Supporting compassionate use of technology to support functioning in daily activities among people with cognitive decline - a scoping review.

Cognitive decline is becoming more prevalent as population ages. Technology offers solutions to help people with cognitive decline age in place. A compassionate approach to care can promote engagement in technology use by older adults with cognitive decline and equitable access. This scoping review summarized research literature on approaches to design and selection of technology that could support a compassionate approach to technology use for daily functioning among adults with cognitive decline and their care partners. We used the framework of Arksey and O'Malley. Key words capturing constructs of compassion, technology, and cognitive decline were searched in CINAHL, Medline, and PsycINFO. Peer-reviewed articles about the design for or use of technology by persons with cognitive decline or their care partners were included. Two reviewers screened and extracted data. Data informing compassionate technology use were analysed thematically. Fifty-five included articles represented a variety of technologies and purposes with ethics being the predominant perspective (n = 15). Analysis identified four categories: 1) Person- and care partner-centered approach, 2) Tailoring design to abilities, 3) Tailoring selection and application, and 4) Training and support. Using study findings, we developed a framework for compassionate use of technology for people living with cognitive decline and their care partners.

Compassionate approach to technology design and selection for person with cognitive decline and their care partners involves supporting autonomy, and consideration of ethical issues and specific technology purposeA family-centered care with a strong relational component is important when selecting technology with people with cognitive declineHealthcare providers and industry representatives require training to understand and adapt their approach to meet the needs of individuals living with cognitive decline and their care partners.

Measurement of Adverse Events in Studies of Digital Health Interventions for Psychosis: Guidance and Recommendations Based on a Literature Search and Framework Analysis of Standard Operating Procedures.

BACKGROUND: Given the rapid expansion of research into digital health interventions (DHIs) for severe mental illness (SMI; eg, schizophrenia and other psychosis diagnoses), there is an emergent need for clear safety measures. Currently, measurement and reporting of adverse events (AEs) are inconsistent across studies. Therefore, an international network, iCharts, was assembled to systematically identify and refine a set of standard operating procedures (SOPs) for AE reporting in DHI studies for SMI. DESIGN: The iCharts network comprised experts on DHIs for SMI from seven countries (United Kingdom, Belgium, Germany, Pakistan, Australia, United States, and China) and various professional backgrounds. Following a literature search, SOPs of AEs were obtained from authors of relevant studies, and from grey literature. RESULTS: A thorough framework analysis of SOPs (n = 32) identified commonalities for best practice for certain domains, along with significant gaps in others; particularly around the classification of AEs during trials, and the provision of training/supervision for research staff in measuring and reporting AEs. Several areas which could lead to the observed inconsistencies in AE reporting and handling were also identified. CONCLUSIONS: The iCharts network developed best-practice guidelines and a practical resource for AE monitoring in DHI studies for psychosis, based on a systematic process which identified common features and evidence gaps. This work contributes to international efforts to standardize AE measurement and reporting in this emerging field, ensuring that safety aspects of DHIs for SMI are well-studied across the translational pathway, with monitoring systems set-up from the outset to support safe implementation in healthcare systems.

Encapsulation of copper phenanthroline within horse spleen apoferritin: characterisation, cytotoxic activity and ability to retain temozolomide.

Protein capsules are promising drug delivery vehicles for cancer research therapies. Apoferritin (AFt) is a self-assembling 12 nm diameter hollow nanocage with many desirable features for drug delivery, however, control of drug retention inside the protein cage remains challenging. Here we report the encapsulation of copper(ii)-1,10-phenanthroline (Cu(phen)) within the horse spleen AFt (HSAFt) nanocage, by diffusion of the metal through the pores between the protein subunits. Transmission electron microscopy revealed the formation of organised copper adducts inside HSAFt, without affecting protein integrity. These structures proved stable during storage (>4 months at -20 °C). Exposure to physiologically relevant conditions (37 °C) showed some selectivity in cargo release after 24 h at pH 5.5, relevant to the internalisation of AFt within the endosome (60% release), compared to pH 7.4, relevant to the bloodstream (40% release). Co-encapsulation of temozolomide, a prodrug used to treat glioblastoma multiforme, and Cu(phen) enabled entrapment of an average of 339 TMZ molecules per cage. In vitro results from MTT and clonogenic assays identified cytotoxic activity of the Cu(phen), HSAFt-Cu(phen) and HSAFt-Cu(phen)-TMZ adducts against colorectal cancer cells (HCT-116) and glioblastoma cells (U373V, U373M). However, the presence of the metal also contributed to more potent activity toward healthy MRC5 fibroblasts, a result that requires further investigation to assess the clinical viability of this system.

