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BACKGROUND: Telemonitoring is not consistently superior to standard care for inflammatory bowel disease (IBD), yet non-inferiority may be an acceptable outcome if remote care is more efficient. OBJECTIVE: To compare the remission time and quality of life of patients with an active IBD controlled by standard care or through the TECCU App (Telemonitoring of Crohn´s Disease and Ulcerative Colitis). METHODS: A 2-arm, randomized, multicentre trial with a non-inferiority design was performed at 24 Spanish hospitals on adult patients with IBD who initiated immunosuppressant or biological therapy. Patients were randomized into telemonitoring (G_TECCU) or standard care groups (G_Control). The follow-up schedule was based on telemonitoring contacts through the TECCU App in G_TECCU, and on in-person visits and telephone calls in G_Control, as in clinical practice. In both groups, treatment was adjusted according to the evolution of disease activity and medication adherence, which were measured through specific indices and biological markers at each check-up. The primary outcome was time in remission after 12-weeks, with quality of life, medication adherence, adverse events and patient satisfaction as secondary outcomes. RESULTS: Of 169 patients enrolled, 158 were randomized, and 150 were analyzed per protocol: telemonitoring (n=71); control (n=79). After 12-week, the time in clinical remission was not inferior after telemonitoring (4.20 ±3.73 weeks) to that in the controls (4.32 ±3.28 weeks), with a mean difference between arms of -0.12 weeks (95% CI -1.25-,1.01), non-inferiority p=0.017). The mean reduction of CRP values was -15.40 mg/L (SD=90.15, P =0.195) in G_TECCU and -13.16 mg/L (SD=54.61, P =0.053) in G_control, without significant differences between the two arms (P=.726). Similarly, the mean improvement of FC levels was 832.3 mg/L (SD=1825.0, P=.003) in G_TECCU and 1073.5 mg/L in G_Control (SD=3105.7, P=.03), but differences were not significant (P=.965). Quality of life improved in both groups, with a mean rise in the IBDQ-9 score of 13.44 points in G_TECCU (SD=19.1; P<.001) and 18.23 points [SD=22.9]; P=.001) in G_Control. Moreover, the proportion of patients who adhered to their medication rose significantly from 35.2% (25/71) to 67.6% (48/71) in G_TECCU (P=.001) and from 45.6% (36/79) to 73.4% (58/79) in G_Control (P=.001). Satisfaction remained stable around 90%, although non-inferiority was not demonstrated for secondary outcomes. CONCLUSIONS: Telemonitoring patients with active IBD is not inferior to standard care to achieve and maintain short-term remission. TECCU may be an alternative follow-up tool if the improved health outcomes and costs are confirmed in the long-term. CLINICALTRIAL: The trial is registered at ClinicalTrials.gov with the identifier NCT06031038; https://classic.clinicaltrials.gov/ct2/show/NCT06031038. INTERNATIONAL REGISTERED REPORT: RR2-10.2196/resprot.9639.
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MacroH2A has been linked to transcriptional silencing, cell identity, and is a hallmark of the inactive X chromosome (Xi). However, it remains unclear whether macroH2A plays a role in DNA replication. Using knockdown/knockout cells for each macroH2A isoform, we show that macroH2A-containing nucleosomes slow down replication progression rate in the Xi reflecting the higher nucleosome stability. Moreover, macroH2A1, but not macroH2A2, regulates the number of nano replication foci in the Xi, and macroH2A1 downregulation increases DNA loop sizes corresponding to replicons. This relates to macroH2A1 regulating replicative helicase loading during G1 by interacting with it. We mapped this interaction to a phenylalanine in macroH2A1 that is not conserved in macroH2A2 and the C-terminus of Mcm3 helicase subunit. We propose that macroH2A1 enhances the licensing of pre-replication complexes via DNA helicase interaction and loading onto the Xi.
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BACKGROUND: Simulation is an innovative tool for developing complex skills required for surgical training. The objective of this study was to determine the advancement of laparoscopic and robotic skills through simulation in participants with limited or no previous experience. METHODS: This is a systematic review and meta-analysis of randomized controlled trials (RCTs) in keeping with the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. We conducted searches using MEDLINE (PubMed), Web of Science, Google Scholar, and Cochrane Library. Variables analyzed were study characteristics, participant demographics, and characteristics of the learning program. Our main measures were effectiveness, surgical time, and errors. These were reported using standardized mean difference (SMD) with 95% CI (P < .05). Secondary measures included skill transfer and learning curve. RESULTS: A total of 17 RCTs were included and comprised 619 participants: 354 participants (57%) were in the simulation group and 265 (43%) in the control group. Results indicated that laparoscopic simulation effectively enhanced surgical skills (SMD, 0.59 [0.18-1]; P = .004) and was significantly associated with shorter surgical duration (SMD, -1.08 [-1.57 to -0.59]; P < .0001) and a fewer errors made (SMD, -1.91 [-3.13 to -0.70]; P = .002). In the robotic simulation, there was no difference in effectiveness (SMD, 0.17 [-0.19 to 0.52]; P = .36) or surgical time (SMD, 0.27 [-0.86 to 1.39]; P = .64). Furthermore, skills were found to be transferable from simulation to a real-life operating room (P < .05). CONCLUSION: Simulation is an effective tool for optimizing laparoscopic skills, even in participants with limited or no previous experience. This approach not only contributes to the reduction of surgical time and errors but also facilitates the transfer of skills to the surgical environment. In contrast, robotic simulation fails to maximize skill development, requiring previous experience in laparoscopy to achieve optimal levels of effectiveness.
