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We present Dystrophic Epidermolysis Bullosa Cell Therapy (DEBCT), a scalable platform producing autologous organotypic iPS cell-derived induced skin composite (iSC) grafts for definitive treatment. Clinical-grade manufacturing integrates CRISPR-mediated genetic correction with reprogramming into one step, accelerating derivation of COL7A1-edited iPS cells from patients. Differentiation into epidermal, dermal and melanocyte progenitors is followed by CD49f-enrichment, minimizing maturation heterogeneity. Mouse xenografting of iSCs from four patients with different mutations demonstrates disease modifying activity at 1 month. Next-generation sequencing, biodistribution and tumorigenicity assays establish a favorable safety profile at 1-9 months. Single cell transcriptomics reveals that iSCs are composed of the major skin cell lineages and include prominent holoclone stem cell-like signatures of keratinocytes, and the recently described Gibbin-dependent signature of fibroblasts. The latter correlates with enhanced graftability of iSCs. In conclusion, DEBCT overcomes manufacturing and safety roadblocks and establishes a reproducible, safe, and cGMP-compatible therapeutic approach to heal lesions of DEB patients.
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Terapia Baseada em Transplante de Células e Tecidos , Colágeno Tipo VII , Epidermólise Bolhosa Distrófica , Células-Tronco Pluripotentes Induzidas , Humanos , Epidermólise Bolhosa Distrófica/terapia , Epidermólise Bolhosa Distrófica/genética , Animais , Células-Tronco Pluripotentes Induzidas/transplante , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Camundongos , Colágeno Tipo VII/genética , Colágeno Tipo VII/metabolismo , Terapia Baseada em Transplante de Células e Tecidos/métodos , Fibroblastos/metabolismo , Diferenciação Celular , Queratinócitos/metabolismo , Queratinócitos/transplante , Pele/metabolismo , Transplante Autólogo , Masculino , Mutação , Feminino , Transplante de Pele/métodos , Edição de Genes/métodos , Sistemas CRISPR-CasRESUMO
Background: 22q11 Deletion Syndrome (22q11DS) is the most common microdeletion syndrome with broad phenotypic variability, leading to significant morbidity and some mortality. The varied health problems associated with 22q11DS and the evolving phenotype (both medical and developmental/behavioural) across the lifespan can strongly impact the mental health of patients as well as their caregivers. Like caregivers of children with other chronic diseases, caregivers of children with 22q11DS may experience an increased risk of traumatisation and mental health symptoms.Objective: The study's primary objective was to assess the frequency of traumatic experiences and mental health symptoms among mothers of children with 22q11DS. The secondary objective was to compare their traumatic experiences to those of mothers of children with other neurodevelopmental disorders (NDDs).Method: A total of 71 mothers of children diagnosed with 22q11DS completed an online survey about their mental health symptoms and traumatic experiences. Descriptive statistics were used to summarise the prevalence of their mental health symptoms and traumatic experiences. Logistic regression models were run to compare the traumatic experiences of mothers of children with 22q11DS to those of 335 mothers of children with other neurodevelopmental disorders (NDDs).Results: Many mothers of children with 22q11DS experienced clinically significant mental health symptoms, including depression (39%), anxiety (25%), and post-traumatic stress disorder (PTSD) symptoms (30%). The types of traumatic events experienced by mothers of children with 22q11DS differed from those of mothers of children with other NDDs as they were more likely to observe their child undergoing a medical procedure, a life-threatening surgery, or have been with their child in the intensive care unit.Conclusion: 22q11DS caregivers are likely to require mental health support and trauma-informed care, tailored to the specific needs of this population as they experience different kinds of traumatic events compared to caregivers of children with other NDDS.
Mothers of children with 22q11DS experience clinically significant levels of depression, anxiety, and PTSD.Mothers of children with 22q11DS experience many and diverse trauma particularly related to medical interventions of their child.The types of traumatic events experienced by mothers of children with 22q11DS are different from those of the mothers of children with other neurodevelopmental disorders.