Interdisciplinary perspectives on digital technologies for global mental health.

Digital Mental Health Technologies (DMHTs) have the potential to close treatment gaps in settings where mental healthcare is scarce or even inaccessible. For this, DMHTs need to be affordable, evidence-based, justice-oriented, user-friendly, and embedded in a functioning digital infrastructure. This viewpoint discusses areas crucial for future developments of DMHTs. Drawing back on interdisciplinary scholarship, questions of health equity, consumer-, patient- and developer-oriented legislation, and requirements for successful implementation of technologies across the globe are discussed. Economic considerations and policy implications complement these aspects. We discuss the need for cultural adaptation specific to the context of use and point to several benefits as well as pitfalls of DMHTs for research and healthcare provision. Nonetheless, to circumvent technology-driven solutionism, the development and implementation of DMHTs require a holistic, multi-sectoral, and participatory approach.

Correction to "Apoferritin-Encapsulated Jerantinine A for Transferrin Receptor Targeting and Enhanced Selectivity in Breast Cancer Therapy".

[This corrects the article DOI: 10.1021/acsomega.2c00997.].

Methodological Characteristics and Feasibility of Ecological Momentary Assessment Studies in Psychosis: a Systematic Review and Meta-Analysis.

BACKGROUND: Ecological momentary assessment (EMA) involves completing multiple surveys over time in daily life, capturing in-the-moment experiences in real-world contexts. EMA use in psychosis studies has surged over several decades. To critically examine EMA use in psychosis research and assist future researchers in designing new EMA studies, this systematic review aimed to summarize the methodological approaches used for positive symptoms in psychosis populations and evaluate feasibility with a focus on completion rates. METHODS: A systematic review of PubMed, PsycINFO, MEDLINE, Web of Science, EBSCOhost, and Embase databases using search terms related to EMA and psychosis was conducted. Excluding duplicate samples, a meta-analysis was conducted of EMA survey completion rates and meta-regression to examine predictors of completion. RESULTS: Sixty-eight studies were included in the review. Characteristics and reporting of EMA methodologies were variable across studies. The meta-mean EMA survey completion computed from the 39 unique studies that reported a mean completion rate was 67.15% (95% CI = 62.3, 71.9), with an average of 86.25% of the sample meeting a one-third EMA completion criterion. No significant predictors of completion were found in the meta-regression. A variety of EMA items were used to measure psychotic experiences, of which few were validated. CONCLUSIONS: EMA methods have been widely applied in psychosis studies using a range of protocols. Completion rates are high, providing clear evidence of feasibility in psychosis populations. Recommendations for reporting in future studies are provided.

The Phenomenology of Visual and Other Nonauditory Hallucinations in Affective and Nonaffective Psychosis: A Mixed Methods Analysis.

ABSTRACT: Nonauditory hallucinations in psychosis have not received as much attention relative to voice-hearing experiences. The current paper aimed to document the characteristics of these hallucinations in affective and nonaffective psychosis. Participants were selected from a primary voice-hearing sample, who had endorsed visual, tactile, or olfactory hallucinations ( N = 55-75). A comprehensive, semistructured phenomenological interview was conducted, followed by mixed methods analysis. Visual hallucinations typically occurred daily, for a few minutes per episode, within one's direct line of sight; persons and/or animals were most commonly seen, with low controllability and mostly engendered negative affective outcomes. Tactile and olfactory hallucinations were endorsed by 46.8% and 39.0% of participants, respectively. The affective psychosis group ( n = 33) reported significantly greater awareness and lower functional impairment relative to the nonaffective psychosis group ( n = 42). Qualitative thematic analysis revealed notable themes and subthemes across each of these hallucinations modes. Further phenomenological investigations should be carried out in lesser known hallucination modalities, assisted by the development of appropriate assessment tools.

Multi-modal hallucinations across diagnoses: What relationships do they have with voice-related distress?

