Short-Chain Fatty Acid Production by Gut Microbiota Predicts Treatment Response in Multiple Myeloma.

PURPOSE: The gut microbiota plays important roles in health and disease. We questioned whether the gut microbiota and related metabolites are altered in monoclonal gammopathies and evaluated their potential role in multiple myeloma and its response to treatment. EXPERIMENTAL DESIGN: We used 16S rRNA sequencing to characterize and compare the gut microbiota of patients with monoclonal gammopathy of undetermined significance (n = 11), smoldering multiple myeloma (n = 9), newly diagnosed multiple myeloma (n = 11), relapsed/refractory multiple myeloma (n = 6), or with complete remission (n = 9). Short-chain fatty acids (SCFA) were quantified in serum and tested in cell lines. Relevant metabolites were validated in a second cohort of 62 patients. RESULTS: Significant differences in alpha- and beta diversity were present across the groups and both were lower in patients with relapse/refractory disease and higher in patients with complete remission after treatment. Differences were found in the abundance of several microbiota taxa across disease progression and in response to treatment. Bacteria involved in SCFA production, including Prevotella, Blautia, Weissella, and Agathobacter, were more represented in the premalignant or complete remission samples, and patients with higher levels of Agathobacter showed better overall survival. Serum levels of butyrate and propionate decreased across disease progression and butyrate was positively associated with a better response. Both metabolites had antiproliferative effects in multiple myeloma cell lines. CONCLUSIONS: We demonstrate that SCFAs metabolites and the gut microbiota associated with their production might have beneficial effects in disease evolution and response to treatment, underscoring its therapeutic potential and value as a predictor.

Test Strip Platform Spin-Off for Telomerase Activity Detection: Development of an Electrochemical Biosensor.

Telomerase overexpression has been associated directly with cancer, and the enzyme itself is recognized within the scientific community as a cancer biomarker. BIDEA's biosensing strip (BBS) is an innovative technology capable of detecting the presence of telomerase activity (TA) using electrochemical impedance spectroscopy (EIS). This BBS is an interdigital gold (GID) electrode array similar in size and handling to a portable glucose sensor. For the detection of the biomarker, BBS was modified by the immobilization of a telomere-like single strand DNA (ssDNA) on its surface. The sensor was exposed to telomerase-positive extract from commercially available cancer cells, and the EIS spectra were measured. Telomerase recognizes the sequence of this immobilized ssDNA probe on the BBS, and the reverse transcription process that occurs in cancer cells is replicated, resulting in the ssDNA probe elongation. This surface process caused by the presence of TA generates changes in the capacitive process on the electrode array microchip surface, which is followed by EIS as the sensing tool and correlated with the presence of cancer cells. The telomerases' total cell extraction protocol results demonstrate significant changes in the charge-transfer resistance (R ct) change rate after exposure to telomerase-positive extract with a detection limit of 2.94 × 104 cells/mL. Finally, a preliminary study with a small set of "blind" uterine biopsy samples suggests the feasibility of using the changes in the R ct magnitude change rate (Δ(ΔR ct/R cti)/Δt) to distinguish positive from negative endometrial adenocarcinoma samples by the presence or absence of TA.

Two independently evolved natural mutations additively deregulate TyrA enzymes and boost tyrosine production in planta.

l-Tyrosine is an essential amino acid for protein synthesis and is also used in plants to synthesize diverse natural products. Plants primarily synthesize tyrosine via TyrA arogenate dehydrogenase (TyrAa or ADH), which are typically strongly feedback inhibited by tyrosine. However, two plant lineages, Fabaceae (legumes) and Caryophyllales, have TyrA enzymes that exhibit relaxed sensitivity to tyrosine inhibition and are associated with elevated production of tyrosine-derived compounds, such as betalain pigments uniquely produced in core Caryophyllales. Although we previously showed that a single D222N substitution is primarily responsible for the deregulation of legume TyrAs, it is unknown when and how the deregulated Caryophyllales TyrA emerged. Here, through phylogeny-guided TyrA structure-function analysis, we found that functionally deregulated TyrAs evolved early in the core Caryophyllales before the origin of betalains, where the E208D amino acid substitution in the active site, which is at a different and opposite location from D222N found in legume TyrAs, played a key role in the TyrA functionalization. Unlike legumes, however, additional substitutions on non-active site residues further contributed to the deregulation of TyrAs in Caryophyllales. The introduction of a mutation analogous to E208D partially deregulated tyrosine-sensitive TyrAs, such as Arabidopsis TyrA2 (AtTyrA2). Moreover, the combined introduction of D222N and E208D additively deregulated AtTyrA2, for which the expression in Nicotiana benthamiana led to highly elevated accumulation of tyrosine in planta. The present study demonstrates that phylogeny-guided characterization of key residues underlying primary metabolic innovations can provide powerful tools to boost the production of essential plant natural products.