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Mães , Humanos , Feminino , Mães/psicologia , Adulto , Criança , Masculino , Inquéritos e Questionários , Saúde Mental , Transtornos de Estresse Pós-Traumáticos/psicologia , Síndrome da Deleção 22q11/psicologia , Adolescente , Transtornos do Neurodesenvolvimento/psicologia , Pessoa de Meia-Idade , Cuidadores/psicologiaRESUMO
BACKGROUND: Anxiety disorders are the most common psychiatric problems among Canadian youth and typically have an onset in childhood or adolescence. They are characterized by high rates of relapse and chronicity, often resulting in substantial impairment across the lifespan. Genetic factors play an important role in the vulnerability toward anxiety disorders. However, genetic contribution to anxiety in youth is not well understood and can change across developmental stages. Large-scale genetic studies of youth are needed with detailed assessments of symptoms of anxiety disorders and their major comorbidities to inform early intervention or preventative strategies and suggest novel targets for therapeutics and personalization of care. METHODS: The Genetic Architecture of Youth Anxiety (GAYA) study is a Pan-Canadian effort of clinical and genetic experts with specific recruitment sites in Calgary, Halifax, Hamilton, Toronto, and Vancouver. Youth aged 10-19 (n = 13,000) will be recruited from both clinical and community settings and will provide saliva samples, complete online questionnaires on demographics, symptoms of mental health concerns, and behavioural inhibition, and complete neurocognitive tasks. A subset of youth will be offered access to a self-managed Internet-based cognitive behavioral therapy resource. Analyses will focus on the identification of novel genetic risk loci for anxiety disorders in youth and assess how much of the genetic risk for anxiety disorders is unique or shared across the life span. DISCUSSION: Results will substantially inform early intervention or preventative strategies and suggest novel targets for therapeutics and personalization of care. Given that the GAYA study will be the biggest genomic study of anxiety disorders in youth in Canada, this project will further foster collaborations nationally and across the world.
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Transtornos de Ansiedade , Ansiedade , Humanos , Adolescente , Canadá , Transtornos de Ansiedade/diagnóstico , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/terapia , Ansiedade/psicologia , Saúde Mental , Fatores de RiscoRESUMO
BACKGROUND: Headache disorders are common, debilitating health problems. Cognitive-behavioral therapy (CBT) is recommended but rarely easily available. With the use of the internet and communication technologies among youth and young adults, these individuals could be self-trained in CBT skills. There is an increasing number of internet-based interventions for headaches, but there has been little research into the usability of these interventions because evaluating usability across the intervention development life cycle is costly. We developed an internet-based CBT program, the Specialized Program for Headache Reduction (SPHERE). While developing it, we aimed to improve SPHERE through rapid usability testing cycles. OBJECTIVE: This study aims to presents a rapid and affordable usability testing approach that can be performed throughout the intervention development life cycle. This paper also provides evidence of the usability of SPHERE. METHODS: We used the "think aloud" usability testing method based on Krug's approach to test user interaction within a lab setting. This was followed by a short posttest interview. We planned to test SPHERE with 3-5 participants testing the same part of the program each cycle. Both the design and development team and the research team actively participated in the usability testing process. Observers independently identified the top 3 usability issues, rated their severity, and conducted debriefing sessions to come to consensus on major issues and generate potential solutions. RESULTS: The testing process allowed major usability issues to be identified and rectified rapidly before piloting SPHERE in a real-world context. A total of 2 cycles of testing were conducted. Of the usability issues encountered in cycles 1 and 2, a total of 68% (17/25) and 32% (12/38), respectively, were rated as major, discussed, and fixed. CONCLUSIONS: This study shows that rapid usability testing is an essential part of the design process that improves program functionality and can be easy and inexpensive to undertake.
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Terapia Cognitivo-Comportamental , Design Centrado no Usuário , Humanos , Adolescente , Adulto Jovem , Interface Usuário-Computador , CefaleiaRESUMO
Selfish genetic elements can promote their transmission at the expense of individual survival, creating conflict between the element and the rest of the genome. Recently, a large number of toxin-antidote (TA) post-segregation distorters have been identified in non-obligate outcrossing nematodes. Their origin and the evolutionary forces that keep them at intermediate population frequencies are poorly understood. Here, we study a TA element in Caenorhabditis elegans called zeel-1;peel-1. Two major haplotypes of this locus, with and without the selfish element, segregate in C. elegans. We evaluate the fitness consequences of the zeel-1;peel-1 element outside of its role in gene drive in non-outcrossing animals and demonstrate that loss of the toxin peel-1 decreased fitness of hermaphrodites and resulted in reductions in fecundity and body size. These findings suggest a biological role for peel-1 beyond toxin lethality. This work demonstrates that a TA element can provide a fitness benefit to its hosts either during their initial evolution or by being co-opted by the animals following their selfish spread. These findings guide our understanding on how TA elements can remain in a population where gene drive is minimized, helping resolve the mystery of prevalent TA elements in selfing animals.
