Ligilactobacillus salivarius V4II-90 eradicates Group B Streptococcus colonisation during pregnancy: a randomised, double-blind, placebo-controlled trial.

Group B Streptococcus (GBS) is the leading cause of bacterial neonatal sepsis. This study aimed to confirm the effect of Ligilactobacillus salivarius V4II-90 on GBS colonisation during pregnancy. A randomised, multicentre, double-blind, placebo-controlled, parallel-group study was conducted in seven hospitals in Madrid, Spain. The sample was broken down into two groups with 20 participants each (n = 40) in order to show reduced GBS colonisation frequency in the probiotic versus the placebo group. Pregnant participants positive for vaginal-rectal colonisation before or during the 13th week of gestation were randomly assigned to either the placebo or the probiotic group. The probiotic, L. salivarius V4II-90 at 1 × 109 cfu/day was administered for 12 weeks, starting at week 21-23 of gestation. The primary outcome was the percentage of participants with vaginal and/or rectal GBS colonisation at the end of the intervention period (35 weeks of gestation). Secondary outcomes were changes in the microbial composition of vaginal and rectal exudates; premature delivery; premature rupture of membranes; intrapartum antibiotics; new-borns with early or late-onset GBS sepsis; adverse events (AEs); and GBS test results performed at the hospital at week 35 of gestation. Of the 481 participants included, 44 were vaginal-rectal colonised with GBS and randomised. 43 completed the study (20 in the probiotic group and 23 in the placebo group). After intervention, GBS was eradicated in six participants (27%) from the placebo group and in twelve participants (63%) from the probiotic group ( P = 0.030). None of the 185 AEs reported were identified as possibly, probably, or definitely related to the investigational product. In conclusion, oral administration of L. salivarius V4II-90 is a safe and successful strategy to significantly decrease the rates of GBS colonisation at the end of pregnancy and, therefore, to reduce the exposure of subjects and their infants to intrapartum antibiotic prophylaxis. Trial registered at ClinicalTrials.gov: number NCT03669094.

A shared neoantigen vaccine combined with immune checkpoint blockade for advanced metastatic solid tumors: phase 1 trial interim results.

Therapeutic vaccines that elicit cytotoxic T cell responses targeting tumor-specific neoantigens hold promise for providing long-term clinical benefit to patients with cancer. Here we evaluated safety and tolerability of a therapeutic vaccine encoding 20 shared neoantigens derived from selected common oncogenic driver mutations as primary endpoints in an ongoing phase 1/2 study in patients with advanced/metastatic solid tumors. Secondary endpoints included immunogenicity, overall response rate, progression-free survival and overall survival. Eligible patients were selected if their tumors expressed one of the human leukocyte antigen-matched tumor mutations included in the vaccine, with the majority of patients (18/19) harboring a mutation in KRAS. The vaccine regimen, consisting of a chimp adenovirus (ChAd68) and self-amplifying mRNA (samRNA) in combination with the immune checkpoint inhibitors ipilimumab and nivolumab, was shown to be well tolerated, with observed treatment-related adverse events consistent with acute inflammation expected with viral vector-based vaccines and immune checkpoint blockade, the majority grade 1/2. Two patients experienced grade 3/4 serious treatment-related adverse events that were also dose-limiting toxicities. The overall response rate was 0%, and median progression-free survival and overall survival were 1.9 months and 7.9 months, respectively. T cell responses were biased toward human leukocyte antigen-matched TP53 neoantigens encoded in the vaccine relative to KRAS neoantigens expressed by the patients' tumors, indicating a previously unknown hierarchy of neoantigen immunodominance that may impact the therapeutic efficacy of multiepitope shared neoantigen vaccines. These data led to the development of an optimized vaccine exclusively targeting KRAS-derived neoantigens that is being evaluated in a subset of patients in phase 2 of the clinical study. ClinicalTrials.gov registration: NCT03953235 .

[Preliminary results of hybrid fixation modular implant in revision knee arthroplasty]. / Resultados preliminares de la artroplastía de revisión de rodilla con implante modular de fijación híbrida.

