Replication and reliability of Parkinson's disease clinical subtypes.

BACKGROUND: We recently identified three distinct Parkinson's disease subtypes: "motor only" (predominant motor deficits with intact cognition and psychiatric function); "psychiatric & motor" (prominent psychiatric symptoms and moderate motor deficits); "cognitive & motor" (cognitive and motor deficits). OBJECTIVE: We used an independent cohort to replicate and assess reliability of these Parkinson's disease subtypes. METHODS: We tested our original subtype classification with an independent cohort (N = 100) of Parkinson's disease participants without dementia and the same comprehensive evaluations assessing motor, cognitive, and psychiatric function. Next, we combined the original (N = 162) and replication (N = 100) datasets to test the classification model with the full combined dataset (N = 262). We also generated 10 random split-half samples of the combined dataset to establish the reliability of the subtype classifications. Latent class analyses were applied to the replication, combined, and split-half samples to determine subtype classification. RESULTS: First, LCA supported the three-class solution - Motor Only, Psychiatric & Motor, and Cognitive & Motor- in the replication sample. Next, using the larger, combined sample, LCA again supported the three subtype groups, with the emergence of a potential fourth group defined by more severe motor deficits. Finally, split-half analyses showed that the three-class model also had the best fit in 13/20 (65%) split-half samples; two-class and four-class solutions provided the best model fit in five (25%) and two (10%) split-half replications, respectively. CONCLUSIONS: These results support the reproducibility and reliability of the Parkinson's disease behavioral subtypes of motor only, psychiatric & motor, and cognitive & motor groups.

Long-term results of per-operative knee arthroscopy in confirming suitability for unicompartmental arthroplasty.

BACKGROUND: Patient selection is key to the success of medial unicondylar knee arthroplasty (UKA). Progression of arthritis is the most common indication for revision surgery. Per-operative arthroscopy is a means of directly assessing the integrity of the lateral compartment. The aim of the study is to assess the long-term survivorship of UKA performed when per-operative arthroscopy is used as a final means of deciding whether to proceed with UKA. METHODS: We used per-operative arthroscopy as a means to confirm suitability for UKA in a consecutive series of 279 Oxford medial UKA. Our series of UKA with per-operative arthroscopy (Group 1) was compared to all Oxford UKA (Group 2) and all UKA in the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) (Group 3). RESULTS: The 14-year cumulative percentage revision (CPR) was 18.5% (95% CI 12.7, 26.4) for group 1, 19.7% (95% CI 18.8, 20.6) for group 2, and 19.2% (95% CI 18.5, 19.8) for group 3. There was no statistically significant difference in the (CPR) for the entire period when group 1 was compared to groups 2 or 3. Progression of arthritis was least in Group 1 compared to groups 2 and 3; 3.6 versus 4.4 and 4.1% respectively. Following per-operative arthroscopy 21.6% (77/356) of knees underwent a change of surgical plan from UKA to TKA. CONCLUSION: In our practice, which includes per-operative arthroscopy, we have identified a reduced risk of revision due to progression of arthritis but no difference in overall long-term implant survivorship.

Attaching protein-adsorbing silica particles to the surface of cotton substrates for bioaerosol capture including SARS-CoV-2.

The novel coronavirus pandemic (COVID-19) has necessitated a global increase in the use of face masks to limit the airborne spread of the virus. The global demand for personal protective equipment has at times led to shortages of face masks for the public, therefore makeshift masks have become commonplace. The severe acute respiratory syndrome caused by coronavirus-2 (SARS-CoV-2) has a spherical particle size of ~97 nm. However, the airborne transmission of this virus requires the expulsion of droplets, typically ~0.6-500 µm in diameter (by coughing, sneezing, breathing, and talking). In this paper, we propose a face covering that has been designed to effectively capture SARS-CoV-2 whilst providing uncompromised comfort and breathability for the wearer. Herein, we describe a material approach that uses amorphous silica microspheres attached to cotton fibres to capture bioaerosols, including SARS CoV-2. This has been demonstrated for the capture of aerosolised proteins (cytochrome c, myoglobin, ubiquitin, bovine serum albumin) and aerosolised inactivated SARS CoV-2, showing average filtration efficiencies of ~93% with minimal impact on breathability.

