Skull Density Ratio as Arm-Allocation Parameter for a Controlled Focused Ultrasound Trial in Parkinson's Disease.

BACKGROUND: MR-guided focused ultrasound (FUS) thermoablation is an established therapy for movement disorders. FUS candidates must meet a predefined threshold of skull density ratio (SDR), a parameter that accounts for the efficiency in reaching ablative temperatures. Randomized sham-controlled trials to provide definitive therapeutic evidence employ pure randomization of subjects into active treatment or control arms. The latter design has several general limitations. OBJECTIVE: To demonstrate that SDR values are not associated with clinically and demographically relevant variables in patients with Parkinson's disease (PD). This in turn would allow using SDR as an arm-allocation parameter, separating patients who will receive active FUS treatment and best medical management treatment (BMT). METHODS: We studied a cohort of 215 PD patients who were candidates for FUS subthalamotomy to determine if the SDR was correlated with demographic or clinical variables that could introduce bias for group allocation in a controlled trial. RESULTS: SDR was unassociated with age, gender, and clinical motor features nor with levodopa daily dose in our cohort of PD patients. A negative association with age was found for the female subgroup. CONCLUSIONS: Our results show that in a PD population considered for FUS subthalamotomy treatment, the SDR may be a valid group-allocation parameter. This could be considered as the basis for a controlled study comparing FUS subthalamotomy vs BMT.

Staged Bilateral MRI-Guided Focused Ultrasound Subthalamotomy for Parkinson Disease.

Importance: Unilateral magnetic resonance imaging (MRI)-guided focused ultrasound subthalamotomy (FUS-STN) improves cardinal motor features among patients with asymmetrical Parkinson disease (PD). The feasibility of bilateral FUS-STN is as yet unexplored. Objective: To assess the safety and effectiveness of staged bilateral FUS-STN to treat PD. Design, Setting, and Participants: This prospective, open-label, case series study was conducted between June 18, 2019, and November 7, 2023, at HM-CINAC, Puerta del Sur University Hospital, Madrid, Spain, and included 6 patients with PD who had been treated with unilateral FUS-STN contralateral to their most affected body side and whose parkinsonism on the untreated side had progressed and was not optimally controlled with medication. Intervention: Staged bilateral FUS-STN. Main Outcomes and Measures: Primary outcomes were assessed 6 months after the second treatment and included safety (incidence and severity of adverse events after second treatment) and effectiveness in terms of motor change (measured with the Movement Disorders Society Unified Parkinson's Disease Rating Scale part III [MDS-UPDRS III]) in the off-medication state (ie, after at least 12 hours of antiparkinsonian drug withdrawal) compared with baseline (ie, prior to the first side ablation). Secondary outcomes included motor change in patients in the on-medication state (ie, after usual antiparkinsonian medication intake), motor complications (measured with the MDS-UPDRS IV), daily living activities (measured with the MDS-UPDRS I-II), quality of life (measured with the 39-item Parkinson's Disease Questionnaire), change in dopaminergic treatment, patient's global impression of change (measured with the Global Impression of Change [PGI-C] scale), and long-term (24-month) follow-up. Results: Of 45 patients previously treated with unilateral FUS-STN, 7 were lost to follow-up, and 4 were excluded due to adverse events. Of the remaining 34 patients, 6 (median age at first FUS-STN, 52.6 years [IQR, 49.0-57.3 years]; 3 women [50%]) experienced progression of parkinsonism on the untreated body side and were included. At the time of the first FUS-STN, patients' median duration of disease was 5.7 years (IQR, 4.7-7.3 years). The median time between procedures was 3.2 years (IQR, 1.9-3.5 years). After the second FUS-STN, 4 patients presented with contralateral choreic dyskinesia, which resolved by 3 months. Four patients developed speech disturbances, which gradually improved but remained in a mild form for 2 patients at 6 months; 1 patient experienced mild imbalance and dysphagia during the first week after treatment, which subsided by 3 months. No behavioral or cognitive disturbances were found on neuropsychological testing. For patients in the off-medication state, MDS-UPDRS III scores improved by 52.6% between baseline and 6 months after the second FUS-STN (from 37.5 [IQR, 34.2-40.0] to 20.5 [IQR, 8.7-24.0]; median difference, 23.0 [95% CI, 7.0-33.7]; P = .03). The second treated side improved by 64.3% (MDS-UPDRS III score, 17.0 [IQR, 16.0-19.5] prior to the second treatment vs 5.5 [IQR, 3.0-10.2]; median difference, 9.5 [95% CI, 3.2-17.7]; P = .02). After the second procedure, all self-reported PGI-C scores were positive. Conclusions: Findings of this pilot study suggest that staged bilateral FUS-STN was safe and effective for the treatment of PD, although mild but persistent speech-related adverse events were observed among a small number of patients.

