Impact of hormone receptor status and tumor subtypes of breast cancer in young BRCA carriers.

BACKGROUND: Hormone receptor expression is a known positive prognostic and predictive factor in breast cancer; however, limited evidence exists on its prognostic impact on prognosis of young patients harboring a pathogenic variant (PV) in the BRCA1 and/or BRCA2 genes. PATIENTS AND METHODS: This international, multicenter, retrospective cohort study included young patients (aged ≤40 years) diagnosed with invasive breast cancer and harboring germline PVs in BRCA genes. We investigated the impact of hormone receptor status on clinical behavior and outcomes of breast cancer. Outcomes of interest [disease-free survival (DFS), breast cancer-specific survival (BCSS), and overall survival (OS)] were first investigated according to hormone receptor expression (positive versus negative), and then according to breast cancer subtype [luminal A-like versus luminal B-like versus triple-negative versus human epidermal growth factor receptor 2 (HER2)-positive breast cancer]. RESULTS: From 78 centers worldwide, 4709 BRCA carriers were included, of whom 2143 (45.5%) had hormone receptor-positive and 2566 (54.5%) hormone receptor-negative breast cancer. Median follow-up was 7.9 years. The rate of distant recurrences was higher in patients with hormone receptor-positive disease (13.1% versus 9.6%, P < 0.001), while the rate of second primary breast cancer was lower (9.1% versus 14.7%, P < 0.001) compared to patients with hormone receptor-negative disease. The 8-year DFS was 65.8% and 63.4% in patients with hormone receptor-positive and negative disease, respectively. The hazard ratio of hormone receptor-positive versus negative disease changed over time for DFS, BCSS, and OS (P < 0.05 for interaction of hormone receptor status and survival time). Patients with luminal A-like breast cancer had the worst long-term prognosis in terms of DFS compared to all the other subgroups (8-year DFS: 60.8% in luminal A-like versus 63.5% in triple-negative versus 65.5% in HER2-positive and 69.7% in luminal B-like subtype). CONCLUSIONS: In young BRCA carriers, differences in recurrence pattern and second primary breast cancer among hormone receptor-positive versus negative disease warrant consideration in counseling patients on treatment, follow-up, and risk-reducing surgery.

Parameter subset reduction for imaging-based digital twin generation of patients with left ventricular mechanical discoordination.

BACKGROUND: Integration of a patient's non-invasive imaging data in a digital twin (DT) of the heart can provide valuable insight into the myocardial disease substrates underlying left ventricular (LV) mechanical discoordination. However, when generating a DT, model parameters should be identifiable to obtain robust parameter estimations. In this study, we used the CircAdapt model of the human heart and circulation to find a subset of parameters which were identifiable from LV cavity volume and regional strain measurements of patients with different substrates of left bundle branch block (LBBB) and myocardial infarction (MI). To this end, we included seven patients with heart failure with reduced ejection fraction (HFrEF) and LBBB (study ID: 2018-0863, registration date: 2019-10-07), of which four were non-ischemic (LBBB-only) and three had previous MI (LBBB-MI), and six narrow QRS patients with MI (MI-only) (study ID: NL45241.041.13, registration date: 2013-11-12). Morris screening method (MSM) was applied first to find parameters which were important for LV volume, regional strain, and strain rate indices. Second, this parameter subset was iteratively reduced based on parameter identifiability and reproducibility. Parameter identifiability was based on the diaphony calculated from quasi-Monte Carlo simulations and reproducibility was based on the intraclass correlation coefficient ( ICC ) obtained from repeated parameter estimation using dynamic multi-swarm particle swarm optimization. Goodness-of-fit was defined as the mean squared error ( χ 2 ) of LV myocardial strain, strain rate, and cavity volume. RESULTS: A subset of 270 parameters remained after MSM which produced high-quality DTs of all patients ( χ 2 < 1.6), but minimum parameter reproducibility was poor ( ICC min = 0.01). Iterative reduction yielded a reproducible ( ICC min = 0.83) subset of 75 parameters, including cardiac output, global LV activation duration, regional mechanical activation delay, and regional LV myocardial constitutive properties. This reduced subset produced patient-resembling DTs ( χ 2 < 2.2), while septal-to-lateral wall workload imbalance was higher for the LBBB-only DTs than for the MI-only DTs (p < 0.05). CONCLUSIONS: By applying sensitivity and identifiability analysis, we successfully determined a parameter subset of the CircAdapt model which can be used to generate imaging-based DTs of patients with LV mechanical discoordination. Parameters were reproducibly estimated using particle swarm optimization, and derived LV myocardial work distribution was representative for the patient's underlying disease substrate. This DT technology enables patient-specific substrate characterization and can potentially be used to support clinical decision making.

