Putaminal dopamine modulates movement motivation in Parkinson's disease.

The relative inability to produce effortful movements is the most specific motor sign of Parkinson's disease, which is primarily characterized by loss of dopaminergic terminals in the putamen. The motor motivation hypothesis suggests that this motor deficit may not reflect a deficiency in motor control per se, but a deficiency in cost-benefit considerations for motor effort. For the first time, we investigated the quantitative effect of dopamine depletion on the motivation of motor effort in Parkinson's disease. A total of 21 early-stage, unmedicated patients with Parkinson's disease and 26 healthy controls were included. An incentivized force task was used to capture the amount of effort participants were willing to invest for different monetary incentive levels and dopamine transporter depletion in the bilateral putamen was assessed. Our results demonstrate that patients with Parkinson's disease applied significantly less grip force than healthy controls, especially for low incentive levels. Congruously, decrease of motor effort with greater loss of putaminal dopaminergic terminals was most pronounced for low incentive levels. This signifies that putaminal dopamine is most critical to motor effort when the trade-off with the benefit is poor. Taken together, we provide direct evidence that the reduction of effortful movements in Parkinson's disease depends on motivation and that this effect is associated with putaminal dopaminergic degeneration.

Dynamic properties in functional connectivity changes and striatal dopamine deficiency in Parkinson's disease.

Recent studies in Parkinson's disease (PD) patients reported disruptions in dynamic functional connectivity (dFC, i.e., a characterization of spontaneous fluctuations in functional connectivity over time). Here, we assessed whether the integrity of striatal dopamine terminals directly modulates dFC metrics in two separate PD cohorts, indexing dopamine-related changes in large-scale brain network dynamics and its implications in clinical features. We pooled data from two disease-control cohorts reflecting early PD. From the Parkinson's Progression Marker Initiative (PPMI) cohort, resting-state functional magnetic resonance imaging (rsfMRI) and dopamine transporter (DaT) single-photon emission computed tomography (SPECT) were available for 63 PD patients and 16 age- and sex-matched healthy controls. From the clinical research group 219 (KFO) cohort, rsfMRI imaging was available for 52 PD patients and 17 age- and sex-matched healthy controls. A subset of 41 PD patients and 13 healthy control subjects additionally underwent 18F-DOPA-positron emission tomography (PET) imaging. The striatal synthesis capacity of 18F-DOPA PET and dopamine terminal quantity of DaT SPECT images were extracted for the putamen and the caudate. After rsfMRI pre-processing, an independent component analysis was performed on both cohorts simultaneously. Based on the derived components, an individual sliding window approach (44 s window) and a subsequent k-means clustering were conducted separately for each cohort to derive dFC states (reemerging intra- and interindividual connectivity patterns). From these states, we derived temporal metrics, such as average dwell time per state, state attendance, and number of transitions and compared them between groups and cohorts. Further, we correlated these with the respective measures for local dopaminergic impairment and clinical severity. The cohorts did not differ regarding age and sex. Between cohorts, PD groups differed regarding disease duration, education, cognitive scores and L-dopa equivalent daily dose. In both cohorts, the dFC analysis resulted in three distinct states, varying in connectivity patterns and strength. In the PPMI cohort, PD patients showed a lower state attendance for the globally integrated (GI) state and a lower number of transitions than controls. Significantly, worse motor scores (Unified Parkinson's Disease Rating Scale Part III) and dopaminergic impairment in the putamen and the caudate were associated with low average dwell time in the GI state and a low total number of transitions. These results were not observed in the KFO cohort: No group differences in dFC measures or associations between dFC variables and dopamine synthesis capacity were observed. Notably, worse motor performance was associated with a low number of bidirectional transitions between the GI and the lesser connected (LC) state across the PD groups of both cohorts. Hence, in early PD, relative preservation of motor performance may be linked to a more dynamic engagement of an interconnected brain state. Specifically, those large-scale network dynamics seem to relate to striatal dopamine availability. Notably, most of these results were obtained only for one cohort, suggesting that dFC is impacted by certain cohort features like educational level, or disease severity. As we could not pinpoint these features with the data at hand, we suspect that other, in our case untracked, demographical features drive connectivity dynamics in PD. PRACTITIONER POINTS: Exploring dopamine's role in brain network dynamics in two Parkinson's disease (PD) cohorts, we unraveled PD-specific changes in dynamic functional connectivity. Results in the Parkinson's Progression Marker Initiative (PPMI) and the KFO cohort suggest motor performance may be linked to a more dynamic engagement and disengagement of an interconnected brain state. Results only in the PPMI cohort suggest striatal dopamine availability influences large-scale network dynamics that are relevant in motor control.