Estudio transversal sobre factores relacionados con el dolor crónico y su atención, según sexo / Cross-sectional study on factors related to chronic pain and its care, according to sex

Objetivo: Describir las características sociodemográficas, clínicas y terapéuticas de las personas con dolor crónico no oncológico, según sexo.Pacientes y método: Estudio transversal en la Unidad del Dolor del Complejo Asistencial Universitario de Salamanca entre marzo y septiembre de 2020. Se realizó un muestreo consecutivo, obteniendo 105 pacientes. Los datos se extrajeron de las historias clínicas (HHCC) para las variables clínicas y un cuestionario realizado ad hoc para las variables demográficas y socioeconómicas. Se realizó un análisis descriptivo de las variables, según sexo.Resultados: La mayoría de los pacientes con dolor crónico son mujeres (61,9 %) de 56 años, españolas, con residencia en Salamanca y con pareja. Su nivel de estudios es medio/bajo y están en situación de desempleo (p = 0,007). No son las principales proveedoras económicas del núcleo familiar (p < 0,00) y sus ingresos son inferiores a 950 euros al mes (p = 0,001). Poseen vivienda y conviven con otras personas. Su principal actividad son labores domésticas o de cuidados (p = 0,008). Padecen dolor musculoesquelético secundario crónico asociado a alteraciones estructurales, con lumbalgia crónica inespecífica como el diagnóstico más frecuente. Tienen más patologías concomitantes que los hombres, siendo la HTA la más frecuente, y los trastornos psiquiátricos más prevalentes en ellas. Están tratadas con analgésicos y bloqueos de nervios periféricos, respondiendo favorablemente.Conclusión: Identificar la mayor frecuencia de mujeres, con su contexto sociodemográfico y clínico específico, refleja la necesidad de abordar el sexo y los roles de género, y así tenerlos en cuenta a la hora de evaluar cómo influyen ambos en la vivencia del dolor crónico y de cómo llevar a cabo la asistencia y el manejo de nuestros pacientes.(AU)

Objective: To describe the sociodemographic, clinical and therapeutic characteristics of people with chronic non-oncologic pain, according to sex.Patients and method: Cross-sectional study in the Pain Unit of the Complejo Asistencial Universitario de Salamanca between March and September 2020. Consecutive sampling was performed, obtaining 105 patients. Data were extracted from the medical records (HHCC) for clinical variables and an ad hoc questionnaire for demographic and socioeconomic variables. A descriptive analysis of the variables was performed according to sex.Results: Most of the patients with chronic pain were women (61.9 %) aged 56 years, Spanish, living in Salamanca and with a partner. Their level of education is medium/low and they are unemployed (p = 0.007). They are not the main economic providers of the family nucleus (p < 0.00) and their income is less than 950 euros per month (p = 0.001). They own a house and live with other people. Their main activity is domestic or care work (p = 0.008). They suffer from chronic secondary musculoskeletal pain associated with structural alterations, with non-specific chronic low back pain as the most frequent diagnosis. They have more concomitant pathologies than men, with HT being the most frequent, and psychiatric disorders more prevalent in them. They are treated with analgesics and peripheral nerve blocks, responding favorably.Conclusion: Identifying the higher frequency of women, with their specific sociodemographic and clinical context, reflects the need to address sex and gender roles and thus take them into account when assessing how both influence the experience of chronic pain and how to carry out the care and management of our patients.(AU)

Sustainable Food Support during an Ultra-Endurance and Mindfulness Event: A Case Study in Spain.

