Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson's disease study.

Estimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.

Perspectives on the diagnosis and management of functional cognitive disorder: An international Delphi study.

BACKGROUND: Current proposed criteria for functional cognitive disorder (FCD) have not been externally validated. We sought to analyse the current perspectives of cognitive specialists in the diagnosis and management of FCD in comparison with neurodegenerative conditions. METHODS: International experts in cognitive disorders were invited to assess seven illustrative clinical vignettes containing history and bedside characteristics alone. Participants assigned a probable diagnosis and selected the appropriate investigation and treatment. Qualitative, quantitative and inter-rater agreement analyses were undertaken. RESULTS: Eighteen diagnostic terminologies were assigned by 45 cognitive experts from 12 countries with a median of 13 years of experience, across the seven scenarios. Accurate discrimination between FCD and neurodegeneration was observed, independently of background and years of experience: 100% of the neurodegenerative vignettes were correctly classified and 75%-88% of the FCD diagnoses were attributed to non-neurodegenerative causes. There was <50% agreement in the terminology used for FCD, in comparison with 87%-92% agreement for neurodegenerative syndromes. Blood tests and neuropsychological evaluation were the leading diagnostic modalities for FCD. Diagnostic communication, psychotherapy and psychiatry referral were the main suggested management strategies in FCD. CONCLUSIONS: Our study demonstrates the feasibility of distinguishing between FCD and neurodegeneration based on relevant patient characteristics and history details. These characteristics need further validation and operationalisation. Heterogeneous labelling and framing pose clinical and research challenges reflecting a lack of agreement in the field. Careful consideration of FCD diagnosis is advised, particularly in the presence of comorbidities. This study informs future research on diagnostic tools and evidence-based interventions.

'If we take the engine out, how will the car go?': beliefs, understanding and access to vasectomy services in Timor-Leste.

Vasectomy is a safe, highly effective and affordable method of permanent contraception, and one of the few currently available contraceptive methods for men. Despite this, vasectomy uptake remains overall low, making up just 2% of the global contraceptive method mix. To better understand access to vasectomy in a country with negligible uptake, we conducted participatory and operational research in the Democratic Republic of Timor-Leste (Timor-Leste). We held 14 participatory group discussions with 175 community participants (84 men, 91 women; aged 18-72) across seven municipalities (Ainaro, Baucau, Bobonaro, Dili, Lautem, Manufahi, and Oecusse), and individual in-depth interviews with 24 healthcare providers (16 women, 8 men; aged 25-56 years). Data were analysed using reflexive thematic analysis. Community awareness and understanding about vasectomy were limited, with concerns expressed about physical and social side effects. Healthcare providers had limited experience and knowledge about vasectomy, and about male sexual and reproductive health more generally. However, our findings also indicate a small but existing demand for vasectomy services that could be grown and better met through health systems strengthening initiatives. Insights from our research have informed programmatic decision-making in Timor-Leste and can be further used to inform national health policy and practice.

Augenblickdiagnose in neurology: Revisiting 'diagnosis in the blink of an eye'.

BACKGROUND AND PURPOSE: The art of diagnosis in clinical neurology requires attentive listening and careful observation. In certain situations, a fragment of the history or a physical sign may be so distinctive that it allows clinicians to evoke a specific diagnosis. This quick mental process was previously referred to as 'Augenblickdiagnose' ('diagnosis in the blink of an eye') in a seminal paper by Dr. William Campbell in 1998. We aimed to revisit this concept by providing additional clinical vignettes. METHODS: The authors wrote clinical vignettes using examples from their own clinical practice and performed a non-systematic review of influential neurology textbooks using the words 'pathognomonic' and 'highly suggestive'. RESULTS: Twenty examples from various fields of neurology are presented in a table, stratified by major fields of neurology. A short educational reflection is provided for each diagnosis considered. CONCLUSION: 'Augenblickdiagnose' is an engaging teaching resource that also contributes to 'neurophilia', that is, a fascination for neurology, perhaps increasingly in today's modern neurology practice. However, multiple cognitive biases underlying mental shortcuts may lead to an incorrect diagnosis. It is important to stress that good clinical practice in neurology requires taking a thorough history and performing a careful neurological examination.