Mapping of Interventions of Social Protection for Tuberculosis Patients in Africa: A Scoping Review Protocol.

BACKGROUND: Tuberculosis (TB) is a public health problem worldwide, particularly in resource-limited countries. It is considered a social disease with a medical component that persists over time due to several social determinants, most of which are closely linked to poverty and difficult socioeconomic conditions. The objective of this exploratory study is to describe the social protection interventions available for people with TB in Africa. METHODS: Searches will be carried out systematically in MEDLINE (PubMed), Embase (Ovid), Web of Science, Scopus and The Cochrane Library, Africa-Wide Information (EBSCOhost), Google Scholar. Articles will be considered if they describe the social protection, successes and challenges associated with the implementation and delivery of social protection interventions offered to people with TB in African countries. Data from the grey literature will also be considered. PRESENTATION OF RESULTS: We will present a narrative description highlighting the successes and challenges of the social protection interventions identified, and a synthesis accompanied by maps (Africa), figures or tables to summarize the data. CONCLUSION: This exploratory study will map the existing literature on social protection interventions for TB patients and guide future research to inform policy and practice decisions.

CONTEXTE: La tuberculose (TB) est un problème de santé publique dans le monde entier, en particulier dans les pays à ressources limitées. Elle est considérée comme une maladie sociale avec une composante médicale qui persiste dans le temps en raison de plusieurs déterminants sociaux, dont la plupart sont étroitement liés à la pauvreté et à des conditions socio-économiques difficiles. L'objectif de cette étude exploratoire est de décrire les interventions de protection sociale disponibles pour les personnes atteintes de TB dans les pays d'Afrique. METHODE: Des recherches seront effectuées systématiquement dans MEDLINE (PubMed), Embase (Ovid), Web Of Science, Scopus et The Cochrane Library, Africa-Wide Information (EBSCOhost), Google Scholar. Les articles seront pris en considération s'ils décrivent la protection sociale, les succès et les défis associés à la mise en œuvre et à l'exécution des interventions de protection sociale offertes aux personnes atteintes de TB dans les pays d'Afrique. Les données issues de la littérature grise seront également prises en compte. PRESENTATION DES RESULTATS: Nous présenterons une description narrative soulignant les succès et les défis des interventions de protection sociale identifiées, ainsi qu'une synthèse accompagnée de cartes (Afrique), de figures ou de tableaux pour résumer les données. CONCLUSION: Cette étude exploratoire permettra de cartographier la littérature existante sur les interventions de protection sociale pour les patients atteints de tuberculose et d'orienter les recherches futures afin d'éclairer les décisions politiques et pratiques.

Clear-headed into old age: Resilience and resistance against brain aging-A PET imaging perspective.

With the advances in modern medicine and the adaptation towards healthier lifestyles, the average life expectancy has doubled since the 1930s, with individuals born in the millennium years now carrying an estimated life expectancy of around 100 years. And even though many individuals around the globe manage to age successfully, the prevalence of aging-associated neurodegenerative diseases such as sporadic Alzheimer's disease has never been as high as nowadays. The prevalence of Alzheimer's disease is anticipated to triple by 2050, increasing the societal and economic burden tremendously. Despite all efforts, there is still no available treatment defeating the accelerated aging process as seen in this disease. Yet, given the advances in neuroimaging techniques that are discussed in the current Review article, such as in positron emission tomography (PET) or magnetic resonance imaging (MRI), pivotal insights into the heterogenous effects of aging-associated processes and the contribution of distinct lifestyle and risk factors already have and are still being gathered. In particular, the concepts of resilience (i.e. coping with brain pathology) and resistance (i.e. avoiding brain pathology) have more recently been discussed as they relate to mechanisms that are associated with the prolongation and/or even stop of the progressive brain aging process. Better understanding of the underlying mechanisms of resilience and resistance may one day, hopefully, support the identification of defeating mechanism against accelerating aging.

A positive neighborhood walkability is associated with a higher magnitude of leisure walking in adults upon COVID-19 restrictions: a longitudinal cohort study.

