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PURPOSE A COVID-19 lockdown in India posed significant challenges to the continuation of radiotherapy (RT) and systemic therapy services. Although several COVID-19 service guidelines have been promulgated, implementation data are yet unavailable. We performed a comprehensive audit of the implementation of services in a clinical oncology department. METHODS A departmental protocol of priority-based treatment guidance was developed, and a departmental staff rotation policy was implemented. Data were collected for the period of lockdown on outpatient visits, starting, and delivery of RT and systemic therapy. Adherence to protocol was audited, and factors affecting change from pre-COVID standards analyzed by multivariate logistic regression. RESULTS Outpatient consults dropped by 58%. Planned RT starts were implemented in 90%, 100%, 92%, 90%, and 75% of priority level 1-5 patients. Although 17% had a deferred start, the median time to start of adjuvant RT and overall treatment times were maintained. Concurrent chemotherapy was administered in 89% of those eligible. Systemic therapy was administered to 84.5% of planned patients. However, 33% and 57% of curative and palliative patients had modifications in cycle duration or deferrals. The patient’s inability to come was the most common reason for RT or ST deviation. Factors independently associated with a change from pre-COVID practice was priority-level allocation for RT and age and palliative intent for systemic therapy. CONCLUSION Despite significant access limitations, a planned priority-based system of delivery of treatment could be implemented.

Numerous studies have reported on the high accuracy of using voice tasks for the remote detection and monitoring of Parkinson’s Disease (PD). Most of these studies, however, report findings on a small number of voice recordings, often collected under acoustically controlled conditions, and therefore cannot scale at large without specialized equipment. In this study, we aimed to evaluate the potential of using voice as a population-based PD screening tool in resource-constrained settings. Using the standard telephone network, we processed 11,942 sustained vowel /a/ phonations from a US-English cohort comprising 1078 PD and 5453 control participants. We characterized each phonation using 304 dysphonia measures to quantify a range of vocal impairments. Given that this is a highly unbalanced problem, we used the following strategy: we selected a balanced subset (n = 3000 samples) for training and testing using 10-fold cross-validation (CV), and the remaining (unbalanced held-out dataset, n = 8942) samples for further model validation. Using robust feature selection methods we selected 27 dysphonia measures to present into a radial-basis-function support vector machine and demonstrated differentiation of PD participants from controls with 67.43% sensitivity and 67.25% specificity. These findings could help pave the way forward toward the development of an inexpensive, remote, and reliable diagnostic support tool for PD using voice as a digital biomarker.

ObjectiveWe sought to identify an abbreviated test of impaired olfaction amenable for use in busy clinical environments in prodromal (isolated REM sleep behavior disorder [iRBD]) and manifest Parkinson disease (PD).MethodsEight hundred ninety individuals with PD and 313 controls in the Discovery cohort study underwent Sniffin’ Stick odor identification assessment. Random forests were initially trained to distinguish individuals with poor (functional anosmia/hyposmia) and good (normosmia/super-smeller) smell ability using all 16 Sniffin’ Sticks. Models were retrained using the top 3 sticks ranked by order of predictor importance. One randomly selected 3-stick model was tested in a second independent PD dataset (n = 452) and in 2 iRBD datasets (Discovery n = 241, Marburg n = 37) before being compared to previously described abbreviated Sniffin’ Stick combinations.ResultsIn differentiating poor from good smell ability, the overall area under the curve (AUC) value associated with the top 3 sticks (anise/licorice/banana) was 0.95 in the Development dataset (sensitivity 90%, specificity 92%, positive predictive value 92%, negative predictive value 90%). Internal and external validation confirmed AUCs ≥0.90. The combination of the 3-stick model determined poor smell, and an RBD screening questionnaire score of ≥5 separated those with iRBD from controls with a sensitivity, specificity, positive predictive value, and negative predictive value of 65%, 100%, 100%, and 30%.ConclusionsOur 3-Sniffin’-Stick model holds potential utility as a brief screening test in the stratification of individuals with PD and iRBD according to olfactory dysfunction.Classification of EvidenceThis study provides Class III evidence that a 3-Sniffin’-Stick model distinguishes individuals with poor and good smell ability and can be used to screen for individuals with iRBD.

