Algorithm Validation for Quantifying ActiGraph™ Physical Activity Metrics in Individuals with Chronic Low Back Pain and Healthy Controls.

Assessing physical activity is important in the treatment of chronic conditions, including chronic low back pain (cLBP). ActiGraph™, a widely used physical activity monitor, collects raw acceleration data, and processes these data through proprietary algorithms to produce physical activity measures. The purpose of this study was to replicate ActiGraph™ algorithms in MATLAB and test the validity of this method with both healthy controls and participants with cLBP. MATLAB code was developed to replicate ActiGraph™'s activity counts and step counts algorithms, to sum the activity counts into counts per minute (CPM), and categorize each minute into activity intensity cut points. A free-living validation was performed where 24 individuals, 12 cLBP and 12 healthy, wore an ActiGraph™ GT9X on their non-dominant hip for up to seven days. The raw acceleration data were processed in both ActiLife™ (v6), ActiGraph™'s data analysis software platform, and through MATLAB (2022a). Percent errors between methods for all 24 participants, as well as separated by cLBP and healthy, were all less than 2%. ActiGraph™ algorithms were replicated and validated for both populations, based on minimal error differences between ActiLife™ and MATLAB, allowing researchers to analyze data from any accelerometer in a manner comparable to ActiLife™.

A porcine model of thoracic aortic aneurysms created with a retrievable drug infusion stent graft mirrors human aneurysm pathophysiology.

Objective: Aneurysm pathophysiology remains poorly understood, in part from the disparity of murine models with human physiology and the requirement for invasive aortic exposure to apply agents used to create aneurysm models. A retrievable drug infusion stent graft (RDIS) was developed to isolate the aortic wall intraluminally for drug exposure. We hypothesized that an RDIS could deliver aneurysm-promoting enzymes to create a porcine model of thoracic aneurysms without major surgical exposure. Methods: Retrievable nitinol stent graft frames were designed with an isolated drug delivery chamber, covered with polytetrafluoroethylene, and connected to a delivery wire with a drug infusion catheter installed to the outer chamber. Institutional Animal Care and Use Committee-approved Yorkshire pigs (n = 5) underwent percutaneous access of the femoral artery, baseline aortogram and stent placement in the thoracic aorta followed by 30-minute exposure to a cocktail of elastase, collagenase, and trypsin. After aspiration of excess drug, stent retrieval, and femoral artery repair, animals were recovered, with angiograms at 1 and 4 weeks followed by explant. Histological analysis, in situ zymography, and multiplex cytokine assays were performed. Results: The RDIS isolated a segment of anterior aorta angiographically, while the center lumen preserved distal perfusion during drug treatment (baseline femoral mean arterial pressure, 70 ± 14 mm Hg; after RDIS, 75 ± 12; P = .55). Endovascular induction of thoracic aneurysms did not require prior mechanical injury and animals revealed no evidence of toxicity. Within 1 week, significant aneurysmal growth was observed in all five animals (1.4 ± 0.1 cm baseline to 2.9 ± 0.7 cm; P = .002) and only within the treated region of the aorta. Aneurysms persisted out to 4 weeks. Aneurysm histology demonstrated loss of elastin and collagen that was otherwise preserved in untreated aorta. Proinflammatory cytokines and increased matrix metalloproteinase activity were increased significantly within the aneurysm. Conclusions: An RDIS achieves isolated drug delivery while preserving distal perfusion to achieve an endovascular porcine model of thoracic aneurysms without major surgery. This model may have value for surgical training, device testing, and to better understand aneurysm pathogenesis. Most important, although the RDIS was used to simulate aortic pathology, this tool offers intriguing horizons for focused therapeutic drug delivery directly to aneurysms and, more broadly, focused locoregional drug delivery to vessels and vascular beds.

Poor Sleep is Common in Treatment-Resistant Late-life Depression and Associated With Poorer Antidepressant Response: Findings From the OPTIMUM Clinical Trial.