BACKGROUND: Previous cross-sectional and longitudinal observational studies revealed positive relationships between contextual built environment components and walking behavior. Due to severe restrictions during COVID-19 pandemic lockdowns, physical activity was primarily performed within the immediate living area. Using this unique opportunity, we evaluated whether built environment components were associated with the magnitude of change in walking activity in adults during COVID-19 restrictions. METHODS: Data on self-reported demographic characteristics and walking behaviour were extracted from the prospective longitudinal Lifelines Cohort Study in the Netherlands of participants ≥ 18 years. For our analyses, we made use of the data acquired between 2014-2017 (n = 100,285). A fifth of the participants completed the questionnaires during COVID-19 restrictive policies in July 2021 (n = 20,806). Seven spatial components were calculated for a 500m and 1650m Euclidean buffer per postal code area in GIS: population density, retail and service destination density, land use mix, street connectivity, green space density, sidewalk density, and public transport stops. Additionally, the walkability index (WI) of these seven components was calculated. Using multivariable linear regression analyses, we analyzed the association between the WI (and separate components) and the change in leisure walking minutes/week. Included demographic variables were age, gender, BMI, education, net income, occupation status, household composition and the season in which the questionnaire was filled in. RESULTS: The average leisure walking time strongly increased by 127 min/week upon COVID-19 restrictions. All seven spatial components of the WI were significantly associated with an increase in leisure walking time; a 10% higher score in the individual spatial component was associated with 5 to 8 more minutes of leisure walking/week. Green space density at the 500m Euclidean buffer and side-walk density at the 1650m Euclidean buffer were associated with the highest increase in leisure walking time/week. Subgroup analysis revealed that the built environment showed its strongest impact on leisure walking time in participants not engaging in leisure walking before the COVID-19 pandemic, compared to participants who already engaged in leisure walking before the COVID-19 pandemic. CONCLUSIONS: These results provide strong evidence that the built environment, corrected for individual-level characteristics, directly links to changes observed in leisure walking time during COVID-19 restrictions. Since this relation was strongest in those who did not engage in leisure walking before the COVID-19 pandemic, our results encourage new perspectives in health promotion and urban planning.

Randomized Controlled Study in the Use of Aromatherapy for Pain Reduction and to Reduce Opioid Use in the Emergency Department.

INTRODUCTION: This study aimed to evaluate the effects of aromatherapy on emergency department patients' perception of pain and its ability to reduce the use of opioids in an emergency department. METHODS: This randomized, controlled, single-blinded study was conducted in a suburban/rural freestanding emergency department with a therapeutic group, sham group, and control group. RESULTS: A total of 230 patients, 171 females and 59 males, completed the study. Of those who received the therapeutic agent, an average reduction in pain of 1.04 points on the pain scale was reported, whereas the sham group averaged 0.38 and the control group 0.23. There was a statistically significant reduction of pain scores in the therapeutic group. A total of 13 received opioid pain medication during their visit. Of these, the therapeutic group averaged a total of 2.67 morphine milligram equivalents for their visit compared with 3.63 in the sham group and 4.36 in the control group; however, statistical significance was not achieved. DISCUSSION: This study supported what other studies have found, indicating that aromatherapy is effective in reducing pain. A difference between the placebo effect and a true therapeutic effect was seen by using a control group apart from the sham and therapeutic groups. Despite the small effect size (0.3), implementation of aromatherapy into standard practice may be practical considering the anxiolytic effects that have been shown in other studies. Aromatherapy with essential oils should be considered as another tool to use in a multimodal approach in the treatment of pain in the emergency department setting.

Gray Matter Volume Loss in Proposed Brain-First and Body-First Parkinson's Disease Subtypes.

