Hypomyelinating leukodystrophies are heritable disorders defined by lack of development of brain myelin, but the cellular mechanisms of hypomyelination are often poorly understood. Mutations in TUBB4A, encoding the tubulin isoform tubulin beta class IVA (Tubb4a), result in the symptom complex of hypomyelination with atrophy of basal ganglia and cerebellum (H-ABC). Additionally, TUBB4A mutations are known to result in a broad phenotypic spectrum, ranging from primary dystonia (DYT4), isolated hypomyelination with spastic quadriplegia, and an infantile onset encephalopathy, suggesting multiple cell types may be involved. We present a study of the cellular effects of TUBB4A mutations responsible for H-ABC (p.Asp249Asn), DYT4 (p.Arg2Gly), a severe combined phenotype with hypomyelination and encephalopathy (p.Asn414Lys), as well as milder phenotypes causing isolated hypomyelination (p.Val255Ile and p.Arg282Pro). We used a combination of histopathological, biochemical and cellular approaches to determine how these different mutations may have variable cellular effects in neurons and/or oligodendrocytes. Our results demonstrate that specific mutations lead to either purely neuronal, combined neuronal and oligodendrocytic or purely oligodendrocytic defects that closely match their respective clinical phenotypes. Thus, the DYT4 mutation that leads to phenotypes attributable to neuronal dysfunction results in altered neuronal morphology, but with unchanged tubulin quantity and polymerization, with normal oligodendrocyte morphology and myelin gene expression. Conversely, mutations associated with isolated hypomyelination (p.Val255Ile and p.Arg282Pro) and the severe combined phenotype (p.Asn414Lys) resulted in normal neuronal morphology but were associated with altered oligodendrocyte morphology, myelin gene expression, and microtubule dysfunction. The H-ABC mutation (p.Asp249Asn) that exhibits a combined neuronal and myelin phenotype had overlapping cellular defects involving both neuronal and oligodendrocyte cell types in vitro. Only mutations causing hypomyelination phenotypes showed altered microtubule dynamics and acted through a dominant toxic gain of function mechanism. The DYT4 mutation had no impact on microtubule dynamics suggesting a distinct mechanism of action. In summary, the different clinical phenotypes associated with TUBB4A reflect the selective and specific cellular effects of the causative mutations. Cellular specificity of disease pathogenesis is relevant to developing targeted treatments for this disabling condition.
Because adolescents and emerging adults are frequently not offered HIV testing, and often decline tests when offered, we developed and tested a tablet-based intervention to increase HIV test rates among emergency department (ED) patients aged 13-24 years. Pediatric and adult ED patients in a high volume New York City hospital (N = 295) were randomized to receive a face-to-face HIV test offer, or to complete a tablet-based intervention that contained an HIV test offer delivered via computer. Test rates in both conditions were then compared to historic test rates in the same ED during the previous six months. Among participants aged 19 years and younger who were offered HIV testing and declined before enrollment in the study, participants in the tablet-based condition were 1.7 times more likely to test for HIV compared to participants in the face-to-face condition. Participants aged 19 years and younger were three times as likely to test for HIV compared to patients the same age who were treated in the previous six months (26.39%, n = 71 study participants vs. 10.29%, n = 189 prior patients, OR = 3.13, 2 = 54.76, p < 0.001). Protocols designed to offer HIV testing to all eligible patients can significantly increase adolescent test rates compared to standard practice. Because tablets are equally effective compared to face-to-face offers, and in some cases more so, EDs may consider tablet-based interventions that require fewer staff resources and may integrate more easily into high-volume workflows.
Background Health care providers (HCPs) in the emergency department (ED) frequently must decide whether to conduct or forego confidential conversations with adolescent patients about sensitive topics, such as those related to mental health, substance use, and sexual and reproductive health. The objective of this multicenter qualitative analysis was to identify factors that influence the conduct of confidential conversations with adolescent patients in the ED. Methods In this qualitative study, we conducted semistructured interviews of ED HCPs from five academic, pediatric EDs in distinct geographic regions. We purposively sampled HCPs across gender, professional title, and professional experience. We used the Theoretical Domains Framework (TDF) to develop an interview guide to assess individual and system‐level factors affecting HCP behavior regarding the conduct of confidential conversations with adolescents. Enrollment continued until we reached saturation. Interviews were recorded, transcribed, and coded by three investigators based on thematic analysis. We used the coded transcripts to collaboratively generate belief statements, which are first‐person statements that reflect shared perspectives. Results We conducted 38 interviews (18 physicians, 11 registered nurses, five nurse practitioners, and four physician assistants). We generated 17 belief statements across nine TDF domains. Predominant influences on having confidential conversations included self‐efficacy in speaking with adolescents alone, wanting to address sexual health complaints, maintaining patient flow, experiencing parental resistance and limited space, and having inadequate resources to address patient concerns and personal preconceptions about patients. Perspectives divided between wanting to provide focused medical care related only to their chief complaint versus self‐identifying as a holistic medical HCP. Conclusions The factors influencing the conduct of confidential conversations included multiple TDF domains, elucidating how numerous intersecting factors influence whether ED HCPs address sensitive adolescent health needs. These data suggest methods to enhance and facilitate confidential conversations when deemed appropriate in the care of adolescents in the ED.
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