A novel digital tool for detection and monitoring of amyotrophic lateral sclerosis motor impairment and progression via keystroke dynamics.

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative condition leading to progressive muscle weakness, atrophy, and ultimately death. Traditional ALS clinical evaluations often depend on subjective metrics, making accurate disease detection and monitoring disease trajectory challenging. To address these limitations, we developed the nQiALS toolkit, a machine learning-powered system that leverages smartphone typing dynamics to detect and track motor impairment in people with ALS. The study included 63 ALS patients and 30 age- and sex-matched healthy controls. We introduce the three core components of this toolkit: the nQiALS-Detection, which differentiated ALS from healthy typing patterns with an AUC of 0.89; the nQiALS-Progression, which separated slow and fast progression at specific thresholds with AUCs ranging between 0.65 and 0.8; and the nQiALS-Fine Motor, which identified subtle progression in fine motor dysfunction, suggesting earlier prediction than the state-of-the-art assessment. Together, these tools represent an innovative approach to ALS assessment, offering a complementary, objective metric to traditional clinical methods and which may reshape our understanding and monitoring of ALS progression.

Exploring Asymmetric Fine Motor Impairment Trends in Early Parkinson's Disease via Keystroke Typing.

Background: The nQiMechPD algorithm transforms natural typing data into a numerical index that characterizes motor impairment in people with Parkinson's Disease (PwPD). Objectives: Use nQiMechPD to compare asymmetrical progression of PD-related impairment in dominant (D-PD) versus non-dominant side onset (ND-PD) de-novo patients. Methods: Keystroke data were collected from 53 right-handed participants (15 D-PD, 13 ND-PD, 25 controls). We apply linear mixed effects modeling to evaluate participants' right, left, and both hands nQiMechPD relative change by group. Results: The 6-month nQiMechPD trajectories of right (**P = 0.002) and both (*P = 0.043) hands showed a significant difference in nQiMechPD trends between D-PD and ND-PD participants. Left side trends were not significantly different between these two groups (P = 0.328). Conclusions: Significant differences between D-PD and ND-PD groups were observed, likely driven by contrasting dominant hand trends. Our findings suggest disease onset side may influence motor impairment progression, medication response, and functional outcomes in PwPD.

A novel framework to estimate cognitive impairment via finger interaction with digital devices.

Measuring cognitive function is essential for characterizing brain health and tracking cognitive decline in Alzheimer's Disease and other neurodegenerative conditions. Current tools to accurately evaluate cognitive impairment typically rely on a battery of questionnaires administered during clinical visits which is essential for the acquisition of repeated measurements in longitudinal studies. Previous studies have shown that the remote data collection of passively monitored daily interaction with personal digital devices can measure motor signs in the early stages of synucleinopathies, as well as facilitate longitudinal patient assessment in the real-world scenario with high patient compliance. This was achieved by the automatic discovery of patterns in the time series of keystroke dynamics, i.e. the time required to press and release keys, by machine learning algorithms. In this work, our hypothesis is that the typing patterns generated from user-device interaction may reflect relevant features of the effects of cognitive impairment caused by neurodegeneration. We use machine learning algorithms to estimate cognitive performance through the analysis of keystroke dynamic patterns that were extracted from mechanical and touchscreen keyboard use in a dataset of cognitively normal (n = 39, 51% male) and cognitively impaired subjects (n = 38, 60% male). These algorithms are trained and evaluated using a novel framework that integrates items from multiple neuropsychological and clinical scales into cognitive subdomains to generate a more holistic representation of multifaceted clinical signs. In our results, we see that these models based on typing input achieve moderate correlations with verbal memory, non-verbal memory and executive function subdomains [Spearman's ρ between 0.54 (P < 0.001) and 0.42 (P < 0.001)] and a weak correlation with language/verbal skills [Spearman's ρ 0.30 (P < 0.05)]. In addition, we observe a moderate correlation between our typing-based approach and the Total Montreal Cognitive Assessment score [Spearman's ρ 0.48 (P < 0.001)]. Finally, we show that these machine learning models can perform better by using our subdomain framework that integrates the information from multiple neuropsychological scales as opposed to using the individual items that make up these scales. Our results support our hypothesis that typing patterns are able to reflect the effects of neurodegeneration in mild cognitive impairment and Alzheimer's disease and that this new subdomain framework both helps the development of machine learning models and improves their interpretability.