BACKGROUND: Research into hallucinatory experiences has focused primarily upon hallucinations within the auditory modality, to the relative neglect of other modalities. Furthermore, the exploration of auditory hallucinations (or 'voices') has focused primarily upon the experiences of people with a diagnosis of psychosis. The presence of multi-modal hallucinations may have implications across diagnoses for levels of distress, formulation and the targeting of psychological interventions. METHODS: This study presents a cross-sectional analysis of observational data from the PREFER survey (N = 335). Linear regression was used to explore the relationships between voice-related distress and the presence, number, type and timing of multi-modal hallucinations. RESULTS: Simple relationships were not found between distress and the presence of hallucinations in visual, tactile, olfactory or gustatory modalities, or in the number of modalities experienced. When considering the degree to which another modality hallucination was experienced simultaneously with voices, there was some evidence that the degree of co-occurrence with visual hallucinations was predictive of distress. CONCLUSIONS: The co-occurrence of voices with visual hallucinations may be associated with relatively greater distress, but not consistently, and the association between multimodal hallucinations and clinical impact appear complex and potentially variable from individual to individual. Further study of associated variables such as perceived voice power may further illuminate these relationships.

Intersections of phenomenology, voice beliefs and distress in bipolar disorder: a comparison with schizophrenia.

BACKGROUND: Auditory verbal hallucinations (AVH), or voice-hearing, can be a prominent symptom during fluctuating mood states in bipolar disorder (BD). AIMS: The current study aimed to: (i) compare AVH-related distress in BD relative to schizophrenia (SCZ), (ii) examine correlations between phenomenology and voice beliefs across each group, and (iii) explore how voice beliefs may uniquely contribute to distress in BD and SCZ. METHOD: Participants were recruited from two international sites in Australia (BD=31; SCZ=50) and the UK (BD=17). Basic demographic-clinical information was collected, and mood symptoms were assessed. To document AVH characteristics, a 4-factor model of the Psychotic Symptoms Rating Scale and the Beliefs about Voices Questionnaire-Revised were used. Statistical analyses consisted of group-wise comparisons, Pearson's correlations and multiple hierarchical regressions. RESULTS: It was found that AVH-related distress was not significantly higher in BD than SCZ, but those with BD made significantly more internal attributions for their voices. In the BD group, AVH-related distress was significantly positively correlated with malevolence, omnipotence and resistance, However, only resistance, alongside mania and depressive symptoms, significantly contributed to AVH-related distress in BD. DISCUSSION: Our findings have several clinical implications, including identification of voice resistance as a potential therapeutic target to prioritise in BD. Factoring in the influence of mood symptoms on AVH-related distress as well as adopting more acceptance-oriented therapies may also be of benefit.

Health Service Utilisation of People Living with Psychosis: Validity of Self-report Compared with Administrative Data in a Randomised Controlled Trial.

BACKGROUND: Self-reported service use informs resource utilisation and cost estimates, though its validity for use within economic evaluations is uncertain. OBJECTIVE: The aim of this study is to assess agreement in health resource-use measurement between self-reported and administrative data across different resource categories, over time and between different recall periods by subgroups among Australians living with psychosis. METHODS: Data were obtained for 104 participants with psychotic disorders from a randomised controlled trial. Agreement between self-reported resource-use questionnaires and administrative data on community-based services and medication use was assessed through estimating differences of group mean number of visits and medications used and intraclass correlation coefficients (ICC) over multiple time periods. RESULTS: ICC showed moderate agreement across most time periods for general practitioners, psychiatrists and mental health medications. No clear trends were discernible over time, between varying lengths of recall periods nor across participant subgroups. CONCLUSION: Despite poor agreement, when measuring visits to psychologists and other health professionals, small overall differences in group mean number of visits indicate that self-reported data may still be valid for use in economic evaluations in people living with psychosis.

Predictive value of functional disability scales among stroke survivors: A long-term mortality evaluation in a Brazilian stroke cohort.

OBJECTIVE: To assess the influence of two functional scales- Modified Rankin Scale (m-RS) and Modified Katz Index (m-Katz Index) on long-term mortality in a stroke cohort. MATERIAL AND METHODS: Among 760 stroke survivors (median age: 66 (IQR:56-75), 56.4 % women) m-Katz Index and m-RS scales applied at 1 and 6 months after stroke, were investigated in relation to 12-years of all-cause mortality. Kaplan-Meier survival curves were computed, and time-varying covariate Cox regression models were fitted to calculate hazard ratios (HRs) with 95 % confidence intervals (CIs) in all sample and by sex. The prognostic ability of the fitted models was computed for each model by six different measures. RESULTS: After 12 years of follow-up (median survival time: 7.3 years), 311 participants died. Overall survival curves show lower survival rates among those with the highest levels of disability/dependence (all log-rank p-values <0.0001). These findings were confirmed in all regression models for both sexes, particularly in men who had higher levels of dependence on Activities of Daily Living (ADLs) by m-Katz Index and severe disability by m-RS and presented the highest HR of dying (HR: 3.34 (95 %CI: 2.27-4.92) and HR: 4.94 (95 % CI: 3.15-7.75), respectively). CONCLUSIONS: Both the m-Katz Index and the m-RS scale were good predictors of long-term mortality, which is of importance for guiding the functional rehabilitation of stroke patients. Besides, high levels of disability and dependence were implicated with high mortality risks, regardless of sex.

