The ability to remotely monitor cognitive skills is increasing with the ubiquity of smartphones. The Mobile Toolbox (MTB) is a new measurement system that includes measures assessing Executive Functioning (EF) and Processing Speed (PS): Arrow Matching, Shape-Color Sorting, and Number-Symbol Match. The purpose of this study was to assess their psychometric properties.

MTB measures were developed for smartphone administration based on constructs measured in the NIH Toolbox® (NIHTB). Psychometric properties of the resulting measures were evaluated in three studies with participants ages 18 to 90. In Study 1 (N = 92), participants completed MTB measures in the lab and were administered both equivalent NIH TB measures and other external measures of similar cognitive constructs. In Study 2 (N = 1,021), participants completed the equivalent NIHTB measures in the lab and then took the MTB measures on their own, remotely. In Study 3 (N = 168), participants completed MTB measures twice remotely, two weeks apart.

All three measures exhibited very high internal consistency and strong test-retest reliability, as well as moderately high correlations with comparable NIHTB tests and moderate correlations with external measures of similar constructs. Phone operating system (iOS vs. Android) had a significant impact on performance for Arrow Matching and Shape-Color Sorting, but no impact on either validity or reliability.

Results support the reliability and convergent validity of MTB EF and PS measures for use across the adult lifespan in remote, self-administered designs.

Research using latent variable models demonstrates that pre-attentive measures of early auditory processing (EAP) and cognition may initiate a cascading effect on daily functioning in schizophrenia. However, such models fail to account for relationships among individual measures of cognition and EAP, thereby limiting their utility. Hence, EAP and cognition may function as complementary and interacting measures of brain function rather than independent stages of information processing. Here, we apply a data-driven approach to identifying directional relationships among neurophysiologic and cognitive variables.

Using data from the Consortium on the Genetics of Schizophrenia 2, we estimated Gaussian Graphical Models and Bayesian networks to examine undirected and directed connections between measures of EAP, including mismatch negativity and P3a, and cognition in 663 outpatients with schizophrenia and 630 control participants.

Chain structures emerged among EAP and attention/vigilance measures in schizophrenia and control groups. Concerning differences between the groups, object memory was an influential variable in schizophrenia upon which other cognitive domains depended, and working memory was an influential variable in controls.

Measures of EAP and attention/vigilance are conditionally independent of other cognitive domains that were used in this study. Findings also revealed additional causal assumptions among measures of cognition that could help guide statistical control and ultimately help identify early-stage targets or surrogate endpoints in schizophrenia.

Unsupervised remote digital cognitive assessment makes frequent testing feasible and allows for measurement of learning across days on participants’ own devices. More rapid detection of diminished learning may provide a potentially valuable metric that is sensitive to cognitive change over short intervals. In this study we examine feasibility and predictive validity of a novel digital assessment that measures learning of the same material over 7 days in older adults.

The Boston Remote Assessment for Neurocognitive Health (BRANCH) (Papp et al., 2021) is a web-based assessment administered over 7 consecutive days repeating the same stimuli each day to capture multi-day-learning slopes. The assessment includes Face-Name (verbal-visual associative memory), Groceries-Prices (numeric-visual associative memory), and Digits-Signs (speeded processing of numeric-visual associations). Our sample consisted of200 cognitively unimpaired older adults enrolled in ongoing observational studies (mean age=74.5, 63% female, 87% Caucasian, mean education=16.6) who completed the tasks daily, at home, on their own digital devices. Participants had previously completed in-clinic paper-and-pencil tests to compute a Preclinical Alzheimer’s Cognitive Composite (PACC-5). Mixed-effects models controlling for age, sex, and education were used to observe the associations between PACC-5 scores and both initial performance and multi-day learning on the three BRANCH measures.

