JEWELFISH: 24-month results from an open-label study in non-treatment-naïve patients with SMA receiving treatment with risdiplam.

Risdiplam is a once-daily oral, survival of motor neuron 2 (SMN2) splicing modifier approved for the treatment of spinal muscular atrophy (SMA). JEWELFISH (NCT03032172) investigated the safety, tolerability, pharmacokinetics (PK), and PK/pharmacodynamic (PD) relationship of risdiplam in non-treatment-naïve patients with SMA. JEWELFISH enrolled adult and pediatric patients (N = 174) with confirmed diagnosis of 5q-autosomal recessive SMA who had previously received treatment with nusinersen (n = 76), onasemnogene abeparvovec (n = 14), olesoxime (n = 71), or were enrolled in the MOONFISH study (NCT02240355) of the splicing modifier RG7800 (n = 13). JEWELFISH was an open-label study with all participants scheduled to receive risdiplam. The most common adverse event (AE) was pyrexia (42 patients, 24%) and the most common serious AE (SAE) was pneumonia (5 patients, 3%). The rate of AEs and SAEs decreased by > 50% from the first to the second year of treatment, and there were no treatment-related AEs that led to withdrawal from treatment. An increase in SMN protein in blood was observed following risdiplam treatment and sustained over 24 months of treatment irrespective of previous treatment. Exploratory efficacy assessments of motor function showed an overall stabilization in mean total scores as assessed by the 32-item Motor Function Measure, Hammersmith Functional Motor Scale-Expanded, and Revised Upper Limb Module. The safety profile of risdiplam in JEWELFISH was consistent with previous clinical trials of risdiplam in treatment-naïve patients. Exploratory efficacy outcomes are reported but it should be noted that the main aim of JEWELFISH was to assess safety and PK/PD, and the study was not designed for efficacy analysis. TRIAL REGISTRATION: The study was registered (NCT03032172) on ClinicalTrials.gov on January 24, 2017; First patient enrolled: March 3, 2017.

Vitamin D Deficiency Is Associated with Advanced Liver Fibrosis and Impaired Fasting Glucose in Alcohol Use Disorder.

BACKGROUND: Vitamin D deficiency is a risk factor for liver disease, insulin resistance, and beta cell dysfunction. Individuals with alcohol use disorder (AUD) have many comorbidities, with a heavy burden of liver disease and metabolic complications, including type 2 diabetes mellitus (T2DM). OBJECTIVE: We aimed to analyze the prevalence and associations of vitamin D deficiency in patients admitted for in-hospital treatment of AUD. METHODS: A cross-sectional study was conducted in patients consecutively admitted for the treatment of AUD between January 2017 and October 2023. Sociodemographic data, substance use characteristics, and blood parameters were available at admission. Vitamin D status was assessed through the serum concentrations of 25-hydroxyvitamin D [25(OH)D] levels using a direct competitive chemiluminescent immunoassay method. Deficiency of vitamin D was defined as a concentration less than 20 ng/mL; impaired fasting glucose (IFG) was defined by fasting blood glucose >100 mg/dL (5.6 mmol/L), and advanced liver fibrosis by an FIB-4 index >3.25. RESULTS: Two hundred and forty-three patients were included (75% male) with a mean age of 49 ± 10 years, mean BMI of 26.4 ± 7.3, mean alcohol consumption of 163 ± 81 g/day, and a mean duration of AUD of 18.1 ± 11.2 years. Mean 25(OH)D, fasting blood glucose, AST, ALT, and platelets were 14.4 ± 10.2 ng/mL, 103.4 ± 40.9 mg/dL, 55.1 ± 75.8 U/L, 44.8 ± 76.6 U/L, and 206.3 ± 84.8 × 109/L, respectively. The prevalence of vitamin D deficiency was 80.6%, and 41.1% of patients had levels less than 10 ng/mL. IFG was present in 32.3% of patients, and 20.5% had FIB-4 values >3.25. In the multivariable analysis, IFG (OR, 2.51; 95% CI: 1.02-6.17, p = 0.04) and advanced liver fibrosis (OR, 4.27; 95% CI: 1.21-15.0, p = 0.02) were the only factors associated with vitamin D deficiency. CONCLUSIONS: Vitamin D deficiency was very prevalent in this series of patients with AUD and was associated with impaired fasting glucose and advanced liver fibrosis.