Prevalence and Burden of Migraine in Switzerland: Cross-Sectional Study in ten Specialised Headache Centres from the BECOME Study.

INTRODUCTION: There is limited real-world evidence on the burden of migraine among patients with prior preventive treatment failure (PPTF). In the BECOME Swiss subanalysis, we aimed to assess current prevalence of PPTF in patients with migraine seen at specialised headache centres in Switzerland and burden of migraine in these patients. Furthermore, we assessed this burden in subgroups stratified by monthly migraine days (MMDs) and number of PPTFs. METHODS: BECOME was a prospective, multicentre, non-interventional two-part study conducted in 17 countries across Europe and Israel. This subanalysis includes patients visiting ten headache specialist centres in Switzerland. In part 1, patients visiting the centres over 3 months were screened by physicians for frequency of PPTF, MMD and other migraine characteristics. Patients with ≥ 1 PPTF and ≥ 4 MMDs were invited to take part in part 2. The primary endpoint was the proportion of patients with ≥ 1 PPTF (part 1). Other endpoints included proportion of patients specified by number of PPTF and MMD (part 1, part 2), and impact of migraine on patient-reported outcomes (PROs; part 2). RESULTS: Patients (1677) from ten Swiss centres were included in part 1, of which 855 (51.0%) reported ≥ 1 PPTF. One hundred fifty-five patients were included in part 2: 6.5% reported ≥ 4 PPTFs and 43.2% reported ≥ 15 MMDs. Mean EuroQoL 5 and EuroQoL visual analogue scale (EQ-VAS) were 0.8 ± 0.2 and 69.6 ± 20.2, respectively, suggesting a mild level of impairment in the daily functioning and self-reported health of the patients. Mean six-item Headache Impact Test (HIT-6) and modified Migraine Disability Assessment (mMIDAS) scores were 63.3 ± 6.5 and 22.7 ± 21.8, respectively, corresponding to severe migraine burden. Patients also reported impairment in work-related productivity and general activities (48.6 ± 22.8) but no associations of anxiety (7.2 ± 4.4) or depression (6.0 ± 4.4) with migraine were noted. Burden of migraine increased with increasing frequency of PPTF and MMD. CONCLUSIONS: Migraine-related quality of life, as well as work productivity are significantly affected in Swiss patients with migraine. Increasing migraine burden is associated with increasing migraine frequency and prior treatment failures.

Proteinopathy and Longitudinal Cognitive Decline in Parkinson Disease.

BACKGROUND AND OBJECTIVES: People with Parkinson disease (PD) commonly experience cognitive decline, which may relate to increased α-synuclein, tau, and ß-amyloid accumulation. This study examines whether the different proteins predict longitudinal cognitive decline in PD. METHODS: All participants (PD n = 152, controls n = 52) were part of a longitudinal study and completed a lumbar puncture for CSF protein analysis (α-synuclein, total tau [tau], and ß-amyloid42 [ß-amyloid]), a ß-amyloid PET scan, and/or provided a blood sample for APOE genotype (ε4+, ε4-), which is a risk factor for ß-amyloid accumulation. Participants also had comprehensive, longitudinal clinical assessments of overall cognitive function and dementia status, as well as cognitive testing of attention, language, memory, and visuospatial and executive function. We used hierarchical linear growth models to examine whether the different protein metrics predict cognitive change and multivariate Cox proportional hazard models to predict time to dementia conversion. Akaike information criterion was used to compare models for best fit. RESULTS: Baseline measures of CSF ß-amyloid predicted decline for memory (p = 0.04) and overall cognitive function (p = 0.01). APOE genotypes showed a significant group (ε4+, ε4-) effect such that ε4+ individuals declined faster than ε4- individuals in visuospatial function (p = 0.03). Baseline ß-amyloid PET significantly predicted decline in all cognitive measures (all p ≤ 0.004). Neither baseline CSF α-synuclein nor tau predicted cognitive decline. All 3 ß-amyloid--related metrics (CSF, PET, APOE) also predicted time to dementia. Models with ß-amyloid PET as a predictor fit the data the best. DISCUSSION: Presence or risk of ß-amyloid accumulation consistently predicted cognitive decline and time to dementia in PD. This suggests that ß-amyloid has high potential as a prognostic indicator and biomarker for cognitive changes in PD.