BACKGROUND: Adults with treatment-resistant late-life depression (TRLLD) have high rates of sleep problems; however, little is known about the occurrence and change in sleep during pharmacotherapy of TRLLD. This analysis examined: (1) the occurrence of insufficient sleep among adults with TRLLD; (2) how sleep changed during pharmacotherapy; and (3) whether treatment outcomes differed among participants with persistent insufficient sleep, worsened sleep, improved sleep, or persistent sufficient sleep. METHODS: Secondary analysis of data from 634 participants age 60+ years in the OPTIMUM clinical trial for TRLLD. Sleep was assessed using the sleep item from the Montgomery-Asberg Depression Rating Scale at the beginning (week-0) and end (week-10) of treatment. The analyses examined whether treatment outcomes differed among participants with persistent insufficient sleep, worsened sleep, improved sleep, or persistent sufficient sleep during depression treatment. RESULTS: About half (51%, n = 323) of participants reported insufficient sleep at baseline. Both persistent insufficient sleep (25%, n = 158) and worsened sleep (10%, n = 62) during treatment were associated with antidepressant nonresponse. Participants who maintained sufficient sleep (26%, n = 164) or who improved their sleep (n = 25%, n = 158) were three times more likely to experience a depression response than those with persistent insufficient sleep or worsened sleep. CONCLUSION: Insufficient sleep is common in TRLLD and it is associated with poorer treatment response to antidepressants.

Design, manufacture, and control of a low-cost positive airway pressure device.

Current positive airway pressure devices cost NZ$800-$2500, posing a financial barrier for the estimated 1 billion individuals worldwide with sleep apnea and those researching respiratory diseases. Increasing diagnoses and research interest in the area necessitate a low-cost, easily accessible alternative. Thus, the mePAP, a high-quality, multipurpose, low-cost (∼NZ$250) positive airway pressure device, was designed and prototyped specifically for respiratory disease research, particularly for sleep apnea. The mePAP allows user customization and provides researchers with an affordable tool for testing positive airway pressure algorithms. Unlike typical commercial devices, the mePAP offers adaptability with open-source data collection and easily modifiable software for implementing and analysing different control and diagnostic algorithms. It features three control modes: constant; bilevel; and automatic; and provides pressures from 4 to 20 cmH2O, controlled via a phone app through Wi-Fi, with a mini-sensor added at the mask for increased accuracy. Validation tests showed the mePAP's performance is comparable to a gold-standard Fisher & Paykel device, with extremely similar output pressures. The mePAP's low cost enhances accessibility and equity, allowing researchers to test ventilation algorithms for sleep apnea and other respiratory conditions, with all data openly available for analysis. Its adaptability and multiple applications increase its usability and usefulness across various research and clinical settings.

Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2D6, ADRB1, ADRB2, ADRA2C, GRK4, and GRK5 Genotypes and Beta-Blocker Therapy.

Beta-blockers are widely used medications for a variety of indications, including heart failure, myocardial infarction, cardiac arrhythmias, and hypertension. Genetic variability in pharmacokinetic (e.g., CYP2D6) and pharmacodynamic (e.g., ADRB1, ADRB2, ADRA2C, GRK4, GRK5) genes have been studied in relation to beta-blocker exposure and response. We searched and summarized the strength of the evidence linking beta-blocker exposure and response with the six genes listed above. The level of evidence was high for associations between CYP2D6 genetic variation and both metoprolol exposure and heart rate response. Evidence indicates that CYP2D6 poor metabolizers experience clinically significant greater exposure and lower heart rate in response to metoprolol compared with those who are not poor metabolizers. Therefore, we provide therapeutic recommendations regarding genetically predicted CYP2D6 metabolizer status and metoprolol therapy. However, there was insufficient evidence to make therapeutic recommendations for CYP2D6 and other beta-blockers or for any beta-blocker and the other five genes evaluated (updates at www.cpicpgx.org).

CD39 Is Expressed on Functional Effector and Tissue-resident Memory CD8+ T Cells.

