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Rab GTPases are compartment-specific molecular switches that regulate intracellular vesicular transport in eukaryotes. GDP/GTP exchange factors (GEFs) control Rab activation, and current models propose that localised and regulated GEF activity is important in targeting Rabs to specific membranes. Here, we investigated the mechanism of GEF function using the Rab27a GEF, Rab3GEP (also known as MADD), in melanocytes as a model. We show that Rab3GEP-deficient melanocytes (melan-R3GKO) manifest partial disruption of melanosome dispersion, a read-out of Rab27a activation and targeting. Using rescue of melanosome dispersion in melan-R3GKO cells and effector pull-down approaches we show that the DENN domain of Rab3GEP (conserved among RabGEFs) is necessary, but insufficient, for its cellular function and GEF activity. Finally, using a mitochondrial re-targeting strategy, we show that Rab3GEP can target Rab27a to specific membranes in a GEF-dependent manner. We conclude that Rab3GEP facilitates the activation and targeting of Rab27a to specific membranes, but that it differs from other DENN-containing RabGEFs in requiring DENN and non-DENN elements for both of these activities and by lacking compartment-specific localisation.
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Transporte Biológico/fisiologia , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Proteínas rab27 de Ligação ao GTP/metabolismo , Animais , Melanócitos/citologia , Melanócitos/metabolismo , Melanossomas/metabolismo , Camundongos , Deficiência Múltipla de Acil Coenzima A Desidrogenase/metabolismo , Cultura Primária de Células , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas rab3 de Ligação ao GTP/metabolismoRESUMO
The ability to perform sit-to-stand (STS) transfers has a significant impact on the functional mobility of an individual. Wearable technology has the potential to enable the objective, long-term monitoring of STS transfers during daily life. However, despite several recent efforts, most algorithms for detecting STS transfers rely on multiple sensing modalities or device locations and have predominantly been used for assessment during the performance of prescribed tasks in a lab setting. A novel wavelet-based algorithm for detecting STS transfers from data recorded using an accelerometer on the lower back is presented herein. The proposed algorithm is independent of device orientation and was validated on data captured in the lab from younger and older healthy adults as well as in people with Parkinson's disease (PwPD). The algorithm was then used for processing data captured in free-living conditions to assess the ability of multiple features extracted from STS transfers to detect age-related group differences and assess the impact of monitoring duration on the reliability of measurements. The results show that performance of the proposed algorithm was comparable or significantly better than that of a commercially available system (precision: 0.990 vs. 0.868 in healthy adults) and a previously published algorithm (precision: 0.988 vs. 0.643 in persons with Parkinson's disease). Moreover, features extracted from STS transfers at home were able to detect age-related group differences at a higher level of significance compared to data captured in the lab during the performance of prescribed tasks. Finally, simulation results showed that a monitoring duration of 3 days was sufficient to achieve good reliability for measurement of STS features. These results point towards the feasibility of using a single accelerometer on the lower back for detection and assessment of STS transfers during daily life. Future work in different patient populations is needed to evaluate the performance of the proposed algorithm, as well as assess the sensitivity and reliability of the STS features.
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Acelerometria , Nível de Saúde , Dispositivos Eletrônicos Vestíveis , Adulto , Algoritmos , Dorso , Humanos , Reprodutibilidade dos TestesRESUMO
Objective monitoring and assessment of human motor behavior can improve the diagnosis and management of several medical conditions. Over the past decade, significant advances have been made in the use of wearable technology for continuously monitoring human motor behavior in free-living conditions. However, wearable technology remains ill-suited for applications which require monitoring and interpretation of complex motor behaviors (e.g., involving interactions with the environment). Recent advances in computer vision and deep learning have opened up new possibilities for extracting information from video recordings. In this paper, we present a hierarchical vision-based behavior phenotyping method for classification of basic human actions in video recordings performed using a single RGB camera. Our method addresses challenges associated with tracking multiple human actors and classification of actions in videos recorded in changing environments with different fields of view. We implement a cascaded pose tracker that uses temporal relationships between detections for short-term tracking and appearance based tracklet fusion for long-term tracking. Furthermore, for action classification, we use pose evolution maps derived from the cascaded pose tracker as low-dimensional and interpretable representations of the movement sequences for training a convolutional neural network. The cascaded pose tracker achieves an average accuracy of 88% in tracking the target human actor in our video recordings, and overall system achieves average test accuracy of 84% for target-specific action classification in untrimmed video recordings.
