RESUMEN
BACKGROUND: In response to surges in demand for intensive care unit (ICU) care related to the COVID-19 pandemic, health care systems have had to increase hospital capacity. One institution redeployed certified registered nurse anesthetists (CRNAs) as ICU clinicians, which necessitated training in ICU-specific electronic health record (EHR) workflows prior to redeployment. Under time- and resource-constrained settings, clinical informatics (CI) fellows could effectively be lead instructors for such training. OBJECTIVE: This study aimed to deploy CI fellows as lead EHR instructional trainers for clinician redeployment as part of an organization's response to disaster management. METHODS: CI fellows led a multidisciplinary team alongside subject matter experts to develop and deploy a tailored EHR curriculum comprising in-person classes and online video modules, leveraging high-fidelity simulated patient cases. The participants completed surveys immediately after the in-person training session and after deployment. RESULTS: Eighteen CRNAs participated, with 15 completing the postactivity survey (83%). All felt the training was useful and improved their EHR skills with a Net Promoter score of +87. Most (93%) respondents indicated the pace of the session was "just right," and 100% felt the clarity of instruction was "just right" or "extremely easy" to understand. Twelve participants (67%) completed the postdeployment survey. The training increased comfort in the ICU for all respondents, and 91% felt the training prepared them to work in the ICU with minimal guidance. All stated that the concepts learned would be useful in their anesthesia role. Fifty-eight percent viewed the online video library. CONCLUSION: This case report demonstrates that CI fellows with dual domain expertise in their clinical specialty and informatics are uniquely poised to deliver clinician redeployment EHR training in response to operational crises. Such opportunities can achieve fellowship educational goals while conserving physician resources which can be a strategic option as organizations plan for disaster management.
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COVID-19 , COVID-19/epidemiología , Curriculum , Registros Electrónicos de Salud , Becas , Humanos , PandemiasRESUMEN
OBJECTIVE: To explore the role of LAL (lysosomal acid lipase) in macrophage cholesterol efflux and whole-body reverse cholesterol transport. APPROACH AND RESULTS: Immortalized peritoneal macrophages from lal-/- mice showed reduced expression of ABCA1 (ATP-binding cassette transporter A1) and ABCG1 (ATP-binding cassette transporter G1), reduced production of the regulatory oxysterol 27-hydroxycholesterol, and impaired suppression of cholesterol synthesis on exposure to acetylated low-density lipoprotein when compared with lal+/+ macrophages. LAL-deficient mice also showed reduced hepatic ABCG5 (ATP-binding cassette transporter G5) and ABCG8 (ATP-binding cassette transporter G8) expression compared with lal+/+ mice. LAL-deficient macrophages loaded with [3H]-cholesteryl oleate-labeled acetylated low-density lipoprotein showed impaired efflux of released [3H]-cholesterol to apoA-I (apolipoprotein A-I), with normalization of [3H]-cholesteryl ester levels and partial correction of ABCA1 expression and cholesterol efflux to apoA-I when treated with exogenous rhLAL (recombinant human LAL protein). LAL-deficient mice injected intraperitoneally with lal-/- macrophages cholesterol loaded and labeled in the same way exhibited only 1.55±0.35% total injected [3H]-cholesterol counts appearing in the feces for 48 h (n=30), compared with 5.38±0.92% in lal+/+ mice injected with labeled lal+/+ macrophages (n=27), P<0.001. To mimic the therapeutic condition of delivery of supplemental LAL in vivo, injection of labeled lal-/- macrophages into lal+/+ mice resulted in a significant increase in reverse cholesterol transport (2.60±0.46% of 3H-cholesterol counts in feces at 48 hours [n=19]; P<0.001 when compared with injection into lal-/- mice). CONCLUSIONS: These results indicate a critical role for LAL in promoting both macrophage and whole-body reverse cholesterol transport and the ability of supplemental LAL to be taken up and correct reverse cholesterol transport in vivo.
