NSF DARE-transforming modeling in neurorehabilitation: a patient-in-the-loop framework.

In 2023, the National Science Foundation (NSF) and the National Institute of Health (NIH) brought together engineers, scientists, and clinicians by sponsoring a conference on computational modelling in neurorehabiilitation. To facilitate multidisciplinary collaborations and improve patient care, in this perspective piece we identify where and how computational modelling can support neurorehabilitation. To address the where, we developed a patient-in-the-loop framework that uses multiple and/or continual measurements to update diagnostic and treatment model parameters, treatment type, and treatment prescription, with the goal of maximizing clinically-relevant functional outcomes. This patient-in-the-loop framework has several key features: (i) it includes diagnostic and treatment models, (ii) it is clinically-grounded with the International Classification of Functioning, Disability and Health (ICF) and patient involvement, (iii) it uses multiple or continual data measurements over time, and (iv) it is applicable to a range of neurological and neurodevelopmental conditions. To address the how, we identify state-of-the-art and highlight promising avenues of future research across the realms of sensorimotor adaptation, neuroplasticity, musculoskeletal, and sensory & pain computational modelling. We also discuss both the importance of and how to perform model validation, as well as challenges to overcome when implementing computational models within a clinical setting. The patient-in-the-loop approach offers a unifying framework to guide multidisciplinary collaboration between computational and clinical stakeholders in the field of neurorehabilitation.

Real-world outcomes in non-small-cell lung cancer patients with MET Exon 14 skipping mutation and brain metastases treated with capmatinib.

Aim: To assess real-world clinical outcomes in patients with non-small-cell lung cancer with MET exon 14 skipping mutation and brain metastases (BM) who received capmatinib, a recently approved MET inhibitor, in routine US clinical practice. Materials & methods: Patient data were collected using a retrospective medical record review, led by participating oncologists. Eligible patients initiated treatment with capmatinib in any line, after BM diagnosis, between May 2020 and June 2021. Data on real-world overall response rate (rwORR) and real-world progression-free survival (rwPFS) were descriptively analyzed. Results: 68 eligible patients were analyzed. In patients treated with first-line (1L) capmatinib (n = 55), the rwORR was 90.9% systemically and 87.3% intracranially; median systemic rwPFS was 14.1 months. Among radiation-naive patients on 1L capmatinib (n = 20), rwORR was 85.0%, both systemically and intracranially; median systemic rwPFS was 14.1 months. Conclusion: This study showed substantial systemic and intracranial effectiveness for capmatinib in real-world setting; findings were consistent for RT-naive patients.

Inclusion of actuator dynamics in simulations of assisted human movement.

Simulation of musculoskeletal systems using dynamic optimization is a powerful approach for studying the biomechanics of human movements and can be applied to human-robot interactions. The simulation results of human movements augmented by robotic devices may be used to evaluate and optimize the device design and controller. However, simulations are limited by the accuracy of the models which are usually simplified for computation efficiency. Typically, the powered robotic devices are often modeled as massless, ideal torque actuators that is without mass and internal dynamics, which may have significant impacts on the simulation results. This article investigates the effects of including the mass and internal dynamics of the device in simulations of assisted human movement. The device actuator was modeled in various ways with different detail levels. Dynamic optimization was used to find the muscle activations and actuator commands in motion tracking and predictive simulations. The results showed that while the effects of device mass and inertia can be small, the electrical dynamics of the motor can significantly impact the results. This outcome suggests the importance of using an accurate actuator model in simulations of human movement augmented by assistive devices. NOVELTY: Demonstrating the effects of including mass and internal dynamics of the actuator in simulations of assisted human movement A new OpenSim electric motor actuator class to capture the electromechanical dynamics for use in simulation of human movement assisted by powered robotic devices.

A model-based motion capture marker location refinement approach using inverse kinematics from dynamic trials.

Marker-based motion capture techniques are commonly used to measure human body kinematics. These techniques require an accurate mapping from physical marker position to model marker position. Traditional methods utilize a manual process to achieve marker positions that result in accurate tracking. In this work, we present an optimization algorithm for model marker placement to minimize marker tracking error during inverse kinematics analysis of dynamic human motion. The algorithm sequentially adjusts model marker locations in 3-D relative to the underlying rigid segment. Inverse kinematics is performed for a dynamic motion capture trial to calculate the tracking error each time a marker position is changed. The increase or decrease of the tracking error determines the search direction and number of increments for each marker coordinate. A final marker placement for the model is reached when the total search interval size for every coordinate falls below a user-defined threshold. Individual marker coordinates can be locked in place to prevent the algorithm from overcorrecting for data artifacts such as soft tissue artifact. This approach was used to refine model marker placements for eight able-bodied subjects performing walking trials at three stride frequencies. Across all subjects and stride frequencies, root mean square (RMS) tracking error decreased by 38.4% and RMS tracking error variance decreased by 53.7% on average. The resulting joint kinematics were in agreement with expected values from the literature. This approach results in realistic kinematics with marker tracking errors well below accepted thresholds while removing variance in the model-building procedure introduced by individual human tendencies.