Duration of the first prone positioning maneuver and its association with 90-day mortality in patients with acute respiratory failure due to COVID-19: A retrospective study of time terciles.

OBJECTIVE: To investigate the association between the duration of the first prone positioning maneuver (PPM) and 90-day mortality in patients with C-ARDS. DESIGN: Retrospective, observational, and analytical study. SETTING: COVID-19 ICU of a tertiary hospital. PATIENTS: Adults over 18 years old, with a confirmed diagnosis of SARS-CoV-2 disease requiring PPM. INTERVENTIONS: Multivariable analysis of 90-day survival. MAIN VARIABLES OF INTEREST: Duration of the first PPM, number of PPM sessions, 90-day mortality. RESULTS: 271 patients undergoing PPM were analyzed: first tertile (n = 111), second tertile (n = 95) and third tertile (n = 65). The results indicated that the median duration of PDP was 14 h (95% CI: 10-16 h) in the first tertile, 19 h (95% CI: 18-20 h) in the second tertile and 22 h (95% CI: 21-24 h) in the third tertile. Comparison of survival curves using the Logrank test did not reach statistical significance (p = 0.11). Cox Regression analysis showed an association between the number of pronation sessions (patients receiving between 2 and 5 sessions (HR = 2.19; 95% CI: 1.07-4.49); and those receiving more than 5 sessions (HR = 6.05; 95% CI: 2.78-13.16) and 90-day mortality. CONCLUSIONS: while the duration of PDP does not appear to significantly influence 90-day mortality, the number of pronation sessions is identified as a significant factor associated with an increased risk of mortality.

Incidence of sexually transmitted infections and screening models among pre-exposure prophylaxis users.

INTRODUCTION: There is discussion about the frequency of STI screening among pre-exposure prophylaxis (PrEP) users. The aim of this study was to analyse the incidence of STIs and to evaluate different screening models in order to optimise the follow-up. METHODOLOGY: A prospective study was conducted between 2017 and 2023, including 138 PrEP users in a STI clinic. Participants were tested for STIs every three months. Unscheduled visits were performed for those with STI-related symptoms or for people who were notified for an STI by a sexual partner. We performed a survival analysis of repeated events, estimating the cumulative incidence (CI) and incidence rate (IR). RESULTS: The overall CI by quarterly screening was 8.3 (95% CI: 7.6-9.1) infections per person over six years, with a decreasing trend. The most frequently diagnosed pathogen was Neisseria gonorrhoeae, with a IR of 0.76 (95% CI: 0.68-0.84). If the frequency of screening is reduced to every six months, the IR of STIs is reduced by (95% CI: 0.5-0.66) infections per user per year, and at 12 months by 0.82 (95% CI: 0.73-0.89). In the case of no pharyngeal or urethral screening, IR is reduced by 0.37 (95% CI: 0.32-0.42) infections per person per year and in those over 35 years of age by 0.33 (95% CI: 0.25-0.4). Eliminating unscheduled visits, the reduction in IR is 0.33 (95% CI: 0.24-0.42). CONCLUSIONS: The incidence of STIs among PrEP users is high, especially in the rectum, but it does not increase over time. STI screening could be optimised reducing the frequency of pharyngeal and urethral testing, particularly in those over 35 years of age. It is essential to redistribute health resources for unscheduled visits, which have been shown to be the most cost-effective screening.

Model for managing scientific research in a public hospital: case study: Chilean National Cancer Institute, from 2015-2022.

Research is an essential element in the practice of healthcare, and hospitals play a fundamental role in its promotion. Research in hospitals can improve the quality of care, knowledge of diseases and the discovery of new therapies. Hospitals can conduct research in various fields, including basic research, clinical research, population-based research and even hospital management research. The findings of hospital research can be directly applied to clinical practice and management, thereby enhancing the quality of patient care, a central paradigm in translational health. This article details the experience of the National Cancer Institute of Chile over the past 8 years in its role as a high-complexity public hospital, specialised institute, healthcare centre, teaching institution, and research facility. It reviews the work of generating and strengthening its institutional research model since its redesign in 2018, the key elements that underpin it, and discusses the challenges the institute faces in its growth amidst the increasing cancer epidemiology in Chile, the recent enactment of a National Cancer Law, the post-pandemic scenario that has left a significant waiting list of oncology patients, and the initiation of the design and construction process for the new institute building.