The present industrial food-production system is not suitably ecological for the environment. Mindful nutrition in sport is a relevant emergent sub-discipline that could help reduce environmental degradation. This case study describes a sustainable support diet during an ultra-endurance running (UR) event called the "Indoor Everest Challenge". This UR challenge involved attaining the altitude of Mount Everest (8849 m) in a simulated way, in less than 24 h, without using ultra-processed food and without wasting plastics. During this challenge, a male athlete (34 years, weight: 78 kg, and height: 173 cm) wore a SenseWear Armband® (BodyMedia Inc., Pittsburg, PA, USA) accelerometer on his right arm to estimate energy expenditure. To supply his nutritional requirements, the athlete consumed only specially prepared homemade and organic food. All consumption was weighed and recorded in real-time; we determined nutrients using two databases: a food composition software, Dial Alce Ingenieria® (Madrid, Spain), to measure energy and macro- and micro-nutrients, and Phenol Explorer Database® (INRA Institut National de Recherche pour l'Alimentation, Paris, France) precisely to determine polyphenolic content. Most energy intake (up to 96%) came from plant foods. We found that subject consumed 15.8 g/kg-1/d-1 or 1242 g of carbohydrates (CHO), (2.4 g/kg-1/d-1) or 190 g of proteins (P), and 10,692 mL of fluid. The total energy intake (7580 kcal) showed a distribution of 65% CHO, 10% P, and 25% lipids (L). Furthermore, this sustainable diet lead to a high antioxidant intake, specifically vitamin C (1079 mg), vitamin E (57 mg), and total polyphenols (1910 mg). This sustainable approach was suitable for meeting energy, CHO, and P recommendations for UR. Physical and mental training (mindfulness) were integrated from the specific preliminary phase to the day of the challenge. The athlete completed this challenge in 18 h with a low environmental impact. This sports event had an educational component, as it awakened curiosity towards food sustainability.

Cadaverine regulates biotin synthesis to modulate primary root growth in Arabidopsis.

Cadaverine, a polyamine, has been linked to modification of root growth architecture and response to environmental stresses in plants. However, the molecular mechanisms that govern the regulation of root growth by cadaverine are largely unexplored. Here we conducted a forward genetic screen and isolated a mutation, cadaverine hypersensitive 3 (cdh3), which resulted in increased root-growth sensitivity to cadaverine, but not other polyamines. This mutation affects the BIO3-BIO1 biotin biosynthesis gene. Exogenous supply of biotin and a pathway intermediate downstream of BIO1, 7,8-diaminopelargonic acid, suppressed this cadaverine sensitivity phenotype. An in vitro enzyme assay showed cadaverine inhibits the BIO3-BIO1 activity. Furthermore, cadaverine-treated seedlings displayed reduced biotinylation of Biotin Carboxyl Carrier Protein 1 of the acetyl-coenzyme A carboxylase complex involved in de novo fatty acid biosynthesis, resulting in decreased accumulation of triacylglycerides. Taken together, these results revealed an unexpected role of cadaverine in the regulation of biotin biosynthesis, which leads to modulation of primary root growth of plants.

Surveillance for Enteroviruses Associated with Hand, Foot, and Mouth Disease, and Other Mucocutaneous Symptoms in Spain, 2006-2020.

Hand, foot, and mouth disease (HFMD) is a mild illness caused by enteroviruses (EV), although in some Asian countries, large outbreaks have been reported in the last 25 years, with a considerable incidence of neurological complications. This study describes epidemiological and clinical characteristics of EV infections involved in HFMD and other mucocutaneous symptoms from 2006 to 2020 in Spain. EV-positive samples from 368 patients were included. EV species A were identified in 85.1% of those typed EV. Coxsackievirus (CV) A6 was the prevalent serotype (60.9%), followed by EV-A71 (9.9%) and CVA16 (7.7%). Infections affected children (1-6 years old) mainly, and show seasonality with peaks in spring-summer and autumn. Clinical data indicated few cases of atypical HFMD as well as those with neurological complications (associated with the 2016 EV-A71 outbreak). Phylogenetic analysis of CVA6 VP1 sequences showed different sub-clusters circulating from 2010 to present. In conclusion, HFMD or exanthemas case reporting has increased in Spain in recent years, probably associated with an increase in circulation of CVA6, although they did not seem to show greater severity. However, EV surveillance in mucocutaneous manifestations should be improved to identify the emergence of new types or variants causing outbreaks and more severe pathologies.