Dynamic optimization of Gait with a Generalized Lower-Limb Prosthesis Model.

Predictive simulation of gait is a promising tool for robotic lower limb prosthesis design, but has been limited in its application to models of existing design types. We propose a modeling approach to find optimal prosthesis dynamics in gait simulations without constraining the prosthesis to follow kinematics allowed by a specific joint mechanism. To accomplish this, we render a transtibial prosthetic device as the composition of its resultant forces and moments as they act upon the prosthetic foot and socket and allow3 degree-of-freedom planar motion. The model is implemented into a human musculoskeletal model and used to solve dynamic optimizations of muscle and prosthesis controls to minimize muscle effort and loading on the residual limb during walking. The emphasis on muscle effort vs. limb loading is varied in the minimization objective and the resulting optimal prosthesis dynamics are compared. We found that muscle effort and socket loading measures were reduced for our prosthesis model compared to a revolute joint prosthesis model. We interpret large displacements in the linear axes to transfer energy to the plantarflexion action before toe-off and reduce loading at the socket-limb interface. Our results suggest this approach could assist in the design of non-biomimetic prostheses but requires experimental validation to assess our modeling assumptions, as well as progress toward increased fidelity of predictive simulation approaches more generally.

Design Optimization in Lower Limb Prostheses: A Review.

This paper aims to develop a knowledge base and identify the promising research pathways toward designing lower limb prostheses for optimal biomechanical and clinical outcomes. It is based on the literature search representing the state of the art in the lower limb prosthesis joint design and biomechanical analysis. Current design solutions are organized in terms of fulfilling four key functional roles: body support, propulsion, task flexibility, and loading relief. Biomechanical analyses of these designs reveal that the hypothesized outcomes are not consistently observed. We suggest that these outcomes may be improved by incorporating tools that can predict user performance metrics to optimize the device during the initial design process. We also note that the scope of the solution space of most current designs is limited by focusing on the anthropomorphic design approaches that do not account for the person's altered anatomy post-amputation. The effects of the prosthetic joint behavior on whole-body gait biomechanics and user experience are likewise under-explored. Two research paths to support the goal of better predicting the user outcomes are proposed: experimental parameterization of designs and model-based simulations. However, while work in these areas has introduced promising new possibilities, connecting both to improve real-world performance remains a challenge.

Administration options for pegfilgrastim prophylaxis: patient and physician preferences from a cross-sectional survey.

OBJECTIVE: Although clinical guidelines recommend administration of pegfilgrastim 1-4 days after a myelosuppressive chemotherapy cycle to decrease the incidence of febrile neutropenia (FN), some physicians administer pegfilgrastim on the same day as chemotherapy administration. A novel on-body injector (OBI) that automatically delivers pegfilgrastim the day after chemotherapy is also available. Our objective was to estimate patient and physician preferences among the pegfilgrastim administration options. METHODS: We conducted a cross-sectional survey of patients receiving pegfilgrastim and physicians prescribing pegfilgrastim. Respondents' preferences for pegfilgrastim administration options were elicited using direct elicitation; the relative importance of features associated with the options was estimated in a point-allocation exercise. Physicians considered two hypothetical patient profiles when completing the exercises. RESULTS: The samples included 200 patients and 200 physicians. Patients generally preferred the administration option with which they had experience. Among patients, 48.5% with previous in-clinic injections 24 hours after chemotherapy preferred this option; 56.8% with previous OBI administration preferred this option. For a clinically compromised patient, 37.5% of physicians preferred an in-clinic injection option; 49.5% preferred the OBI. For a less compromised patient, 55.5% preferred an in-clinic injection option; 28.0% preferred the OBI. Avoiding the need to return to the clinic was chosen most often as the most important treatment feature for patients and physicians. CONCLUSIONS: Patients and physicians identified that returning clinic visits for pegfilgrastim administration may be burdensome. A potential solution to mitigate this burden is the OBI, which allows adherence to the labeled use of pegfilgrastim without return visits to the clinic.