Nigrostriatal blood-brain barrier opening in Parkinson's disease.

BACKGROUND: The nigrostriatal system is especially vulnerable to neurodegeneration in Parkinson's disease (PD) and the blood-brain barrier (BBB) is a limiting factor for delivery of therapeutic agents to the brain. This pilot study aimed to demonstrate safety, feasibility and tissue penetration (by 18F-Choline-positron emission tomography (PET)) of MR-guided focused ultrasound (MRgFUS) simultaneous BBB opening (BBB-O) in the substantia nigra (SN) and putamen in PD. METHODS: Three patients underwent MRgFUS for midbrain and putamen BBB-O. Patients were evaluated clinically and underwent brain MRI with gadolinium (baseline, 24 hours, 14 days and 3 months postprocedure). In two patients, BBB-O was repeated after 2-3 weeks, and 18F-Choline-PET was performed immediately after. RESULTS: The right SN and putamen were simultaneously opened unilaterally in 3 patients once and the left SN in 1 patient in a different session. No severe clinical or neuroimaging adverse events developed in any patient. 18F-Choline-PET uptake was enhanced in the targeted SN and putamen regions. CONCLUSION: BBB-O of the nigrostriatal system is a feasible and well-tolerated approach in patients with PD. 18F-Choline-PET uptake indicates penetration into the parenchyma after BBB-O, which suggests that the opening is functionally effective. This minimally invasive technique could facilitate delivery of putative neurorestorative molecules to brain regions vulnerable to neurodegeneration.

MgO/KH2PO4 and Curing Moisture Content in MKPC Matrices to Optimize the Immobilization of Pure Al and Al-Mg Alloys.

Magnesium Potassium Phosphate Cements (MKPCs) are considered a good alternative for the immobilization of aluminium radioactive waste. MKPC composition and moisture curing conditions are relevant issues to be evaluated. The corrosion of pure aluminium (A1050) and AlMg alloys (AA5754) with 3.5% of Mg is studied in MKPC systems prepared with different MgO/KH2PO4 (M/P) molar ratios (1, 2, and 3M) and moisture curing conditions (100% Relative Humidity (RH) and isolated in plastic containers (endogenous curing)). The Al corrosion potential (Ecorr) and corrosion kinetic (icorr and Vcorr) are evaluated over 90 days. Additionally, the pore ion evolution, the matrix electrical resistance, the pore structure, and compressive strength are analysed. The corrosion process of Al alloy is affected by the pH and ion content in the pore solution. The pore pH increases from near neutral for the 1M M/P ratio to 9 and 10 for the 2 and 3M M/P ratio, increasing in the same way the corrosion of pure Al (AA1050) and AlMg alloys (AA5754). The effect of Mg content in the alloy (AA5754) becomes more relevant with the increase in the M/P ratio. The presence of phosphate ions in the pore solution inhibits the corrosion process in both Al alloys. The MKPC physicochemical stability improved with the increase in the M/P ratio, higher mechanical strength, and more refined pore structure.

MR-guided focused ultrasound in movement disorders and beyond: Lessons learned and new frontiers.

