RESUMO
Activation of RIPK1 controls TNF-mediated apoptosis, necroptosis and inflammatory pathways1. Cleavage of human and mouse RIPK1 after residues D324 and D325, respectively, by caspase-8 separates the RIPK1 kinase domain from the intermediate and death domains. The D325A mutation in mouse RIPK1 leads to embryonic lethality during mouse development2,3. However, the functional importance of blocking caspase-8-mediated cleavage of RIPK1 on RIPK1 activation in humans is unknown. Here we identify two families with variants in RIPK1 (D324V and D324H) that lead to distinct symptoms of recurrent fevers and lymphadenopathy in an autosomal-dominant manner. Impaired cleavage of RIPK1 D324 variants by caspase-8 sensitized patients' peripheral blood mononuclear cells to RIPK1 activation, apoptosis and necroptosis induced by TNF. The patients showed strong RIPK1-dependent activation of inflammatory signalling pathways and overproduction of inflammatory cytokines and chemokines compared with unaffected controls. Furthermore, we show that expression of the RIPK1 mutants D325V or D325H in mouse embryonic fibroblasts confers not only increased sensitivity to RIPK1 activation-mediated apoptosis and necroptosis, but also induction of pro-inflammatory cytokines such as IL-6 and TNF. By contrast, patient-derived fibroblasts showed reduced expression of RIPK1 and downregulated production of reactive oxygen species, resulting in resistance to necroptosis and ferroptosis. Together, these data suggest that human non-cleavable RIPK1 variants promote activation of RIPK1, and lead to an autoinflammatory disease characterized by hypersensitivity to apoptosis and necroptosis and increased inflammatory response in peripheral blood mononuclear cells, as well as a compensatory mechanism to protect against several pro-death stimuli in fibroblasts.
Assuntos
Caspase 8/metabolismo , Doenças Hereditárias Autoinflamatórias/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Sequência de Bases , Criança , Pré-Escolar , Feminino , Células HEK293 , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/patologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Proteína Serina-Treonina Quinases de Interação com Receptores/deficiência , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Alinhamento de Sequência , Homologia de Sequência de AminoácidosRESUMO
Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.
Assuntos
Transtornos Cromossômicos/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos X/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a RNA/genética , Adolescente , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Criança , Pré-Escolar , Deleção Cromossômica , Transtornos Cromossômicos/fisiopatologia , Metilação de DNA/genética , Epigênese Genética/genética , Feminino , Haploinsuficiência/genética , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Masculino , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , Fenótipo , Adulto JovemRESUMO
The etiology of sirenomelia is currently unknown. Data are limited in comparing external and internal abnormalities using modern imaging technologies and molecular genetic analysis. The purpose of the current study was designed to compare external and internal anatomical defects in two cases of sirenomelia and Potter's sequence. Considered rare, Potter's sequence is a fetal disorder with characteristic features of bilateral renal agenesis, obstructive uropathy, atypical facial appearance, and limb malformations. The internal and external malformations of two term fetuses with sirenomelia and Potter's sequence were compared using assessment of external features, radiography and MRI on internal structures, and molecular genetic studies on sex determination. Data reveal that both fetuses were male and manifested with an overlapping but distinct spectrum of abnormalities. Principal differences were noted in the development of the ears, brain, urogenital system, lower limbs, pelvis, and vertebral column. Defects of the axial mesoderm are likely to underlie the abnormalities seen in both fetuses. The first one, which had only caudal defects, was found to have a spectrum of abnormalities most similar to those associated with more severe forms of the small pelvic outlet syndrome, although the structure and orientation of the sacrum and iliae were different from previously reported cases. The other had both caudal and cranial defects, and was most similar to those described in the axial mesodermal dysplasia syndrome. Defects associated with sirenomelia can be evaluated with standard gross anatomy examination, radiology, MRI, and modified PCR techniques to determine anatomical abnormalities and the sex of preserved specimens, respectively. Evidence indicated that sirenomelia could be developed via various etiologies.