Quantifying the relative importance to patients of avoiding symptoms and outcomes of heart failure.

OBJECTIVE: To evaluate heart failure (HF) patients' disease knowledge and preferences for avoiding different disease outcomes. METHODS: An online survey was administered to 400 individuals with a self-reported diagnosis of HF to elicit relative importance weights (RIWs) for avoiding 11 potential HF symptoms and outcomes using best-worst scaling. The survey also included questions about individuals' HF knowledge, and demographic and disease-experience characteristics. Differences in RIWs among sub-groups, defined by HF knowledge, caregiver support, age, recent hospitalization or emergency room visit for HF, health-related quality-of-life, and cardiac device experience were examined. RESULTS: Relative to limitations in usual activities (RIW 1.00), respondents preferred avoiding severe, infrequent cardiovascular events (e.g. stroke [RIW 8.51], heart transplant [RIW 7.84], or heart attack [RIW 5.3]) most, followed by difficulty breathing (RIW 2.55), inability to enjoy life (RIW 1.84), cardiac device implantation (RIW 1.74), and atrial fibrillation (RIW 1.57). Patients preferred avoiding swelling (RIW 0.47) and fatigue (RIW 0.58) least. RIWs for avoiding severe, infrequent events were higher among those with high disease knowledge, those without caregivers, and those without a recent hospitalization or emergency room visit. CONCLUSIONS: Patients' preferences for avoiding HF outcomes vary across outcomes and by individuals' knowledge, caregiver status, and age. Healthcare providers should solicit and incorporate insights about patients' knowledge of HF and their preferences for avoiding HF outcomes into HF education and management planning efforts.

Mortality and Causes of Death in Patients with Sporadic Inclusion Body Myositis: Survey Study Based on the Clinical Experience of Specialists in Australia, Europe and the USA.

BACKGROUND: There is a paucity of data on mortality and causes of death (CoDs) in patients with sporadic inclusion body myositis (sIBM), a rare, progressive, degenerative, inflammatory myopathy that typically affects those aged over 50 years. OBJECTIVE: Based on patient records and expertise of clinical specialists, this study used questionnaires to evaluate physicians' views on clinical characteristics of sIBM that may impact on premature mortality and CoDs in these patients. METHODS: Thirteen physicians from seven countries completed two questionnaires online between December 20, 2012 and January 15, 2013. Responses to the first questionnaire were collated and presented in the second questionnaire to seek elaboration and identify consensus. RESULTS: All 13 physicians completed both questionnaires, providing responses based on 585 living and 149 deceased patients under their care. Patients were reported to have experienced dysphagia (60.2%) and injurious falls (44.3%) during their disease. Over half of physicians reported that a subset of their patients with sIBM had a shortened lifespan (8/13), and agreed that bulbar dysfunction/dysphagia/oropharyngeal involvement (12/13), early-onset disease (8/13), severe symptoms (8/13), and falls (7/13) impacted lifespan. Factors related to sIBM were reported as CoDs in 40% of deceased patients. Oropharyngeal muscle dysfunction was ranked as the leading feature of sIBM that could contribute to death. The risk of premature mortality was higher than the age-matched comparison population. CONCLUSIONS: In the absence of data from traditional sources, this study suggests that features of sIBM may contribute to premature mortality and may be used to inform future studies.

"Same-Day" administration of pegfilgrastim following myelosuppressive chemotherapy: clinical practice and provider rationale.

PURPOSE: To describe patient- and practice-related factors that physicians report affect their clinical decision to administer prophylactic pegfilgrastim to patients <24 h after completion of a myelosuppressive chemotherapy cycle (i.e., "same-day" pegfilgrastim). METHODS: Oncologists, hematologists, and hematologist-oncologists enrolled in a US national physician panel were invited to participate in a cross-sectional, web-based survey to assess physicians' reasons for prescribing "same-day" pegfilgrastim. Physicians were screened as eligible if they reported prescribing "same-day" pegfilgrastim within the previous 6 months. The survey assessed physician perspectives and physician-perceived patient/caregiver preferences. RESULTS: Of 17,478 invited physicians, 386 answered the screening questions; 151 (39.1 %) were eligible, agreed to participate, and completed the survey. Physicians estimated that overall 41.3 % of their patients treated with myelosuppressive chemotherapy received pegfilgrastim and that 31.6 % treated with pegfilgrastim received it on a "same-day" schedule. Approximately 36 % of physicians relied primarily on their clinical judgment when deciding to administer "same-day" pegfilgrastim. The clinical consideration reported most commonly by physicians as moderately or very important when deciding to administer "same-day" pegfilgrastim was previous febrile neutropenia (77.6 %). The most important patient-related consideration in the decision to administer "same-day" pegfilgrastim was patient/caregiver travel distance, and the most important practice-related consideration was the burden to the physician's practice of "next-day" administration (vs. same-day), reported by 84.7 % and 65.1 % of physicians as moderately or very important, respectively. CONCLUSIONS: While clinical judgment, patients' risk factors, and practice burden were principal influences favoring "same-day" pegfilgrastim administration, physician-perceived patient preferences and logistical barriers also have important roles in this decision.

