Desensitizing the autonomic nervous system to mitigate anti-GD2 monoclonal antibody side effects.

Background: Anti-GD2 monoclonal antibodies (mAbs) have shown to improve the overall survival of patients with high-risk neuroblastoma (HR-NB). Serious adverse events (AEs), including pain, within hours of antibody infusion, have limited the development of these therapies. In this study, we provide evidence of Autonomic Nervous System (ANS) activation as the mechanism to explain the main side effects of anti-GD2 mAbs. Methods: Through confocal microscopy and computational super-resolution microscopy experiments we explored GD2 expression in postnatal nerves of infants. In patients we assessed the ANS using the Sympathetic Skin Response (SSR) test. To exploit tachyphylaxis, a novel infusion protocol (the Step-Up) was mathematically modelled and tested. Results: Through confocal microscopy, GD2 expression is clearly visible in the perineurium surrounding the nuclei of nerve cells. By computational super-resolution microscopy experiments we showed the selective expression of GD2 on the cell membranes of human Schwann cells in peripheral nerves (PNs) significantly lower than on NB. In patients, changes in the SSR were observed 4 minutes into the anti-GD2 mAb naxitamab infusion. SSR latency quickly shortened followed by gradual decrease in the amplitude before disappearance. SSR response did not recover for 24 hours consistent with tachyphylaxis and absence of side effects in the clinic. The Step-Up protocol dissociated on-target off-tumor side effects while maintaining serum drug exposure. Conclusion: We provide first evidence of the ANS as the principal non-tumor target of anti-GD2 mAbs in humans. We describe the development and modeling of the Step-Up protocol exploiting the tachyphylaxis phenomenon we demonstrate in patients using the SSR test.

Barriers and Benefits of the Scheduled Telephone Referral Model (DETELPROG): A Qualitative Approach.

The recently developed scheduled mobile-telephone referral model (DETELPROG) has achieved especially important results in reducing waiting days for patients, but it has been decided to explore what barriers and positive aspects were detected by both primary care physicians (PCPs) and hospital attending physicians (HAPs) regarding its use. For this, a qualitative descriptive study was carried out through six semi-structured interviews and two focus groups in a sample of eleven PCPs and five HAPs. Interviews were carried out from September 2019 to February 2020. Data were analysed by creating the initial categories, recording the sessions, transcribing the information, by doing a comprehensive reading of the texts obtained, and analysing the contents. The results show that DETELPROG gives the PCP greater prominence as a patient's health coordinator by improving their relationship and patient safety; it also improves the relationship between PCP and HAP, avoiding unnecessary face-to-face referrals and providing safety to the PCP when making decisions. The barriers for DETELPROG to be used by PCP were defensive medicine, patients' skepticism in DETELPROG, healthcare burden, and inability to focus on the patient or interpret a sign, symptom, or diagnostic test. For HAP, the barriers were lack of confidence in the PCP and complexity of the patient. As a conclusion, DETELPROG referral model provides a lot of advantages and does not pose any new barrier to face-to-face referral or other non-face-to-face referral models, so it should be implemented in primary care.

Pediatric SMA patients with complex spinal anatomy: Implementation and evaluation of a decision-tree algorithm for administration of nusinersen.

The approval of nusinersen for the treatment of spinal muscular atrophy (SMA) has significantly changed the natural history of the disease. Nevertheless, scoliosis secondary to axial muscle weakness occurs at some point in most of patients with SMA and a conventional posterior interlaminar approach for intrathecal administration of nusinersen can be particularly challenging to perform in patients with severe scoliosis and/or previous spine fusion surgeries. We developed a protocol for the administration of nusinersen in pediatric patients, which includes a decision-tree algorithm that categorizes patients according to the estimated technical difficulty for the intrathecal administration. Complex spine patients were defined as those with a Cobb angle greater than 50° and/or a history of spinal surgery, while the rest of patients were considered non-complex. Nusinersen was successfully administered through a conventional non-CT-guided lumbar puncture in all 14 non-complex spine patients (110 out of 110 procedures; 100%). The feasibility of the intrathecal injection in the 15 complex spine patients was assessed by 3D CT. Administration was considered unfeasible in 7 out of these 15 patients according to imaging. In the 8 complex spine patients in whom the administration was considered feasible, conventional non-CT-guided lumbar punctures were successful only in 19 out of 53 procedures (36%). The remaining 34 procedures (64%) were guided by CT scan, all successful. Our work demonstrates that a cut-off point of 50° in Cobb angle and history of spinal surgery can reliably be used to anticipate the need for CT guidance in nusinersen administration.