Detection of Mental Fatigue in the General Population: Feasibility Study of Keystroke Dynamics as a Real-world Biomarker.

BACKGROUND: Mental fatigue is a common and potentially debilitating state that can affect individuals' health and quality of life. In some cases, its manifestation can precede or mask early signs of other serious mental or physiological conditions. Detecting and assessing mental fatigue can be challenging nowadays as it relies on self-evaluation and rating questionnaires, which are highly influenced by subjective bias. Introducing more objective, quantitative, and sensitive methods to characterize mental fatigue could be critical to improve its management and the understanding of its connection to other clinical conditions. OBJECTIVE: This paper aimed to study the feasibility of using keystroke biometrics for mental fatigue detection during natural typing. As typing involves multiple motor and cognitive processes that are affected by mental fatigue, our hypothesis was that the information captured in keystroke dynamics can offer an interesting mean to characterize users' mental fatigue in a real-world setting. METHODS: We apply domain transformation techniques to adapt and transform TypeNet, a state-of-the-art deep neural network, originally intended for user authentication, to generate a network optimized for the fatigue detection task. All experiments were conducted using 3 keystroke databases that comprise different contexts and data collection protocols. RESULTS: Our preliminary results showed area under the curve performances ranging between 72.2% and 80% for fatigue versus rested sample classification, which is aligned with previously published models on daily alertness and circadian cycles. This demonstrates the potential of our proposed system to characterize mental fatigue fluctuations via natural typing patterns. Finally, we studied the performance of an active detection approach that leverages the continuous nature of keystroke biometric patterns for the assessment of users' fatigue in real time. CONCLUSIONS: Our results suggest that the psychomotor patterns that characterize mental fatigue manifest during natural typing, which can be quantified via automated analysis of users' daily interaction with their device. These findings represent a step towards the development of a more objective, accessible, and transparent solution to monitor mental fatigue in a real-world environment.

Total retinal detachments due to retinoblastoma: Outcomes following intra-arterial chemotherapy/ophthalmic artery chemosurgery.

PURPOSE: To report on the rate and timing of retinal reattachment and outcomes for retinoblastoma children who have total retinal detachments at presentation to our center and were treated with intra-arterial chemotherapy (ophthalmic artery chemosurgery, OAC). PATIENTS AND METHODS: Single-center retrospective review of retinoblastoma patients who presented with total retinal detachments and were subsequently treated with OAC at MSKCC between May 2006 and July 2016. Endpoints were retinal detachment resolution, visual function, ERG amplitude, ocular survival, and patient survival from metastases. RESULTS: 87 eyes of 84 retinoblastoma patients were included. Using a survival multistate model, by 36 months of follow-up, there was a 54% cumulative probability of complete retinal reattachment and a 76% probability of partial reattachment. 24% of eyes that completely reattached received only OAC without any prior or adjuvant treatments. Eyes that completely reattached were significantly more likely to have been diagnosed at a younger age (p<0.0001) and to have greater initial ERG values (p = 0.006). At final follow-up, 14% of eyes had gained at least 25 µV of ERG activity, and 8.0% had achieved hand motion vision or better, including one to 20/60. 13% of eyes were enucleated. No patient died from metastatic disease, and only one developed metastases. CONCLUSION: OAC can successfully treat previously considered "non-salvageable" retinoblastoma eyes with total retinal detachments, promote retinal reattachment in the majority of eyes, and preserve ocular and patient survival.

Efficacy and Toxicity of Intravitreous Chemotherapy for Retinoblastoma: Four-Year Experience.