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Colesterol/metabolismo , Macrófagos Peritoneales/enzimología , Esterol Esterasa/metabolismo , Transportador 1 de Casete de Unión a ATP/genética , Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5/metabolismo , Transportador de Casete de Unión a ATP, Subfamilia G, Miembro 8/genética , Transportador de Casete de Unión a ATP, Subfamilia G, Miembro 8/metabolismo , Animales , Apolipoproteína A-I/metabolismo , Transporte Biológico , Línea Celular , Colesterol/sangre , Heces/química , Lipoproteínas/genética , Lipoproteínas/metabolismo , Hígado/metabolismo , Ratones de la Cepa 129 , Ratones Noqueados , Esterol Esterasa/deficiencia , Esterol Esterasa/genéticaRESUMEN
BACKGROUND: Neurogenetic developmental conditions represent a heterogeneous group of rare inherited disorders with neurological manifestation during development. Treatments for these conditions have largely been supportive; however, a number of treatments are emerging which target the underlying physiology and offer great potential. Our aim was to present a state-of-the-art overview of the current and potential causal treatments available or under development for neurogenetic developmental conditions. METHODS: In this review, we focus on the following neurogenetic developmental conditions: (1) inborn errors of metabolism causing neurogenetic developmental conditions, (2) fragile X syndrome, (3) Rett syndrome, (4) tuberous sclerosis complex, 5) Down syndrome and other neurogenetic developmental conditions. RESULTS: A large group of inborn errors of metabolism leads to neurodevelopmental disability, affecting the central nervous system during infancy or childhood and can present with comorbidities such as intellectual developmental disability, epilepsy, atypical cerebral palsy, autism spectrum disorder, behavioral and psychiatric disturbances, for which causal treatments are discussed. CONCLUSIONS: The advent of these new disease-modifying therapies has the potential to reverse the underlying neural mechanisms of these debilitating conditions, which may provide prospect to affected individuals.
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Terapia de Reemplazo Enzimático/tendencias , Pruebas Genéticas/tendencias , Terapia Genética/tendencias , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/terapia , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/terapia , Niño , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/terapia , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Síndrome de Down/terapia , Predicción , Síndrome del Cromosoma X Frágil/diagnóstico , Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/terapia , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Discapacidad Intelectual/terapia , Trastornos del Neurodesarrollo/diagnóstico , Síndrome de Rett/diagnóstico , Síndrome de Rett/genética , Síndrome de Rett/terapia , Resultado del Tratamiento , Esclerosis Tuberosa/diagnóstico , Esclerosis Tuberosa/genética , Esclerosis Tuberosa/terapiaRESUMEN
Deep brain stimulation (DBS) has been used to treat secondary dystonias caused by inborn errors of metabolism with varying degrees of effectiveness. Here we report for the first time the application of DBS as treatment for secondary dystonia in a 22-year-old male with X-linked adrenoleukodystrophy (X-ALD). The disease manifested at age 6 with ADHD, tics, and dystonic gait, and deteriorated to loss of ambulation by age 11, and speech difficulties, seizures, and characteristic adrenal insufficiency by age 16. DBS in the globus pallidus internus was commenced at age 18. However, after 25 months, no improvement in dystonia was observed (Burke-Fahn-Marsden (BFM) scores of 65.5 and 62 and disability scores of 28 and 26, pre- and post-DBS, respectively) and the DBS device was removed. Treatment with dantrolene reduced skeletal muscle tone and improved movement (Global Dystonia Rating Scores from 5 to 1 and BFM score 42). Therefore, we conclude that DBS was a safe but ineffective intervention in our case with long-standing dystonia, whereas treatment of spasticity with dantrolene did improve the movement disorder in this young man with X-ALD.
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BACKGROUND: Inborn errors of metabolism (IEMs) have been anecdotally reported in the literature as presenting with features of cerebral palsy (CP) or misdiagnosed as 'atypical CP'. A significant proportion is amenable to treatment either directly targeting the underlying pathophysiology (often with improvement of symptoms) or with the potential to halt disease progression and prevent/minimize further damage. METHODS: We performed a systematic literature review to identify all reports of IEMs presenting with CP-like symptoms before 5 years of age, and selected those for which evidence for effective treatment exists. RESULTS: We identified 54 treatable IEMs reported to mimic CP, belonging to 13 different biochemical categories. A further 13 treatable IEMs were included, which can present with CP-like symptoms according to expert opinion, but for which no reports in the literature were identified. For 26 of these IEMs, a treatment is available that targets the primary underlying pathophysiology (e.g. neurotransmitter supplements), and for the remainder (n = 41) treatment exerts stabilizing/preventative effects (e.g. emergency regimen). The total number of treatments is 50, and evidence varies for the various treatments from Level 1b, c (n = 2); Level 2a, b, c (n = 16); Level 4 (n = 35); to Level 4-5 (n = 6); Level 5 (n = 8). Thirty-eight (57%) of the treatable IEMs mimicking CP can be identified by ready available metabolic screening tests in blood or urine, while the remaining IEMs require more specific and sometimes invasive tests. CONCLUSIONS: Limited by the rare nature of IEMs and incomplete information in the literature, we conclude that (1) A surprisingly large number of IEMs can present with CP symptoms, as 'CP mimics', (2) although individually rare, a large proportion of these diseases are treatable such that neurological damage can either be reversed or prevented, (3) clinician awareness of treatable CP mimics is important for appropriate screening, diagnosis, and early intervention, and (4) systematic studies are required to elucidate the collective frequency of treatable IEMs in CP.