Assuntos
Ectromelia , Humanos , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/diagnóstico por imagem , Ectromelia/genética , Ectromelia/diagnóstico por imagem , Ectromelia/patologia , Feto/anormalidades , Feto/diagnóstico por imagem , Imageamento por Ressonância MagnéticaRESUMO
INTRODUCTION: Children with chronic conditions have greater health care needs than the general paediatric population but may not receive care that centres their needs and preferences as identified by their families. Clinicians and researchers are interested in developing interventions to improve family-centred care need information about the characteristics of existing interventions, their development and the domains of family-centred care that they address. We conducted a scoping review that aimed to identify and characterize recent family-centred interventions designed to improve experiences with care for children with chronic conditions. METHODS: We searched Medline, Embase, PsycInfo and Cochrane databases, and grey literature sources for relevant articles or documents published between 1 January 2019 and 11 August 2020 (databases) or 7-20 October 2020 (grey literature). Primary studies with ≥10 participants, clinical practice guidelines and theoretical articles describing family-centred interventions that aimed to improve experiences with care for children with chronic conditions were eligible. Following citation and full-text screening by two reviewers working independently, we charted data covering study characteristics and interventions from eligible reports and synthesized interventions by domains of family-centred care. RESULTS: Our search identified 2882 citations, from which 63 articles describing 61 unique interventions met the eligibility criteria and were included in this review. The most common study designs were quasiexperimental studies (n = 18), randomized controlled trials (n = 11) and qualitative and mixed-methods studies (n = 9 each). The most frequently addressed domains of family-centred care were communication and information provision (n = 45), family involvement in care (n = 37) and access to care (n = 30). CONCLUSION: This review, which identified 61 unique interventions aimed at improving family-centred care for children with chronic conditions across a range of settings, is a concrete resource for researchers, health care providers and administrators interested in improving care for this high-needs population. PATIENT OR PUBLIC CONTRIBUTION: This study was co-developed with three patient partner co-investigators, all of whom are individuals with lived experiences of rare chronic diseases as parents and/or patients and have prior experience in patient engagement in research (I. J., N. P., M. S.). These patient partner co-investigators contributed to this study at all stages, from conceptualization to dissemination.
Assuntos
Assistência Centrada no Paciente , Humanos , Doença Crônica/terapia , Criança , FamíliaRESUMO
BACKGROUND: Generating rigorous evidence to inform care for rare diseases requires reliable, sustainable, and longitudinal measurement of priority outcomes. Having developed a core outcome set for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, we aimed to assess the feasibility of prospective measurement of these core outcomes during routine metabolic clinic visits. METHODS: We used existing cohort data abstracted from charts of 124 children diagnosed with MCAD deficiency who participated in a Canadian study which collected data from birth to a maximum of 11 years of age to investigate the frequency of clinic visits and quality of metabolic chart data for selected outcomes. We recorded all opportunities to collect outcomes from the medical chart as a function of visit rate to the metabolic clinic, by treatment centre and by child age. We applied a data quality framework to evaluate data based on completeness, conformance, and plausibility for four core MCAD outcomes: emergency department use, fasting time, metabolic decompensation, and death. RESULTS: The frequency of metabolic clinic visits decreased with increasing age, from a rate of 2.8 visits per child per year (95% confidence interval, 2.3-3.3) among infants 2 to 6 months, to 1.0 visit per child per year (95% confidence interval, 0.9-1.2) among those ≥ 5 years of age. Rates of emergency department visits followed anticipated trends by child age. Supplemental findings suggested that some emergency visits occur outside of the metabolic care treatment centre but are not captured. Recommended fasting times were updated relatively infrequently in patients' metabolic charts. Episodes of metabolic decompensation were identifiable but required an operational definition based on acute manifestations most commonly recorded in the metabolic chart. Deaths occurred rarely in these patients and quality of mortality data was not evaluated. CONCLUSIONS: Opportunities to record core outcomes at the metabolic clinic occur at least annually for children with MCAD deficiency. Methods to comprehensively capture emergency care received at outside institutions are needed. To reduce substantial heterogeneous recording of core outcome across treatment centres, improved documentation standards are required for recording of recommended fasting times and a consensus definition for metabolic decompensations needs to be developed and implemented.