Preconceptional Counseling in Women with Hyperthyroidism.

Preconception evaluation of couples wishing to conceive is an important step toward a healthy pregnancy and it is especially important in people with a chronic condition or at genetic risk. The most common endocrine disorders in women at reproductive age are those involving the thyroid gland and it is well recognized that hyperthyroidism (HT), over-function of the thyroid gland, is associated with risks of maternal, fetal, and neonatal complications. The aim of this paper is to review the latest evidence regarding the components of preconception counseling in women with HT that contemplate a pregnancy. We also want to raise awareness among healthcare professionals about the importance of periconceptional counseling in improving pregnancy outcomes and avoid maternal and fetal complications related to thyroid dysfunction. In women with Graves' disease seeking pregnancy, it is essential to discuss all the treatment options along with the associated risks and benefits. Extensive prospective studies are still needed to understand the implications of current recommended strategies for the management of HT in preconception and during pregnancy.

Impact of a Cardiogenic Shock Program on Mortality in a Non-Transplant Hospital.

INTRODUCTION: Cardiogenic shock is associated with high in-hospital morbidity and mortality. Improvements in this care process could lead to better outcomes. METHODS: This retrospective study of patients with cardiogenic shock compared two periods: no specific program to address cardiogenic shock and implementation of a cardiogenic shock program. This program included the establishment of a multidisciplinary team (shock team), early alert to the transplant hospital, initiation of a ventricular assist extracorporeal membrane oxygenation (ECMO) program, and extension of continuous care by acute cardiovascular care specialists. The primary objective was to analyse whether there were differences between in-hospital mortality and mortality during follow-up. Predictors of in-hospital mortality were examined as a secondary objective. RESULTS: A total of 139 patients were enrolled: 69 of them in the previous period and 70 in the cardiogenic shock program period. There was a significant reduction in in-hospital mortality (55.1% vs 37.1%; p=0.03) and mortality during follow-up (62.7% vs 44.6%; p=0.03) in the second period. Diabetes mellitus, ejection fraction, out-of-hospital cardiac arrest, and implementation of the cardiogenic shock program were independent predictors of in-hospital mortality. CONCLUSIONS: The implementation of a comprehensive cardiogenic shock program in a non-transplanting hospital improved in-hospital and follow-up mortality of patients in cardiogenic shock.

Recently acquired hepatitis C: Epidemiological characteristics and treatment response in a large cohort of MSM living with HIV in Madrid.

INTRODUCTION: We analyzed epidemiological, clinical characteristics, and the response to treatment in people living with HIV (PLHIV) who recently acquired hepatitis C (RAHC) in a multicentre study in Madrid (Spain). METHODS: Multicenter, ambispective, observational study of RAHC in men who have sex with men (MSM) infected with HIV. Clinical, epidemiological, and RAHC evolution were recorded prospectively in 2019 and 2020 and retrospectively in 2017 and 2018. In patients who received HCV treatment, sustained virological response (SVR) was provided 12 weeks after the end of treatment in an intention to treat analysis (ITT): all treated patients were included; and in analysis per-protocol (PP): missing patients were excluded. RESULTS: Overall, 133 patients were included. Median (IQR) age was 40 (34.3-46.1) years, 90.9% had at least one previous sexual transmission disease (STD), and 33.6% had previously hepatitis C. More than half of the prospective sample included patients using chemsex related drugs (57.3%), 45.7% of them intravenously. The most prevalent genotype was G1a (66.2%), followed by G4 (11.3%). Ten of 90 patients evaluated for spontaneous cure (11%) cured the infection spontaneously, and 119 had treatment after a median time of 1.8 (0.7-4.6) months: sustained virological response (SVR) was achieved in 90.7% in the ITT and 94.7% in the PP analysis, with no differences regarding the direct-acting antiviral agents (DAA) combination used. CONCLUSIONS: MSM infected by HIV with a RAHC were exposed to high-risk sexual behavior. Spontaneous cure rate was low, while SVR after treatment was achieved by more than 90%.

