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.

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.

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].

[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.

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.

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.

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.

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.

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.

Neurovestibular Dysfunction and Falls in Parkinson's Disease and Atypical Parkinsonism: A Prospective 1 Year Follow-Up Study.

Our primary aim was to determine whether neurovestibular laboratory tests can predict future falls in patients with either Parkinson's disease (PD) or atypical parkinsonism (AP). We included 25 healthy subjects, 30 PD patients (median Hoehn and Yahr stage 2.5, range 1-4), and 14 AP patients (6 multiple system atrophy, 3 progressive supranuclear palsy, and 5 vascular parkinsonism) in a case-control study design (all matched for age and gender). At baseline, all subjects underwent clinical neurological and neurotological assessments, cervical and ocular vestibular evoked myogenic potentials (VEMP), brainstem auditory evoked potentials (BAEP), subjective visual vertical measurements (SVV), and video nystagmography with caloric and rotary test stimulation. After 1 year follow-up, all subjects were contacted by telephone for an interview about their fall frequency (based upon fall diaries) and about their balance confidence (according to the ABC-16 questionnaire); only one participant was lost to follow-up (attrition bias of 1.4%). Cervical and ocular VEMPs combined with clinical tests for postural imbalance predicted future fall incidents in both PD and AP groups with a sensitivity of 100%. A positive predictive value of 68% was achieved, if only one VEMP test was abnormal, and of 83% when both VEMP tests were abnormal. The fall frequency at baseline and after 1 year was significantly higher and the balance confidence scale (ABC-16) was significantly lower in both the PD and AP groups compared to healthy controls. Therefore, VEMP testing can predict the risk of future fall incidents in PD and AP patients with postural imbalance.

C-Mannosylation Enhances the Structural Stability of Human RNase 2.

C-Mannosylation is a relatively rare form of protein glycosylation involving the attachment of an α-mannopyranosyl residue to C-2 of the indole moiety of the amino acid tryptophan. This type of linkage was initially discovered in RNase 2 from human urine but later confirmed to be present in many other important proteins. Based on NMR experiments and extensive molecular dynamics simulations on the hundred microsecond timescale we demonstrate that, for isolated glycopeptides and denatured RNase 2, the C-linked mannopyranosyl residue exists as an ensemble of conformations, among which 1C4 is the most abundant. However, for native RNase 2, molecular dynamics and NMR studies revealed that the mannopyranosyl residue favors a specific conformation, which optimally stabilizes the protein fold through a network of hydrogen bonds and which leads to a significant reduction of the protein dynamics on the microsecond timescale. Our findings contribute to the understanding of the biological role of C-mannosylation.

The Prevalence and Determinants of Neuropsychiatric Symptoms in Late-Stage Parkinsonism.

BACKGROUND: Late-stage parkinsonism and Parkinson's disease (PD) are insufficiently studied population. Although neuropsychiatric symptoms (eg, psychosis, depression, anxiety, behavioral problems) are frequently present, their prevalence and clinical predictors remain unknown. OBJECTIVE: To determine the prevalence and predictors of neuropsychiatric symptoms in late-stage PD. METHODS: We conducted a multinational study of patients with PD with ≥7 years disease duration and either a Hoehn and Yahr stage ≥4 or a Schwab and England score ≤ 50% in the on stage. Neuropsychiatric symptoms were assessed through interviews with carers using the Neuropsychiatric Inventory, with a frequency × severity score ≥ 4, indicating clinically relevant symptoms. The determinants analyzed were demographic characteristics, medication, and motor and nonmotor symptoms. Univariate and multivariate logistic analyses were performed on predictors of clinically relevant neuropsychiatric symptoms. RESULTS: A total of 625 patients were recruited in whom the Neuropsychiatric Inventory could be completed. In 92.2% (576/625) of the patients, at least 1 neuropsychiatric symptom was present, and 75.5% (472/625) had ≥1 clinically relevant symptom. The most common clinically relevant symptoms were apathy (n = 242; 38.9%), depression (n = 213; 34.5%), and anxiety (n = 148; 23.8%). The multivariate analysis revealed unique sets of predictors for each symptom, particularly the presence of other neuropsychiatric features, cognitive impairment, daytime sleepiness. CONCLUSION: Neuropsychiatric symptoms are common in late-stage PD. The strongest predictors are the presence of other neuropsychiatric symptoms. Clinicians involved in the care for patients with late-stage PD should be aware of these symptoms in this specific disease group and proactively explore other psychiatric comorbidities once a neuropsychiatric symptom is recognized.

Optimizing Treatment in Undertreated Late-Stage Parkinsonism: A Pragmatic Randomized Trial.

BACKGROUND: Treatment of patients with late-stage parkinsonism is often sub-optimal. OBJECTIVE: To test the effectiveness of recommendations by a movement disorder specialist with expertise in late-stage parkinsonism. METHODS: Ninety-one patients with late-stage parkinsonism considered undertreated were included in apragmatic a pragmatic multi-center randomized-controlled trial with six-month follow-up. The intervention group received a letter with treatment recommendations to their primary clinician based on an extensive clinical assessment. Controls received care as usual. The primary outcome was the Unified Parkinson Disease Rating Scale (UPDRS)part-II (Activities of Daily Living). Other outcomes included quality-of-life (PDQ-8), mental health (UPDRS-I), motor function (UPDRS-III), treatment complications (UPDRS-IV), cognition (Mini-mental-state-examination), non-motor symptoms (Non-Motor-Symptoms-scale), health status (EQ-5D-5L) and levodopa-equivalent-daily-dose (LEDD). We also assessed adherence to recommendations. In addition to intention-to-treat analyses, a per-protocol analysis was conducted. RESULTS: Sample size calculation required 288 patients, but only 91 patients could be included. Treating physicians followed recommendations fully in 16 (28%) and partially in 21 (36%) patients. The intention-to-treat analysis showed no difference in primary outcome (between-group difference = -1.2, p = 0.45), but there was greater improvement for PDQ-8 in the intervention group (between-group difference = -3.7, p = 0.02). The per-protocol analysis confirmed these findings, and showed less deterioration in UPDRS-part I, greater improvement on UPDRS-total score and greater increase in LEDD in the intervention group. CONCLUSIONS: The findings suggest that therapeutic gains may be reached even in this vulnerable group of patients with late-stage parkinsonism, but also emphasize that specialist recommendations need to be accompanied by better strategies to implement these to further improve outcomes.

