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Background: The Essential Tremor Rating Assessment Scale (TETRAS) is a popular scale for essential tremor (ET), but its activities of daily living (ADL) and performance (P) subscales are based on a structured interview and physical exam. No patient-reported outcome (PRO) scale for ET has been developed according to US regulatory guidelines. Objective: Develop and validate a TETRAS PRO subscale. Methods: Fourteen items, rated 0-4, were derived from TETRAS ADL and structured cognitive interviews of 18 ET patients. Convergent validity analyses of TETRAS PRO versus TETRAS ADL, TETRAS-P, and the Quality of Life in Essential Tremor Questionnaire (QUEST) were computed for 67 adults with ET or ET plus. Test-retest reliability was computed at intervals of 1 and 30 days. The influence of mood (Hospital Anxiety and Depression Scale, HADS) and coping behaviors (Essen Coping Questionnaire, ECQ) was examined with multiple linear regression. Results: TETRAS PRO was strongly correlated (r > 0.7) with TETRAS ADL, TETRAS-P, and QUEST and exhibited good to excellent reliability (Cronbach alpha 95%CI = 0.853-0.926; 30-day test-retest intraclass correlation 95%CI = 0.814-0.921). The 30-day estimate of minimum detectable change (MDC) was 6.6 (95%CI 5.2-8.0). TETRAS-P (rsemipartial = 0.607), HADS depression (rsemipartial = 0.384), and the coping strategy of information seeking and exchange of experiences (rsemipartial = 0.176) contributed statistically to TETRAS PRO in a multiple linear regression (R2 = 0.67). Conclusions: TETRAS PRO is a valid and reliable scale that is influenced strongly by tremor severity, moderately by mood (depression), and minimally by coping skills. The MDC for TETRAS PRO is probably sufficient to detect clinically important change.
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Actividades Cotidianas , Temblor Esencial , Medición de Resultados Informados por el Paciente , Humanos , Temblor Esencial/fisiopatología , Temblor Esencial/psicología , Temblor Esencial/diagnóstico , Femenino , Masculino , Persona de Mediana Edad , Anciano , Reproducibilidad de los Resultados , Anciano de 80 o más Años , Calidad de Vida , Adulto , Encuestas y CuestionariosRESUMEN
Translation fidelity relies on accurate aminoacylation of transfer RNAs (tRNAs) by aminoacyl-tRNA synthetases (AARSs). AARSs specific for alanine (Ala), leucine (Leu), serine, and pyrrolysine do not recognize the anticodon bases. Single nucleotide anticodon variants in their cognate tRNAs can lead to mistranslation. Human genomes include both rare and more common mistranslating tRNA variants. We investigated three rare human tRNALeu variants that mis-incorporate Leu at phenylalanine or tryptophan codons. Expression of each tRNALeu anticodon variant in neuroblastoma cells caused defects in fluorescent protein production without significantly increased cytotoxicity under normal conditions or in the context of proteasome inhibition. Using tRNA sequencing and mass spectrometry we confirmed that each tRNALeu variant was expressed and generated mistranslation with Leu. To probe the flexibility of the entire genetic code towards Leu mis-incorporation, we created 64 yeast strains to express all possible tRNALeu anticodon variants in a doxycycline-inducible system. While some variants showed mild or no growth defects, many anticodon variants, enriched with G/C at positions 35 and 36, including those replacing Leu for proline, arginine, alanine, or glycine, caused dramatic reductions in growth. Differential phenotypic defects were observed for tRNALeu mutants with synonymous anticodons and for different tRNALeu isoacceptors with the same anticodon. A comparison to tRNAAla anticodon variants demonstrates that Ala mis-incorporation is more tolerable than Leu at nearly every codon. The data show that the nature of the amino acid substitution, the tRNA gene, and the anticodon are each important factors that influence the ability of cells to tolerate mistranslating tRNAs.
