Retos en la aplicación de la hipotermia terapéutica no servo-controlada durante el transporte neonatal en Cataluña / Challenges in the application of non-servocontrolled therapeutic hypothermia during neonatal transport in Catalonia

Introducción: La hipotermia terapéutica (HTT) es el único tratamiento que ha demostrado aumentar la posibilidad de supervivencia libre de secuelas en los recién nacidos (RNs) afectos de encefalopatía hipóxico-isquémica (EHI), recomendándose iniciarla lo antes posible. Lo más frecuente es que los pacientes tributarios de HTT no nazcan en los centros de referencia (CR) .requiriendo ser transportados. Métodos: Estudio observacional descriptivo prospectivo de RNs con EHI moderada-grave trasladados en hipotermia terapéutica no servo-controlada por los dos equipos de transporte neonatal y pediátrico terrestres de Cataluña (abril 2018-noviembre 2019). Resultados: 51 pacientes. Mediana de tiempo de estabilización 68 minutos (p25-75, 45 – 85min), traslado 30 minutos (p25-75, 15 – 45min). Media de edad a la llegada al CR 4 horas y 18 minutos (DE 96min). Medidas terapéuticas adoptadas: apagar la incubadora 43 (84,3%), bolsas de hielo 11 (21,6%) y ambas 11 (21,5%) pacientes. Se consiguió la temperatura rectal (TR) diana en 19 (37,3%) pacientes. No hubo diferencias en el sobre-enfriamiento según las medidas usadas para la aplicación de la HTT no servo-controlada (HTTnc). La duración del traslado no se relacionó con diferencias en la estabilización de la temperatura ni en la consecución de la temperatura objetivo.Conclusiones: La monitorización de la TR en el centro emisor es un pilar fundamental en la estabilización del paciente y la aplicación de la HTTnc. Existe una clara área de mejora en la eficacia de la HTTnc durante el transporte. La HTT servo-controlada sería una opción para poder ofrecer las mismas posibilidades terapéuticas a los RNs extramuros de los CR. (AU)

Introduction: Therapeutic hypothermia (TH) improves survival and neurological prognosis in hypoxic-ischemic encephalopathic (HIE) babies, being better the sooner TH is implemented. HIE babies are born more frequently in a non-cooling centre and need to be referred.Methods: Prospective-observational study (April 18–November 19). Newborns (≥34 weeks of gestational age (GA) and >1800g) with moderate/severe HIE on non-servocontrolled therapeutic hypothermia by the two neonatal transport teams in Catalonia.Results: 51 newborns. The median stabilisation and transport time were 68min (p25–75, 45–85min) and 30min (p25–75, 15–45min), respectively. The mean age at arrival at the receiving unit was 4h and 18min (SD 96.6). The incubator was set off in 43 (84%), iced-packs 11 (21.5%) and both (11, 21.5%). Target temperature was reached in 19 (37.3%) babies. There was no differences in the overcooling in relation to the measures applied. The transport duration was not related with temperature stabilisation or target temperature reachiness.Conclusions: Rectal temperature monitorisation is compulsory for the stabilisation and the application of non-servocontrolled hypothermia during transport. There is still time for improving in the administration of this treatment during transport. Servo-controlled hypothermia would be a better alternative to improve the management of HIE babies. (AU)

Challenges in the application of non-servocontrolled therapeutic hypothermia during neonatal transport in Catalonia.

INTRODUCTION: Therapeutic hypothermia (TH) improves survival and neurological prognosis in hypoxic-ischemic encephalopathic (HIE) babies, being better the sooner TH is implemented. HIE babies are born more frequently in a non-cooling centre and need to be referred. METHODS: Prospective-observational study (April 18 2018 - November 19 2019). Newborns (≥34 weeks of gestational age (GA) and >1800 g) with moderate/severe HIE on non-servocontrolled therapeutic hypothermia by the two neonatal transport teams in Catalonia. RESULTS: 51 newborns. The median stabilisation and transport time were 68 min (p25-75, 45-85 min) and 30 min (p25-75, 15-45 min), respectively. The mean age at arrival at the receiving unit was 4 h and 18 min (SD 96.6). The incubator was set off in 43 (84%), iced-packs 11 (21.5%) and both (11, 21.5%). Target temperature was reached in 19 (37.3%) babies. There were no differences in the overcooling in relation to the measures applied. The transport duration was not related with temperature stabilisation or target temperature reachiness. CONCLUSIONS: Rectal temperature monitorisation is compulsory for the stabilisation and the application of non-servocontrolled hypothermia during transport. There is still time for improving in the administration of this treatment during transport. Servo-controlled hypothermia would be a better alternative to improve the management of HIE babies.