Lateral Extra-Articular Tenodesis Combined With Anterior Cruciate Ligament Reconstruction Is Effective in Knees With Additional Features of Lateral, Hyperextension, or Increased Rotational Laxity: A Matched Cohort Study.

PURPOSE: To investigate the patient-reported outcome measures (PROMs) and graft survival of combined anterior cruciate ligament reconstruction (ACLR) and lateral extra-articular tenodesis (ACLR-LET) compared with a matched cohort having ACLR alone. METHODS: Patients were retrospectively recruited from a consecutive series of primary ACLR-LET, between 1996 and 2015, with a minimum postsurgical time of 4 years. ACLR-LET were matched with isolated ACLR for age, gender, and operation year. The indications for adding lateral extra-articular tenodesis were lateral laxity of grade 1 or 2, hyperextension laxity, and/or increased rotational laxity of 5° to 10°. The technique used involved detaching a strip of iliotibial band proximally, before being passed deep to the lateral collateral ligament, looped through Kaplan's fibers, and sutured back onto itself at physiological tension. The PROMs used were the Lysholm Knee Scoring Scale, Tegner Activity Scale, Oxford Knee Score, and International Knee Documentation Committee subjective knee form. Failure was defined as graft rupture. Student's t-test was used to compare the matched groups and Kaplan-Meier analysis for survivorship. RESULTS: Eighty-three patients had ACLR-LET between 1996 and 2015. Nine revision cases and 2 with less than 4 years follow-up were excluded. The remaining 72 ACLR-LET patients were matched and included in the survival analysis. Seventy percent of patients completed the PROMs. In both groups, 76% were males, and the mean age was 25 years (standard deviation ± 8.5). The median follow-up was 10 years (interquartile range, 6.7 years). There was no significant change of PROMs (Lysholm Knee Scoring Scale: P = .82, 95% confidence interval (CI) -13 to 11; International Knee Documentation Committee: P = .07, CI -1 to 24; Oxford Knee Score: P = .5, CI -8 to 4; Tegner Activity Scale: P = .5, CI -1 to 3) between the groups. The pre- to postoperative PROMs, except the Tegner Activity Scale, improved significantly, clinically and statistically. There was no statistically significant difference in graft failure between the ACLR-LET group (n = 4, 5%) and the ACLR group (n = 9, 11%) (log-rank P = .099). CONCLUSION: ACLR-LET shows good graft survival and PROMs in a high-risk population. This suggests that lateral extra-articular tenodesis is an effective technique to restore joint stability to a knee with additional features of laxity. LEVEL OF EVIDENCE: III, matched cohort study.

Silica Microspheres-in-Pores Composite Monoliths with Fluorescence and Potential for Water Remediation.

Water pollution is a severe worldwide issue. Constructing advanced porous composite materials has been an efficient route to water remediation via adsorption. In this study, a unique microspheres-in-pores monolithic structure was fabricated. An emulsion-templated polymer monolith was first prepared and silica microspheres were subsequently formed in the porous polymer. A silica precursor was modified with a fluorescent dye and co-condensed with other precursors to fabricate porous composites with fluorescent properties, which were enhanced by the presence of Ag nanoparticles in the polymer matrix. This unique material showed good promise in water remediation by removing organic dyes and heavy metal ions from wastewater via a flowing filter or monolithic column separation.

Distinct progression patterns across Parkinson disease clinical subtypes.