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Laparoscopia , Procedimentos Cirúrgicos Robóticos , Humanos , Competência Clínica , Simulação por Computador , Laparoscopia/educação , Procedimentos Cirúrgicos Robóticos/educaçãoRESUMO
Huntington disease (HD) is a neurodegenerative disorder caused by ≥36 CAGs in the HTT gene. Intermediate alleles (IAs) (27-35 CAGs) are not considered HD-causing, but their potential association with neurocognitive symptoms remains controversial. As HTT somatic CAG expansion influences HD onset, we hypothesised that IAs are somatically unstable, and that somatic CAG expansion may drive phenotypic presentation in some IA carriers. We quantified HTT somatic CAG expansions by MiSeq sequencing in the blood DNA of 164 HD subjects and 191 IA (symptomatic and control) carriers, and in the brain DNA of a symptomatic 33 CAG carrier. We also performed genotype-phenotype analysis. The phenotype of symptomatic IA carriers was characterised by motor (85%), cognitive (27%) and/or behavioural (29%) signs, with a late (58.7 ± 18.6 years), but not CAG-dependent, age at onset. IAs displayed somatic expansion that were CAG and age-dependent in blood DNA, with 0.4% and 0.01% of DNA molecules expanding by CAG and year, respectively. Somatic expansions of +1 and +2 CAGs were detected in the brain of the individual with 33 CAGs, with the highest expansion frequency in the putamen (10.3%) and the lowest in the cerebellum (4.8%). Somatic expansion in blood DNA was not different in symptomatic vs. control IA carriers. In conclusion, we show that HTT IAs are somatically unstable, but we found no association with HD-like phenotypes. It is plausible, however, that some IAs, close to the HD pathological threshold and with a predisposing genetic background, could manifest with neurocognitive symptoms.
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Alelos , Proteína Huntingtina , Doença de Huntington , Fenótipo , Expansão das Repetições de Trinucleotídeos , Humanos , Doença de Huntington/genética , Doença de Huntington/patologia , Proteína Huntingtina/genética , Pessoa de Meia-Idade , Masculino , Feminino , Adulto , Idoso , Heterozigoto , Encéfalo/patologia , Encéfalo/metabolismoRESUMO
Age estimation is a major challenge in anthropology and forensic odontology laboratories, as well as in judicial settings, as one of the tools used in human identification. The aim of this study was to evaluate the usefulness of age estimation methods based on the accurate measurement of tooth color changes. A systematic review was carried out following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and in compliance with Cochrane criteria recommendations (PROSPERO registration number CRD 42022343371). An electronic search was performed in the following databases: Pubmed, Web of Science, Medline, Current Contents Connect, SciELO, KCI-Korean Journal Database, Derwent Innovations Index and Russian Citation Index. The search strategy yielded a total of 18 articles. A randomized meta-analysis model of the results for the CIE L*a*b* color variables stratified by age (less than 30 years, 30-60 years, 60 years and older) was performed with 9 of the 18 studies included in this systematic review. According to our results, sex and location of color measurement are the most influential factors in color estimation. All studies were carried out in healthy anterior teeth by spectrophotometry as the most commonly used method for color measurement, with CIE L*a*b* being the most commonly analyzed parameters. Studies based on age as a dependent variable showed R2 values between 0.28 and 0.56, being higher in ex vivo teeth. Studies based on age as an independent variable showed R2 values ranging from 0.10 to 0.48. The random model showed high heterogeneity for the L*, a* and b* parameters in all age groups, which is explained by discrepancies in age range and non-standardized conditions for color measurement. This systematic review highlights the need to protocolize age estimation studies that measure tooth color, in order to apply this method in different forensic settings.