INTRODUCTION: revision total knee arthroplasty (TKA) is a challenging procedure that requires proper alignment, restoration of bone loss, and prevention of instability. Modern revision systems offer progressive implant constriction with multiple options for offset, augmentation, and fixation stems. OBJECTIVE: to evaluate the clinical outcomes of a modular implant with hybrid fixation in revision TKA with a minimum follow-up of two years. MATERIAL AND METHODS: we retrospectively included all revision TKA surgeries performed between September 2018 and September 2019, using the same implant. Patient demographics, comorbidities, and data on bone defects were recorded. Clinical outcomes were assessed using subjective roles and Maudsley scores and the Knee Society Score (KSS). Complications during follow-up were also documented. RESULTS: a total of 23 patients were analyzed, comprising 65% females and 35% males, with a median age of 71.1 years. Bone defects following implant removal were classified as F2.T2 in 39.13% of cases, F1.T2 in 8.69%, and F1.T1 in the remaining 52.17%. There were significant improvements in the KSS score (preoperative: 53 points, postoperative: 79 points; p < 0.001). Three (13%) complications were reported, two of which were directly related to the surgery, and two patients required subsequent revision surgery. The 2-year survival rate was 91.3%. CONCLUSION: the use of a modular implant with hybrid fixation in revision TKA demonstrated a high 2-year survival rate, significant improvements in clinical scores, and a low incidence of short-term complications. These findings support the efficacy and safety of this approach, providing favorable clinical outcomes and high patient satisfaction.

INTRODUCCIÓN: la artroplastía total de rodilla (ATR) de revisión es un procedimiento desafiante que requiere alineación adecuada, restauración ósea y estabilidad. Los sistemas modernos de revisión ofrecen opciones de implantes modulares con fijación híbrida. OBJETIVO: evaluar los resultados clínicos de un implante modular de fijación híbrida con seguimiento mínimo de dos años. MATERIAL Y MÉTODOS: se incluyeron retrospectivamente cirugías de revisión de ATR realizadas entre Septiembre de 2018 y Septiembre de 2019 con el mismo implante. Se registraron datos demográficos, comorbilidades y se evaluaron los resultados clínicos utilizando puntuaciones subjetivas y la Knee Society Score (KSS). RESULTADOS: se analizaron 23 pacientes (65% mujeres, 35% hombres; edad mediana: 71.1 años). Los defectos óseos posteriores a la extracción del implante se clasificaron como F2.T2 en 39.13% de los casos, F1.T2 en 8.69%, y F1.T1 en 52.17%. Se observaron mejoras significativas en la puntuación de la KSS (preoperatoria: 53 puntos, postoperatoria: 79 puntos; p < 0.001). Se registraron tres (13%) complicaciones totales, dos relacionadas directamente con la cirugía, y dos casos requirieron una nueva cirugía de revisión. La tasa de supervivencia a los dos años fue de 91.3%. CONCLUSIÓN: el uso del implante modular con fijación híbrida en la revisión de ATR mostró una alta tasa de supervivencia a dos años, mejoras significativas en las puntuaciones clínicas y baja incidencia de complicaciones a corto plazo. Estos resultados respaldan la eficacia y seguridad de este enfoque, proporcionando resultados clínicos favorables y alta satisfacción del paciente.

Impacto clínico de no aplicar el protocolo ERAS en los pacientes sometidos a cistectomía durante la pandemia COVID-19 / Clinical impact of the suspension of the ERAS protocol on patients undergoing radical cystectomy during the COVID-19 pandemic

Introducción Al inicio de la pandemia por COVID-19 no se pudo implementar ni prehabilitación ni rehabilitación multimodal por sobrecarga del sistema sanitario. Nuestro objetivo fue analizar evolución, complicaciones y supervivencia hasta el año de pacientes sometidos a cistectomía radical en nuestro centro desde el 1 de marzo hasta el 31 de mayo de 2020 (primera ola). Comparamos resultados con pacientes también cistectomizados fuera de pandemia donde sí estaba instaurado el protocolo ERAS. Material y métodos Estudio de cohortes retrospectivo, unicéntrico, de pacientes programados para cistectomía radical desde el 1 de marzo de 2020 hasta el 31 de mayo de 2020; se emparejaron con pacientes intervenidos anteriormente a través de score de emparejamiento por propensión 1:2. Las variables de emparejamiento fueron datos demográficos, condiciones clínicas preoperatorias e intraoperatorias. Resultados Se realizaron 23 cistectomía en este periodo; en ningún caso se aplicó ni prehabilitación ni seguimiento del protocolo ERAS, y esta fue la única diferencia en el tratamiento entre grupos. Tres pacientes se diagnosticaron de COVID-19 durante su ingreso presentando complicaciones respiratorias graves y alta mortalidad intrahospitalaria. La tasa de transfusión sanguínea fue mayor en el grupo pandemia. La estancia hospitalaria aumentó en tres días en grupo pandemia. Conclusiones Los pacientes sometidos a cistectomía en nuestro centro durante la primera ola de pandemia por COVID-19 presentaron complicaciones respiratorias y no respiratorias en mayor número y más graves que los cistectomizados fuera de este periodo. La no aplicación del protocolo ERAS fue la principal diferencia en el tratamiento entre grupos (AU)