Assuntos
Erros Inatos do Metabolismo Lipídico , Avaliação de Resultados em Cuidados de Saúde , Criança , Humanos , Acil-CoA Desidrogenase , Canadá , Estudos Prospectivos , Pré-EscolarRESUMO
Interpretation of variants of uncertain significance, especially chromosomal rearrangements in non-coding regions of the human genome, remains one of the biggest challenges in modern molecular diagnosis. To improve our understanding and interpretation of such variants, we used high-resolution three-dimensional chromosomal structural data and transcriptional regulatory information to predict position effects and their association with pathogenic phenotypes in 17 subjects with apparently balanced chromosomal abnormalities. We found that the rearrangements predict disruption of long-range chromatin interactions between several enhancers and genes whose annotated clinical features are strongly associated with the subjects' phenotypes. We confirm gene-expression changes for a couple of candidate genes to exemplify the utility of our analysis of position effect. These results highlight the important interplay between chromosomal structure and disease and demonstrate the need to utilize chromatin conformational data for the prediction of position effects in the clinical interpretation of non-coding chromosomal rearrangements.
Assuntos
Efeitos da Posição Cromossômica/genética , Mapeamento Cromossômico , Cromossomos Humanos/genética , Rearranjo Gênico/genética , Predisposição Genética para Doença/genética , Genoma Humano/genética , Pontos de Quebra do Cromossomo , Regulação da Expressão Gênica/genética , Variação Genética/genética , Humanos , Hibridização in Situ Fluorescente , Cariótipo , Fenótipo , Translocação Genética/genéticaRESUMO
Identification of over 500 epigenetic regulators in humans raises an interesting question regarding how chromatin dysregulation contributes to different diseases. Bromodomain and PHD finger-containing protein 1 (BRPF1) is a multivalent chromatin regulator possessing three histone-binding domains, one non-specific DNA-binding module, and several motifs for interacting with and activating three lysine acetyltransferases. Genetic analyses of fish brpf1 and mouse Brpf1 have uncovered an important role in skeletal, hematopoietic, and brain development, but it remains unclear how BRPF1 is linked to human development and disease. Here, we describe an intellectual disability disorder in ten individuals with inherited or de novo monoallelic BRPF1 mutations. Symptoms include infantile hypotonia, global developmental delay, intellectual disability, expressive language impairment, and facial dysmorphisms. Central nervous system and spinal abnormalities are also seen in some individuals. These clinical features overlap with but are not identical to those reported for persons with KAT6A or KAT6B mutations, suggesting that BRPF1 targets these two acetyltransferases and additional partners in humans. Functional assays showed that the resulting BRPF1 variants are pathogenic and impair acetylation of histone H3 at lysine 23, an abundant but poorly characterized epigenetic mark. We also found a similar deficiency in different lines of Brpf1-knockout mice. These data indicate that aberrations in the chromatin regulator gene BRPF1 cause histone H3 acetylation deficiency and a previously unrecognized intellectual disability syndrome.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Cromatina/metabolismo , Histonas/metabolismo , Deficiência Intelectual/genética , Mutação , Proteínas Nucleares/genética , Acetilação , Adolescente , Alelos , Animais , Proteínas de Transporte/genética , Criança , Cromatina/química , Proteínas de Ligação a DNA , Deficiências do Desenvolvimento/genética , Face/anormalidades , Feminino , Histona Acetiltransferases/genética , Humanos , Lisina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hipotonia Muscular/genética , SíndromeRESUMO
Background: Patients desire information about health care costs because they are increasingly responsible for these costs. Public Web sites that offer cost information could inform provider-patient discussions of costs at the point of care. Objective: To evaluate tools to facilitate the use of publicly available cost information during clinical visits for low back pain (LBP). Design: Qualitative study using individual and group interviews and surveys. Setting: 6 rural primary care practices in 2 health systems in Maine. Participants: Practice staff (n = 50) and adult patients with LBP (n = 72). Intervention: Participating health systems and practices were offered financial incentives, a series of trainings, and technical assistance to pilot tools for discussing costs of LBP care using CompareMaine.org, Maine's cost and quality transparency Web site. Measurements: Integration of tools into workflow, awareness and value to providers, and patient experience were identified through 11 group interviews with practice staff (n = 25) and health system leaders (n = 11), provider (n = 25), and patient (n = 47) surveys; patient interviews (n = 5); and administrative data. Results: The intervention increased provider and consumer awareness of CompareMaine.org, but minimally changed use in clinical discussions as a result of fewer-than-expected patients with LBP, limited system support, workflow barriers, and providers' reluctance to adopt the tools because of perceptions of limited value for their patients. In contrast, patients valued cost conversations and found the tools useful, and over one half reported intending to use CompareMaine.org during future care decisions. Limitations: Generalizability was limited by the small number of practices and participants. Lower-than-anticipated participation precluded examination of the effect of the tool on the frequency of cost-of-care conversations. Conclusion: This multicomponent intervention to introduce publicly reported cost information into LBP clinical discussions had low provider uptake. Whereas cost conversations and CompareMaine.org were perceived as useful by participating patients with LBP, providers were uncomfortable discussing cost variation at the point of care. Successful use of public cost information during clinical visits will require normalizing use to a broader group of patients and greater provider outreach and health system engagement. Primary Funding Source: Robert Wood Johnson Foundation.