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Monitorização Fisiológica , Atividade Motora/fisiologia , Gravação em Vídeo/métodos , Algoritmos , Humanos , Processamento de Imagem Assistida por Computador , Redes Neurais de ComputaçãoRESUMO
We report an evidence-based management algorithm for benign lymphoepithelial cysts (BLEC) of the parotid glands in HIV patients based on long-term outcomes after radiation therapy. From 1987 to 2013, 72 HIV-positive patients with BLEC of the parotid glands treated at our institutions were identified and their medical records were reviewed and analyzed. The primary endpoint of our study was to determine a dose response in HIV patients with BLEC. In group A (≤18 Gy), which received a median dose of 10 Gy (8-18), overall response (OvR), complete response (CR), partial response (PR), and local failure (LF) was experienced by 7, 7, 0, and 93 %, respectively. In group B (≥22.5 Gy), which received a median dose of 24 Gy (22.5-30), OvR, CR, PR, and LF was experienced by 88, 65, 23, and 12 %. Logistic regression revealed that higher dose (≥22.5 Gy) predicted for cosmetic control (p = 0.0003). Multiple regression analysis revealed higher dose predicted for cosmetic control (p = 0.0001) after adjusting for confounding variables (age, gender, race, HAART use, BLEC duration, and fractionation size). No patients in either group experienced RTOG grade ≥3 toxicities. A radiation dose of 24 Gy delivered in 12-16 fractions of 1.5-2 Gy per fraction provides long-term cosmetic control in HIV-positive patients with BLEC of the parotid glands.
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Algoritmos , Cisto Epidérmico/radioterapia , Cisto Epidérmico/virologia , Infecções por HIV/complicações , Doenças Parotídeas/radioterapia , Doenças Parotídeas/virologia , Adulto , Idoso , Fracionamento da Dose de Radiação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
INTRODUCTION: Creutzfeldt-Jakob disease (CJD) is a rare prion disease classically manifesting with rapidly progressive dementia, abnormal movements and typical electroencephalographic (EEG) changes. CASE REPORT: A 74 year-old Caucasian man was recently discharged from another centre diagnosed with a stroke. He re-presented to our acute medical unit with worsening symptoms, and stroke remained the working diagnosis. Collateral history revealed a progressive cognitive decline and unilateral myoclonus. Further investigations supported the diagnosis of probable CJD, confirmed by the national CJD surveillance centre. DISCUSSION: Signs and symptoms atypical of stroke should raise the possibility of alternative diagnoses, including prion disease. CJD can present with unilateral symptoms, EEG and MRI changes. Early diagnosis prevents unnecessary investigations and treatments, allowing early palliative care input, where appropriate.
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Síndrome de Creutzfeldt-Jakob/diagnóstico , Eletroencefalografia/métodos , Imageamento por Ressonância Magnética/métodos , Acidente Vascular Cerebral/diagnóstico , Idoso , Síndrome de Creutzfeldt-Jakob/diagnóstico por imagem , Diagnóstico Diferencial , Progressão da Doença , Serviço Hospitalar de Emergência , Seguimentos , Humanos , Masculino , Testes Neuropsicológicos , Medição de Risco , Índice de Gravidade de Doença , Acidente Vascular Cerebral/diagnóstico por imagemRESUMO
Photoprotective melanins in the skin are synthesised by epidermal melanocytes within specialised lysosome-related organelles called melanosomes. Melanosomes coexist with lysosomes; thus, melanocytes employ specific trafficking machineries to ensure correct cargo delivery to either the endolysosomal system or maturing melanosomes. Mutations in some of the protein complexes required for melanogenic cargo delivery, such as biogenesis of lysosome-related organelles complex 1 (BLOC-1), result in hypopigmentation due to mistrafficking of cargo to endolysosomes. We show that hypopigmented BLOC-1-deficient melanocytes retain melanogenic capacity that can be enhanced by treatment with cAMP elevating agents despite the mislocalisation of melanogenic proteins. The melanin formed in BLOC-1-deficient melanocytes is not generated in melanosomes but rather within late endosomes/lysosomes to which some cargoes mislocalise. Although these organelles generally are acidic, a cohort of late endosomes/lysosomes have a sufficiently neutral pH to facilitate melanogenesis, perhaps due to mislocalised melanosomal transporters and melanogenic enzymes. Modulation of the pH of late endosomes/lysosomes by genetic manipulation or via treatment with lysosomotropic agents significantly enhances the melanin content of BLOC-1-deficient melanocytes. Our data suggest that upregulation of mistargeted cargoes can facilitate reprogramming of a subset of endolysosomes to generate some functions of lysosome-related organelles.
