We aim to describe a cohort of patients with KCNQ2-related epilepsy and evaluate the relationship between epileptic activity and developmental outcome. This topic is relevant for the selection of ...clinical end points in future clinical trials, since cessation of seizures may or may not be the most important outcome.
This retrospective cohort study of children with self-limited (familial) neonatal epilepsy and developmental and epileptic encephalopathy due to pathogenic variants in KCNQ2 was conducted between 2019 and 2021. We collected clinical, therapeutic, and genetic information. Available electroencephalographic recordings were reviewed by a neurophysiologist. Gross motor function was determined using the Gross Motor Function Classification System (GMFCS). The Vineland Adaptive Behavior Composite standard score (ABC SS) was used to measure adaptive functioning.
Among 44 children (mean age 8.1 ± 4.0 years, 45.5% were male), 15 of 44 had S(F)NE, and 29 of 44 had DEE. Delayed seizure freedom was more frequent in DEE than in S(F)NE (P = 0.025), but no correlation was observed between age at seizure freedom and developmental outcome in patients with DEE. Multifocal interictal epileptiform abnormalities at epilepsy onset were more frequent in DEE than in S(F)NE (P = 0.014), and were associated with higher GMFCS (P = 0.027) and lower ABC SS (P = 0.048) in patients with DEE. Disorganized background activity at follow-up was more frequent in DEE than in S(F)NE (P = 0.001), and was associated with higher GMFCS levels (P = 0.009) and lower ABC SS (P = 0.005) in patients with DEE.
This study shows a partial correlation between epileptic activity and developmental outcome in KCNQ2-related epilepsy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Glaucoma is one of the leading causes of irreversible blindness and can result from abnormalities in anterior segment structures required for aqueous humor outflow, including the trabecular meshwork ...(TM) and Schlemm's canal (SC). Transcription factors such as AP‐2β play critical roles in anterior segment development. Here, we show that the Mgp‐Cre knock‐in (Mgp‐Cre.KI) mouse can be used to target the embryonic periocular mesenchyme giving rise to the TM and SC. Fate mapping of male and female mice indicates that AP‐2β loss causes a decrease in iridocorneal angle cells derived from Mgp‐Cre.KI‐expressing populations compared to controls. Moreover, histological analyses revealed peripheral iridocorneal adhesions in AP‐2β mutants that were accompanied by a decrease in expression of TM and SC markers, as observed using immunohistochemistry. In addition, rebound tonometry showed significantly higher intraocular pressure (IOP) that was correlated with a progressive significant loss of retinal ganglion cells, reduced retinal thickness, and reduced retinal function, as measured using an electroretinogram, in AP‐2β mutants compared with controls, reflecting pathology described in late‐stage glaucoma patients. Importantly, elevated IOP in AP‐2β mutants was significantly reduced by treatment with latanoprost, a prostaglandin analog that increases unconventional outflow. These findings demonstrate that AP‐2β is critical for TM and SC development, and that these mutant mice can serve as a model for understanding and treating progressive human primary angle‐closure glaucoma.
Conditional deletion of transcription factor activating protein 2‐beta (AP‐2β) from the developing trabecular meshwork region (AP‐2β trabecular meshwork region knockouts/AP‐2β TMR KOs) results in a reduction in expression of trabecular meshwork markers, such as αSMA (panels a,b), accompanied by an increased intraocular pressure (IOP) (panel c). Increased IOP is correlated with a reduction in the number of Brn3a‐positive cells (panels d,e), in addition to reduced retinal function (panels f,g), making the AP‐2β TMR KO a model of human primary angle‐closure glaucoma that can be used to test IOP‐lowering drugs and neuroprotective strategies.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Highlights•ESTRO-HERO tool, applied to Europalia, generates economic evidence for radiotherapy. •Detailed cost estimates capture RT treatments diversity, techniques and complexity. •First TD-ABC ...model aims to support RT national-wide policy, e.g. reimbursement. •Also, estimation of actual resources utilization informs national resource planning. •The tool can be applied to countries to generate real-world RT data.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Safety and toxic effects of nanoparticles are still largely unexplored due to the multiple aspects that influence their behaviour toward biological systems. Here, we focus the attention on 12 nm ...spherical gold nanoparticle coated or not with hyaluronic acid compared to its precursor counterpart salt. Results ranging from the effects of a 10-days exposure in an in vitro model with BALB/c 3T3 fibroblast cells show how 12 nm spherical gold nanoparticles are internalized from 3T3 cells by endo-lysosomal pathway by an indirect measurement technique; and how gold nanoparticles, though not being a severe cytotoxicant, induce DNA damage probably through an indirect mechanism due to oxidative stress. While coating them with hyaluronic acid reduces gold nanoparticles cytotoxicity and slows their cell internalization. These results will be of great interest to medicine, since they indicate that gold nanoparticles (with or without coating) are suitable for therapeutic applications due to their tunable cell uptake and low toxicity.