El método del factor de Bayes en el análisis de la energía mecánica en pacientes con insuficiencia respiratoria grave por SARS-CoV-2 / The Bayes factor in the analysis of mechanical power in patients with severe respiratory failure due to SARS-CoV-2

Objetivo: Precisar el grado de fuerza probatoria de las hipótesis estadísticas con relación a la mortalidad a 28 días y el valor umbral de 17J/min de potencia mecánica (PM) en pacientes con insuficiencia respiratoria secundaria a SARS-CoV-2. Diseño: Estudio de cohortes, longitudinal y analítico. Ámbito: Unidad de cuidados intensivos de un hospital de tercer nivel en España. Pacientes: Enfermos ingresados por infección por SARS-CoV-2 con ingreso en la UCI entre marzo de 2020 y marzo de 2022. Intervenciones: Análisis bayesiano con el modelo binomial beta. Variables de interés principales: Factor de Bayes, mechanical power. Resultados: Fueron analizados 253 pacientes. La frecuencia respiratoria inicial (BF10: 3,83×106), el valor de la presión pico (BF10: 3,72×1013) y el desarrollo de neumotórax (BF10: 17.663) fueron los valores con más probabilidad de ser diferentes entre los 2 grupos de pacientes comparados. En el grupo de pacientes con PM<17J/min se estableció un BF10 de 12,71 y un BF01 de 0,07 con un IdC95% de 0,27-0,58; Para el grupo de pacientes con PM≥17J/min el BF10 fue de 36.100 y el BF01 de 2,77e-05 con un IdC95% de 0,42-0,72. Conclusiones: Un valor de PM≥17J/min se asocia con una evidencia extrema con la mortalidad a 28 días en pacientes que necesitaron ventilación mecánica por insuficiencia respiratoria secundaria a enfermedad por SARS-CoV-2. (AU)

Objective: To specify the degree of probative force of the statistical hypotheses in relation to mortality at 28 days and the threshold value of 17J/min mechanical power (MP) in patients with respiratory failure secondary to SARS-CoV-2. Design: Cohort study, longitudinal, analytical. Setting: Intensive care unit of a third level hospital in Spain. Patients: Patients admitted for SARS-CoV-2 infection with admission to the ICU between March 2020 and March 2022. Interventions: Bayesian analysis with the beta binomial model. Main variables of interest: Bayes factor, mechanical power. Results: A total of 253 patients were analyzed. Baseline respiratory rate (BF10: 3.83×106), peak pressure value (BF10: 3.72×1013) and neumothorax (BF10: 17,663) were the values most likely to be different between the two groups of patients compared. In the group of patients with MP<17J/min, a BF10 of 12.71 and a BF01 of 0.07 were established with an 95%CI of 0.27-0.58. For the group of patients with MP≥17J/min the BF10 was 36,100 and the BF01 of 2.77e-05 with an 95%CI of 0.42-0.72. Conclusions: A MP≥17J/min value is associated with extreme evidence with 28-day mortality in patients requiring MV due to respiratory failure secondary to SARS-CoV-2 disease. (AU)

Assessment and safety of the new esthesiometer BRILL: Comparison with the Cochet-Bonnet Esthesiometer.

BACKGROUND: Corneal sensitivity can decrease by several ocular conditions, such as dry eye or refractive surgery, which favor ocular epithelial lesions and is measured using an esthesiometer. The study's primary objective was to demonstrate the efficacy and safety of the non-contact esthesiometer BRILL, which delivers air pulses to the corneal surface to assess corneal sensitivity. METHODS: A single-center, prospective, controlled pilot study was carried out in adult patients with healthy eyes and or with pathology. Corneal sensitivity measurements were made in triplicate for both eyes at three consecutive visits. The esthesiometer BRILL was used in all visits, and on the last visit, the contact esthesiometer Cochet-Bonnet was also used. The results of both devices were compared by transforming them into force values. RESULTS: 54 subjects with a mean age of 50.43 (SD 16.55, interval 18-87), 77.78% women, were included. Comparing the forces applied by both esthesiometers in the healthy eyes, in the eyes with pathology in all the groups, and in the dry eyes showed significant differences, p = 0.03603, p = 0.00614, and p = 0.0001, respectively. CONCLUSION: The BRILL esthesiometer proved to be an effective and safe tool for non-contact assessment of corneal sensitivity with operator-independent repeatability. The measurements had a good agreement and comparable range with the Cochet-Bonet aesthesiometer measurements in healthy and dry eyes but with no interchangeable values. This portable device can help ophthalmologists and optometrists to diagnose eye pathologies that cause decreased corneal sensitivity and to assess the efficacy of therapy and disease progression.