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PURPOSE: Several theories exist regarding the underlying mechanism of type V endoleaks (T5EL), which remains unclear. Torikai et al. (2018) describe sac expansion in cases with patchy heterogenous enhancement of peripheral thrombus and postulate these are due to atypical type II endoleaks (T2EL) from proliferated vasa vasora. These cases of apparent endotension pose a therapeutic challenge as continued sac expansion warrants active intervention. MATERIALS AND METHODS: Retrospective review of T5EL cases was performed who underwent multidisciplinary discussion at our institution between 2020-2021. Clinical history and imaging were reviewed by a vascular interventional radiologist aiming to identify the underlying mechanism of sac expansion. RESULTS: Two cases of these specific T5ELs were identified. One patient underwent endovascular management and image-guided aspiration of intra-sac fluid whilst another underwent open surgical ligation and sac plication. In both cases, fluid re-accumulated with re-expansion of the aneurysmal sac on follow-up. Careful review of CT imaging showed subtle foci of peripheral sac enhancement, suggestive of vasa vasora causing occult T2ELs. This was not visible on single phase CTA, super-selective angiography or cone beam CT. CONCLUSION: We identified two complex cases with unexplained sac expansion following EVAR suggestive of T2ELs from proliferated vasa vasora. Transcatheter embolisation of this network of vessels although challenging has been previously considered to stunt sac expansion. We suggest this phenomenon is under-diagnosed. Nevertheless, long-term surveillance is warranted as continued sac expansion risks changes in aneurysm morphology leading to potential loss of the proximal/distal seal zones.
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Continuous monitoring using commercial-grade wearable technology was used to quantify the physiological response to reported COVID-19 infections and vaccinations in five biometric measurements. Larger responses were observed following confirmed COVID-19 infection reported by unvaccinated versus vaccinated individuals. Responses following reported vaccination were smaller in both magnitude and duration compared to infection and mediated by both dose number and age. Our results suggest commercial-grade wearable technology as a potential platform on which to build screening tools for early detection of illness, including COVID-19 breakthrough cases.
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PURPOSE: To describe the long-term outcomes following transarterial embolisation for type Ia endoleaks (ELIa) in patients who failed or were unsuitable for standard endovascular/surgical options. MATERIALS AND METHODS: A retrospective single-centre observational study was performed between October 2010 and April 2018. Technical success rates and long-term outcomes were evaluated. A sub-analysis was performed comparing outcomes of covered aortic endografts and Nellix endovascular aneurysm sealing systems. RESULTS: A total of 34 transcatheter embolisations were performed for ELIa in 27 patients (13 endografts and 14 patients with Nellix systems). A combination of Onyx and coils was used most frequently (18/34), followed by Onyx alone (14/34) and coils alone (2/34). Technical success was achieved in 33/34 (97%) procedures . Seven early complications occurred with no immediate mortality, 5 of which involved migration/reflux of embolic into the endograft-all successfully managed via endovascular approach. Following the surveillance period (mean 25 months), 13/26 (50%) of patients were free from recurrent endoleak. Sac expansion occurred in 42% (11/26). 21/26 patients died; 6 due to aneurysm sac rupture, 10 due to unrelated causes, and 5 had no cause of death available. No significant difference in survival was found between patients with an endograft or Nellix graft-Chi-squared value - 0.011 (p < 0.05 = 3.84). CONCLUSIONS: Transcatheter embolisation for type Ia endoleaks is a safe and effective option in a select patient cohort-where traditional endovascular and surgical options are unsuitable or have failed. The procedure may prevent recurrence in some whilst delaying rupture and death in others.