OBJECTIVE: To examine specific symptom progression patterns and possible disease staging in Parkinson disease clinical subtypes. METHODS: We recently identified Parkinson disease clinical subtypes based on comprehensive behavioral evaluations, "Motor Only," "Psychiatric & Motor," and "Cognitive & Motor," which differed in dementia and mortality rates. Parkinson disease participants ("Motor Only": n = 61, "Psychiatric & Motor": n = 17, "Cognitive & Motor": n = 70) and controls (n = 55) completed longitudinal, comprehensive motor, cognitive, and psychiatric evaluations (average follow-up = 4.6 years). Hierarchical linear modeling examined group differences in symptom progression. A three-way interaction among time, group, and symptom duration (or baseline age, separately) was incorporated to examine disease stages. RESULTS: All three subtypes increased in motor dysfunction compared to controls. The "Motor Only" subtype did not show significant cognitive or psychiatric changes compared to the other two subtypes. The "Cognitive & Motor" subtype's cognitive dysfunction at baseline further declined compared to the other two subtypes, while also increasing in psychiatric symptoms. The "Psychiatric & Motor" subtype's elevated psychiatric symptoms at baseline remained steady or improved over time, with mild, steady decline in cognition. The pattern of behavioral changes and analyses for disease staging yielded no evidence for sequential disease stages. INTERPRETATION: Parkinson disease clinical subtypes progress in clear, temporally distinct patterns from one another, particularly in cognitive and psychiatric features. This highlights the importance of comprehensive clinical examinations as the order of symptom presentation impacts clinical prognosis.

Resting-state functional connectivity associated with gait characteristics in people with Parkinson's disease.

INTRODUCTION: Parkinson's disease (PD) is a movement disorder caused by dysfunction in the basal ganglia (BG). Clinically relevant gait deficits, such as decreased velocity and increased variability, may be caused by underlying neural dysfunction. Reductions in resting-state functional connectivity (rs-FC) between networks have been identified in PD compared to controls; however, the association between gait characteristics and rs-FC of brain networks in people with PD has not yet been explored. The present study aimed to investigate these associations. METHODS: Gait characteristics and rs-FC MRI data were collected for participants with PD (N = 50). Brain networks were identified from a set of seeds representing cortical, subcortical, and cerebellar regions. Gait outcomes were correlated with the strength of rs-FC within and between networks of interest. A stepwise regression analysis was also conducted to determine whether the rs-FC strength of brain networks, along with clinical motor scores, were predictive of gait characteristics. RESULTS: Gait velocity was associated with rs-FC within the visual network and between motor and cognitive networks, most notably BG-thalamus internetwork rs-FC. The stepwise regression analysis showed strength of BG-thalamus internetwork rs-FC and clinical motor scores were predictive of gait velocity. CONCLUSION: The results of the present study demonstrate gait characteristics are associated with functional organization of the brain at the network level, providing insight into the neural mechanisms of clinically relevant gait characteristics. This knowledge could be used to optimize the design of gait rehabilitation interventions for people with neurological conditions.

Parkinson disease clinical subtypes: key features & clinical milestones.

OBJECTIVES: Based on multi-domain classification of Parkinson disease (PD) subtypes, we sought to determine the key features that best differentiate subtypes and the utility of PD subtypes to predict clinical milestones. METHODS: Prospective cohort of 162 PD participants with ongoing, longitudinal follow-up. Latent class analysis (LCA) delineated subtypes based on score patterns across baseline motor, cognitive, and psychiatric measures. Discriminant analyses identified key features that distinguish subtypes at baseline. Cox regression models tested PD subtype differences in longitudinal conversion to clinical milestones, including deep brain stimulation (DBS), dementia, and mortality. RESULTS: LCA identified distinct subtypes: "motor only" (N = 63) characterized by primary motor deficits; "psychiatric & motor" (N = 17) characterized by prominent psychiatric symptoms and moderate motor deficits; "cognitive & motor" (N = 82) characterized by impaired cognition and moderate motor deficits. Depression, executive function, and apathy best discriminated subtypes. Since enrollment, 22 had DBS, 48 developed dementia, and 46 have died. Although there were no subtype differences in rate of DBS, dementia occurred at a higher rate in the "cognitive & motor" subtype. Surprisingly, mortality risk was similarly elevated for both "cognitive & motor" and "psychiatric & motor" subtypes compared to the "motor only" subtype (relative risk = 3.15, 2.60). INTERPRETATION: Psychiatric and cognitive features, rather than motor deficits, distinguish clinical PD subtypes and predict greater risk of subsequent dementia and mortality. These results emphasize the value of multi-domain assessments to better characterize clinical variability in PD. Further, differences in dementia and mortality rates demonstrate the prognostic utility of PD subtypes.

Furo[3,2-c]coumarin-derived Fe3+ Selective Fluorescence Sensor: Synthesis, Fluorescence Study and Application to Water Analysis.