Introduction During the beginning of the COVID-19 pandemic in our center, neither prehabilitation nor multimodal rehabilitation could be applied due to the excessive patient load on the health system and to reduce SARS-CoV-2 transmission. The objective of our study was to analyze the evolution, complications, and survival up to one year of patients who underwent radical cystectomy in our hospital from March 1st to May 31st, 2020 (period of the first wave COVID-19 pandemic in Spain). We also compared the results with cystectomized patients outside the pandemic period and with application of the ERAS (Enhanced Recovery After Surgery) protocol. Material and methods Single-center, retrospective cohort study of patients scheduled for radical cystectomy from March 1st,2020 to May 31st, 2020. They were matched with previously operated patients using a 1:2 propensity matching score. The matching variables were demographic data, preoperative and intraoperative clinical conditions. Results A total of 23 radical cystectomies with urinary diversion were performed in the period described. In none of the cases the prehabilitation or the follow-up of our ERAS protocol could be applied, and this was the only difference we found between the 2 groups. Although the minimally invasive approach was more frequent in the pandemic group, the difference was not statistically significant. Three patients were diagnosed with COVID-19 during their admission, presenting severe respiratory complications and high in-hospital mortality. Apart from respiratory complications secondary to SARS-CoV-2, we also found statistically significant differences in other postoperative complications. The hospital stay increased by 3 days in the pandemic group (AU)

Effects of low nitrogen supply on biochemical and physiological parameters related to nitrate and water, involving nitrate transporters and aquaporins in Citrus macrophylla.

A reduction in chemical N-based fertillizer was investigated in Citrus plants. As N and water uptake are connected, the relationship between the physiological response to reductions in N was studied in relation to N metabolism and water. We examined the response of new and mature leaves and roots of Citrus macrophylla, grown under controlled conditions, and given different concentrations of N: 16, 8 or 4 mM. Differences in growth and development were determined for biochemical (mineral content, photosynthetic pigments, proteins and nitrate and nitrite reductase activity), physiological (photosynthesis and transpiration), and molecular (relative expression of nitrate transporters and aquaporins) parameters. Only plants given 4 mM N showed a reduction in growth. Although there were changes in NR activity, protein synthesis, and chlorophyll content in both 8 and 4 mM N plants that were highly related to aquaporin and nitrate transporter expression. The results revealed new findings on the relationship between aquaporins and nitrate transporters in new leaves of Citrus, suggesting a mechanism for ensuring growth under low N when new tissues are being formed.

How the COVID-19 pandemic affects the moral reasoning of pediatric residents and the general population.

BACKGROUND: Kohlberg's theory of moral development asserts that people progress through different stages of moral reasoning as their cognitive abilities and social interactions mature. Individuals at the lowest stage of moral reasoning (preconventional stage) judge moral issues based on self-interest, those with a medium stage (conventional stage) judge them based on compliance with rules and norms, and those at the highest stage (postconventional stage) judge moral issues based on universal principles and shared ideals. Upon attaining adulthood, it can be considered that there is stability in the stage of individuals' moral development; however, the effect of a global population crisis such as the one experienced in March 2020, when the World Health Organization (WHO) declared the COVID-19 pandemic, is unknown. The purpose of this study was to evaluate the changes in the moral reasoning of pediatric residents before and after one year of the COVID-19 pandemic and compare them with a general population group. METHODS: This is a naturalistic quasi-experimental study conducted with two groups, one comprised 47 pediatric residents of a tertiary hospital converted into a COVID hospital during the pandemic and another group comprised 47 beneficiaries of a family clinic who were not health workers. The defining issues test (DIT) was applied to the 94 participants during March 2020, before the pandemic initiated in Mexico, and later during March 2021. To assess intragroup changes, the McNemar-Bowker and Wilcoxon tests were used. RESULTS: Pediatric residents showed higher baseline stages of moral reasoning: 53% in the postconventional group compared to the general population group (7%). In the preconventional group, 23% were residents and 64% belonged to the general population. In the second measurement, one year after the start of the pandemic, the group of residents had a significant decrease of 13 points in the P index, unlike the general population group in which a decrease of 3 points was observed. This decrease however, did not equalize baseline stages. Pediatric residents remained 10 points higher than the general population group. Moral reasoning stages were associated with age and educational stage. CONCLUSIONS: After a year of the COVID-19 pandemic, we found a decrease in the stage of moral reasoning development in pediatric residents of a hospital converted for the care of patients with COVID-19, while it remained stable in the general population group. Physicians showed higher stages of moral reasoning at baseline than the general population.

Minimum in the pressure dependence of the interfacial free energy between ice Ih and water.