Tumor suppressor p53 regulates the expression of p53-induced genes (PIG) that trigger apoptosis. PIG3 or TP53I3 is the only known member of the medium chain dehydrogenase/reductase superfamily ...induced by p53 and is used as a proapoptotic marker. Although the participation of PIG3 in the apoptotic pathway is proven, the protein and its mechanism of action were never characterized. We analyzed human PIG3 enzymatic function and found NADPH-dependent reductase activity with ortho-quinones, which is consistent with the classification of PIG3 in the quinone oxidoreductase family. However, the activity is much lower than that of ζ-crystallin, a better known quinone oxidoreductase. In addition, we report the crystallographic structure of PIG3, which allowed the identification of substrate- and cofactor-binding sites, with residues fully conserved from bacteria to human. Tyr-59 in ζ-crystallin (Tyr-51 in PIG3) was suggested to participate in the catalysis of quinone reduction. However, kinetics of Tyr/Phe and Tyr/Ala mutants of both enzymes demonstrated that the active site Tyr is not catalytic but may participate in substrate binding, consistent with a mechanism based on propinquity effects. It has been proposed that PIG3 contribution to apoptosis would be through oxidative stress generation. We found that in vitro activity and in vivo overexpression of PIG3 accumulate reactive oxygen species. Accordingly, an inactive PIG3 mutant (S151V) did not produce reactive oxygen species in cells, indicating that enzymatically active protein is necessary for this function. This supports that PIG3 action is through oxidative stress produced by its enzymatic activity and provides essential knowledge for eventual control of apoptosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Aims
To evaluate specific process components of the Urban Health Centres Europe (UHCE) approach; a coordinated preventive care approach aimed at healthy ageing by decreasing falls, polypharmacy, ...loneliness and frailty among older persons in community settings of five cities in the United Kingdom, Greece, Croatia, the Netherlands and Spain.
Design
Mixed methods evaluation of specific process components of the UHCE approach: reach of the target population, dose of the intervention actually delivered and received by participants and satisfaction and experience of main stakeholders involved in the approach.
Methods
The UHCE approach intervention consisted of a preventive assessment, shared decision‐making on a care plan and enrolment in one or more of four coordinated care‐pathways that targeted falls, polypharmacy, loneliness and frailty. Quantitative data from a questionnaire and quantitative/qualitative data from logbooks were collected among older persons involved in the approach. Qualitative data from focus groups were collected among older persons, informal caregivers and professionals involved in the approach. Quantitative data were analysed by means of descriptive statistics and multilevel logistic regression models. Qualitative data were analysed through thematic analysis.
Results
Having limited function was associated with non‐enrolment in falls and loneliness care‐pathways (both p < .01). The mean rating of the approach was 8.3/10 (SD 1.9). Feeling supported by a care professional and meeting people were main benefits for older persons. Mistrust towards unfamiliar care providers, lack of confidence to engage in care activities and health constraints were main barriers towards engagement in care.
Conclusions
Although the UHCE approach was received generally positively, health constraints and psychosocial barriers prevented older person's engagement in care.
Impact
Coordinated preventive care approaches for older community‐dwelling persons should address health constraints and psychosocial barriers that hinder older person's engagement in care. Trial registration: ISRCTN registry number is ISRCTN52788952. Date of registration is 13/03/2017.