Identification and prioritisation of risks in a hospital pharmacy using healthcare failure mode and effect analysis.

OBJECTIVES: The goals of this project included identifying the processes and subprocesses performed in hospital pharmacies, identifying potential adverse events, detecting failure modes and the causes of errors, prioritising the risks identified and designing a map of risks for hospital pharmacies. METHODS: A task force composed of hospital pharmacy staff was committed to update the diagram of processes and design a map of processes performed in hospital pharmacies. Risks were identified by failure mode and effect analysis annd prioritised according to their risk priority index (RPI) and criticality. A risk map of adverse events was designed based on the diagram of processes and/or primary activities where the prioritised failure modes were most frequent. RESULTS: In total, 99 failure modes associated with 80 adverse events and 129 causes were identified in eight hospital pharmacy areas/subprocesses. The three areas with the highest percentages of failure modes were inpatient pharmaceutical care, pharmacy laboratory and pharmaceutical technology, and medication management. The 25 failure modes (first quartile) with the highest RPI scores (RPI≥20) and the 25 failure modes with the highest frequency and criticality scores were classified as priority. CONCLUSIONS: According to their RPI, priority failure modes mostly occurred in the area of inpatient pharmaceutical care (92%). However, according to their criticality, priority failure modes were found to homogeneously occur across all pharmaceutical care areas. As general recommendations pharmacists should assume responsibility and leadership in the implementation of safe medication use practices in healthcare centres.

DETELPROG Study. Effectiveness of a New Model of Scheduled Telephone Referral from Primary Care to Internal Medicine. A Randomised Controlled Study.

In Spain, the average waiting time for a specialist consultation is 58 days. A determinant factor that contributes to this situation is the poor communication between primary care and specialised care, which is mainly due to the waiting days for a consultation, number of avoided/avoidable face-to-face referrals, and waiting days for the resolution of the process. DETELPROG is a referral system in which the family physician requests a scheduled outpatient internal medicine consultation, integrated into the usual consultations agenda of both physicians, the family, and the outpatient clinic physician, in order to have a telephone consultation. A randomized controlled clinical trial has been carried out to assess the effectiveness of DELTELPROG. In a sample of 255 patients, the experimental group was referred via a scheduled telephone call, and those in the control group, by face-to-face hospital consultation area. The results showed statistically significant differences between both groups of 27 days (95% confidence interval (CI): 20-33) regarding specialised consultation, 47 days (95% CI: 17-74) as for the resolution of the process, and 91.7% for avoided face-to-face consultations. The DETELPROG resulted as a low coverage system (53%), which makes it a complementary referral model. It is necessary to make an in-depth analysis of the causes that have led to this technologically low coverage.

Efectividad de un nuevo modelo de derivación telefónica compartida entre atención primaria y atención hospitalaria / Effectiveness of a new model of telephone derivation shared between primary care and hospital care

Objetivo: Averiguar si la derivación telefónica desde Atención Primaria a consultas externas de Medicina Interna (CCEE de MI) reduce días de espera, con respecto a la derivación presencial. Averiguar la aceptación de la consulta telefónica por parte de los médicos de familia (MF) de Atención Primaria y de sus pacientes. Diseño: Ensayo clínico controlado aleatorizado sin enmascaramiento. Emplazamiento: Área de Gestión Sanitaria Norte de Huelva. Participantes: Ciento cincuenta y cuatro pacientes. Intervenciones: Los pacientes de los MF del grupo experimental fueron derivados vía telefónica (salvo cumplimiento criterios exclusión) y los del grupo control vía presencial. Mediciones: Número de días desde la solicitud de derivación hasta la consulta en MI. Número de derivaciones telefónicas y presenciales. Número de médicos y de pacientes rechazados. Causas de los rechazos. Resultados: Diferencia estadísticamente significativa, estimándose en 27 (21-34) días entre ambos grupos. De los 58 MF, 8 prealeatorización, y 6 de los 20 asignados al grupo experimental rechazaron participar por «suponer consumo excesivo de tiempo y esfuerzo». Para un 50% de los pacientes derivados por los 14 MF que quedaron finalmente en el grupo experimental se rechazó la vía telefónica, siendo la complejidad de los pacientes la principal causa. Conclusiones: La derivación telefónica reduce considerablemente los días de espera para CCEE de MI, elimina las principales barreras de la consulta telefónica a tiempo real, no supuso un mayor gasto de tiempo ni de esfuerzo para los médicos y no se consideró tan beneficiosa en pacientes complejo

