CYP26B1-related disorder: expanding the ends of the spectrum through clinical and molecular evidence.

CYP26B1 metabolizes retinoic acid in the developing embryo to regulate its levels. A limited number of individuals with pathogenic variants in CYP26B1 have been documented with a varied phenotypic spectrum, spanning from a severe manifestation involving skull anomalies, craniosynostosis, encephalocele, radio-humeral fusion, oligodactyly, and a narrow thorax, to a milder presentation characterized by craniosynostosis, restricted radio-humeral joint mobility, hearing loss, and intellectual disability. Here, we report two families with CYP26B1-related phenotypes and describe the data obtained from functional studies of the variants. Exome and Sanger sequencing were used for variant identification in family 1 and family 2, respectively. Family 1 reflects a mild phenotype, which includes craniofacial dysmorphism with brachycephaly (without craniosynostosis), arachnodactyly, reduced radioulnar joint movement, conductive hearing loss, learning disability-and compound heterozygous CYP26B1 variants: (p.[(Pro118Leu)];[(Arg234Gln)]) were found. In family 2, a stillborn fetus presented a lethal phenotype with spina bifida occulta, hydrocephalus, poor skeletal mineralization, synostosis, limb defects, and a synonymous homozygous variant in CYP26B1: c.1083C > A. A minigene assay revealed that the synonymous variant created a new splice site, removing part of exon 5 (p.Val361_Asp382del). Enzymatic activity was assessed using a luciferase assay, demonstrating a notable reduction in exogenous retinoic acid metabolism for the variant p.Val361_Asp382del. (~ 3.5 × decrease compared to wild-type); comparatively, the variants p.(Pro118Leu) and p.(Arg234Gln) demonstrated a partial loss of metabolism (1.7× and 2.3× reduction, respectively). A proximity-dependent biotin identification assay reaffirmed previously reported ER-resident protein interactions. Additional work into these interactions is critical to determine if CYP26B1 is involved with other biological events on the ER. Immunofluorescence assay suggests that mutant CYP26B1 is still localized in the endoplasmic reticulum. These results indicate that novel pathogenic variants in CYP26B1 result in varying levels of enzymatic activity that impact retinoic acid metabolism and relate to the distinct phenotypes observed.

Hypomorphic GINS3 variants alter DNA replication and cause Meier-Gorlin syndrome.

The eukaryotic CDC45/MCM2-7/GINS (CMG) helicase unwinds the DNA double helix during DNA replication. The GINS subcomplex is required for helicase activity and is, therefore, essential for DNA replication and cell viability. Here, we report the identification of 7 individuals from 5 unrelated families presenting with a Meier-Gorlin syndrome-like (MGS-like) phenotype associated with hypomorphic variants of GINS3, a gene not previously associated with this syndrome. We found that MGS-associated GINS3 variants affecting aspartic acid 24 (D24) compromised cell proliferation and caused accumulation of cells in S phase. These variants shortened the protein half-life, altered key protein interactions at the replisome, and negatively influenced DNA replication fork progression. Yeast expressing MGS-associated variants of PSF3 (the yeast GINS3 ortholog) also displayed impaired growth, S phase progression defects, and decreased Psf3 protein stability. We further showed that mouse embryos homozygous for a D24 variant presented intrauterine growth retardation and did not survive to birth, and that fibroblasts derived from these embryos displayed accelerated cellular senescence. Taken together, our findings implicate GINS3 in the pathogenesis of MGS and support the notion that hypomorphic variants identified in this gene impaired cell and organismal growth by compromising DNA replication.

ATRX proximal protein associations boast roles beyond histone deposition.

The ATRX ATP-dependent chromatin remodelling/helicase protein associates with the DAXX histone chaperone to deposit histone H3.3 over repetitive DNA regions. Because ATRX-protein interactions impart functions, such as histone deposition, we used proximity-dependent biotinylation (BioID) to identify proximal associations for ATRX. The proteomic screen captured known interactors, such as DAXX, NBS1, and PML, but also identified a range of new associating proteins. To gauge the scope of their roles, we examined three novel ATRX-associating proteins that likely differed in function, and for which little data were available. We found CCDC71 to associate with ATRX, but also HP1 and NAP1, suggesting a role in chromatin maintenance. Contrastingly, FAM207A associated with proteins involved in ribosome biosynthesis and localized to the nucleolus. ATRX proximal associations with the SLF2 DNA damage response factor help inhibit telomere exchanges. We further screened for the proteomic changes at telomeres when ATRX, SLF2, or both proteins were deleted. The loss caused important changes in the abundance of chromatin remodelling, DNA replication, and DNA repair factors at telomeres. Interestingly, several of these have previously been implicated in alternative lengthening of telomeres. Altogether, this study expands the repertoire of ATRX-associating proteins and functions.