Optimizing Excipient Properties to Prevent Aggregation in Biopharmaceutical Formulations.

Excipients are included within protein biotherapeutic solution formulations to improve colloidal and conformational stability but are generally not designed for the specific purpose of preventing aggregation and improving cryoprotection in solution. In this work, we have explored the relationship between the structure and antiaggregation activity of excipients by utilizing coarse-grained molecular dynamics modeling of protein-excipient interaction. We have studied human serum albumin as a model protein, and we report the interaction of 41 excipients (polysorbates, fatty alcohol ethoxylates, fatty acid ethoxylates, phospholipids, glucosides, amino acids, and others) in terms of the reduction of solvent accessible surface area of aggregation-prone regions, proposed as a mechanism of aggregation prevention. Polyoxyethylene sorbitan had the greatest degree of interaction with aggregation-prone regions, decreasing the solvent accessible surface area of APRs by 20.7 nm2 (40.1%). Physicochemical descriptors generated by Mordred are employed to probe the structure-property relationship using partial least-squares regression. A leave-one-out cross-validated model had a root-mean-square error of prediction of 4.1 nm2 and a mean relative error of prediction of 0.077. Generally, longer molecules with a large number of alcohol-terminated PEG units tended to interact more, with qualitatively different protein interactions, wrapping around the protein. Shorter or less ethoxylated compounds tend to form hemimicellar clusters at the protein surface. We propose that an improved design would feature many short chains of 5 to 10 PEG units in many distinct branches and at least some hydrophobic content in the form of medium-length or greater aliphatic chains (i.e., six or more carbon atoms). The combination of molecular dynamics simulation and quantitative modeling is an important first step in an all-purpose protein-independent model for the computer-aided design of stabilizing excipients.

A qualitative exploration of the lived experiences of Body Dysmorphic Disorder.

Body Dysmorphic Disorder (BDD) is characterized by an intense preoccupation with one or more perceived "defects" in physical appearance. Despite the distress and impairment associated with BDD, the disorder remains understudied and poorly understood. In particular, there are limited studies available which give voice to those with firsthand experiences of the disorder. A qualitative approach was employed to study lived experience of BDD. In-depth semi-structured interviews were conducted with 12 participants with BDD, aiming to understand their subjective experiences of the disorder. Data was analyzed using Interpretative Phenomenological Analysis (IPA). The results identified three superordinate themes; (1) consumed by the disorder, (2) the flawed self, and (3) intolerance of uncertainty about appearance. The qualitative findings of this study are discussed in relation to current conceptual understandings of BDD, including the cognitive behavioral model.

Usability of a Community-Based Dementia Resource Website: Mixed Methods Study.

BACKGROUND: Many individuals living with dementia want to live in their own homes for as long as possible. To do so, they frequently require assistance with activities of daily living, which is often provided by friends and relatives acting as informal care partners. In Canada, many informal care partners are currently overworked and overwhelmed. Although community-based dementia-inclusive resources are available to support them, care partners often struggle to find them. Dementia613.ca was created to make the process of finding community dementia-inclusive resources simpler and more straightforward by bringing them together in one eHealth website. OBJECTIVE: The objective of our study was to determine if dementia613.ca is meeting the goal of connecting care partners and persons living with dementia to dementia-inclusive resources in their community. METHODS: A review and assessment of the website was conducted using 3 evaluation methods: web analytics, questionnaires, and task analysis. Google Analytics was used to collect data related to website use over a 9-month period. Data on site content and user characteristics were collected. Furthermore, 2 web-based self-administered questionnaires were developed: one intended for care partners and persons living with dementia, and the other intended for businesses and organizations interested in serving persons living with dementia. Both gathered data on user characteristics and included standard questions used in website evaluations. Responses were collected over a 6-month period. Scenarios, tasks, and questions were developed for the moderated, remote, and task-analysis sessions. These tasks and questions determined how effectively persons living with dementia and their care partners can use dementia613.ca. Overall, 5 sessions were held with persons experiencing moderate cognitive decline and with care partners of persons living with dementia. RESULTS: This evaluation showed that the idea behind dementia613.ca is strong and appeals to persons living with dementia, their care partners, and the businesses and organizations serving this market. Participants indicated that it is a useful community resource that meets a previously unfulfilled need in the area, and highlighted the benefits of bringing community resources together on 1 website. In our questionnaire, >60% (19/29, 66%) of people living with dementia and their care partners and 70% (7/10) of businesses and organizations agreed that the website made it easier to find relevant dementia-inclusive resources. There is room for improvement; participants indicated that the navigation and search features could be further developed. CONCLUSIONS: We believe that the dementia613.ca model could be used to inspire and guide the creation of dementia resource websites in other regions in Ontario and beyond. The framework behind it is generalizable and could be replicated to help care partners and persons living with dementia find local resources more easily.

