FDA Public Workshop Summary-Coccidioidomycosis (Valley Fever): Considerations for Development of Antifungal Drugs.

Coccidioidomycosis is a fungal disease endemic to the southwestern United States, Mexico, and Central and South America. Prevalence rates are increasing steadily, and new endemic areas of Coccidioides are emerging. Standard treatment is often administered for months to decades, and intolerance to medications and treatment failures are common. No new treatments for coccidioidomycosis have been approved in the United States in nearly 40 years. On 5 August 2020, the US Food and Drug Administration convened experts in coccidioidomycosis from academia, industry, patient groups, and other government agencies to discuss the disease landscape and strategies to facilitate product development for treatment of coccidioidomycosis. This article summarizes the key topics concerning drug development for coccidioidomycosis presented by speakers and panelists during the workshop, such as unmet need, trial designs, endpoints, incentives, research and development support, and collaborations to facilitate antifungal drug development.

Multimodal Mental Practice Versus Repetitive Task Practice Only to Treat Chronic Stroke: A Randomized Controlled Pilot Study.

IMPORTANCE: Occupational therapists are the primary clinicians tasked with management of the more affected upper extremity (UE) after stroke. However, there is a paucity of efficacious, easy-to-use, inexpensive interventions to increase poststroke UE function. OBJECTIVE: To compare the effect of a multimodal mental practice (MMMP) regimen with a repetitive task practice (RTP)-only regimen on paretic UE functional limitation. DESIGN: Secondary analysis of randomized controlled pilot study data. SETTING: Outpatient clinical rehabilitation laboratory. PARTICIPANTS: Eighteen chronic stroke survivors exhibiting moderate, stable UE impairment. INTERVENTION: Participants administered RTP only participated in 45-min, one-on-one occupational therapy sessions 3 times per week for 10 wk; participants administered MMMP completed time-matched UE training sessions consisting of action observation, RTP, and mental practice, delivered in 15-min increments. Outcomes and Measures: The Action Research Arm Test, the UE section of the Fugl-Meyer Scale, and the Hand subscale of the Stroke Impact Scale (Version 3.0) were administered 1 wk before and 1 wk after intervention. RESULTS: The MMMP group exhibited significantly larger (p < .01) increases on all three outcome measures compared with the RTP group and surpassed minimal clinically important difference standards for all three UE outcome measures. CONCLUSIONS AND RELEVANCE: Because of the time-matched duration of MMMP and RTP, findings suggest that MMMP may be just as feasible as RTP to implement in clinical settings. Efforts to replicate results of this study in a large-scale trial are warranted. What This Article Adds: This study shows the efficacy of an easy-to-use protocol that significantly increased affected arm function even years after stroke.

Long-term spatial tracking of cells affected by environmental insults.

BACKGROUND: Harsh environments surrounding fetuses and children can induce cellular damage in the developing brain, increasing the risk of intellectual disability and other neurodevelopmental disorders such as schizophrenia. However, the mechanisms by which early damage leads to disease manifestation in later life remain largely unknown. Previously, we demonstrated that the activation of heat shock (HS) signaling can be utilized as a unique reporter to label the cells that undergo specific molecular/cellular changes upon exposure to environmental insults throughout the body. Since the activation of HS signaling is an acute and transient event, this approach was not intended for long-term tracing of affected cells after the activation has diminished. In the present study, we generated new reporter transgenic mouse lines as a novel tool to achieve systemic and long-term tracking of affected cells and their progeny. METHODS: The reporter transgenic mouse system was designed so that the activation of HS signaling through HS response element (HSE) drives flippase (FLPo)-flippase recognition target (FRT) recombination-mediated permanent expression of the red fluorescent protein (RFP), tdTomato. With a priority on consistent and efficient assessment of the reporter system, we focused on intraperitoneal (i.p.) injection models of high-dose, short prenatal exposure to alcohol (ethanol) and sodium arsenite (ethanol at 4.0 g/kg/day and sodium arsenite at 5.0 mg/kg/day, at embryonic day (E) 12 and 13). Long-term reporter expression was examined in the brain of reporter mice that were prenatally exposed to these insults. Electrophysiological properties were compared between RFP+ and RFP- cortical neurons in animals prenatally exposed to arsenite. RESULTS: We detected RFP+ neurons and glia in the brains of postnatal mice that had been prenatally exposed to alcohol or sodium arsenite. In animals prenatally exposed to sodium arsenite, we also detected reduced excitability in RFP+ cortical neurons. CONCLUSION: The reporter transgenic mice allowed us to trace the cells that once responded to prenatal environmental stress and the progeny derived from these cells long after the exposure in postnatal animals. Tracing of these cells indicates that the impact of prenatal exposure on neural progenitor cells can lead to functional abnormalities in their progeny cells in the postnatal brain. Further studies using more clinically relevant exposure models are warranted to explore this mechanism.