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BACKGROUND: In the different published studies, there is no consensus on the efficacy of virtual reality as an adjuvant treatment of mood states. AIM: The aim of this study is to evaluate the impact of no immersive virtual reality with the Nintendo Switch device in rehabilitation treatment on mood, anxiety and depression in stroke patients admitted to neurorehabilitation units. METHODS: Fifty-eight patients admitted to neurorehabilitation units underwent a 1:3 multicentre randomised clinical trial. The intervention group consisted of 17 patients and the control group of 41 patients. The intervention group performed 6 virtual reality sessions together with the conventional treatment, and the control group performed only the conventional rehabilitation sessions. Primary and secondary clinical outcomes were measured before and six weeks after the intervention. RESULTS: Comparing the intervention group and control group, the anxiety levels of the intervention group decreased compared to the results observed in the control group (p = 0.01), as did the dependence of the intervention group (0.015). On the other hand, the results obtained after the intervention by the control group for anxiety (0.479) and depression (0.292) were not statistically significant. CONCLUSION: Rehabilitation VR used as an adjuvant treatment to conventional treatment has a beneficial impact on the neurological status and state of anxiety of stroke patients admitted to neurorehabilitation units. TRIAL REGISTRATION: Registered in the https://clinicaltrials.gov/ repository (NTC NCT05143385). Protocol registration date 7 October 2021, retrospectively registered.
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Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral , Jogos de Vídeo , Humanos , Reabilitação do Acidente Vascular Cerebral/métodos , Depressão/etiologia , Depressão/terapia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/terapia , Ansiedade/etiologia , Ansiedade/terapiaRESUMO
BACKGROUND: Post-stroke depression is the most common neuropsychiatric consequence and reduces rehabilitation effectiveness. However, the efficacy of virtual reality (VR) on mental health treatment for patients after a stroke is uncertain. AIMS: The aim of this study was to evaluate the efficacy of VR as a co-adjuvant form of treatment to reduce depression in stroke patients admitted to neurorehabilitation units. METHODS: We systematically searched medical databases including PubMed, CINAHL, PsycINFO, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov from inception to November 16, 2023. Clinical trials comparing the use of VR as an adjuvant form of treatment in stroke patients' rehabilitation with the usual treatment were included. Pooled standardized mean differences were calculated using a random-effects model. Subgroup analyses were performed according to type of stroke, VR characteristics, and the scale used to measure depression. Meta-regression analysis was performed for intervention duration and to determine the mean age of the participants. RESULTS: Eight studies and 388 stroke patients were included. The VR interventions were associated with a lower risk of depression in patients (ES = -0.69; 95% CI [-1.05, -0.33]; I2 = 57.6%; p ≤ .02). The estimates were not affected by the type of stroke, the type of VR used, the blinding process, the type of scale used to detect depression, the duration of the intervention (weeks and minutes), and the total number of sessions. Meta-regression shows that younger samples (p = .00; 95% CI [0.01, 0.08) and longer interventions (p = < .05; 95% CI [-0.00, -0.00) lead to a greater reduction in depression. LINKING EVIDENCE TO ACTION: This review provides an important basis for treating depression in patients after a stroke. Professionals working in stroke neurorehabilitation units should consider VR as a form of co-adjuvant treatment for depression in patients. SYSTEMATIC REVIEW REGISTRATION: CRD42022303968.
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Depressão , Ensaios Clínicos Controlados Aleatórios como Assunto , Acidente Vascular Cerebral , Humanos , Depressão/etiologia , Depressão/terapia , Depressão/psicologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/psicologia , Realidade Virtual , Reabilitação do Acidente Vascular Cerebral/métodos , Reabilitação do Acidente Vascular Cerebral/psicologia , Terapia de Exposição à Realidade Virtual/métodosRESUMO
The National Institute of Cardiology has previously used the CoaguChek® XS Plus system (Roche Diagnostics International Ltd), comparing capillary blood prothrombin time/international normalized ratio (PT/INR) results with those obtained using BCS-XP/Thromborel (Siemens). We assessed the reliability of PT/INR results using the third-generation CoaguChek Pro II system, the CoaguChek XS Plus system, and cobas® t 411 for citrated plasma analysis. Venous and capillary PT/INR were measured (N = 204). Spearman's correlation, Bland-Altman, and concordance analysis between methods were conducted. Spearman's correlation coefficients between venous/capillary INR were high for CoaguChek Pro II versus CoaguChek XS Plus (r = 0.994), CoaguChek Pro II versus cobas t 411 (r = 0.967), and CoaguChek XS Plus versus cobas t 411 (r = 0.968). Good concordance was observed among capillary methods (concordance coefficient [κ] = 0.888) and remaining relationships (P < .001 for all): cobas t 411 versus CoaguChek XS Plus (κ = 0.696) and cobas t 411 versus CoaguChek Pro II (κ = 0.684). In conclusion, good agreement was observed between CoaguChek Pro II, CoaguChek XS Plus, and cobas t 411.