Cocamidopropyl Betaine Surfactant 0.075% Solution in Physiological Serum for Hygiene Process of COVID-19 Intubated Patients.

When using ventilators in the management of the coronavirus disease 2019 patient, dense and abundant mucous secretions are formed, obstructing the endotracheal tube and making its aspiration difficult. This situation is worsened if in order to minimize the risk of infection of the medical personnel, the humidifier is disconnected. This circumstance forces the tube to be removed, cleaned, or changed, increasing the workload of the intensive care unit staff. Other therapies tested until now, like mesna, acetylcysteine, or hypertonic saline solution, are valid alternatives, although they have not shown great efficacy for this specific procedure in the past. The sanitary emergency forced the collaboration between a pharmacist and an otorhinolaryngologist to develop the cocamidopropyl betaine surfactant formula, after several tests with different concentrations of the surfactant. The objective of this compounding formula was to resolve a mechanical problem and avoid reintubation due to obstruction of the ventilator tube. The cocamidopropyl betaine surfactant solution 0.075% in saline 0.9% (physiological serum) solution demonstrated to be a well-tolerated formula, using inexpensive materials, was simple to prepare, and was easy to use in clinical practice.

Does the right ventricle experiment morphologic and functional changes similarly to the left ventricle during pregnancy?

OBJECTIVE: Morphological and functional right ventricular (RV) changes during normal pregnancy remain poorly characterized. Similar to left ventricle, RV load and function are expected to change, and establishing reference values for RV during a healthy pregnancy is critical for the evaluation of pregnancy-related heart disease. The aim of the study was to describe RV adaptation in a prospective cohort. METHODS: Serial echocardiographic examinations were performed in second trimester (24 ± 2 weeks), third (32 ± 2 week) trimester, and postpartum (>3 months after delivery). Nulliparous women were evaluated as control group. RV linear dimensions, areas, and function were assessed and compared. RESULTS: Forty-three pregnant women were evaluated and compared with nineteen nulliparous women as control. Function parameters decreased along gestation. RV fractional area fell from second to third trimester (52.01 ± 0.92 vs 48.73 ± 0.97, P < .05), as well as tricuspid annular plane systolic excursion (2.62 ± 0.05 vs 2.41 ± 0.05, P < .05); however, RV longitudinal strain (L) decreased earlier, showing main changes from second trimester (26.17 ± 0.86 vs 22.71 ± 0.57, P < .003, control vs second trimester). S'-wave velocity followed a different pattern without changes during pregnancy. RV diameters significantly increased during pregnancy: basal (3.65 ± 0.06 vs 3.90 ± 0.06, P < .05), mid- (2.70 ± 0.06 vs 3.00 ± 0.07, P < .05), longitudinal (6.90 ± 0.09 vs 7.32 ± 0.11, P < .05), and right ventricle outflow tract proximal diameter (3.20 ± 0.06 vs 3.44 ± 0.06, P < .05). RV areas also suffered early variation during pregnancy. In postpartum evaluation, all these changes were reversed. CONCLUSION: During pregnancy, RV experiments important variations. RV size increases, and its function decreases. Changes in LS were earlier compared with other function measures.

Novel Indices of Coronary Physiology: Do We Need Alternatives to Fractional Flow Reserve?

Fractional flow reserve is the current invasive gold standard for assessing the ischemic potential of an angiographically intermediate coronary stenosis. Procedural cost and time, the need for coronary vessel instrumentation, and the need to administer adenosine to achieve maximal hyperemia remain integral components of invasive fractional flow reserve. The number of new alternatives to fractional flow reserve has proliferated over the last ten years using techniques ranging from alternative pressure wire metrics to anatomic simulation via angiography or intravascular imaging. This review article provides a critical description of the currently available or under-development alternatives to fractional flow reserve with a special focus on the available evidence, pros, and cons for each with a view towards their clinical application in the near future for the functional assessment of coronary artery disease.