Desarrollo de un sistema de indicadores para la evaluación de la calidad en transporte interhospitalario: proyecto multicéntrico / Quality indicators in interhospital transport: multicentre project

Introducción: El traslado interhospitalario se realiza por equipos muy diferentes en las distintas regiones de nuestro país, lo que dificulta la comparación de su calidad asistencial. Objetivo: Seleccionar y definir una lista consensuada de indicadores de calidad aplicable a todas las unidades de transporte, especializadas o no, a nivel nacional. Material y métodos: Realización de una propuesta inicial de indicadores por el comité coordinador con representantes del transporte especializado de nuestro país. Valoración del listado por especialistas en transporte de las unidades participantes y los grupos de trabajo de SECIP y SENeo. Selección de los indicadores mediante el método Delphi según su relevancia y factibilidad. Resultados: El listado inicial incluyó 35 posibles indicadores. Fueron valorados por 22 especialistas pertenecientes a siete unidades de transporte. En una primera fase se eligieron por consenso cuatro indicadores, que pasaron directamente al listado definitivo. Se enviaron a los encuestados los resultados del resto de indicadores y las observaciones realizadas por los participantes, y tras ello se realizó una segunda valoración, en la que alcanzaron un consenso aceptable otros 11 indicadores. Tras la elaboración del listado, se estableció de forma consensuada la definición final de cada indicador elegido. Conclusiones: Utilizando un sistema de búsqueda de consenso, definimos una lista de 15 indicadores comunes, que podría ser utilizada por las unidades especializadas de nuestro país y personal asistencial no especializado que realiza traslados pediátricos. Permitirá evaluar el rendimiento individual y comparar las diferentes unidades para encontrar oportunidades de mejora y asegurar la máxima calidad durante el transporte. (AU)

Introduction: Interhospital transport is carried out by variable teams in different regions of our country, and this makes quality evaluation and benchmarking complicated. Project objective: select and define a consensual list of quality measurement that may be used by national transport units, whether specialised or not. Methods: Initial set of quality indicators was proposed by coordinators (members of representative specialised transport units in Spain). Evaluation by selected transport specialists from participating units and SECIP (Society of Paediatric Intensive Care) and SENeo (Spanish Neonatology Society) work teams. Selection of definitive indicators by Delphi method according to relevance and feasibility. Results: A total of 35 quality indicators were included in the initial set. Evaluation was carried out by 22 specialists from seven transport teams. In a first round, four indicators were consensually included in the definitive list. Results for the rest of metrics and comments were sent to all participants, and after a second assessment, 11 other indicators reached enough consensus. After list accomplishment, a consensual final definition for every indicator was established. Conclusions: Using a consensual research method, a list of 15 common indicators was obtained, which may be used by specialised transport teams in our country, and by non-specialised clinics in charge of interhospital paediatric transport. It will allow individual performance to be assessed, as well as benchmarking, in order to find improvement opportunities and ensure the highest quality during interhospital transport. (AU)

Quality indicators in interhospital transport: Multicentre project.