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Anticoagulantes , Coagulação Sanguínea , Humanos , Coeficiente Internacional Normatizado/métodos , Anticoagulantes/farmacologia , Reprodutibilidade dos Testes , Sistemas Automatizados de Assistência Junto ao Leito , Tempo de Protrombina/métodos , Monitoramento de MedicamentosRESUMO
OBJECTIVE: We aim to determine a comprehensive set of requirements, perceptions, and expectations that people with spinal cord injury (SCI) and the clinicians in charge of their rehabilitation have regarding the use of wearable robots (WR) for gait rehabilitation. BACKGROUND: There are concerns due to the limited user acceptance of WR for gait rehabilitation. Developers need to emphasize understanding the needs and constraints of all stakeholders involved, including the real-life dynamics of rehabilitation centers. METHODS: 15 people with SCI, 9 without experience with WR and 6 with experience with these technologies, and 10 clinicians from 3 rehabilitation centers in Spain were interviewed. A directed content analysis approach was used. RESULTS: 78 codes grouped into 9 categories (physical results, usability, psychology-related codes, technical characteristics, activities, acquisition issues, context of use, development of the technologies and clinical rehabilitation context) were expressed by at least 20% of the users interviewed, of whom 16 were not found in the literature. The agreement percentage between each group and subgroup included in the study, calculated as the number of codes that more than 20% of both groups expressed, divided over the total amount of codes any of those two groups agreed on (≥ 20%), showed limited agreement between patients and clinicians (50.00%) and between both types of patients (55.77%). The limited accessibility and availability of lower limb exoskeletons for gait rehabilitation arose in most of the interviews. CONCLUSIONS: The limited agreement percentage between patients and clinicians indicates that including both types of users in the design process of these technologies is important, given that their requirements are complementary. Engaging users with prior technology experience is recommended, as they often exhibit strong internal consensus and articulate well-defined requirements. This study adds up the knowledge available in the literature and the new codes found in our data, which enlighten important aspects that ought to be addressed in the field to develop technologies that respond to users' needs, are usable and feasible to implement in their intended contexts. APPLICATION: The set of criteria summarized in our study will be useful to guide the design, development, and evaluation of WR for gait rehabilitation to meet user's needs and allow them to be implemented in their intended context of use.
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Exoesqueleto Energizado , Traumatismos da Medula Espinal , Dispositivos Eletrônicos Vestíveis , Humanos , Traumatismos da Medula Espinal/reabilitação , Marcha , Extremidade InferiorRESUMO
In 2020, Spain ranked fourth among European countries with the highest excess mortality due to COVID-19 disease. This study evaluates the impact of the COVID-19 pandemic on non-COVID patients in a tertiary hospital during the second pandemic wave in Spain (22 June 2020-6 December 2020). Data from Virgen del Rocío University Hospital in Seville during that timeframe were compared with the data from the same period in the preceding two years (2018-2019). Between-group comparisons were performed using the Chi-squared test, Student's t-test, or Mann-Whitney U tests, as appropriate. A total of 63,137 non-COVID patients were included in this study. During the second pandemic wave, a 19% decrease was observed in the annual number of non-COVID admissions overall (18,260 vs. 22,439, p < 0.001), but a 10% increase in the proportion of emergency admissions (60.6% vs. 54.93%, p < 0.001), a higher severity level of patients (1.79 vs. 1.72, p < 0.001), a longer in-hospital stay (7.02 vs. 6.74 days, p < 0.001), a 26% increase in non-COVID mortality (4.9% vs. 3.9%, p < 0.001), and a 50% increase in global mortality (5.9 vs. 3.9, p < 0.001) were also observed. In terms of both medical and surgical diagnoses, a significant reduction in the number of admissions and an increase in in-hospital mortality were observed. These results demonstrate the significant impact of the pandemic on hospital care, similar to what was previously observed during the initial wave in the same hospital. Our findings emphasize the need to include non-COVID patients when assessing the broad impact of the pandemic on healthcare, beyond its direct effects on COVID-19 patients.