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Proteínas de Caenorhabditis elegans , Toxinas Biológicas , Animais , Caenorhabditis elegans/genética , Antídotos , Sequências Repetitivas de Ácido Nucleico , Fertilidade , Frequência do Gene , Proteínas de Caenorhabditis elegans/genéticaRESUMO
The probabilistic reward task (PRT) has identified reward learning impairments in those with major depressive disorder (MDD), as well as anhedonia-specific reward learning impairments. However, attempts to validate the anhedonia-specific impairments have produced inconsistent findings. Thus, we seek to determine whether the Reward Behavior Disengagement (RBD), our proposed economic augmentation of PRT, differs between MDD participants and controls, and whether there is a level at which RBD is high enough for depressed participants to be considered objectively disengaged. Data were gathered as part of the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study, a double-blind, placebo-controlled clinical trial of antidepressant response. Participants included 195 individuals with moderate to severe MDD (Quick Inventory of Depressive Symptomatology (QIDS-SR) score ≥ 15), not in treatment for depression, and with complete PRT data. Healthy controls (n = 40) had no history of psychiatric illness, a QIDS-SR score < 8, and complete PRT data. Participants with MDD were treated with sertraline or placebo for 8 weeks (stage I of the EMBARC trial). RBD was applied to PRT data using discriminant analysis, and classified MDD participants as reward task engaged (n = 137) or reward task disengaged (n = 58), relative to controls. Reward task engaged/disengaged groups were compared on sociodemographic features, reward-behavior, and sertraline/placebo response (Hamilton Depression Rating Scale scores). Reward task disengaged MDD participants responded only to sertraline, whereas those who were reward task engaged responded to sertraline and placebo (F(1293) = 4.33, p = 0.038). Reward task engaged/disengaged groups did not differ otherwise. RBD was predictive of reward impairment in depressed patients and may have clinical utility in identifying patients who will benefit from antidepressants.
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Social behaviors are diverse in nature, but it is unclear how conserved genes, brain regions, and cell populations generate this diversity. Here we investigate bower-building, a recently-evolved social behavior in cichlid fishes. We use single nucleus RNA-sequencing in 38 individuals to show signatures of recent behavior in specific neuronal populations, and building-associated rebalancing of neuronal proportions in the putative homolog of the hippocampal formation. Using comparative genomics across 27 species, we trace bower-associated genome evolution to a subpopulation of glia lining the dorsal telencephalon. We show evidence that building-associated neural activity and a departure from quiescence in this glial subpopulation together regulate hippocampal-like neuronal rebalancing. Our work links behavior-associated genomic variation to specific brain cell types and their functions, and suggests a social behavior has evolved through changes in glia.
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Ciclídeos , Animais , Ciclídeos/genética , Comportamento Social , Genoma , Genômica , Sequência de BasesRESUMO
Analyses of the contributions of genetic variants in wild strains to phenotypic differences have led to a more complete description of the pathways underlying cellular functions. Causal loci are typically identified via interbreeding of strains with distinct phenotypes in order to establish recombinant inbred lines (RILs). Since the generation of RILs requires growth for multiple generations, their genomes may contain not only different combinations of parental alleles but also genetic changes that arose de novo during the establishment of these lines. Here, we report that in the course of generating RILs between Caenorhabditis elegans strains that exhibit distinct thermotaxis behavioral phenotypes, we identified spontaneously arising variants in the ttx-1 locus. ttx-1 encodes the terminal selector factor for the AFD thermosensory neurons, and loss-of-function mutations in ttx-1 abolish thermotaxis behaviors. The identified genetic changes in ttx-1 in the RIL are predicted to decrease ttx-1 function in part via specifically affecting a subset of AFD-expressed ttx-1 isoforms. Introduction of the relevant missense mutation in the laboratory C. elegans strain via gene editing recapitulates the thermotaxis behavioral defects of the RIL. Our results suggest that spontaneously occurring genomic changes in RILs may complicate identification of loci contributing to phenotypic variation, but that these mutations may nevertheless lead to the identification of important causal molecules and mechanisms.