Empathic Resonance: A Case of Dissociative Identity Disorder (DID)

Dissociative identity disorder (DID) also referred as multiple personality disorder can be accompanied by related alterations in affect, behavior and sensory-motor functioning. This article describes the case of a 33-year-old woman with a diagnostic of DID and who required intensive treatment, who suffered bullying at the age of 15 with a demon personality. Despite psychopharmacological treatment there was no improvement until the emphatic resonance therapy was carried out. Our case report shows the complexity of providing treatment for patient with DID (AU)

Validation of deep learning techniques for quality augmentation in diffusion MRI for clinical studies.

The objective of this study is to evaluate the efficacy of deep learning (DL) techniques in improving the quality of diffusion MRI (dMRI) data in clinical applications. The study aims to determine whether the use of artificial intelligence (AI) methods in medical images may result in the loss of critical clinical information and/or the appearance of false information. To assess this, the focus was on the angular resolution of dMRI and a clinical trial was conducted on migraine, specifically between episodic and chronic migraine patients. The number of gradient directions had an impact on white matter analysis results, with statistically significant differences between groups being drastically reduced when using 21 gradient directions instead of the original 61. Fourteen teams from different institutions were tasked to use DL to enhance three diffusion metrics (FA, AD and MD) calculated from data acquired with 21 gradient directions and a b-value of 1000 s/mm2. The goal was to produce results that were comparable to those calculated from 61 gradient directions. The results were evaluated using both standard image quality metrics and Tract-Based Spatial Statistics (TBSS) to compare episodic and chronic migraine patients. The study results suggest that while most DL techniques improved the ability to detect statistical differences between groups, they also led to an increase in false positive. The results showed that there was a constant growth rate of false positives linearly proportional to the new true positives, which highlights the risk of generalization of AI-based tasks when assessing diverse clinical cohorts and training using data from a single group. The methods also showed divergent performance when replicating the original distribution of the data and some exhibited significant bias. In conclusion, extreme caution should be exercised when using AI methods for harmonization or synthesis in clinical studies when processing heterogeneous data in clinical studies, as important information may be altered, even when global metrics such as structural similarity or peak signal-to-noise ratio appear to suggest otherwise.

The impact of obesity on postoperative complications and short-term survival after liver transplantation.

BACKGROUND AND AIMS: Obesity is considered a risk factor for perioperative complications, but its effect on patients undergoing liver transplantation (LT) remains unclear. This study was conducted to analyze the impact of obesity on early morbidity and mortality risk following LT. METHODS: A multicenter study of outcomes in patients submitted to LT between 2009 and 2019 was conducted. Recipients were stratified into obese (BMI ≥ 30 kg/m2) and nonobese patients (BMI < 30 kg/m2). Early postoperative complications were compared and 30-day and 1-year patient and graft survival were assessed by Kaplan-Meier method. Primary graft nonfunction (PGNF) was defined as the presence of total bilirubin > 10 mg/dl, INR > 1.6 or ALT > 2000 U/l within the first week after LT. RESULTS: A total of 1608 patients were included after applying exclusion criteria, nonobese (1149, 71.46%) and obese patients (459, 28.54%). There were no significant differences in age, sex, Model for End-stage Liver Disease, Charlson comorbidity score, ethnicity, waiting list time and ischemia time. There were significantly higher rates of vascular (17.58% vs 23.53%, P = 0.021) and biliary complications (27.68% vs 35.73%, P = 0.006) and PGNF (11.40% vs 12.20%, P = 0.021) in obese patients. There was a significantly increased risk for long-term graft failure; however, there was no significant difference in patient survival after LT. CONCLUSION: Obese patients have significantly increased morbidity in terms of vascular and biliary complications and PGNF after LT. They have a higher risk for worse 1-year graft survival in comparison to controls.

Biofilm formation on polyethylene microplastics and their role as transfer vector of emerging organic pollutants.