Discovery of 6-Amino-2-{[(1S)-1-methylbutyl]oxy}-9-[5-(1-piperidinyl)pentyl]-7,9-dihydro-8H-purin-8-one (GSK2245035), a Highly Potent and Selective Intranasal Toll-Like Receptor 7 Agonist for the Treatment of Asthma.

Induction of IFNα in the upper airways via activation of TLR7 represents a novel immunomodulatory approach to the treatment of allergic asthma. Exploration of 8-oxoadenine derivatives bearing saturated oxygen or nitrogen heterocycles in the N-9 substituent has revealed a remarkable selective enhancement in IFNα inducing potency in the nitrogen series. Further potency enhancement was achieved with the novel (S)-pentyloxy substitution at C-2 leading to the selection of GSK2245035 (32) as an intranasal development candidate. In human cell cultures, compound 32 resulted in suppression of Th2 cytokine responses to allergens, while in vivo intranasal administration at very low doses led to local upregulation of TLR7-mediated cytokines (IP-10). Target engagement was confirmed in humans following single intranasal doses of 32 of ≥20 ng, and reproducible pharmacological response was demonstrated following repeat intranasal dosing at weekly intervals.

Cognitive interviewing in risk minimization survey development: patient and healthcare professional surveys.

Risk minimization programs are often required for selected drugs and other products to ensure that the benefits of these prescription products outweigh their risks. Regulators in the USA and Europe have recently called for more rigorous standards in developing measures for risk minimization program assessment. Cognitive pretesting interviews are a critical step in the development of survey instruments used to evaluate patients' and healthcare professionals' knowledge and behaviors associated with the safe use of products requiring a risk minimization program. This article is intended as a guide for the researcher who is charged with the development of survey instruments used in these programs and focuses on the role of cognitive pretesting interviews in successful survey instrument design, data analysis and interpretation.

Successful implementation of cognitive interviews in special populations.

The cognitive interview, with a focus on debriefing methods, was developed in the 1980s to identify sources of potential response error in surveys or questionnaires. With the release of the final US FDA guidance, titled 'Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims', cognitive interviews have gained importance and relevance both for concept elicitation and debriefing purposes in the context of instrument development. This article is intended as a guide for the researcher working with special populations in methods to foster successful cognitive interviews that meet FDA standards. While many of these techniques are broadly applicable, specific recommendations are provided for working with pediatric and cognitively challenged populations, as well as with individuals with communication difficulties.

Development, reliability, and validity of a new Preference and Satisfaction Questionnaire.

OBJECTIVES: Existing questionnaires that assess preference and/or satisfaction with postmenopausal bone loss treatments were reviewed and determined to be inadequate for the assessment of an oral pill versus a subcutaneous injection. The Preference and Satisfaction Questionnaire (PSQ) was developed to assess preference, satisfaction, and bother with a weekly oral tablet versus a once every 6 months subcutaneous injection for treatment of postmenopausal bone loss. METHODS: Questions were developed based on literature review and expert input. Content validity of the PSQ in this patient population was assessed among current or previous bisphosphonate users in group interviews, and item comprehension and readability were also evaluated. Reliability, validity, and structure of the questionnaire were assessed in two phase 3 randomized clinical trials. RESULTS: Twenty-four women participated in cognitive interviews and found the PSQ understandable and acceptable. Subsequently, 1583 trial participants took the PSQ. Interitem correlations, ranging from 0.50 to 0.97 for preference items, 0.85 to 0.94 for pill-satisfaction items, and 0.84 to 0.92 for injection-satisfaction items, and a well-fitting confirmatory factor analysis (root mean square error of approximation 0.04, nonnormed fit index 0.99, and root mean square residual 0.08) supported the structure of the instrument. Cronbach's alpha reliability values for pill satisfaction, injection satisfaction, pill bother, and injection bother were 0.93, 0.89, 0.82, and 0.61, respectively. Discriminative validity was indicated with better satisfaction and bother scores being related to adherence and the absence of adverse events. CONCLUSIONS: The PSQ is a valid and reliable measure and may be a valuable tool to assess patient preference and satisfaction with a weekly oral tablet and 6-month subcutaneous injection for postmenopausal bone loss.

