A microbial supply chain for production of the anti-cancer drug vinblastine.

Monoterpene indole alkaloids (MIAs) are a diverse family of complex plant secondary metabolites with many medicinal properties, including the essential anti-cancer therapeutics vinblastine and vincristine1. As MIAs are difficult to chemically synthesize, the world's supply chain for vinblastine relies on low-yielding extraction and purification of the precursors vindoline and catharanthine from the plant Catharanthus roseus, which is then followed by simple in vitro chemical coupling and reduction to form vinblastine at an industrial scale2,3. Here, we demonstrate the de novo microbial biosynthesis of vindoline and catharanthine using a highly engineered yeast, and in vitro chemical coupling to vinblastine. The study showcases a very long biosynthetic pathway refactored into a microbial cell factory, including 30 enzymatic steps beyond the yeast native metabolites geranyl pyrophosphate and tryptophan to catharanthine and vindoline. In total, 56 genetic edits were performed, including expression of 34 heterologous genes from plants, as well as deletions, knock-downs and overexpression of ten yeast genes to improve precursor supplies towards de novo production of catharanthine and vindoline, from which semisynthesis to vinblastine occurs. As the vinblastine pathway is one of the longest MIA biosynthetic pathways, this study positions yeast as a scalable platform to produce more than 3,000 natural MIAs and a virtually infinite number of new-to-nature analogues.

Granulocytes and mast cells in AllergoOncology-Bridging allergy to cancer: An EAACI position paper.

Derived from the myeloid lineage, granulocytes, including basophils, eosinophils, and neutrophils, along with mast cells, play important, often disparate, roles across the allergic disease spectrum. While these cells and their mediators are commonly associated with allergic inflammation, they also exhibit several functions either promoting or restricting tumor growth. In this Position Paper we discuss common granulocyte and mast cell features relating to immunomodulatory functions in allergy and in cancer. We highlight key mechanisms which may inform cancer treatment and propose pertinent areas for future research. We suggest areas where understanding the communication between granulocytes, mast cells, and the tumor microenvironment, will be crucial for identifying immune mechanisms that may be harnessed to counteract tumor development. For example, a comprehensive understanding of allergic and immune factors driving distinct neutrophil states and those mechanisms that link mast cells with immunotherapy resistance, might enable targeted manipulation of specific subpopulations, leading to precision immunotherapy in cancer. We recommend specific areas of investigation in AllergoOncology and knowledge exchange across disease contexts to uncover pertinent reciprocal functions in allergy and cancer and allow therapeutic manipulation of these powerful cell populations. These will help address the unmet needs in stratifying and managing patients with allergic diseases and cancer.

Association of immigrant status with self-rated health in Spain: 2014-2020.

OBJECTIVE: To examine inequalities in self-rated health between immigrant and native populations in 2014 and 2020, and whether these inequalities vary by sex/gender and social support. METHODS: This cross-sectional study used information from adults aged ≥18 years who participated in the European Health Interview Survey in Spain in 2014 and 2020. Self-rated health was specified as good or bad/poor. Immigration status and length of stay were considered to specify the exposure. Poisson regression was used to estimate prevalence ratios (PR) and 95% confidence intervals (CI) in each survey. Interaction terms between immigration status and survey; and immigration status, survey, and sex/gender or social support were tested. RESULTS: The adjusted analyses showed that when compared with Spanish native adults, immigrants with 6-15 years residing in Spain had a 1.34 (95%CI:1.18, 1.53) greater probability of rating their health as bad/poor in 2014. This probability was 1.48 (95%CI:1.28, 1.75) in 2020. No heterogeneity was observed for the associations of immigrant status/length of stay with self-rated health for sex/gender or social support in either survey (p-interactions for sex/gender: 0.41 and social support: 0.71). CONCLUSION: Given the growth of the immigrant population in Spain and the importance of immigration as a social determinant of health, these findings call attention to a deeper examination of inequalities, with the aim of identifying potential factors leading to bad/poor rating of health over time.

Monocyte distribution width (MDW): study of reference values in blood donors.

OBJECTIVES: Monocyte distribution width (MDW) is a new biomarker used as an early indicator of sepsis (ESId). It is often aids in the identification of patients who may develop sepsis. This study aims to establish the MDW reference interval (RI) within the healthy population of blood donors using EDTA-K2 as anticoagulant. Many hospitals use this biomarker as a means of identifying patients who present to the hospital with sepsis. METHODS: A total of 274 samples obtained from healthy donors were analyzed. MDW measurements were taken within 2 h post-extraction. The RI was estimated using various statistical methodologies, including the recommended CLSI EP28-A3c guideline, non-parametric and robust methods, along with the Harrell-Davis bootstrap method applied to the entire sample. RESULTS: The RI estimated through non-parametric method was 14.77 CI90 % (14.36-14.97)-21.13 CI90 % (20.89-21.68); RI using the robust method was 15.64-19.05 and RI using the Harrell-Davis bootstrap method was 14.73 CI90 % (14.53-14.92)-21.14 CI90 % (20.88-21.40). CONCLUSIONS: Based on clinical applicability, we recommend utilizing the RI derived from the non-parametric method, aligning with the CLSI recommendations. Furthermore, we consider that our results can be taken as a reference in other laboratories that serve a population similar to our study cohort.

Radiological insights into rheumatoid meningitis - a rare central nervous system manifestation of rheumatoid arthritis: a retrospective review of six cases.

