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.

Does the effect of walking balance perturbations generalize across contexts?

Balance perturbations are used to study locomotor instability. However, these perturbations are designed to provoke a specific context of instability that may or may not generalize to a broader understanding of falls risk. The purpose of this study was to determine if the effect of balance perturbations on instability generalizes across contexts. 29 younger adults and 28 older adults completed four experimental trials, including unperturbed walking and walking while responding to three perturbation contexts: mediolateral optical flow, treadmill-induced slips, and lateral waist-pulls. We quantified the effect of perturbations as an absolute change in margin of stability from unperturbed walking. We found significant changes in mediolateral and anteroposterior margin of stability for all perturbations compared to unperturbed walking in both cohorts (p-values ≤ 0.042). In older adults, the mediolateral effects of lateral waist-pulls significantly correlated with those of optical flow perturbations and treadmill-induced slips (r ≥ 0.398, p-values ≤ 0.036). In younger adults but not in older adults, we found positive and significant correlations between the anteroposterior effect of waist-pull perturbations and optical flow perturbations, and the anteroposterior and mediolateral effect of treadmill-induced slips (r ≥ 0.428, p-values ≤ 0.021). We found no "goldilocks" perturbation paradigm to endorse that would support universal interpretations about locomotor instability. Building the most accurate patient profiles of instability likely requires a series of perturbation paradigms designed to emulate the variety of environmental contexts in which falls may occur.

Genomic Resources for the First Federally Endangered Lichen: The Florida Perforate Cladonia (Cladonia perforata).

Thirty years after its designation as a federally endangered species, the Florida Perforate Cladonia (FPC) remains imperiled in isolated populations in the Florida scrub in the southeastern USA. For threatened and endangered species, such as FPC, reference genomes provide critical insight into genomic diversity, local adaptations, landscape-level genetics, and phylogenomics. Using high-throughput sequencing, we assemble the first draft nuclear and mitochondrial genomes for the FPC mycobiont-Cladonia perforata. We also assess genetic diversity within and among populations in southeastern Florida using genome-scale data and investigate diversity across the entire nuclear ribosomal cistron, including the standard DNA barcoding marker for fungi. The draft nuclear genome spanned 33.6 Mb, and the complete, circular mitochondrial genome was 59 Kb. We also generated the first chloroplast genome, to our knowledge, for the photobiont genus associated with FPC, an undescribed Asterochloris species. We inferred the presence of multiple, distinct mycobiont parental genotypes (genets) occurring at local scales in southeastern Florida, and strikingly, no genets were shared among even the closest sample sites. All sampled thalli shared identical mitochondrial genomes, while the nuclear ribosomal cistron showed limited variability-highlighting the genetic resolution provided by nuclear genome-scale datasets. The genomic resources generated here provide critical resources for informed conservation efforts for the FPC.

A novel method to quantify individual limb contributions to standing postural control.

BACKGROUND: Understanding individual limb contributions to standing postural control is valuable when evaluating populations with asymmetric function (e.g., stroke, amputations). We propose a method of quantifying three contributions to controlling the net anteroposterior center of pressure (CoP) during quiet standing: CoP moving under left and right limbs and weight shifting between the two limbs. RESEARCH QUESTION: Can these contributions to standing postural control be quantified from CoP trajectories in neurotypical adults? METHODS: Instantaneous contributions can be negative or larger than one, and integrated contributions sum to equal one. Proof-of-concept demonstrations validated these calculated contributions by restricting CoP motion under one or both feet. We evaluated these contributions in 30 neurotypical young adults who completed two (eyes opened; eyes closed) 30-s trials of bipedal standing. We evaluated the relationships between limb contributions, self-reported limb dominance, and between-limb weight distributions. RESULTS: All participants self-reported as right-limb dominant; however, a range of mean limb contributions were observed with eyes opened (Left: mean [range] = 0.52 [0.37-0.63]; Right: 0.48 [0.31-0.63]) and with eyes closed (Left: 0.51 [0.39-0.63]; Right: 0.49 [0.37-0.61]). Weight-shift contributions were small with eyes opened (0.00 [-0.01 to 0.01]) and eyes closed (0.00 [-0.01 to 0.02]). We did not identify any between-limb differences in contributions when grouped by self-reported limb dominance (p > 0.10, d < 0.31). Contributions did not significantly correlate with Waterloo Footedness scores (-0.22 < r < 0.21, p > 0.25) or between-limb weight distributions (0 < r < 0.24, p > 0.20). SIGNIFICANCE: Across neurotypical participants, we observed a notable range of limb contributions not related to self-reported limb dominance or between-limb weight distributions. With this tool, we can characterize differences in the amount of CoP motion and the underlying control strategies. Changes in limb contribution can be measured longitudinally (i.e., across rehabilitation programs, disease progression, aging) representative of limb function, which may be particularly useful in populations with asymmetric function.