Despite the importance of ice nucleation, this process has been barely explored at negative pressures. Here, we study homogeneous ice nucleation in stretched water by means of molecular dynamics seeding simulations using the TIP4P/Ice model. We observe that the critical nucleus size, interfacial free energy, free energy barrier, and nucleation rate barely change between isobars from -2600 to 500 bars when they are represented as a function of supercooling. This allows us to identify universal empirical expressions for homogeneous ice nucleation in the pressure range from -2600 to 500 bars. We show that this universal behavior arises from the pressure dependence of the interfacial free energy, which we compute by means of the mold integration technique, finding a shallow minimum around -2000 bars. Likewise, we show that the change in the interfacial free energy with pressure is proportional to the excess entropy and the slope of the melting line, exhibiting in the latter a reentrant behavior also at the same negative pressure. Finally, we estimate the excess internal energy and the excess entropy of the ice Ih-water interface.

Clarifying the muddy concept of home healthcare coordination: A comprehensive theoretical framework.

Effective healthcare coordination is vital when such care is provided as a collaborative effort by many individuals and their task activities are interdependent. Coordination is necessary to ensure that care not only meets the needs of patients, but also avoids negative consequences for them due to omitted, inefficient, unnecessary, or even incorrect treatments. It also helps conserve resources. This has contributed to a rapid increase in articles on this subject. Still, while care coordination topics are gaining the attention of researchers, there are a number of issues experienced, including the delineation of limitations, inconsistent definitions, and problems with measurement. Therefore, the aim of this article is to refine the concept of homecare coordination and provide a comprehensive theoretical framework, illustrated with examples from practice. Focusing on this goal, we have reviewed the extant literature on the subject to develop a theoretical homecare coordination framework. The first intermediary goal was to integrate relevant concepts across multiple theories and frameworks into a unified synthesis. We do so in two parts: (1) analysis of extant coordination frameworks and theories; and (2) the presentation of our newly developed theoretical framework for homecare coordination. The new framework differentiates clearly between coordination as a process-i.e., what people do to coordinate and coordination as an outcome-i.e., the state of coordination. Applying this distinction to both, measurement and interpretation of results helps avoid misleading conclusions. As a research outcome, our framework builds upon the extant coordination literature, considers the complex relationships among the various coordination-related factors and, while focusing on homecare, is applicable to various healthcare settings in general. A nuanced differentiation and explanation of the elements involved enable a more consistent operationalization of the coordination concept. Additionally, as they explicitly address the healthcare system's micro, meso, and macro levels, they can be applied across diverse healthcare settings to investigate homecare coordination.

[CLINICAL IMPACT OF THE SUSPENSION OF THE ERAS PROTOCOL ON PATIENTS UNDERGOING RADICAL CYSTECTOMY DURING THE COVID-19 PANDEMIC.] / IMPACTO CLÍNICO DE NO APLICAR EL PROTOCOLO ERAS EN LOS PACIENTES SOMETIDOS A CISTECTOMÍA DURANTE LA PANDEMIA COVID-19.

INTRODUCTION: During the beginning of the COVID-19 pandemic in our center, neither prehabilitation nor multimodal rehabilitation could be applied due to the excessive patient load on the health system and to reduce SARS-CoV-2 transmission. The objective of our study was to analyze the evolution, complications, and survival up to one year of patients who underwent radical cystectomy in our hospital from March 1st to May 31st, 2020 (period of the first wave COVID-19 pandemic in Spain). We also compared the results with cystectomized patients outside the pandemic period and with application of the ERAS (Enhanced Recovery After Surgery) protocol. MATERIAL AND METHODS: Single-center, retrospective cohort study of patients scheduled for radical cystectomy from March 1st,2020 to May 31st, 2020. They were matched with previously operated patients using a 1:2 propensity matching score. The matching variables were demographic data, preoperative and intraoperative clinical conditions. RESULTS: A total of 23 radical cystectomies with urinary diversion were performed in the period described. In none of the cases the prehabilitation or the follow-up of our ERAS protocol could be applied, and this was the only difference we found between the 2 groups. Although the minimally invasive approach was more frequent in the pandemic group, the difference was not statistically significant. Three patients were diagnosed with COVID-19 during their admission, presenting severe respiratory complications and high in-hospital mortality. Apart from respiratory complications secondary to SARS-CoV-2, we also found statistically significant differences in other postoperative complications. The hospital stay increased by 3 days in the pandemic group. CONCLUSIONS: Patients who underwent radical cystectomy at our center during the first wave of the COVID-19 pandemic had a higher number and severity of respiratory and non-respiratory complications. Discontinuation of the ERAS protocol was the main difference in treatment between groups.

Clinical impact of the suspension of the ERAS protocol on patients undergoing radical cystectomy during the COVID-19 pandemic.