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Proteínas de Caenorhabditis elegans , Resposta Táctica , Animais , Caenorhabditis elegans/metabolismo , Neurônios/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Mutação , Animais de LaboratórioRESUMO
Firefighters are at increased risk for developing posttraumatic stress disorder (PTSD) and face numerous barriers to accessing mental health care. Innovative ways to increase access to evidence-based interventions are needed. This study was a case series testing the acceptability, feasibility, and preliminary effectiveness of a paraprofessional-delivered, virtual narrative exposure therapy (eNET) intervention for PTSD. Participants were 21 firefighters who met the criteria for clinical or subclinical probable PTSD and completed 10-12 sessions of eNET via videoconference. Participants completed self-report measures pre- and postintervention and at 2- and 6-month follow-ups as well as a postintervention qualitative interview. Paired samples t tests evidenced statistically significant decreases in PTSD, anxiety, and depressive symptom severity and functional impairment from pre- to postintervention, ds = 1.08-1.33, and in PTSD and anxiety symptom severity and functional impairment from preintervention to 6-month follow-up, ds = 0.69-1.10. The average PTSD symptom severity score fell from above to below the clinical cutoff for probable PTSD at postintervention and follow-ups. Qualitative interviews indicated that paraprofessionals were considered central to participants' success and experience with the intervention. No adverse events or safety concerns were raised. This study is an important step in demonstrating that appropriately trained and supervised paraprofessionals can effectively deliver eNET to firefighters with PTSD.
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Bombeiros , Terapia Implosiva , Terapia Narrativa , Transtornos de Estresse Pós-Traumáticos , Humanos , Transtornos de Estresse Pós-Traumáticos/psicologia , Bombeiros/psicologia , Ansiedade/terapia , Ansiedade/psicologiaRESUMO
Background: Gene editing in induced pluripotent stem (iPS) cells has been hailed to enable new cell therapies for various monogenetic diseases including dystrophic epidermolysis bullosa (DEB). However, manufacturing, efficacy and safety roadblocks have limited the development of genetically corrected, autologous iPS cell-based therapies. Methods: We developed Dystrophic Epidermolysis Bullosa Cell Therapy (DEBCT), a new generation GMP-compatible (cGMP), reproducible, and scalable platform to produce autologous clinical-grade iPS cell-derived organotypic induced skin composite (iSC) grafts to treat incurable wounds of patients lacking type VII collagen (C7). DEBCT uses a combined high-efficiency reprogramming and CRISPR-based genetic correction single step to generate genome scar-free, COL7A1 corrected clonal iPS cells from primary patient fibroblasts. Validated iPS cells are converted into epidermal, dermal and melanocyte progenitors with a novel 2D organoid differentiation protocol, followed by CD49f enrichment and expansion to minimize maturation heterogeneity. iSC product characterization by single cell transcriptomics was followed by mouse xenografting for disease correcting activity at 1 month and toxicology analysis at 1-6 months. Culture-acquired mutations, potential CRISPR-off targets, and cancer-driver variants were evaluated by targeted and whole genome sequencing. Findings: iPS cell-derived iSC grafts were reproducibly generated from four recessive DEB patients with different pathogenic mutations. Organotypic iSC grafts onto immune-compromised mice developed into stable stratified skin with functional C7 restoration. Single cell transcriptomic characterization of iSCs revealed prominent holoclone stem cell signatures in keratinocytes and the recently described Gibbin-dependent signature in dermal fibroblasts. The latter correlated with enhanced graftability. Multiple orthogonal sequencing and subsequent computational approaches identified random and non-oncogenic mutations introduced by the manufacturing process. Toxicology revealed no detectable tumors after 3-6 months in DEBCT-treated mice. Interpretation: DEBCT successfully overcomes previous roadblocks and represents a robust, scalable, and safe cGMP manufacturing platform for production of a CRISPR-corrected autologous organotypic skin graft to heal DEB patient wounds.