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Aminoacil-ARNt Sintetasas , Saccharomyces cerevisiae , Animales , Humanos , Saccharomyces cerevisiae/genética , Anticodón/genética , Leucina/genética , ARN de Transferencia de Leucina/genética , Código Genético , Codón , ARN de Transferencia/genética , Aminoacil-ARNt Sintetasas/genética , Aminoacil-ARNt Sintetasas/metabolismo , Alanina/genética , Mamíferos/genéticaRESUMEN
Background and Objectives: In clinical practice, we have observed that patients with Parkinson disease (PD) often have blepharoclonus, but its prevalence is not well described in the literature. Understanding the relative frequencies of blepharoclonus in PD and atypical parkinsonian syndromes may shed light on the diagnostic utility of this clinical sign. We aimed to assess (1) the frequency of blepharoclonus in patients with PD in a single-center cohort; (2) the association of blepharoclonus with disease stage, tremor severity, and non-motor symptoms; and (3) the frequency of blepharoclonus in synucleinopathy vs non-synucleinopathy-associated parkinsonism. Methods: We prospectively enrolled 85 patients, 75 with PD and 10 with atypical parkinsonism. Blepharoclonus was considered present if eyelid fluttering was sustained for >5 seconds after gentle eye closure. For each patient, demographics were collected, and we completed selected questions from the MDS-UPDRS (Unified Parkinson's Disease Rating Scale) part 2, REM Sleep Behavior Disorder Questionnaire, and MDS-UPDRS part 3 tremor assessments and recorded the presence/absence of dyskinesia. Results: 63 of 75 patients with PD (84%) had blepharoclonus. Among the 10 patients with atypical parkinsonism, 5 had synucleinopathy syndromes. Blepharoclonus was present in 3 of 5 patients with synucleinopathy and 0 of 5 patients with non-synucleinopathy-associated parkinsonian syndromes. Discussion: Blepharoclonus is prevalent in our PD cohort, suggesting possible utility as a clinical marker for PD. The absence of blepharoclonus in a patient with parkinsonism may suggest a non-synucleinopathy (e.g., tauopathy). Analysis of a larger cohort of both PD and atypical parkinsonism would be needed to establish whether blepharoclonus distinguishes PD from atypical parkinsonism, or synucleinopathy from non-synucleinopathy.
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Background: Myoclonus dystonia syndrome typically results from autosomal dominant mutations in the epsilon-sarcoglycan gene (SGCE) via the paternally expressed allele on chromosome 7q21. There is evidence that deep brain stimulation (DBS) is beneficial for this genotype, however, there are few prior case reports on DBS for myoclonus dystonia syndrome secondary to other confirmed genetic etiologies. Case Report: A 20-year-old female with concomitant Russell-Silver syndrome and myoclonus dystonia syndrome secondary to maternal uniparental disomy of chromosome 7 (mUPD7) presented for medically refractory symptoms. She underwent DBS surgery targeting the bilateral globus pallidus interna with positive effects that persisted 16 months post-procedure. Discussion: We present a patient with the mUPD7 genotype for myoclonus dystonia syndrome who exhibited a similar, if not superior, response to DBS when compared to patients with other genotypes. Highlights: This report outlines the first described case of successful deep brain stimulation treatment for a rare genetic variant of myoclonus dystonia syndrome caused by uniparental disomy at chromosome 7. These findings may expand treatment options for patients with similar conditions.
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Estimulación Encefálica Profunda , Distonía , Mioclonía , Síndrome de Silver-Russell , Femenino , Humanos , Adulto Joven , Adulto , Síndrome de Silver-Russell/genética , Distonía/complicaciones , Distonía/genética , Distonía/terapia , Disomía Uniparental , Mioclonía/complicaciones , Mioclonía/genética , Mioclonía/terapia , Estimulación Encefálica Profunda/métodosRESUMEN
Codon usage of each genome is closely correlated with the abundance of tRNA isoacceptors. How codon usage bias is resolved by tRNA post-transcriptional modifications is largely unknown. Here we demonstrate that the N1-methylation of guanosine at position 37 (m1G37) on the 3'-side of the anticodon, while not directly responsible for reading of codons, is a neutralizer that resolves differential decoding of proline codons. A genome-wide suppressor screen of a non-viable Escherichia coli strain, lacking m1G37, identifies proS suppressor mutations, indicating a coupling of methylation with tRNA prolyl-aminoacylation that sets the limit of cell viability. Using these suppressors, where prolyl-aminoacylation is decoupled from tRNA methylation, we show that m1G37 neutralizes differential translation of proline codons by the major isoacceptor. Lack of m1G37 inactivates this neutralization and exposes the need for a minor isoacceptor for cell viability. This work has medical implications for bacterial species that exclusively use the major isoacceptor for survival.