Young adults use whole-body feedback and ankle proprioception to perceive small locomotor disturbances.

To prevent a fall when a disturbance to walking is encountered requires sensory information about the disturbance to be sensed, integrated, and then used to generate an appropriate corrective motor response. Prior research has shown that feedback of whole-body motion (e.g., center-of-mass kinematics) drives this corrective response. Here, we hypothesized that young adults also use whole-body motion to perceive locomotor disturbances. 15 subjects performed a locomotor discrimination task in which the supporting leg was slowed during stance every 8-12 steps to emulate subtle slips. The perception threshold of these disturbances was determined using a psychometrics approach and found to be 0.08 ± 0.03 m/s. Whole-body feedback was examined through center-of-mass (CoM) kinematics and whole-body angular momentum (WBAM). Perturbation-induced deviations of CoM and WBAM were calculated in response to the two perturbation levels nearest each subject's perception threshold. Consistent with our hypothesis, we identified significantly higher perturbation induced deviations for perceived perturbations in sagittal-plane WBAM, anteroposterior CoM velocity, and vertical CoM velocity and acceleration. Because whole body motion is not sensed directly but instead arises from the integration of various sensory feedback signals, we also explored local sensory feedback contributions to the perception of locomotor disturbances. Local sensory feedback was estimated through kinematic analogues of vision (head angle), vestibular (head angular velocity), proprioception (i.e., sagittal hip, knee, and ankle angles), and somatosensation (i.e., anterior-posterior & mediolateral center-of-pressure, COP). We identified significantly higher perturbation induced deviations for perceived perturbations in sagittal-plane ankle angle. These results provide evidence for both whole-body feedback and ankle proprioception as important for the perception of subtle slip-like locomotor disturbances in young adults. Our interpretation is ankle proprioception is a dominant contributor to estimates of whole-body motion to perceive locomotor disturbances.

Evaluation of the matrix metalloproteinase 9 (MMP9) inhibitor Andecaliximab as an Anti-invasive therapeutic in Head and neck squamous cell carcinoma.

OBJECTIVES: Locoregional and lymphovascular involvement of invasive head and neck squamous cell carcinoma (HNSCC) complicates curative treatment. Matrix metalloproteinase (MMP) 9 is a negative prognostic marker in HNSCC and targets multiple extracellular matrix (ECM) substrates, where it contributes to breaching basement membrane and stromal barriers enabling invasive spread. Andecaliximab (ADX) is a second-generation MMP9 inhibitor well tolerated in clinical trials of gastric and pancreatic adenocarcinoma. The impact of selective MMP9 targeting by ADX in HNSCC has not been evaluated. MATERIALS AND METHODS: Established and patient-derived xenograft (PDX) cell lines were utilized in HNSCC invasion assays to determine the inhibitory ability of MMP9-mediated invasion by ADX. MMP9 expression was confirmed using immunohistochemistry (IHC) and immunoblotting. ECM degradation was evaluated with confocal microscopy. Cell invasion from tumor spheroids was monitored by phase microscopy. Histological evaluation was used to determine ADX efficacy in three-dimensional organotypic cultures containing cancer associated fibroblasts (CAFs). RESULTS: MMP9 was expressed in all established and PDX-derived cell lines. While the broad spectrum clinical MMP inhibitor marimastat (BB2516) blocked HNSCC invadopodia function and tumor spheroid invasion, ADX treatment failed to inhibit invadopodia-based matrix degradation, tumor cell or fibroblast-driven ECM invasion in collagen I-based matrices. CONCLUSION: ADX monotherapy was ineffective at blocking initial MMP-dependent events of HNSCC invasion, likely due to redundant functions of additional non-targeted MMPs produced by tumor cells and microenvironment. Combination of ADX with existing and emerging therapies targeting additional MMP activation pathways may warrant future investigation.