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INTRODUCTION: Whole exome sequencing (WES) has increasingly become integrated into prenatal care and genetic testing pathways. Current studies of prenatal WES have focused on diagnostic yield. The possibility of obtaining a variant of uncertain significance and lack of provider expertise are frequently described as common barriers to clinical integration of prenatal WES. We describe the implementation and workflow for a multidisciplinary approach to effectively integrate prenatal WES into maternal-fetal care to overcome these barriers. METHODS: A multidisciplinary team reviews and approves potential cases for WES. This team reviews WES results, reclassifying variants as appropriate and provides recommendations for postnatal care. A detailed description of this workflow is provided, and a case example is included to demonstrate effectiveness of this approach. Our team has approved 62 cases for WES with 45 patients ultimately pursuing WES. We have achieved a diagnostic yield of 40% and the multidisciplinary team has played a role in variant interpretation in 50% of the reported variants of uncertain significance. CONCLUSIONS: This approach facilitates communication between prenatal and postnatal care teams and provides accurate interpretation and recommendations for identified fetal variants. This model can be replicated to ensure appropriate patient care and effective integration of novel genomic technologies into prenatal settings.
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Feto , Cuidado Pré-Natal , Gravidez , Feminino , Humanos , Sequenciamento do Exoma , Fluxo de Trabalho , Testes GenéticosRESUMO
OBJECTIVE: The objective of this review was to determine whether electronic health (eHealth) educational interventions about infant procedural pain and pain management impact parental outcomes (eg, mental health, knowledge uptake), eHealth outcomes (eg, acceptance, use), and pain management outcomes (eg, parental involvement, infant pain response). INTRODUCTION: Pain in infants is a common concern for parents. Routine postpartum care for infants in early life requires them to endure painful procedures, such as immunizations, yet infants often receive little to no pain management. Parents are an essential component of effective pain management, although they may not be aware of the roles they play. Despite the increased number of eHealth resources available to educate parents about infant pain management, their impact has yet to be synthesized. INCLUSION CRITERIA: This review considered studies that evaluated eHealth educational interventions targeted at parents during pregnancy and up to 1 year postpartum. Interventions included, but were not limited to, mobile applications, web-based applications, websites, videos, interactive training, hands-on direct simulation, short message service (SMS), and desktop applications. Primary outcomes included parental outcomes (eg, stress or anxiety, self-efficacy, knowledge, attitudes), eHealth outcomes (eg, acceptance, use), and pain management outcomes (eg, parental involvement, infant pain response). Experimental, quasi-experimental, and observational study designs were included. METHODS: MEDLINE, CINAHL, PsycINFO, Embase, Scopus, Web of Science, and SciELO were searched for studies published in English up to June 14, 2021. Citation lists of relevant reviews and included studies were also searched for additional peer-reviewed articles. Two independent reviewers conducted critical appraisal using standardized tools from JBI, and data extraction, using a data extraction form designed by the authors. Statistical pooling of quantitative data was not possible due to heterogeneity; thus, the findings were reported narratively. RESULTS: A total of 4163 unique studies were screened, with 11 studies ultimately included for synthesis. Five articles were randomized controlled trials, 5 articles were analytical cross-sectional studies, and 1 article was quasi-experimental. Studies reported on 4 unique eHealth educational interventions, all of which used video format and primarily targeted the postnatal period. The findings for all primary outcomes were mixed but suggested either improvements in outcomes or no impact. The certainty of evidence was determined as low or very low across primary outcomes for reasons related to imprecision, risk of bias, and indirectness. CONCLUSIONS: Although heterogeneity of findings limited quantitative synthesis of data, this review suggests that short and engaging educational videos have the potential to positively impact parents' knowledge, confidence, and desire to be involved in procedural pain management for their children. Most of the interventions presented in this review describe evidence-based information about procedural pain management strategies that are known to be effective for infant populations. Thus, it is reasonable to assume that infant pain response should be lower when parents appropriately apply the strategies. However, the findings of this review were not able to confirm this assumption. More research is needed to evaluate the impact of parent-targeted pain management education on infant pain response. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42020151569.