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La atención es definida como un constructo multidimensional, encargado de regular sobre qué estímulos se dirigirán los recursos perceptivos, filtrando información irrelevante con el fin de favorecer la retención de información durante un período antes de actuar sobre ella. La evaluación computarizada de la atención ha ido cobrando relevancia tanto en la investigación como en las prácticas del quehacer profesional. Los objetivos de este estudio fueron: 1) analizar la consistencia interna y la validez concurrente del Test de Atención Infantil 6.0 (tai), versión computarizada; y 2) obtener los valores de referencia preliminares para cada subtest del tai. Los estudios de confiabilidad y validez del tai corresponden a una muestra de 122 escolares de Mendoza (Argentina). Al analizar la consistencia interna se obtuvieron valores satisfactorios para cada uno de los subtests (Test 1, kr 20 = 0.78; Test 2, kr 20 =0.74; Test 3, kr20 = 0.73). Se obtuvieron valores satisfactorios al explorar la estabilidad del instrumento. Al analizar la validez concurrente, los resultados indicaron correlaciones positivas moderadas y significativas (p <0.01) entre el test Caras-R y los subtests 1 y 2 del tai, utiliza-do para evaluar desempeño atencional. Se observaron asociaciones positivas significativas (p <0.01) entre el subtest 3 del tai y el Test de Bloques de Corsi, usado para evaluar memoria de trabajo visoespacial. Estos resultados señalan que el tai, instrumento desarrolla-do para evaluar la atención y memoria de trabajo visuoespacial en escolares, presenta indicadores adecuados de validez y confiabilidad. Se discuten los hallazgos, limitaciones y futuras líneas de investigación.
Attention has been defined as a multidimensional construct, dealing with regulation of which stimuli the perceptual resources are directed to, filtering irrelevant information out to favor the retention of relevant information for a period of time, before acting on it. The computerized evaluation of attention has been gaining relevance both in research and in professional practice. The objectives are: 1) to analyze internal consistency and concurrent validity of the Child Attention Test 6.0 (tai), computerized version 6.0; and, 2) to obtain the preliminary reference values for each of the tai subtests done. The data for the validity and reliability studies of the tai corresponds to a sample of 122 schoolchildren in Mendoza (Argentina). When analyzing the internal consistency, satisfactory values were obtained for each subtest (Test 1, kr 20 = 0.78; Test 2, kr 20 = 0.74; and Test 3, kr 20 = 0.73). Satisfactory values were obtained when exploring the stability of the instrument. For concurrent validity, the results indicate significant moderate positive correlations (p <0.01) between the scores obtained in the Caras-R test and subtests 1 and 2 of the tai, used to evaluate attentional performance. Significant positive associa-tions (p <0.01) were observed between tai subtest 3 and the Corsi Block Test, used to assess visuospatial working memory. These results indicate that the tai, an instrument developed in order to evaluate attention and visuospatial working memory of school children, presents adequate indicators of validity and reliability. The findings, limitations, and future lines of research are discussed
A atenção é definida como um construto multidimensio-nal, responsável por regular quais estímulos os recursos perceptivos irão direcionar, filtrando informações irrelevantes de forma a favorecer a retenção da informação por um período de tempo, antes de agir sobre ela. A avaliação informatizada da atenção vem ganhando relevância tanto na pesquisa quanto na prática profissional. Os objetivos deste estudo foram: 1) analisar a consistência interna e a validade concorrente do Teste de Atenção Infantil 6.0 (tai), versão computadorizada, e 2) obter valores de referência preliminares para cada subteste do tai. Os estudos de confiabilidade e validade do tai correspondem a uma amostra de 122 estudantes de Mendoza (Argentina). Na análise da consistência interna foram obtidos valores satisfatórios para cada um dos subtestes (Teste 1, kr 20 = 0.78; Teste 2, kr20 = 0.74; Teste 3, kr 20 = 0.73). Valores satisfatórios foram obtidos ao explorar a estabilidade do instrumento. Ao analisar a validade concorrente, os resultados indicaram correlações positivas moderadas e significativas (p <0.01) entre o teste Caras-r e os subtestes 1 e 2 do tai, utilizados para avaliar o desempenho atencional. Foram observadas associações positivas significativas (p <0.01) entre o subteste 3 do tai e o Teste em Blocos de Corsi, utilizado para avaliar a memória de trabalho visuoespacial. Esses resultados indicam que o tai, instrumento desenvolvido para avaliar a atenção 3Test de Atención Infantil: análisis de las características psicométricas y valores de referencia preliminaresAvances en Psicología Latinoamericana / Bogotá (Colombia) / Vol. 41(3) / pp. 1-20 / 2023 / ISSNe2145-4515e a memória operacional visuoespacial em estudantes, apresenta indicadores adequados de validade e confiabilidade. As descobertas, limitações e futuras linhas de pesquisa são discutidas.
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Humanos , Criança , Comportamento Infantil , Desenvolvimento InfantilRESUMO
Epigenetic modifications of DNA, and especially cytosine, play a crucial role in regulating basic cellular processes and thereby the overall cellular metabolism. Their levels change during organismic and cellular development, but especially also in pathogenic aberrations such as cancer. Levels of respective modifications are often addressed in bulk by specialized mass spectrometry techniques or by employing dedicated ChIP-seq protocols, with the latter giving information about the sequence context of the modification. However, to address modification levels on a single cell basis, high- or low-content microscopy techniques remain the preferred methodology. The protocol presented here describes a straightforward method to detect and quantify different DNA modifications in human cell lines, which can also be adapted to other cultured mammalian cell types. To this end, cells are immunostained against two different cytosine modifications in combination with DNA counterstaining. Image acquisition takes place on a confocal microscopy system. A semi-automated analysis pipeline helps to gather data in a fast and reliable fashion. The protocol is comparatively simple, fast, and cost effective. By employing methodologies that are often well established in most molecular biology laboratories, many researchers are able to apply the described protocol straight away in-house.