Slowing down to preserve balance in the presence of optical flow perturbations.

BACKGROUND: The use of sensory and mechanical perturbations applied during walking has grown in popularity due to their ability to elicit instability relevant to falls. However, the vast majority of perturbation studies on walking balance are performed on a treadmill at a fixed speed. RESEARCH QUESTION: The aim of this study was to quantify the effects of mediolateral optical flow perturbations on walking speed and balance outcomes in young adults walking with fixed-speed and self-paced treadmill controllers. METHODS: Fifteen healthy young adults (8 female, age: 23.1 ± 4.6 yrs) completed four five-minute randomized walking trials in a speed-matched virtual reality hallway. In two of the trials, we added continuous mediolateral optical flow perturbations to the virtual hallway. Trials with and without optical flow perturbations were performed with either a fixed-speed or self-paced treadmill controller. We measured walking speed, balance outcomes (step width, margin of stability, local dynamic instability) and gait variability (step width variability and margin of stability variability). RESULTS: We found significant increases in step width (+20%, p = 0.004) and local dynamic instability (+11%, p = 0.008) of participants while responding to optical flow perturbations at a fixed treadmill speed. We found no significant differences in these outcome measures when perturbations were applied on a self-paced treadmill. Instead, participants walked 5.7% slower between the self-paced treadmill controller conditions when responding to optical flow perturbations (1.48 ± 0.13 m/s vs. 1.57 ± 0.16 m/s, p = 0.005). SIGNIFICANCE: Our findings suggest that during walking, when presented with a balance challenge, an individual will instinctively reduce their walking speed in order to better preserve stability. However, comparisons to prior literature suggest that this response may depend on environmental and/or perturbation context. Cumulatively, our results point to opportunities for leveraging self-paced treadmill controllers as a more ecologically-relevant option in balance research with potential clinical applications in diagnostics and rehabilitation.

A call to reconceptualize lichen symbioses.

Several decades of research across disciplines have overturned historical perspectives of symbioses dominated by binary characterizations of highly specific species-species interactions. This paradigm shift has unlocked the previously underappreciated and overlooked dynamism of fungal mutualisms such as mycorrhizae. Lichens are another example of important fungal mutualisms where reconceptualization is urgently needed to realize their potential as model systems. This reconceptualization requires both an objective synthesis of new data and envisioning a revised integrative approach that unifies the spectrum of ecology and evolution. We propose a ten-theme framework that if pursued would propel lichens to the vanguard of symbiotic theory.

Young adults perceive small disturbances to their walking balance even when distracted.

BACKGROUND: The ability to perceive disturbances to ongoing locomotion (e.g., slips and trips) may play an important role in walking balance control. However, how well young adults can perceive such disturbances is unknown. RESEARCH QUESTION: The purpose of this study was to identify the perception threshold in young adults to subtle slip-like locomotor disturbances. METHODS: Subjects (n = 12) walked on a split-belt treadmill performing a perturbation discrimination task at their preferred walking speed while randomly experiencing locomotor balance disturbances every 8-12 strides. Balance disturbances were imposed through a short-duration decrease in velocity of a single treadmill belt triggered at heel-strike. The treadmill belt returned to the subject's preferred walking speed during the subsequent swing phase. Locomotor disturbances were given with eight different velocity changes ranging from 0 to 0.4 m/s and were randomized and repeated 5 times. Subjects were prompted to respond when asked if they perceived each disturbance. Using a psychophysical approach, we determined the perception thresholds of slip-like locomotor disturbances (i.e., just noticeable difference). The perturbation discrimination task was repeated with subjects performing a secondary cognitive distraction (counting backward by threes). RESULTS: Subjects perceived small locomotor disturbances during both normal walking (dominant: 0.07 ± 0.03 m/s, non-dominant: 0.08 ± 0.03 m/s) and while performing the secondary cognitive task (dominant: 0.08 ± 0.01 m/s, non-dominant: 0.09 ± 0.02 m/s). There was no significant difference between legs (p = 0.466), with the addition of the cognitive task (p = 0.08), or interaction between leg and task (p = 0.994). SIGNIFICANCE: The ability to perceive subtle slip-like locomotor disturbances was maintained even when performing a cognitively distracting task, suggesting that young adults can perceive very small locomotor disturbances.

