Characterizing Heart Rate Response During Upper Extremity Repetitive Task Practice in Chronic Stroke.

IMPORTANCE: Although the cardiopulmonary benefits of aerobic exercise poststroke are well-established, typical stroke rehabilitation does not elicit an aerobic response. OBJECTIVE: To characterize heart rate response during upper extremity repetitive task practice (RTP) and determine factors that predict a higher aerobic intensity during RTP. DESIGN: Secondary analysis of a subset of data from a randomized clinical trial. SETTING: Research laboratory in a large academic medical center. PARTICIPANTS: Patients with chronic stroke (N = 19). INTERVENTION: Participants received 90 min of RTP for 24 sessions across 8 wk. OUTCOMES AND MEASURES: Aerobic intensity as measured by heart rate reserve (HRR) during RTP. RESULTS: A total of 2,968 tasks were included in the analysis. Of the tasks performed, approximately 79.5% elicited a very light aerobic response (<30% HRR), 10.2% elicited a light aerobic response (30%-39% HRR), and 10.3% elicited a moderate to vigorous intensity aerobic response (≥40% HRR). Of the tasks that elicited a moderate to vigorous intensity aerobic response, 54.1% were performed in standing, 79.7% were gross motor in nature, and 27.9% had targets at or above shoulder height. Standing position, targets at or above shoulder height, and gross motor tasks predicted higher HRR (all ps < .001). CONCLUSIONS AND RELEVANCE: To maximize aerobic intensity during poststroke RTP, therapists should include gross motor tasks trained in standing with targets at or above shoulder height. Plain-Language Summary: The study characterizes heart rate response in stroke rehabilitation and identifies factors that predict a higher aerobic intensity during upper extremity repetitive task practice. Certain task characteristics were more likely to produce an aerobic response, including gross motor, targets at or above the shoulder, and a standing position. Occupational therapists should include gross motor tasks trained in standing with targets at or above shoulder height to maximize aerobic intensity during poststroke repetitive task practice. Monitoring heart rate may improve awareness of aerobic response to training.

Gait patterns during overground and virtual omnidirectional treadmill walking.

BACKGROUND: Omnidirectional treadmills (ODTs) offer a promising solution to the virtual reality (VR) locomotion problem, which describes the mismatch between visual and somatosensory information and contributes to VR sickness. However, little is known about how walking on ODTs impacts the biomechanics of gait. This project aimed to compare overground and ODT walking and turning in healthy young adults. METHODS: Fifteen young adults completed forward walk, 180° turn, and 360° turn tasks under three conditions: (1) overground, (2) on the Infinadeck ODT in a virtual environment without a handrail, and (3) on the ODT with a handrail. Kinematic data for all walking trials were gathered using 3D optical motion capture. RESULTS: Overall, gait speed was slower during ODT walking than overground. When controlling for gait speed, ODT walking resulted in shorter steps and greater variability in step length. There were no significant differences in other spatiotemporal metrics between ODT and overground walking. Turning on the ODT required more steps and slower rotational speeds than overground turns. The addition of the stability handrail to the ODT resulted in decreased gait variability relative to the ODT gait without the handrail. CONCLUSION: Walking on an ODT resembles natural gait patterns apart from slower gait speed and shorter step length. Slower walking and shorter step length are likely due to the novelty of physically navigating a virtual environment which may result in a more conservative approach to gait. Future work will evaluate how older adults and those with neurological disease respond to ODT walking.

A Novel Peritoneal Packing Method for Management of Hyperkalemia During Acute Kidney Injury in Trauma.