The development of MR-guided focused ultrasound (MRgFUS) has provided a new therapeutic tool for neuropsychiatric disorders. In contrast to previously available neurosurgical techniques, MRgFUS allows precise impact on deep brain structures without the need for incision and yields an immediate effect. In its high-intensity modality (MRgHIFU), it produces accurate therapeutic thermoablation in previously selected brain targets. Importantly, the production of the lesion is progressive and highly controlled in real-time by both neuroimaging and clinical means. MRgHIFU ablation is already an accepted and widely used treatment for medically-refractory Parkinson's disease and essential tremor. Notably, other neurological disorders and diverse brain targets, including bilateral treatments, are currently under examination. Conversely, the low-intensity modality (MRgLIFU) shows promising prospects in neuromodulation and transient blood-brain barrier opening (BBBO). In the former circumstance, MRgLIFU could serve as a powerful clinical and research tool for non-invasively modulating brain activity and function. BBBO, on the other hand, emerges as a potentially impactful method to influence disease pathogenesis and progression by increasing brain target engagement of putative therapeutic agents. While promising, these applications remain experimental. As a recently developed technology, MRgFUS is not without challenges and questions to be addressed. Further developments and broader experience are necessary to enhance MRgFUS capabilities in both research and clinical practice, as well as to define device constraints. This clinical mini-review aims to provide an overview of the main evidence of MRgFUS application and to highlight unmet needs and future potentialities of the technique.

Unilateral focused ultrasound subthalamotomy in early Parkinson's disease: a pilot study.

BACKGROUND: Unilateral focused ultrasound subthalamotomy (FUS-STN) improves motor features of Parkinson's disease (PD) in moderately advanced patients. The less invasive nature of FUS makes its early application in PD feasible. We aim to assess the safety and efficacy of unilateral FUS-STN in patients with PD of less than 5 years from diagnosis (early PD). METHODS: Prospective, open-label study. Eligible patients with early PD had highly asymmetrical cardinal features. The primary outcome was safety, defined as treatment-related adverse events at 6 months. Secondary outcomes included efficacy, assessed as motor improvement in the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), motor fluctuations, non-motor symptoms, daily living activities, quality of life, medication and patients' impression of change. RESULTS: Twelve patients with PD (median age 52.0 (IQR 49.8-55.3) years, median time from diagnosis 3.0 (2.1-3.9) years) underwent unilateral FUS-STN. Within 2 weeks after treatment, five patients developed dyskinesia on the treated side, all resolved after levodopa dose adjustment. One patient developed mild contralateral motor weakness which fully resolved in 4 weeks. One patient developed dystonic foot and another hand and foot dystonia. The latter impaired gait and became functionally disabling initially. Both cases were well controlled with botulinum toxin injections. The off-medication motor MDS-UPDRS score for the treated side improved at 12 months by 68.7% (from 14.5 to 4.0, p=0.002), and the total motor MDS-UPDRS improved by 49.0% (from 26.5 to 13.0, p=0.002). Eleven patients (92%) reported global improvement 12 months after treatment. CONCLUSION: Unilateral FUS-STN may be safe and effective to treat motor manifestations in patients with early PD. A larger confirmatory trial is warranted. TRIAL REGISTRATION NUMBER: NCT04692116.

Teachers' teaching and professional competences assessment.

This research is part of a project led by the Catholic University of Santiago de Guayaquil (Ecuador) and the National Distance Education University - UNED (Spain) aiming at designing a teaching/professional competences training model for teachers. The purpose of this study is to assess the meaning of professional competences and their significance within teachers' teaching and training processes. Using the mixed methods approach, an ad hoc questionnaire was designed and given to discussion groups, achieving participation of more than a hundred teachers. Quantitative data analysis was carried out using the Logit model while Atlas ti 23 allowed analysis of the qualitative data. The results evidenced high scores in the competences evaluated, being leadership and research the lowest. In general, the teachers value, preferably, planning, communication, evaluation, methodology, digital, and tutoring competences, with a lower value among teachers ranging from 25 to 30 years old; those older than 55 stressed the importance of digital and innovation competences. Thus, it is recommended that training programs for teachers should focus on the set of related competences, especially on the digital competence, considering the challenges represented by investigation and pedagogical leadership.