Whole-genome sequencing reveals a complex African population demographic history and signatures of local adaptation.

We conduct high coverage (>30×) whole-genome sequencing of 180 individuals from 12 indigenous African populations. We identify millions of unreported variants, many predicted to be functionally important. We observe that the ancestors of southern African San and central African rainforest hunter-gatherers (RHG) diverged from other populations >200 kya and maintained a large effective population size. We observe evidence for ancient population structure in Africa and for multiple introgression events from "ghost" populations with highly diverged genetic lineages. Although currently geographically isolated, we observe evidence for gene flow between eastern and southern Khoesan-speaking hunter-gatherer populations lasting until ∼12 kya. We identify signatures of local adaptation for traits related to skin color, immune response, height, and metabolic processes. We identify a positively selected variant in the lightly pigmented San that influences pigmentation in vitro by regulating the enhancer activity and gene expression of PDPK1.

Accuracy and Precision of a Novel Photogate System to Measure Toe Clearance on Stairs.

Background: Toe clearance on stairs is typically measured using optoelectronic systems, though these are often constrained to the laboratory, due to their complex setups. Here we measured stair toe clearance through a novel prototype photogate setup and compared this to optoelectronic measurements. Methods: Twelve participants (age 22 ± 3 years) completed 25 stair ascent trials, each on a seven-step staircase. Toe clearance over the fifth step edge was measured using Vicon and the photogates. Twenty-two photogates were created in rows through laser diodes and phototransistors. The height of the lowest photogate broken at step-edge crossing was used to determine photogate toe clearance. A limits of agreement analysis and Pearson's correlation coefficient compared the accuracy, precision and relationship between systems. Results: We found a mean difference of -1.5 mm (accuracy) between the two measurement systems, with upper and lower limits (precision) of 10.7 mm and -13.8 mm, respectively. A strong positive correlation was also found (r = 70, n = 12, p = 0.009) between the systems. Discussion: The results suggest that photogates could be an option for measuring real-world stair toe clearances, where optoelectronic systems are not routinely used. Improvements to the design and measurement factors may help to improve the precision of the photogates.

Risk of progression from pre-diabetes to type 2 diabetes in a large UK adult cohort.

AIMS: People with pre-diabetes are at high risk of progressing to type 2 diabetes. This progression is not well characterised by ethnicity, deprivation and age, which we describe in a large cohort of individuals with pre-diabetes. METHODS: A retrospective cohort study with The Health Improvement Network (THIN) database was conducted. Patients aged 18 years and over and diagnosed with pre-diabetes [HbA1c 42 mmol/mol (6.0%) to 48 mmol/mol (6.5%) were included]. Cox proportional hazards regression was used to calculate adjusted hazard rate ratios (aHR) for the risk of progression from pre-diabetes to type 2 diabetes for each of the exposure categories [ethnicity, deprivation (Townsend), age and body mass index (BMI)] separately. RESULTS: Of the baseline population with pre-diabetes (n = 397,853), South Asian (aHR 1.31; 95% CI 1.26-1.37) or Mixed-Race individuals (aHR 1.22; 95% CI 1.11-1.33) had an increased risk of progression to type 2 diabetes compared with those of white European ethnicity. Likewise, deprivation (aHR 1.17; 95% CI 1.14-1.20; most vs. least deprived) was associated with an increased risk of progression. Both younger (aHR 0.63; 95% CI 0.58-0.69; 18 to <30 years) and older individuals (aHR 0.85; 95% CI 0.84-0.87; ≥65 years) had a slower risk of progression from pre-diabetes to type 2 diabetes, than middle-aged (40 to <65 years) individuals. CONCLUSIONS: South Asian or Mixed-Race individuals and people with social deprivation had an increased risk of progression from pre-diabetes to type 2 diabetes. Clinicians need to recognise the differing risk across their patient populations to implement appropriate prevention strategies.