Draft Genome Sequence of the Lichenized Fungus Bacidia gigantensis.

The draft genome sequence of Bacidia gigantensis, a lichenized fungus in the order Lecanorales, was sequenced directly from a herbarium specimen collected from the type locality at Sleeping Giant Provincial Park in Ontario, Canada. Using long-read sequencing on the Oxford Nanopore PromethION platform, we assembled a nearly complete genome sequence.

Population genetics and biogeography of the lungwort lichen in North America support distinct Eastern and Western gene pools.

PREMISE: Populations of species with large spatial distributions are shaped by complex forces that differ throughout their ranges. To maintain the genetic diversity of species, genepool-based subsets of widespread species must be considered in conservation assessments. METHODS: The population genetics of the lichenized fungus Lobaria pulmonaria and its algal partner, Symbiochloris reticulata, were investigated using microsatellite markers to determine population structure, genetic diversity, and degree of congruency in eastern and western North America. Data loggers measuring temperature and humidity were deployed at selected populations in eastern North America to test for climatic adaptation. To better understand the role Pleistocene glaciations played in shaping population patterns, a North American, range-wide species distribution model was constructed and hindcast to 22,000 years before present and at 500-year time slices from then to the present. RESULTS: The presence of two gene pools with minimal admixture was supported, one in the U.S. Pacific Northwest and one in eastern North America. Western populations were significantly more genetically diverse than eastern populations. There was no evidence for climatic adaptation among eastern populations, though there was evidence for range-wide adaptation to evapotranspiration rates. Hindcast distribution models suggest that observed genetic diversity may be due to a drastic Pleistocene range restriction in eastern North America, whereas a substantial coastal refugial area is inferred in the west. CONCLUSIONS: Taken together the results show different, complex population histories of L. pulmonaria in eastern and western North America, and suggest that conservation planning for each gene pool should be considered separately.

Young adults recruit similar motor modules across walking, turning, and chair transfers.

Moving about in the world during daily life requires executing and successfully shifting between a variety of functional tasks, such as rising from a chair or bed, walking, turning, and navigating stairs. Moreover, moving about during daily life requires not only navigating between different functional tasks, but also performing these tasks in the presence of mental distractions. However, little is known about underlying neuromuscular control for executing and shifting between these different tasks. In this study, we investigated muscle coordination across walking, turning, and chair transfers by applying motor module (a.k.a. muscle synergy) analysis to the Timed-Up-and-Go (TUG) test with and without a secondary cognitive dual task. We found that healthy young adults recruit a small set of common motor modules across the subtasks of the TUG test and that their composition is robust to cognitive distraction. Instead, cognitive distraction impacted motor module activation timings such that they became more consistent. This work is the first to demonstrate motor module generalization across multiple tasks that are both functionally different and crucial for healthy mobility. Overall, our results suggest that the central nervous system may draw from a "library" of modular control strategies to navigate the variety of movements and cognitive demands required of daily life.

Copy number alterations identify a smoking-associated expression signature predictive of poor outcome in head and neck squamous cell carcinoma.