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Type 1 diabetes (T1D) is a complex autoimmune disease that develops in genetically susceptible individuals. Most T1D-associated single nucleotide polymorphisms (SNPs) are located in non-coding regions of the human genome. Interestingly, SNPs in long non-coding RNAs (lncRNAs) may result in the disruption of their secondary structure, affecting their function, and in turn, the expression of potentially pathogenic pathways. In the present work, the function of a virus-induced T1D-associated lncRNA named ARGI (Antiviral Response Gene Inducer) is characterized. Upon a viral insult, ARGI is upregulated in the nuclei of pancreatic ß cells and binds to CTCF to interact with the promoter and enhancer regions of IFNß and interferon-stimulated genes, promoting their transcriptional activation in an allele-specific manner. The presence of the T1D risk allele in ARGI induces a change in its secondary structure. Interestingly, the T1D risk genotype induces hyperactivation of type I IFN response in pancreatic ß cells, an expression signature that is present in the pancreas of T1D patients. These data shed light on the molecular mechanisms by which T1D-related SNPs in lncRNAs influence pathogenesis at the pancreatic ß cell level and opens the door for the development of therapeutic strategies based on lncRNA modulation to delay or avoid pancreatic ß cell inflammation in T1D.
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Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Ativação Transcricional/genética , Inflamação/metabolismoRESUMO
AIMS/HYPOTHESIS: Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene. It is characterised by insulin-dependent diabetes mellitus, optic nerve atrophy, diabetes insipidus, hearing loss and neurodegeneration. Considering the unmet treatment need for this orphan disease, this study aimed to evaluate the therapeutic potential of glucagon-like peptide 1 receptor (GLP-1R) agonists under wolframin (WFS1) deficiency with a particular focus on human beta cells and neurons. METHODS: The effect of the GLP-1R agonists dulaglutide and exenatide was examined in Wfs1 knockout mice and in an array of human preclinical models of Wolfram syndrome, including WFS1-deficient human beta cells, human induced pluripotent stem cell (iPSC)-derived beta-like cells and neurons from control individuals and individuals affected by Wolfram syndrome, and humanised mice. RESULTS: Our study shows that the long-lasting GLP-1R agonist dulaglutide reverses impaired glucose tolerance in WFS1-deficient mice, and that exenatide and dulaglutide improve beta cell function and prevent apoptosis in different human WFS1-deficient models including iPSC-derived beta cells from people with Wolfram syndrome. Exenatide improved mitochondrial function, reduced oxidative stress and prevented apoptosis in Wolfram syndrome iPSC-derived neural precursors and cerebellar neurons. CONCLUSIONS/INTERPRETATION: Our study provides novel evidence for the beneficial effect of GLP-1R agonists on WFS1-deficient human pancreatic beta cells and neurons, suggesting that these drugs may be considered as a treatment for individuals with Wolfram syndrome.
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Células-Tronco Pluripotentes Induzidas , Células Secretoras de Insulina , Atrofia Óptica , Síndrome de Wolfram , Humanos , Animais , Camundongos , Síndrome de Wolfram/tratamento farmacológico , Síndrome de Wolfram/genética , Exenatida/uso terapêutico , Atrofia Óptica/patologia , Células Secretoras de Insulina/patologia , Camundongos KnockoutRESUMO
Introducción. En las unidades de cuidados intensivos pediátricos, se utiliza gran cantidad de medicamentos, muchos prescritos fuera de las condiciones establecidas en su ficha técnica (prescripciones off-label y unlicensed). El objetivo de este estudio fue describir el uso de medicamentos y estimar la prevalencia de fármacos off-label y unlicensed en una unidad de cuidados intensivos pediátricos de un hospital de tercer nivel español. Población y métodos. Estudio transversal, observacional, de una cohorte de niños ingresados en una unidad de cuidados intensivos pediátricos. El estudio se llevó a cabo en 2017. Se revisó cada fármaco prescrito, sus condiciones de uso y administración. Además, se analizaron las fichas técnicas de los fármacos implicados con la finalidad de identificar si el uso de los medicamentos se realizaba según sus condiciones de autorización, o bien se hacía fuera de prospecto (off-label) o como unlicensed. Resultados. La muestra fue de 97 pacientes. El 74,2 % (n = 72) de los pacientes recibieron algún fármaco off-label o unlicensed. El 23,8 % (n = 243) de las prescripciones fueron off-label y el 8,7 % (n = 89), unlicensed. El subanálisis realizado por grupos de edad mostró que el grupo de edad que recibió mayor número de prescripciones totales (n = 611) y el mayor porcentaje de fármacos prescritos en condiciones off-label y/o unlicensed (38,4 %) fue el de menores de 2 años. Conclusiones. La prescripción de fármacos off-label y/o unlicensed es una práctica habitual en la unidad de cuidados intensivos pediátricos. Este estudio permite documentar la complejidad de la terapéutica en niños.