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Aneurisma Roto , Aneurisma da Aorta Abdominal , Implante de Prótese Vascular , Procedimentos Endovasculares , Humanos , Endoleak/diagnóstico por imagem , Endoleak/terapia , Endoleak/etiologia , Prótese Vascular/efeitos adversos , Implante de Prótese Vascular/métodos , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/cirurgia , Aneurisma da Aorta Abdominal/complicações , Estudos Retrospectivos , Resultado do Tratamento , Procedimentos Endovasculares/métodos , Aneurisma Roto/cirurgia , Fatores de RiscoRESUMO
BACKGROUND: Uterine artery embolisation is well established as a treatment for symptomatic fibroids, however, there remain some uncertainties. We have carried out a focused literature review on three particularly challenging aspects - post-procedure fertility, symptomatic adenomyosis and large volume fibroids and uteri, to enable operators to utilise evidence-based guidance in patient selection, consent, and management. REVIEW: Literature searches were performed of the PubMed/Medline, Google scholar, EMBASE and Cochrane databases. The outcomes of our analysis of studies which recorded fertility rates in women desiring pregnancy following UAE for symptomatic fibroids found an overall mean pregnancy rate of 39.4%, live birth rate of 69.2% and miscarriage rate of 22%. The major confounding factor was patient age with many studies including women over 40 years who already have lower fertility compared to younger cohorts. Miscarriage rates and pregnancy rates in the studies analysed were comparable to the age matched population. Treatment of pure adenomyosis and adenomyosis with co-existing uterine fibroids with UAE has been shown to produce symptomatic improvement with better outcomes in those with combined disease. Although the effectiveness is not as high as it is in pure fibroid disease, UAE provides a viable and safe alternative for patients seeking symptom relief and uterine preservation. Our analysis of studies assessing the outcomes of UAE in patients with large volume uteri and giant fibroids (> 10 cm) demonstrate no significant difference in major complication rates demonstrating that fibroid size should not be a contraindication to UAE. CONCLUSION: Our findings suggest uterine artery embolisation can be offered to women desiring pregnancy with fertility and miscarriage rates comparable to that of the age-matched general population. It is also an effective therapeutic option for symptomatic adenomyosis as well as for the treatment of large fibroids > 10 cm in diameter. Caution is advised in those with uterine volumes greater than 1000cm3. It is however clear that the quality of evidence needs to be improved on with an emphasis on well-designed randomised controlled trials addressing all three areas and the consistent use of validated quality of life questionnaires for outcome assessment to enable effective comparison of outcomes in different studies.
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The aim of this review paper is to summarize recent developments in the field of wearable sensors and systems that are relevant to the field of rehabilitation. The growing body of work focused on the application of wearable technology to monitor older adults and subjects with chronic conditions in the home and community settings justifies the emphasis of this review paper on summarizing clinical applications of wearable technology currently undergoing assessment rather than describing the development of new wearable sensors and systems. A short description of key enabling technologies (i.e. sensor technology, communication technology, and data analysis techniques) that have allowed researchers to implement wearable systems is followed by a detailed description of major areas of application of wearable technology. Applications described in this review paper include those that focus on health and wellness, safety, home rehabilitation, assessment of treatment efficacy, and early detection of disorders. The integration of wearable and ambient sensors is discussed in the context of achieving home monitoring of older adults and subjects with chronic conditions. Future work required to advance the field toward clinical deployment of wearable sensors and systems is discussed.
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Vestuário , Diagnóstico por Computador/instrumentação , Pessoas com Deficiência/reabilitação , Monitorização Ambulatorial/instrumentação , Terapia Assistida por Computador/instrumentação , Adulto , Diagnóstico por Computador/métodos , Desenho de Equipamento , Humanos , Monitorização Ambulatorial/métodos , Terapia Assistida por Computador/métodosRESUMO
Voice analysis is an emerging technology which has the potential to provide low-cost, at-home monitoring of symptoms associated with a variety of health conditions. While voice has received significant attention for monitoring neurological disease, few studies have focused on voice changes related to flu-like symptoms. Herein, we investigate the relationship between changes in acoustic features of voice and self-reported symptoms during recovery from a flu-like illness in a cohort of 29 subjects. Acoustic features were automatically extracted from "sick" and "well" visit data collected in the laboratory setting, and feature down-selection was used to identify those that change significantly between visits. The selected acoustic features were extracted from at-home data and used to construct a combined distance metric that correlated with self-reported symptoms (0.63 rank correlation). Changes in self-reported symptoms corresponding to 10% of the ordinal scale used in the study were detected with an area under the curve of 0.72. The results show that acoustic features derived from voice recordings may provide an objective measure for diagnosing and monitoring symptoms of respiratory illnesses.