A double-blind, randomized, controlled study of two dose strengths of dalfampridine extended release on walking deficits in ischemic stroke.

BACKGROUND: Stroke-induced ischemia affects both cortex and underlying white matter. Dalfampridine extended release tablets (D-ER) enhance action potential conduction in demyelinated axons, which may positively affect post-stroke recovery. OBJECTIVE: Based on promising preliminary data, we compared efficacy of D-ER administered at 7.5 mg or 10 mg with placebo on post-stroke ambulation. Primary study outcome (response) was a ≥20% increase on the 2-minute walk test (2 MinWT) at 12 weeks after first drug administration. METHODS: This was a multicenter, randomized, placebo-controlled, 3-arm, parallel-group, safety and efficacy trial. After obtaining baseline measures of 2 MinWT, Walk-12, and Timed Up and Go, subjects entered a 2-week, single-blind placebo run-in period and were randomized 1:1:1 to receive 7.5 mg D-ER, 10 mg D-ER, or placebo, dosed twice-daily for 12 weeks. Follow-up evaluations occurred at weeks 14 and 16 when subjects were off study drug. RESULTS: The study was terminated early with 377 of planned 540 patients enrolled, due to no treatment effect. At week 12, mean increase in distances walked in 2 minutes were similar among the 3 study groups (14.9±40.0 feet; 19.4±39.6 feet; and 20.4±38.3 feet for placebo, 7.5 mg D-ER, and 10 mg D-ER, respectively). The proportion of subjects who showed ≥20% improvement on 2 MinWT at week 12 was 13.5%, 14.0%, and 19.0%, for placebo, 7.5 mg D-ER, and 10 mg D-ER, respectively; these were nonsignificant changes from baseline for all groups. CONCLUSIONS: D-ER at either a 7.5-mg or 10-mg dose did not significantly increase performance on the 2 MinWT in stroke survivors with gait impairment, although this study was terminated early before full enrollment. (Clinical Trial # NCT02271217).

Kcnn2 blockade reverses learning deficits in a mouse model of fetal alcohol spectrum disorders.

Learning disabilities are hallmarks of congenital conditions caused by prenatal exposure to harmful agents. These include fetal alcohol spectrum disorders (FASDs) with a wide range of cognitive deficiencies, including impaired motor skill development. Although these effects have been well characterized, the molecular effects that bring about these behavioral consequences remain to be determined. We previously found that the acute molecular responses to alcohol in the embryonic brain are stochastic, varying among neural progenitor cells. However, the pathophysiological consequences stemming from these heterogeneous responses remain unknown. Here we show that acute responses to alcohol in progenitor cells altered gene expression in their descendant neurons. Among the altered genes, an increase of the calcium-activated potassium channel Kcnn2 in the motor cortex correlated with motor learning deficits in a mouse model of FASD. Pharmacologic blockade of Kcnn2 improves these learning deficits, suggesting Kcnn2 blockers as a new intervention for learning disabilities in FASD.

An exploratory study of creating dementia-friendly businesses in the visitor economy: evidence from the UK.