Trial of Globus Pallidus Focused Ultrasound Ablation in Parkinson's Disease.

BACKGROUND: Unilateral focused ultrasound ablation of the internal segment of globus pallidus has reduced motor symptoms of Parkinson's disease in open-label studies. METHODS: We randomly assigned, in a 3:1 ratio, patients with Parkinson's disease and dyskinesias or motor fluctuations and motor impairment in the off-medication state to undergo either focused ultrasound ablation opposite the most symptomatic side of the body or a sham procedure. The primary outcome was a response at 3 months, defined as a decrease of at least 3 points from baseline either in the score on the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, part III (MDS-UPDRS III), for the treated side in the off-medication state or in the score on the Unified Dyskinesia Rating Scale (UDysRS) in the on-medication state. Secondary outcomes included changes from baseline to month 3 in the scores on various parts of the MDS-UPDRS. After the 3-month blinded phase, an open-label phase lasted until 12 months. RESULTS: Of 94 patients, 69 were assigned to undergo ultrasound ablation (active treatment) and 25 to undergo the sham procedure (control); 65 patients and 22 patients, respectively, completed the primary-outcome assessment. In the active-treatment group, 45 patients (69%) had a response, as compared with 7 (32%) in the control group (difference, 37 percentage points; 95% confidence interval, 15 to 60; P = 0.003). Of the patients in the active-treatment group who had a response, 19 met the MDS-UPDRS III criterion only, 8 met the UDysRS criterion only, and 18 met both criteria. Results for secondary outcomes were generally in the same direction as those for the primary outcome. Of the 39 patients in the active-treatment group who had had a response at 3 months and who were assessed at 12 months, 30 continued to have a response. Pallidotomy-related adverse events in the active-treatment group included dysarthria, gait disturbance, loss of taste, visual disturbance, and facial weakness. CONCLUSIONS: Unilateral pallidal ultrasound ablation resulted in a higher percentage of patients who had improved motor function or reduced dyskinesia than a sham procedure over a period of 3 months but was associated with adverse events. Longer and larger trials are required to determine the effect and safety of this technique in persons with Parkinson's disease. (Funded by Insightec; ClinicalTrials.gov number, NCT03319485.).

Evaluation of Fillers for Magnesium Potassium Phosphate Cement (MKPC) for the Encapsulation of Low and Intermediate Level Metallic Radioactive Wastes.

This study investigates the effect of coal fly ash (FA), wollastonite (WO), pumice (PM), and metakaolin (MK) as filler materials in the rheological, mechanical, chemical, and mineralogical properties of a magnesium potassium phosphate cement (MKPC), designed for the encapsulation of low and intermediate level radioactive wastes containing reactive metals. Workability, compression strength, dimensional stability, pH, chemical composition, and mineralogical properties were studied in different pastes and mortars of MKPC with a fixed molar ratio of MgO/KH2PO4 = 1. No new mineral phases were found with the addition of the fillers, denoting their low chemical impact on the MKPC system. Moreover, all formulations with a water/cement mass ratio of <0.65 presented compressive strengths higher than 30 MPa after 90 days, and pH values lower than 8.5, corresponding to the passivation zone of aluminum corrosion.

Prospective Long-term Follow-up of Focused Ultrasound Unilateral Subthalamotomy for Parkinson Disease.