Adherence was high with 96% of participants completing all seven days of consecutive assessment; demographic factors were not associated with differences in adherence. Younger participants had higher Day 1 scores all three measures, and learning slopes on Digit-Sign. Female participants performed better on Face-Name (T=3.35, p<.001) and Groceries-Prices (T=2.00, p=0.04) on Day 1 but no sex differences were seen in learning slopes; there were no sex differences on Digit-Sign. Black participants had lower Day 1 scores on Face-Name (T=-3.34, p=0.003) and Digit Sign (T=3.44, p=0.002), but no racial differences were seen on learning slopes for any measure. Education was not associated with any measure. First day performance on Face-Name (B=0.39, p<.001), but not learning slope B=0.008, p=0.302) was associated with the PACC5. For Groceries-Prices, both Day 1 (B=0.27, p<.001) and learning slope (B=0.02, p=0.03) were associated with PACC-5. The Digit-Sign scores at Day 1 (B=0.31, p<.001) and learning slope (B=0.06, p<.001) were also both associated with PACC-5.

Seven days of remote, brief cognitive assessment was feasible in a sample of cognitively unimpaired older adults. Although various demographic factors were associated with initial performance on the tests, multi-day-learning slopes were largely unrelated to demographics, signaling the possibility of its utility in diverse samples. Both initial performance and learning scores on an associative memory and processing speed test were independently related to baseline cognition indicating that these tests’ initial performance and learning metrics are convergent but unique in their contributions. The findings signal the value of measuring differences in learning across days as a means towards sensitively identifying differences in cognitive function before signs of frank impairment are observed. Next steps will involve identifying the optimal way to model multi-day learning on these subtests to evaluate their potential associations with Alzheimer’s disease biomarkers.

Early administration of antibiotics in sepsis is associated with improved patient outcomes, but safe and generalizable approaches to de-escalate or discontinue antibiotics after suspected sepsis events are unknown.

We used a modified Delphi approach to identify safety criteria for an opt-out protocol to guide de-escalation or discontinuation of antibiotic therapy after 72 hours in non-ICU patients with suspected sepsis. An expert panel with expertise in antimicrobial stewardship and hospital epidemiology rated 48 unique criteria across 3 electronic survey rating tools. Criteria were rated primarily based on their impact on patient safety and feasibility for extraction from electronic health record review. The 48 unique criteria were rated by anonymous electronic survey tools, and the results were fed back to the expert panel participants. Consensus was achieved to either retain or remove each criterion.

After 3 rounds, 22 unique criteria remained as part of the opt-out safety checklist. These criteria included high-risk comorbidities, signs of severe illness, lack of cultures during sepsis work-up or antibiotic use prior to blood cultures, or ongoing signs and symptoms of infection.

The modified Delphi approach is a useful method to achieve expert-level consensus in the absence of evidence suifficient to provide validated guidance. The Delphi approach allowed for flexibility in development of an opt-out trial protocol for sepsis antibiotic de-escalation. The utility of this protocol should be evaluated in a randomized controlled trial.

Individuals with schizophrenia are at higher risk of physical illnesses, which are a major contributor to their 20-year reduced life expectancy. It is currently unknown what causes the increased risk of physical illness in schizophrenia.

To link genetic data from a clinically ascertained sample of individuals with schizophrenia to anonymised National Health Service (NHS) records. To assess (a) rates of physical illness in those with schizophrenia, and (b) whether physical illness in schizophrenia is associated with genetic liability.

We linked genetic data from a clinically ascertained sample of individuals with schizophrenia (Cardiff Cognition in Schizophrenia participants, n = 896) to anonymised NHS records held in the Secure Anonymised Information Linkage (SAIL) databank. Physical illnesses were defined from the General Practice Database and Patient Episode Database for Wales. Genetic liability for schizophrenia was indexed by (a) rare copy number variants (CNVs), and (b) polygenic risk scores.

Individuals with schizophrenia in SAIL had increased rates of epilepsy (standardised rate ratio (SRR) = 5.34), intellectual disability (SRR = 3.11), type 2 diabetes (SRR = 2.45), congenital disorders (SRR = 1.77), ischaemic heart disease (SRR = 1.57) and smoking (SRR = 1.44) in comparison with the general SAIL population. In those with schizophrenia, carrier status for schizophrenia-associated CNVs and neurodevelopmental disorder-associated CNVs was associated with height (P = 0.015–0.017), with carriers being 7.5–7.7 cm shorter than non-carriers. We did not find evidence that the increased rates of poor physical health outcomes in schizophrenia were associated with genetic liability for the disorder.

This study demonstrates the value of and potential for linking genetic data from clinically ascertained research studies to anonymised health records. The increased risk for physical illness in schizophrenia is not caused by genetic liability for the disorder.