BACKGROUND: α-Synuclein pathology is associated with neuronal degeneration in Parkinson's disease (PD) and considered to sequentially spread across the brain (Braak stages). According to a new hypothesis of distinct α-synuclein spreading directions based on the initial site of pathology, the "brain-first" spreading subtype would be associated with a more asymmetric cerebral and nigrostriatal pathology than the "body-first" subtype. OBJECTIVE: Here, we tested if proposed markers of brain-first PD (ie, higher dopamine transporter [DaT] asymmetry; absence of rapid eye movement sleep behavior disorder [RBD]) are associated with a greater or more asymmetric reduction in gray matter volume (GMV) in comparison to body-first PD. METHODS: Data of 255 de novo PD patients and 110 healthy controls (HCs) were retrieved from the Parkinson's Progression Markers Initiative. Structural magnetic resonance images were preprocessed, and GMVs and their hemispherical asymmetry were obtained for each of the neuropathologically defined Braak stages. Group and correlation comparisons were performed to assess differences in GMV and GMV asymmetry between PD subtypes. RESULTS: PD patients demonstrated significantly smaller bilateral GMVs compared to HCs, in a pattern denoting stage-dependent disease-related brain atrophy. However, the degree of putaminal DaT asymmetry was not associated with reduced GMV or higher GMV asymmetry. Furthermore, RBD-negative and RBD-positive patients did not demonstrate a significant difference in GMV or GMV asymmetry. CONCLUSIONS: Our findings suggest that putative brain-first and body-first patients do not present diverging brain atrophy patterns. Although certainly not disproving the brain-first/body-first spreading hypothesis, this study fails to provide evidence in support of it. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Impact of Dutch COVID-19 restrictive policy measures on physical activity behavior and identification of correlates of physical activity changes: a cohort study.

BACKGROUND: Identification of characteristics of individuals that are related to decreases in physical activity (PA) levels during lockdown is needed to develop targeted-interventions. This study aims to evaluate changes in domain-specific (i.e. leisure time, transportation, occupational, and household) and total PA due to the Dutch COVID-19 lockdown, which started on March 15 2020. Furthermore, we aim to identify demographic, health-related, and psychological correlates of these changes. METHODS: Individuals who participated in the Nijmegen Exercise Study during 2017-2019 were invited to this study, which was conducted between April 16 and May 12 2020. Participant characteristics (i.e. age, sex, body mass index (BMI), marital status, education, household composition, and occupation status), living environment (i.e. housing type and degree of urbanization), psychological characteristics (i.e. resilience, outcome expectations, vitality, and mental health), and medical history were collected via an online questionnaire. Short Questionnaire to Assess Health-enhancing physical activity was used to assess PA behavior before and during lockdown. Wilcoxon signed-rank test was used to compare PA levels, in metabolic equivalent of task (MET)-minutes per week (min/wk), before and during lockdown. Multivariable linear regression analyses were performed to examine correlates of PA changes. RESULTS: 4033 participants (57% male; 59 ± 13 years) were included. PA decreased significantly during lockdown with mean ± SD changes of 393 ± 2735 MET-min/wk for total, 133 ± 785 MET-min/wk for transportation, 137 ± 1469 MET-min/wk for occupation, and 136 ± 1942 MET-min/wk for leisure time PA. Household PA did not change significantly. Unemployment, COVID-19-related occupational changes, higher BMI, and living in an apartment or semi-detached/terraced house were significantly related to larger decreases in total and domain-specific PA. Higher vitality was related to smaller decreases in total and domain-specific PA. Higher age was significantly associated with a larger decrease in leisure time PA. Lower education was associated with smaller decreases in transportation and occupational PA compared to higher education. CONCLUSION: PA levels significantly reduced during lockdown compared to before lockdown. Declines were observed during transportation and occupation, but were not compensated by an increase in leisure time PA. We identified subgroups that were more susceptible to reductions in domain-specific or total PA levels and should therefore be encouraged to increase their PA levels during lockdown.

Indication of retrograde tau spreading along Braak stages and functional connectivity pathways.

PURPOSE: Tau pathology progression in Alzheimer's disease (AD) is explained through the network degeneration hypothesis and the neuropathological Braak stages; however, the compatibility of these models remains unclear. METHODS: We utilized [18F]AV-1451 tau-PET scans of 39 subjects with AD and 39 sex-matched amyloid-negative healthy controls (HC) in the ADNI (Alzheimer's Disease Neuroimaging Initiative) dataset. The peak cluster of tau-tracer uptake was identified in each Braak stage of neuropathological tau deposition and used to create a seed-based functional connectivity network (FCN) using 198 HC subjects, to identify healthy networks unaffected by neurodegeneration. RESULTS: Voxel-wise tau deposition was both significantly higher inside relative to outside FCNs and correlated significantly and positively with levels of healthy functional connectivity. Within many isolated Braak stages and regions, the correlation between tau and intrinsic functional connectivity was significantly stronger than it was across the whole brain. In this way, each peak cluster of tau was related to multiple Braak stages traditionally associated with both earlier and later stages of disease. CONCLUSION: We show specificity of healthy FCN topography for AD-pathological tau as well as positive voxel-by-voxel correlations between pathological tau and healthy functional connectivity. We propose a model of "up- and downstream" functional tau progression, suggesting that tau pathology evolves along functional connectivity networks not only "downstream" (i.e., along the expected sequence of the established Braak stages) but also in part "upstream" or "retrograde" (i.e., against the expected sequence of the established Braak stages), with pathology in earlier Braak stages intensified by its functional relationship to later disease stages.