Specialized Versus Generic Allied Health Therapy and the Risk of Parkinson's Disease Complications.

BACKGROUND: Specialized versus generic physiotherapy (PT) reduces Parkinson's disease (PD)-related complications. It is unclear (1) whether other specialized allied heath disciplines, including occupational therapy (OT) and speech and language therapy (S<), also reduce complications; (2) whether there is a synergistic effect among multiple specialized disciplines; and (3) whether each allied health discipline prevents specific complications. OBJECTIVES: To longitudinally assessed whether the level of expertise (specialized vs. generic training) of PT, OT, and S< was associated with the incidence rate of PD-related complications. METHODS: We used claims data of all insured persons with PD in the Netherlands between January 1, 2010, and December 31, 2018. ParkinsonNet-trained therapists were classified as specialized, and other therapists as generic. We used mixed-effects Poisson regression models to estimate rate ratios adjusting for sociodemographic and clinical characteristics. RESULTS: The population of 51,464 persons with PD (mean age, 72.4 years; standard deviation 9.8) sustained 10,525 PD-related complications during follow-up (median 3.3 years). Specialized PT was associated with fewer complications (incidence rate ratio [IRR] of specialized versus generic = 0.79; 95% confidence interval, [0.74-0.83]; P < 0.0001), as was specialized OT (IRR = 0.88 [0.77-0.99]; P = 0.03). We found a trend of an association between specialized S< and a lower rate of PD-related complications (IRR = 0.88 [0.74-1.04]; P = 0.18). The inverse association of specialized OT persisted in the stratum, which also received specialized PT (IRR = 0.62 [0.42-0.90]; P = 0.001). The strongest inverse association of PT was seen with orthopedic injuries (IRR = 0.78 [0.73-0.82]; P < 0.0001) and of S< with pneumonia (IRR = 0.70 [0.53-0.93]; P = 0.03). CONCLUSIONS: These findings support a wider introduction of specialized allied health therapy expertise in PD care and conceivably for other medical conditions. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Randomized Delayed-Start Trial of Levodopa in Parkinson's Disease.

BACKGROUND: Levodopa is the main treatment for symptoms of Parkinson's disease. Determining whether levodopa also has a disease-modifying effect could provide guidance as to when in the course of the disease the treatment with this drug should be initiated. METHODS: In a multicenter, double-blind, placebo-controlled, delayed-start trial, we randomly assigned patients with early Parkinson's disease to receive levodopa (100 mg three times per day) in combination with carbidopa (25 mg three times per day) for 80 weeks (early-start group) or placebo for 40 weeks followed by levodopa in combination with carbidopa for 40 weeks (delayed-start group). The primary outcome was the between-group difference in the mean change from baseline to week 80 in the total score on the Unified Parkinson's Disease Rating Scale (UPDRS; scores range from 0 to 176, with higher scores signifying more severe disease). Secondary analyses included the progression of symptoms, as measured by the UPDRS score, between weeks 4 and 40 and the noninferiority of early initiation of treatment to delayed initiation between weeks 44 and 80, with a noninferiority margin of 0.055 points per week. RESULTS: A total of 445 patients were randomly assigned: 222 to the early-start group and 223 to the delayed-start group. The mean (±SD) UPDRS score at baseline was 28.1±11.4 points in the early-start group and 29.3±12.1 points in the delayed-start group. The change in UPDRS score from baseline to week 80 was -1.0±13.1 points and -2.0±13.0 points, respectively (difference, 1.0 point; 95% confidence interval [CI], -1.5 to 3.5; P=0.44); this finding of no significant between-group difference at week 80 implies that levodopa had no disease-modifying effect. Between weeks 4 and 40, the rate of progression of symptoms, as measured in UPDRS points per week, was 0.04±0.23 in the early-start group and 0.06±0.34 in the delayed-start group (difference, -0.02; 95% CI, -0.07 to 0.03). The corresponding rates between weeks 44 and 80 were 0.10±0.25 and 0.03±0.28 (difference, 0.07; two-sided 90% CI, 0.03 to 0.10); the difference in the rate of progression between weeks 44 and 80 did not meet the criterion for noninferiority of early receipt of levodopa to delayed receipt. The rates of dyskinesia and levodopa-related fluctuations in motor response did not differ significantly between the two groups. CONCLUSIONS: Among patients with early Parkinson's disease who were evaluated over the course of 80 weeks, treatment with levodopa in combination with carbidopa had no disease-modifying effect. (Funded by the Netherlands Organization for Health Research and Development and others; LEAP Current Controlled Trials number, ISRCTN30518857 .).