Assuntos
Comunicação , Gastos em Saúde , Dor Lombar/economia , Relações Médico-Paciente , Atenção Primária à Saúde/economia , Atenção Primária à Saúde/organização & administração , Adulto , Efeitos Psicossociais da Doença , Pesquisas sobre Atenção à Saúde , Humanos , Entrevistas como Assunto , Maine , Pesquisa Qualitativa , Fluxo de TrabalhoRESUMO
BACKGROUND: The rapid expansion of genetic knowledge, and the implications for healthcare has resulted in an increased role for Primary Care Providers (PCPs) to incorporate genetics into their daily practice. The objective of this study was to explore the self-identified needs, including educational needs, of both urban and rural Primary Care Providers (PCPs) in order to provide genetic care to their patients. METHODS: Using a qualitative grounded theory approach, ten key informant interviews, and one urban and two rural PCP focus groups (FGs) (n = 19) were conducted. All PCPs practiced in Southeastern Ontario. Data was analyzed using a constant comparative method and thematic design. The data reported here represent a subset of a larger study. RESULTS: Participants reported that PCPs have a responsibility to ensure patients receive genetic care. However, specific roles and responsibilities for that care were poorly defined. PCPs identified a need for further education and resources to enable them to provide care for individuals with genetic conditions. Based on the findings, a progressive stepped model that bridges primary and specialty genetic care was developed; the model ranged from PCPs identifying patients with genetic conditions that they could manage alone, to patients who they could manage with informal or electronic consultation to those who clearly required specialist referral. CONCLUSIONS: PCPs identified a need to integrate genetics into primary care practice but they perceived barriers including a lack of knowledge and confidence, access to timely formal and informal consultation and clearly defined roles for themselves and specialists. To address gaps in PCP confidence in providing genetic care, interventions that are directed at accessible just-in-time support and consultation have the potential to empower PCPs to manage patients' genetic conditions. Specific attention to content, timing, and accessibility of educational interventions is critical to address the needs of both urban and rural PCPs. A progressive framework for bridging primary to specialty care through a 'stepped' model for providing continuing medical education, and genetic care can was developed and can be used to guide future design and delivery of educational interventions and resources.
Assuntos
Genética Médica , Avaliação das Necessidades , Médicos de Atenção Primária , Adulto , Feminino , Grupos Focais , Genética Médica/educação , Teoria Fundamentada , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Ontário , Médicos de Atenção Primária/educaçãoRESUMO
Parents have the opportunity to educate their children to facilitate behaviours and lifestyle habits that may prevent or delay genetic disease, or mitigate predispositions within the family. We sought to determine parents' understanding of genetic knowledge and heritability. Using a quantitative survey methodology 108 volunteer participants were surveyed from a convenience sample of all parents/caregivers within the waiting room of a general children's outpatient clinic. Results indicated that average genetic knowledge levels were fairly high, with the majority of participants scoring 70-80 % correct on knowledge-based questions. Further, scores were found to be positively correlated with education, but inversely correlated with self-perceived knowledge. This finding suggests that participants with less experience tended to overestimate their knowledge. We suggest that gaps in knowledge of genetics and heritability could be improved by using educational interventions such as media campaigns, provision of informational brochures, or changes to current high school curriculum which would increase exposure to genetics and heritability for both parents and children.