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Dor Processual , Telemedicina , Criança , Feminino , Gravidez , Humanos , Lactente , Dor Processual/prevenção & controle , Estudos Transversais , Pais , Ansiedade , Telemedicina/métodos , Estudos Observacionais como AssuntoRESUMO
BACKGROUND: Major depressive disorder (MDD) is often accompanied by changes in appetite and weight. Prior task-based functional magnetic resonance imaging (fMRI) findings suggest these MDD phenotypes are associated with altered reward and interoceptive processing. METHODS: Using resting-state fMRI data, we compared the fractional amplitude of low-frequency fluctuations (fALFF) and seed-based connectivity (SBC) among hyperphagic (n = 77), hypophagic (n = 66), and euphagic (n = 42) MDD groups and a healthy comparison group (n = 38). We examined fALFF and SBC in a mask restricted to reward [nucleus accumbens (NAcc), putamen, caudate, ventral pallidum, and orbitofrontal cortex (OFC)] and interoceptive (anterior insula and hypothalamus) regions and also performed exploratory whole-brain analyses. SBC analyses included as seeds the NAcc and also regions demonstrating group differences in fALFF (i.e. right lateral OFC and right anterior insula). All analyses used threshold-free cluster enhancement. RESULTS: Mask-restricted analyses revealed stronger fALFF in the right lateral OFC, and weaker fALFF in the right anterior insula, for hyperphagic MDD v. healthy comparison. We also found weaker SBC between the right lateral OFC and left anterior insula for hyperphagic MDD v. healthy comparison. Whole-brain analyses revealed weaker fALFF in the right anterior insula, and stronger SBC between the right lateral OFC and left precentral gyrus, for hyperphagic MDD v. healthy comparison. Findings were no longer significant after controlling for body mass index, which was higher for hyperphagic MDD. CONCLUSIONS: Our results suggest hyperphagic MDD may be associated with altered activity in and connectivity between interoceptive and reward regions.
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Transtorno Depressivo Maior , Humanos , Transtorno Depressivo Maior/diagnóstico por imagem , Apetite , Imageamento por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico/métodos , FenótipoRESUMO
PURPOSE: Several systematic reviews have examined parent training programs for families of children with autism spectrum disorder (ASD). The present review expands on this literature by describing the components, delivery methods, and level of parent involvement in parent training programs that target families of children with any neurodisability and comorbid disruptive behavior or other mental health problem. MATERIALS AND METHODS: Following a scoping review protocol, the search strategy included randomized controlled trials of parent training programs conducted with families of children with neurodisabilities and comorbid disruptive behavior or mental health problems. Study characteristics, program content, delivery methods, and theoretical frameworks were extracted from eligible studies. RESULTS: A total of 22 articles were included from the 453 full-text articles initially screened. Thirteen different programs fell into two general categories based on whether they targeted child disruptive behavior or anxiety. Analysis of the content yielded five themes: child skill enhancement, parenting as enacted, parenting as experienced, disability-related parenting, and parent-child relationships. The theoretical underpinnings were identified, when possible, from each study. CONCLUSIONS: Parent training programs for parents of children with neurodisabilities targeting child anxiety involved parents in a complementary role in treatment while those targeting disruptive behavior involved parents in a primary role in creating behavior change. We suggest that the extent of parent involvement in interventions be guided by theory rather than diagnosis of the child.Implications for rehabilitationParents of children living with neurodisabilities play a key role in delivering interventions to address comorbid mental health or behavioral problems.Parent training programs for families of children with neurodisabilities vary in relation to their aims, involvement of parents in delivering interventions, disability-specific content, and delivery methods.When referring families, rehabilitation professionals should be aware of aspects of child, parent, and family relational well-being targeted by parent training programs and, when feasible, give families a choice of the style of program to meet their needs.
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Transtorno do Espectro Autista , Comportamento Problema , Humanos , Transtorno do Espectro Autista/psicologia , Saúde Mental , Pais/psicologia , Poder Familiar/psicologia , Comportamento Problema/psicologiaRESUMO
BACKGROUND: Gabapentin is an antiepileptic medication with evidence of benefit in alcohol use disorder patients. The mechanism of action of gabapentin may also benefit patients suffering from acute alcohol withdrawal syndrome (AWS). METHODS: A systematic review and meta-analysis were conducted to examine if gabapentin can effectively replace/reduce the use of benzodiazepines for the treatment of acute alcohol withdrawal symptoms in hospitalized patients. Time to alcohol withdrawal symptom resolution, amount of benzodiazepines administered, rate of resolution of alcohol withdrawal symptoms, serious withdrawal-related complications, and hospital length of stay (LOS) were examined. RESULTS: Eight retrospective studies (n = 2030) were included in this meta-analysis. There were no studies that examined study outcomes for patients who received only gabapentin and no benzodiazepines; in all studies, gabapentin-treated patients may have received benzodiazepines prior to gabapentin. There were no significant differences between gabapentin-treated and benzodiazepine-treated groups in time to symptom resolution, amount benzodiazepines administered, withdrawal-related complications, or LOS. There was a significant difference in the rate of symptom resolution favoring gabapentin-treated patients (p = 0.05); however, this analysis included only one study. Subgroup analyses of severe AWS patients revealed a significant decrease in LOS (p = 0.04) and a decrease in amount of benzodiazepines administered (p = 0.02) in gabapentin-treated patients, but these analyses included only one study. Subgroup analysis of patients receiving only gabapentin without benzodiazepines found a significantly decreased LOS in the gabapentin group compared to the benzodiazepine group (p < 0.001), but this analysis included only two studies. CONCLUSIONS: There is insufficient evidence to support the widespread use of gabapentin to treat inpatients suffering AWS. All studies included in this meta-analysis are retrospective with high risk of confounding. Well-designed, randomized, controlled studies of gabapentin to treat patients with AWS are required.