INTRODUCTION: Interhospital transport is carried out by variable teams in different regions of our country, and this makes quality evaluation and benchmarking complicated. Project objective: Select and define a consensual list of quality measurement that may be used by national transport units, whether specialised or not. METHODS: Initial set of quality indicators was proposed by coordinators (members of representative specialised transport units in Spain). Evaluation by selected transport specialists from participating units and SECIP (Society of Paediatric Intensive Care) and SENeo (Spanish Neonatology Society) work teams. Selection of definitive indicators by Delphi method according to relevance and feasibility. RESULTS: A total of 35 quality indicators were included in the initial set. Evaluation was carried out by 22 specialists from 7 transport teams. In a first round, 4 indicators were consensually included in the definitive list. Results for the rest of metrics and comments were sent to all participants, and after a second assessment, 11 other indicators reached enough consensus. After list accomplishment, a consensual final definition for every indicator was established. CONCLUSIONS: Using a consensual research method, a list of 15 common indicators was obtained, which may be used by specialised transport teams in our country, and by non-specialised clinics in charge of interhospital paediatric transport. It will allow individual performance to be assessed, as well as benchmarking, in order to find improvement opportunities and ensure the highest quality during interhospital transport.

[Challenges in the application of non-servocontrolled therapeutic hypothermia during neonatal transport in Catalonia]. / Retos en la aplicación de la hipotermia terapéutica no servo-controlada durante el transporte neonatal en Cataluña.

INTRODUCTION: Therapeutic hypothermia (TH) improves survival and neurological prognosis in hypoxic-ischemic encephalopathic (HIE) babies, being better the sooner TH is implemented. HIE babies are born more frequently in a non-cooling centre and need to be referred. METHODS: Prospective-observational study (April 18-November 19). Newborns (≥34 weeks of gestational age (GA) and >1800g) with moderate/severe HIE on non-servocontrolled therapeutic hypothermia by the two neonatal transport teams in Catalonia. RESULTS: 51 newborns. The median stabilisation and transport time were 68min (p25-75, 45-85min) and 30min (p25-75, 15-45min), respectively. The mean age at arrival at the receiving unit was 4h and 18min (SD 96.6). The incubator was set off in 43 (84%), iced-packs 11 (21.5%) and both (11, 21.5%). Target temperature was reached in 19 (37.3%) babies. There was no differences in the overcooling in relation to the measures applied. The transport duration was not related with temperature stabilisation or target temperature reachiness. CONCLUSIONS: Rectal temperature monitorisation is compulsory for the stabilisation and the application of non-servocontrolled hypothermia during transport. There is still time for improving in the administration of this treatment during transport. Servo-controlled hypothermia would be a better alternative to improve the management of HIE babies.

Controlled, double-blind, randomized trial to assess the efficacy and safety of hydroxychloroquine chemoprophylaxis in SARS CoV2 infection in healthcare personnel in the hospital setting: A structured summary of a study protocol for a randomised controlled trial.