Assuntos
Aconselhamento Genético , Doenças Genéticas Inatas , Predisposição Genética para Doença , Conhecimentos, Atitudes e Prática em Saúde , Pais , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Untreated profound biotinidase deficiency results in a wide range of clinical features, including optic atrophy, cutaneous abnormalities, hearing loss and developmental delay. Ontario, Canada incorporated this treatable deficiency in newborn screening over the past 8years. This study elucidates the molecular, biochemical, and clinical findings from the pilot project. Information from initial screens, serum biotinidase activity level assays, molecular testing, and family history for 246 positive newborns screens were analyzed. A mutation spectrum was created for the province of Ontario, including common mutations such as D444H, D444H/A171T, Q456H, C33fs, and R157H. Individuals with partial deficiency were separated into 3 groups: D444H homozygotes (Group 1); compound heterozygotes for D444H with another profound allele (Group 2); compound heterozygotes with two non-D444H alleles (Group 3). Biochemical phenotype-genotype associations in partial deficiency showed a significant difference in serum biotinidase activity in between any given two groups. Three children with partial deficiency discontinued biotin for varied lengths of time. Two of whom became symptomatic with abnormal gait, alopecia, skin rashes and developmental delay. A need for more congruency in diagnostic, treatment and educational practices was highlighted across the province. Heterogeneity and variation in clinical presentations and management was observed in patients with the partial deficiency.
Assuntos
Deficiência de Biotinidase/enzimologia , Deficiência de Biotinidase/genética , Triagem Neonatal , Alelos , Amidoidrolases/genética , Biotina/uso terapêutico , Biotinidase/sangue , Biotinidase/genética , Deficiência de Biotinidase/diagnóstico , Deficiência de Biotinidase/epidemiologia , Criança , Pré-Escolar , Gerenciamento Clínico , Feminino , Estudos de Associação Genética , Perda Auditiva/etiologia , Heterozigoto , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Ontário/epidemiologia , Projetos PilotoRESUMO
The ease of use and versatility of the Baculovirus Expression Vector System (BEVS) has made it one of the most widely used systems for recombinant protein production However, co-expression systems currently in use mainly make use of the very strong very late p10 and polyhedron (polh) promoters to drive expression of foreign genes, which does not provide much scope for tailoring expression ratios within the cell. This work demonstrates the use of different Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) promoters to control the timing and expression of two easily traceable fluorescent proteins, the enhanced green fluorescent protein (eGFP), and a red fluorescent protein (DsRed2) in a BEVS co-expression system. Our results show that gene expression levels can easily be controlled using this strategy, and also that modulating the expression level of one protein can influence the level of expression of the other protein within the system, thus confirming the concept of genes "competing" for limited cellular resources. Plots of "expression ratios" of the two model genes over time were obtained, and may be used in future work to tightly control timing and levels of foreign gene expression in an insect cell co-expression system.
Assuntos
Baculoviridae/genética , Biotecnologia/métodos , Proteínas de Fluorescência Verde/metabolismo , Proteínas Luminescentes/metabolismo , Regiões Promotoras Genéticas/genética , Proteínas Recombinantes/metabolismo , Proliferação de Células , Genes Reporter/genética , Vetores Genéticos/genética , Proteínas de Fluorescência Verde/análise , Proteínas de Fluorescência Verde/genética , Proteínas Luminescentes/análise , Proteínas Luminescentes/genética , Proteínas Recombinantes/análise , Proteínas Recombinantes/genética , Células Sf9 , Proteína Vermelha FluorescenteRESUMO
We collected data on 48 patients from 38 families with guanidinoacetate methyltransferase (GAMT) deficiency. Global developmental delay/intellectual disability (DD/ID) with speech/language delay and behavioral problems as the most affected domains was present in 44 participants, with additional epilepsy present in 35 and movement disorder in 13. Treatment regimens included various combinations/dosages of creatine-monohydrate, l-ornithine, sodium benzoate and protein/arginine restricted diets. The median age at treatment initiation was 25.5 and 39 months in patients with mild and moderate DD/ID, respectively, and 11 years in patients with severe DD/ID. Increase of cerebral creatine and decrease of plasma/CSF guanidinoacetate levels were achieved by supplementation with creatine-monohydrate combined with high dosages of l-ornithine and/or an arginine-restricted diet (250 mg/kg/d l-arginine). Therapy was associated with improvement or stabilization of symptoms in all of the symptomatic cases. The 4 patients treated younger than 9 months had normal or almost normal developmental outcomes. One with inconsistent compliance had a borderline IQ at age 8.6 years. An observational GAMT database will be essential to identify the best treatment to reduce plasma guanidinoacetate levels and improve long-term outcomes.