BACKGROUND: The objective is to analyze and review the clinical, laboratory, and neuroimaging characteristics of rheumatoid meningitis (RM) in six patients with known rheumatoid arthritis (RA). METHODS: We performed a retrospective review of patients diagnosed with RM from August 2012 to June 2023. To identify the cases, we used medical term search engines and the hospital´s radiology case database. Clinical information and laboratory findings were gathered from the medical records. A neuroradiologist with five years of experience reviewed and analyzed the RM to determine the characteristics findings of RM. RESULTS: Six patients with RM are included. Seizures along with headaches were among the clinical signs that were documented. All the patients had high levels of rheumatoid factor (RF) and anti-cyclic citrullinated peptides (ACPA) in the peripheral blood. Biopsy in two cases confirmed typical rheumatoid nodules. Leptomeningeal enhancement was found bilaterally in all cases and was predominantly found in the frontoparietal region. "Mismatch DWI/FLAIR" was found in five patients. Bilateral subdural collections could be found in two patients. Brain PET scan revealed increased metabolism in two cases. CONCLUSION: Rheumatoid meningitis is a rare complication of rheumatoid arthritis (RA) with challenging clinical diagnosis due to non-specific symptoms. This study highlights the importance of MR in detecting characteristic neuroimaging patterns, including "mismatch DWI/FLAIR", to aid in early diagnosis. Increased awareness of this condition may facilitate timely intervention and improve prognosis. These results still need to be verified by large studies.

Defining a competency framework for health and social professionals to promote healthy aging throughout the lifespan: an international Delphi study.

The promotion of healthy aging has become a priority in most parts of the world and should be promoted at all ages. However, the baseline training of health and social professionals is currently not adequately tailored to these challenges. This paper reports the results of a Delphi study conducted to reach expert agreement about health and social professionals' competencies to promote healthy aging throughout the lifespan within the SIENHA project. Materials and methods: This study was developed following the CREDES standards. The initial version of the competence framework was based on the results of a scoping review and following the CanMEDS model. The expert panel consisted of a purposive sample of twenty-two experts in healthy aging with diverse academic and clinical backgrounds, fields and years of expertise from seven European countries. Agreement was reached after three rounds. The final framework consisted of a set of 18 key competencies and 80 enabling competencies distributed across six domains. The SIENHA competence framework for healthy aging may help students and educators enrich their learning and the academic content of their subjects and/or programs and incentivize innovation.

The VR leadless pacemaker: Results of an expert panel using the RAND/UCLA method.

BACKGROUND: Leadless pacemakers were developed to reduce complications associated with transvenous pacemaker implantation and long-term follow-up. Existing international guidelines lack detailed instructions on patients suitable for leadless pacemaker implantation. Our aim was to develop a consensus document that provides medical guidance for all health professionals involved in the indication and implantation of Transcatheter Pacing System single-chamber device (VR leadless) pacemakers for patients with atrial fibrillation or in sinus rhythm. METHODS: A panel of experts, including interventional and non-interventional cardiologists, used the Research ANd Development/University of California at Los Angeles (RAND/UCLA) method to rate the appropriateness of leadless pacemaker implantation for 64 scenarios in patients with atrial fibrillation and 192 scenarios in sinus rhythm. The scenarios were rated individually and again during a moderated group session. Median ratings and level of agreement were calculated to classify each scenario as appropriate, inappropriate, or questionable. RESULTS: This consensus statement, based on available literature and the experts' opinions, summarizes recommendations for standardizing and optimizing leadless pacemaker implantation. The limitation for vascular access via the superior vena cava was the most influential variable when indicating leadless pacemaker implantation in both patients with atrial fibrillation and patients in sinus rhythm. CONCLUSIONS: Life expectancy, risk of infection, prosthetic valve, left ventricular ejection fraction (LVEF), limitation for vascular access via the superior vena cava, and mobility and exercise capacity determine who is advised to undergo VR leadless pacemaker implantation. More prospective studies are needed to optimize existing recommendations.

Global warming modifies the seasonal distribution of clutches on a Mediterranean great tit population.

Global warming has multiple effects on phenological events on a wide range of plants and animals. Specifically, many bird species have advanced the start of their breeding season, which could also imply an extension in its duration and also a change in the distribution of clutches throughout the breeding season. We have tested whether this occurred in a population of Great Tits (Parus major), in Sagunto (eastern Spain). The increase of March temperatures between 1986 and 2019 was related to an advancement of the breeding season. Although the breeding season was longer in years with higher June temperatures, the length did not show a temporal trend throughout the study period. The clutches were more concentrated at the beginning of the season (increase in the skewness), while the kurtosis ("tailedness" of the distribution) or the modality did not change significantly. Finally, the number of "equally good months" for breeding (a combined measure of length and distribution) has not changed throughout the years. Overall, all these phenological changes probably caused the observed increased proportion of pairs laying two clutches per year. It remains to be studied whether this increase in reproductive effort has positive or negative impact on fitness.

Aortoesophageal fistula as a fatal complication of esophageal perforation.

Aortoesophageal fistula is a very rare cause of upper gastrointestinal bleeding, however its interest lies in the high mortality rate associated with it. Due to this, early diagnosis and treatment of this entity is essential to increase survival. The typical symptoms known as the Chiari´s triad are only present in 45% of reported cases. We present the case of a patient with upper gastrointestinal bleeding due to an aortoesophageal fistula as well as the importance of endoscopic use for its differential diagnosis.

Prevalence of drug use before and during imprisonment in seven European countries (2014-2018).

Substance use is a global phenomenon that is particularly affecting the prison population. This study aimed to describe the prevalence of drug use among people in prison before and during incarceration in seven European countries and to compare it with the prevalence in the general population. Individual data collection was carried out between 2014 and 2018 with a model European Questionnaire on Drug Use among people in prison. A total of 12,918 people living in prison filled in the survey. People in prison report higher level of drug use when compared with the general population and the use of drug inside prison exist, although at lower levels when compared with predetention. Prisons can represent a point of access to engage individuals who use drugs in interventions that address drug use and risk factors related to both drug use and imprisonment.