Introduction. In pediatric intensive care units, a large number of drugs are used, many of which are prescribed for condition beyond those established in their summary of product characteristics (off-label and unlicensed drug prescriptions). The objective of this study was to describe drug use and estimate the prevalence of off-label and unlicensed drugs in a pediatric intensive care unit of a tertiary care Spanish hospital. Population and methods. Cross-sectional, observational study with a single cohort of children admitted to a pediatric intensive care unit. The study was conducted in 2017. Each drug prescription, its conditions of use and administration were reviewed. In addition, the summary of product characteristics of drugs used were analyzed in order to identify whether they were used according to their conditions of authorization, or whether they were used in an off-label or unlicensed manner. Results. The sample included 97 patients. At least one off-label or unlicensed drug was administered to 74.2% (n = 72) of patients; 23.8% (n = 243) corresponded to off-label prescriptions and 8.7% (n = 89), unlicensed prescriptions. A sub-analysis by age group showed that the age group that received a higher number of total prescriptions (n = 611) and a higher percentage of off-label and/or unlicensed drug prescriptions (38.4%) was under 2 years of age. Conclusions. Off-label and/or unlicensed drug prescription is a common practice in the pediatric intensive care unit. This study allowed us to document the complexity of therapeutics in children.
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Humanos , Lactente , Pré-Escolar , Criança , Adolescente , Unidades de Terapia Intensiva Pediátrica , Uso Off-Label , Atenção Terciária à Saúde , Preparações Farmacêuticas , Estudos Transversais , Estudos Prospectivos , HospitaisRESUMO
We aimed to determine the genetic diversity and molecular characteristics of the Huntington disease (HD) gene (HTT) in Spain. We performed an extended haplotype and exon one deep sequencing analysis of the HTT gene in a nationwide cohort of population-based controls (n = 520) and families with symptomatic individuals referred for HD genetic testing. This group included 331 HD cases and 140 carriers of intermediate alleles. Clinical and family history data were obtained when available. Spanish normal alleles are enriched in C haplotypes (40.1%), whereas A1 (39.8%) and A2 (31.6%) prevail among intermediate and expanded alleles, respectively. Alleles ≥ 50 CAG repeats are primarily associated with haplotypes A2 (38.9%) and C (32%), which are also present in 50% and 21.4%, respectively, of HD families with large intergenerational expansions. Non-canonical variants of exon one sequence are less frequent, but much more diverse, in alleles of ≥27 CAG repeats. The deletion of CAACAG, one of the six rare variants not observed among smaller normal alleles, is associated with haplotype C and appears to correlate with larger intergenerational expansions and early onset of symptoms. Spanish HD haplotypes are characterized by a high genetic diversity, potentially admixed with other non-Caucasian populations, with a higher representation of A2 and C haplotypes than most European populations. Differences in haplotype distributions across the CAG length range support differential germline expansion dynamics, with A2 and C showing the largest intergenerational expansions. This haplotype-dependent germline instability may be driven by specific cis-elements, such as the CAACAG deletion.
Assuntos
Doença de Huntington , Humanos , Alelos , Haplótipos/genética , Doença de Huntington/genética , Éxons , Células Germinativas , Proteína Huntingtina/genéticaRESUMO
Introduction. In pediatric intensive care units, a large number of drugs are used, many of which are prescribed for condition beyond those established in their summary of product characteristics (off-label and unlicensed drug prescriptions). The objective of this study was to describe drug use and estimate the prevalence of off-label and unlicensed drugs in a pediatric intensive care unit of a tertiary care Spanish hospital. Population and methods. Cross-sectional, observational study with a single cohort of children admitted to a pediatric intensive care unit. The study was conducted in 2017. Each drug prescription, its conditions of use and administration were reviewed. In addition, the summary of product characteristics of drugs used were analyzed in order to identify whether they were used according to their conditions of authorization, or whether they were used in an off-label or unlicensed manner. Results. The sample included 97 patients. At least one off-label or unlicensed drug was administered to 74.2% (n = 72) of patients; 23.8% (n = 243) corresponded to off-label prescriptions and 8.7% (n = 89), unlicensed prescriptions. A sub-analysis by age group showed that the age group that received a higher number of total prescriptions (n = 611) and a higher percentage of off-label and/or unlicensed drug prescriptions (38.4%) was under 2 years of age. Conclusions. Off-label and/or unlicensed drug prescription is a common practice in the pediatric intensive care unit. This study allowed us to document the complexity of therapeutics in children.