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Parálisis Cerebral/diagnóstico , Parálisis Cerebral/terapia , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/terapia , Parálisis Cerebral/epidemiología , Diagnóstico Diferencial , Humanos , Errores Innatos del Metabolismo/epidemiología , Resultado del TratamientoRESUMEN
ATP-binding cassette transporter A1 (ABCA1) mediates the rate-limiting step in high density lipoprotein (HDL) particle formation, and its expression is regulated primarily by oxysterol-dependent activation of liver X receptors. We previously reported that ABCA1 expression and HDL formation are impaired in the lysosomal cholesterol storage disorder Niemann-Pick disease type C1 and that plasma HDL-C is low in the majority of Niemann-Pick disease type C patients. Here, we show that ABCA1 regulation and activity are also impaired in cholesteryl ester storage disease (CESD), caused by mutations in the LIPA gene that result in less than 5% of normal lysosomal acid lipase (LAL) activity. Fibroblasts from patients with CESD showed impaired up-regulation of ABCA1 in response to low density lipoprotein (LDL) loading, reduced phospholipid and cholesterol efflux to apolipoprotein A-I, and reduced α-HDL particle formation. Treatment of normal fibroblasts with chloroquine to inhibit LAL activity reduced ABCA1 expression and activity, similar to that of CESD cells. Liver X receptor agonist treatment of CESD cells corrected ABCA1 expression but failed to correct LDL cholesteryl ester hydrolysis and cholesterol efflux to apoA-I. LDL-induced production of 27-hydroxycholesterol was reduced in CESD compared with normal fibroblasts. Treatment with conditioned medium containing LAL from normal fibroblasts or with recombinant human LAL rescued ABCA1 expression, apoA-I-mediated cholesterol efflux, HDL particle formation, and production of 27-hydroxycholesterol by CESD cells. These results provide further evidence that the rate of release of cholesterol from late endosomes/lysosomes is a critical regulator of ABCA1 expression and activity, and an explanation for the hypoalphalipoproteinemia seen in CESD patients.
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Transportadoras de Casetes de Unión a ATP/metabolismo , Enfermedad de Acumulación de Colesterol Éster/genética , Lipoproteínas HDL/metabolismo , Enfermedad de Wolman/genética , Transportador 1 de Casete de Unión a ATP , Cloroquina/metabolismo , Colesterol/metabolismo , Enfermedad de Acumulación de Colesterol Éster/metabolismo , Medios de Cultivo Condicionados/farmacología , Fibroblastos/metabolismo , Humanos , Lipoproteínas/metabolismo , Mutación , Fosfolípidos/metabolismo , Proteínas Recombinantes/metabolismo , Piel/metabolismo , Esteroles/química , Enfermedad de Wolman/metabolismo , Enfermedad de WolmanRESUMEN
Oxysterol binding to liver X receptors (LXR) increases the transcription of genes involved in cholesterol efflux and disposal, such as ABCA1 (ATP-binding cassette transporter A1). Other cytoplasmic sterol-binding proteins could interact with this pathway by sequestering or delivering substrates and ligands. One potential regulator is OSBP (oxysterol-binding protein), which is implicated in the integration of sterol sensing/transport with sphingomyelin synthesis and cell signaling. Since these activities could impact the cholesterol efflux pathway, we examined whether OSBP was involved in LXR regulation and in expression and activity of ABCA1. Suppression of OSBP in Chinese hamster ovary cells by RNA interference resulted in increased ABCA1 protein expression and cholesterol efflux activity following induction with oxysterols or the synthetic LXR agonist TO901317. OSBP knockdown in J774 macrophages also increased ABCA1 expression in the presence and absence of LXR agonists. OSBP depletion did not affect ABCA1 mRNA levels or LXR activity. Rather, OSBP silencing increased the half-life of ABCA1 protein by 3-fold. Sphingomyelin synthesis was suppressed in OSBP-depleted cells treated with 25-hydroxycholesterol but not TO901317 or 22-hydroxycholesterol and did not correlate with ABCA1 stabilization. Moreover, co-transfection experiments revealed that reduction of ABCA1 protein by OSBP was prevented by a mutation in the sterol-binding domain but not by mutations that abrogated interaction with the Golgi apparatus or endoplasmic reticulum. Thus, OSBP opposes the activity of LXR by negatively regulating ABCA1 activity in the cytoplasm by sterol-binding domain-dependent protein destabilization.