INTRODUCTION: United States Military operations in resource limited areas are increasing. Furthermore, future peer or near-peer conflicts will require caring for larger numbers of casualties with limited resources. In this setting, traditional renal replacement therapy is not feasible and novel methods are required to address severe acute kidney injury in austere environments lacking definitive therapies. Here, we describe experiments designed to determine the efficacy of a novel peritoneal packing material (Potassium Binding Pack-PBP, CytoSorbents INC) for the acute management of severe hyperkalemia. MATERIALS AND METHODS: Male swine (52 ±1 kg) were nephrectomized via midline laparotomy under a plane of anesthesia and randomized into one of two experimental groups (PBP & CON). Exogenous potassium was infused to achieve a serum potassium level of 7.5 mEq/L. Novel potassium absorbing packs (PBP) or sham packs (CON) were placed in the right and left upper quadrants, and the right and left paracolic gutters of the abdomen to simulate four-quadrant packing (n = 6, n = 5, respectively). Two liters of peritoneal dialysis fluid was instilled into the abdomen and temporary closure performed. Animals were observed for 12 hours. Serum and peritoneal fluid (dialysate) potassium levels were sampled at T = 15, 30, 60 min, and Q60min thereafter. Animals were humanely euthanized at the end of the observation period. RESULTS: Baseline characteristics were similar between groups. Pairwise analysis showed that serum potassium concentrations were significantly lower in the PBP group compared to CON at T = 540 and T = 720 (P = 0.006 and P = 0.015, respectively). Potassium concentrations were significantly lower in dialysate of the PBP group compared to CON at all time points after T = 15 (T = 30, P = 0.017; T = 60 through T = 720, P < 0.001). CONCLUSIONS: This is the first demonstration of an effective technology for the management of hyperkalemia in trauma in the absence of standard of care; renal replacement therapy. We identified that PBP was able to consistently maintain a concentration gradient between dialysate in the peritoneum and system potassium concentration throughout the experiment. Furthermore, systemic potassium concentrations were reduced in a clinically relevant manner in the PBP group compared to CON. This suggests that peritoneal packing technology for the management of metabolic disturbances in trauma has potential for clinical application. These results are preliminary and should be interpreted with caution.

An Augmented Reality Rifle Qualification Test for Return-to-Duty Assessment in Service Members.

INTRODUCTION: Variability in return-to-duty (RTD) decision-making following mild traumatic brain injury (mTBI) is a threat to troop readiness. Current RTD assessments lack military-specific tasks and quantitative outcomes to inform stakeholders of a service member's (SM) capacity to successfully perform military duties. Augmented reality (AR), which places digital assets in a user's physical environment, provides a technological vehicle to deliver military-relevant tasks to a SM to be used in the RTD decision-making process. In addition to delivering digital content, AR headsets provide biomechanical data that can be used to assess the integrity of the central nervous system in movement control following mTBI. The objective of this study was to quantify cognitive and motor performance on an AR rifle qualification test (RQT) in a group of neurologically healthy military SMs. MATERIALS AND METHODS: Data were collected from 111 healthy SMs who completed a basic (single-task) and complex (dual-task) RQT with a simulated M4 rifle. The complex scenario required the SM to perform the RQT while simultaneously answering arithmetic problems. Position data from the AR headset were used to capture postural sway, and the built-in microphone gathered responses to the arithmetic problems. RESULTS: There were no differences in the number of targets hit, trigger pull reaction time, and transition time from kneeling to standing between the basic and complex scenarios. A significant worsening in postural sway following kneel-to-stand transition was observed in the complex scenario. The average reaction time to answer the arithmetic problems was nearly 2 times slower than the average reaction time to pull the trigger to a displayed target in the complex scenario. CONCLUSION: The complex scenario provoked dual-task interference in SMs as evidenced by worsening postural sway and reaction time differences between the cognitive and motor tasks. An AR RQT provides objective and quantitative outcomes during a military-specific task. Greater precision in evaluating cognitive and motor performance during a military-relevant task has the potential to aid in the detection and management of SMs and their RTD following MTBI.

Older adults are impaired in the release of grip force during a force tracking task.

Age-related changes in force generation have been implicated in declines in older adult manual dexterity. While force generation is a critical aspect of the successful manipulation of objects, the controlled release of force represents the final component of dexterous activities. The impact of advancing age on the release of grip force has received relatively little investigation despite its importance in dexterity. The primary aim of this project was to determine the effects of age on the control of force release during a precision grip tracking task. Young adults (N = 10, 18-28 years) and older adults (N = 10, 57-77 years) completed a ramp-hold-release (0-35% of maximum grip force) force tracking task with their dominant hand. Compared to young adults, older adults were disproportionately less accurate (i.e., less time within target range) and had more error (i.e., greater relative root mean squared error) in the release of force, compared to generation of grip force. There was a significant difference between groups in two-point discrimination of the thumb, which was moderately correlated to force control across all phases of the task. The decline in force release performance associated with advanced age may be a result of sensory deficits and changes in central nervous system circuitry.