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Anticodón , Uso de Codones , Metilación , Supervivencia Celular/genética , ARN de Transferencia/genética , ARN de Transferencia/metabolismo , Codón/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Guanosina , Prolina/genéticaRESUMEN
Introduction: The Cervical Dystonia Patient Registry for Observation of OnabotulinumtoxinA Efficacy (CD PROBE) study (ClinicalTrials.gov identifier: NCT00836017), a multicenter, prospective, observational registry, was designed to identify real-world practices and outcomes for patients with cervical dystonia (CD) treated with onabotulinumtoxinA (onabotA). This secondary analysis from CD PROBE aims to determine the impact of presentation subtype on onabotA utilization and CD severity. Materials and Methods: The study cohort includes those who completed all 3 treatments, 4 office visits, and had data recorded for all assessments. Patient outcomes were assessed with the Cervical Dystonia Impact Profile (CDIP-58), Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), and determination of CD severity. Treatment interval, dose, and adverse events (AEs) were also recorded. Data were stratified according to prior exposure to botulinum toxins (BoNTs) and analyzed with descriptive statistics. Results: Torticollis was the most common presentation subtype in the study cohort (N = 350); the proportion of patients with torticollis was highest in those with severe disease. At each treatment, between 40.7 and 65.2% of those categorized as severe shifted to moderate or mild severity after treatment. Sustained improvements in CDIP-58 and TWSTRS were observed regardless of prior exposure to BoNTs. Dosing of onabotA generally increased from injection 1 to injection 3 and tended to be lower for patients naïve to BoNT. Median time interval between injections for the study cohort was 94.0 to 97.5 days. The most common AEs (dysphagia, muscular weakness) and injection intervals were similar between naïve vs. non-naïve patients; there were no serious treatment-related AEs. Conclusions: This secondary cohort analysis from CD PROBE demonstrates that three repeat treatments with onabotA at intervals consistent with labeling attenuated disease severity and neck pain, resulting in sustained improvements in physician- and patient-reported outcomes. No new safety signals were identified.
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Neurodegenerative disorders and leukodystrophies are progressive neurologic conditions that can occur following the disruption of intricately coordinated patterns of gene expression. Exome sequencing has been adopted as an effective diagnostic tool for determining the underlying genetic etiology of Mendelian neurologic disorders, however genome sequencing offer advantages in its ability to identify and characterize copy number, structural, and sequence variants in noncoding regions. Genome sequencing from peripheral leukocytes was performed on two patients with progressive neurologic disease of unknown etiology following negative genetic investigations including exome sequencing. RNA sequencing from peripheral blood was performed to determine gene expression patterns in one of the patients. Potential causative variants were matched to the patients' clinical presentation. The first proband was found to be heterozygous for a likely pathogenic missense variant in PLA2G6 (c.386T>C; p.Leu129Pro) and have an additional deep intronic variant in PLA2G6 (c.2035-926G>A). RNA sequencing indicated this latter variant created a splice acceptor site leading to the incorporation of a pseudo-exon introducing a premature termination codon. The second proband was heterozygous for a 261 kb deletion upstream of LMNB1 that included an enhancer region. Previous reports of copy number variants spanning this region of cis-acting regulatory elements corroborated its pathogenicity. When combined with clinical presentations, these findings led to a definitive diagnosis of autosomal recessive infantile neuroaxonal dystrophy and autosomal dominant adult-onset demyelinating leukodystrophy, respectively. In patients with progressive neurologic disease of unknown etiology, genome sequencing with the addition of RNA analysis where appropriate should be considered for the identification of causative noncoding pathogenic variants.