Microplastic (MP)-colonizing microorganisms are important links for the potential impacts on environmental, health, and biochemical circulation in various ecosystems but are not yet well understood. In addition, biofilms serve as bioindicators for the evaluation of pollutant effects on ecosystems. This study describes the ability of three polyethylene-type microplastics, white (W-), blue (B-), and fluorescent blue (FB-) MPs, to support microbial colonization of Pseudomonas aeruginosa, the effect of mixed organic contaminants (OCs: amoxicillin, ibuprofen, sertraline, and simazine) on plastic-associated biofilms, and the role of biofilms as transfer vectors of such emerging pollutants. Our results showed that P. aeruginosa had a strong ability to produce biofilms on MPs, although the protein amount of biomass formed on FB-MP was 1.6- and 2.4-fold higher than that on B- and W-MP, respectively. When OCs were present in the culture medium, a decrease in cell viability was observed in the W-MP biofilm (65.0%), although a general impairing effect of OCs on biofilm formation was ruled out. Microbial colonization influenced the ability of MPs to accumulate OCs, which was higher for FB-MP. In particular, the sorption of amoxicillin was lower for all bacterial-colonized MPs than for the bare MPs. Moreover, we analysed oxidative stress production to assess the impact of MPs or MPs/OCs on biofilm development. The exposure of biofilms to OCs induced an adaptive stress response reflected in the upregulation of the katB gene and ROS production, particularly on B- and FB-MP. This study improves our understanding of MP biofilm formation, which modifies the ability of MPs to interact with some organic pollutants. However, such pollutants could hinder microbial colonization through oxidative stress production, and thus, considering the key role of biofilms in biogeochemical cycles or plastic degradation, the co-occurrence of MPs/OCs should be considered to assess the potential risks of MPs in the environment.

Pharmacogenetic Sex-Specific Effects of Methotrexate Response in Patients with Rheumatoid Arthritis.

Methotrexate (MTX) is a commonly used drug for the treatment of rheumatoid arthritis (RA), but its effectiveness can vary greatly among patients. Pharmacogenetics, the study of how genetic variations can affect drug response, has the potential to improve the personalized treatment of RA by identifying genetic markers that can predict a patient's response to MTX. However, the field of MTX pharmacogenetics is still in its early stages and there is a lack of consistency among studies. This study aimed to identify genetic markers associated with MTX efficacy and toxicity in a large sample of RA patients, and to investigate the role of clinical covariates and sex-specific effects. Our results have identified an association of ITPA rs1127354 and ABCB1 rs1045642 with response to MTX, polymorphisms of FPGS rs1544105, GGH rs1800909, and MTHFR genes with disease remission, GGH rs1800909 and MTHFR rs1801131 polymorphisms with all adverse events, and ADA rs244076 and MTHFR rs1801131 and rs1801133, However, clinical covariates were more important factors to consider when building predictive models. These findings highlight the potential of pharmacogenetics to improve personalized treatment of RA, but also emphasize the need for further research to fully understand the complex mechanisms involved.

[The Bayes factor in the analysis of mechanical power in patients with severe respiratory failure due to SARS-CoV-2]. / El método del factor de Bayes en el análisis de la energía mecánica en pacientes con insuficiencia respiratoria grave por SARS-CoV-2.

Objective: To specify the degree of probative force of the statistical hypotheses in relation to mortality at 28 days and the threshold value of 17 J/min mechanical power (MP) in patients with respiratory failure secondary to SARS-CoV-2. Design: Cohort study, longitudinal, analytical. Setting: Intensive care unit of a third level hospital in Spain. Patients: Patients admitted for SARS-CoV-2 infection with admission to the ICU between March 2020 and March 2022. Interventions: Bayesian analysis with the beta binomial model. Main variables of interest: Bayes factor, mechanical power. Results: A total of 253 patients were analyzed. Baseline respiratory rate (BF10: 3.83 × 106), peak pressure value (BF10: 3.72 × 1013) and neumothorax (BF10: 17,663) were the values most likely to be different between the two groups of patients compared. In the group of patients with MP < 17 J/min, a BF10 of 12.71 and a BF01 of 0.07 were established with an 95%CI of 0.27-0.58. For the group of patients with MP ≥ 17 J/min the BF10 was 36,100 and the BF01 of 2.77e-05 with an 95%CI of 0.42-0.72. Conclusions: A MP ≥ 17 J/min value is associated with extreme evidence with 28-day mortality in patients requiring MV due to respiratory failure secondary to SARS-CoV-2 disease.