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Alcoolismo , Síndrome de Abstinência a Substâncias , Humanos , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Alcoolismo/tratamento farmacológico , Gabapentina/uso terapêutico , Estudos Retrospectivos , Benzodiazepinas/uso terapêuticoRESUMO
Insulin/insulin-like growth factor (IGF) receptor signaling (IIS) supports context-dependent learning in vertebrates and invertebrates. Here, we identify cell-specific mechanisms of IIS that integrate sensory information with food context to drive synaptic plasticity and learning. In the nematode Caenorhabditis elegans, pairing food deprivation with an odor such as butanone suppresses attraction to that odor. We find that aversive olfactory learning requires the insulin receptor substrate (IRS) protein IST-1 and atypical signaling through the insulin/IGF-1 receptor DAF-2. Cell-specific knockout and rescue demonstrate that DAF-2 acts in the AWCON sensory neuron, which detects butanone, and that learning preferentially depends upon the axonally localized DAF-2c isoform. Acute food deprivation increases DAF-2 levels in AWCON post-transcriptionally through an insulin- and insulin receptor substrate-1 (ist-1)-dependent process. Aversive learning alters the synaptic output of AWCON by suppressing odor-regulated glutamate release in wild-type animals, but not in ist-1 mutants, suggesting that axonal insulin signaling regulates synaptic transmission to support aversive memory.
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Proteínas de Caenorhabditis elegans , Somatomedinas , Animais , Insulina/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Ácido Glutâmico , Caenorhabditis elegans/metabolismo , Células Receptoras Sensoriais/metabolismo , ButanonasRESUMO
Caring for children with intellectual and developmental disabilities (IDD) can cause an enormous physical and emotional burden, and therefore these parents have an elevated risk to experience mental health problems. The characteristics of current healthcare systems and parents' responsibilities to care for their children seem to impede their access to mental healthcare. There is so far a lack of instruments to screen for such obstacles. The aim of this study was to develop and validate a scale for measuring barriers to accessing mental healthcare. The Parental Healthcare Barriers Scale (PHBS) was developed on the basis of an extensive literature research, input and discussion from experts and parents with lived experience. A cross-sectional survey was used to collect data from 456 parents of children with IDD. Physical health, mental health, social support, and parenting were measured for concurrent and discriminant validity of the PHBS. The PHBS scale revealed acceptable to good reliability and validity. It consists of four subscales (i.e., support accessibility, personal belief, emotional readiness, and resource availability). The PHBS found parents prioritized their children's treatments over their own mental health challenges (93.4%), did not have enough time (90.4%), and had financial concerns (85.8%). Parents in rural and remote areas had more limited resources. Findings from our study suggest increasing financial support for the parents seeking mental health services, introducing evidence-based treatments, increasing the availability of healthcare services for parents, and adjusting current services to their needs.