BACKGROUND: SARS-CoV-2 infection presents a high transmission in the group of health professionals in Spain (12-15% infected). Currently there is no accepted chemoprophylaxis but hydroxychloroquine (HDQ) is known to inhibit the coronavirus in vitro. Our hypothesis is that oral administration of hydroxychloroquine to healthcare professionals can reduce the incidence and prevalence of infection as well as its severity in this group. METHODS: Design: Prospective, single center, double blind, randomised, controlled trial (RCT). PARTICIPANTS: Adult health-care professionals (18-65 years) working in areas of high exposure and high risk of transmission of SARS-COV-2 (COVID areas, Intensive Care Unit -ICUs-, Emergency, Anesthesia and all those performing aerosol-generating procedures) will be included. Exclusion criteria include previous infection with SARS CoV2 (positive SARS-CoV-2 PCR or IgG serology), pregnancy or lactation, any contraindication to hydroxychloroquine or evidence of unstable or clinically significant systemic disease. INTERVENTIONS: Patients will be randomized (1:1) to receive once-daily oral Hydroxychloroquine 200mg for two months (HC group) or placebo (P group) in addition to the protective measures appropriate to the level of exposure established by the hospital. A serological evaluation will be carried out every 15 days with PCR in case of seroconversion, symptoms or risk exposure. Primary outcome is the percentage of subjects presenting infection (seroconversion and/or PCR +ve) by the SARS-Cov-2 virus during the observation period. Additionally, both the percentage of subjects in each group presenting Pneumonia with severity criteria (Curb 65 ≥2) and that of subjects requiring admission to ICU will be determined. DISCUSSION: While awaiting a vaccine, hygiene measures, social distancing and personal protective equipment are the only primary prophylaxis measures against SARS-CoV-2, but they have not been sufficient to protect our healthcare professionals. Some evidence of the in vitro efficacy of hydroxychloroquine against this virus is known, along with some clinical data that would support the study of this drug in the chemoprophylaxis of infection. However, there are still no data from controlled clinical trials in this regard. If our hypothesis is confirmed, hydroxychloroquine can help professionals fight this infection with more guarantees. PARTICIPANTS: This is a single-center study that will be carried out at the Marqués de Valdecilla University Hospital. 450 health professionals working at the Hospital Universitario Marqués de Valdecilla in areas of high exposure and high risk of transmission of SARS COV2 (COVID hospital areas, Intensive Care Unit, Emergency, Anesthesia and all those performing aerosol-generating procedures) will be included. INCLUSION CRITERIA: 1) Health professionals aged between 18 and 65 years (inclusive) at the time of the first screening visit; 2) They must provide signed written informed consent and agree to comply with the study protocol; 3) Active work in high exposure areas during the last two weeks and during the following weeks. EXCLUSION CRITERIA: 1) Previous infection with SARS CoV2 (positive coronavirus PCR or positive serology with SARS Cov2 negative PCR and absence of symptoms); 2) Current treatment with hydroxychloroquine or chloroquine; 3) Hypersensitivity, allergy or any contraindication for taking hydroxychloroquine, in the technical sheet; 4) Previous or current treatment with tamoxifen or raloxifene; 5) Previous eye disease, especially maculopathy; 6) Known heart failure (Grade III to IV of the New York Heart Association classification) or prolonged QTc; 7) Any type of cancer (except basal cell) in the last 5 years; 6) Refusal to give informed consent; 8) Evidence of any other unstable or clinically significant untreated immune, endocrine, hematological, gastrointestinal, neurological, neoplastic or psychiatric illness; 9) Antibodies positive for the human immunodeficiency virus; 10) Significant kidney or liver disease; 11) Pregnancy or lactation. INTERVENTION AND COMPARATOR: Two groups will be analyzed with a 1: 1 randomization rate. 1)Intervention: (n = 225): One 200 mg hydroxychloroquine sulfate coated tablet once daily for two months.2)Comparator (control group) (n = 225): One hydroxychloroquine placebo tablet (identical to that of the drug) once daily for two months MAIN OUTCOMES: The primary outcome of this study will be to evaluate: number and percentage of healthcare personnel presenting symptomatic and asymptomatic infection (see "Diagnosis of SARS CoV2 infection" below) by the SARS-Cov2 virus during the study observation period (8 weeks) in both treatment arms;number and percentage of healthcare personnel in each group presenting with Pneumonia with severity criteria (Curb 65 ≥2) and number and percentage of healthcare personnel requiring admission to the Intensive Care Unit (ICU) in both treatment arms. DIAGNOSIS OF SARS COV2 INFECTION: Determination of IgA, IgM and IgG type antibodies against SARS-CoV-2 using the Anti-SARS-CoV-2 ELISA kit (EUROIMMUN Medizinische Labordiagnostika AG, Germany) every two weeks. In cases of seroconversion, a SARS-CoV-2 PCR will be performed to rule out / confirm an active infection (RT-PCR in One Step: RT performed with mastermix (Takara) and IDT probes, following protocol published and validated by the CDC Evaluation of COVID-19 in case of SARS-CoV-2 infection RANDOMISATION: Participants will be allocated to intervention and comparator groups according to a balanced randomization scheme (1: 1). The assignment will be made through a computer-generated numeric sequence for all participants BLINDING (MASKING): Both participants and investigators responsible for recruiting and monitoring participants will be blind to the assigned arm. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Taking into account the current high prevalence of infection in healthcare personnel in Spain (up to 15%), to detect a difference equal to or greater than 8% in the percentage estimates through a two-tailed 95% CI, with a statistical power of 80% and a dropout rate of 5%, a total of 450 participants will need to be included (250 in each arm). TRIAL STATUS: The protocol approved by the health authorities in Spain (Spanish Agency for Medicines and Health Products "AEMPS") and the Ethics and Research Committee of Cantabria (CEIm Cantabria) corresponds to version 1.1 of April 2, 2020. Currently, recruitment has not yet started, with the start scheduled for the second week of May 2020. TRIAL REGISTRATION: Eudra CT number: 2020-001704-42 (Registered on 29 March 2020) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Blastic plasmacytoid dendritic cell neoplasm frequently shows occult central nervous system involvement at diagnosis and benefits from intrathecal therapy.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare aggressive myeloid neoplasm which shows a high rate of central nervous system (CNS) recurrence and overall survival (OS) of <1 year. Despite this, screening for CNS involvement is not routinely performed at diagnosis and intrathecal (IT) prophylaxis is not regularly administered in BPDCN. Here, we prospectively evaluated 13 consecutive BPDCN patients for the presence of CNS involvement by flow cytometry. Despite none of the patients presented with neurological symptoms, occult CNS involvement was detected in 6/10 cases evaluated at diagnosis and 3/3 studied at relapse/progression. BPDCN patients evaluated at diagnosis received IT treatment -either CNS prophylaxis (n = 4) or active therapy (n = 6)- and all but one remain alive (median follow-up of 20 months). In contrast, all three patients assessed at relapse/progression died. The potential benefit of IT treatment administered early at diagnosis on OS and CNS recurrence-free survival of BPDCN was further confirmed in a retrospective cohort of another 23 BPDCN patients. Our results show that BPDCN patients studied at diagnosis frequently display occult CNS involvement; moreover, they also indicate that treatment of occult CNS disease might lead to a dramatically improved outcome of BPDCN.