Quantitative and individualized assessment of the learning curve in preoperative planning of the acetabular cup size in primary total hip arthroplasty.

INTRODUCTION: The aim of the present study was to investigate the learning curves of 2 trainees with different experience levels to reach proficiency in preoperative planning of the cup size based on learning curve cumulative summation (LC-CUSUM) statistics and a cumulative summation (CUSUM) test. MATERIALS AND METHODS: One-hundred-twenty patients who had undergone primary total hip arthroplasty with a cementless cup were selected. Preoperative planning was performed by an experienced orthopedic surgeon. Trainee 1 (student) and trainee 2 (resident) planned the cup size. The trainees were blinded to the preoperative plan and the definitive cup size. Only after a cup size was chosen, the trainees were unblinded to the preoperative plan of the surgeon. LC-CUSUM was applied to both trainees to determine when proficiency in determining the appropriate cup size was reached. A CUSUM test was applied to ensure retention of proficiency. RESULTS: With reference to the preoperative plan of the surgeon, LC-CUSUM indicated proficiency after 94 planning attempts for trainee 1 and proficiency after 66 attempts for trainee 2, respectively. Trainee 1 and 2 maintained proficiency thereafter. With reference to the definitive cup size, LC-CUSUM did not signal competency within the first 120 planning attempts for trainee 1. Trainee 2 was declared competent after 103 attempts and retained competency thereafter. CONCLUSIONS: LC-CUSUM/CUSUM allow for an individualized, quantitative and continuous assessment of planning quality. Based on LC-CUSUM statistics, the two trainees of this study gain proficiency in planning of the acetabular cup size after 50-100 attempts when an immediate feedback is provided. Previous experience positively influences the performance. The study serves as basis for the medical education of students and residents in joint replacement procedures.

Dopamine metabolism of the nucleus accumbens and fronto-striatal connectivity modulate impulse control.

Impulsive-compulsive behaviours like pathological gambling or hypersexuality are a frequent side effect of dopamine replacement therapy in patients with Parkinson's disease. Multiple imaging studies suggest a significant reduction of presynaptic dopamine transporters in the nucleus accumbens to be a predisposing factor, reflecting either a reduction of mesolimbic projections or, alternatively, a lower presynaptic dopamine transporter expression per se. Here, we aimed to test the hypothesis of fewer mesolimbic projections as a risk factor by using dopamine synthesis capacity as a proxy of dopaminergic terminal density. Furthermore, previous studies have demonstrated a reduction of fronto-striatal connectivity to be associated with increased risk of impulsive-compulsive behaviour in Parkinson's disease. Therefore, another aim of this study was to investigate the relationship between severity of impulsive-compulsive behaviour, dopamine synthesis capacity and fronto-striatal connectivity. Eighty participants underwent resting state functional MRI and anatomical T1-weighted images [mean age: 68 ± 9.9 years, 67% male (patients)]. In 59 participants, 18F-DOPA-PET was obtained and voxel-wise Patlak slopes indicating dopamine synthesis capacity were calculated. All participants completed the QUIP-RS questionnaire, a well validated test to quantify severity of impulsive-compulsive behaviour in Parkinson's disease. A voxel-wise correlation analysis between dopamine synthesis capacity and QUIP-RS score was calculated for striatal regions. To investigate the relationship between symptom severity and functional connectivity, voxel-wise correlations were performed. A negative correlation was found between dopamine synthesis capacity and QUIP-RS score in the nucleus accumbens (r = -0.57, P = 0.001), a region functionally connected to the rostral anterior cingulate cortex. The connectivity strength was modulated by QUIP-RS, i.e. patients with more severe impulsive-compulsive behaviours had a weaker functional connectivity between rostral anterior cingulate cortex and the nucleus accumbens. In addition, cortical thickness and severity of impulsive-compulsive behaviour were positively correlated in the subgenual rostral anterior cingulate cortex. We found three factors to be associated with severity of impulsive-compulsive behaviour: (i) decreased dopamine synthesis capacity in the nucleus accumbens; (ii) decreased functional connectivity of the rostral anterior cingulate cortex with the nucleus accumbens; and (iii) increased cortical thickness of the subgenual rostral anterior cingulate cortex. Rather than a downregulation of dopamine transporters, a reduction of mesolimbic dopaminergic projections in conjunction with a dysfunctional rostral anterior cingulate cortex-a region known to play a key role in impulse control-could be the most crucial neurobiological risk factor for the development of impulsive-compulsive behaviours in patients with Parkinson's disease under dopamine replacement therapy.