Participatory Qualitative Research in a Multilingual Context: The Use of Panel Translation to Better Understand and Improve Sexual and Reproductive Health in Timor-Leste.

Understanding and respecting different linguistic and socio-cultural needs of health service users is critical to design, adapt and provide appropriate health services. We explored access to male family planning methods in The Democratic Republic of Timor-Leste, a linguistically and culturally diverse nation, by conducting 14 participatory group discussions (PGDs) with 175 participants across seven municipalities. Participants (84 men and 91 women, aged 18 to 72) spoke 13 different languages. PGDs were audio-recorded and translated to English using a multilingual panel translation approach that enabled rigorous and reflexive discussion and learning between researchers about context and meaning. Planning for language diversity helped us to centre participant voices and to hear perspectives that may have otherwise been excluded or misrepresented. Our study affirms the need for research teams to include diverse members who help ensure meaning and voice is not lost across cultural and linguistic differences. Linguistic respect, inclusion and transparency are required to realise improved health and development outcomes.

Teleneurology in Parkinson's disease: A step-by-step video guide.

BACKGROUND: The COVID-19 pandemic forced the implementation of social distancing and circulation restrictions. This affected all aspects of society including health care. In the field of chronic neurological disorders such as Parkinson's disease (PD), teleneurology is employed in scenarios where face-to-face interactions are not possible. A growing number of clinicians and institutions are turning to teleneurology in order to providing medical care. AIMS OF THE ARTICLE: In this manuscript, we present a practical, 'how we do it in real life', example of a teleneurology appointment with a person with PD (PwP). METHODS: We elaborated a step-by-step approach of the main aspects of a consultation with a PwP and provide video illustration. RESULTS: The key aspects of a teleneurology appointment were separated into: (1) In the office, before the appointment; (2) History taking; (3) Examination; and (4) Finishing up. CONCLUSIONS: We discuss the strengths and weaknesses of this approach and provide our experience in overcoming commonly encountered difficulties.

Acute phase treatment in central retinal artery occlusion: thrombolysis, hyperbaric oxygen therapy or both?

Central retinal artery occlusion (CRAO) is a neuro-ophthalmological emergency. There is a finite time window for acute interventions such as revascularization (e.g. intravenous thrombolysis-IVT) and retinal oxygenation (e.g. hyperbaric oxygen therapy-HBOT) therapies. Case 1: A 35-year-old female presented with CRAO in the right eye (OD) confirmed by fluorescein angiography (FA) and optical coherence tomography (OCT). She underwent 4 sessions of HBOT (100% O2 at 2.4 atmosphere absolute for 90 min). Afterwards, visual defect on the nasal field was kept but visual acuity (VA) improved from counting fingers to 1.0. Case 2: A 65-year-old male presented with CRAO in his left eye (OS) with 1.5 h of evolution. Orbital sonography and OCT confirmed the presence of an embolus and he underwent IVT with rTPA (0.9 mg/kg). VA improved from light perception to 0.1. Case 3: A 21-year-old male presented acute visual loss in his OD with 2.5 h of evolution. OCT and retinography identified CRAO. He was submitted to IVT (rTPA-0.9 mg/kg) followed by 12 sessions of HBOT. VA improved from hand motion to 1.0. Our case series depicts the approaches and possible outcomes in acute management of an infrequent, but highly morbid, cerebroretinovascular disorder. Future clinical trials are warranted to tackle current difficulties in CRAO treatment.

Dynamic Model and Inverse Kinematic Identification of a 3-DOF Manipulator Using RLSPSO.