2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists. 3. Synthesis, pharmacokinetics, and in vivo potency.

A short, efficient, and highly stereoselective synthesis of a series of (3R,6R,7R)-2,5-diketopiperazine oxytocin antagonists and their pharmacokinetics in rat and dog is described. Prediction of the estimated human oral absorption (EHOA) using measured lipophilicity (CHI log D) and calculated size (cMR) has allowed us to rank various 2,5-diketopiperazine templates and enabled us to focus effort on those templates with the greatest chance of high bioavailability in humans. This rapidly led to the 2',4'-difluorophenyl-dimethylamide 25 and the benzofuran 4 with high levels of potency (pK(i)) and good bioavailability in the rat and dog. Dimethylamide 25 is more potent (>20-fold) than 4 in vivo and has a high degree of selectivity toward the vasopressin receptors, >10,000 for hV1a/hV1b and approximately 500 for hV2. It has a good Cyp450 profile with no time dependent inhibition and was negative in the genotoxicity screens with a satisfactory oral safety profile in rats.

Potential urinary and plasma biomarkers of peroxisome proliferation in the rat: identification of N-methylnicotinamide and N-methyl-4-pyridone-3-carboxamide by 1H nuclear magnetic resonance and high performance liquid chromatography.

This study identified two potential novel biomarkers of peroxisome proliferation in the rat. Three peroxisome proliferator-activated receptor (PPAR) ligands, chosen for their high selectivity towards the PPARalpha, -delta and -gamma subtypes, were given to rats twice daily for 7 days at doses known to cause a pharmacological effect or peroxisome proliferation. Fenofibrate was used as a positive control. Daily treatment with the PPARalpha and -delta agonists produced peroxisome proliferation and liver hypertrophy. 1H nuclear magnetic resonance spectroscopy and multivariate statistical data analysis of urinary spectra from animals given the PPARalpha and -delta agonists identified two new potential biomarkers of peroxisome proliferation--N-methylnicotinamide (NMN) and N-methyl-4-pyridone-3-carboxamide (4PY)--both endproducts of the tryptophan-nicotinamide adenine dinucleotide (NAD+) pathway. After 7 days, excretion of NMN and 4PY increased 24- and three-fold, respectively, following high doses of fenofibrate. The correlation between total NMN excretion over 7 days and the peroxisome count was r=0.87 (r2=0.76). Plasma NMN, measured using a sensitive high performance liquid chromatography method, was increased up to 61-fold after 7 days' treatment with high doses of fenofibrate. Hepatic gene expression of aminocarboxymuconate-semialdehyde decarboxylase (EC 4.1.1.45) was downregulated following treatment with the PPARalpha and -delta agonists. The decrease was up to 11-fold compared with controls in the groups treated with high doses of fenofibrate. This supports the link between increased NMN and 4PY excretion and regulation of the tryptophan-NAD+ pathway in the liver. In conclusion, NMN, and possibly other metabolites in the pathway, are potential non-invasive surrogate biomarkers of peroxisome proliferation in the rat.

Alpha-glutathione S-transferase in the assessment of hepatotoxicity--its diagnostic utility in comparison with other recognized markers in the Wistar Han rat.

The diagnostic utility of alpha-glutathione S-transferase (alphaGST) in the assessment of acute hepatotoxicity was compared with a range of markers including alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Rats were given a single oral dose of either alpha-naphthylisothiocynate (AN IT), bromobenzene (BrB). or thioacetamide (TAM) at concentrations previously shown to induce marked hepatotoxicity. The progression of each hepatic lesion was monitored by the measurement of a battery of markers, including alphaGST, in plasma collected at time points ranging from 3 h to 7 days after dosing. alphaGST was seen to increase significantly at 24 h (ANIT/BrB) and 3 h (TAM) postdosing, corresponding with histopathological findings. For each compound, when the degree of insult was most severe, fold increases in alphaGST were greater than those seen with ALT and AST, yet lower than those seen with glutamate dehydrogenase (BrB and ANIT). sorbitol dehydrogenase (TAM), or total bilirubin and bile acids (ANIT). Elevations in alphaGST were also detected no earlier than any other marker. AlphaGST in the rat was shown to be a valid marker of hepatotoxicity; however, its measurement offered no additional information in detecting either the time of onset/recovery or the severity of each type of hepatic injury induced.