BACKGROUND AND OBJECTIVES: Unilateral magnetic resonance-guided focused ultrasound subthalamotomy (FUS-STN) has been shown to improve the cardinal motor features of Parkinson disease (PD). Whether this effect is sustained is not known. This study aims to report the long-term outcome of patients with PD treated with unilateral FUS-STN. METHODS: We conducted a prospective open-label study of patients with asymmetrical PD who underwent unilateral FUS-STN. All patients were evaluated up to 36 months after treatment. The primary outcome was the difference from baseline to 36 months after FUS-STN in the score of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor part (III) for the treated hemibody in the off-medication state. The safety outcome included all adverse events occurring during follow-up. Secondary outcomes were the change in the MDS-UPDRS III score on-medication; subscores of rigidity, bradykinesia, tremor, and axial features; total MDS-UPDRS III; and the MDS-UPDRS part IV. Functional disability and quality of life were assessed using the MDS-UPDRS II and the PDQ39, respectively. Patient impression of change and satisfaction with the treatment were self-assessed. The Wilcoxon signed-rank test with subsequent Bonferroni's correction was used for data analysis. RESULTS: Thirty-two patients with PD were evaluated at 36 months after treatment. The mean (±SD) age at baseline was 56.0 ± 10.1 years, with a mean disease duration of 6.8 ± 2.8 years. The MDS-UPDRS III score for the treated hemibody off-medication was improved by 52.3% from baseline to 3 years (score reduction from 19.0 ± 3.2 to 8.9 ± 3.3, 95% CI 8.7 to 11.6, p < 0.001), and all specific motor features were improved from baseline. No disabling or delayed adverse events were reported. The total MDS-UPDRS III off-medication score was 22.9% lower at 3 years than before treatment (36.8 ± 7.4 vs 27.4 ± 6.2, 95% CI 6.0 to 11.5, p < 0.001). The MDS-UPDRS II, IV, and PDQ39 scores and levodopa dose were equivalent to those at baseline. DISCUSSION: The benefit of unilateral FUS-STN on PD motor features is sustained in the long term. FUS-STN contributes to better clinical control over several years of evolution. NCT02912871/03454425. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence on the utility of focused ultrasound unilateral subthalamotomy in the treatment of people with Parkinson disease.

A circuit-based approach to modulate hypersexuality in Parkinson's disease.

AIM: Impulse-control disorder is a common neuropsychiatric complication in Parkinson's disease (PD) under dopamine replacement therapy. Prior studies tested the balance between enhanced desire towards reward and cognitive control deficits, hypothesized to be biased towards the former in impulse control disorders. We provide evidence for this hypothesis by measuring behavioral and neural patterns behind the influence of sexual desire over response inhibition and tools towards functional restoration using repetitive transcranial stimulation in patients with hypersexuality as predominant impulsive disorder. METHODS: The effect of sexual cues on inhibition was measured with a novel erotic stop-signal task under on and off dopaminergic medication. Task-related functional and anatomical connectivity models were estimated in 16 hypersexual and 17 nonhypersexual patients with PD as well as in 17 healthy controls. Additionally, excitatory neuromodulation using intermittent theta-burst stimulation (sham-controlled) was applied over the pre-supplementary motor area in 20 additional hypersexual patients with PD aiming to improve response inhibition. RESULTS: Compared with their nonhypersexual peers, patients with hypersexuality recruited caudate, pre-supplementary motor area, ventral tegmental area, and anterior cingulate cortex while on medication. Reduced connectivity was found between pre-supplementary motor area and caudate nucleus in hypersexual compared with nonhypersexual patients (while medicated), a result paralleled by compensatory enhanced anatomical connectivity. Furthermore, stimulation over the pre-supplementary motor area improved response inhibition in hypersexual patients with PD when exposed to sexual cues. CONCLUSION: This study, therefore, has identified a specific fronto-striatal and mesolimbic circuitry underlying uncontrolled sexual responses in medicated patients with PD where cortical neuromodulation halts its expression.

The effectiveness of a "EspaiJove.net"- a school-based intervention programme in increasing mental health knowledge, help seeking and reducing stigma attitudes in the adolescent population: a cluster randomised controlled trial.

