUN" has been created which distributes, in real time, all the information to optimise MVI management. A full-scale simulation, held on the Spain-Portugal border and featuring contributions from different institutions on both sides of the border, put to the test the role of information digitalisation in this type of incidents. OBJECTIVE: To evaluate the impact of the synchronous digitalisation of information on the optimal management of Multiple Victim Incidents. METHOD: Clinical evaluation study carried out on a cross-border simulation between Spain and Portugal. A Minimum Data Set (MDS) was established by means of a modified Delphi by a group of experts. The digital platform "SIGRUN" integrated all the information, relaying it in real time to the chain of command and control. Each country assigned two teams that would carry out digital and analogue triage synchronously. Analogue triage variables were gathered by observers accompanying the first responders. Digital triage times were recorded automatically. Each case was evaluated and classified simultaneously by the two participating teams, to carry out a reliability study in a real time scenario. RESULTS: The total duration of the managing of the incident in the A group of countries involved compared to the B group was 72.5 minutes as opposed to 73 minutes. The total digital assistance triage (AT) time was 37.5 seconds in the digital group, as opposed to 32 minutes in the analogue group. Total evacuation (ET) time was 28 minutes in the digital group compared with 65 minutes in the analogue group. The average differences in total times between the analogue and the digital system, both for primary and secondary evaluation, were statistically significant: p = 0.048 and p = 0.000 respectively. For the "red" category, AT obtained a sensitivity of 100%, also for ET, while with regard to AT safety it obtained a PPV of 61.54% and an NPV of 100%, and for ET it obtained a PPV of 83.33% and an NPV of 100%. For the analogue group, for AT it obtained a sensitivity of 62.50%, for ET, 70%, for AT safety it obtained a PPV of 45.45% and an NPV of 92.31%, while for ET it obtained a PPV of 70% and an NPV of 92.50%. The gap analysis obtained a Kappa index of 0.7674. CONCLUSION: The triage system using the developed digital tool demonstrated its validity compared to the analogue tool, as a result of which its use is recommended.

Motor competence and compliance with physical activity recommendations in Chilean schoolchildren.

The development of motor competence is thought to be a crucial precursor to raising the trajectory of PA throughout a person's life. The objectives of this study are to determine motor competence and the daily time of moderate and vigorous physical activity of students in 5th and 6th grade elementary in Chile, and to establish whether there are differences in motor competence according to sex and compliance with physical activity recommendations. 368 schoolchildren (M = 11.10 years; 54.3% girls) participated. To assess motor competence, the MOBAK 5-6 test was used. Physical activity was measured using ActiGraph wGT3X-BT® accelerometers. Boys (M = 3.65, SD = 2.14) showed better performance than girls (M = 2.39, SD = 1.80) in Object Control (p ≤ 0.001, PS = 0.67). For Self-Movement, the girls (M = 2.72, SD = 2.14) performed better than the boys (M = 2.40, SD = 1.86); however, there were no significant differences between the two sexes (p = 0.257). Boys (M = 48.4, SD = 22.8) presented more daily minutes of moderate and vigorous physical activity than girls (M = 35.9, SD = 16.9), with statistically significant differences (p ≤ 0.001, PS = 0.67). About MC according to compliance with the physical activity recommendations, only in Object Control there is a statistically significant difference (p ≤ 0.001; PS = 0.29) between the students who comply with the recommendations (M = 4.28, SD = 2.12) and those who do not achieve the recommended minutes (M = 2.67, SD = 1.29). By contrast, an analysis of Self-Movement found no significant difference (complies: M = 2.73, SD = 1.97; does not comply: M = 2.54, SD = 2.04; p = 0.408) between the two groups. It is necessary to generate instances that develop motor competence in all its dimensions to promote higher levels of moderate to vigorous physical activity.

Transparency in Cognitive Training Meta-analyses: A Meta-review.

Meta-analyses often present flexibility regarding their inclusion criteria, outcomes of interest, statistical analyses, and assessments of the primary studies. For this reason, it is necessary to transparently report all the information that could impact the results. In this meta-review, we aimed to assess the transparency of meta-analyses that examined the benefits of cognitive training, given the ongoing controversy that exists in this field. Ninety-seven meta-analytic reviews were included, which examined a wide range of populations with different clinical conditions and ages. Regarding the reporting, information about the search of the studies, screening procedure, or data collection was detailed by most reviews. However, authors usually failed to report other aspects such as the specific meta-analytic parameters, the formula used to compute the effect sizes, or the data from primary studies that were used to compute the effect sizes. Although some of these practices have improved over the years, others remained the same. Moreover, examining the eligibility criteria of the reviews revealed a great heterogeneity in aspects such as the training duration, age cut-offs, or study designs that were considered. Preregistered meta-analyses often specified poorly how they would deal with the multiplicity of data or assess publication bias in their protocols, and some contained non-disclosed deviations in their eligibility criteria or outcomes of interests. The findings shown here, although they do not question the benefits of cognitive training, illustrate important aspects that future reviews must consider.