In vivo analysis of the origin and characteristics of gaseous microemboli during catheter-mediated irreversible electroporation.

AIMS: Irreversible electroporation (IRE) ablation is a non-thermal ablation method based on the application of direct current between a multi-electrode catheter and skin electrode. The delivery of current through blood leads to electrolysis. Some studies suggest that gaseous (micro)emboli might be associated with myocardial damage and/or (a)symptomatic cerebral ischaemic events. The aim of this study was to compare the amount of gas generated during IRE ablation and during radiofrequency (RF) ablation. METHODS AND RESULTS: In six 60-75 kg pigs, an extracorporeal femoral shunt was outfitted with a bubble-counter to detect the size and total volume of gas bubbles. Anodal and cathodal 200 J IRE applications were delivered in the left atrium (LA) using a 14-electrode circular catheter. The 30 and 60 s 40 W RF point-by-point ablations were performed. Using transoesophageal echocardiography (TOE), gas formation was visualized. Average gas volumes were 0.6 ± 0.6 and 56.9 ± 19.1 µL (P < 0.01) for each anodal and cathodal IRE application, respectively. Also, qualitative TOE imaging showed significantly less LA bubble contrast with anodal than with cathodal applications. Radiofrequency ablations produced 1.7 ± 2.9 and 6.7 ± 7.4 µL of gas, for 30 and 60 s ablation time, respectively. CONCLUSION: Anodal IRE applications result in significantly less gas formation than both cathodal IRE applications and RF applications. This finding is supported by TOE observations.

WOrk-Related Questionnaire for UPper extremity disorders (WORQ-UP): Factor Analysis and Internal Consistency.

OBJECTIVE: To test a 17-item questionnaire, the WOrk-Related Questionnaire for UPper extremity disorders (WORQ-UP), for dimensionality of the items (factor analysis) and internal consistency. DESIGN: Cross-sectional study. SETTING: Outpatient clinic. PARTICIPANTS: A consecutive sample of patients (N=150) consisting of all new referral patients (either from a general physician or other hospital) who visited the orthopedic outpatient clinic because of an upper extremity musculoskeletal disorder. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Number and dimensionality of the factors in the WORQ-UP. RESULTS: Four factors with eigenvalues (EVs) >1.0 were found. The factors were named exertion, dexterity, tools & equipment, and mobility. The EVs of the factors were, respectively, 5.78, 2.38, 1.81, and 1.24. The factors together explained 65.9% of the variance. The Cronbach alpha values for these factors were, respectively, .88, .74, .87, and .66. CONCLUSIONS: The 17 items of the WORQ-UP resemble 4 factors-exertion, dexterity, tools & equipment, and mobility-with a good internal consistency.

Cerebellar function and ischemic brain lesions in migraine patients from the general population.