目的
评估欧洲城市保健中心(UHCE)方法具体流程组成部分;采取致力于通过减少英国、希腊、克罗地亚、荷兰和西班牙五个城市的社区中老人跌倒、多重用药、孤独和脆弱的协调预防护理方法。
设计
对欧洲城市保健中心(UHCE)方法具体流程部分的评估:目标人群范围、实际提供和受试者接收到的干预剂量以及参与方法的主要利益相关者的满意度和体验。
方法
欧洲城市保健中心(UHCE)方法干预包括预防评估、共享护理计划决策以及以减少跌倒、多重用药、孤独和脆弱为目标的四种协调护理方式之一或其中多个。问卷调查中的定量数据以及日志中的定量或定性数据是从参与该方法的老年人中收集而来。焦点小组的定性数据是从参与该方法的老年人、非正式护理人员以及健康专家中收集而来。采用描述性统计和多层逻辑回归模型对定量数据进行分析。采用专题分析对定性数据进行分析。
结果
功能受限与跌倒和孤独感护理方法并未注册相关(两者均p<.01)。该方法的平均评分为8.3/10(标准差(SD)为1.9)。老年人主要受益在于得到专业人员的护理以及与人见面。不信任不熟悉的护理人员以及缺乏参与护理活动的信心和健康约束是参与护理的主要障碍。
结论
虽然欧洲城市保健中心(UHCE)方法普遍被积极接受,健康约束和心理障碍阻碍了老年人参与护理。
影响
针对社区老年人的协调预防护理方法应解决阻碍老年人参与护理的健康约束和心理障碍。
试验注册
ISRCTN注册号是ISRCTN52788952。注册日期为2017年3月13日。
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Determinants of chronic obstructive pulmonary disease (COPD) in the early stages of its natural history are not well known. Improving our knowledge of these factors will help to ...design interventions that can modify prognosis.
Study objectives are: (a) to characterize a COPD population of young adults aged 35–50 years from a multidimensional point of view; (b) to compare these patients with smokers with normal lung function; and (c) to create a cohort of young adults aged 35–50 years (smokers or former smokers), with and without COPD, who will be followed in the future to improve understanding of the natural history of the disease.
This is a case–control multicenter study aimed at establishing a well-characterized cohort of young adults, smokers or former-smokers, with and without COPD, for subsequent follow-up.
A total of 311 participants (101 cases and 210 controls) were selected from approximately 30 primary care settings and 12 hospitals in 8 Spanish regions. Subjects were smokers or former smokers (>10 pack-years) aged 35–50 years. Diagnosis of COPD was based on a post-bronchodilator result of FEV1/FVC<70%.
The main study variables were: questionnaires on health, symptoms, exacerbations and daily physical activity, lung function tests, blood and sputum samples, and low-dose computed tomography. In the statistical analysis, COPD patient characteristics will be described and compared with control subjects using a logistic regression analysis.
Los determinantes en fases iniciales de la historia natural de la enfermedad pulmonar obstructiva crónica (EPOC) son poco conocidos. Entenderlos mejor es de capital importancia para poder diseñar intervenciones dirigidas a modificar su pronóstico. Los principales objetivos del estudio son: a) caracterizar a una población de adultos jóvenes con EPOC de forma multidimensional; b) comparar estos pacientes con sujetos fumadores con función pulmonar normal; y c) establecer una cohorte de adultos jóvenes con y sin EPOC, que pueda ser seguida a largo plazo para conocer mejor la historia natural de la enfermedad.
EARLY COPD es un estudio multicéntrico de casos y controles que permitirá establecer una cohorte de sujetos para su seguimiento posterior. Se seleccionaron 311 (101 casos y 210 controles) participantes reclutados en una treintena de centros de atención primaria y 12 hospitales de 8 comunidades autónomas españolas. Los participantes eran fumadores o exfumadores (>10 paquetes año) de entre 35–50 años de edad. Los casos presentaban una espirometría obstructiva con un FEV1/FVC<70% y los controles una espirometría normal con un FEV1/FVC≥70%. Las principales variables de estudio que se han determinado son las siguientes: cuestionarios de salud, síntomas, exacerbaciones y actividad física, pruebas de función respiratoria, análisis biológicos de sangre y esputo y TAC de baja radiación. Para el análisis estadístico de los resultados se describirán las características de los pacientes con EPOC y se compararán con los sujetos del grupo control mediante un modelo de regresión logística.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pain in cancer patients is recognized as a major health problem, yet few studies of both inpatient and outpatient populations have been carried out.