Pulmonary vein isolation plus adjunctive therapy for the treatment of atrial fibrillation: a systematic review and meta-analysis.

BACKGROUND: Pulmonary vein isolation (PVI) is the primary technique for ablation of atrial fibrillation (AF). It is unclear whether adjunctive therapies in addition to PVI can reduce atrial arrhythmia recurrence (AAR) compared to PVI alone in patients with AF. METHODS: A meta-analysis of randomized controlled trials comparing PVI plus an adjunctive therapy (autonomic modulation, linear ablation, non-pulmonary vein trigger ablation, epicardial PVI [hybrid ablation], or left atrial substrate modification) to PVI alone was conducted. The primary outcome was AAR. Cumulative odd's ratios (OR) and 95% confidence intervals (CI) were calculated for each treatment type. RESULTS: Forty-six trials were identified that included 8,500 participants. The mean age (± standard deviation) was 60.2 (±4.1) years, and 27.2% of all patients were female. The mean follow-up time was 14.6 months. PVI plus autonomic modulation and PVI plus hybrid ablation were associated with a relative 53.1% (OR 0.47; 95% CI 0.32 to 0.69; p < 0.001) and 59.1% (OR 0.41; 95% CI 0.23 to 0.75; p = 0.003) reduction in AAR, respectively, compared to PVI alone. All categories had at least moderate interstudy heterogeneity except for hybrid ablation. CONCLUSION: Adjunctive autonomic modulation and epicardial PVI may improve the effectiveness of PVI. Larger, multi-center randomized controlled trials are needed to evaluate the efficacy of these therapies.

The Microsoft HoloLens 2 Provides Accurate Biomechanical Measures of Performance During Military-Relevant Activities in Healthy Adults.

INTRODUCTION: Augmented reality systems, like the HoloLens 2 (HL2), have the potential to provide accurate assessments of mild traumatic brain injury (mTBI) symptoms in military personnel by simulating complex military scenarios while objectively measuring the user's movements with embedded motion sensors. The aim of this project was to determine if biomechanical measures of marching and squatting, derived from the HL2 motion sensors, were statistically equivalent, within 5%, to metrics derived from the gold-standard three-dimensional motion capture (MoCap) system. MATERIALS AND METHODS: Sixty-four adults (18-45 years; 34 males) completed a squatting and a marching task under single- (motor) and dual-task (motor + cognitive) conditions. Positional data from the HL2 and MoCap were simultaneously collected during the tasks and used to calculate and compare biomechanical outcomes. The HL2's augmented reality capabilities were utilized to deliver the cognitive component of the marching dual task. RESULTS: Equivalence testing indicated the HL2 and MoCap measures were within 5% in all squatting metrics-trial time, squat duration, squat velocity, squat depth, and dwell time. Marching metrics, including trial time, step count, stepping rate, and step interval, were also equivalent between the two systems. The mean reaction time for responses during the Stroop test was 810 (125) milliseconds per response. CONCLUSIONS: Biomechanical outcomes characterizing performance during two common military movements, squatting and marching, were equivalent between the HL2 and MoCap systems in healthy adults. Squatting and marching are two military-relevant tasks that require strength, motor coordination, and balance to perform, all of which are known to be affected by mTBI. Taken together, the data provide support for using the HL2 platform to deliver military-specific assessment scenarios and accurately measure performance during these activities. Utilizing objective and quantitative measures of motor function may enhance the management of military mTBI and reduce unnecessary risk to service members.

Development of the Troop Readiness Evaluation With Augmented Reality Return-to-Duty (Troop READY) Platform to Aid in the Detection and Treatment of Military Mild Traumatic Brain Injury.