Aim: The purpose of this study is to find out whether telephone referral from Primary Health Care to Internal Medicine Consult manages to reduce waiting days as compared to traditional referral. This study also aims to know how acceptable is the telephone referral to general practitioners and their patients. Design: No blind randomized controlled clinical trial. Setting: Northern Huelva Health District. Participants: 154 patients. Interventions: Patients referrals from intervention clinicians were sent via telephone consultation, whereas patients referrals from control clinicians were sent by traditional via. Measurements: Number of days from referral request to Internal Medicine Consult. Number of telephone and traditional referrals. Number of doctors and patients denied. Denial reasons. Results: A statistically significant difference was found between groups, with an average of 27 (21-34) days. Among General Practitioners, 8 of the first 58 total doctors after randomization and, subsequently, 6 of the 20 doctors of the test group refused to engage in the trial because they considered "excessive time and effort consuming". 50% of patients referred by the 14 General Practitioners finally randomized to the intervention group were denied referral by telephone due to patient's complexity. Conclusions: Telephone referral significantly reduces waiting days for Internal Medicine consult. This type of referral did not mean an "excessive time and effort consuming" to General Practitioners and was not all that beneficial to complex patients

[Effectiveness of a new model of telephone derivation shared between primary care and hospital care]. / Efectividad de un nuevo modelo de derivación telefónica compartida entre atención primaria y atención hospitalaria.

AIM: The purpose of this study is to find out whether telephone referral from Primary Health Care to Internal Medicine Consult manages to reduce waiting days as compared to traditional referral. This study also aims to know how acceptable is the telephone referral to general practitioners and their patients. DESIGN: No blind randomized controlled clinical trial. SETTING: Northern Huelva Health District. PARTICIPANTS: 154 patients. INTERVENTIONS: Patients referrals from intervention clinicians were sent via telephone consultation, whereas patients referrals from control clinicians were sent by traditional via. MEASUREMENTS: Number of days from referral request to Internal Medicine Consult. Number of telephone and traditional referrals. Number of doctors and patients denied. Denial reasons. RESULTS: A statistically significant difference was found between groups, with an average of 27 (21-34) days. Among General Practitioners, 8 of the first 58 total doctors after randomization and, subsequently, 6 of the 20 doctors of the test group refused to engage in the trial because they considered "excessive time and effort consuming". 50% of patients referred by the 14 General Practitioners finally randomized to the intervention group were denied referral by telephone due to patient's complexity. CONCLUSIONS: Telephone referral significantly reduces waiting days for Internal Medicine consult. This type of referral did not mean an "excessive time and effort consuming" to General Practitioners and was not all that beneficial to complex patients.

Rendimiento y optimización de la herramienta trigger en la detección de eventos adversos en pacientes adultos hospitalizados / Performance and optimisation of a trigger tool for the detection of adverse events in hospitalised adult patients

Objetivo: Caracterizar el rendimiento de los triggers utilizados en la detección de eventos adversos (EA) de pacientes adultos hospitalizados y definir un panel de triggers simplificado suficientemente sensible y específico, para la detección de EA. Método: Estudio transversal de altas de pacientes de un servicio de medicina interna para la detección de EA mediante revisión sistemática de la historia clínica y la identificación de 41 triggers (evento clínico relacionado frecuentemente con EA), determinando si hubo EA según el contexto en que apareció el trigger. Una vez identificado el EA, se procedió a la caracterización de los triggers que lo detectaron. Se aplicó regresión logística para la selección de los triggers con mayor capacidad de detección de EA. Resultados: Se revisaron 291 historias clínicas y se detectaron 562 triggers en 103 pacientes, de los cuales 163 estuvieron implicados en la detección de un EA. Los triggers que detectaron más EA fueron «A.1. Úlcera por presión» (9,82%), «B.5. Laxante o enema» (8,59%), «A.8. Agitación» (8,59%), «A.9. Sobresedación» (7,98%), «A.7. Hemorragia» (6,75%) y «B.4. Antipsicótico» (6,75%). Se obtuvo un modelo simplificado de triggers que incluyó la variable «Número de fármacos» y los triggers «Sobresedación», «Sondaje», «Reingreso en 30 días», «Laxante o enema» y «Cese brusco de la medicación». Este modelo obtuvo una probabilidad del 81% de clasificar correctamente las historias con EA y sin EA (p <0,001; intervalo de confianza del 95%: 0,763-0,871). Conclusiones: Un número elevado de triggers estuvieron asociados a EA. El modelo resumido permite detectar una gran cantidad de EA con un mínimo de elementos (AU)