Assuntos
Arginina/metabolismo , Arginina/uso terapêutico , Creatina/metabolismo , Creatina/uso terapêutico , Glicina/análogos & derivados , Guanidinoacetato N-Metiltransferase/deficiência , Deficiência Intelectual/terapia , Transtornos do Desenvolvimento da Linguagem/terapia , Transtornos dos Movimentos/congênito , Ornitina/uso terapêutico , Benzoato de Sódio/uso terapêutico , Adolescente , Adulto , Encéfalo/metabolismo , Criança , Pré-Escolar , Terapia Combinada , Feminino , Glicina/sangue , Glicina/líquido cefalorraquidiano , Guanidinoacetato N-Metiltransferase/metabolismo , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/metabolismo , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Transtornos do Desenvolvimento da Linguagem/metabolismo , Masculino , Pessoa de Meia-Idade , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/metabolismo , Transtornos dos Movimentos/terapia , Guias de Prática Clínica como Assunto , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND AND PURPOSE: The inaugural "Spinal CSF Leak: Bridging the Gap" Conference was organized to address the complexities of diagnosing and treating spinal CSF leaks. This event aimed to converge the perspectives of clinicians, researchers, and patients with a patient-centered focus to explore the intricacies of spinal CSF leaks across 3 main domains: diagnosis, treatment, and aftercare. MATERIALS AND METHODS: Physician and patient speakers were invited to discuss the varied clinical presentations and diagnostic challenges of spinal CSF leaks, which often lead to misdiagnosis or delayed treatment. Patient narratives were interwoven with discussions on advanced radiologic techniques and clinical assessments. Treatment-focused sessions highlighted patient experiences with various therapeutic options, including epidural blood patches, surgical interventions, and percutaneous and endovascular therapies. The intricacies of immediate and long-term postprocedural management were explored. RESULTS: Key outcomes from the conference included the recognition of the need for increased access to specialized CSF leak care for patients and heightened awareness among health care providers, especially for atypical symptoms and presentations. Discussions underscored the variability in individual treatment responses and the necessity for personalized diagnostic and treatment algorithms. Postprocedural challenges such as managing incomplete symptom relief and rebound intracranial hypertension were also addressed, emphasizing the need for effective patient monitoring and follow-up care infrastructures. CONCLUSIONS: The conference highlighted the need for adaptable diagnostic protocols, collaborative multidisciplinary care, and enhanced patient support. These elements are vital for improving the recognition, diagnosis, and management of spinal CSF leaks, thereby optimizing patient outcomes and quality of life. The event established a foundation for future advancements in spinal CSF leak management, advocating for a patient-centered model that harmonizes procedural expertise with an in-depth understanding of patient experiences.