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Voz , Acústica , Biomarcadores , Humanos , Taxa Respiratória , AutorrelatoRESUMO
BACKGROUND: A prospective study of motor milestones achieved in severe clubfeet treated by Ponseti method and comparison between unilateral and bilateral clubfoot will help us gain further insight of motor milestones in these children. METHODS: Prospective study of 150 consecutive children with idiopathic clubfoot who were treated by Ponseti method and in whom percutaneous tendoachilles tenotomy was performed. The gross motor milestones recorded were: rolls from back to stomach, sitting without support, standing with assistance, walks with assistance, standing alone, walking alone. This was compared with published regional and World Health Organization (WHO) normal data. RESULT: 15 patients were excluded due to non-compliance and recurrence. Children with unilateral clubfoot (80 children) and bilateral clubfoot (55 children) showed a delay of 0.2-2.1 months in various milestones, and this was statistically significant when compared with both normal data. 95% children with unilateral clubfoot had independent ambulation by 17 months and in bilateral ambulation by 17.8 months. There was also a statistically significant difference in unilateral and bilateral clubfeet in all variables except sitting without support and walking with support. CONCLUSION: There is a delay in achievement in all children with clubfoot, with more delay in bilateral clubfoot as compared to unilateral clubfoot. The probable reasons could be plaster treatment, possible weakness due to tendoachilles tenotomy, use of orthosis or the inherent pathology associated with clubfeet. Parents hence need to be explained about this delay.
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Patients with atopic dermatitis experience increased nocturnal pruritus which leads to scratching and sleep disturbances that significantly contribute to poor quality of life. Objective measurements of nighttime scratching and sleep quantity can help assess the efficacy of an intervention. Wearable sensors can provide novel, objective measures of nighttime scratching and sleep; however, many current approaches were not designed for passive, unsupervised monitoring during daily life. In this work, we present the development and analytical validation of a method that sequentially processes epochs of sample-level accelerometer data from a wrist-worn device to provide continuous digital measures of nighttime scratching and sleep quantity. This approach uses heuristic and machine learning algorithms in a hierarchical paradigm by first determining when the patient intends to sleep, then detecting sleep-wake states along with scratching episodes, and lastly deriving objective measures of both sleep and scratch. Leveraging reference data collected in a sleep laboratory (NCT ID: NCT03490877), results show that sensor-derived measures of total sleep opportunity (TSO; time when patient intends to sleep) and total sleep time (TST) correlate well with reference polysomnography data (TSO: r = 0.72, p < 0.001; TST: r = 0.76, p < 0.001; N = 32). Log transformed sensor derived measures of total scratching duration achieve strong agreement with reference annotated video recordings (r = 0.82, p < 0.001; N = 25). These results support the use of wearable sensors for objective, continuous measurement of nighttime scratching and sleep during daily life.
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Centrosomes duplicate only once in coordination with the DNA replication cycle and have an important role in segregating genetic material. In contrast, most cancer cells have centrosome aberrations, including supernumerary centrosomes, and this correlates with aneuploidy and genetic instability. The tumor suppressors p16 (CDKN2A) and p15 (CDKN2B) (encoded by the familial melanoma CDKN2 locus) inhibit CDK4/6 activity and have important roles in cellular senescence. p16 is also associated with suppressing centrosomal aberrations in breast cancer; however, the role of p15 in centrosome amplification is unknown. Here, we investigated the relationship between p15 and p16 expression, centrosome number abnormalities, and melanoma progression in cell lines derived from various stages of melanoma progression. We found that normal human melanocyte lines did not exhibit centrosome number abnormalities, whereas those from later stages of melanoma did. Additionally, under conditions of S-phase block, p15 and p16 status determined whether centrosome overduplication would occur. Indeed, removal of p15 from p16-negative cell lines derived from various stages of melanoma progression changed cells that previously would not overduplicate their centrosomes into cells that did. Although this study used cell lines in vitro, it suggests that, during clinical melanoma progression, sequential loss of p15 and p16 provides conditions for centrosome duplication to become deregulated with consequences for genome instability.
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Centrossomo/metabolismo , Inibidor de Quinase Dependente de Ciclina p15/deficiência , Inibidor p16 de Quinase Dependente de Ciclina/deficiência , Melanoma/genética , Neoplasias Cutâneas/genética , Aneuploidia , Ciclo Celular/genética , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Regulação Neoplásica da Expressão Gênica , Instabilidade Genômica , Humanos , Melanoma/patologia , Pele/citologia , Pele/patologia , Neoplasias Cutâneas/patologiaRESUMO
Desmoid type fibromatosis (DTF) is a rare benign tumor of connective tissue origin. While these tumors are typically not malignant, they can exhibit aggressive growth patterns causing mass effect on surrounding organs. These tumors typically present in the extremities and abdominal wall, rarely occurring in the mesentery, and abdominal organs. Due to the rarity of this tumor and the variable size and origin, it is difficult to provide exact prognosis, recurrence, and treatment efficacy regarding desmoid tumors arising from the ileocolic mesentery. We present a case of a young male with a sporadic 31 × 25 × 12 cm DTF arising from the ileocolic mesentery that was complicated by mass effect on bowel and intra-abdominal organs requiring surgical intervention. On presentation, the patient exhibited weight gain and abdominal pressure. Abdominal distension without tenderness on palpation was noted on physical examination. The tumor biopsy confirmed the diagnosis of DTF. No evidence of familial adenomatous polyposis or Gardner syndrome was identified. The tumor was surgically excised and intimately associated with the bowel requiring ileocolonic resection with primary anastomosis. At 3-months follow up, surveillance MRI showed no residual or recurrent lesion. A multi-disciplinary approach to this patient's diagnosis and treatment allowed for an accurate diagnosis, efficient treatment, and follow up plan.