Level of education mitigates the impact of tau pathology on neuronal function.

PURPOSE: Using PET imaging in a group of patients with Alzheimer's disease (AD), we investigated whether level of education, a proxy for resilience, mitigates the harmful impact of tau pathology on neuronal function. METHODS: We included 38 patients with mild-to-moderate AD (mean age 67 ± 7 years, mean MMSE score 24 ± 4, mean years of education 14 ± 4; 20 men, 18 women) in whom a [18F]AV-1451 scan (a measure of tau pathology) and an [18F]FDG scan (a measure of neuronal function) were available. The preprocessed PET scans were z-transformed using templates for [18F]AV-1451 and [18F]FDG from healthy controls, and subsequently thresholded at a z-score of ≥3.0, representing an one-tailed p value of 0.001. Next, three volumes were computed in each patient: the tau-specific volume (tau pathology without neuronal dysfunction), the FDG-specific volume (neuronal dysfunction without tau pathology), and the overlap volume (tau pathology and neuronal dysfunction). Mean z-scores and volumes were extracted and used as dependent variables in regression analysis with years of education as predictor, and age and MMSE score as covariates. RESULTS: Years of education were positively associated with tau-specific volume (ß = 0.362, p = 0.022), suggesting a lower impact of tau pathology on neuronal function in patients with higher levels of education. Concomitantly, level of education was positively related to tau burden in the overlap volume (ß = 0.303, p = 0.036) implying that with higher levels of education more tau pathology is necessary to induce neuronal dysfunction. CONCLUSION: In patients with higher levels of education, tau pathology is less paralleled by regional and remote neuronal dysfunction. The data suggest that early life-time factors such as level of education support resilience mechanisms, which ameliorate AD-related effects later in life.

Networks of tau distribution in Alzheimer's disease.

See Whitwell (doi:10.1093/brain/awy001) for a scientific commentary on this article.A stereotypical anatomical propagation of tau pathology has been described in Alzheimer's disease. According to recent concepts (network degeneration hypothesis), this propagation is thought to be indicative of misfolded tau proteins possibly spreading along functional networks. If true, tau pathology accumulation should correlate in functionally connected brain regions. Therefore, we examined whether independent components could be identified in the distribution pattern of in vivo tau pathology and whether these components correspond with specific functional connectivity networks. Twenty-two 18F-AV-1451 PET scans of patients with amnestic Alzheimer's disease (mean age = 66.00 ± 7.22 years, 14 males/eight females) were spatially normalized, intensity standardized to the cerebellum, and z-transformed using the mean and deviation image of a healthy control sample to assess Alzheimer's disease-related tau pathology. First, to detect distinct tau pathology networks, the deviation maps were subjected to an independent component analysis. Second, to investigate if regions of high tau burden are associated with functional connectivity networks, we extracted the region with the maximum z-value in each of the generated tau pathology networks and used them as seeds in a subsequent resting-state functional MRI analysis, conducted in a group of healthy adults (n = 26) who were part of the 1000 Functional Connectomes Project. Third, to examine if tau pathology co-localizes with functional connectivity networks, we quantified the spatial overlap between the seed-based networks and the corresponding tau pathology network by calculating the Dice similarity coefficient. Additionally, we assessed if the tau-dependent seed-based networks correspond with known functional resting-state networks. Finally, we examined the relevance of the identified components in regard to the neuropathological Braak stages. We identified 10 independently coherent tau pathology networks with the majority showing a symmetrical bi-hemispheric expansion and coinciding with highly functionally connected brain regions such as the precuneus and cingulate cortex. A fair-to-moderate overlap was observed between the tau pathology networks and corresponding seed-based networks (Dice range: 0.13-0.57), which in turn resembled known resting-state networks, particularly the default mode network (Dice range: 0.42-0.56). Moreover, greater tau burden in the tau pathology networks was associated with more advanced Braak stages. Using the data-driven approach of an independent component analysis, we observed a set of independently coherent tau pathology networks in Alzheimer's disease, which were associated with disease progression and coincided with functional networks previously reported to be impaired in Alzheimer's disease. Together, our results provide novel information regarding the impact of tau pathology networks on the mechanistic pathway of Alzheimer's disease.