End-to-end learning of multiple sequence alignments with differentiable Smith-Waterman.

MOTIVATION: Multiple sequence alignments (MSAs) of homologous sequences contain information on structural and functional constraints and their evolutionary histories. Despite their importance for many downstream tasks, such as structure prediction, MSA generation is often treated as a separate pre-processing step, without any guidance from the application it will be used for. RESULTS: Here, we implement a smooth and differentiable version of the Smith-Waterman pairwise alignment algorithm that enables jointly learning an MSA and a downstream machine learning system in an end-to-end fashion. To demonstrate its utility, we introduce SMURF (Smooth Markov Unaligned Random Field), a new method that jointly learns an alignment and the parameters of a Markov Random Field for unsupervised contact prediction. We find that SMURF learns MSAs that mildly improve contact prediction on a diverse set of protein and RNA families. As a proof of concept, we demonstrate that by connecting our differentiable alignment module to AlphaFold2 and maximizing predicted confidence, we can learn MSAs that improve structure predictions over the initial MSAs. Interestingly, the alignments that improve AlphaFold predictions are self-inconsistent and can be viewed as adversarial. This work highlights the potential of differentiable dynamic programming to improve neural network pipelines that rely on an alignment and the potential dangers of optimizing predictions of protein sequences with methods that are not fully understood. AVAILABILITY AND IMPLEMENTATION: Our code and examples are available at: https://github.com/spetti/SMURF. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Using a digital personal recovery resource in routine mental health practice: feasibility, acceptability and outcomes.

BACKGROUND: Digital technologies enable the dissemination of multimedia resources to support adults with serious mental illness in their self-management and personal recovery. However, delivery needs to accommodate engagement and accessibility challenges. AIMS: We examined how a digital resource, designed for mental health workers and consumers to use together in session, would be used in routine practice. METHODS: Thirty consumers and their workers participated. The web-based resource, Self-Management And Recovery Technology (SMART), was available to use within and between sessions, for a 6-month period. Workers initiated in-session use where relevant. Feasibility was explored via uptake and usage data; and acceptability and impact via questionnaires. A pre-post design assessed recovery outcomes for consumers and relationship outcomes for consumers and workers. RESULTS: In participating mental health practitioner-consumer dyads, consumers gave strong acceptability ratings, and reported improved working relationships. However, the resource was typically used in one-third or fewer appointments, with consumers expressing a desire for greater in-session use. Improvements in self-rated personal recovery were not observed, possibly contributed to by low usage. CONCLUSIONS: In-session use was found helpful by consumers but may be constrained by other demands in mental health care delivery: collaborative use may require dedicated staff time or more formal implementation.

Functional genomics of OCTN2 variants informs protein-specific variant effect predictor for Carnitine Transporter Deficiency.

Genetic variants in SLC22A5, encoding the membrane carnitine transporter OCTN2, cause the rare metabolic disorder Carnitine Transporter Deficiency (CTD). CTD is potentially lethal but actionable if detected early, with confirmatory diagnosis involving sequencing of SLC22A5. Interpretation of missense variants of uncertain significance (VUSs) is a major challenge. In this study, we sought to characterize the largest set to date (n = 150) of OCTN2 variants identified in diverse ancestral populations, with the goals of furthering our understanding of the mechanisms leading to OCTN2 loss-of-function (LOF) and creating a protein-specific variant effect prediction model for OCTN2 function. Uptake assays with 14C-carnitine revealed that 105 variants (70%) significantly reduced transport of carnitine compared to wild-type OCTN2, and 37 variants (25%) severely reduced function to less than 20%. All ancestral populations harbored LOF variants; 62% of green fluorescent protein (GFP)-tagged variants impaired OCTN2 localization to the plasma membrane of human embryonic kidney (HEK293T) cells, and subcellular localization significantly associated with function, revealing a major LOF mechanism of interest for CTD. With these data, we trained a model to classify variants as functional (>20% function) or LOF (<20% function). Our model outperformed existing state-of-the-art methods as evaluated by multiple performance metrics, with mean area under the receiver operating characteristic curve (AUROC) of 0.895 ± 0.025. In summary, in this study we generated a rich dataset of OCTN2 variant function and localization, revealed important disease-causing mechanisms, and improved upon machine learning-based prediction of OCTN2 variant function to aid in variant interpretation in the diagnosis and treatment of CTD.