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BACKGROUND: Measuring free-living gait using wearable devices may offer higher granularity and temporal resolution than the current clinical assessments for patients with Parkinson disease (PD). However, increasing the number of devices worn on the body adds to the patient burden and impacts the compliance. OBJECTIVE: This study aimed to investigate the impact of reducing the number of wearable devices on the ability to assess gait impairments in patients with PD. METHODS: A total of 35 volunteers with PD and 60 healthy volunteers performed a gait task during 2 clinic visits. Participants with PD were assessed in the On and Off medication state using the Movement Disorder Society version of the Unified Parkinson Disease Rating Scale (MDS-UPDRS). Gait features derived from a single lumbar-mounted accelerometer were compared with those derived using 3 and 6 wearable devices for both participants with PD and healthy participants. RESULTS: A comparable performance was observed for predicting the MDS-UPDRS gait score using longitudinal mixed-effects model fit with gait features derived from a single (root mean square error [RMSE]=0.64; R2=0.53), 3 (RMSE=0.64; R2=0.54), and 6 devices (RMSE=0.54; R2=0.65). In addition, MDS-UPDRS gait scores predicted using all 3 models differed significantly between On and Off motor states (single device, P=.004; 3 devices, P=.004; 6 devices, P=.045). CONCLUSIONS: We observed a marginal benefit in using multiple devices for assessing gait impairments in patients with PD when compared with gait features derived using a single lumbar-mounted accelerometer. The wearability burden associated with the use of multiple devices may offset gains in accuracy for monitoring gait under free-living conditions.
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Objective assessment of Parkinson's disease symptoms during daily life can help improve disease management and accelerate the development of new therapies. However, many current approaches require the use of multiple devices, or performance of prescribed motor activities, which makes them ill-suited for free-living conditions. Furthermore, there is a lack of open methods that have demonstrated both criterion and discriminative validity for continuous objective assessment of motor symptoms in this population. Hence, there is a need for systems that can reduce patient burden by using a minimal sensor setup while continuously capturing clinically meaningful measures of motor symptom severity under free-living conditions. We propose a method that sequentially processes epochs of raw sensor data from a single wrist-worn accelerometer by using heuristic and machine learning models in a hierarchical framework to provide continuous monitoring of tremor and bradykinesia. Results show that sensor derived continuous measures of resting tremor and bradykinesia achieve good to strong agreement with clinical assessment of symptom severity and are able to discriminate between treatment-related changes in motor states.
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Technological advances in multimodal wearable and connected devices have enabled the measurement of human movement and physiology in naturalistic settings. The ability to collect continuous activity monitoring data with digital devices in real-world environments has opened unprecedented opportunity to establish clinical digital phenotypes across diseases. Many traditional assessments of physical function utilized in clinical trials are limited because they are episodic, therefore, cannot capture the day-to-day temporal fluctuations and longitudinal changes in activity that individuals experience. In order to understand the sensitivity of gait speed as a potential endpoint for clinical trials, we investigated the use of digital devices during traditional clinical assessments and in real-world environments in a group of healthy younger (n = 33, 18-40 years) and older (n = 32, 65-85 years) adults. We observed good agreement between gait speed estimated using a lumbar-mounted accelerometer and gold standard system during the performance of traditional gait assessment task in-lab, and saw discrepancies between in-lab and at-home gait speed. We found that gait speed estimated in-lab, with or without digital devices, failed to differentiate between the age groups, whereas gait speed derived during at-home monitoring was able to distinguish the age groups. Furthermore, we found that only three days of at-home monitoring was sufficient to reliably estimate gait speed in our population, and still capture age-related group differences. Our results suggest that gait speed derived from activities during daily life using data from wearable devices may have the potential to transform clinical trials by non-invasively and unobtrusively providing a more objective and naturalistic measure of functional ability.