INTRODUCTION: During the beginning of the COVID-19 pandemic in our center, neither prehabilitation nor multimodal rehabilitation could be applied due to the excessive patient load on the health system and to reduce SARS-CoV-2 transmission. The objective of our study was to analyze the evolution, complications, and survival up to one year of patients who underwent radical cystectomy in our hospital from March 1st to May 31st, 2020 (period of the first wave COVID-19 pandemic in Spain). We also compared the results with cystectomized patients outside the pandemic period and with application of the ERAS (Enhanced Recovery After Surgery) protocol. MATERIAL AND METHODS: Single-center, retrospective cohort study of patients scheduled for radical cystectomy from March 1st, 2020 to May 31st, 2020. They were matched with previously operated patients using a 1:2 propensity matching score. The matching variables were demographic data, preoperative and intraoperative clinical conditions. RESULTS: A total of 23 radical cystectomies with urinary diversion were performed in the period described. In none of the cases the prehabilitation or the follow-up of our ERAS protocol could be applied, and this was the only difference we found between the 2 groups. Although the minimally invasive approach was more frequent in the pandemic group, the difference was not statistically significant. Three patients were diagnosed with COVID-19 during their admission, presenting severe respiratory complications and high in-hospital mortality. Apart from respiratory complications secondary to SARS-CoV-2, we also found statistically significant differences in other postoperative complications. The hospital stay increased by 3 days in the pandemic group. CONCLUSIONS: Patients who underwent radical cystectomy at our center during the first wave of the COVID-19 pandemic had a higher number and severity of respiratory and non-respiratory complications. Discontinuation of the ERAS protocol was the main difference in treatment between groups.

Recomendaciones para el tratamiento oral de pacientes adultos con enfermedad de Gaucher tipo 1 / Recommendations for oral treatment for adult patients with type 1 Gaucher disease

Revisión de la evidencia científica sobre el tratamiento oral de pacientes adultos con enfermedad de Gaucher tipo 1 (EG1), con formato de guía clínica, según la normativa Agree II. Se describen las principales diferencias entre los 2 tratamientos orales disponibles actualmente para el tratamiento de esta entidad (miglustat y eliglustat).En esta revisión se recuerda que los criterios para iniciar el tratamiento oral en los pacientes con EG1 deben valorarse de forma individualizada. Si bien miglustat y eliglustat son inhibidores de la enzima glucosilceramida sintetasa, los 2 presentan diferentes mecanismos de acción y propiedades farmacológicas y nunca se deben considerar como equivalentes. Miglustat está indicado en pacientes con EG1 no grave que no pueden recibir otro tratamiento de primera línea, mientras que eliglustat está indicado en pacientes con EG1 con cualquier gravedad, en primera línea y sin necesidad de estabilización previa con tratamiento de reemplazo enzimático. Es importante enfatizar que para iniciar tratamiento con eliglustat debemos conocer el fenotipo metabólico CYP2D6 y que su asociación con fármacos metabolizados a través de los citocromos CYP2D6 y CYP3A4 –o bien que utilicen la glucoproteína P– se debe evaluar individualmente. Durante el embarazo se debe evitar el uso de eliglustat, pudiéndose emplear únicamente el tratamiento de reemplazo enzimático. A diferencia de miglustat, cuyos efectos adversos han limitado su utilización, eliglustat no solo ha demostrado una eficacia similar a la del tratamiento de reemplazo enzimático, sino que ha demostrado mejoría en la calidad de vida de los pacientes EG1. (AU)

This work is a review of the scientific evidence on the oral treatment of adult patients with Gaucher disease type 1 (GD1) with a clinical guideline format according to the Agree II regulations. It describes the main differences between the 2 oral treatments currently available for treating this disease (miglustat and eliglustat).This review reminds us that the criteria for starting oral treatment in patients with GD1 must be assessed individually. Although miglustat and eliglustat are both glucosylceramide synthase enzyme inhibitors, they have different mechanisms of action and pharmacological properties and should never be considered equivalent. Miglustat is indicated in patients with non-severe GD1 who cannot receive other first-line treatments, while eliglustat is indicated as first-line treatment for patients with GD1 of any severity without the need for prior stabilization with enzyme replacement therapy. It is important to emphasize that in order to start treatment with eliglustat, we must know the CYP2D6 metabolic phenotype and its association with drugs metabolized through the CYP2D6 and CYP3A4 cytochromes –or alternatively those that use P-Glycoprotein– must be evaluated on an individual basis. During pregnancy, the use of eliglustat should be avoided; only enzyme replacement therapy can be used. Unlike miglustat, whose adverse effects have limited its use, eliglustat has not only demonstrated similar efficacy to enzyme replacement therapy but has also been shown to improve the quality of life of patients with GD1. (AU)

Differences in moral reasoning among medical graduates, graduates with other degrees, and nonprofessional adults.