Many governments have promoted the development of a civil society to encourage citizen involvement in addressing many of the grand social challenges such as the growing prevalence of dementia, as ageing becomes a major trend in developed societies. One outcome has been the development of Dementia Friendly Communities, created via Dementia Action Alliances (DAAs) in England, to enhance awareness, care and the experience of people with dementia in accessing services and facilities. These initiatives are based on engaging the business community and yet no research studies have examined this theme to date. Given the growing significance of leisure and tourism activities that people with dementia and family members engage in, this study examines the experience of business engagement with DAAs in the visitor economy in England. The notion of shared value articulated by Porter and Kramer (2011) is used as a basis for understanding the type of business engagement.

Classification of Mild Stroke: A Mapping Review.

Persons with mild stroke experience motor and cognitive impairments that negatively affect their health and quality of life. To address these deficits, it is essential for clinicians and researchers to precisely identify mild stroke survivors. Despite the fact that half of all strokes are categorized as mild, no standards exist on what constitutes a "mild" stroke. The purpose of this study is to summarize the current classification of mild stroke using a mapping review approach. Strategies to categorize "mild stroke" severity were explored in 188 papers indexed in the PubMed database. The results indicate that there was substantial variability in the procedures and scoring criteria used to determine mild stroke. To identify persons with mild stroke, researchers have largely applied assessment instruments developed to inform acute stroke care (eg, National Institutes of Health Stroke Scale, Modified Rankin Scale, Barthel Index). Unfortunately, these approaches demonstrate floor effects and fail to detect the long-term disabling impairments that often limit the outcomes of mild stroke survivors. Additional research is warranted to suggest an evidence-based mild stroke categorization strategy that enhances diagnosis, treatment, and referral decisions to the benefit of mild stroke survivors.

Interpreting Action Research Arm Test Assessment Scores to Plan Treatment.

Rasch keyforms can help interpret clinical assessment scores. The Action Research Arm Test (ARAT) is a commonly used assessment, yet no keyform currently exists. The aim is to provide a keyform for the ARAT and demonstrate how a clinician can use the keyform to design optimally challenging rehabilitation sessions. Secondary analysis of ARAT data ( n = 122) using confirmatory factor and Rasch analyses were used to examine the measurement properties and generate a keyform. The item standardized factor loadings were >0.40 (range = 0.82-0.96) and R2 values were >.60 (range = .65-.96). All items exhibited adequate infit statistics with point measure correlations >.60 (range = .72-.97). Person reliability was .98, and person separation was 7.07. Item-difficulty measures ranged from -2.78 logits to 2.64 logits. The ARAT has strong measurement properties, and a keyform was provided. We showed how the keyform can be utilized by clinicians to interpret scores, set goals, and plan treatment.

Effects of acute and chronic nicotine on catecholamine neurons of the nucleus of the solitary tract.

Nicotine is an addictive drug that has broad effects throughout the brain. One site of action is the nucleus of the solitary tract (NTS), where nicotine initiates a stress response and modulates cardiovascular and gastric function through nicotinic acetylcholine receptors (nAChRs). Catecholamine (CA) neurons in the NTS influence stress and gastric and cardiovascular reflexes, making them potential mediators of nicotine's effects; however nicotine's effect on these neurons is unknown. Here, we determined nicotine's actions on NTS-CA neurons by use of patch-clamp techniques in brain slices from transgenic mice expressing enhanced green fluorescent protein driven by the tyrosine hydroxylase promoter (TH-EGFP). Picospritzing nicotine both induced a direct inward current and increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in NTS-CA neurons, effects blocked by nonselective nAChR antagonists TMPH and MLA. The increase in sEPSC frequency was mimicked by nAChRα7 agonist AR-R17779 and blocked by nAChRα7 antagonist MG624. AR-R17779 also increased the firing of TH-EGFP neurons, an effect dependent on glutamate inputs, as it was blocked by the glutamate antagonist NBQX. In contrast, the nicotine-induced current was mimicked by nAChRα4ß2 agonist RJR2403 and blocked by nAChRα4ß2 antagonist DHßE. RJR2403 also increased the firing rate of TH-EGFP neurons independently of glutamate. Finally, both somatodendritic and sEPSC nicotine responses from NTS-CA neurons were larger in nicotine-dependent mice that had under gone spontaneous nicotine withdrawal. These results demonstrate that 1) nicotine activates NTS-CA neurons both directly, by inducing a direct current, and indirectly, by increasing glutamate inputs, and 2) NTS-CA nicotine responsiveness is altered during nicotine withdrawal.