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Fosfolipasas A2 Grupo VI , Lamina Tipo B , Distrofias Neuroaxonales , Adulto , Secuencia de Bases , Fosfolipasas A2 Grupo VI/genética , Fosfolipasas A2 Grupo VI/metabolismo , Heterocigoto , Humanos , Lamina Tipo B/genética , Lamina Tipo B/metabolismo , Distrofias Neuroaxonales/genética , Distrofias Neuroaxonales/metabolismo , Sitios de Empalme de ARN , Secuenciación del ExomaRESUMEN
Intrapericardial diaphragmatic hernia (IPDH) is rare and most often a sequela of blunt thoracic trauma. The trans-abdominal or thoracic repair approaches are based on the acuteness of presentation and the expectation of encountering intrapericardial adhesions. We present an acute IPDH in an 80-year-old female patient managed with a laparoscopic trans-abdominal repair. Misdiagnosis and complications from the delayed presentation can be avoided with careful attention to the initial exam, imaging, and early operative repair if the patient is a candidate for the trans-abdominal approach.
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PURPOSE: To explore and compare the perceptions of nurses and parent/family advisors regarding pediatric nurses' moral obligations to children and families during an active shooter event in a children's hospital. DESIGN AND METHODS: This was a descriptive, exploratory study using survey methodology. A convenience sample of all licensed nurses and parent/family advisors from four children's hospitals across the United States were recruited. Surveys consisted of five primary domains including Appropriateness of National Guidelines, Personal Preparedness, Moral Accountability, Professional/Legal Concerns, and Personal Risk Expectations. Frequency counts and percentages were calculated for each survey item. RESULTS: Data from 874 pediatric nurses and 81 parent/family advisors were analyzed. Most respondents believed the Run-Hide-Fight campaign should be changed to Secure-Preserve-Fight. Only 30% of nurses felt mentally prepared to respond to an active shooter event. Most respondents agreed that nurses have a professional duty to protect their patients, but agreed that it was a personal choice, not a moral obligation, to accept potentially fatal risks. Hospital setting and patient vulnerability often influenced nurses' perceived obligations to patients. Most respondents reported they would not leave their patient/child during an active shooter event. CONCLUSIONS: Nurses feel morally obligated to patients, but must balance their own personal risk tolerance level against the need to protect patients and families. PRACTICE IMPLICATIONS: Hospitals need in-depth active shooter training for both nurses and parents as well as safety plans that address both evacuation protocols and measures to secure in place to protect the lives of patients, families, and staff.
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Obligaciones Morales , Enfermeras Pediátricas , Actitud del Personal de Salud , Niño , Hospitales Pediátricos , Humanos , Percepción , Encuestas y Cuestionarios , Estados UnidosRESUMEN
Background Anxiety and sleep disturbances are prevalent in Parkinson's disease (PD). Benzodiazepines (BZDs) are commonly used to treat these symptoms; however, they are associated with unfavorable side effects such as falls and cognitive slowing in the general non-PD population. Examining the effects of BZDs in PD is imperative as these medications could pose an increased risk to PD patients who are already vulnerable to falls and cognitive deficits. Methods Eighty-four patients diagnosed with idiopathic PD, of which 60% were Hispanic, underwent clinical evaluations including the Unified Parkinson's Disease Rating Scale (UPDRS) and comprehensive neuropsychological testing examining global cognition, language, visuospatial skills, memory, executive function, mood, and sleep quality. Thirty-six patients taking BZDs (BZD+) were compared to forty-eight patients not using any BZDs (BZD-) employing appropriate statistical tests depending on the measures' characteristics. Results BZD+ PD patients performed below the BZD- group on short-term memory but not on delayed recall, and performed better on a measure of visuospatial judgment. The BZD+ group endorsed more symptoms of anxiety and depression as well as poorer sleep quality. No significant differences were noted on other measures of cognition or motor function. Conclusion PD patients taking BZDs may experience select changes in cognition and mood. These changes are isolated and mild, and suggest that for some patients, BZDs may be a viable pharmacologic intervention that does not alter cognitive and motor function compared to those not taking these medications.
