Choosing the right time granularity for analysis of digital biomarker trajectories.

INTRODUCTION: The use of digital biomarker data in dementia research provides the opportunity for frequent cognitive and functional assessments that was not previously available using conventional approaches. Assessing high-frequency digital biomarker data can potentially increase the opportunities for early detection of cognitive and functional decline because of improved precision of person-specific trajectories. However, we often face a decision to condense time-stamped data into a coarser time granularity, defined as the frequency at which measurements are observed or summarized, for statistical analyses. It is important to find a balance between ease of analysis by condensing data and the integrity of the data, which is reflected in a chosen time granularity. METHODS: In this paper, we discuss factors that need to be considered when faced with a time granularity decision. These factors include follow-up time, variables of interest, pattern detection, and signal-to-noise ratio. RESULTS: We applied our procedure to real-world data which include longitudinal in-home monitored walking speed. The example shed lights on typical problems that data present and how we could use the above factors in exploratory analysis to choose an appropriate time granularity. DISCUSSION: Further work is required to explore issues with missing data and computational efficiency.

Differentiating among stages of cognitive impairment in aging: Version 3 of the Uniform Data Set (UDS) neuropsychological test battery and MoCA index scores.

INTRODUCTION: Federally funded Alzheimer's Disease Centers in the United States have been using a standardized neuropsychological test battery as part of the National Alzheimer's Coordinating Center Uniform Data Set (UDS) since 2005. Version 3 (V3) of the UDS replaced the previous version (V2) in 2015. We compared V2 and V3 neuropsychological tests with respect to their ability to distinguish among the Clinical Dementia Rating (CDR) global scores of 0, 0.5, and 1. METHODS: First, we matched participants receiving V2 tests (V2 cohort) and V3 tests (V3 cohort) in their cognitive functions using tests common to both versions. Then, we compared receiver-operating characteristic (ROC) area under the curve in differentiating CDRs for the remaining tests. RESULTS: Some V3 tests performed better than V2 tests in differentiating between CDR 0.5 and 0, but the improvement was limited to Caucasian participants. DISCUSSION: Further efforts to improve the ability for early identification of cognitive decline among diverse racial groups are required.

Seizure occurrence and related mortality in dementia with Lewy bodies.

Dementia is a risk factor for epilepsy. While seizures have a well-established association with Alzheimer's disease (AD), their association with dementia with Lewy bodies (DLB) is not established. We utilized the National Alzheimer's Coordinating Centers' Uniform Data Set (NACC-UDS V1-3) to analyze occurrence of seizures in DLB and seizure occurrence associations with mortality. We excluded subjects with conventional seizure risk factors. Seizure occurrence was noted in 36 subjects (2.62%) out of 1376 subjects with DLB. Among 500 subjects with pathologically confirmed DLB, seizure occurrence was documented in 19 (3.8%) subjects. Half of the subjects had onset of seizures three years before or after DLB diagnosis. Two-year mortality for subjects with DLB with seizures was high at 52.8% but no increased risk was noted as compared with subjects with DLB without seizures. More prospective and long-term longitudinal studies are needed to clarify relationships between DLB, seizure occurrence, and risk of increased mortality.

Single-Cell Transcriptomics Analysis Identifies Nuclear Protein 1 as a Regulator of Docetaxel Resistance in Prostate Cancer Cells.

The majority of patients with prostate cancer treated with docetaxel develop resistance to it. To better understand the mechanism behind the acquisition of resistance, we conducted single-cell RNA-sequencing (scRNA-seq) of docetaxel-sensitive and -resistant variants of DU145 and PC3 prostate cancer cell lines. Overall, sensitive and resistant cells clustered separately. Differential gene expression analysis between resistant and sensitive cells revealed 182 differentially expressed genes common to both prostate cancer cell lines. A subset of these genes gave a gene expression profile in the resistant transcriptome-like-sensitive cells similar to the resistant cells. Exploration for functional gene pathways identified 218 common pathways between the two cell lines. Protein ubiquitination was the most differentially regulated pathway and was enriched in the resistant cells. Transcriptional regulator analysis identified 321 potential regulators across both cell lines. One of the top regulators identified was nuclear protein 1 (NUPR1). In contrast to the single-cell analysis, bulk analysis of the cells did not reveal NUPR1 as a promising candidate. Knockdown and overexpression of NUPR1 in the prostate cancer cells demonstrated that NUPR1 confers docetaxel resistance in both cell lines. Collectively, these data demonstrate the utility of scRNA-seq to identify regulators of drug resistance. Furthermore, NUPR1 was identified as a mediator of prostate cancer drug resistance, which provides the rationale to explore NUPR1 and its target genes for reversal of docetaxel resistance. IMPLICATIONS: Using single-cell sequencing of prostate cancer, we show that NUPR1 plays a role in docetaxel resistance.

Writing the Curriculum Vitae and Personal Statement.

Two of the most important components of the medical student's application for the National Resident Matching Program are the curriculum vitae (CV) and personal statement (PS). The aim of the CV is to give an itemized account of the applicant's accomplishments since the beginning of their undergraduate studies, with the main emphasis on their activities and performance in medical school. The PS, on the other hand, is the applicant's chance to give program directors (PDs) a sense of who they are. The purpose of the PS is to complement but not rehash the CV. It is an opportunity to convey what makes them fit for a residency in emergency medicine (EM). A well-written statement should guide the reader through the heartbreaks, triumphs, and inspirations that drive the applicant. Applicants should remember that the CV and PS are the first impression they brand. Both the CV and PS should be brief; easy to read; professional; honest; consistent; and free of clichés, spelling mistakes, and grammatical errors.