This paper presents the identification of the inverse kinematics of a cylindrical manipulator using identification techniques of Least Squares (LS), Recursive Least Square (RLS), and a dynamic parameter identification algorithm based on Particle Swarm Optimization (PSO) with search space defined by RLS (RLSPSO). A helical trajectory in the cartesian space is used as input. The dynamic model is found through the Lagrange equation and the motion equations, which are used to calculate the torque values of each joint. The torques are calculated from the values of the inverse kinematics, identified by each algorithm and from the manipulator joint speeds and accelerations. The results obtained for the trajectories, speeds, accelerations, and torques of each joint are compared for each algorithm. The computational costs as well as the Multi-Correlation Coefficient ( R 2 ) are computed. The results demonstrated that the identification accuracy of RLSPSO is better than that of LS and PSO. This paper brings an improvement in RLS because it is a method with high complexity, so the proposed method (hybrid) aims to improve the computational cost and the results of the classic RLS.

Listen to your patient: A fiddler's tale.

A professional violinist reported increasing difficulties playing the violin. He executed the initial half of the musical piece well, but produced an increasing number of mistakes during the second half. Neurological examination was remarkable for bradykinesia and tremor. Formal acoustic analysis of finger taps and pronation-supination showed a decrement in sound intensity and number of taps over time. Oscillations in performance correlated with a parkinsonian tremor. We interpret these findings as the audible equivalent of bradykinesia and tremor. Listening to bradykinesia and quantifying its decrement using acoustic analysis may offer a simple, objective, and reliable supplement to the neurological examination. Ann Neurol 2018;84:931-933.

The Waiting Room: neurological observations made outside the movement disorder specialist's consulting office.

The neurological examination should always begin before the patient enters the doctor's office. Movement disorders in particular lend themselves to a spot diagnosis. In today's busy buzzing world, it seems wasteful not to make use of the various diagnostic clues that can be picked up readily while the patient is still in the waiting room. We present several illustrative examples, drawn from the literature and from our own experience. These are divided according to the different waiting room 'stages': the patient sitting in the waiting room, the response on being summoned to enter the consulting room-including rising from the chair, exchanging initial pleasantries and the way of walking. We also discuss the importance of paying attention to the patient's behaviour, clothing, posture, breathing patterns, facial expression and major gait abnormalities.

What Do We Know About the Development of Personal and Social Skills within the Sport Education Model: A Systematic Review.

The purpose of the present study was to conduct a review of the research on the Sport Education (SE) studies that have examined the development of students' personal and social skills. Research articles selected were found through Web of Science, SCOPUS, Academic Search Complete, ERIC, SPORTDiscus with Full Text, Education Source, PsycINFO and PsycARTICLES databases. The keywords "Sport Education" and "physical education" were used in different combinations. The articles were included for analysis if the following criteria were met: (i) were published in peer-reviewed international journals indexed in JCR (Journal Citation Reports) or SJR (Scientific Journal Rankings); (ii) were available in full-text; (iii) examined personal and social variables included or measured as main outcomes within the SE model. The quality of the selected studies was scored using a quality assessment list. Fifty-one studies were included. Results showed that, considering the development of social and personal competencies, the majority of SE research took place in Spain and USA in a co-educational PE context (high school). Enjoyment/satisfaction, enthusiasm and engagement were the predominant outcome measures, using a non-experimental design and multiple qualitative tools in more than half of the studies. Few studies established the fidelity of the model implementation. There is a need for future research to consider other samples, contexts, cultures and types of sports seeking to reinforce the positive impact of SE on the personal and social competencies. Longer units with a good planning, mixed and quantitative methodological designs and the report of the model fidelity would be also particularly important for future investigations.

The Head Turning Sign in Dementia and Mild Cognitive Impairment: Its Relationship to Cognition, Behavior, and Cerebrospinal Fluid Biomarkers.

BACKGROUND/AIMS: The head turning sign (HTS) is frequently noticed in clinical practice, but few studies have investigated its etiological and neuropsychological correlates. METHODS: The presence and frequency of the HTS was operationalized and prospectively evaluated in patients with Alzheimer's disease (AD), amnestic mild cognitive impairment (MCI), and behavioral-variant frontotemporal dementia (bvFTD). Cerebrospinal fluid (CSF) samples for AD biomarkers were collected. Mini-Mental State Examination, Montreal Cognitive Assessment, Geriatric Depression Scale (GDS), and insight scale scores were ascertained. RESULTS: A total of 84 patients were included. The HTS was more prevalent in AD than in MCI or bvFTD. It correlated negatively with cognitive measures and depression. It also had a positive correlation with CSF total tau and hyperphosphorylated tau proteins. Total tau protein and GDS score were the only variables independently associated with the HTS. CONCLUSIONS: The presence of the HTS in a cognitively impaired individual suggests a diagnosis of AD. A higher HTS frequency correlates with higher CSF total tau levels, a smaller GDS score, and worse cognitive measures. In the MCI subgroup, the HTS may suggest a higher risk of progression.