Contact isolation versus standard precautions to decrease acquisition of extended-spectrum ß-lactamase-producing Enterobacterales in non-critical care wards: a cluster-randomised crossover trial.

BACKGROUND: The effectiveness of contact isolation for decreasing the spread of extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-E) has been questioned. The aim of this study was to establish the benefits of contact isolation over standard precautions for reducing the incidence density of ESBL-E colonisation and infection in adult medical and surgical wards with an active surveillance culture programme. METHODS: We did a cluster-randomised crossover trial in adult wards in four European university hospitals. Medical, surgical, or combined medical-surgical wards without critical care were randomised to continue standard precautions alone or implement contact isolation alongside standard precautions for 12 months, followed by a 1 month washout period and 12 months of the alternate strategy. Randomisation was done via a computer-generated sequence, with a block size of two consecutive wards. Only laboratory technicians and data analysts were masked to allocation. Patients were screened for ESBL-E carriage within 3 days of admission, once a week thereafter, and on discharge. The primary outcome was the incidence density of ESBL-E, defined as the acquisition rate per 1000 patient-days at risk at the ward level and assessed in the per-protocol population, which included all patients screened at least twice with a length of stay of more than 1 week for each intervention period. No specific safety measures were assessed given the minimal risk of adverse events. The trial is registered, ISRCTN57648070. FINDINGS: We enrolled 20 wards from four hospitals in Germany (eight wards), the Netherlands (four wards), Spain (four wards), and Switzerland (four wards). Between Jan 6, 2014, and Aug 31, 2016, 38 357 patients were admitted to these wards. Among 15 184 patients with a length of stay of more than 1 week, 11 368 patients (75%) were screened at least twice. The incidence density of ward-acquired ESBL-E was 6·0 events per 1000 patient-days at risk (95% CI 5·4-6·7) during periods of contact isolation and 6·1 (5·5-6·7) during periods of standard precautions (p=0·9710). Multivariable analysis adjusted for length of stay, percentage of patients screened, and prevalence in first screening cultures yielded an incidence rate ratio of 0·99 (95% CI 0·80-1·22; p=0·9177) for care under contact isolation compared with standard precautions. INTERPRETATION: Contact isolation showed no benefit when added to standard precautions for controlling the spread of ESBL-E on non-critical care wards with extensive surveillance screening. FUNDING: European Commission.

Evolution of l-DOPA 4,5-dioxygenase activity allows for recurrent specialisation to betalain pigmentation in Caryophyllales.

The evolution of l-DOPA 4,5-dioxygenase activity, encoded by the gene DODA, was a key step in the origin of betalain biosynthesis in Caryophyllales. We previously proposed that l-DOPA 4,5-dioxygenase activity evolved via a single Caryophyllales-specific neofunctionalisation event within the DODA gene lineage. However, this neofunctionalisation event has not been confirmed and the DODA gene lineage exhibits numerous gene duplication events, whose evolutionary significance is unclear. To address this, we functionally characterised 23 distinct DODA proteins for l-DOPA 4,5-dioxygenase activity, from four betalain-pigmented and five anthocyanin-pigmented species, representing key evolutionary transitions across Caryophyllales. By mapping these functional data to an updated DODA phylogeny, we then explored the evolution of l-DOPA 4,5-dioxygenase activity. We find that low l-DOPA 4,5-dioxygenase activity is distributed across the DODA gene lineage. In this context, repeated gene duplication events within the DODA gene lineage give rise to polyphyletic occurrences of elevated l-DOPA 4,5-dioxygenase activity, accompanied by convergent shifts in key functional residues and distinct genomic patterns of micro-synteny. In the context of an updated organismal phylogeny and newly inferred pigment reconstructions, we argue that repeated convergent acquisition of elevated l-DOPA 4,5-dioxygenase activity is consistent with recurrent specialisation to betalain synthesis in Caryophyllales.