Are there clinically relevant anatomical differences of the proximal femur in patients with mild dysplastic and primary hip osteoarthritis? A CT-based matched-pairs cohort study.

AIM: To investigate the three-dimensional anatomy and shape of the proximal femur, comparing patients with secondary osteoarthritis (OA) due to mild developmental dysplasia of the hip (DDH) and primary hip OA. MATERIALS AND METHODS: This retrospective radiographic computed tomography (CT)-based study investigated proximal femoral anatomy in a consecutive series of 84 patients with secondary hip OA due to mild DDH (Crowe type I&II/Hartofilakidis A) compared to 84 patients with primary hip OA, matched for gender, age at surgery, and body mass index. RESULTS: Men with DDH showed higher neck shaft angles (127±5° vs. 123±4°; p<0.001), whereas women with DDH had a larger femoral head diameter (46±4 vs. 44±3 mm; p=0.002), smaller femoral offset (36±5 vs. 40±4 mm; p<0.001), decreased leg torsion (25±13° vs. 31±16°; p=0.037), and a higher neck shaft angle (128±7° vs. 123±4°; p<0.001) compared to primary OA patients. Similar patterns of the three-dimensional endosteal canal shape of the proximal femur, but a high inter-individual variability for femoral canal torsion at the meta-diaphyseal level were found for DDH and primary OA patients. CONCLUSION: Standard cementless stem designs are suitable to treat patients with secondary hip OA due to mild DDH; however, high patient variability and subtle anatomical differences in the proximal femur should be respected.

Resampling: An improvement of importance sampling in varying population size models.

Sequential importance sampling algorithms have been defined to estimate likelihoods in models of ancestral population processes. However, these algorithms are based on features of the models with constant population size, and become inefficient when the population size varies in time, making likelihood-based inferences difficult in many demographic situations. In this work, we modify a previous sequential importance sampling algorithm to improve the efficiency of the likelihood estimation. Our procedure is still based on features of the model with constant size, but uses a resampling technique with a new resampling probability distribution depending on the pairwise composite likelihood. We tested our algorithm, called sequential importance sampling with resampling (SISR) on simulated data sets under different demographic cases. In most cases, we divided the computational cost by two for the same accuracy of inference, in some cases even by one hundred. This study provides the first assessment of the impact of such resampling techniques on parameter inference using sequential importance sampling, and extends the range of situations where likelihood inferences can be easily performed.

Sports and physical activity after cementless total hip arthroplasty with a minimum follow-up of 10 years.

The present retrospective cohort study was conducted to compare sporting activity levels before and a minimum of 10 years after primary cementless total hip arthroplasty (THA). A consecutive series of 86 patients with a mean age at surgery of 52 years (range, 21-60 years) was evaluated 11 years after surgery (range, 10-12 years). Pre- and post-operative sporting activities were assessed at routine follow-up using the University of California, Los Angeles activity score and the Schulthess Clinic sports and activity questionnaire. Post-operative health-related quality of life was measured using the Short-Form 36 (SF-36) questionnaire and compared with age-matched reference populations from the SF-36 database. Eleven years after THA, 89% of preoperatively active patients had returned to sport. Comparing sports activity preoperatively (before the onset of symptoms) and 11 years after THA, no significant difference was found for the mean number of disciplines or session length. A significant decline in high-impact activities was observed, while participation in low-impact activities significantly increased. Health-related quality of life compared well against a healthy age-matched reference population and was significantly higher than in a reference group of patients with osteoarthritis. The majority of patients were able to maintain their physical activity level in the long term after primary cementless THA, compared with the activity level before the onset of restricting osteoarthritis symptoms. However, a change in disciplines toward low-impact activities was observed.