Assuntos
Vazamento de Líquido Cefalorraquidiano , Humanos , Vazamento de Líquido Cefalorraquidiano/terapia , Vazamento de Líquido Cefalorraquidiano/diagnóstico por imagem , Congressos como AssuntoRESUMO
From November 2011 through March 2012, we surveyed 272 babies in our neonatal intensive care unit for rectal colonization with vancomycin-resistant enterococci (VRE). Using Spectra VRE medium (Remel Diagnostics, Lenexa, KS), we identified one neonate colonized with vancomycin-resistant Enterococcus faecium. In addition, 55 (13%) of the surveillance cultures yielded false-positive results with vancomycin-susceptible Enterococcus faecalis. During the same time period, 580 rectal swabs were collected from adult patients resulting in 20 (3%) false-positive cultures. The difference in false-positive rates between cultures from babies and adults was statistically significant (P < 0.001), prompting an investigation of factors that might influence the elevated false-positive rate in the neonates including patient demographics, nutrition, and topical ointments applied at the time of testing. Older neonates, with a median age of 6 weeks, were more likely to have false-positive cultures than younger neonates with a median age of 3 weeks (P < 0.001). The younger neonates receiving Similac Expert Care products were less likely to have false-positive surveillance cultures than those receiving other formulas (P < 0.001). Application of topical products was not associated with false-positive cultures. The false-positive E. faecalis strains were typed by Diversilab Rep-PCR (bioMérieux, Marcy l'Etoile, France) and found to represent eight different groups of isolates. The utility of the Spectra VRE media appeared to be significantly impacted by the age of the patients screened.
Assuntos
Infecção Hospitalar/epidemiologia , Meios de Cultura/química , Surtos de Doenças , Enterococcus/isolamento & purificação , Reações Falso-Positivas , Infecções por Bactérias Gram-Positivas/epidemiologia , Resistência a Vancomicina , Adulto , Infecção Hospitalar/microbiologia , Enterococcus/efeitos dos fármacos , Feminino , França/epidemiologia , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Lactente , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Masculino , Reto/microbiologiaRESUMO
OBJECTIVE: To explore views of women and health care providers (HCPs) about the changing recommendations regarding maternal age-based prenatal screening. DESIGN: Mixed-methods design. SETTING: Ontario. PARTICIPANTS: A sample of women who had given birth within the previous 2 years and who had attended a family medicine centre, midwifery practice, or baby and mother wellness program (n = 42); and a random sample of family physicians (n = 1600), and all Ontario obstetricians (n = 694) and midwives (n = 334) who provided prenatal care. METHODS: We used focus groups (FGs) to explore women's views. Content analysis was used to uncover themes and delineate meaning. To explore HCPs' views, we conducted a cross-sectional self-completion survey. MAIN FINDINGS: All FG participants (42 women in 6 FGs) expressed the importance of individual choice of prenatal screening modality, regardless of age. They described their perception that society considers women older than 35 to be at high obstetric risk and raised concerns that change in the maternal age-related screening policy would require education. The HCP survey response rate was 40%. Results showed 24% of HCPs agreed that women of any age should be eligible for invasive diagnostic testing regardless of prenatal screening results; 15% agreed that the age for diagnostic testing should be increased to 40 years, 14% agreed that diagnostic testing should be reserved for women with positive prenatal screening results, and 45% agreed that prenatal screening should remain unchanged. CONCLUSION: Maternity care organizations have recommended that maternal age-based prenatal screening is no longer appropriate. Informed choice is of paramount importance to women and should be part of any change. Health care providers need to be engaged in and educated about any change to screening guidelines to offer women informed choices.
Assuntos
Atitude do Pessoal de Saúde , Transtornos Cromossômicos/diagnóstico , Testes Genéticos/métodos , Conhecimentos, Atitudes e Prática em Saúde , Idade Materna , Diagnóstico Pré-Natal/psicologia , Adulto , Estudos Transversais , Medicina de Família e Comunidade/métodos , Feminino , Grupos Focais , Humanos , Masculino , Pessoa de Meia-Idade , Tocologia/métodos , Obstetrícia/métodos , Preferência do Paciente , Seleção de Pacientes , Guias de Prática Clínica como Assunto , Gravidez , Diagnóstico Pré-Natal/métodos , Inquéritos e Questionários , Adulto JovemRESUMO
BACKGROUND: In rural areas with health professional workforce shortages, telehealth offers an opportunity to address service gaps and meet the health needs of students. Few studies have examined telehealth implementation in rural schools. This study explores facilitators and barriers to the implementation of telehealth programs in rural schools and identifies strategies for successful implementation to inform future school-based telehealth initiatives. METHODS: We conducted semi-structured qualitative interviews with 50 key informants involved in the implementation of telehealth programs funded through the School-Based Telehealth Network Grant Program. Researchers completed a thematic analysis of interview transcripts. RESULTS: The most commonly cited barriers were technology, reimbursement for services, and facilitating acceptance of the telehealth among school staff, clinicians, parents, and students. Key informants identified strategies for facilitating program implementation, including technology training and support, marketing efforts, and integration into existing school processes. CONCLUSIONS: School-based telehealth can augment clinical capacity in areas with clinician shortages. Entities interested in such an approach to care must engage with their school community to ensure successful implementation. For rural, school-based telehealth to gain greater adoption and be sustained, these services must be reimbursable by Medicaid and private insurers.