BACKGROUND: Reasoning and moral action are necessary to resolve day-to-day moral conflicts, and there are certain professions where a greater moral character is expected, e.g., medicine. Thus, it is desirable that medical students develop skills in this field. Some studies have evaluated the level of moral reasoning among medical students; however, there are no comparative studies involving other types of populations. Therefore, the objective of this study was to compare the moral reasoning among medical graduates with that of a group of young graduates with other degrees and of a group of nonprofessional adults. METHODS: An exploratory cross-sectional study was conducted. Pediatric residents and pediatric subspecialty residents at a pediatric hospital were invited to participate, forming the group of "medical graduates". A group of young people from a social program and students with a master's degree in a science from the same pediatric hospital were also invited to participate, comprising the group of "graduates with other degrees". Finally, a group of beneficiaries of a family clinic was invited to participate, which we categorized as "nonprofessionals". To evaluate the differences in moral reasoning between these 3 groups, we applied the Defining Issues Test (DIT), a moral reasoning questionnaire designed by James Rest using Kohlberg's theory of moral development. RESULTS: The moral reasoning of 237 subjects-88 from the "medical graduates" group, 82 from the "graduates with other degrees" group and 67 from the "nonprofessionals" group- was evaluated. We found differences in the profiles of moral development of the groups. The profile of the "nonprofessionals" showed a very high predominance of subjects at the preconventional level, 70%, but only 4.5% at the postconventional level. Among the "medical graduates", we observed 37.5% at the preconventional level and 34% at the postconventional level (X2 p < 0.001); this group had the highest percentage in this category. This large difference could be because the differences in the ages and socioeducational levels of nonprofessionals are much wider than those among medical graduates. However, significant differences were also found when the profiles of medical graduates were compared with those of graduates with other degrees, since the latter demonstrated 56% at the preconventional level and 18% at the postconventional level (X2 test, p = 0.02). CONCLUSIONS: Significant differences were found in moral reasoning among the groups that we evaluated. Among the group of medical graduates, there was a higher percentage of subjects at the postconventional level than among the group of graduates with other degrees and a much higher percentage than among the group of nonprofessionals. Our conclusions give the first evidence that studying medicine seems to influence the development of moral reasoning in its students. Therefore, we consider it relevant to develop educational strategies where the student is involved in simulated but realistic decision-making situations, where there are moral dilemmas to resolve from their early years of training.

Recommendations for oral treatment for adult patients with type 1 Gaucher disease.

This work is a review of the scientific evidence on the oral treatment of adult patients with Gaucher disease type 1 (GD1) with a clinical guideline format according to the Agree II regulations. It describes the main differences between the two oral treatments currently available for treating this disease (miglustat and eliglustat). This review reminds us that the criteria for starting oral treatment in patients with GD1 must be assessed individually. Although miglustat and eliglustat are both glucosylceramide synthase (GCS) enzyme inhibitors, they have different mechanisms of action and pharmacological properties and should never be considered equivalent. Miglustat is indicated in patients with non-severe GD1 who cannot receive other first-line treatments, while eliglustat is indicated as first-line treatment for patients with GD1 of any severity without the need for prior stabilization with enzyme replacement therapy (ERT). It is important to emphasize that in order to start treatment with eliglustat, we must know the CYP2D6 metabolic phenotype and its association with drugs metabolized through the CYP2D6 and CYP3A4 cytochromes-or alternatively those that use P-Glycoprotein must be evaluated on an individual basis. During pregnancy, the use of eliglustat should be avoided; only ERT can be used. Unlike miglustat, whose adverse effects have limited its use, eliglustat has not only demonstrated similar efficacy to ERT but has also been shown to improve the quality of life of patients with GD1.

Low-dose self-amplifying mRNA COVID-19 vaccine drives strong protective immunity in non-human primates against SARS-CoV-2 infection.

The coronavirus disease 2019 (COVID-19) pandemic continues to spread globally, highlighting the urgent need for safe and effective vaccines that could be rapidly mobilized to immunize large populations. We report the preclinical development of a self-amplifying mRNA (SAM) vaccine encoding a prefusion stabilized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein and demonstrate strong cellular and humoral immune responses at low doses in mice and rhesus macaques. The homologous prime-boost vaccination regimen of SAM at 3, 10 and 30 µg induced potent neutralizing antibody (nAb) titers in rhesus macaques following two SAM vaccinations at all dose levels, with the 10 µg dose generating geometric mean titers (GMT) 48-fold greater than the GMT of a panel of SARS-CoV-2 convalescent human sera. Spike-specific T cell responses were observed with all tested vaccine regimens. SAM vaccination provided protective efficacy against SARS-CoV-2 challenge as both a homologous prime-boost and as a single boost following ChAd prime, demonstrating reduction of viral replication in both the upper and lower airways. The SAM vaccine is currently being evaluated in clinical trials as both a homologous prime-boost regimen at low doses and as a boost following heterologous prime.