Hábitos, preferencias y habilidades culinarias de estudiantes de primer curso de la universidad de Huelva / Habits, preferences and culinary skills of first-year students at the university of Huelva

Introducción: los estudiantes universitarios se encuentran en un periodo crítico para el desarrollo y consolidación de estilos de vida futuros. El objetivo fue conocer los hábitos alimentarios, preferencias alimentarias y habilidades culinarias del alumnado de primer curso de las distintas titulaciones de la Universidad de Huelva. Material y Método: estudio descriptivo transversal durante el año académico 2015-2016 de una muestra final de 756 alumnos. La adherencia a la Dieta Mediterránea se ha medido a través del cuestionario KIDMED. El resto de variables se han recogido mediante un cuestionario ad hoc. El análisis de datos se realizó mediante el PSPP, calculándose medias, desviaciones típicas y porcentajes para el análisis descriptivo, prueba de Chi-cuadrado y ANOVA para el análisis relacional. Resultados: el 20,4% del alumnado tiene un nivel óptimo de adherencia a la Dieta Mediterránea, frente al 65,3% que posee un nivel medio y un 14,3% bajo. Los alimentos preferidos son pollo (62,2%), pasta (58,2%), cerdo (50,4%) y las patatas fritas (45,9%). Entre los alimentos que saben preparar están la pasta, (93,8%), patatas con huevo (90.2 %), pizza precocinada (88.7 %), zumo (86.1 %) y carne a la plancha (85.8 %). Conclusiones: la dieta de los estudiantes onubenses es muy similar a la de otras poblaciones universitarias estudiadas. Se encontró preferencia por las carnes y alimentos ricos en glúcidos, en detrimento de la fruta y la verdura. Se observó un déficit en las habilidades culinarias, lo cual podría explicar el deterioro del patrón alimentario de éstos y orientar futuras intervenciones

Introduction: students attending university are at a critical period for the development and consolidation of future lifestyles. The objective of this study was to know the eating habits, food preferences and culinary skills of first-year students on different degree courses at the University of Huelva. Material and Method: cross-sectional descriptive study in academic year 2015-2016 of a sample of 756 students. Adherence to the Mediterranean Diet was measured by the KIDMED questionnaire. The rest of the variables were measured by an ad hoc questionnaire. Data analysis was performed using the PSPP programme, calculating arithmetic means, standard deviations and percentages for the descriptive analysis, with Chi-square test and ANOVA for the relational analysis. Results: 20.4% of students have an optimal level of adherence to the Mediterranean Diet, compared to 65.3% % with an average level and 14.3% with low adherence. Favourite foods cited were chicken (62.2%), pasta (58.2%), pork (50.4%) and chips (45.9%). The types of food the students knew how to prepare included pasta (93.8%), egg and chips (90.2%), precooked pizza (88.7%), fruit juices (86.1%) and grilled meat (85.8%). Conclusions: Huelva university students diet is very similar to that of other university populations studied. We found a preference for meat and foods rich in carbohydrates, to the detriment of fruit and vegetables. A lack of culinary skills was observed, which could explain the deterioration in eating habits; this is a pointer to future interventions

The evolution of betalain biosynthesis in Caryophyllales.

Within the angiosperm order Caryophyllales, an unusual class of pigments known as betalains can replace the otherwise ubiquitous anthocyanins. In contrast to the phenylalanine-derived anthocyanins, betalains are tyrosine-derived pigments which contain the chromophore betalamic acid. The origin of betalain pigments within Caryophyllales and their mutual exclusion with anthocyanin pigments have been the subject of considerable research. In recent years, numerous discoveries, accelerated by -omic scale data, phylogenetics and synthetic biology, have shed light on the evolution of the betalain biosynthetic pathway in Caryophyllales. These advances include the elucidation of the biosynthetic steps in the betalain pathway, identification of transcriptional regulators of betalain synthesis, resolution of the phylogenetic history of key genes, and insight into a role for modulation of primary metabolism in betalain synthesis. Here we review how molecular genetics have advanced our understanding of the betalain biosynthetic pathway, and discuss the impact of phylogenetics in revealing its evolutionary history. In light of these insights, we explore our new understanding of the origin of betalains, the mutual exclusion of betalains and anthocyanins, and the homoplastic distribution of betalain pigmentation within Caryophyllales. We conclude with a speculative conceptual model for the stepwise emergence of betalain pigmentation.