Cigarette smoking is a risk factor for the development of head and neck squamous cell carcinoma (HNSCC), partially due to tobacco-induced large-scale chromosomal copy-number alterations (CNAs). Identifying CNAs caused by smoking is essential in determining how gene expression from such regions impact tumor progression and patient outcome. We utilized The Cancer Genome Atlas (TCGA) whole genome sequencing data for HNSCC to directly identify amplified or deleted genes correlating with smoking pack-year based on linear modeling. Internal cross-validation identified 35 CNAs that significantly correlated with patient smoking, independent of human papillomavirus (HPV) status. The most abundant CNAs were chromosome 11q13.3-q14.4 amplification and 9p23.1/9p24.1 deletion. Evaluation of patient amplicons reveals four different patterns of 11q13 gene amplification in HNSCC resulting from breakage-fusion-bridge (BFB) events. . Predictive modeling identified 16 genes from these regions that denote poorer overall and disease-free survival with increased pack-year use, constituting a smoking-associated expression signature (SAES). Patients with altered expression of signature genes have increased risk of death and enhanced cervical lymph node involvement. The identified SAES can be utilized as a novel predictor of increased disease aggressiveness and poor outcome in smoking-associated HNSCC.

A BAFF/APRIL axis regulates obesogenic diet-driven weight gain.

The impact of immune mediators on weight homeostasis remains underdefined. Interrogation of resistance to diet-induced obesity in mice lacking a negative regulator of Toll-like receptor signaling serendipitously uncovered a role for B cell activating factor (BAFF). Here we show that overexpression of BAFF in multiple mouse models associates with protection from weight gain, approximating a log-linear dose response relation to BAFF concentrations. Gene expression analysis of BAFF-stimulated subcutaneous white adipocytes unveils upregulation of lipid metabolism pathways, with BAFF inducing white adipose tissue (WAT) lipolysis. Brown adipose tissue (BAT) from BAFF-overexpressing mice exhibits increased Ucp1 expression and BAFF promotes brown adipocyte respiration and in vivo energy expenditure. A proliferation-inducing ligand (APRIL), a BAFF homolog, similarly modulates WAT and BAT lipid handling. Genetic deletion of both BAFF and APRIL augments diet-induced obesity. Lastly, BAFF/APRIL effects are conserved in human adipocytes and higher BAFF/APRIL levels correlate with greater BMI decrease after bariatric surgery. Together, the BAFF/APRIL axis is a multifaceted immune regulator of weight gain and adipose tissue function.

Generalization of motor module recruitment across standing reactive balance and walking is associated with beam walking performance in young adults.

BACKGROUND: Recent studies provide compelling evidence that recruiting a common pool of motor modules across behaviors (i.e., motor module generalization) may facilitate motor performance. In particular, motor module generalization across standing reactive balance and walking is associated with both walking speed and endurance in neurologically impaired populations (e.g., stroke survivors and individual's with Parkinson's disease). To test whether this phenomenon is a general neuromuscular strategy associated with well-coordinated walking and not limited to motor impairment, this relationship must be confirmed in neurologically intact adults. RESEARCH QUESTION: Is motor module generalization across standing reactive balance and walking related to walking performance in neurologically intact young adults? METHODS: Two populations of young adults were recruited to capture a wide range of walking performance: professionally-trained ballet dancers (i.e., experts, n = 12) and novices (n = 8). Motor modules (a.k.a. muscle synergies) were extracted from muscles spanning the trunk, hip, knee and ankle during walking and multidirectional perturbations to standing. Motor module generalization was calculated as the number of modules common to these behaviors. Walking performance was assessed using self-selected walking speed and beam-walking proficiency (i.e., distance walked on a narrow beam). Motor module generalization between experts and novices was compared using rank-sum tests and the association between generalization and walking performance was assessed using correlation analyses. RESULTS: Experts generalized more motor modules across standing reactive balance and walking than novices (p = 0.009). Across all subjects, motor module generalization was moderately associated with increased beam walking proficiency (r = 0.456, p = 0.022) but not walking speed (r = 0.092, p = 0.349). SIGNIFICANCE: Similar relationships between walking performance and motor module generalization exist in neurologically intact and impaired populations, suggesting that motor module generalization across standing reactive balance and walking may be a general neuromuscular mechanism contributing to the successful control of walking.

Reorganization of motor modules for standing reactive balance recovery following pyridoxine-induced large-fiber peripheral sensory neuropathy in cats.