The study objective was to assess the frequency, ...type, and characteristics of pain in adult cancer patients, including both inpatients and outpatients.
This cross-sectional study involved 1064 adult cancer patients (437 outpatients and 627 inpatients) from 44 hospitals and/or long-term-care centers in Catalonia, Spain. Cancer patients suffering from pain of any etiology for ≥2 weeks and/or under analgesic treatment ≥2 weeks were enrolled. Demographic and pain data were collected. The Spanish version of the Brief Pain Inventory was used to assess pain.
Pain frequency was 55.3%. Pain was less frequent in outpatients than inpatients (41.6% versus 64.7%; p<0.001), although median pain duration was longer in outpatients (20 versus 6 weeks; p<0.001). Pain was assessable in 333 patients, and intensity was similar in both out- and inpatients; however, outpatients reported less improvement, less pain interference with daily life, and less pain related to the cancer per se. In both groups, patients with multiple myeloma (73%), breast (65%), and lung cancer (61%) were most likely to report pain.
Pain in cancer patients, both ambulatory and hospitalized, remains a challenge for health care professionals, health administrators, and stakeholders. Our study reveals the high level of pain and distress that cancer patients continue to suffer, a problem that is particularly notable in outpatients due to the intensity and duration of the pain.
Background: Anti-COVID-19 hyperimmune immunoglobulin (hIG) can provide standardized and controlled antibody content. Data from controlled clinical trials using hIG for the prevention or treatment of ...COVID-19 outpatients have not been reported. We assessed the safety and efficacy of subcutaneous anti-COVID-19 hyperimmune immunoglobulin 20% (C19-IG20%) compared to placebo in preventing development of symptomatic COVID-19 in asymptomatic individuals with SARS-CoV-2 infection. Methods: We did a multicentre, randomized, double-blind, placebo-controlled trial, in asymptomatic unvaccinated adults (≥18 years of age) with confirmed SARS-CoV-2 infection within 5 days between April 28 and December 27, 2021. Participants were randomly assigned (1:1:1) to receive a blinded subcutaneous infusion of 10 mL with 1 g or 2 g of C19-IG20%, or an equivalent volume of saline as placebo. The primary endpoint was the proportion of participants who remained asymptomatic through day 14 after infusion. Secondary endpoints included the proportion of individuals who required oxygen supplementation, any medically attended visit, hospitalisation, or ICU, and viral load reduction and viral clearance in nasopharyngeal swabs. Safety was assessed as the proportion of patients with adverse events. The trial was terminated early due to a lack of potential benefit in the target population in a planned interim analysis conducted in December 2021. ClinicalTrials.gov registry: NCT04847141. Findings: 461 individuals (mean age 39.6 years SD 12.8) were randomized and received the intervention within a mean of 3.1 (SD 1.27) days from a positive SARS-CoV-2 test. In the prespecified modified intention-to-treat analysis that included only participants who received a subcutaneous infusion, the primary outcome occurred in 59.9% (91/152) of participants receiving 1 g C19-IG20%, 64.7% (99/153) receiving 2 g, and 63.5% (99/156) receiving placebo (difference in proportions 1 g C19-IG20% vs. placebo, −3.6%; 95% CI -14.6% to 7.3%, p = 0.53; 2 g C19-IG20% vs placebo, 1.1%; −9.6% to 11.9%, p = 0.85). None of the secondary clinical efficacy endpoints or virological endpoints were significantly different between study groups. Adverse event rate was similar between groups, and no severe or life-threatening adverse events related to investigational product infusion were reported. Interpretation: Our findings suggested that administration of subcutaneous human hyperimmune immunoglobulin C19-IG20% to asymptomatic individuals with SARS-CoV-2 infection was safe but did not prevent development of symptomatic COVID-19. Funding: Grifols.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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