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Sustained Treatment Response and Global Improvements With Long-Term Valbenazine in Patients With Tardive Dyskinesia
No full textPurpose/Background Using data from KINECT® 4, a phase 3, 48-week study of valbenazine, post hoc analyses were conducted to assess long-term outcomes that are relevant to the real-world management of tardive dyskinesia (TD). Methods/Procedures Post hoc analyses of the participants of the KINECT 4 study who completed 48 weeks of open-label valbenazine (40 or 80 mg) treatment were conducted. Valbenazine effects on TD were evaluated using the Abnormal Involuntary Movement Scale (AIMS), Clinical Global Impression of Change - TD (CGI-TD), and Patient Global Impression of Change (PGIC). Findings/Results Of 103 participants completing 48 weeks of treatment, 55% experienced clinically meaningful improvement (defined as ≥2-point reduction in AIMS total score [sum of items 1-7, evaluated by site raters]) by week 4; at week 48, 97% met this threshold. The percentage of completers who achieved AIMS total score response thresholds of ≥10% to ≥90% increased over time, with 86% of completers reaching ≥50% improvement. Of the 40 (39%) completers with AIMS ≥50% response at week 8, 38 (95%) sustained this response at week 48; 81% of those who did not meet this threshold at week 8 had achieved it by week 48. At week 48, more than 85% of completers achieved CGI-TD and PGIC ratings of much improved or very much improved. Implications/Conclusions The majority of participants who completed 48 weeks of treatment with once-daily valbenazine experienced substantial clinically meaningful and sustained TD improvements. These findings indicate that valbenazine can be a highly effective long-term treatment in patients with TD
Genetic Counseling Access and Service Delivery in New York State Is Variable for Parents of Infants With Complex CFTR Genotypes Conferring Uncertain Phenotypes
No full textBackground: New York State (NYS) utilizes a three-tiered cystic fibrosis newborn screening (CFNBS) algorithm that includes cystic fibrosis transmembrane conductance regulator (CFTR) gene sequencing. Infants with \u3e1 CFTR variant of potential clinical relevance, including variants of uncertain significance or varying clinical consequence are referred for diagnostic evaluation at NYS cystic fibrosis (CF) Specialty Care Centers (SCCs). Aims: As part of ongoing quality improvement efforts, demographic, screening, diagnostic, and clinical data were evaluated for 289 CFNBS-positive infants identified in NYS between December 2017 and November 2020 who did not meet diagnostic criteria for CF and were classified as either: CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis (CRMS/CFSPID) or CF carriers. Results: Overall, 194/289 (67.1%) had CFTR phasing to confirm whether the infant\u27s CFTR variants were in cis or in trans. Eighteen complex alleles were identified in cis; known haplotypes (p.R117H+5T, p.F508del+p.L467F, and p.R74W+p.D1270N) were the most common identified. Thirty-two infants (16.5%) with all variants in cis were reclassified as CF carriers rather than CRMS/CFSPID. Among 263 infants evaluated at an NYS SCC, 70.3% were reported as having received genetic counseling about their results by any provider, with 96/263 (36.5%) counseled by a certified genetic counselor. Conclusion: Given the particularly complex genetic interpretation of results generated by CFNBS algorithms including sequencing analysis, additional efforts are needed to ensure families of infants with a positive CFNBS result have CFTR phasing when needed to distinguish carriers from infants with CRMS/CFSPID, and access to genetic counseling to address implications of CFNBS results
The Efficacy & Molecular Mechanisms of a Terpenoid Compound Ganoderic Acid C1 on Corticosteroid-Resistant Neutrophilic Airway Inflammation: In Vivo and in Vitro Validation
No full textIntroduction: Neutrophil predominant airway inflammation is associated with severe and steroid-resistant asthma clusters. Previously, we reported efficacy of ASHMI, a three-herb TCM asthma formula in a steroid-resistant neutrophil-dominant murine asthma model and further identified Ganoderic Acid C1 (GAC1) as a key ASHMI active compound in vitro. The objective of this study is to investigate GAC1 effect on neutrophil-dominant, steroid-resistant asthma in a murine model. Methods: In this study, Balb/c mice were systematically sensitized with ragweed (RW) and alum and intranasally challenged with ragweed. Unsensitized/PBS challenged mice served as normal controls. Post sensitization, mice were given 4 weeks of oral treatment with GAC1 or acute dexamethasone (Dex) treatment at 48 hours prior to challenge. Pulmonary cytokines were measured by ELISA, and lung sections were processed for histology by H&E staining. Furthermore, GAC1 effect on MUC5AC expression and on reactive oxygen species (ROS) production in human lung epithelial cell line (NCI-H292) was determined by qRT-PCR and ROS assay kit, respectively. Computational analysis was applied to select potential targets of GAC1 in steroid-resistant neutrophil-dominant asthma. Molecular docking was performed to predict binding modes between GAC1 and Dex with TNF-α. Results: The result of the study showed that chronic GAC1 treatment, significantly reduced pulmonary inflammation (P \u3c 0.01–0.001 vs Sham) and airway neutrophilia (P \u3c 0.01 vs Sham), inhibited TNF-α, IL-4 and IL-5 levels (P \u3c 0.05–0.001 vs Sham). Acute Dex treatment reduced eosinophilic inflammation and IL-4, IL-5 levels, but had no effect on neutrophilia and TNF-α production. GAC1 treated H292 cells showed decreased MUC5AC gene expression and production of ROS (P \u3c 0.001 vs stimulated/untreated cells). Molecular docking results showed binding energy of complex GAC1-TNF was −10.8 kcal/mol. Discussion: GAC1 may be a promising anti-asthma botanical drug for treatment of steroid-resistant asthma
Ultra-Early Hemostatic Therapy for Acute Intracerebral Hemorrhage: An Updated Review