Task-level goals such as maintaining standing balance are achieved through coordinated muscle activity. Consistent and individualized groupings of synchronously activated muscles can be estimated from muscle recordings in terms of motor modules or muscle synergies, independent of their temporal activation. The structure of motor modules can change with motor training, neurological disorders, and rehabilitation, but the central and peripheral mechanisms underlying motor module structure remain unclear. To assess the role of peripheral somatosensory input on motor module structure, we evaluated changes in the structure of motor modules for reactive balance recovery following pyridoxine-induced large-fiber peripheral somatosensory neuropathy in previously collected data in four adult cats. Somatosensory fiber loss, quantified by postmortem histology, varied from mild to severe across cats. Reactive balance recovery was assessed using multidirectional translational support-surface perturbations over days to weeks throughout initial impairment and subsequent recovery of balance ability. Motor modules within each cat were quantified by non-negative matrix factorization and compared in structure over time. All cats exhibited changes in the structure of motor modules for reactive balance recovery after somatosensory loss, providing evidence that somatosensory inputs influence motor module structure. The impact of the somatosensory disturbance on the structure of motor modules in well-trained adult cats indicates that somatosensory mechanisms contribute to motor module structure, and therefore may contribute to some of the pathological changes in motor module structure in neurological disorders. These results further suggest that somatosensory nerves could be targeted during rehabilitation to influence pathological motor modules for rehabilitation.NEW & NOTEWORTHY Stable motor modules for reactive balance recovery in well-trained adult cats were disrupted following pyridoxine-induced peripheral somatosensory neuropathy, suggesting somatosensory inputs contribute to motor module structure. Furthermore, the motor module structure continued to change as the animals regained the ability to maintain standing balance, but the modules generally did not recover pre-pyridoxine patterns. These results suggest changes in somatosensory input and subsequent learning may contribute to changes in motor module structure in pathological conditions.

Disparate survival of late-stage male oropharyngeal cancer in Appalachia.

The United States Appalachian region harbors a higher cancer burden than the rest of the nation, with disparate incidence of head and neck squamous cell carcinomas (HNSCC), including oral cavity and pharynx (OC/P) cancers. Whether elevated HNSCC incidence generates survival disparities within Appalachia is unknown. To address this, HNSCC survival data for 259,737 tumors from the North American Association for Central Cancer Registries 2007-2013 cohort were evaluated, with age-adjusted relative survival (RS) calculated based on staging, race, sex, and Appalachian residence. Tobacco use, a primary HNSCC risk factor, was evaluated through the Behavioral Risk Factor Surveillance System from Appalachian states. Decreased OC/P RS was found in stage IV Appalachian white males within a subset of states. The survival disparity was confined to human papillomavirus (HPV)-associated oropharyngeal cancers, specifically the oropharynx subsite. This correlated with significantly higher smoking and male smokeless tobacco use in most Appalachian disparity states. Lower survival of Appalachian males with advanced-stage HPV-associated oropharyngeal cancers suggests pervasive tobacco consumption likely generates more aggressive tumors at HPV-associated oropharynx subsites than national averages. Comprehensive tobacco and HPV status should therefore be evaluated prior to considering treatment de-intensification regimens for HPV-associated oropharyngeal cancers in populations with high tobacco consumption.

Complete, high-quality genomes from long-read metagenomic sequencing of two wolf lichen thalli reveals enigmatic genome architecture.

Fungal genomes display incredible levels of complexity and diversity, and are exceptional study systems for genome evolution. Here we used the Oxford Nanopore MinION sequencing platform to generate high-quality fungal genomes from complex metagenomic samples of lichen thalli. We sequenced two wolf lichens using one flow cell per sample, generating 17.1 Gbps for Letharia lupina and 14.3 Gbps for Letharia columbiana. The resulting L. lupina genome is one of the most contiguous lichen genomes available to date, with 49.2 Mbp contained on 31 contigs. The L. columbiana genome, while less contiguous, is still relatively high quality, with 52.3 Mbp on a total of 161 contigs. Each thallus for both species contained multiple distinct haplotypes, a phenomenon that has rarely been empirically demonstrated. The Oxford Nanopore sequencing technologies are robust and effective when applied to complex symbioses, and have the potential to fundamentally transform our understanding of fungal genetics.