Speech impairment in Parkinson’s Disease (PD) has been extensively studied. Our understanding of speech in people who are at an increased risk of developing PD is, however, rather limited. It is known that isolated Rapid Eye Movement (REM) sleep Behavior Disorder (RBD) is associated with a high risk of developing PD. The aim of this study is to investigate smartphone speech testing to: (1) distinguishparticipants with RBD from controls and PD, and (2) predict a range of self- or researcher-administered clinical scores that quantify participants’ motor symptoms, cognition, daytime sleepiness, depression, and the overall state of health. The rationale of our analyses is to test an initial hypothesis that speech can be used to detect and quantify the symptoms associated with RBD and PD. We analyzed 4242 smartphone voice recordings collected in clinic and at home from 92 Controls, 112 RBD and 335 PD participants. We used acoustic signal analysis and machine learning, employing 337 features that quantify different properties of speech impairment. Using a leave-one-subject-out cross-validation scheme, we were able to distinguish RBD from controls (sensitivity 60.7%, specificity 69.6%) and RBD from PD participants (sensitivity 74.9%, specificity 73.2%), and predict clinical assessments with clinically useful accuracy. These promising findings warrant further investigation in using speech as a digital biomarker for PD and RBD to facilitate intervention in the early and prodromal stages of PD.

Progress in exploring speech and Parkinson’s Disease (PD) has been hindered due to the use of different protocols across research labs/countries, single-site studies with relatively small numbers, and no external validation. We had recently reported on the Parkinson’s Voice Initiative (PVI), a large study where we collected 19,000+ sustained vowel phonations (control and PD groups) across seven countries, under acoustically non-controlled conditions. In this study, we explored how well findings generalize in the three English-speaking PVI cohorts (data collected in Boston, Oxford, and Toronto). We acoustically characterized each sustained vowel /a/ phonation using 307 dysphonia measures which had previously been successfully employed in speech-PD applications. We used the previously identified feature subset from the Boston cohort and explored hierarchical clustering with Ward’s linkage combined with 2D-data projections using t-distributed stochastic neighbor embedding to facilitate visual exploration of PD subgroups. Furthermore, we computed feature weights using LOGO to assess feature selection consistency towards differentiating PD from controls. Overall, findings are very consistent across the three cohorts, strongly suggesting the presence of four main PD clusters, and consistent identification of key contributing features. Collectively, these findings support the generalization of sustained vowels and robustness of the presented methodology across the English-speaking PVI cohorts.

Eighty-five percent of multiple sclerosis cases begin with a discrete attack termed clinically isolated syndrome, but 37% of clinically isolated syndrome patients do not experience a relapse within 20 years of onset. Thus, the identification of biomarkers able to differentiate between individuals who are most likely to have a second clinical attack from those who remain in the clinically isolated syndrome stage is essential to apply a personalized medicine approach. We sought to identify biomarkers from biochemical, metabolic and proteomic screens that predict clinically defined conversion from clinically isolated syndrome to multiple sclerosis and generate a multi-omics-based algorithm with higher prognostic accuracy than any currently available test. An integrative multi-variate approach was applied to the analysis of cerebrospinal fluid samples taken from 54 individuals at the point of clinically isolated syndrome with 2–10 years of subsequent follow-up enabling stratification into clinical converters and non-converters. Leukocyte counts were significantly elevated at onset in the clinical converters and predict the occurrence of a second attack with 70% accuracy. Myo-inositol levels were significantly increased in clinical converters while glucose levels were decreased, predicting transition to multiple sclerosis with accuracies of 72% and 63%, respectively. Proteomics analysis identified 89 novel gene products related to conversion. The identified biochemical and protein biomarkers were combined to produce an algorithm with predictive accuracy of 83% for the transition to clinically defined multiple sclerosis, outperforming any individual biomarker in isolation including oligoclonal bands. The identified protein biomarkers are consistent with an exaggerated immune response, perturbed energy metabolism and multiple sclerosis pathology in the clinical converter group. The new biomarkers presented provide novel insight into the molecular pathways promoting disease while the multi-omics algorithm provides a means to more accurately predict whether an individual is likely to convert to clinically defined multiple sclerosis., Graphical Abstract Graphical Abstract