BACKGROUND: The aim of this study is to evaluate the short- and long-term effects of the universal mental health literacy intervention "EspaiJove.net" in increasing mental health knowledge, help seeking and reducing stigma attitudes in the adolescent population. We also examine whether these effects depend on the intervention intensity.  METHODS: A clustered school-based randomised controlled trial (cRCT) design. SUBJECTS: 1,298 secondary pupils aged 13 and 14 were recruited from 18 schools in Barcelona (Spain) between September 2016 and January 2018. INTERVENTION: Three programmes were assessed: 1) Sensitivity Programme (SP; 1 h); 2) Mental Health Literacy (MHL; 6 h); 3) MHL plus a first-person Stigma Reduction Programme (MHL + SR; 7 h); 4) Control group (CG): waiting list. OUTCOME MEASURES: 1) MHL: EspaiJove.net EMHL Test (First part and Second Part); 2) Stigma: RIBS and CAMI; 3) Help-seeking and use of treatment: GHSQ. ANALYSIS: The data was collected at baseline, post-intervention and 6 and 12 months later. An intention-to-treat analysis and imputation method was used to analyse the missing data. Intervention effects were analysed using multilevel modelling. RESULTS: One thousand thirty-two students were included (SP = 225; MHL = 261; MHL + SR = 295 and CG = 251). The MHL and MHL + SR interventions showed short- and long-term an increase in knowledge compared to SP and CG, but no significant change post-intervention or over time (First part p = 0.52 and Second part p = 0.62) between intervention groups and CG. No significant changes were found in stigma scores post-intervention or over time (CAMI p = 0.61 and RIBS p = 0.98) or in help-seeking scores (parent p = 0.69; teacher p = 0.23 and healthcare professional p = 0.75). The MHL + SR intervention was the best valued and recommended (p < 0.005). CONCLUSIONS: The three interventions of the EspaiJove.net programme (SP, MHL and MHL + SR) seem not to be effective in terms MHL, Stigma and help-seeking behaviours. The contact with a person who has experimented mental illness first-hand did not reduce stigma attitudes. Further research should deal with the heterogeneity of MHL interventions (concept, duration and measures) and identify which components of stigma interventions are effective. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03215654 (registration date 12 July 2017).

COVID-19 en Costa Rica: análisis longitudinal de las tasas de contagio y de fallecimiento desde el enfoque de la desigualdad social

Introducción: este artículo aborda la relación entre las tasas brutas de contagio y las tasas netas de fallecimiento por la COVID-19 -variables de estudio-, con indicadores socioeconómicos y de la salud -variables de contraste- en cuatro momentos de observación durante el primer año de la sindemia en Costa Rica. Los objetivos del trabajo fueron a) identificar los momentos de observación a partir de la cantidad de casos acumulados por semana epidemiológica; b) establecer la correlación estadística entre las tasas brutas de contagio y las variables de contraste; c) establecer la correlación estadística entre las tasas netas de fallecimientos y las variables de contraste; d) describir el desarrollo de las tasas de contagio y fallecimiento a nivel cantonal; e) caracterizar socioeconómicamente los cantones con valores muy altos en dichas tasas. Metodología: se desarrolló un estudio con enfoque cuantitativo mediante el método estadístico y la aplicación de pruebas de hipótesis de tipo bivariado, a saber, correlaciones Pearson y Spearman. Resultados: los principales resultados indicaron que el contagio está estrechamente vinculado, mayoritariamente, con factores socioeconómicos -densidad poblacional, índice de desarrollo social (IDS), índice de desarrollo humano (IDH) y tasas de delito contra el patrimonio-, mientras que los fallecimientos se asocian a factores biológicos como las tasas de enfermedades -hipertensión y respiratorias- Conclusiones: se demuestra la relación existente entre la enfermedad y las desigualdades sociales, es decir, cómo estas últimas se reproducen en el campo de la salud.