The ecto-ATPase CD39 is expressed on exhausted CD8+ T cells in chronic viral infection and has been proposed as a marker of tumor-specific CD8+ T cells in cancer, but the role of CD39 in an effector and memory T cell response has not been clearly defined. We report that CD39 is expressed on Ag-specific CD8+ short-lived effector cells, while it's co-ectoenzyme, CD73, is found on memory precursor effector cells (MPECs) in vivo. Inhibition of CD39 enzymatic activity during in vitro T cell priming enhances MPEC differentiation in vivo after transfer and infection. The enriched MPEC phenotype is associated with enhanced tissue resident memory T cell (TRM cell) establishment in the brain and salivary gland following an acute intranasal viral infection, suggesting that CD39 ATPase activity plays a role in memory CD8+ T cell differentiation. We also show that CD39 is expressed on human and murine TRM cells across several nonlymphoid tissues and melanoma, whereas CD73 is expressed on both circulating and resident memory subsets in mice. In contrast to exhausted CD39+ T cells in chronic infection, CD39+ TRM cells are fully functional when stimulated ex vivo with cognate Ag, further expanding the identity of CD39 beyond a T cell exhaustion marker.

Mapping MAVE data for use in human genomics applications.

The large-scale experimental measures of variant functional assays submitted to MaveDB have the potential to provide key information for resolving variants of uncertain significance, but the reporting of results relative to assayed sequence hinders their downstream utility. The Atlas of Variant Effects Alliance mapped multiplexed assays of variant effect data to human reference sequences, creating a robust set of machine-readable homology mappings. This method processed approximately 2.5 million protein and genomic variants in MaveDB, successfully mapping 98.61% of examined variants and disseminating data to resources such as the UCSC Genome Browser and Ensembl Variant Effect Predictor.

Relationship between Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) total scores in older adults with major depressive disorder: An analysis of the OPTIMUM clinical trial.

BACKGROUND: The Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) are commonly used scales to measure depression severity in older adults. METHODS: We utilized data from the Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM) clinical trial to produce conversion tables relating PHQ-9 and MADRS total scores. We split the sample into training (N = 555) and validation samples (N = 187). Equipercentile linking was performed on the training sample to produce conversion tables for PHQ-9 and MADRS. We compared the original and estimated scores in the validation sample with Bland-Altman analysis. We compared the depression severity level using the original and estimated scores with Chi-square tests. RESULTS: The Bland-Altman analysis confirmed that differences between the original and estimated scores for at least 95 % of the sample fit within 1.96 standard deviations of the mean difference. Chi-square tests showed a significant difference in the proportion of participants at each depression severity category determined using the original and estimated scores. LIMITATIONS: The conversion tables should be used with caution when comparing depression severity at the individual level. CONCLUSIONS: Our conversion tables relating PHQ-9 and MADRS scores can be used to compare treatment outcomes using aggregate data in studies that only used one of these scales.

Alcohol and substance use in older adults with treatment-resistant depression.

INTRODUCTION: Alcohol and substance use are increasing in older adults, many of whom have depression, and treatment in this context may be more hazardous. We assessed alcohol and other substance use patterns in older adults with treatment-resistant depression (TRD). We examined patient characteristics associated with higher alcohol consumption and examined the moderating effect of alcohol on the association between clinical variables and falls during antidepressant treatment. METHODS: This secondary and exploratory analysis used baseline clinical data and data on falls during treatment from a large randomized antidepressant trial in older adults with TRD (the OPTIMUM trial). Multivariable ordinal logistic regression was used to identify variables associated with higher alcohol use. An interaction model was used to evaluate the moderating effect of alcohol on falls during treatment. RESULTS: Of 687 participants, 51% acknowledged using alcohol: 10% were hazardous drinkers (AUDIT-10 score ≥5) and 41% were low-risk drinkers (score 1-4). Benzodiazepine use was seen in 24% of all participants and in 21% of drinkers. Use of other substances (mostly cannabis) was associated with alcohol consumption: it was seen in 5%, 9%, and 15% of abstainers, low-risk drinkers, and hazardous drinkers, respectively. Unexpectedly, use of other substances predicted increased risk of falls during antidepressant treatment only in abstainers. CONCLUSIONS: One-half of older adults with TRD in this study acknowledged using alcohol. Use of alcohol concurrent with benzodiazepine and other substances was common. Risks-such as falls-of using alcohol and other substances during antidepressant treatment needs further study.

Alarm functions of PD-1+ brain resident memory T cells.