3D printed bioresorbable scaffolds for articular cartilage tissue engineering: a comparative study between neat polycaprolactone (PCL) and poly(lactide-b-ethylene glycol) (PLA-PEG) block copolymer.

This work identifies and describes different material-scaffold geometry combinations for cartilage tissue engineering (CTE). Previously reported potentially interesting scaffold geometries were tuned and printed using bioresorbable polycaprolactone and poly(lactide-b-ethylene) block copolymer. Medical grades of both polymers were 3D printed with fused filament fabrication technology within an ISO 7 classified cleanroom. Resulting scaffolds were then optically, mechanically and biologically tested. Results indicated that a few material-scaffold geometry combinations present potential for excellent cell viability as well as for an enhance of the chondrogenic properties of the cells, hence suggesting their suitability for CTE applications.

Homogeneous nucleation of NaCl in supersaturated solutions.

The seeding method is an approximate approach to investigate nucleation that combines molecular dynamics simulations with classical nucleation theory. Recently, this technique has been successfully implemented in a broad range of nucleation studies. However, its accuracy is subject to the arbitrary choice of the order parameter threshold used to distinguish liquid-like from solid-like molecules. We revisit here the crystallization of NaCl from a supersaturated brine solution and show that consistency between seeding and rigorous methods, like Forward Flux Sampling (from previous work) or spontaneous crystallization (from this work), is achieved by following a mislabelling criterion to select such threshold (i.e. equaling the fraction of the mislabelled particles in the bulk parent and nucleating phases). This work supports the use of seeding to obtain fast and reasonably accurate nucleation rate estimates and the mislabelling criterion as one giving the relevant cluster size for classical nucleation theory in crystallization studies.

Biallelic variants in genes previously associated with dominant inheritance: CACNA1A, RET and SLC20A2.

A subset of families with co-dominant or recessive inheritance has been described in several genes previously associated with dominant inheritance. Those recessive families displayed similar, more severe, or even completely different phenotypes to their dominant counterparts. We report the first patients harboring homozygous disease-related variants in three genes that were previously associated with dominant inheritance: a loss-of-function variant in the CACNA1A gene and two missense variants in the RET and SLC20A2 genes, respectively. All patients presented with a more severe clinical phenotype than the corresponding typical dominant form. We suggest that co-dominant or recessive inheritance for these three genes could explain the phenotypic differences from those documented in their cognate dominant phenotypes. Our results reinforce that geneticists should be aware of the possible different forms of inheritance in genes when WES variant interpretation is performed. We also evidence the need to refine phenotypes and inheritance patterns associated with genes in order to avoid failures during WES analysis and thus, raising the WES diagnostic capacity in the benefit of patients.

Initial findings in chest X-rays as predictors of worsening lung infection in patients with COVID-19: correlation in 265 patients.

BACKGROUND AND AIMS: We aimed to analyze the relationship between the initial chest X-ray findings in patients with severe acute respiratory syndrome due to infection with SARS-CoV-2 and eventual clinical worsening and to compare three systems of quantifying these findings. MATERIAL AND METHODS: This retrospective study reviewed the clinical and radiological evolution of 265 adult patients with COVID-19 attended at our center between March 2020 and April 2020. We recorded data related to patients' comorbidities, hospital stay, and clinical worsening (admission to the ICU, intubation, and death). We used three scoring systems taking into consideration 6 or 8 lung fields (designated 6A, 6B, and 8) to quantify lung involvement in each patient's initial pathological chest X-ray and to classify its severity as mild, moderate, or severe, and we compared these three systems. We also recorded the presence of alveolar opacities and linear opacities (fundamentally linear atelectasis) in the first chest X-ray with pathologic findings. RESULTS: In the χ2 analysis, moderate or severe involvement in the three classification systems correlated with hospital admission (P = .009 in 6A, P = .001 in 6B, and P = .001 in 8) and with death (P = .02 in 6A, P = .01 in 6B, and P = .006 in 8). In the regression analysis, the most significant associations were 6B with alveolar involvement (OR 2.3; 95%CI 1.1.-4.7; P = .025;) and 8 with alveolar involvement (OR 2.07; 95% CI 1.01.-4.25; P = .046). No differences were observed in the ability of the three systems to predict clinical worsening by classifications of involvement in chest X-rays as moderate or severe. CONCLUSION: Moderate/severe extension in the three chest X-ray scoring systems evaluating the extent of involvement over 6 or 8 lung fields and the finding of alveolar opacities in the first pathologic X-ray correlated with mortality and the rate of hospitalization in the patients studied. No significant difference was found in the predictive ability of the three classification systems proposed.

