Raíces y alas: recuerdos y ficciones

El segundo número de la colección Laboratorio Transmedia (ISSN: 2794-0861) contiene 36 relatos escritos durante el curso 2021/2022 por estudiantes de la Universidad para Mayores

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

CARB-ES-19 Multicenter Study of Carbapenemase-Producing Klebsiella pneumoniae and Escherichia coli From All Spanish Provinces Reveals Interregional Spread of High-Risk Clones Such as ST307/OXA-48 and ST512/KPC-3

ObjectivesCARB-ES-19 is a comprehensive, multicenter, nationwide study integrating whole-genome sequencing (WGS) in the surveillance of carbapenemase-producing K. pneumoniae (CP-Kpn) and E. coli (CP-Eco) to determine their incidence, geographical distribution, phylogeny, and resistance mechanisms in Spain.MethodsIn total, 71 hospitals, representing all 50 Spanish provinces, collected the first 10 isolates per hospital (February to May 2019); CPE isolates were first identified according to EUCAST (meropenem MIC &gt; 0.12 mg/L with immunochromatography, colorimetric tests, carbapenem inactivation, or carbapenem hydrolysis with MALDI-TOF). Prevalence and incidence were calculated according to population denominators. Antibiotic susceptibility testing was performed using the microdilution method (EUCAST). All 403 isolates collected were sequenced for high-resolution single-nucleotide polymorphism (SNP) typing, core genome multilocus sequence typing (cgMLST), and resistome analysis.ResultsIn total, 377 (93.5%) CP-Kpn and 26 (6.5%) CP-Eco isolates were collected from 62 (87.3%) hospitals in 46 (92%) provinces. CP-Kpn was more prevalent in the blood (5.8%, 50/853) than in the urine (1.4%, 201/14,464). The cumulative incidence for both CP-Kpn and CP-Eco was 0.05 per 100 admitted patients. The main carbapenemase genes identified in CP-Kpn were blaOXA–48 (263/377), blaKPC–3 (62/377), blaVIM–1 (28/377), and blaNDM–1 (12/377). All isolates were susceptible to at least two antibiotics. Interregional dissemination of eight high-risk CP-Kpn clones was detected, mainly ST307/OXA-48 (16.4%), ST11/OXA-48 (16.4%), and ST512-ST258/KPC (13.8%). ST512/KPC and ST15/OXA-48 were the most frequent bacteremia-causative clones. The average number of acquired resistance genes was higher in CP-Kpn (7.9) than in CP-Eco (5.5).ConclusionThis study serves as a first step toward WGS integration in the surveillance of carbapenemase-producing Enterobacterales in Spain. We detected important epidemiological changes, including increased CP-Kpn and CP-Eco prevalence and incidence compared to previous studies, wide interregional dissemination, and increased dissemination of high-risk clones, such as ST307/OXA-48 and ST512/KPC-3

Myelination processes as a biomarker in Mct8-deficiency

Comunicación presentada en la XIII Reunión Anual CIBERER, celebrada en modalidad virtual del 1 al 3 de julio de 2020.Thyroid hormones (TH) are essential in brain development, regulating processes such as the differentiation of neural cells and myelination. TH are secreted to the blood from the thyroid gland, mainly as T4, which is converted in the astrocytes into T3, the nuclear active form, by the enzyme deiodinase type 2 (DIO2). Allan-Herndon-Dudley Syndrome (AHDS or MCT8 deficiency) is an X-linked rare disease caused by mutations in the monocarboxilate transporter 8 (MCT8), a transmembrane transporter specific for TH. AHDS is characterized by altered serum TH levels and severe neurological damage including profound psychomotor impairment. The neurological syndrome in MCT8 deficiency is mainly due to cerebral hypothyroidism, since TH access across brain barriers is impaired. MCT8-deficient mice replicate the alterations in circulating TH levels but not the neurological syndrome observed in patients, due to compensatory mechanisms involving the DIO2 enzyme. This led us to characterize the neurological phenotype of the double Mct8/Dio2 knockout mouse (KO) to validate it as a possible model of the disease. Previous results from brain samples of an 11-year-old MCT8-deficient subject showed alterations in myelination, which led us to study oligodendroglial populations and myelination in the absence of MCT8 in mice. To this aim, we used postnatal day 21 (P21) and P90 Mct8/Dio2KO mice as an animal model for MCT8 deficiency. Mct8/Dio2KO mice brain exhibits an altered phenotype both in the population dynamics of oligodendroglial cells, and in myelin formation, consistently with human data, showing low and aberrant myelination at P21 that is not fully reversed at P90