Objective The objective of this article is to obtain detailed quantitative assessment of cerebellar function and structure in unselected migraine patients and controls from the general population. Methods A total of 282 clinically well-defined participants (migraine with aura n = 111; migraine without aura n = 89; non-migraine controls n = 82; age range 43-72; 72% female) from a population-based study were subjected to a range of sensitive and validated cerebellar tests that cover functions of all main parts of the cerebellar cortex, including cerebrocerebellum, spinocerebellum, and vestibulocerebellum. In addition, all participants underwent magnetic resonance imaging (MRI) of the brain to screen for cerebellar lesions. As a positive control, the same cerebellar tests were conducted in 13 patients with familial hemiplegic migraine type 1 (FHM1; age range 19-64; 69% female) all carrying a CACNA1A mutation known to affect cerebellar function. Results MRI revealed cerebellar ischemic lesions in 17/196 (8.5%) migraine patients and 3/79 (4%) controls, which were always located in the posterior lobe except for one control. With regard to the cerebellar tests, there were no differences between migraine patients with aura, migraine patients without aura, and controls for the: (i) Purdue-pegboard test for fine motor skills (assembly scores p = 0.1); (ii) block-design test for visuospatial ability (mean scaled scores p = 0.2); (iii) prism-adaptation task for limb learning (shift scores p = 0.8); (iv) eyeblink-conditioning task for learning-dependent timing (peak-time p = 0.1); and (v) body-sway test for balance capabilities (pitch velocity score under two-legs stance condition p = 0.5). Among migraine patients, those with cerebellar ischaemic lesions performed worse than those without lesions on the assembly scores of the pegboard task ( p < 0.005), but not on the primary outcome measures of the other tasks. Compared with controls and non-hemiplegic migraine patients, FHM1 patients showed substantially more deficits on all primary outcomes, including Purdue-peg assembly ( p < 0.05), block-design scaled score ( p < 0.001), shift in prism-adaptation ( p < 0.001), peak-time of conditioned eyeblink responses ( p < 0.05) and pitch-velocity score during stance-sway test ( p < 0.001). Conclusions Unselected migraine patients from the general population show normal cerebellar functions despite having increased prevalence of ischaemic lesions in the cerebellar posterior lobe. Except for an impaired pegboard test revealing deficits in fine motor skills, these lesions appear to have little functional impact. In contrast, all cerebellar functions were significantly impaired in participants with FHM1.

Development of a novel WOrk-Related Questionnaire for UPper extremity disorders (WORQ-UP).

PURPOSE: The aim of this study is to develop a patient-reported outcome measure (PROM) that identifies work-related limitations among patients with upper extremity musculoskeletal disorders in order to enhance work-directed care in daily orthopaedic practice, and to assess its content validity. METHODS: The questionnaire was developed following the evaluation of existing PROMs and consensus within the research team. The content validity was assessed in three steps: (1) one on one interviews with patients (n = 14) were held to discuss the clarity and possible adaptation of items; (2) experts from the field (physiotherapists, insurance physicians, occupational health physicians, rehabilitation physicians and orthopaedic surgeons) were approached to participate in an interview to discuss the clarity, relevance and missing items; (3) patients (n = 12) were interviewed one on one to discuss the final version. RESULTS: The first version of the WOrk-Related Questionnaire for UPper extremity disorders (WORQ-UP) consisted of 18 items based on the criteria: exertion, dexterity, handling tools & equipment, and mobility. According to patients (n = 14), 44% of the items were not easy enough to understand. Twenty-one experts [10 men, mean age 46 (SD = 8.5) and mean years of experience 16 (SD = 9.9)] participated in the interviews and adaptations were made. The final version of the WORQ-UP consisted of 17 items, all easy enough to understand according to patients (n = 12). CONCLUSIONS: A PROM specific for work-related limitations in patients with upper extremity musculoskeletal disorders was developed. According to patients and experts, it has sufficient content validity. The WORQ-UP can be used to assist in enhancing communication among healthcare workers to improve work-directed care and to evaluate effects of treatment on limitations at work.

What a neurologist should know about depression in Parkinson's disease.

Depression is a frequent non-motor symptom of Parkinson's disease. Its prevalence varies widely across studies (between 2.7% and 90%); around 35% have clinically significant depressive symptoms. Although depression can have an immense impact on the quality of life of affected patients and their caregivers, depressive symptoms in Parkinson's disease frequently remain unrecognised and, as a result, remain untreated. Here we overview the diagnostic challenges and pitfalls, including the factors contributing to the underdiagnosis of depression. We also discuss current ideas on the underlying pathophysiology. Finally, we offer a treatment approach based on currently available evidence.