Influencia del tratamiento de los puntos gatillo miofasciales en pacientes con ictus isquémico agudo: estudio piloto aleatorizado, doble ciego / Influence of the treatment of miofascial trigger points in acute ischaemic stroke patients: Randomized pilot study, double blind

Objetivos Evaluar la influencia del tratamiento de los puntos gatillo miofasciales (PGM) en el balance motor y en la autonomía funcional en pacientes con ictus isquémico agudo. Participantes y métodos Se incluyeron 22 pacientes con ictus isquémico de menos de cinco días de evolución, con paresia braquial y/o crural en un estudio piloto, aleatorizado, a doble ciego, de tratamiento experimental vs. control. Durante la hospitalización, ambos grupos recibieron la fisioterapia. Adicionalmente, al grupo experimental (GE) se le trataron los PGM detectados en hombro y cadera paréticos y al grupo control (GC) se le aplicó un tratamiento sin efectos sobre los PGM. Fueron registrados al alta y a los 90 días postictus el grado fuerza de las extremidades paréticas mediante la National Institute of Health Stroke Scale, y el grado de autonomía funcional mediante la escala de Rankin modificada. Resultados Se detectó una mejoría tanto en la fuerza de las extremidades paréticas (probabilidad al alta de un mejor balance motor del 75,6% en la extremidad superior y del 69% en la extremidad inferior), como en la autonomía funcional (probabilidad de una mejor funcionalidad del 68%) en el GE comparado con el GC. Estos resultados no se mantuvieron a los 90 días de seguimiento. Conclusiones El tratamiento de los PGM como complemento al tratamiento de fisioterapia durante el ingreso hospitalario parece mejorar el balance motor y el grado de autonomía funcional al alta. Son necesarios futuros estudios que permitan confirmar nuestros resultados y evaluar el beneficio de una intervención más allá del ingreso hospitalario (AU)

Objectives To assess the influence of treatment of MTrPs on motor balance and functional autonomy in patients with acute ischaemic stroke. Patients and methods 22 patients with ischaemic stroke of less than 5 days’ evolution, with brachial and / or leg paresis were included in a randomized, double-blind, pilot study of experimental versus control treatment. During hospitalization, both groups received physiotherapy. In addition, the MTrPs detected in the paretic shoulder and hip were treated in the experimental group (EG). In contrast, the control group (CG) were given treatment without effects on the MTrPs. At the time of hospital discharge and 90 days post-stroke, we recorded the degree of strength of the paretic limbs using the National Institute of Health Stroke Scale, and the degree of functional autonomy using the modified Rankin Scale. Results We detected an improvement both in the strength of the paretic limbs (probability at discharge of a better motor balance of 75.6% in the upper limb and 69% in the lower limb) and in functional autonomy (68% probability of better functionality) in the EG compared to the CG. These results were not maintained at 90 days of follow-up. Conclusions Treatment of MTrPs as a complement to physiotherapy treatment during hospital admission seems to improve the degree of strength of paretic limbs and the degree of functional autonomy at hospital discharge. Future studies are necessary to confirm our results and evaluate the benefit of an intervention beyond hospital admission (AU)

Do cone age and heating mode determine the opening of serotinous cones during wildfires? A new bench scale approach applied to Pinus halepensis Mill.

Serotiny is a well-known fire adaptive trait in some species, as the Mediterranean conifer Pinus halepensis. However, information about cone opening mechanisms during wildfires and consequences on post fire dispersal is scarce. In addition, standardized methods allowing a realistic simulation of heating modes at bench-scale are not available. In this study, we address for the first time the interacting effects of radiation, convection and direct flame on the opening and seed release of serotinous cones, following a novel repeatable methodology. Using a Mass Loss Calorimeter (MLC) device and a wide range of heat exposures (between 5 and 75 kW m-2) with or without ignition, we intended to simulate realistic cone heating during surface and crown fires in laboratory conditions. Additionally, we included the effect of contrasting serotinous cone ages interacting with heating mode and considering the random individual variation. The proposed methodology has shown a high potential to simulate the complex process of crown fires in relation to cone opening under controlled conditions, detecting a threshold of heat exposure (25-30 kW m-2) for cone opening. We confirmed that heating mode had a highly significant effect in cone opening, interacting with cone age, while cone age effect on its own was marginal. Particularly, ignition significantly increased the efficacy of cone opening and seed release. Moreover, young and old cones behave differently in seed release, both in surface and crown fire simulations. Implementing and adjusting this methodology in other species will allow more realistic and reliable quantitative comparisons than previously attained.