INTRODUCTION: Mild traumatic brain injury (mTBI) is prevalent in service members (SMs); however, there is a lack of consensus on the appropriate approach to return to duty (RTD). Head-mounted augmented reality technology, such as the HoloLens 2, can create immersive, salient environments to more effectively evaluate relevant military task performance. The Troop Readiness Evaluation with Augmented Reality Return-to-Duty (READY) platform was developed to objectively quantify cognitive and motor performance during military-specific activities to create a comprehensive approach to aid in mTBI detection and facilitate appropriate RTD. The aim of this project was to detail the technical development of the Troop READY platform, the outcomes, and its potential role in the aiding detection and RTD decision-making post mTBI. The secondary aim included evaluating the safety, feasibility, and SM usability of the Troop READY platform. MATERIALS AND METHODS: The Troop READY platform comprises three assessment modules of progressing complexity: (1) Static and Dynamic Mobility, (2) Rifle Qualification Test, and (3) Small Unit Operations Capacity-Room Breach/Clearing Exercise. The modules were completed by 137 active duty SMs. Safety was assessed through monitoring of adverse events. Feasibility was assessed using the self-directed module completion rate. Usability was measured using the Systems Usability Scale. RESULTS: No adverse events occurred. Completion rates of the three modules ranged from 98 to 100%. In terms of usability, the mean Systems Usability Scale score of all participants was 83.92 (13.95), placing the Troop READY platform in the good-to-excellent category. Objective motor and cognitive outcomes were generated for each module. CONCLUSION: The Troop READY platform delivers self-directed, salient assessment modules to quantify single-task, dual-task, and unit-based performance in SMs. The resultant data provide insight into SM performance through objective outcomes and identify specific areas of executive or motor function that may be slow to recover following mTBI.

A Randomized Clinical Trial to Evaluate a Digital Therapeutic to Enhance Gait Function in Individuals With Parkinson's Disease.

BACKGROUND: Postural instability and gait dysfunction (PIGD) is a cardinal symptom of Parkinson's disease (PD) and is exacerbated under dual-task conditions. Dual-task training (DTT), enhances gait performance, however it is time and cost intensive. Digitizing DTT via the Dual-task Augmented Reality Treatment (DART) platform can expand the availability of an effective intervention to address PIGD. OBJECTIVE: The aim of this project was to evaluate DART in the treatment of PIGD in people with PD compared to a Traditional DTT intervention. It was hypothesized that both groups would exhibit significant improvements in gait, and the improvements for the DART group would be non-inferior to Traditional DTT. METHODS: A single-blind randomized controlled trial was conducted with 47 PD participants with PIGD. Both groups completed 16 therapeutic sessions over 8 weeks; the DART platform delivered DTT via the Microsoft HoloLens2. Primary outcomes included clinical ratings and single- and dual-task gait biomechanical outcomes. RESULTS: Clinical measures of PD symptoms remained stable for DART and Traditional DTT groups. However, both groups exhibited a significant increase in gait velocity, cadence, and step length during single- and multiple dual-task conditions following the interventions. Improvements in gait velocity in the DART group were non-inferior to Traditional DTT under the majority of conditions. CONCLUSION: Non-inferior improvements in gait parameters across groups provides evidence of the DART platform being an effective digital therapeutic capable of improving PIGD. Effective digital delivery of DTT has the potential to increase use and accessibility to a promising, yet underutilized and difficult to administer, intervention for PIGD. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Dual-task Augmented Reality Treatment for Parkinson's Disease (DART) NCT04634331; posted November 18, 2020.

Digitizing a Therapeutic: Development of an Augmented Reality Dual-Task Training Platform for Parkinson's Disease.