Assuntos
Serviços de Saúde Rural , Telemedicina , Humanos , Medicaid , População Rural , Instituições AcadêmicasRESUMO
PURPOSE: Caregivers of individuals with Alzheimer's disease require support across the full disease trajectory. The aim of this study was to develop a conceptual framework of caregiving phases across the Alzheimer's disease and caregiving trajectories and the corresponding caregiver support needs. MATERIALS AND METHODS: Constructivist grounded theory informed data collection and analysis. 40 spousal (n = 20) and adult children (n = 20) caregivers were interviewed. Recruitment was completed when theoretical saturation was achieved. Member-checking interviews occurred with 10 participants. RESULTS: Participants described five phases of caregiving related to their responsibilities to support people with Alzheimer's disease including monitoring initial symptoms, navigating their diagnosis, assisting with instrumental activities of daily living, assisting with basic activities of daily living, and preparing for the future. Support (i.e., informational, emotional, instrumental, and appraisal) needs were often specific to the phase of care. For example, during the initial symptoms phase, caregivers reported needing information to assist them to distinguish normal aging from cognitive impairment. In contrast, during the preparing for the future phase, caregivers emphasized support for accessing institutional long term-care placement. CONCLUSIONS: Findings highlight caregiver-identified phases of caregiving and corresponding support needs across the Alzheimer's disease trajectory. Findings can inform the development, evaluation and implementation of programs and services to meet caregivers' changing needs across the disease trajectory.IMPLICATIONS FOR REHABILITATIONCaregivers for individuals with Alzheimer's disease can experience distinct caregiving phases across the disease trajectory with corresponding support needs.Rehabilitation clinicians can use these findings to help caregivers navigate available supports at appropriate times to ensure that their needs are addressed across the disease trajectory.Occupational therapists and other rehabilitation professionals can enable caregivers with timely education and support as they progress across the disease trajectory.
Assuntos
Doença de Alzheimer , Adulto , Humanos , Atividades Cotidianas , Doença de Alzheimer/psicologia , Cuidadores/psicologia , Teoria Fundamentada , Assistência de Longa Duração , Filhos AdultosRESUMO
Ischemic stroke often co-occurs with Alzheimer's disease (AD) leading to a worsened clinical outcome. Neuroinflammation is a critical process implicated in AD and ischemic pathology, associated with cognitive decline. We sought to investigate the combined effects of ischemic stroke induced by endothelin-1 injection in two AD rat models, using motor function, memory and microglial inflammation in the basal forebrain and striatum as readouts. In addition, we sought to determine the effectiveness of the antioxidant biologic CAT-SKL in one of the models. The early AD model employed the bilateral intracerebroventricular injections of the toxic ß-amyloid peptide Aß25-35, the prodromal AD model used the transgenic Fischer 344 rat overexpressing a pathological mutant human amyloid precursor protein. Motor function was assessed using a cylinder, modified sticky tape and beam-walk tasks; learning and memory were tested in the Morris water maze. Microglial activation was examined using immunohistochemistry. Aß25-35 toxicity and stroke combination greatly increased microglial inflammation in the basal forebrain. Prodromal AD-pathology coupled with ischemia in the transgenic rat resulted in a greater microgliosis in the striatum. Combined transgenic rats showed balance alterations, comorbid Aß25-35 rats showed a transient sensorimotor deficit, and both demonstrated spatial reference memory deficit. CAT-SKL treatment ameliorated memory impairment and basal forebrain microgliosis in Aß25-35 rats with stroke. Our results suggest that neuroinflammation could be one of the early processes underlying the interaction of AD with stroke and contributing to the cognitive impairment, and that therapies such as antioxidant CAT-SKL could be a potential therapeutic strategy.