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Deficiências do Desenvolvimento , Serviços de Saúde Mental , Criança , Humanos , Estudos Transversais , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/terapia , Pais/psicologia , Psicometria , Reprodutibilidade dos Testes , Acessibilidade aos Serviços de Saúde , Cuidadores/psicologiaRESUMO
Adolescents' use of online resources to self-manage anxiety is growing. The objective of the current trial was to assess the effectiveness of an online, primarily self-led cognitive behavioral therapy (CBT) program in reducing anxiety symptoms compared to an active comparator, access to anxiety resources on a static website. A total of 563 adolescents (13-19 years) with self-identified anxiety concerns were enrolled. Self-reported anxiety symptoms were assessed pre- and post-intervention (6 weeks). Adolescents were further assessed 3 months post-intervention. Other outcomes assessed at the three time-points were quality of life (QOL) and healthcare utilization. Both interventions reduced anxiety symptoms after use. Group differences in symptom change were not significant post-intervention (p = 0.16), but were at 3 months (favouring online CBT; p = 0.04) with male participants reporting more symptom change (p = 0.03). Across time-points, as anxiety symptoms decreased, QOL increased (p < 0.001). Among participants that provided healthcare utilization before and after intervention use, the greatest changes in use were among online CBT users particularly for mental health provider visits (psychiatrist, -41.0 % vs. +18.5 %; social worker, -42.5 % vs. -22.1 %), hospital-based care (emergency department visits, -80.0 % vs. +79.4 %; hospital admissions, -76.1 % vs. +42.9 %), and use of self-help or alternative treatments (-60.0 % vs. +6.6 %). Results suggest that, over time, use of online CBT by adolescents can result in improved anxiety symptoms and fewer use of other healthcare resources compared to traditional online information seeking.
Assuntos
Terapia Cognitivo-Comportamental , Qualidade de Vida , Adolescente , Masculino , Humanos , Ansiedade/terapia , Terapia Cognitivo-Comportamental/métodos , Internet , Cognição , Resultado do TratamentoRESUMO
BACKGROUND: Online support groups (OSGs) are distance-delivered, easily accessible health interventions offering emotional, informational, and experience-based support and companionship or network support for caregivers managing chronic mental and physical health conditions. OBJECTIVE: This study aimed to examine the relative contribution of extraversion, agreeableness, neuroticism, positive attitudes toward OSGs on social networking sites, and typical past OSG use patterns in predicting perceived OSG benefit in an OSG for parents and caregivers of children with neurodevelopmental disorders. METHODS: A mixed methods, longitudinal design was used to collect data from 81 parents across Canada. Attitudes toward OSGs and typical OSG use patterns were assessed using the author-developed Attitudes Toward OSGs subscale (eg, "Online support groups are a place to get and give emotional support") and Past Behaviors in OSGs subscale (eg, "How often would you typically comment on posts?") administered at baseline-before OSG membership. The personality traits of extraversion, agreeableness, and neuroticism were assessed at baseline using the Ten-Item Personality Inventory. Perceived OSG benefit was assessed using the author-developed Perceived OSG Benefit scale (eg, "Overall, did you feel supported by other members in this group?"), administered 2 months after the initiation of OSG membership. RESULTS: A hierarchical regression analysis found that extraversion was the only variable that significantly predicted perceived OSG benefit (R2=0.125; P<.001). CONCLUSIONS: The key suggestions for improving future OSGs were facilitating more in-depth, customized, and interactive content in OSGs.
RESUMO
Introduction: Coronavirus disease 2019 is a global health threat often accompanied with coagulopathy. Despite use of thromboprophylaxis in this population, thrombotic event rates are high. Materials and methods: This was a multicenter, retrospective cohort study comparing the safety and effectiveness of thromboprophylaxis strategies at 2 institutions in hospitalized patients with coronavirus disease 2019. Regimen A utilized a higher-than-standard thromboprophylaxis dosage and Regimen B received full-dose anticoagulation for any D-dimer 3 mcg/mL or greater and prophylactic for less than 3 mcg/mL. The primary outcome compared the rate of thrombotic events between treatment groups. Secondary endpoints compared rates of major or clinically relevant non-major bleeding as well as the proportion of patients in each group experiencing thrombotic events within 30 days of discharge. Results: One-hundred fifty-three patients were included in the analysis, 64 receiving Regimen A and 89 receiving Regimen B. Seven (4.6%) thrombotic events occurred, 3 (4.7%) in patients receiving Regimen A, and 4 (4.5%) in Regimen B (P = 1.0). Twelve patients (13.5%) receiving Regimen B had a bleeding event versus 2 (3.1%) in Regimen A (P = .04), half of which were major in each group. All patients who bled in either treatment group were receiving mechanical ventilation, and 12 of 14 were receiving full-dose anticoagulation. One patient receiving Regimen A was readmitted with a pulmonary embolism. Conclusions: In this study, the thromboprophylactic regimen impacted bleeding, but no significant difference was seen with thrombotic outcomes. Almost all patients who experienced a bleed were mechanically ventilated and receiving full-dose anticoagulation. The use of full-dose anticoagulation should be cautioned in this population without an additional indication.