Introduction: This article addresses the relationship between the gross rates of transmission and the net death rates from COVID-19 -study variables-, with socioeconomic and health indicators -contrast variables- at four moments of observation during the first year of the syndemic in Costa Rica. The objectives of the research work are: a) identify the moments of observation based on the number of accumulated cases per epidemiological week; b) establish the statistical correlation between the crude rates of transmission and the contrast variables; c) establish the statistical correlation between the net death rates and the contrast variables; d) describe the development of transmission and death rates at the cantonal level, and e) socioeconomically characterize the cantons with very high values in those rates. Methods: A study with a quantitative approach is developed through the statistical method and the application of hypothesis tests at a bivariate level, namely, Pearson and Spearman correlations. Results: The main results indicate that transmission is closely related, mostly, to socioeconomic factors -population density; Social Development Index (IDS); Human Development Index (HDI) and crime rates against property-, while deaths they are related to biological factors such as the rates of diseases -hypertension and respiratory-. Conclusion: The study demonstrates the relationship between disease and social inequalities, that is, how social inequality is reproduced in the field of health.

Validation of the OPTIMIPARK Questionnaire: A Tool to Optimize Treatment in Parkinson's Disease.

Background: Dopamine replacement therapy reduces most motor and nonmotor features of Parkinson's disease. However, with disease progression, adjustments of dopaminergics and the application of advanced therapies must be considered. Objectives: To validate the OPTIMIPARK questionnaire as a tool to help clinicians make therapeutic decisions on patients treated with levodopa. Methods: We tested a questionnaire including 9 items encompassing motor and nonmotor signs, complications, and disability in a multicenter, observational, cross-sectional study. A neurologist (neurologist 1 [N1]) assessed patients according to regular clinical practice and blinded to the OPTIMIPARK questionnaire score. Therapeutic decisions were classified as "no changes," "adjustment of conventional treatment," and "advanced therapy indicated." External neurologists (neurologist 3 [N3] and neurologist 4 [N4]), who only knew the patient age, years of disease, and current treatment, made their therapeutic decisions based on the OPTIMIPARK score. Concordance between the criterion of the N1 versus the OPTIMIPARK-based N3-N4 consensus was analyzed applying weighted κ. The area under Receiving Operating Characteristic (ROC) curves was calculated for OPTIMIPARK scores. Results: A total of 113 patients with Parkinson's disease were included. The OPTIMIPARK-based decision led to a higher proportion of patients requiring therapeutic modification than N1 assessment (74% vs. 60%; P = 0.002). Concordance between the N1 and N3-N4 decisions was moderate, whereas interobserver agreement among N3 and N4 was high. Area Under the Curve(AUC) values of 0.83 and 0.82 were found for "no changes" and "advanced therapy indicated" decisions by the N1 neurologist. Conclusions: OPTIMIPARK might be more sensitive than regular clinical practice in suggesting the need for a therapeutic change. Furthermore, the low and high scores identify with high accuracy well-adjusted patients and candidates for advanced therapy, respectively.

Update in the clinical application of focused ultrasound.

PURPOSE OF REVIEW: To review the most recent evidence about the clinical applicability of transcranial MRI-guided focused ultrasound (MRgFUS), including clinical evidence and indications, recent technical developments for its use and future prospects. RECENT FINDINGS: Unilateral MRgFUS thalamotomy for both essential and parkinsonian tremors is an approved and well established therapy. Recent studies have focused on its long-term safety and efficacy as well as technical advances for refining the approach. Moreover, ultrasound has expanded its application in Parkinson's disease, with clinical trials successfully targeting other brain regions like the subthalamic nucleus, the globus pallidus and the pallidothalamic tract, providing benefits for features that thalamotomy neglects. New indications, such as focal dystonia or neuropsychiatric conditions (namely obsessive-compulsive disorder and depression) have also been explored, with encouraging preliminary results. Finally, the application of ultrasound in low-intensity modality allows other approaches like focal blood-brain barrier opening and neuromodulation, which promise to be highly relevant in translational research. SUMMARY: MRgFUS is a growing emergent technique. Its application in clinical routine is becoming widely accepted as a therapeutic option. Novel approaches and new potential applications are anticipated.

Defining a Standard Set of Patient-Reported Outcomes for Patients With Advanced Ovarian Cancer.