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BACKGROUND: Randomized clinical trials (RCTs) in Parkinson's disease (PD) have historically enrolled a low number of underrepresented minorities, lessening the generalizability of therapeutic developments. Although there are racial disparities in PD, little is known regarding neuropsychiatric symptoms and other nonmotor manifestations across all races/ethnicities. OBJECTIVE: To assess minority participation in PD trials evaluating the treatment of neuropsychiatric symptoms and explore underlying reasons. METHODS: We systematically searched PubMed and Embase for RCTs with a primary goal of treating neuropsychiatric symptoms in PD patients from 2000-2019. The pooled prevalence and 95% confidence interval (CI) of being white and enrolled in a clinical trial was calculated using the inverse variance method. I-square was calculated as a measure of heterogeneity and meta-regression was used to evaluate temporal trends. RESULTS: We included 63 RCTs with a total of 7,973 patients. In pooled analysis, 11 (17.5%) RCTs reported race/ethnicity. Of studies reporting this data, 5 African American (0.2%), 16 Hispanics (0.64%), and 539 Asians (21.44%) were enrolled. The pooled prevalence of being white in clinical trials was 98% (CI 0.97-0.98, pâ<â0.001), with 1,908 patients (75.8%). NIH-funded studies were most likely to report racial data when compared to non-NIH trials (pâ=â0.032). CONCLUSION: This large pooled analysis found a small percentage of RCTs reporting race/ethnicity when evaluating treatment of neuropsychiatric symptoms in PD. There was a disproportionally high number of white patients when compared to African Americans and Hispanics. More studies are needed to investigate this discrepancy and improve rates of & minority enrollment in PD trials.
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Síntomas Conductuales/terapia , Trastornos Mentales/terapia , Grupos Minoritarios/estadística & datos numéricos , Trastornos Neurocognitivos/terapia , Enfermedad de Parkinson/terapia , Selección de Paciente , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Síntomas Conductuales/etiología , Humanos , Trastornos Mentales/etiología , Trastornos Neurocognitivos/etiología , Enfermedad de Parkinson/complicacionesRESUMEN
INTRODUCTION: Palliative care in Parkinson's Disease (PD) is an effective intervention to improve quality of life, although historically, access and availability have been very restricted. METHODS: We performed a retrospective cohort study using the National Inpatient Sample (NIS) data from 2007 to 2014. Diagnostic codes were used to identify patients with PD and palliative care referral. Trends were calculated and logistic analysis performed to identify predictors of palliative care use. RESULTS: We identified 397,963 hospitalizations from 2007 to 2014 for patients with PD. Of these, 10,639 (2.67%) were referred to palliative care. The rate of consultation increased from 0.85% in 2007 to 4.49% in 2014. For 1 unit in year increase, there was 1.23 time the odds of receiving palliative consultation (OR 1.23, CI 1.21-1.25, p < 0.0001). Hispanics (OR 0.90, CI 0.81-1.01, p = 0.0550), Black (OR 0.90, CI 0.81-1.01, p = 0.0747) and White patients had similar rates of referral after adjustment. Women were less likely to be referred to palliative care (OR 0.90, CI 0.87-0.94, p < 0.0001). Other factors strongly associated with a higher rate of referrals included private insurance when compared to Medicare (OR 2.14, CI 1.89-2.41, p < 0.0001) and higher income (OR 1.41, CI 1.30-1.53, p < 0.0001). CONCLUSION: There has been a significant increase in palliative care referrals among hospitalized patients with PD in the US, although the overall rate remains low. After controlling for confounders, racial and ethnic disparities were not found. Women, patients with Medicare/Medicaid, and those with lower income were less likely to be referred to palliative care.