Furocoumarin (furo[3,2-c]coumarin) derivatives have been synthesized from single step, high yielding (82-92%) chemistry involving a 4-hydroxycoumarin 4 + 1 cycloaddition reaction. They are characterized by FTIR, 1H-NMR, and, for the first time, a comprehensive UV-Vis and fluorescence spectroscopy study has been carried out to determine if these compounds can serve as useful sensors. Based on the fluorescence data, the most promising furocoumarin derivative (2-(cyclohexylamino)-3-phenyl-4H-furo[3,2-c]chromen-4-one, FH), exhibits strong fluorescence (ФF = 0.48) with long fluorescence lifetime (5.6 ns) and large Stokes' shift, suggesting FH could be used as a novel fluorescent chemosensor. FH exhibits a highly selective, sensitive and instant turn-off fluorescence response to Fe3+ over other metal ions which was attributed to a charge transfer mechanism. Selectivity was demonstrated against 13 other competing metal ions (Na+, K+, Mg2+, Ca2+, Mn2+, Fe2+, Al3+, Ni2+, Cu2+, Zn2+, Co2+, Pb2+ and Ru3+) and aqueous compatibility was demonstrated in 10% MeOH-H2O solution. The FH sensor coordinates Fe3+ in a 1:2 stoichiometry with a binding constant, Ka = 5.25 × 103 M-1. This novel sensor has a limit of detection of 1.93 µM, below that of the US environmental protection agency guidelines (5.37 µM), with a linear dynamic range of ~28 (~2-30 µM) and an R2 value of 0.9975. As an exemplar application we demonstrate the potential of this sensor for the rapid measurement of Fe3+ in mineral and tap water samples demonstrating the real-world application of FH as a "turn off" fluorescence sensor.

Dual-task costs of texting while walking forward and backward are greater for older adults than younger adults.

Cognitive-motor dual-tasking involves concurrent performance of two tasks with distinct cognitive and motor demands and is associated with increased fall risk. In this hypothesis-driven study, younger (18-30 years, n = 24) and older (60-75 years, n = 26) adults completed six walking tasks in triplicate. Participants walked forward and backward along a GAITRite mat, in isolation or while performing a verbal fluency task. Verbal fluency tasks involved verbally listing or typing on a smartphone as many words as possible within a given category (e.g., clothes). Using repeated measures MANOVA models, we examined how age, method of fluency task (verbal or texting), and direction of walking altered dual-task performance. Given that tasks like texting and backward walking require greater cognitive resources than verbal and forward walking tasks, respectively, we hypothesized older adults would show higher dual-task costs (DTCs) than younger adults across different task types and walking directions, with degree of impairment more apparent in texting dual-task trials compared to verbal dual-task trials. We also hypothesized that both age groups would have greater DTCs while walking backward than while walking forward, regardless of task. Independent of age group, velocity and stride length were reduced for texting compared to the verbal task during both forward and backward walking; cadence and velocity were reduced while walking forward compared to walking backward for the texting task; and stride length was reduced for forward walking compared to backward walking during the verbal task. Younger adults performed better than older adults on all tasks with the most pronounced differences seen in velocity and stride length during forward-texting and backward-texting. Interaction effects for velocity and stride length while walking forward indicated younger adults performed better than older adults for the texting task but similarly during the verbal task. An interaction for cadence during the verbal task indicated younger adults performed better than older adults while walking backward but similarly while walking forward. In summary, older adults experienced greater gait decrement for all dual-task conditions. The greater declines in velocity and stride length in combination with cadence being stable suggest reductions in velocity during texting were due to shorter strides rather than a reduced rate of stepping. Contrary to our hypotheses, we found greater DTCs while walking forward rather than backward, which may be due to reduced gait performance during single-task backward walking; thus, further decrements with dual-tasking are unlikely. These findings underscore the need for further research investigating fall risk potential associated with texting and walking among aging populations and how interventions targeting stride length during dual-task circumstances may improve performance.

Cross-Sectional Analysis of Backward, Forward, and Dual Task Gait Kinematics in People With Parkinson Disease With and Without Freezing of Gait.