Design of the Park-in-Shape study: a phase II double blind randomized controlled trial evaluating the effects of exercise on motor and non-motor symptoms in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder with a wide range of motor and non-motor symptoms. Despite optimal medical management, PD still results in a high disability rate and secondary complications and many patients lead a sedentary lifestyle, which in turn is also associated with a higher co-morbidity and mortality. Exercise has been explored as a strategy to reduce secondary complications and results suggests that it not only provides general health benefits, but may also provide symptomatic relief. If this holds true exercise would be a very attractive addition to the therapeutic arsenal in PD. The supportive evidence remains incomplete. Here, we describe the design of the Park-in-Shape study, which primarily aims to evaluate whether aerobic exercise affords clinically relevant improvements in motor symptoms in sedentary PD patients. A specific new element is the introduction of gaming to optimize compliance to the exercise intervention. METHODS/DESIGN: The Park-in-Shape study is a randomized controlled, assessor- and patient-blinded single center study. Two parallel groups will include a total of 130 patients, receiving either aerobic exercise on a home trainer equipped with gaming elements ("exergaming"), or a non-aerobic intervention (stretching, flexibility and relaxation exercises). Both groups are supported by a specifically designed motivational app that uses gaming elements to stimulate patients to exercise and rewards them after having completed the exercise. Both interventions are delivered at home at least 3 times a week for 30-45 minutes during 6 months. Eligible patients are community-dwelling, sedentary patients diagnosed with mild-moderate PD. The primary outcome is the MDS-UPDRS motor score (tested in the off state) after 6 months. Secondary outcomes include various motor and non-motor symptoms, quality of life, physical fitness, and adherence. DISCUSSION: This Park-in-Shape study is anticipated to answer the question whether high intensity aerobic exercise combined with gaming elements ("exergaming") provides symptomatic relief in PD. Strong elements include the double-blinded randomized controlled trial design, the MDS-UPDRS as valid primary outcome, the large sample size and unique combination of home-based pure aerobic exercise combined with gaming elements and motivational aspects. TRIAL REGISTRATION: Dutch trial register NTR4743.

Treatment of aggression regulation problems with virtual reality: study protocol for a randomized controlled trial.

Background: Aggressive conduct among delinquents presents a pervasive issue, bearing substantial implications for not only society at large but also for the victims and the individuals displaying the aggression. Traditional approaches to treating aggression regulation deficiencies generally employ Cognitive Behavioral Therapy (CBT) in conjunction with analog role-playing exercises. A body of research supports the efficacy of various therapeutic models for aggression regulation, including Responsive Aggression Regulation Therapy (Re-ART). Role-playing within a therapeutic context has been shown to contribute significantly to reductions in violent reoffending. However, the practical application of these skills in real-world settings remains challenging due to the inherent risk of aggressive outbreaks. Additionally, the conventional role-playing scenarios, often conducted in a therapy room, lack contextual realism and may induce role confusion between the patient and the therapist. Virtual Reality (VR) technology could offer a viable solution to these limitations by allowing for skill training in both behavioral and cognitive domains within a realistic yet safe and controlled setting. The technology also facilitates real-time awareness of emotional states and tension levels in the patient. This paper describes the study protocol of a randomized controlled trial in which Re-ART offered in a virtual environment (Re-ART VR) is compared to Re-ART offered as treatment as usual. Methods and analysis: Adult forensic outpatients with aggression regulation problems are randomly assigned to either Re-ART VR or Re-ART. The Controlling Skills, Influence of Thinking and Handling Conflicts modules will be offered to both groups during 3-6 months. Pre- and post-intervention measurements are performed. The primary outcome measurement is the degree of aggression regulation, while secondary outcome measurements include impulsivity and cognitive biases. Additionally, patient motivation and therapist motivation are expected to act as moderating factors. Discussion: To date, scarcely previous research has been done on the effectiveness of VR in treatment of aggression regulation problems in forensic outpatients. Forensic outpatients who do not benefit sufficiently from mainly CBT-based interventions may benefit more from experiential learning. The unique capabilities of VR in this regard have the potential to enhance the treatment effect.Clinical trial registration: [https://clinicaltrials.gov/], identifier [NL78265.018.21].

Effect of Early Levodopa Treatment on Mortality in People with Parkinson's Disease.