Objective: To characterise the performance of the triggers used in the detection of adverse events (AE) of hospitalised adult patients and to define a simplified panel of triggers to facilitate the detection of AE. Method: Cross-sectional study of charts of patients from a service of internal medicine to detect EA through systematic review of the charts and identification of triggers (clinical event often related to AE), determining if there was AE as the context in which it appeared the trigger. Once the EA was detected, we proceeded to the characterization of the triggers that detected it. Logistic regression was applied to select the triggers with greater AE detection capability. Results: A total of 291 charts were reviewed, with a total of 562 triggers in 103 patients, of which 163 were involved in detecting an AE. The triggers that detected the most AE were 'A.1. Pressure ulcer' (9.82%), 'B.5. Laxative or enema' (8.59%), 'A.8. Agitation' (8.59%), 'A.9. Over-sedation' (7.98%), 'A.7. Haemorrhage' (6.75%) and 'B.4. Antipsychotic' (6.75%). A simplified model was obtained using logistic regression, and included the variable 'Number of drugs' and the triggers 'Over-sedation', 'Urinary catheterisation', 'Readmission in 30 days', 'Laxative or enema' and 'Abrupt medication stop'. This model showed a probability of 81% to correctly classify charts with EA or without EA (p <0.001; 95% confidence interval: 0.763-0.871). Conclusions: A high number of triggers were associated with AE. The summary model is capable of detecting a large amount of AE, with a minimum of elements (AU)

[Performance and optimisation of a trigger tool for the detection of adverse events in hospitalised adult patients]. / Rendimiento y optimización de la herramienta trigger en la detección de eventos adversos en pacientes adultos hospitalizados.

OBJECTIVE: To characterise the performance of the triggers used in the detection of adverse events (AE) of hospitalised adult patients and to define a simplified panel of triggers to facilitate the detection of AE. METHOD: Cross-sectional study of charts of patients from a service of internal medicine to detect EA through systematic review of the charts and identification of triggers (clinical event often related to AE), determining if there was AE as the context in which it appeared the trigger. Once the EA was detected, we proceeded to the characterization of the triggers that detected it. Logistic regression was applied to select the triggers with greater AE detection capability. RESULTS: A total of 291 charts were reviewed, with a total of 562 triggers in 103 patients, of which 163 were involved in detecting an AE. The triggers that detected the most AE were "A.1. Pressure ulcer" (9.82%), "B.5. Laxative or enema" (8.59%), "A.8. Agitation" (8.59%), "A.9. Over-sedation" (7.98%), "A.7. Haemorrhage" (6.75%) and "B.4. Antipsychotic" (6.75%). A simplified model was obtained using logistic regression, and included the variable "Number of drugs" and the triggers "Over-sedation", "Urinary catheterisation", "Readmission in 30 days", "Laxative or enema" and "Abrupt medication stop". This model showed a probability of 81% to correctly classify charts with EA or without EA (p <0.001; 95% confidence interval: 0.763-0.871). CONCLUSIONS: A high number of triggers were associated with AE. The summary model is capable of detecting a large amount of AE, with a minimum of elements.

Salinity-induced changes in S-nitrosylation of pea mitochondrial proteins.

Together with reactive oxygen species, nitric oxide is an essential part of the signal transduction induced by stress conditions. In this work we study the pattern of S-nitrosylated proteins from mitochondria of pea plants subjected to 150mM NaCl for 5 and 14days. A differential pattern of target proteins was found during plant development and salt stress, with a minor number of S-nitrosylated proteins at 14 days specifically some key enzymes related to respiration and photorespiration. At this time of stress, only ATP synthase ß subunit, peroxiredoxin and Hsp90 were S-nitrosylated and no changes in protein levels were observed, although the activity of PrxII F may be reduced by S-nitrosylation. The NADH/NAD(+) ratio was also high at 14days but not the NADPH/NADP(+). An enhancement in NO measured by fluorimetry and confocal microscopy was observed in leaves, being part of the NO localized in mitochondria. An increase in mitochondrial GSNOR activity was produced in response to short and long-term NaCl treatment, where a higher number of nitrated proteins were also observed. The results indicated that posttranslational modifications seem to modulate respiratory and photorespiratory pathways, as well as some antioxidant enzymes, through differential S-nitrosylation/denitrosylation in control conditions and under salt stress.