Augmented reality (AR) may be a useful tool for the delivery of dual-task training. This manuscript details the development of the Dual-task Augmented Reality Treatment (DART) platform for individuals with Parkinson's disease (PD) and reports initial feasibility, usability, and efficacy of the DART platform in provoking dual-task interference in individuals with PD. The DART platform utilizes the head-mounted Microsoft HoloLens2 AR device to deliver concurrent motor and cognitive tasks. Biomechanical metrics of gait and cognitive responses are automatically computed and provided to the supervising clinician. To assess feasibility, individuals with PD (N = 48) completed a bout of single-task and dual-task walking using the DART platform. Usability was assessed by the System Usability Scale (SUS). Dual-task interference was assessed by comparing single-task walking and walking during an obstacle course while performing a cognitive task. Average gait velocity decreased from 1.06 to 0.82 m/s from single- to dual-task conditions. Mean SUS scores were 81.3 (11.3), which placed the DART in the "good" to "excellent" category. To our knowledge, the DART platform is the first to use a head-mounted AR system to deliver a dual-task paradigm and simultaneously provide biomechanical data that characterize cognitive and motor performance. Individuals with PD were able to successfully use the DART platform with satisfaction, and dual-task interference was provoked. The DART platform should be investigated as a platform to treat dual-task declines associated with PD.

Community-based high-intensity cycling improves disease symptoms in individuals with Parkinson's disease: A six-month pragmatic observational study.

Participation in supervised, laboratory-based aerobic exercise protocols holds promise in slowing the progression of Parkinson's disease (PD). Gaps remain regarding exercise adherence and effectiveness of laboratory protocols translated to community-based programs. The aim of the project was to monitor exercise behaviour and evaluate its effect on disease progression over a 6 month period in people with PD participating in a community-based Pedalling for Parkinson's (PFP) cycling program. A pragmatic, observational study design was utilised to monitor exercise behaviour at five community sites. The Movement Disorders Society-Unified Parkinson's disease Rating Scale Motor III (MDS-UPDRS-III) and other motor and non-motor outcomes were gathered at enrollment and following 6 months of exercise. Attendance, heart rate, and cadence data were collected for each exercise session. On average, people with PD (N = 41) attended nearly 65% of the offered PFP classes. Average percent of age-estimated maximum heart rate was 69.3 ± 11.9%; average cadence was 74.9 ± 9.0 rpms. The MDS-UPDRS III significantly decreased over the 6-month exercise period (37.2 ± 11.7 to 33.8 ± 11.7, p = 0.001) and immediate recall significantly improved (42.3 ± 12.4 to 47.1 ± 12.7, p = 0.02). Other motor and non-motor metrics did not exhibit significant improvement. Participants who attended ~74% or more of available PFP classes experienced the greatest improvement in MDS-UPDRS III scores; of those who attended less than 74% of classes, cycling greater than or equal to 76 rpms lead to  improvement. Attendance and exercise intensity data indicated that a laboratory-based exercise protocol can be successfully translated to a community setting. Consistent attendance and pedalling at a relatively high cadence may be key variables to PD symptom mitigation. Improvement in clinical ratings coupled with lack of motor and non-motor symptom progression over 6 months provides rationale for further investigation of the real-world, disease-modifying potential of aerobic exercise for people with PD.

Components of a successful community-based exercise program for individuals with Parkinson's disease: Results from a participant survey.

OBJECTIVES: The aim of the project was to examine the personal beliefs, motivators, and barriers in people with Parkinson's disease (PwPD) relating to their participation in a year-round community-based cycling program, Pedaling for Parkinson's (PFP). DESIGN: Cross-sectional survey from a 12-month pragmatic study. SETTING: Five community-based PFP sites. MAIN OUTCOME MEASURES: A survey was designed to capture the attitudes and beliefs of those participating in a PFP program. Survey responses were rated on a 5-point Likert scale (1-5; higher number representing a more positive response) assessing the subdomains of Personal Beliefs and Knowledge, Health and Disability, Program, and Fitness Environment following a 12-month exercise observational period. RESULTS: A total of 40 PwPD completed the survey. Mean subdomain scores were as follows: 4.37 (0.41) for Personal Beliefs and Knowledge, 4.25 (0.65) for Health and Disability, 4.11 (0.53) for Program, and 4.35 (0.44) for Fitness Environment. There were no significant correlations between survey subdomains and demographic variables (age, years of education, years since diagnosis, years attending the PFP program, and disease severity) or subdomains and exercise behavior (cadence, attendance, and heart rate). CONCLUSIONS: Regardless of demographic variables and disease severity, PwPD who attended a PFP program enjoyed the class, felt that their PD symptoms benefited from exercise, and were motivated to exercise by their PD diagnosis. Factors such as location of the gym, cost, and transportation were important. With the growing body of PD literature supporting the role of exercise in potentially altering the disease trajectory, it is critical that communities adopt and implement exercise programs that meet the needs of PwPD and facilitate compliance.