Introducción. En las unidades de cuidados intensivos pediátricos, se utiliza gran cantidad de medicamentos, muchos prescritos fuera de las condiciones establecidas en su ficha técnica (prescripciones off-label y unlicensed). El objetivo de este estudio fue describir el uso de medicamentos y estimar la prevalencia de fármacos off-label y unlicensed en una unidad de cuidados intensivos pediátricos de un hospital de tercer nivel español. Población y métodos. Estudio transversal, observacional, de una cohorte de niños ingresados en una unidad de cuidados intensivos pediátricos. El estudio se llevó a cabo en 2017. Se revisó cada fármaco prescrito, sus condiciones de uso y administración. Además, se analizaron las fichas técnicas de los fármacos implicados con la finalidad de identificar si el uso de los medicamentos se realizaba según sus condiciones de autorización, o bien se hacía fuera de prospecto (off-label) o como unlicensed. Resultados. La muestra fue de 97 pacientes. El 74,2 % (n = 72) de los pacientes recibieron algún fármaco off-label o unlicensed. El 23,8 % (n = 243) de las prescripciones fueron off-label y el 8,7 % (n = 89), unlicensed. El subanálisis realizado por grupos de edad mostró que el grupo de edad que recibió mayor número de prescripciones totales (n = 611) y el mayor porcentaje de fármacos prescritos en condiciones off-label y/o unlicensed (38,4 %) fue el de menores de 2 años. Conclusiones. La prescripción de fármacos off-label y/o unlicensed es una práctica habitual en la unidad de cuidados intensivos pediátricos. Este estudio permite documentar la complejidad de la terapéutica en niños.
Assuntos
Unidades de Terapia Intensiva Pediátrica , Uso Off-Label , Criança , Humanos , Lactente , Pré-Escolar , Estudos Transversais , Atenção Terciária à Saúde , Estudos Prospectivos , Preparações Farmacêuticas , HospitaisRESUMO
Resumen ANTECEDENTES: Las anomalías en la inserción placentaria son cada vez más frecuentes en nuestro medio. En la atención de la paciente embarazada es importante la prevención de la pérdida hemática con balones de contrapulsación intraaórticos, como una opción útil. CASO CLÍNICO: Paciente de 38 años, embarazada, con antecedente de parto eutócico y sin enfermedades de interés, ni intervenciones quirúrgicas previas. El seguimiento prenatal se inició a las 17 semanas, con retraso diagnóstico debido a que continuaba en tratamiento anticonceptivo. La invasión trofoblástica estaba limitada al miometrio, sin evidencia de invasión a los órganos vecinos. Se le expusieron a la paciente las posibles complicaciones a fin de minimizar los riesgos de hemorragia masiva, potencialmente mortal en el momento del parto. Puesto que la paciente expresó no desear volver a embarazarse, se le recomendó la histerectomía poscesárea, dejando la placenta in situ. CONCLUSIONES: La oclusión endovascular con balón de contrapulsación intraaórtico es una opción segura y eficaz para minimizar la pérdida de sangre en casos de anomalías en la inserción placentaria. Además del clásico acceso por vía femoral es posible colocarlo por vía axilar, con igual efectividad. La baja tasa de complicaciones maternas y la seguridad, en términos de irradiación fetal, la convierten en una opción razonable en la atención de pacientes embarazadas en quienes se espera una alta pérdida sanguínea.
Abstract BACKGROUND: Anomalies of placental insertion are becoming increasingly common. Prevention of blood loss with intra-aortic counterpulsation balloons is a useful option in the care of pregnant patients. CLINICAL CASE: 38-year-old pregnant woman with a history of euthyroid delivery and no medical or surgical history. Prenatal follow-up was initiated at 17 weeks, with a delay in diagnosis due to the fact that she was still on contraceptive treatment. Trophoblastic invasion was limited to the myometrium with no evidence of invasion into adjacent organs. The patient was counseled on the potential complications to minimize the risk of massive, potentially fatal hemorrhage at delivery. As the patient did not wish to become pregnant again, a post-cesarean hysterectomy was recommended, leaving the placenta in situ. CONCLUSIONS: Endovascular occlusion with intra-aortic balloon counterpulsation is a safe and effective option to minimize blood loss in cases of placental insertion anomalies. In addition to the classical femoral approach, the axillary route can be used with equal efficacy. The low rate of maternal complications and the safety with respect to fetal irradiation make it a reasonable option in the management of pregnant patients in whom high blood loss is expected.