BACKGROUND: The ideal timing for initiating levodopa in newly diagnosed people with Parkinson's disease (PD) is uncertain due to limited data on the long-term effects of levodopa. OBJECTIVE: The aim was to investigate whether early levodopa initiation postpones mortality (primary outcome), the requirement of device-aided therapies, and the incidence of PD-related complications, such as fall-induced injuries. METHODS: Using nationwide claims data from Dutch hospitals (2012-2020), we grouped newly diagnosed PD individuals as "early initiators" (initiating levodopa within 2 years of diagnosis) or "nonearly initiators." We used the national death registry to assess mortality and health-care claims to assess PD-related complications and device-aided therapies. We used marginal structural models to compare mortality and device-aided therapy rates between groups, and a Poisson regression model to compare PD-related complication rates. RESULTS: Among 29,943 newly diagnosed PD individuals (mean age at diagnosis: 71.6, 38.5% female), there were 24,847 early and 5096 nonearly levodopa initiators. Over a median 4.25 years, 8109 (27.1%) died. The causal risk ratio for mortality was 1.04 (95% confidence interval [CI] 0.92-1.19) for early versus nonearly initiators. The risk ratio of receiving any device-aided therapy was 3.19 (95% CI 2.56-5.80). No association was observed with incidence of PD-related complications (incidence rate ratio: 1.00, 95% CI 0.96-1.05). CONCLUSIONS: Early levodopa initiation in PD does neither postpone nor accelerate mortality or PD-related complications, nor does it precipitate earlier occurrence of PD-related complications or mortality. However, we cannot exclude that the results were influenced by residual confounding due to unmeasured risk factors of mortality.

[Risk factors for Parkinson's disease: possibilities for prevention and intervention]. / Risicofactoren voor de ziekte van Parkinson.

Considering age to be the primary risk factor for developing Parkinson's disease and the observation that the Dutch population is rapidly aging, the parkinson prevalence is expected to increase over the coming years, as there is still no cure available for the disease. This has been confirmed by epidemiological data, which show a steady increase of the disease prevalence in the Netherlands for the period 2010-2021. Genetic risk factors only partially explain the disease pathogenesis. Environmental factors, such as exposure to pesticides and trichloroethylene are associated with a higher risk for developing Parkinson's disease. Lifestyle factors such as exercise, caffeine intake and the Mediterranean diet are associated with a lower risk for developing the disease and possibly delay the disease progression. Policy makers and healthcare providers should employ stricter regulations for pesticide use and should stimulate a healthy lifestyle to slow down the increasing prevalence.

An integrated framework of personalized medicine: from individual genomes to participatory health care.

Promising research developments in both basic and applied sciences, such as genomics and participatory health care approaches, have generated widespread interest in personalized medicine among almost all scientific areas and clinicians. The term personalized medicine is, however, frequently used without defining a clear theoretical and methodological background. In addition, to date most personalized medicine approaches still lack convincing empirical evidence regarding their contribution and advantages in comparison to traditional models. Here, we propose that personalized medicine can only fulfill the promise of optimizing our health care system by an interdisciplinary and translational view that extends beyond traditional diagnostic and classification systems.

Dance classes improve self-esteem and quality of life in persons with Parkinson's disease.

INTRODUCTION: Dance can reduce motor symptoms in persons with Parkinson's disease (PD). However, the effect on psychosocial wellbeing, including self-esteem and quality of life is less clear. METHODS: Forty-nine persons with PD (Hoehn and Yahr stage 1-4) participated in weekly dance classes for a consecutive period of 22 weeks, 36 participants completed the classes. Two baseline measurements (T1a and T1b) were performed during a 2-week control period prior to the dance classes. Post-measurements (T2) were performed immediately after 22 weeks of dance classes. Primary outcome was self-esteem as measured with the Rosenberg Self-Esteem Score. RESULTS: Self-esteem scores were stable across the two baseline measurements and improved significantly after the dance classes (1.5 points improvement between T1b and T2, 95% CI 0.3, 2.7; p = 0.012). Additionally, quality of life as measured with the Parkinson's Disease Questionnaire 39 improved significantly (3.4 points reduction between T1b and T2, 95%CI - 5.7, - 1.2; p = 0.003) as did motor symptoms as measured with the Movement Disorders Society-Unified Parkinson's Disease Rating Scale-part III (6.2 points reduction between T1b and T2, 95%CI - 10.1, - 2.4; p = 0.002). Balance confidence as measured with the Activities-Specific Balance Confidence Scale did not change. DISCUSSION AND CONCLUSIONS: Dance classes seem to improve self-esteem, quality of life and motor symptoms in persons with PD. These effects should be investigated further in a randomized clinical trial. CLINICAL MESSAGE: Dance classes may be a valuable complementary treatment option in people with PD to improve not only motor symptoms, but also self-esteem and quality of life.