Bicyclists injured by automobiles: helmet use and the burden of injury.

Background: Given the widespread use of bicycles on public roadways, bicyclists injured in automobile collisions present a familiar problem to trauma centers worldwide. The aims of this study are to characterize the current injury patterns and to quantify independent risk factors for preventable injury and death, with a focus on helmet utilization and traumatic brain injuries. Methods: This is a retrospective study using the American College of Surgeons Trauma Quality Improvement Program database for the period 2010 to 2016. Data were abstracted for bicyclists ≥16 years of age injured by an automobile. The primary outcome of interest was mortality. The secondary outcomes included intracranial, facial, and cervical spine injuries, as well as polytrauma. We used multivariate logistic regression to identify risk factors associated with outcomes. Results: Of the 980 955 cases in the database, 7159 (0.73%) were bicyclists involved in a collision with an automobile. The median age was 45 years and 85% of patients were male. Polytraumatic occurrences accounted for 58% of injuries. Helmet use was reported in 25.4% of cases, a rate that did not change significantly during the study period. Helmet utilization was higher in those aged >65 years and in patients located in the West and Northeast regions of the USA. Helmet use was associated with an overall lower incidence of all reported forms of intracranial injuries. Overall mortality was 7.4%. Independent risk factors associated with mortality included age >65, lack of helmet use, head injury, and abdominal injury. Discussion: Bicyclists injured in collisions with an automobile are at high risk of severe injury and mortality. Preventive strategies should target older bicyclists, helmet utilization, and increasing helmet accessibility for all bicyclists using roadways. Level of evidence: Level IV.

Lack of pharmacokinetic interaction between the HIV-1 maturation inhibitor GSK3640254 and combination oral contraceptives in healthy women.

AIMS: GSK3640254 is a next-generation maturation inhibitor likely to be coadministered with combined oral contraceptives in HIV-positive women. METHODS: This phase I, open-label, 1-way study assessed pharmacokinetic and pharmacodynamic interactions of GSK3640254 200 mg and ethinyl oestradiol 0.03 mg/levonorgestrel 0.15 mg once daily in healthy female participants who received ethinyl oestradiol/levonorgestrel for 10 days with a moderate-fat meal after which GSK3640254 was added from Days 11 to 21. Primary endpoints were area under the plasma concentration-time curve to the end of the dosing interval (AUC0-t ), maximum observed concentration (Cmax ) and plasma concentration at the end of the dosing interval (Cτ ) for ethinyl oestradiol and levonorgestrel. Serum follicle-stimulating hormone, luteinizing hormone and progesterone concentrations were determined. Adverse events were monitored. RESULTS: Among 23 enrolled participants, 17 completed the study. Geometric least squares mean ratios (with vs. without GSK3640254) of AUC0-t , Cmax and Cτ were 0.974, 0.970 and 1.050 for ethinyl oestradiol and 1.069, 1.032 and 1.083 for levonorgestrel, respectively. Three participants had elevated progesterone levels, which occurred before GSK3640254 administration in 2 participants. No participants had elevated follicle-stimulating hormone or luteinizing hormone values. Fourteen participants (61%) reported adverse events. Four participants reported asymptomatic elevated transaminase levels meeting liver-stopping criteria; of these, 3 events occurred before GSK3640254 administration and led to study withdrawal. CONCLUSION: Ethinyl oestradiol/levonorgestrel plus GSK3640254 coadministration did not affect steady-state pharmacokinetics or pharmacodynamics of ethinyl oestradiol and levonorgestrel in healthy female participants. No major tolerability findings were reported. Elevated liver transaminase levels were probably due to ethinyl oestradiol/levonorgestrel.