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Pacientes Internos/estadística & datos numéricos , Medicare/tendencias , Cuidados Paliativos/tendencias , Enfermedad de Parkinson/rehabilitación , Negro o Afroamericano , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Calidad de Vida , Estudios Retrospectivos , Estados Unidos , Población BlancaRESUMEN
Advanced Parkinson disease (PD) is characterized by the presence of motor fluctuations becoming the focus of treatment, prominent postural instability, significant disability despite levodopa therapy, and the presence of symptoms refractory to levodopa therapy. In this article, the authors review the motor manifestations of patients with advanced PD, as well as the most common pharmacologic and nonpharmacologic available therapies.
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Discinesias , Enfermedad de Parkinson , Manejo de Atención al Paciente/métodos , Trastornos Psicomotores , Anciano , Progresión de la Enfermedad , Discinesias/etiología , Discinesias/terapia , Humanos , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/terapia , Gravedad del Paciente , Trastornos Psicomotores/etiología , Trastornos Psicomotores/terapiaRESUMEN
OBJECTIVES: This study sought to determine whether there is a gender disparity in patients undergoing deep brain stimulation (DBS) surgery for Parkinson's disease (PD) at a single health system, and better understand the reasons for this discrepancy. MATERIALS AND METHODS: We analyzed data from the University of Miami DBS Database, which included 3251 PD patients, using chi-square, repeated measures ANOVA, and t tests to examine gender differences in the number of patients referred for surgery, reasons for referral, number receiving/not receiving surgery, reasons for not receiving surgery, and postsurgical outcomes. RESULTS: During the study period, 207 PD patients were referred for DBS (75.8% male), and 100 underwent surgery (77.0% male). Of those who did not receive surgery, the most common reasons were need for further medical optimization (26.2%), suboptimal performance on neuropsychological evaluation (22.4%), other reason (20.6%), lost to follow-up (18.7%), or patient preference (12.2%). However, in women one of the most common reasons was patient preference (28.0%), and this was significant compared to men (p < 0.001). Men were more likely to be lost to follow-up (p = 0.046). There was no statistically significant difference in postsurgical outcomes. CONCLUSIONS: Despite similar postsurgical improvements, women were less likely to undergo DBS surgery due to their own preference, while men were more likely to be lost to follow-up. These data underscore the need for increased education and awareness of DBS so that all patients with PD who qualify for surgery can benefit from this procedure.
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Estimulación Encefálica Profunda/psicología , Disparidades en Atención de Salud , Enfermedad de Parkinson/psicología , Enfermedad de Parkinson/cirugía , Prioridad del Paciente/psicología , Caracteres Sexuales , Anciano , Estimulación Encefálica Profunda/tendencias , Femenino , Estudios de Seguimiento , Disparidades en Atención de Salud/tendencias , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnósticoRESUMEN
INTRODUCTION: We report the prevalence of abnormal tandem gait (TG) in patients with idiopathic Parkinson disease (PD) and its association with symptoms of subjective unsteadiness, falls, freezing of gait, and cognitive impairment. METHODS: We assessed subjective balance impairment, fall history, antero-posterior postural instability, and TG in PD patients (Hoehn and Yahr (HY) stage 0-4). We recorded the age, sex, current medications, HY stage, Schwab and England (S&E) scale score, and MOCA score for each patient. Logistic regression was used to evaluate age-adjusted associations between TG and other demographic and clinical factors. RESULTS: A total of 102 patients with PD were assessed. Of those, 63.5% of HY 2 patients and 100% of HY 2.5 and 3 patients had a TG abnormality. The presence of TG abnormality was associated with subjective imbalance, falls, freezing of gait, S&Eâ¯<â¯80, and MOCA score <24 after adjustment for age. CONCLUSIONS: TG abnormality is common in PD, precedes the development of antero-posterior postural instability, is associated with cognitive impairment, and may predict fall risk. A longitudinal study will help determine if TG is a predictor of impending progression from HY 2 to HY 3.