The overlapping clinical features of relapsing remitting multiple sclerosis (RRMS), aquaporin-4 (AQP4)-antibody (Ab) neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein (MOG)-Ab disease mean that detection of disease specific serum antibodies is the gold standard in diagnostics. However, antibody levels are not prognostic and may become undetectable after treatment or during remission. Therefore, there is still a need to discover antibody-independent biomarkers. We sought to discover whether plasma metabolic profiling could provide biomarkers of these three diseases and explore if the metabolic differences are independent of antibody titre. Plasma samples from 108 patients (34 RRMS, 54 AQP4-Ab NMOSD, and 20 MOG-Ab disease) were analysed by nuclear magnetic resonance spectroscopy followed by lipoprotein profiling. Orthogonal partial-least squares discriminatory analysis (OPLS-DA) was used to identify significant differences in the plasma metabolite concentrations and produce models (mathematical algorithms) capable of identifying these diseases. In all instances, the models were highly discriminatory, with a distinct metabolite pattern identified for each disease. In addition, OPLS-DA identified AQP4-Ab NMOSD patient samples with low/undetectable antibody levels with an accuracy of 92%. The AQP4-Ab NMOSD metabolic profile was characterised by decreased levels of scyllo-inositol and small high density lipoprotein particles along with an increase in large low density lipoprotein particles relative to both RRMS and MOG-Ab disease. RRMS plasma exhibited increased histidine and glucose, along with decreased lactate, alanine, and large high density lipoproteins while MOG-Ab disease plasma was defined by increases in formate and leucine coupled with decreased myo-inositol. Despite overlap in clinical measures in these three diseases, the distinct plasma metabolic patterns support their distinct serological profiles and confirm that these conditions are indeed different at a molecular level. The metabolites identified provide a molecular signature of each condition which is independent of antibody titre and EDSS, with potential use for disease monitoring and diagnosis. Electronic supplementary material The online version of this article (10.1186/s40478-017-0495-8) contains supplementary material, which is available to authorized users.

Recent studies have demonstrated that analysis of laboratory-quality voice recordings can be used to accurately differentiate people diagnosed with Parkinson's disease (PD) from healthy controls (HC). These findings could help facilitate the development of remote screening and monitoring tools for PD. In this study, we analyzed 2759 telephone-quality voice recordings from 1483 PD and 15321 recordings from 8300 HC participants. To account for variations in phonetic backgrounds, we acquired data from seven countries. We developed a statistical framework for analyzing voice, whereby we computed 307 dysphonia measures that quantify different properties of voice impairment, such as, breathiness, roughness, monopitch, hoarse voice quality, and exaggerated vocal tremor. We used feature selection algorithms to identify robust parsimonious feature subsets, which were used in combination with a Random Forests (RF) classifier to accurately distinguish PD from HC. The best 10-fold cross-validation performance was obtained using Gram-Schmidt Orthogonalization (GSO) and RF, leading to mean sensitivity of 64.90% (standard deviation, SD 2.90%) and mean specificity of 67.96% (SD 2.90%). This large-scale study is a step forward towards assessing the development of a reliable, cost-effective and practical clinical decision support tool for screening the population at large for PD using telephone-quality voice., Comment: 43 pages, 5 figures, 6 tables

We investigate the potential association between leucine-rich repeat kinase 2 (LRRK2) mutations and voice. Sustained phonations ('aaah' sounds) were recorded from 7 individuals with LRRK2-associated Parkinson's disease (PD), 17 participants with idiopathic PD (iPD), 20 non-manifesting LRRK2-mutation carriers, 25 related non-carriers, and 26 controls. In distinguishing LRRK2-associated PD and iPD, the mean sensitivity was 95.4% (SD 17.8%) and mean specificity was 89.6% (SD 26.5%). Voice features for non-manifesting carriers, related non-carriers, and controls were much less discriminatory. Vocal deficits in LRRK2-associated PD may be different than those in iPD. These preliminary results warrant longitudinal analyses and replication in larger cohorts.

ObjectiveWe sought to identify motor features that would allow the delineation of individuals with sleep study-confirmed idiopathic REM sleep behavior disorder (iRBD) from controls and Parkinson disease (PD) using a customized smartphone application.MethodsA total of 334 PD, 104 iRBD, and 84 control participants performed 7 tasks to evaluate voice, balance, gait, finger tapping, reaction time, rest tremor, and postural tremor. Smartphone recordings were collected both in clinic and at home under noncontrolled conditions over several days. All participants underwent detailed parallel in-clinic assessments. Using only the smartphone sensor recordings, we sought to (1) discriminate whether the participant had iRBD or PD and (2) identify which of the above 7 motor tasks were most salient in distinguishing groups.ResultsStatistically significant differences based on these 7 tasks were observed between the 3 groups. For the 3 pairwise discriminatory comparisons, (1) controls vs iRBD, (2) controls vs PD, and (3) iRBD vs PD, the mean sensitivity and specificity values ranged from 84.6% to 91.9%. Postural tremor, rest tremor, and voice were the most discriminatory tasks overall, whereas the reaction time was least discriminatory.ConclusionsProdromal forms of PD include the sleep disorder iRBD, where subtle motor impairment can be detected using clinician-based rating scales (e.g., Unified Parkinson's Disease Rating Scale), which may lack the sensitivity to detect and track granular change. Consumer grade smartphones can be used to accurately separate not only iRBD from controls but also iRBD from PD participants, providing a growing consensus for the utility of digital biomarkers in early and prodromal PD.