People with Parkinson disease demonstrate increased gait variability, but the primary variability sources are poorly understood. People with Parkinson disease and freezing of gait (freezers) have greater gait impairments than people with Parkinson disease without freezing of gait (nonfreezers), which may relate to cerebellar dysfunction. Thirteen freezers and 31 nonfreezers completed backward, forward, and forward with dual task gait trials. Sagittal joint angle waveforms were extracted for the hip, knee, and ankle using 3D motion capture. Decomposition indices were calculated for the 3 joint combinations. Principal component analysis extracted variance sources from the joint waveforms. Freezers had significantly greater decomposition between hip-ankle (F1,42 = 5.1, P = .03) and hip-knee (F1,42 = 5.3, P = .03) movements. The principal component analysis did not differentiate freezers and nonfreezers; however, primary variance sources differed between conditions. Primary variance during forward and forward with dual task gait came from joint angle magnitude and peak angle timing. Backward gait showed primary variance from joint angle magnitude and range of motion. The results show that freezers decompose movement more than nonfreezers, implicating cerebellar involvement in freezing of gait. Primary variance differs between gait conditions, and tailoring gait interventions to address variability sources may improve intervention efficacy.

Changes in Parkinsonian gait kinematics with self-generated and externally-generated cues: a comparison of responders and non-responders.

Purpose: Rhythmic auditory stimulation such as listening to music can alleviate gait bradykinesia in people with Parkinson disease (PD) by increasing spatiotemporal gait features. However, evidence about what specific kinematic alterations lead to these improvements is limited, and differences in responsiveness to cueing likely affect individual motor strategies. Self-generated cueing techniques, such as singing or mental singing, provide similar benefits but no evidence exists about how these techniques affect lower limb joint movement. In this study, we assessed immediate effects of external and self-generated cueing on lower limb movement trajectories during gait.Methods: Using 3D motion capture, we assessed sagittal plane joint angles at the hip, knee, and ankle across 35 participants with PD, divided into responders (n = 23) and non-responders (n = 12) based on a clinically meaningful change in gait speed. Joint motion was assessed as overall range of motion as well as at two key time points during the gait cycle: initial contact and toe-off.Results: Responders used both cue types to increase gait speed and induce increases in overall joint ROM at the hip while only self-generated cues also increased ROM at the ankle. Increased joint excursions for responders were also evident at initial contact and toe-off.Conclusions: Our results indicate that self-generated rhythmic cues can induce similar increases in joint excursions as externally-generated cues and that some people may respond more positively than others. These results provide important insight into how self-generated cueing techniques may be tailored to meet the varied individual needs of people with PD.

Yoga Improves Balance and Low-Back Pain, but Not Anxiety, in People with Parkinson's Disease.

Individuals with Parkinson's disease (PD) experience postural instability, low-back pain (LBP), and anxiety. These symptoms increase the risk of falls and decrease quality of life. Research shows yoga improves balance and decreases LBP and anxiety in healthy adults, but its effects in PD are poorly understood. All participants were part of a larger intervention study. Participants received pretest and posttest evaluations, including the Balance Evaluation Systems Test (BESTest), Beck Anxiety Inventory (BAI), and Revised Oswestry Disability Index (ROSW). Total scores for each measure, as well as individual balance system section scores from the BESTest (biomechanical constraints, stability limits/verticality, transitions/anticipatory, reactive, sensory orientation, and stability in gait) were compared within groups pre- to posttest. Participants in the yoga group (n = 13) completed a twice-weekly 12-week yoga interve n t i o n , whereas controls (n = 13) continued their usual routines for 12 weeks. Both the yoga (Z = -3.20, p = 0.001) and control (Z = -2.10, p = 0.040) groups improved on the BESTest total score. The control group showed no changes in individual balance systems, whereas the yoga group improved in stability limits/verticality (Z = -2.3, p = 0.020), transitions/ anticipatory (Z = -2.50, p = 0.010), reactive (Z = -2.70, p = 0.008), and sensory orientation (Z = -2.30, p = 0.020). ROSW decreased in the yoga group only (Z = -2.10, p = 0.030). BAI did not change in either group. Yoga is a nonpharmacological intervention that can improve balance and LBP in people with PD. This study demonstrated that yoga is feasible for people with PD, and participants reported high levels of enjoyment and intent to practice yoga after the study.

The impact of age, surface characteristics, and dual-tasking on postural sway.