Trisomy 8, a Cytogenetic Abnormality in Myelodysplastic Syndromes, Is Constitutional or Not?

Isolated trisomy 8 is not considered presumptive evidence of myelodysplastic syndrome (MDS) in cases without minimal morphological criteria. One reason given is that trisomy 8 (+8) can be found as a constitutional mosaicism (cT8M). We tried to clarify the incidence of cT8M in myeloid neoplasms, specifically in MDS, and the diagnostic value of isolated +8 in MDS. Twenty-two MDS and 10 other myeloid neoplasms carrying +8 were studied. Trisomy 8 was determined in peripheral blood by conventional cytogenetics (CC) and on granulocytes, CD3+ lymphocytes and oral mucosa cells by fluorescence in situ hybridization (FISH). In peripheral blood CC, +8 was seen in 4/32 patients. By FISH, only one patient with chronic myelomonocytic leukemia showed +8 in all cell samples and was interpreted as a cT8M. In our series +8 was acquired in all MDS. Probably, once discarded cT8M by FISH from CD3+ lymphocytes and non-hematological cells, +8 should be considered with enough evidence to MDS.

Corneal grafting for the treatment of feline corneal sequestrum: a retrospective study of 18 eyes (13 cats).

OBJECTIVE: To determine the clinical outcome of corneal grafting for the treatment of feline corneal sequestrum (FCS). ANIMAL STUDIED: Domestic cats. PROCEDURES: A review of the medical records of cats that underwent keratoplasty as a treatment of FCS at the VTH-UAB, from 2002 to 2012, was carried out. RESULTS: Thirteen cats (18 eyes) of different breed, age, and gender were included. Persian cats were overrepresented (12/13;92%). There were nine males and four females, of a mean age of 3.4 years (0.7-7.1). Ipsilateral chronic corneal ulceration was reported as the most common concurrent ocular disease (6/18;33%). Keratoplasty was performed bilaterally in 5 cats (5/13;38%) and unilaterally in 8 (8/13;62%). Lamellar keratoplasty was performed in 17 eyes (17/18;95%) and full-thickness keratoplasty in 1 (1/18;5%). Mean graft size was 8.3 mm (4-11.5). Fresh homologous graft was performed in 2 eyes (2/18;11%) and frozen graft in 16 (16/18;89%). Of the latter group, homologous graft was performed in 6 eyes (6/16;37.5%) and heterologous in 10 (10/16;62.5%). In all the cats, postoperative treatment included topical antibiotics, corticosteroids, cycloplegics, and 0.2% cyclosporine A. Median follow-up time was 18.2 months, and main postoperative complications were diffuse mild epithelial pigment formation (2/18;11%), graft malacia (1/18;5%), and sequestrum recurrence (1/18;5%). Mean epithelial healing time was 19.2 days. Good visual outcome was achieved in all the eyes (100%), the majority of them having faint or mild corneal opacity (15/18;83%). CONCLUSIONS: Keratoplasty is an effective surgical treatment for FCS. The donor tissue provides excellent tectonic support to the affected corneas, with good visual and cosmetic outcome.