Alteration of Gut Microbiota Composition in the Progression of Liver Damage in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex disorder whose prevalence is rapidly growing in South America. The disturbances in the microbiota-gut-liver axis impact the liver damaging processes toward fibrosis. Gut microbiota status is shaped by dietary and lifestyle factors, depending on geographic location. We aimed to identify microbial signatures in a group of Chilean MASLD patients. Forty subjects were recruited, including healthy controls (HCs), overweight/obese subjects (Ow/Ob), patients with MASLD without fibrosis (MASLD/F-), and MASLD with fibrosis (MASLD/F+). Both MASLD and fibrosis were detected through elastography and/or biopsy, and fecal microbiota were analyzed through deep sequencing. Despite no differences in α- and ß-diversity among all groups, a higher abundance of Bilophila and a lower presence of Defluviitaleaceae, Lachnospiraceae ND3007, and Coprobacter was found in MASLD/F- and MASLD/F+, compared to HC. Ruminococcaceae UCG-013 and Sellimonas were more abundant in MASLD/F+ than in Ow/Ob; both significantly differed between MASLD/F- and MASLD/F+, compared to HC. Significant positive correlations were observed between liver stiffness and Bifidobacterium, Prevotella, Sarcina, and Acidaminococcus abundance. Our results show that MASLD is associated with changes in bacterial taxa that are known to be involved in bile acid metabolism and SCFA production, with some of them being more specifically linked to fibrosis.

Neurotrophic keratopathy: General features and new therapies.

Neurotrophic keratopathy is an uncommon degenerative corneal disorder characterized by compromised corneal sensory innervation resulting in the formation of epithelial defects and nonhealing corneal ulcers. Various treatment modalities are available to stabilize disease progression, improve patient well-being, and prevent vision loss. For eligible patients, medical and surgical reinnervation have emerged as pioneering therapies, holding promise for better management. We present a comprehensive review of the disorder, providing an update relevant to ophthalmologists on pathogenesis, diagnosis, treatment options, and novel therapies targeting pathophysiological pathways.

Effect of pine bark extract and its phenolic compounds on selected pathogenic and probiotic bacterial strains.

Introduction: Inflammatory bowel disease (IBD) comprises a heterogeneous group of chronic diseases as ulcerative colitis (UC) and Crohn's disease (CD). IBD is the result of a dysregulation of intestinal homeostasis with a host's loss of tolerance toward normal enteric microflora. Plant-based extracts as phenolic compounds can play a role by modulating the intestinal inflammation response. Methods: The in vitro antimicrobial activity of French maritime pine bark extract (PBE) and its phenolic constituents has been investigated in this study. Furthermore, the ability of PBE and phenolic compounds (caffeic acid, chlorogenic acid, ferulic acid, gallic acid and taxifolin) to modulate the microbiota has been assessed. Results: Phenolic compounds and PBE showed a great inhibitory effect on the pathogens growth at the highest concentration assessed (1.25 mg/mL). The growth of E. sakazakii and E. faecalis were affected by the effect of caffeic acid and ferulic acid. Taxifolin showed a very strong activity against Listeria sp. (with a reduction ~98%). Gallic acid revealed antibacterial effect on S. aureus at different concentrations. The inhibitory effect of PBE was highly significant on the growth of E. coli O157:H7. PBE, caffeic acid and chlorogenic acid seem to provide the greatest beneficial effect on the probiotic bacteria. However, the highest concentrations of taxifolin may have impaired the growth of beneficial microbiota. Conclusion: Present findings could be of interest for considering PBE and/or its phenolic constituents as protectors against gastrointestinal disturbances which lead to ulcerative colitis and Crohn's disease.

Characterization of content associated with lesbian, gay, bisexual, transgender, intersex, and queer individuals in Chilean medical schools: a cross-sectional survey.

BACKGROUND: Lesbian, gay, bisexual, transgender, intersex, queer, and other sexual and gender identities (LGBTIQ+) individuals face health inequities. Additionally, medical students report a lack of confidence in providing specific health care to LGBTIQ + individuals, and medical schools do not offer the breadth and depth of coverage needed to fully prepare and make them comfortable in caring for these individuals. This study aims to characterize the teaching of curricular content related to LGBTIQ + health issues in medical schools in Chile. METHODS: This was a cross-sectional descriptive mixed-methods study based on a 15-question survey sent to school directors of the 24 medical schools in Chile, conducted between October 2020 and July 2021. The questions included in the study were mostly based on two pre-existing questionnaires covering content, assessment methods, and identification of barriers to teaching this content. RESULTS: The validated questionnaire was answered by 14 of 24 Chilean medical schools, with 11 schools (78.9%) declaring that they included some training in their curriculum. The predominant range of time allocated to LGBTIQ + training in medical programs was between 1 and 5 h. The most addressed topics were HIV (92.85%), sexual orientation (78.57%), and chronic disease risk in LGBTIQ + populations (78.57%). Most schools, accounting for 71.5%, considered the content they delivered to be "moderately insufficient" or "insufficient". Regarding the teaching methodologies, the most used were lectures (92.8%), clinical cases (42.9%), and clinical simulation (28.6%). CONCLUSION: Most surveyed medical schools reported curricular spaces dedicated to teaching health issues of LGBTIQ + individuals, primarily during the pre-internship training period. However, the time allocated is insufficient, and there is little approach to topics beyond the patient's sexual history or sexual orientation. Given the crucial role of medical schools, they must adopt both local and national strategies to enrich training focused on the care of LGBTIQ + patients.