Sport Education and Direct Instruction Units: Comparison of Student Knowledge Development in Athletics.

This study conducted a comparative analysis of students' knowledge development on athletics in Sport Education and in a Direct Instruction unit taking into account sex and initial skill level. The participants were an experienced Physical Education teacher and two sixth-grade classes totaling 47 students (25 boys and 22 girls). Each class was randomly placed in either Sport Education or Direct Instruction classes and participated in 20, 45-minutes lessons focused on shot put, hurdles and triple jump. Knowledge on athletics was assessed through a 25-items written and video-based test. The inter-group differences and improvements across time in the knowledge test were analyzed through the Mann-Whitney and Wilcoxon tests, respectively. There were significant knowledge improvements in both instructional approaches irrespective of students' gender and skill level. In Direct Instruction, the type of task organization, the high rates of repetition of movement patterns and feedback by the teacher were beneficial to student learning. In Sport Education, the autonomy granted to students in the control of the pace of task transitions by making on-going judgments on achievement of performance criteria, implicated students affectively and cognitively with the learning content. It was further supported that several models and teaching strategies should be taken into consideration when teaching Physical Education. Different approaches should be perceived as alternatives and teachers should retain the best in each according with the moment in the unit, student developmental stage, and the specific learning objectives in the task.

A comparative study of students' track and field technical performance in sport education and in a direct instruction approach.

This study examined students' technical performances improvements in three track and field events (hurdles, shot put, and long jump) following either a Sport Education season or a Direct Instruction unit. An experienced Physical Education teacher taught two classes totalling 47 sixth-grade students (25 boys and 22 girls, aged between 10 and 13 years old) in 20, 45-minute lessons over 10 weeks. The students' technical performances were analysed and evaluated through systematic observation of videos. The Wilcoxon signed-rank test was used to compare scores at three time points (pre-test, post-test and retention), and the Mann-Whitney U test was used to examine the differences within each instructional model at each assessment moment, as well as by gender and skill level. The impact of each instructional model in student learning was markedly distinct. While in Sport Education students of both genders and skill levels improved significantly in all events, in Direct Instruction, evidence of significant improvements was limited to boys and students of higher skill level. Key pointsThe impact of each teaching approach in student learning was distinct. While in Sport Education the technical performance improvements spread throughout students of both genders and skill levels, in Direct Instruction significant improvements were exclusive to boys and students of higher skill level.The extended analysis in the current study, taking into account student gender and skill level, permitted a more comprehensive measure of the learning impact of the two approaches. More sophisticated analyses of the tasks and instructional strategies of each approach are encouraged.

The role of international NGOs in health systems strengthening: the case of Timor-Leste.

Achieving the United Nations Millennium Development Goals for health will require that programs supporting health in developing countries focus on strengthening national health care systems. However, the dominant neoliberal model of development mandates reduced public spending on health and other social services, often resulting in increased funding for nongovernmental organizations (NGOs) at the expense of support for government systems. East Timor, later Timor-Leste, is an example of a post-crisis country where international NGO efforts were initially critical to providing relief efforts to a traumatized population. Those groups were not prepared to help develop and support a standardized Timorese national health plan, however, and the cost of their support was unsustainable in the long term. In response, local authorities designed and implemented a post-crisis NGO phase-over plan that addressed risks to service disruption and monitored the process. Since then, some NGOs have worked collaboratively with the Ministry of Health to support specific efforts and initiatives under a framework provided by the ministry. Timor-Leste has shown that ministries of health can facilitate an effective transition of NGO support from crisis to development if they are allowed to plan and manage the process.