A Lumped Two-Compartment Model for Simulation of Ventricular Pump and Tissue Mechanics in Ischemic Heart Disease.

Introduction: Computational modeling of cardiac mechanics and hemodynamics in ischemic heart disease (IHD) is important for a better understanding of the complex relations between ischemia-induced heterogeneity of myocardial tissue properties, regional tissue mechanics, and hemodynamic pump function. We validated and applied a lumped two-compartment modeling approach for IHD integrated into the CircAdapt model of the human heart and circulation. Methods: Ischemic contractile dysfunction was simulated by subdividing a left ventricular (LV) wall segment into a hypothetical contractile and noncontractile compartment, and dysfunction severity was determined by the noncontractile volume fraction ( N C V F ). Myocardial stiffness was determined by the zero-passive stress length ( L s 0 , p a s ) and nonlinearity ( k E C M ) of the passive stress-sarcomere length relation of the noncontractile compartment. Simulated end-systolic pressure volume relations (ESPVRs) for 20% acute ischemia were qualitatively compared between a two- and one-compartment simulation, and parameters of the two-compartment model were tuned to previously published canine data of regional myocardial deformation during acute and prolonged ischemia and reperfusion. In six patients with myocardial infarction (MI), the N C V F was automatically estimated using the echocardiographic LV strain and volume measurements obtained acutely and 6 months after MI. Estimated segmental N C V F values at the baseline and 6-month follow-up were compared with percentage late gadolinium enhancement (LGE) at 6-month follow-up. Results: Simulation of 20% of N C V F shifted the ESPVR rightward while moderately reducing the slope, while a one-compartment simulation caused a leftward shift with severe reduction in the slope. Through tuning of the N C V F , L s 0 , p a s , and k E C M , it was found that manipulation of the N C V F alone reproduced the deformation during acute ischemia and reperfusion, while additional manipulations of L s 0 , p a s and k E C M were required to reproduce deformation during prolonged ischemia and reperfusion. Out of all segments with LGE>25% at the follow-up, the majority (68%) had higher estimated N C V F at the baseline than at the follow-up. Furthermore, the baseline N C V F correlated better with percentage LGE than N C V F did at the follow-up. Conclusion: We successfully used a two-compartment model for simulation of the ventricular pump and tissue mechanics in IHD. Patient-specific optimizations using regional myocardial deformation estimated the N C V F in a small cohort of MI patients in the acute and chronic phase after MI, while estimated N C V F values closely approximated the extent of the myocardial scar at the follow-up. In future studies, this approach can facilitate deformation imaging-based estimation of myocardial tissue properties in patients with cardiovascular diseases.

Cost-Effectiveness and Cost-Utility of Early Levodopa in Parkinson's Disease.

BACKGROUND: In the Levodopa in EArly Parkinson's disease (LEAP) study, 445 patients were randomized to levodopa/carbidopa 100/25 mg three times per day for 80 weeks (early-start) or placebo for 40 weeks followed by levodopa/carbidopa 100/25 mg three times per day for 40 weeks (delayed-start). OBJECTIVE: This paper reports the results of the economic evaluation performed alongside the LEAP-study. METHODS: Early-start treatment was evaluated versus delayed-start treatment, in which the cost-effectiveness analysis (CEA) and the cost-utility analysis (CUA) were performed from the societal perspective, including health care costs among providers, non-reimbursable out-of-pocket expenses of patients, employer costs of sick leave, and lowered productivity while at work. The outcome measure for the CEA was the extra cost per unit decrease on the Unified Parkinson's Disease Rating Scale 80 weeks after baseline. The outcome measure for the CUA was the extra costs per additional quality adjusted life year (QALY) during follow-up. RESULTS: 212 patients in the early-start and 219 patients in the delayed-start group reported use of health care resources. With savings of € 59 per patient (BCa 95% CI: -829, 788) in the early-start compared to the delayed-start group, societal costs were balanced. The early-start group showed a mean of 1.30 QALYs (BCa 95% CI: 1.26, 1.33) versus 1.30 QALYs (BCa 95% CI: 1.27, 1.33) for the delayed-start group. Because of this negligible difference, incremental cost-effectiveness and cost-utility ratios were not calculated. CONCLUSION: From an economic point of view, this study suggests that early treatment with levodopa is not more expensive than delayed treatment with levodopa.