PURPOSE: To investigate the efficacy and toxicity of intravitreous melphalan for treatment of retinoblastoma, as a single agent or with concomitant topotecan. PARTICIPANTS: A total of 130 eyes of 120 patients with retinoblastoma receiving 630 intravitreous (melphalan, topotecan) or topotecan periocular injections. A total of 83 (64%) of these eyes were treated with concomitant ophthalmic artery chemosurgery (OAC). DESIGN: Retrospective cohort study. METHODS: Indirect ophthalmoscopy and clinical imaging were used to evaluate clinical response. Ocular survival and disease-free survival were estimated using Kaplan-Meier methods in 130 eyes. Ocular toxicity was evaluated by clinical findings and electroretinography (ERG) on 244 evaluable injections in 63 patients using 30-Hz flicker responses. Analysis was performed using linear mixed effects models with a random intercept and slope for each patient and a fixed effect for number of injections, in addition to any other fixed effect of interest. MAIN OUTCOME MEASURES: Ocular survival, disease-free survival, ERG: peak-to-peak ERG amplitudes in response to 30-Hz photopic flicker stimulation. RESULTS: There were no disease- or treatment-related deaths, and no patient developed externalization of tumor or metastatic disease. Two-year Kaplan-Meier estimates of ocular survival and disease-free survival were 94.2% (95% confidence interval, 89.2-99.4) and 86.2% (95% confidence interval, 78.7-94.5), respectively. There was a significant association between the number of injections and diminished ERG responses, such that on average each intravitreous melphalan injection was associated with a 5.3-µV decrease in ERG amplitude (P < 0.001). Concomitant intra-arterial chemotherapy (P = 0.01) and greater inherent ocular pigment also were significantly associated with a reduction in ERG (P = 0.045). Patient age and weight, new injection site location, addition of topotecan, concomitant focal treatment, and time interval between injections were not significantly associated with toxicity. CONCLUSIONS: Intravitreous melphalan is an effective treatment for vitreous seeding in retinoblastoma, resulting in high rates of ocular survival and disease-free survival. However, in this study, each injection of melphalan was associated, on average, with a decrement in ERG response. The findings suggest increased toxicity (1) when OAC is given within 1 week of the intravitreous injection and (2) in more deeply pigmented eyes.

Simultaneous Bilateral Ophthalmic Artery Chemosurgery for Bilateral Retinoblastoma (Tandem Therapy).

OBJECTIVE: Report on the 7-year experience with bilateral ophthalmic artery chemosurgery (OAC-Tandem therapy) for bilateral retinoblastoma. DESIGN: Retrospective, single institution study. SUBJECTS: 120 eyes of 60 children with bilateral retinoblastoma treated since March 2008. METHODS: Retrospective review of all children treated at Memorial Sloan Kettering with bilateral ophthalmic artery chemosurgery (Melphalan, Carboplatin, Topotecan, Methotrexate) delivered in the same initial session to both naïve and previously treated eyes. MAIN OUTCOME MEASURES: Ocular survival, metastatic disease, patient survival from metastases, second cancers, systemic adverse effects, need for transfusion of blood products, electroretinogram before and after treatment. RESULTS: 116 eyes were salvaged (4 eyes were enucleated: 3 because of progressive disease, 1 family choice). Kaplan Meier ocular survival was 99.2% at one year, 96.9% at 2 and 3 years and 94.9% for years 4 through 7. There were no cases of metastatic disease or metastatic deaths with a mean follow-up of 3.01 years. Two children developed second cancers (both pineoblastoma) and one of them died. Transfusion of blood products was required in 3 cases (4 transfusions), 1.9%. Two children developed fever/neutropenia requiring hospitalization (0.95%). ERGs were improved in 21.6% and unchanged after treatment in 52.5% of cases (increase or decrease of less than 25µV). CONCLUSIONS: Bilateral ophthalmic artery chemosurgery is a safe and effective technique for managing bilateral retinoblastoma-even when eyes are advanced bilaterally, and if both eyes have progressed after systemic chemotherapy. Ocular survival was excellent (94.9% at 8 years), there were no cases of of metastatic disease and no deaths from metastatic disease, but children remain at risk for second cancers. In 21.6% of cases ERG function improved. Despite using chemotherapy in both eyes in the same session, systemic toxicity was low.