Effectiveness of a combined surf and psychological preventive intervention with children and adolescents in residential childcare: a randomized controlled trial / Efectividad de una intervención preventiva psicológica y de surf combinada con niños y adolescentes en cuidado residencial: un ensayo controlado aleatorizado

Children and adolescents living in residential childcare have a higher prevalence of mental health problems as a result of a history of adverse childhood experiences. Therefore, this population should be a priority target for mental health preventive interventions. The current study analyses the effectiveness of the Wave by Wavesurf therapy program, that combines surfing with a psychological group intervention, through a randomized controlled trial. Seventy-three youth (7-17 years) living in residential care participated in the study. Main mental health outcomes (adjustment problems, depression, anxiety, and wellbeing) and secondary outcomes (self-efficacy, self-regulation, sleep quality, physical activity, pro-social behavior, and social connectivity) were assessed at pre- and post-intervention. The results indicated a significant impact of the intervention on mental health outcomes reported by the key residential worker, with medium to large effect sizes. Specifically, after the intervention, there was a significant reduction in the total emotional and behavioural problems, and a significant increase of youth pro-social behaviour and quality of life that was not observed for the waiting list group. There were no significant effects on other measures reported by the children (e.g., depression and anxiety, self-esteem, emotion regulation, social connectedness, sleep quality, physical activity) and on executive functions measures. The Wave by Wave program seems to be an effective intervention to reduce behavior problems and to promote pro-social behavior in a high-risk sample. The absence of significant effects on other dimensions may indicate the need of some complementary support to address specific difficulties of this population

Los niños y adolescentes que viven en acogimiento residencial tienen una mayor prevalencia de problemas de salud mental. Por lo tanto, esta población debe ser un objetivo prioritario para las intervenciones preventivas de salud mental. El estudio actual analiza la efectividad del programa Wave by Wave, que combina el surf con una intervención psicológica grupal, a través de un ensayo controlado aleatorio. Setenta y tres jóvenes (7-17 años) que viven en acogimiento residencial participaron en el estudio. Los principales resultados de salud mental (problemas de ajuste, depresión, ansiedad y bienestar) y los resultados secundarios (autoeficacia, autorregulación, calidad del sueño, actividad física, comportamiento prosocial y conectividad social) se evaluaron antes y después de intervención. Los resultados indicaron un impacto significativo de la intervención sobre los resultados de salud mental reportados por el cuidador en la residencia. Específicamente, después de la intervención, hubo una reducción significativa en los problemas emocionales y conductuales totales, y un aumento significativo del comportamiento prosocial de los jóvenes y de la calidad de vida que no se observó en el grupo control. No hubo efectos significativos en otras medidas reportadas por los niños (ex., depresión y ansiedad, autoestima) y en las medidas de las funciones ejecutivas. El programa Wave by Wave parece ser una intervención efectiva para reducir los problemas de comportamiento y promover el comportamiento prosocial en una muestra de alto riesgo. La ausencia de efectos significativos en otras dimensiones puede indicar la necesidad de algún apoyo complementario para abordar las dificultades específicas de esta población

Estimating the incidence of adverse events in Portuguese hospitals: a contribution to improving quality and patient safety.