Qualitative Needs Assessment for the Development of Chronic Pain Group Medical Visits.

Group medical visits (GMVs) for patients with chronic pain are becoming more accessible and have been shown to be successful in furthering patient education on multidisciplinary, nonopioid interventions. Unfortunately, evidence suggests that many group visit models lack sustainability due to recruitment issues and retention rates. Additionally, most of the studies surrounding GMVs are located in primarily urban health centers, potentially limiting their generalizability. This study aims to identify patient interest in and barriers to GMVs for chronic pain and to explore how chronic pain impacts daily lives for GMV content optimization in a nonurban population. Nineteen participants age 18 to 65 years participated in semistructured phone interviews to generate a thematic analysis. Participants received their care from family practitioners at a suburban multiclinic academic medical group and were being prescribed at least 50 morphine milligram equivalents (MME) at the time of recruitment. Analysis generated two themes: (1) Participants expressed specific interest in GMVs with few barriers identified, and (2) Pain has a negative impact on mental health and most aspects daily life, creating a foundation for discussion in GMVs. Findings support significant patient interest in group medical visits for chronic pain, but careful planning is necessary to address patient needs, expectations, and barriers in order to ensure GMV sustainability.

A Phase I Evaluation of the Pharmacokinetics and Tolerability of the HIV-1 Maturation Inhibitor GSK3640254 and Tenofovir Alafenamide/Emtricitabine in Healthy Participants.

GSK3640254 is a next-generation maturation inhibitor that would likely be combined with standard antiretroviral agents to form a regimen of ≥2 fully active classes. This phase I, open-label, 2-period, 1-way study assessed potential pharmacokinetic (PK) interactions between GSK3640254 and tenofovir alafenamide/emtricitabine (TAF/FTC; including the metabolite tenofovir [TFV]) in healthy volunteers. Eligible participants received TAF/FTC 25/200 mg once daily (QD) on days 1 through 21 with a moderate-fat meal; GSK3640254 200 mg QD was added on days 15 through 21. Geometric least-squares mean ratios (GMRs) and 90% confidence intervals (CIs) were derived using linear mixed-effect models. Adverse events (AEs) and laboratory, electrocardiogram, and vital sign parameters were monitored. Sixteen participants, all male, received treatment; one withdrew because of treatment-related grade 1 urticaria. After TAF/FTC + GSK3640254 coadministration, TAF steady-state area under the plasma concentration-time curve from time zero to the end of the dosing interval and maximum observed concentration were 11% and 13% lower than when TAF/FTC was administered alone, with GMRs (90% CI) of 0.886 (0.75 to 1.04) and 0.874 (0.68 to 1.12), respectively. Steady-state PK of TFV and FTC was similar when TAF/FTC was administered alone or with GSK3640254. No clinically significant trends in tolerability or safety were observed. GSK3640254 200 mg QD did not meaningfully affect the steady-state PK of TAF, TFV, or FTC in healthy participants under fed conditions and was not associated with major tolerability or safety findings. These data support the further investigation of GSK3640254 for coadministration with TAF/FTC for the treatment of HIV. (This study has been registered at ClinicalTrials.gov under identifier NCT03836729.).

Phase I evaluation of pharmacokinetics and tolerability of the HIV-1 maturation inhibitor GSK3640254 and dolutegravir in healthy adults.