Cytopathological Evaluation of Ocular Surface and Needle Washings Following Intravitreal Melphalan Injections for Retinoblastoma.

PURPOSE: There is concern that injections into eyes with retinoblastoma are dangerous and allow tumor escapement. This study attempted to determine this risk by investigating the presence of malignant cells in ocular surface and needle washings of eyes with retinoblastoma receiving intravitreal injections. METHODS: Two hundred ocular surface and 202 needle washings were obtained from 280 injections into eyes with retinoblastoma. Each specimen underwent cytopathlogical assessment for the presence of malignant cells. RESULTS: Cytopathological results revealed no malignant cells in all 200 ocular surface and 202 needle washing specimens. In the ocular surface washings, squamous cells, red blood cells, and inflammatory cells were found in 15, 2, and 2 specimens, respectively. In the needle washings, 4 specimens contained squamous cells but no red blood cells or inflammatory cells were found in any specimen. CONCLUSION: With this injection and evaluation technique, no malignant cells were recovered, highlighting the low risk of the procedure. [J Pediatr Opthalmol Strabismus. 20XX;XX(XX):XX-XX.].

Sequence-specific alterations of epitope production by HIV protease inhibitors.

Ag processing by intracellular proteases and peptidases and epitope presentation are critical for recognition of pathogen-infected cells by CD8+ T lymphocytes. First-generation HIV protease inhibitors (PIs) alter proteasome activity, but the effect of first- or second-generation PIs on other cellular peptidases, the underlying mechanism, and impact on Ag processing and epitope presentation to CTL are still unknown. In this article, we demonstrate that several HIV PIs altered not only proteasome but also aminopeptidase activities in PBMCs. Using an in vitro degradation assay involving PBMC cytosolic extracts, we showed that PIs altered the degradation patterns of oligopeptides and peptide production in a sequence-specific manner, enhancing the cleavage of certain residues and reducing others. PIs affected the sensitivity of peptides to intracellular degradation, and altered the kinetics and amount of HIV epitopes produced intracellularly. Accordingly, the endogenous degradation of incoming virions in the presence of PIs led to variations in CTL-mediated killing of HIV-infected cells. By altering host protease activities and the degradation patterns of proteins in a sequence-specific manner, HIV PIs may diversify peptides available for MHC class I presentation to CTL, alter the patterns of CTL responses, and provide a complementary approach to current therapies for the CTL-mediated clearance of abnormal cells in infection, cancer, or other immune disease.

Temozolomide or bevacizumab for spinal cord high-grade gliomas.

High-grade gliomas of the spinal cord are rare tumors, traditionally managed with surgery and radiotherapy. Once patients fail standard treatment, many receive some chemotherapy, although the data supporting such is limited. We reviewed our experience treating high-grade gliomas of the spinal cord with standard intracranial regimens including temozolomide and bevacizumab. Outcomes investigated include radiographic response, clinical response, progression-free survival, and overall survival. We identified eight patients who were treated with temozolomide and six who were treated with bevacizumab. Temozolomide was administered to three patients at initial diagnosis and five patients at recurrence after failing prior radiotherapy. For the recurrent patients, the median time-to-progression was 6.6 months (range 1-40 months) and the median overall survival from initiation of temozolomide was 16.6 months (range 1.2-64.5 months). We identified six patients who received bevacizumab at the time of recurrence. MRI demonstrated a partial response in five patients which also correlated with clinical improvement. The median time to progression was 20.7 months (range 3.3-29.9 months) and median overall survival was 22.8 months (range 3.3-31.8 months). This retrospective review suggests that temozolomide and bevacizumab may be beneficial in spinal cord high-grade gliomas. The compact architecture of the spinal cord makes bevacizumab a particularly appealing agent due to the drug's effect on peritumoral edema and mass effect.