Control of Feeding Behavior by Cerebral Ventricular Volume Transmission of Melanin-Concentrating Hormone.

Classical mechanisms through which brain-derived molecules influence behavior include neuronal synaptic communication and neuroendocrine signaling. Here we provide evidence for an alternative neural communication mechanism that is relevant for food intake control involving cerebroventricular volume transmission of the neuropeptide melanin-concentrating hormone (MCH). Results reveal that the cerebral ventricles receive input from approximately one-third of MCH-producing neurons. Moreover, MCH cerebrospinal fluid (CSF) levels increase prior to nocturnal feeding and following chemogenetic activation of MCH-producing neurons. Utilizing a dual viral vector approach, additional results reveal that selective activation of putative CSF-projecting MCH neurons increases food intake. In contrast, food intake was reduced following immunosequestration of MCH endogenously present in CSF, indicating that neuropeptide transmission through the cerebral ventricles is a physiologically relevant signaling pathway for energy balance control. Collectively these results suggest that neural-CSF volume transmission signaling may be a common neurobiological mechanism for the control of fundamental behaviors.

Ohio Modified Arm-Motor Ability Test (OMAAT): An Optimized Measure of Upper Extremity Functional Limitation in Hemiparetic Stroke.

This secondary analysis quantified the psychometric properties of the Ohio Modified Arm-Motor Ability Test (OMAAT) in a sample of neurologically stable chronic stroke survivors (n = 67, 40 men; mean age 59.8 yr, standard deviation = 12.8; 42 White, 23 Black, 2 other; 92.5% right-sided lesion; 44 ischemic stroke). Findings indicate high OMAAT internal consistency (Cronbach's α = .97, ordinal α = .98, Gugiu's bootstrap reliability = .97), unidimensionality, and strong positive factor loadings for all 20 OMAAT items. Convergent validity between OMAAT and Action Research Arm Test total scores was strong (r = .90, p < .0001). The OMAAT is the first short measure of upper extremity functional limitation available to clinicians and researchers that includes an administration manual and that has been examined using nonparametric psychometrics. A detailed administration manual is provided as a supplement to this article.

Visual-Motor Control of Drop Landing After Anterior Cruciate Ligament Reconstruction.

CONTEXT: Visual feedback is crucial in the control of human movement. When vision is obstructed, alterations in landing neuromuscular control may increase movements that place individuals at risk for injury. Anterior cruciate ligament (ACL) injury may further alter the motor-control response to alterations in visual feedback. The development of stroboscopic glasses that disrupt visual feedback without fully obscuring it has enabled researchers to assess visual-motor control during movements that simulate the dynamic demands of athletic activity. OBJECTIVE: To investigate the effect of stroboscopic visual-feedback disruption (SVFD) on drop vertical-jump landing mechanics and to determine whether injury history influenced the effect. DESIGN: Cohort study. SETTING: Movement-analysis laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 15 participants with ACL reconstruction (ACLR; 7 men, 8 women; age = 21.41 ± 2.60 years, height = 1.72 ± 0.09 m, mass = 69.24 ± 15.24 kg, Tegner Activity Scale score = 7.30 ± 1.30, time since surgery = 36.18 ± 26.50 months, hamstrings grafts = 13, patellar tendon grafts = 2) and 15 matched healthy control participants (7 men, 8 women; age = 23.15 ± 3.48 years, height = 1.73 ± 0.09 m, mass = 69.98 ± 14.83 kg, Tegner Activity Scale score = 6.77 ± 1.48). INTERVENTION(S): Drop vertical-jump landings under normal and SVFD conditions. MAIN OUTCOME MEASURE(S): The SVFD effect for knee sagittal- and frontal-plane excursions, peak moments, and vertical ground reaction force were calculated during landing and compared with previously established measurement error and between groups. RESULTS: The SVFD altered knee sagittal-plane excursion (4.04° ± 2.20°, P = .048) and frontal-plane excursion (1.98° ± 1.53°, P = .001) during landing above within-session measurement error. Joint-moment difference scores from full vision to the SVFD condition were not greater than within-session error. We observed an effect of ACLR history only for knee flexion (ACLR group = 3.12° ± 3.76°, control group = -0.84° ± 4.45°; P = .001). We did not observe an effect of side or sex. CONCLUSIONS: The SVFD altered sagittal- and frontal-plane landing knee kinematics but did not alter moments. Anterior cruciate ligament reconstruction may induce alterations in sagittal-plane visual-motor control of the knee. The group SVFD effect was on a level similar to that of an in-flight perturbation, motor-learning intervention, or plyometric-training program, indicating that visual-motor ability may contribute to knee neuromuscular control on a clinically important level. The individual effects of the SVFD indicated possible unique sensorimotor versus visual-motor movement strategies during landing.