AIMS: GSK3640254, a novel, next-generation maturation inhibitor effective against a range of HIV polymorphisms with no cross-resistance to current antiretroviral therapy, could potentially be coadministered with dolutegravir as a 2-drug regimen. In this phase I study, pharmacokinetics and tolerability of GSK3640254 plus dolutegravir were assessed. METHODS: Healthy participants received dolutegravir 50 mg once daily (QD) on Days 1-5 in period 1, GSK3640254 200 mg QD on Days 1-7 in period 2, and dolutegravir 50 mg plus GSK3640254 200 mg QD on Days 1-7 in period 3. All treatments were administered with a moderate-fat meal 30 minutes prior to dosing. Pharmacokinetics parameters were derived by noncompartmental methods, and geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were derived using linear mixed effects models. Adverse events, laboratory measurements, electrocardiography and vital signs were monitored. RESULTS: Sixteen participants completed the study. GMRs (90% CIs) for dolutegravir area under the plasma concentration-time curve from time 0 to the end of the dosing interval at steady state, maximum observed concentration and plasma concentration at the end of the dosing interval were 1.17 (1.118-1.233), 1.09 (1.044-1.138) and 1.24 (1.160-1.315), respectively. The GMRs (90% CIs) for GSK3640254 were 1.04 (0.992-1.094), 0.99 (0.923-1.065) and 0.10 (0.939-1.056), respectively. Dolutegravir plus GSK3640254 coadministration did not meaningfully alter steady-state exposure to dolutegravir or GSK3640254. No clinically significant trends in tolerability or safety were observed. CONCLUSION: Coadministration of GSK3640254 with dolutegravir did not result in clinically significant drug interaction and was well tolerated.

Nimodipine improves cortical efficiency during working memory in healthy subjects.

The L-type calcium channel gene, CACNA1C, is a validated risk gene for schizophrenia and the target of calcium channel blockers. Carriers of the risk-associated genotype (rs1006737 A allele) have increased frontal cortical activity during working memory and higher CACNA1C mRNA expression in the prefrontal cortex. The aim of this study was to determine how the brain-penetrant calcium channel blocker, nimodipine, changes brain activity during working memory and other cognitive and emotional processes. We conducted a double-blind randomized cross-over pharmacoMRI study of a single 60 mg dose of oral nimodipine solution and matching placebo in healthy men, prospectively genotyped for rs1006737. With performance unchanged, nimodipine significantly decreased frontal cortical activity by 39.1% and parietal cortical activity by 42.8% during the N-back task (2-back > 0-back contrast; PFWE < 0.05; n = 28). Higher peripheral nimodipine concentrations were correlated with a greater decrease in activation in the frontal cortex. Carriers of the risk-associated allele, A (n = 14), had a greater decrease in frontal cortical activation during working memory compared to non-risk allele carriers. No differences in brain activation were found between nimodipine and placebo for other tasks. Future studies should be conducted to test if the decreased cortical brain activity after nimodipine is associated with improved working memory performance in patients with schizophrenia, particularly those who carry the risk-associated genotype. Furthermore, changes in cortical activity during working memory may be a useful biomarker in future trials of L-type calcium channel blockers.

Prefrontal cortex modulates firing pattern in the nucleus reuniens of the midline thalamus via distinct corticothalamic pathways.

The thalamus has long been recognized for its role in relaying sensory information from the periphery, a function accomplished by its "first-order" nuclei. However, a second category of thalamic nuclei, termed "higher-order" nuclei, have been shown instead to mediate communication between cortical areas. The nucleus reuniens of the midline thalamus (RE) is a higher-order nucleus known to act as a conduit of reciprocal communication between the medial prefrontal cortex (mPFC) and hippocampus. While anatomical and behavioural studies of RE are numerous, circuit-based electrophysiological studies, particularly those examining the impact of cortical input and the thalamic reticular nucleus (TRN) on RE neuron firing, are sparse. To characterize RE neuron firing properties and dissect the circuit dynamics of the infralimbic subdivision of the mPFC (ilPFC), the TRN and RE, we used in vivo, extracellular, single-unit recordings in male Sprague Dawley rats and manipulated neural activity using targeted pharmacological manipulations, electrical stimulation and a projection-specific implementation of designer receptors exclusively activated by designer drugs (DREADDs). We show that ilPFC inhibition reduces multiple burst firing parameters in RE, whereas ilPFC stimulation drives burst firing and dampens tonic firing. In addition, TRN inhibition reduces the number of spontaneously active neurons in RE. Finally, inhibition of ilPFC terminals in RE selectively enhances a subset of burst firing parameters. These findings demonstrate that ilPFC input, both via direct projections and via the TRN, can modulate RE neuron firing pattern in nuanced and complex ways. They also highlight the ilPFC-TRN-RE circuit as a likely critical component of prefrontal-hippocampal interactions.