Deformation imaging to assess global and regional effects of cardiac regenerative therapy in ischaemic heart disease: A systematic review.

Currently, left ventricular ejection fraction (LVEF) is the most common endpoint in cardiovascular stem cell therapy research. However, this global measure of cardiac function might not be suitable to detect the regional effects sorted by this therapy and is hampered by high operator variability and loading dependency. Deformation imaging might be more accurate in detecting potential regional functional improvements by cardiac regenerative therapy. The aim of this systematic review is to provide a comprehensive overview of current literature on the value of deformation imaging in cardiac regenerative therapy. A systematic review of current literature available on PubMed, Embase, and Cochrane databases was performed regarding both animal and patient studies in which deformation imaging was used to study cardiac cell therapy. After critical appraisal, outcomes regarding study design, type of cell therapy, procedural characteristics, outcome measure, method for measuring strain, and efficacy on both LVEF and deformation parameters were depicted. A total of 30 studies, 15 preclinical and 15 clinical, were included for analysis. Deformation outcomes improved significantly in 14 out of 15 preclinical studies and in 10 out of 15 clinical studies, whereas LVEF improved in 12 and 4 articles, respectively. Study designs and used deformation outcomes varied significantly among the included papers. Six studies found a positive effect on deformation outcomes without LVEF improvement. Hence, deformation imaging seems at least equal, and perhaps superior, to LVEF measurement in the assessment of cardiac regenerative therapy. However, strategies varied substantially and call for a standardized approach.

Slave to the rhythm: Seasonal differences in non-motor symptoms in Parkinson's disease.

INTRODUCTION: Although circadian variation of (motor) symptoms in Parkinson disease (PD) patients has been described, it remains unclear what effect seasonal variation may have on non-motor symptoms (NMS). METHODS: Cross-sectional retrospective study on 372 consecutive PD patients taking part in the Non-motor Longitudinal International Study at King's College Hospital London between November 2011 and July 2018. Patients were divided into three groups based on their date of assessment, using a simplified seasonal model: group 1: November-February (n = 107); group 2: March-15 June (n = 107); and group 3: 16 June-October (n = 158). Primary outcome was a seasonal difference in NMS scale (NMSS) total scores (higher scores reflecting greater disability). We hypothesized that PD patients exhibit circannual NMS burden patterns. RESULTS: All groups were identical concerning disease onset and duration, HY stage, Levodopa equivalent dose, and gender. There was a seasonal difference in NMSS total scores (p = 0.040), with the highest scores (57.1 ±â€¯42.5) in season 1 (winter months) and the lowest (45.1 ±â€¯34.4) in season 3 (summer months) (p = 0.037). Seasonal differences were observed in NMSS domain 1 (cardiovascular symptoms) (p = 0.011), domain 4 (perceptual problems) (p = 0.017) and domain 9 (miscellaneous symptoms) (p = 0.009). A trend was observed for domain 2 (sleep) (p = 0.057). CONCLUSION: NMS in PD fluctuate throughout the year, with worsening of symptoms in the winter months compared to the summer months suggestive of dysfunction of the body's master clock, the suprachiasmatic nuclei. Such variations must be accommodated in daily care to ascertain appropriate changes in medication regimes and in clinical trials for the interpretation of outcomes.

Reconstructive surgery for Ebstein anomaly: three decades of experience.

OBJECTIVES: Since 1988, our centre employs vertical plication repair with deattachment and reattachment of the tricuspid valve for Ebstein anomaly. This study describes the characteristics and long-term outcomes of our single-centre cohort. METHODS: Data from all patients operated on between 1988 and 2016 were retrospectively collected. Kaplan-Meier analyses were done for survival data and mixed models were used to analyse longitudinally collected clinical and echocardiography data. RESULTS: Thirty-six patients (mean age: 25.4 ± 15.9 years, 36% male) were operated on using the Carpentier-Chauvaud 21 (58%) or Cone repair 15 (42%). One patient (3%) died in hospital. Two late deaths were observed, yielding a survival of 97 ± 3% at 25 years. Reoperation was performed in 6 patients after a mean follow-up of 14.1 ± 10.3 years, resulting in a freedom of reoperation of 80 ± 8% at 25 years. During follow-up, predicted probability of being in New York Heart Association III/IV did not exceed 10%. Modelling longitudinal evolution of tricuspid regurgitation showed no major changes over time. Additionally, a rigid ring repair was associated with a higher probability of tricuspid regurgitation, especially after the first years after the operation. A full Cone repair was associated with less progression of tricuspid regurgitation over time. CONCLUSIONS: Repair of Ebstein abnomaly is associated with low mortality and morbidity, acceptable reoperation rate and excellent valve function over time, especially in patients with completed Cone repair. Therefore, we conclude that in our centre, repair of Ebstein abnomaly is a durable technique to treat patients.