EUROCarbDB: An open-access platform for glycoinformatics.

The EUROCarbDB project is a design study for a technical framework, which provides sophisticated, freely accessible, open-source informatics tools and databases to support glycobiology and glycomic research. EUROCarbDB is a relational database containing glycan structures, their biological context and, when available, primary and interpreted analytical data from high-performance liquid chromatography, mass spectrometry and nuclear magnetic resonance experiments. Database content can be accessed via a web-based user interface. The database is complemented by a suite of glycoinformatics tools, specifically designed to assist the elucidation and submission of glycan structure and experimental data when used in conjunction with contemporary carbohydrate research workflows. All software tools and source code are licensed under the terms of the Lesser General Public License, and publicly contributed structures and data are freely accessible. The public test version of the web interface to the EUROCarbDB can be found at http://www.ebi.ac.uk/eurocarb.

Characteristics of Patients with Late-Stage Parkinsonism Who are Nursing Home Residents Compared with those Living at Home.

OBJECTIVES: To determine clinical characteristics and treatment complications of patients with late-stage Parkinsonism living in nursing homes compared with those living at home. DESIGN: Cross-sectional analysis. SETTING AND PARTICIPANTS: This study is an analysis of 692 patients with late stage Parkinsonism recruited to an in-depth international study, Care of Late-Stage Parkinsonism (CLaSP). MEASURES: Sociodemographic characteristics were compared between patients who were living in a nursing home (n = 194) and those living at home (n = 498). Clinical assessments included the Unified Parkinson's Disease Rating Scale (UPDRS), the nonmotor symptom scale, the neuropsychiatric inventory, and a structured interview of patients and carers. Predictors of nursing home status were determined in a multivariate analysis. RESULTS: Nursing home placement was strongly associated with more severe cognitive impairment, worse UPDRS motor scores and disability, and with being unmarried and older. Although nursing home residents had significantly higher axial scores, falls were less common. Despite similar levodopa equivalence doses, they had less dyskinesia. Nonmotor symptom burden, particularly delusion, hallucination, and depression scores were higher in nursing home residents, and they were more frequently on psychotropic medication. They had lower rates of dopamine agonist use and lower rates of impulse control disorders. In multivariate analysis, being unmarried, presence of cognitive impairment, worse disease severity as assessed on the UPDRS parts II and III, severity of delusions, and lower rate of dyskinesia were associated with nursing home placement. CONCLUSIONS AND IMPLICATIONS: These clinical characteristics suggest that in patients with Parkinsonsim who are nursing home residents, presence of cognitive impairment and delusions particularly add to the higher overall symptom burden, and more often require specific treatments, including clozapine. Despite similar levodopa equivalent daily dose, motor severity is higher, and dyskinesias, indicative of a response to levodopa, are less common. Falls, however, also occur less commonly, and dopamine agonists are less frequently used, with lower rates of impulse control disorder.

Insights into the dynamics and molecular recognition features of glycopeptides by protein receptors: the 3D solution structure of hevein bound to the trisaccharide core of N-glycoproteins.

Protein-carbohydrate interactions are at the heart of a variety of essential molecular recognition events. Hevein, a model lectin related to the superantigen family, recognizes the trisaccharide core of N-glycoproteins (1). A combined approach of NMR spectroscopy and molecular modeling has permitted us to demonstrate that an Asn-linked Man(GlcNAc)(2) (2) is bound with even higher affinity than (GlcNAc)(3). The molecular recognition process entails conformational selection of only one of the possibilities existing for chitooligosaccharides. The deduced 3D structure of the hevein/2 complex permits the extension of polypeptide chains from the Asn moiety of 2, as well as glycosylation at Man O-3 and Man O-6 of the terminal sugar. Given the ubiquity of the Man(GlcNAc)(2) core in all mammalian N-glycoproteins, the basic recognition mode presented herein might be extended to a variety of systems with biomedical importance.