Postural control integrates somatosensory, vestibular, and visual input to maintain balance. Age, dual-tasking (DT), and varying surfaces may impact postural control and lead to falls. Research suggests smartphone use is a growing safety hazard, as it reduces situational awareness while increasing dual-task costs (DTCs). Therefore, we examined postural control using a modern, motor-cognitive, dual-task paradigm and examined DTCs associated with age, surface characteristic, and type of DT. Younger (n=24) and older (n=26) participants completed three 30- second trials of six different task conditions. Participants either stood quietly (single-task) or performed a secondary, word generation task (dual-task) that included verbally listing words (verbal) or typing words (texting) on a smartphone within a given category (e.g., vegetables) while on a firm, stable surface (level floor) or compliant, unstable surface (foam pad). Repeated-measures MANOVAs tested differences in postural sway (measured by sway angle, velocity, and acceleration) between age groups and task conditions. Results indicated poorer performance on the verbal DT than texting DT while standing on the level floor; performance was similar between the two DTs when standing on the foam pad. We also found poorer performance on the foam pad compared to level floor while texting; performance was similar between surfaces for the verbal DT. Younger adults generally had better performance than older adults within each task, particularly for texting on the level floor. In summary, older age, verbal tasks, and compliant, unstable surfaces have greater impact on postural control parameters compared to younger age, texting, and firm, stable surfaces.

Homozygous GRN mutations: new phenotypes and new insights into pathological and molecular mechanisms.

Homozygous mutations in the progranulin gene (GRN) are associated with neuronal ceroid lipofuscinosis 11 (CLN11), a rare lysosomal-storage disorder characterized by cerebellar ataxia, seizures, retinitis pigmentosa, and cognitive disorders, usually beginning between 13 and 25 years of age. This is a rare condition, previously reported in only four families. In contrast, heterozygous GRN mutations are a major cause of frontotemporal dementia associated with neuronal cytoplasmic TDP-43 inclusions. We identified homozygous GRN mutations in six new patients. The phenotypic spectrum is much broader than previously reported, with two remarkably distinct presentations, depending on the age of onset. A childhood/juvenile form is characterized by classical CLN11 symptoms at an early age at onset. Unexpectedly, other homozygous patients presented a distinct delayed phenotype of frontotemporal dementia and parkinsonism after 50 years; none had epilepsy or cerebellar ataxia. Another major finding of this study is that all GRN mutations may not have the same impact on progranulin protein synthesis. A hypomorphic effect of some mutations is supported by the presence of residual levels of plasma progranulin and low levels of normal transcript detected in one case with a homozygous splice-site mutation and late onset frontotemporal dementia. This is a new critical finding that must be considered in therapeutic trials based on replacement strategies. The first neuropathological study in a homozygous carrier provides new insights into the pathological mechanisms of the disease. Hallmarks of neuronal ceroid lipofuscinosis were present. The absence of TDP-43 cytoplasmic inclusions markedly differs from observations of heterozygous mutations, suggesting a pathological shift between lysosomal and TDP-43 pathologies depending on the mono or bi-allelic status. An intriguing observation was the loss of normal TDP-43 staining in the nucleus of some neurons, which could be the first stage of the TDP-43 pathological process preceding the formation of typical cytoplasmic inclusions. Finally, this study has important implications for genetic counselling and molecular diagnosis. Semi-dominant inheritance of GRN mutations implies that specific genetic counselling should be delivered to children and parents of CLN11 patients, as they are heterozygous carriers with a high risk of developing dementia. More broadly, this study illustrates the fact that genetic variants can lead to different phenotypes according to their mono- or bi-allelic state, which is a challenge for genetic diagnosis.

Editorial Commentary: Meniscus Message-What Is Possible or What Is Advisable?

Distal femoral varus osteotomy combined with meniscal allograft transplantation is a major surgical undertaking, not without risk and not to be taken on lightly by either the surgeon or the patient. It really is a salvage operation for a knee that is deteriorating and heading for arthroplasty at some future point. It is not an operation that should be offered to patients to allow them to return to sport. The fact that some patients do return to sport is good and is a credit to the operation and the patient's tenacity with rehabilitation, but we must question the rationale of such activity, which will most likely hasten the demise of the joint.