Alzheimer’s disease (AD) studies are increasingly targeting earlier (pre)clinical populations, in which the expected degree of observable cognitive decline over a certain time interval is reduced as compared to the dementia stage. Consequently, endpoints to capture early cognitive changes require refinement. We aimed to determine the sensitivity to decline of widely applied neuropsychological tests at different clinical stages of AD as outlined in the National Institute on Aging – Alzheimer’s Association (NIA-AA) research framework.

Amyloid-positive individuals (as determined by positron emission tomography or cerebrospinal fluid) with longitudinal neuropsychological assessments available were included from four well-defined study cohorts and subsequently classified among the NIA-AA stages. For each stage, we investigated the sensitivity to decline of 17 individual neuropsychological tests using linear mixed models.

1103 participants (age = 70.54 ± 8.7, 47% female) were included: n = 120 Stage 1, n = 206 Stage 2, n = 467 Stage 3 and n = 309 Stage 4. Neuropsychological tests were differentially sensitive to decline across stages. For example, Category Fluency captured significant 1-year decline as early as Stage 1 (β = −.58, p < .001). Word List Delayed Recall (β = −.22, p < .05) and Trail Making Test (β = 6.2, p < .05) became sensitive to 1-year decline in Stage 2, whereas the Mini-Mental State Examination did not capture 1-year decline until Stage 3 (β = −1.13, p < .001) and 4 (β = −2.23, p < .001).

We demonstrated that commonly used neuropsychological tests differ in their ability to capture decline depending on clinical stage within the AD continuum (preclinical to dementia). This implies that stage-specific cognitive endpoints are needed to accurately assess disease progression and increase the chance of successful treatment evaluation in AD.

Pro-vitamin A carotenoids namely α-, β-carotene and β-cryptoxanthin have potential roles in neurocognitive development, but current literature on these carotenoids mainly focused on preventing cognitive decline in the elderly. This study examined the associations of maternal plasma pro-vitamin A carotenoids concentrations with offspring cognitive development up to 54 months in the GUSTO mother-offspring cohort study.

Maternal plasma pro-vitamin A carotenoids concentrations at delivery were determined by ultra-performance liquid chromatography. At age 24 months, the Bayley Scales of Infant and Toddler Development (BSID-III) was used to assess children's development for the following domains: cognitive, receptive and expressive language, and fine and gross motor. At age 54 months, the Kaufman Brief Intelligence Test (KBIT-2) was used to assess children's verbal and non-verbal intelligence. Associations of maternal pro-vitamin A carotenoids with offspring cognitive development at each time point were examined in 419 mother-offspring pairs using linear regressions adjusted for confounders (e.g. maternal demographics, antenatal mental health and breastfeeding duration).

Median (IQR) maternal plasma concentrations (mg/L) were: α-carotene 0.052 (0.032–0.081), β-carotene 0.189 (0.134–0.286), and β-cryptoxanthin 0.199 (0.123–0.304). In 24 months old infants, higher maternal β-cryptoxanthin (per SD increment) were associated with higher scores in most of BSID-III domains: cognitive [β 0.18, (0.08, 0.28) SD], receptive language [β 0.17 (0.07, 0.27) SD], fine motor [β 0.16 (0.06, 0.27) SD], and gross motor [β 0.16 (0.06, 0.27) SD]. Additionally, a 1-SD increment in maternal β-carotene concentrations were associated with 0.16 SD higher scores in BSID-III cognitive domain (95%: 0.04, 0.28), which was attenuated after adjusting for breastfeeding duration. No significant associations were observed between maternal α-carotene concentrations and BSID-III in children at 24 months of age, or between maternal pro-vitamin A carotenoids and KBIT-2 in children at 54 months of age.

Our study provides novel data suggesting a role of maternal pro-vitamin A carotenoids, especially β-cryptoxanthin, in offspring early cognitive development. This adds support to the importance of consuming sufficient amounts of red- and orange-coloured fruit and vegetables (rich sources of β-cryptoxanthin and β-carotene) during pregnancy. Further studies are required in other mother-offspring cohort with larger sample sizes, and intervention trials to confirm an effect of pro-vitamin A carotenoids on neurocognitive development.