Background: Remote, non-invasive and objective tests that can be used to support expert diagnosis for Parkinson's disease (PD) are lacking. Methods: Participants underwent baseline in-clinic assessments, including the Unified Parkinson's Disease Rating Scale (UPDRS), and were provided smartphones with an Android operating system that contained a smartphone application that assessed voice, posture, gait, finger tapping, and response time. Participants then took the smart phones home to perform the five tasks four times a day for a month. Once a week participants had a remote (telemedicine) visit with a Parkinson disease specialist in which a modified (excluding assessments of rigidity and balance) UPDRS performed. Using statistical analyses of the five tasks recorded using the smartphone from 10 individuals with PD and 10 controls, we sought to: (1) discriminate whether the participant had PD and (2) predict the modified motor portion of the UPDRS. Results: Twenty participants performed an average of 2.7 tests per day (68.9% adherence) for the study duration (average of 34.4 days) in a home and community setting. The analyses of the five tasks differed between those with Parkinson disease and those without. In discriminating participants with PD from controls, the mean sensitivity was 96.2% (SD 2%) and mean specificity was 96.9% (SD 1.9%). The mean error in predicting the modified motor component of the UPDRS (range 11-34) was 1.26 UPDRS points (SD 0.16). Conclusion: Measuring PD symptoms via a smartphone is feasible and has potential value as a diagnostic support tool.

This paper presents a case study on short-term load forecasting for France, with emphasis on special days, such as public holidays. We investigate the generalisability to French data of a recently proposed approach, which generates forecasts for normal and special days in a coherent and unified framework, by incorporating subjective judgment in univariate statistical models using a rule-based methodology. The intraday, intraweek, and intrayear seasonality in load are accommodated using a rule-based triple seasonal adaptation of a seasonal autoregressive moving average (SARMA) model. We find that, for application to French load, the method requires an important adaption. We also adapt a recently proposed SARMA model that accommodates special day effects on an hourly basis using indicator variables. Using a rule formulated specifically for the French load, we compare the SARMA models with a range of different benchmark methods based on an evaluation of their point and density forecast accuracy. As sophisticated benchmarks, we employ the rule-based triple seasonal adaptations of Holt-Winters-Taylor (HWT) exponential smoothing and artificial neural networks (ANNs). We use nine years of half-hourly French load data, and consider lead times ranging from one half-hour up to a day ahead. The rule-based SARMA approach generated the most accurate forecasts., Comment: 11 figures, 3 tables

The individual contribution of different progenitor subtypes towards the mature rodent cerebral cortex is not fully understood. Intermediate progenitor cells (IPCs) are key to understanding the regulation of neuronal number during cortical development and evolution, yet their exact contribution is much debated. Intermediate progenitors in the cortical subventricular zone are defined by expression of T-box brain-2 (Tbr2). In this study we demonstrate by using the Tbr2(Cre) mouse line and state-of-the-art cell lineage labeling techniques, that IPC derived cells contribute substantial proportions 67.5% of glutamatergic but not GABAergic or astrocytic cells to all cortical layers including the earliest generated subplate zone. We also describe the laminar dispersion of clonally derived cells from IPCs using a recently described clonal analysis tool (CLoNe) and show that pair-generated cells in different layers cluster closer (142.1 ± 76.8 μm) than unrelated cells (294.9 ± 105.4 μm). The clonal dispersion from individual Tbr2 positive intermediate progenitors contributes to increasing the cortical surface. Our study also describes extracortical contributions from Tbr2+ progenitors to the lateral olfactory tract and ventromedial hypothalamic nucleus.

The aim of this study is to accurately distinguish Parkinson's disease (PD) participants from healthy controls using self-administered tests of gait and postural sway. Using consumer-grade smartphones with in-built accelerometers, we objectively measure and quantify key movement severity symptoms of Parkinson's disease. Specifically, we record tri-axial accelerations, and extract a range of different features based on the time and frequency-domain properties of the acceleration time series. The features quantify key characteristics of the acceleration time series, and enhance the underlying differences in the gait and postural sway accelerations between PD participants and controls. Using a random forest classifier, we demonstrate an average sensitivity of 98.5% and average specificity of 97.5% in discriminating PD participants from controls.

Effects of parameter mismatches in synchronized time series are studied first for an analytical non-linear dynamical system (coupled logistic map, CLM) and then in a real system (Electroencephalograph (EEG) signals). The internal system parameters derived from GP analysis are shown to be quite effective in understanding aspects of synchronization and non-synchronization in the two systems considered. In particular, GP is also successful in generating the CLM coupled equations to a very good accuracy with reasonable multi-step predictions. It is shown that synchronization in the above two systems is well understood in terms of parameter mismatches in the system equations derived by GP approach.