Purpose: Advanced ovarian cancer (AOC) and its treatment cause several symptoms and impact on patients' health-related quality of life (HRQoL). We aim to reach a consensus on the most relevant patient-reported outcome (PROs), the corresponding measures (PROMs), and measurement frequency during AOC patients' follow-up from patients' and healthcare professionals' (HCP) perspective. Methods: The project comprised five steps: 1) a literature review, 2) a focus group with patients, 3) a nominal group with HCP, 4) two round-Delphi consultations with patients and HCP, and 5) a final meeting with HCP. Delphi questionnaire was elaborated based on literature review, focus group (n=5 patients), and nominal group (n=16 HCP). The relevance of each PRO and the appropriateness (A) and feasibility (F) of the proposed PROM were assessed (Likert scale 1=strongly agree; 9=strongly disagree). The consensus was reached when at least 75% of the panelists rated it as 'relevant', 'appropriate', or 'feasible' (score 7-9). Results: A total of 56 HCP [51.8% Hospital Pharmacy; 41.1% Oncology; 3.6% Nursing; and 3.6% Psycho-oncology; mean time in specialty 12.5 (8.0) years] and 10 AOC patients [mean time diagnosis 5.4 (3.0) years] participated in the 1st round. All PROs achieved consensus regarding their relevance, except dry skin (58.0%). Agreement was reached for PRO-CTCAE to be used to assess fatigue (A:84.9%; F:75.8%), neuropathy (A:92.4%; F:77.3%), diarrhea (A:87.9%; F:88.7%), constipation (A:86.4%; F:75.8%), nausea (A:89.4%; F:75.8%), insomnia (A:81.8%; F:88.7%), abdominal bloating (A:82.2%; F:82.2%) and sexuality (A:78.8%; F:88.6%); EQ-5D to determine patients' HRQoL (A:87.9%; F:80.3%), pain (A:87.9%; F:75.8%) and mood (A:77.7%; F:85.5%); to assess treatment adherence the Morisky-Green (A:90.9%; F:84.9%) and the dispensing register (A:80.3%; F:80.3%) were chosen. It was agreed to note in the medical record whether the patient's treatment preferences had been considered during decision-making (A:78.8%; F:78.8%) and to use a 5-point Likert scale to assess treatment satisfaction (A:86.4%; F:86.4%). Panelists agreed (A:92.4%; F: 77.3%) to collect these PROs (1) at the time of diagnosis/relapse; (2) one month after starting treatment/change therapeutic strategy; (3) every three months during the 1st-year of treatment; and later (4) every six months until treatment completion/change. Conclusions: The consensus reached represents the first step towards including the patient's perspective in AOC follow-up. The standardized collection of PROs in clinical practice may contribute to optimizing the follow-up of these patients and thus improving the quality of care.

Neuroimaging signatures predicting motor improvement to focused ultrasound subthalamotomy in Parkinson's disease.

Subthalamotomy using transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) is a novel and promising treatment for Parkinson's Disease (PD). In this study, we investigate if baseline brain imaging features can be early predictors of tcMRgFUS-subthalamotomy efficacy, as well as which are the post-treatment brain changes associated with the clinical outcomes. Towards this aim, functional and structural neuroimaging and extensive clinical data from thirty-five PD patients enrolled in a double-blind tcMRgFUS-subthalamotomy clinical trial were analyzed. A multivariate cross-correlation analysis revealed that the baseline multimodal imaging data significantly explain (P < 0.005, FWE-corrected) the inter-individual variability in response to treatment. Most predictive features at baseline included neural fluctuations in distributed cortical regions and structural integrity in the putamen and parietal regions. Additionally, a similar multivariate analysis showed that the population variance in clinical improvements is significantly explained (P < 0.001, FWE-corrected) by a distributed network of concurrent functional and structural brain changes in frontotemporal, parietal, occipital, and cerebellar regions, as opposed to local changes in very specific brain regions. Overall, our findings reveal specific quantitative brain signatures highly predictive of tcMRgFUS-subthalamotomy responsiveness in PD. The unanticipated weight of a cortical-subcortical-cerebellar subnetwork in defining clinical outcome extends the current biological understanding of the mechanisms associated with clinical benefits.