Multilineage dysplasia is associated with a poorer prognosis in patients with de novo acute myeloid leukemia with intermediate-risk cytogenetics and wild-type NPM1.

Acute myeloid leukemia (AML) with myelodysplasia-related changes is characterized by the presence of multilineage dysplasia (MLD), frequently related to high-risk cytogenetics and poor outcome. However, the presence of MLD does not modify the favorable prognostic impact of NPM1 mutation. The prognosis of patients with AML presenting marked dysplasia lacking high-risk cytogenetics and NPM1 mutation is uncertain. We evaluated the prognostic impact of MLD in 177 patients with intermediate-risk cytogenetics AML (IR-AML) and wild-type NPM1. Patients were categorized as MLD-WHO (WHO myelodysplasia criteria; n = 43, 24 %), MLD-NRW (significant MLD non-reaching WHO criteria; n = 16, 9 %), absent MLD (n = 80, 45 %), or non-evaluable MLD (n = 38, 22 %). No differences concerning the main characteristics were observed between patients with or without MLD. Outcome of patients with MLD-WHO and MLD-NRW was similar, and significantly worse than patients lacking MLD. The presence of MLD (66 vs. 80 %, p = 0.03; HR, 95 % CI = 2.3, 1.08-4.08) and higher leukocyte count at diagnosis was the only variable associated with lower probability of complete remission after frontline therapy. Concerning survival, age and leukocytes showed an independent prognostic value, whereas MLD showed a trend to a negative impact (p = 0.087, HR, 95 % CI = 1.426, 0.95-2.142). Moreover, after excluding patients receiving an allogeneic stem cell transplantation in first CR, MLD was associated with a shorter survival (HR, 95 % CI = 1.599, 1.026-2.492; p = 0.038). In conclusion, MLD identifies a subgroup of patients with poorer outcome among patients with IR-AML and wild-type NPM1.

Leflunomide derivative FK778 inhibits production of antibodies in an experimental model of alloreactive T-B cell interaction.

OBJECTIVES: The contribution of humoral immune response in allograft and xenograft rejection has been clearly demonstrated in recent years. For this reason, inhibition of alloantibody production has become essential in managing transplanted patients. Here, we assessed the effects of the leflunomide derivative FK778 (FK778) in the control of antibody production resulting from semiallogeneic cognate T-B-cell interactions. MATERIALS AND METHODS: BALB/c mice were tolerized at birth with semiallogeneic spleen cells from (BALB/c X C57BL/6) F1 mice, with or without overexpression of human bcl-2 transgene in B cells. These tolerized mice were treated with different dosages of FK778, either from birth, or from the third week of age, when autoantibody production was detected. The production of autoantibodies, used as markers of semiallogeneic cognate T-B - cell interactions, was evaluated at different time points during drug administration or after the interruption of treatment. RESULTS: FK778 treatment started at birth inhibited the production of semiallogeneic-driven antibodies in a dose-dependent manner. In addition, FK778 also reduced the levels of preformed circulating autoantibodies in adult mice, although the dosage required was 4 times higher than that used in neonates. However, the levels of IgG antibodies in these tolerized mice increased after FK778 withdrawal, indicating that FK778 failed to induce tolerance to semiallogeneic host CD4+ Th2 and/or donor B cells. CONCLUSIONS: Our results demonstrate the efficacy of FK778 in the control of antibody production resulting from semiallogeneic cognate T-B - cell interactions.