Functional Brain Stimulation in a Chronic Stroke Survivor With Moderate Impairment.

OBJECTIVE: To determine the impact of transcranial direct current stimulation (tDCS) combined with repetitive, task-specific training (RTP) on upper-extremity (UE) impairment in a chronic stroke survivor with moderate impairment. METHOD: The participant was a 54-yr-old woman with chronic, moderate UE hemiparesis after a single stroke that had occurred 10 yr before study enrollment. She participated in 45-min RTP sessions 3 days/wk for 8 wk. tDCS was administered concurrent to the first 20 min of each RTP session. RESULTS: Immediately after intervention, the participant demonstrated marked score increases on the UE section of the Fugl-Meyer Scale and the Motor Activity Log (on both the Amount of Use and the Quality of Movement subscales). CONCLUSION: These data support the use of tDCS combined with RTP to decrease impairment and increase UE use in chronic stroke patients with moderate impairment. This finding is crucial, given the paucity of efficacious treatment approaches in this impairment level.

Navigated Transcranial Magnetic Stimulation: A Biologically Based Assay of Lower Extremity Impairment and Gait Velocity.

Objectives. (a) To determine associations among motor evoked potential (MEP) amplitude, MEP latency, lower extremity (LE) impairment, and gait velocity and (b) determine the association between the presence of a detectable MEP signal with LE impairment and with gait velocity. Method. 35 subjects with chronic, stable LE hemiparesis were undergone TMS, the LE section of the Fugl-Meyer Impairment Scale (LE FM), and 10-meter walk test. We recorded presence, amplitude, and latency of MEPs in the affected tibialis anterior (TA) and soleus (SO). Results. MEP presence was associated with higher LEFM scores in both the TA and SO. MEP latency was larger in subjects with lower LEFM and difficulty walking. Conclusion. MEP latency appears to be an indicator of LE impairment and gait. Significance. Our results support the precept of using TMS, particularly MEP latency, as an adjunctive LE outcome measurement and prognostic technique.

Giving Them a Hand: Wearing a Myoelectric Elbow-Wrist-Hand Orthosis Reduces Upper Extremity Impairment in Chronic Stroke.