Novel insights into the neurological pathophysiology of MCT8-deficiency

Trabajo presentado en la X Reunión de la Red Glial Española, celebrada en Santiago de Compostela (España) el 4 de septiembre de 2019.Thyroid hormones (TH) are essential in the development of the brain, regulating processes such as the differentiation of neural cells and myelination. TH are secreted to the blood from the thyroid gland, mainly as T4, which in the brain is converted in the astrocytes into T3, the nuclear active form, by the enzyme deiodinase type 2 (DIO2). The Allan-Herndon-Dudley Syndrome (AHDS or MCT8 deficiency) is an X-linked rare disease caused by mutations in the monocarboxilate transporter 8 (MCT8), a transmembrane transporter specific for TH. AHDS is characterized by altered serum TH levels and severe neurological damage including profound psychomotor impairment. Evidences strongly suggest that the neurological syndrome in MCT8 deficiency is mainly due to cerebral hypothyroidism, since TH access across brain barriers is impaired. Mct8-deficient mice replicate the alterations in circulating TH levels but not the neurological syndrome observed in AHDS patients, due to a compensatory mechanism involving the Dio2 enzyme. This led us to characterize the neurological phenotype of the double Mct8/Dio2 knockout mouse (KO) to validate it as a possible model of the disease. Previous results from brain samples of an 11-year-old MCT8-deficient subject diagnosed with AHDS showed a severely altered expression of neuronal proteins, together with a delay in myelination. The goal of this work was to analyse glial populations and myelination in Mct8 absence in mice. To this aim, we used postnatal day 21 (P21) and P90 Mct8/Dio2KO mice as an animal model for Mct8 deficiency. Our results suggest a neuroinflammatory state in Mct8/Dio2KO mice. Evidences suggest that the lack of TH in Mct8/Dio2KO mice brain alters the development of neuroglial cells, which could lead to the sustained neuroinflammatory state observed. Myelin studies were also consistent with human data, showing low and aberrant myelination in Mct8/Dio2KO mice at P21 that is not fully reversed at P90

A CRISPR/Cas9-engineered avatar mouse model of monocarboxylate transporter 8 deficiency displays distinct neurological alterations

International audienceInactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches. Here we have generated by CRISPR/Cas9 an avatar mouse model for MCT8 deficiency with a point mutation found in two MCT8-deficient patients (P253L mice). We have predicted by in silico studies that this mutation alters the substrate binding pocket being the probable cause for impairing thyroid hormone transport. We have characterized the phenotype of MCT8-P253L mice and found endocrine alterations similar to those described in patients and in MCT8-deficient mice. Importantly, we detected brain hypothyroidism, structural and functional neurological alterations resembling the patient's neurological impairments. Thus, the P253L mouse provides a valuable model for studying the pathophysiology of MCT8 deficiency and in the future will allow to test therapeutic alternatives such as in vivo gene therapy and pharmacological chaperone therapy to improve the neurological impairments in MCT8 deficiency

A CRISPR/Cas9-engineered avatar mouse model of monocarboxylate transporter 8 deficiency displays distinct neurological alterations

Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches. Here we have generated by CRISPR/Cas9 an avatar mouse model for MCT8 deficiency with a point mutation found in two MCT8-deficient patients (P253L mice). We have predicted by in silico studies that this mutation alters the substrate binding pocket being the probable cause for impairing thyroid hormone transport. We have characterized the phenotype of MCT8-P253L mice and found endocrine alterations similar to those described in patients and in MCT8-deficient mice. Importantly, we detected brain hypothyroidism, structural and functional neurological alterations resembling the patient's neurological impairments. Thus, the P253L mouse provides a valuable model for studying the pathophysiology of MCT8 deficiency and in the future will allow to test therapeutic alternatives such as in vivo gene therapy and pharmacological chaperone therapy to improve the neurological impairments in MCT8 deficiency.Ministerio de Ciencia e Innovación (MCIN). AEI/10.13039/501100011033 ; AEI/10.13039/501100011033/FEDER; AEI /10.13039/501100011033/FSEConsejo Superior de Investigaciones CientíficasSherman FoundationAsociación Corriendo con el Corazón por HugoBBSRCMinisterio de Ciencia, Innovación y UniversidadesDepto. de Biología CelularFac. de Ciencias BiológicasTRUEpu

A CRISPR/Cas9-engineered avatar mouse model of monocarboxylate transporter 8 deficiency displays distinct neurological alterations

Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches. Here we have generated by CRISPR/Cas9 an avatar mouse model for MCT8 deficiency with a point mutation found in two MCT8-deficient patients (P253L mice). We have predicted by in silico studies that this mutation alters the substrate binding pocket being the probable cause for impairing thyroid hormone transport. We have characterized the phenotype of MCT8-P253L mice and found endocrine alterations similar to those described in patients and in MCT8-deficient mice. Importantly, we detected brain hypothyroidism, structural and functional neurological alterations resembling the patient's neurological impairments. Thus, the P253L mouse provides a valuable model for studying the pathophysiology of MCT8 deficiency and in the future will allow to test therapeutic alternatives such as in vivo gene therapy and pharmacological chaperone therapy to improve the neurological impairments in MCT8 deficiency.This study was supported by MCIN/AEI/10.13039/501100011033 (Grant No. SAF2017-86342-R to AG-F); MCIN/AEI/10.13039/501100011033/FEDER “Una manera de hacer Europa” (Grant No PID2020-113139RB-I00 to AG-F); Consejo Superior de Investigaciones Científicas (Grant No. 2020AEP044 to AG-F); the Sherman Foundation (Grant No. OTR02211 to SB-L and AG-F); Asociación Corriendo con el Corazón por Hugo (Grant No OTR06190 to AG-F) and the BBSRC (grant number BB/R016879/1 to SB-L). VV-H is recipient of a contract from MCIN/AEI /10.13039/501100011033/FSE “El FSE invierte en tu futuro” (Grant No PRE2018–086185), MG-Y and MB-A from the Formación de Profesorado Universitario (FPU, FPU19/02006 and FPU17/01733 respectively) program from the Ministerio de Ciencia, Innovación y Universidades

Incidence and impact of COVID-19 in MS. A survey from a Barcelona MS Unit.

Objective: To investigate the incidence of coronavirus disease 2019 (COVID-19) in a single-center cohort of patients with MS and to explore the contribution of their comorbidities and therapies to the outcome. Methods: A cross-sectional mixed-method study was conducted involving an email-based, self-administered questionnaire sent on May 21, 2020, to 586 patients with MS followed at the MS Unit of Hospital Clinic, University of Barcelona, along with telephone interview, and review of electronic medical records until June 18, 2020. The cumulative incidence of confirmed COVID-19 (positive PCR or antibody test) and all COVID-19 cases (confirmed and suspected) from the start of the pandemic was compared with the population estimates for Barcelona. Results: A total of 407 patients (69.5%) completed the survey. Most of the responders (67%) were female. The responders had a median age of 48 years (range 19–86), relapsing-remitting disease (84%), at least 1 comorbidity (45%), and were on disease-modifying therapy (DMT; 74.7%). COVID-19 was confirmed in 5 patients (1.2%) and suspected in 46 (11.3%). The cumulative incidence of confirmed COVID-19 cases was similar to that of the general population but was almost 2-fold higher when all cases were considered (p < 0.001). Six patients (11.7%) were hospitalized, of which 5 had good recovery and 1 died. Hospitalized patients were more frequently male, had diabetes and had progressive forms of MS (p < 0.05). DMT was not associated with the risk of infection or the outcome. Conclusions: In the studied MS cohort, the incidence of COVID-19 was higher than that of the general population; however, most patients did not require hospitalization and had a good outcome despite the frequent presence of comorbidities and treatment with DMT.Peer ReviewedPostprint (published version

Definition and risk factors for chronicity following acute idiosyncratic drug-induced liver injury.

Chronic outcome following acute idiosyncratic drug-induced liver injury (DILI) is not yet defined. This prospective, long-term follow-up study aimed to analyze time to liver enzyme resolutions to establish the best definition and risk factors of DILI chronicity. 298 out of 850 patients in the Spanish DILI registry with no pre-existing disease affecting the liver and follow-up to resolution or ⩾1year were analyzed. Chronicity was defined as abnormal liver biochemistry, imaging test or histology one year after DILI recognition. Out of 298 patients enrolled 273 (92%) resolved ⩽1year from DILI recognition and 25 patients (8%) were chronic. Independent risk factors for chronicity were older age [OR: 1.06, p=0.011], dyslipidemia [OR: 4.26, p=0.04] and severe DILI [OR: 14.22, p=0.005]. Alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TB) median values were higher in the chronic group during follow-up. Values of ALP and TB >1.1 x upper limit of normal (xULN) and 2.8 xULN respectively, in the second month from DILI onset, were found to predict chronic DILI (p1.1 x upper limit of normal (xULN) and 2.8 xULN respectively, in the second month from DILI onset, were found to predict chronic DILI (p One year is the best cut-off point to define chronic DILI or prolonged recovery, with risk factors being older age, dyslipidemia and severity of the acute episode. Statins are distinctly related to chronicity. ALP and TB values in the second month could help predict chronicity or very prolonged recovery. Drug-induced liver injury (DILI) patients who do not resolve their liver damage during the first year should be considered chronic DILI patients. Risk factors for DILI chronicity are older age, dyslipidemia and severity of the acute episode. Chronic DILI is not a very common condition; normally featuring mild liver profile abnormalities and not being an important clinical problem, with the exception of a small number of cases of early onset cirrhosis