No full textIntracerebral hemorrhage (ICH) is the second most common type of stroke, accounting for approximately 10-20% of all strokes, and is linked to severe neurological disability and death. Since the most accurate predictor of outcome in patients with ICH is hematoma volume, there is a great need for pharmacologic therapy that can reduce hematoma expansion and resultant mass effect and edema. This is especially critical within the ultra-early window of 3-4 hours after the presentation. Hemostatic therapies are exceptionally important for those patients taking antiplatelet or anticoagulant medications to reverse the effects of these medications and therefore prevent hematoma expansion. Furthermore, the recent publication of the 2023 Guideline for the Management of Patients with Aneurysmal Subarachnoid Hemorrhage by the American Heart Association/American Stroke Association, the first update to the guidelines since 2012, underscores the importance of optimizing anticoagulation reversal for this population. The purpose of this selective, nonsystematic review is to examine current literature regarding the use of hemostatic therapies in ICH, with particular attention paid to antiplatelet, anticoagulation, and antifibrinolytic therapies
Robotic Postural Training With Epidural Stimulation for the Recovery of Upright Postural Control in Individuals With Motor Complete Spinal Cord Injury: A Pilot Study
No full textActivity-based training and lumbosacral spinal cord epidural stimulation (scES) have the potential to restore standing and walking with self-balance assistance after motor complete spinal cord injury (SCI). However, improvements in upright postural control have not previously been addressed in this population. Here, we implemented a novel robotic postural training with scES, performed with free hands, to restore upright postural control in individuals with chronic, cervical (n = 5) or high-thoracic (n = 1) motor complete SCI, who had previously undergone stand training with scES using a walker or a standing frame for self-balance assistance. Robotic postural training re-enabled and/or largely improved the participants’ ability to control steady standing, self-initiated trunk movements and upper limb reaching movements while standing with free hands, receiving only external assistance for pelvic control. These improvements were associated with neuromuscular activation pattern adaptations above and below the lesion. These findings suggest that the human spinal cord below the level of injury can generate meaningful postural responses when its excitability is modulated by scES, and can learn to improve these responses. Upright postural control improvements can enhance functional motor recovery promoted by scES after severe SCI
An Evidence-Based Update on Anticholinergic Use for Drug-Induced Movement Disorders
No full textDrug-induced movement disorders (DIMDs) are associated with use of dopamine receptor blocking agents (DRBAs), including antipsychotics. The most common forms are drug-induced parkinsonism (DIP), dystonia, akathisia, and tardive dyskinesia (TD). Although rare, neuroleptic malignant syndrome (NMS) is a potentially life-threatening consequence of DRBA exposure. Recommendations for anticholinergic use in patients with DIMDs were developed on the basis of a roundtable discussion with healthcare professionals with extensive expertise in DIMD management, along with a comprehensive literature review. The roundtable agreed that “extrapyramidal symptoms” is a non-specific term that encompasses a range of abnormal movements. As such, it contributes to a misconception that all DIMDs can be treated in the same way, potentially leading to the misuse and overprescribing of anticholinergics. DIMDs are neurobiologically and clinically distinct, with different treatment paradigms and varying levels of evidence for anticholinergic use. Whereas evidence indicates anticholinergics can be effective for DIP and dystonia, they are not recommended for TD, akathisia, or NMS; nor are they supported for preventing DIMDs except in individuals at high risk for acute dystonia. Anticholinergics may induce serious peripheral adverse effects (e.g., urinary retention) and central effects (e.g., impaired cognition), all of which can be highly concerning especially in older adults. Appropriate use of anticholinergics therefore requires careful consideration of the evidence for efficacy (e.g., supportive for DIP but not TD) and the risks for serious adverse events. If used, anticholinergic medications should be prescribed at the lowest effective dose and for limited periods of time. When discontinued, they should be tapered gradually. Graphical Abstract: (Figure presented.
Change in Neuropsychological Test Performance Seen in a Longitudinal Study of Patients With Post-Acute Sequelae of COVID-19: A 6-Month Follow-Up Study
No full textBackground: Post-acute sequelae of COVID-19 may include physical, psychiatric, and neurocognitive symptoms. Few studies of cognitive symptoms have been longitudinal, with many following participants briefly after infection and relying on subjective complaints, screening instruments, or computerized testing. This group previously reported diminished neuropsychological (NP) test performance in over half of 60 individuals tested in-person 7 months post-COVID-19, particularly those seeking care for cognitive complaints. The current study describes the initial and 6-month follow-up results of an expanded cohort of 75 participants. Objective: To measure longitudinal changes in neuropsychological test performance, as well as medical and psychiatric changes, post-COVID-19. Methods: Participants underwent NP, psychiatric, and medical assessments approximately 7 months after acute COVID-19 infection. Sixty-three (84%) returned approximately 6 months later for repeat evaluation. Results: At the initial visit, 29 (38.7%) met criteria for low NP performance, and 16 (21.3%) met criteria for extremely low NP performance. At 6-month follow-up, several NP domains that were significantly below normative values at the initial visit were no longer abnormal, with the exception of language. Only measures of delayed memory and fatigue showed significant improvements between the 2 time points. Conclusions: A substantial proportion of individuals recovered from acute COVID-19 infection have persistent neuropsychiatric symptoms over 1 year after infection. While the overall sample in this study showed some improvement in NP test performance relative to norms, only fatigue and delayed memory improved significantly between times 1 and 2. No individual declined in NP test performance, though relatively few individuals made significant clinical improvement, indicating the need for serial neuropsychiatric assessment and treatment supports. Longitudinal follow-up of this cohort is in progress