OBJECTIVE: To determine the immediate effect of a portable, myoelectric elbow-wrist-hand orthosis on paretic upper extremity (UE) impairment in chronic, stable, moderately impaired stroke survivors. DESIGN: Observational cohort study. SETTING: Outpatient rehabilitation clinic. PARTICIPANTS: Participants exhibiting chronic, moderate, stable, poststroke, UE hemiparesis (N=18). INTERVENTIONS: Subjects were administered a battery of measures testing UE impairment and function. They then donned a fabricated myoelectric elbow-wrist-hand orthosis and were again tested on the same battery of measures while wearing the device. MAIN OUTCOME MEASURES: The primary outcome measure was the UE Section of the Fugl-Meyer Scale. Subjects were also administered a battery of functional tasks and the Box and Block (BB) test. RESULTS: Subjects exhibited significantly reduced UE impairment while wearing the myoelectric elbow-wrist-hand orthosis (FM: t17=8.56, P<.0001) and increased quality in performing all functional tasks while wearing the myoelectric elbow-wrist-hand orthosis, with 3 subtasks showing significant increases (feeding [grasp]: z=2.251, P=.024; feeding [elbow]: z=2.966, P=.003; drinking [grasp]: z=3.187, P=.001). Additionally, subjects showed significant decreases in time taken to grasp a cup (z=1.286, P=.016) and increased gross manual dexterity while wearing a myoelectric elbow-wrist-hand orthosis (BB test: z=3.42, P<.001). CONCLUSIONS: Results suggest that UE impairment, as measured by the Fugl-Meyer Scale, is significantly reduced when donning a myoelectric elbow-wrist-hand orthosis, and these changes exceeded the Fugl-Meyer Scale's clinically important difference threshold. Further, utilization of a myoelectric elbow-wrist-hand orthosis significantly increased gross manual dexterity and performance of certain functional tasks. Future work will integrate education sessions to increase subjects' ability to perform multijoint functional movements and attain consistent functional changes.

Increased Brain Sensorimotor Network Activation after Incomplete Spinal Cord Injury.

After complete spinal cord injury (SCI), activation during attempted movement of paralyzed limbs is sharply reduced, but after incomplete SCI-the more common form of human injury-it is unknown how attempts to move voluntarily are accompanied by activation of brain motor and sensory networks. Here, we assessed brain activation during ankle movement in subjects with incomplete SCI, among whom voluntary motor function is partially preserved. Adults with incomplete SCI (n = 20) and healthy controls (n = 15) underwent functional magnetic resonance imaging that alternated rest with 0.3-Hz right ankle dorsiflexion. In both subject groups, ankle movement was associated with bilateral activation of primary and secondary sensory and motor areas, with significantly (p < 0.001) greater activation in subjects with SCI within right hemisphere areas, including primary sensorimotor cortex and pre-motor cortex. This result was further evaluated using linear regression analysis with respect to core clinical variables. Poorer locomotor function correlated with larger activation within several right hemisphere areas, including pre- and post-central gyri, possibly reflecting increased movement complexity and effort, whereas longer time post-SCI was associated with larger activation in left post-central gyrus and bilateral supplementary motor area, which may reflect behaviorally useful adaptations. The results indicate that brain adaptations after incomplete SCI differ sharply from complete SCI, are related to functional behavioral status, and evolve with increasing time post-SCI. The results suggest measures that might be useful for understanding and treating incomplete SCI in human subjects.

Portable Myoelectric Brace Use Increases Upper Extremity Recovery and Participation But Does Not Impact Kinematics in Chronic, Poststroke Hemiparesis.

The authors examined the efficacy of an 8-week regimen combining repetitive task-specific practice (RTP) with a myoelectric brace (RTP+Myomo) on paretic upper extremity (UE; use in valued activities, perceived recovery, and reaching kinematics) in 12 subjects (4 men; M age = 53.5 years; mean time poststroke = 61.7 months). Seven subjects were administered RTP+Myomo therapy, and 5 were administered RTP only. Both groups participated in individualized, 45-min therapy sessions occurring 3 days/week over an 8-week period. The arm, hand ability, activities of daily living, and perceptions of recovery subscales of the Stroke Impact Scale (SIS), as well as UE reaching kinematics, assessed before and after the intervention. Subjects in the RTP+Myomo group showed greater improvements on all SIS subscales, with the recovery scale reaching statistical significance (p = .03). Subjects in the RTP-only group showed a greater increase in hand velocity in the reach up task (p = .02), but no changes were observed in the range of shoulder flexion or elbow extension during reaching. None of the changes in kinematic outcome measures significantly correlated with any of the changes in SIS subscales. RTP integrating myoelectric bracing may be more beneficial than RTP only in improving self-reported function and perceptions of overall recovery. The authors observed no changes in the range of elbow extension, and no relationship between self-reported improvements and changes in reaching kinematics.