BACKGROUND: Several review studies have shown that 3.4% to 16.6% of patients in acute care hospitals experience one or more adverse events. Adverse events (AEs) in hospitals constitute a significant problem with serious consequences and a challenge for public health. The occurrence of AEs in Portuguese hospitals has not yet been systematically studied. The main purpose of this study is to estimate the incidence, impact and preventability of adverse events in Portuguese hospitals. It is also our aim to examine the feasibility of applying to Portuguese acute hospitals the methodology of detecting AEs through record review, previously used in other countries. METHODS: This work is based on a retrospective cohort study and was carried out at three acute care hospitals in the Administrative Region of Lisbon. The identification of AEs and their impact was done using a two-stage structured retrospective medical records review based on the use of 18 screening criteria. A random sample of 1,669 medical records (representative of 47,783 hospital admissions) for the year 2009 was analyzed. RESULTS: The main results found in this study were an incidence rate of 11.1% AEs, of which around 53.2% were considered preventable. The majority of AEs were associated with surgical procedures (27%), drug errors (18.3%) and hospital acquired infections (12.2%). Most AEs (61%) resulted in minimal or no physical impairment or disability, and 10.8% were associated with death. In 58.6% of the AEs' cases, the length of stay was prolonged on average 10.7 days. Additional direct costs amounted to €470,380.00. CONCLUSION: The magnitude of these results was critical, reinforcing the need of more detailed studies in this area. The knowledge of the incidence and nature of AEs that occur in hospitals should be seen as a first step towards the improvement of quality and safety in health care.

Meanings of quality of care: perspectives of Portuguese health professionals and patients.

OBJECTIVES: The main goal of this study is to explore what is meant by "quality of care" (QoC) by both health professionals and patients. This research also intends to compare the perspectives of nurses, doctors and patients in order to understand whether these different actors share similar views on what represents QoC. DESIGN AND METHODS: A qualitative study was conducted. The study consisted in 44 semi-structured individual interviews (11 doctors; 23 nurses; 10 patients) and in three focus groups (20 participants: doctors, nurses, patients). Participants were doctors, nurses and patients from several Hospitals in Portugal. Data were analysed using content analysis methodology with MaxQDA software. RESULTS: The main content analysis' results revealed that all participants emphasize technical and interpersonal dimensions of QoC. Nevertheless, professionals stressed the availability of equipment and supplies and the conditions of health care indoor facilities. Patients focused more on their access to health services, namely the availability of health professionals, and on the health status outcome after care. In what the differences between doctors and nurses are concerned, the former tend to highlight the technical aspects of care more than the nurses, who tend to refer interpersonal aspects immediately. CONCLUSIONS: Although nowadays the importance of health care quality has become well-recognized, its definition is still complex. Given that specific aspects are more valued by certain groups than others, it is important to take in consideration all the stakeholder's perspectives when measuring QoC in order to continuously improve it in the 'real' settings.

[Factor XII deficiency]. / Deficit F XII.

The work presents classical form and variant of F XII deficiency. Although a rare disorder, F XII deficiency can lead to bleeding, particularly after injuries and surgeries. Further laboratory investigation of patients with pathological APTT is required.

Various types of the pituitary folliculo-stellate cells involving the Siperstein's corticotroph in the normal rats.

The differentiation of the folliculo-stellate (F-S) cells was electronmicroscopically investigated in the normal male adult rats from the Wistar, Wistar-Imamichi, Holzmann, Spraque-Dowley and Donryu strains. The F-S cells may be divided into the five types according to the granulation. Each type is, however, provided with the common characteristic features, i.e., the stellate shape due to projecting the cytoplasmic processes and a tendency to embrace an acidophil. The first type is an agranular independent or anastomosing immature cell. It is different in shape and arrangement from the follicular cell, but similar in agranularity and immaturity to it. The second is a slightly differentiated cell, in which scanty small secretory granules 50--100 nm in diameter begin to appear near the plasma membrane. The third is a moderately differentiated cell providing the regularly row arrangement of secretory granules 100--200 nm in diameter along the plasma membrane, corresponding, in fine structure, with a corticotroph. The fourth is a fully differentiated cell with heavy granulation, whose secretory granules 150--250 nm in diameter are accumulated in the whole cytoplasm, suggesting the storing type. It is difficult to determine whether the fourth type coincides with a hypergranulated corticotroph or a stellate thyrotroph. The fifth is a kind of fully differenetiated cell which may refer to the releasing phase of the fourth type, being characterized by the dispersion or loss of minute secretory granules of low density as large as 50 nm in diameter, associated with the cored vesicles. The population densith of the above five types increased in the sequence, 5th leads to 4th leads to 1st leads to 3rd type in the gland. Namely, the 3rd (corticotroph) type and 1st (agranular) type are predominantly distributed, and the 5th (releasing) type and 4th (hypergranulated) type are rarely.