Pain-Reducing Effects of Physical Therapist-Delivered Interventions: A Systematic Review of Randomized Trials Among Older Adults With Dementia.

BACKGROUND AND PURPOSE: Pain is common among older adults with dementia. There are nonpharmacological options for managing pain in this population. However, the effects of physical therapist-delivered interventions have not been summarized. The purpose of this systematic review was to summarize the literature on physical therapist-delivered interventions in randomized trials for reducing pain among older adults with dementia. METHODS: A systematic search of MEDLINE/PubMed, CINAHL, PsycINFO, and Web of Science was conducted for randomized trials of pain management in individuals 60 years or older with medically diagnosed dementia of any severity. Included studies addressed the effects of nonpharmacological physical therapist-delivered interventions on pain outcomes. Pain outcomes included patient or caregiver self-report, observational or interactive measures. Independent reviewers extracted relevant data and assessed methodological quality using the PEDro scale. RESULTS AND DISCUSSION: Three studies (total = 222 participants; mean age range = 82.2-84.0 years; 178 [80.2%] females) met inclusion criteria. PEDro scores ranged from 4 to 8/10. Interventions included passive movement and massage. Pain outcomes included the observational measures Pain Assessment Checklist for Seniors with Limited Ability to Communicate (PACSLAC), Pain in Advanced Dementia (PAINAD), and Doloplus-2 Scale. Passive movement did not show better results when compared with no treatment, while massage showed pain-reducing effects in 1 study compared with no treatment. CONCLUSIONS: The evidence supporting pain-reducing physical therapy interventions for patients with dementia is limited. There is a clear gap in knowledge related to evidence-based physical therapy for managing pain in this population. Future studies should examine active physical therapist-delivered interventions and utilize interactive pain measures.

Computational Design of FastFES Treatment to Improve Propulsive Force Symmetry During Post-stroke Gait: A Feasibility Study.

Stroke is a leading cause of long-term disability worldwide and often impairs walking ability. To improve recovery of walking function post-stroke, researchers have investigated the use of treatments such as fast functional electrical stimulation (FastFES). During FastFES treatments, individuals post-stroke walk on a treadmill at their fastest comfortable speed while electrical stimulation is delivered to two muscles of the paretic ankle, ideally to improve paretic leg propulsion and toe clearance. However, muscle selection and stimulation timing are currently standardized based on clinical intuition and a one-size-fits-all approach, which may explain in part why some patients respond to FastFES training while others do not. This study explores how personalized neuromusculoskeletal models could potentially be used to enable individual-specific selection of target muscles and stimulation timing to address unique functional limitations of individual patients post-stroke. Treadmill gait data, including EMG, surface marker positions, and ground reactions, were collected from an individual post-stroke who was a non-responder to FastFES treatment. The patient's gait data were used to personalize key aspects of a full-body neuromusculoskeletal walking model, including lower-body joint functional axes, lower-body muscle force generating properties, deformable foot-ground contact properties, and paretic and non-paretic leg neural control properties. The personalized model was utilized within a direct collocation optimal control framework to reproduce the patient's unstimulated treadmill gait data (verification problem) and to generate three stimulated walking predictions that sought to minimize inter-limb propulsive force asymmetry (prediction problems). The three predictions used: (1) Standard muscle selection (gastrocnemius and tibialis anterior) with standard stimulation timing, (2) Standard muscle selection with optimized stimulation timing, and (3) Optimized muscle selection (soleus and semimembranosus) with optimized stimulation timing. Relative to unstimulated walking, the optimal control problems predicted a 41% reduction in propulsive force asymmetry for scenario (1), a 45% reduction for scenario (2), and a 64% reduction for scenario (3), suggesting that non-standard muscle selection may be superior for this patient. Despite these predicted improvements, kinematic symmetry was not noticeably improved for any of the walking predictions. These results suggest that personalized neuromusculoskeletal models may be able to predict personalized FastFES training prescriptions that could improve propulsive force symmetry, though inclusion of kinematic requirements would be necessary to improve kinematic symmetry as well.