The dual-targeted plant sulfiredoxin retroreduces the sulfinic form of atypical mitochondrial peroxiredoxin.

Sulfiredoxin (Srx) couples the energy of ATP hydrolysis to the energetically unfavorable process of reducing the inactive sulfinic form of 2-cysteine peroxiredoxins (Prxs) to regenerate its active form. In plants, Srx as well as typical 2-cysteine Prx have been considered as enzymes with exclusive chloroplast localization. This work explores the subcellular localization of Srx in pea (Pisum sativum) and Arabidopsis (Arabidopsis thaliana). Immunocytochemistry, analysis of protein extracts from isolated intact organelles, and cell-free posttranslational import assays demonstrated that plant Srx also localizes to the mitochondrion in addition to plastids. The dual localization was in line with the prediction of a signal peptide for dual targeting. Activity tests and microcalorimetric data proved the interaction between Srx and its mitochondrial targets Prx IIF and thioredoxin. Srx catalyzed the retroreduction of the inactive sulfinic form of atypical Prx IIF using thioredoxin as reducing agent. Arabidopsis Srx also reduced overoxidized human Prx V. These results suggest that plant Srx could play a crucial role in the regulation of Prx IIF activity by controlling the regeneration of its overoxidized form in mitochondria, which are sites of efficient reactive oxygen species production in plants.

Acciones para mejorar el servicio de dispensación de metadona en atención primaria / No disponible

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Characterization of plant sulfiredoxin and role of sulphinic form of 2-Cys peroxiredoxin.

The antioxidant function of 2-Cys peroxiredoxin (Prx) involves the oxidation of its conserved peroxidatic cysteine to sulphenic acid that is recycled by a reductor agent. In conditions of oxidative stress, the peroxidatic cysteine can be overoxidized to sulphinic acid inactivating the Prx. An enzyme recently discovered, named sulfiredoxin (Srx), reduces the sulphinic 2-Cys Prx (Prx-SO(2)H). To explore the physiological functions of Srx in plants we have cloned, expressed and purified to homogeneity a Srx from Arabidopsis thaliana (AtSrx), as well as five variants by site-directed mutagenesis on amino acids involved in its activity. The activity of sulfiredoxin, determined by a new method, is dependent on the concentration of the sulphinic form of Prx and the conserved Srx is capable of regenerating the functionality of both pea and Arabidopsis Prx-SO(2)H. Molecular modelling of AtSrx and the facts that the R28Q variant shows a partial inactivation, that the activity of the E76A variant is equivalent to that of the native enzyme and that the double mutation R28Q/E76A abolishes the enzymatic activity suggests that the pair His100-Glu76 may be involved in the activation of C72 in the absence of R28. The knock-out mutant plants without Srx or 2-Cys Prx exhibited phenotypical differences under growth conditions of 16 h light, probably due to the signalling role of the sulphinic form of Prx. These mutants showed more susceptibility to oxidative stress than wild-type plants. This work presents the first systematic biochemical characterization of the Srx/Prx system from plants and contributes to a better understanding of its physiological function.

The oligomeric conformation of peroxiredoxins links redox state to function.

Protein-protein associations, i.e. formation of permanent or transient protein complexes, are essential for protein functionality and regulation within the cellular context. Peroxiredoxins (Prx) undergo major redox-dependent conformational changes and the dynamics are linked to functional switches. While a large number of investigations have addressed the principles and functions of Prx oligomerization, understanding of the diverse in vivo roles of this conserved redox-dependent feature of Prx is slowly emerging. The review summarizes studies on Prx oligomerization, its tight connection to the redox state, and the knowledge and hypotheses on its physiological function in the cell as peroxidase, chaperone, binding partner, enzyme activator and/or redox sensor.

Sistema Español de Acreditación de Competencias Profesionales en Hepatología. Una propuesta de la Asociación Española para el Estudio del Hígado / No disponible

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