Resident memory T cells (T RM ) have been described in barrier tissues as having a 'sensing and alarm' function where, upon sensing cognate antigen, they alarm the surrounding tissue and orchestrate local recruitment and activation of immune cells. In the immunologically unique and tightly restricted CNS, it remains unclear if and how brain T RM , which express the inhibitory receptor PD-1, alarm the surrounding tissue during antigen re-encounter. Here, we reveal that T RM are sufficient to drive the rapid remodeling of the brain immune landscape through activation of microglia, DCs, NK cells, and B cells, expansion of Tregs, and recruitment of macrophages and monocytic dendritic cells. Moreover, we report that while PD-1 restrains granzyme B expression by reactivated brain T RM , it has no effect on cytotoxicity or downstream alarm responses. We conclude that T RM are sufficient to trigger rapid immune activation and recruitment in the CNS and may have an unappreciated role in driving neuroinflammation.

Rationale and design for a pragmatic randomized trial to assess gene-based prescribing for SSRIs in the treatment of depression.

Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, CYP2D6 and CYP2C19. However, the effectiveness of prospectively using pharmacogenetic variants to select or dose SSRIs for depression is uncertain in routine clinical practice. The objective of this prospective, multicenter, pragmatic randomized controlled trial is to determine the effectiveness of genotype-guided selection and dosing of antidepressants on control of depression in participants who are 8 years or older with ≥3 months of depressive symptoms who require new or revised therapy. Those randomized to the intervention arm undergo pharmacogenetic testing at baseline and receive a pharmacy consult and/or automated clinical decision support intervention based on an actionable phenotype, while those randomized to the control arm have pharmacogenetic testing at the end of 6-months. In both groups, depression and drug tolerability outcomes are assessed at baseline, 1 month, 3 months (primary), and 6 months. The primary end point is defined by change in Patient-Reported Outcomes Measurement Information System (PROMIS) Depression score assessed at 3 months versus baseline. Secondary end points include change inpatient health questionnaire (PHQ-8) measure of depression severity, remission rates defined by PROMIS score < 16, medication adherence, and medication side effects. The primary analysis will compare the PROMIS score difference between trial arms among those with an actionable CYP2D6 or CYP2C19 genetic result or a CYP2D6 drug-drug interaction. The trial has completed accrual of 1461 participants, of which 562 were found to have an actionable phenotype to date, and follow-up will be complete in April of 2024.

Empirical clustering to identify individuals for whom insomnia is more closely related to suicidal ideation.

BACKGROUND: Although the effect sizes are modest, insomnia is consistently associated with suicidal thoughts and behaviors. Subgroup analyses can efficiently identify for whom insomnia is most relevant to suicidal ideation. To improve clinical case identification, the present study sought to identify subclusters of lifetime suicidal ideators for whom insomnia was most closely related to current suicidal ideation. METHODS: Data on N = 4750 lifetime suicidal ideators were extracted from the Military Suicide Research Consortium's Common Data Elements. Data on sociodemographic characteristics, severity and history of suicidal thoughts and behaviors, and related clinical characteristics were clustered by unsupervised machine learning algorithms. Robust Poisson regression estimated cluster by insomnia associations with current suicidal ideation. RESULTS: Three clusters were identified: a modest symptom severity cluster (N = 1757, 37.0 %), an elevated severity cluster (N = 1444 30.4 %), and a high severity cluster (N = 1549 32.6 %). In Cluster 1, insomnia was associated with current suicidal ideation (PRR 1.29 [1.13-1.46]) and remained significant after adjusting for sociodemographic and clinical covariates. In Cluster 2, insomnia was associated with current suicidal ideation (PRR 1.14 [1.01-1.30]), but not after adjusting for sociodemographic and clinical covariates. In Cluster 3, insomnia was associated with current suicidal ideation (PRR 1.12 [1.03-1.21]) and remained significant after adjusting for sociodemographic covariates, but not clinical covariates. LIMITATIONS: Cross-sectional design, lack of diagnostic data, non-representative sample. CONCLUSION: Insomnia appears more closely related to current suicidal ideation among modest severity individuals than other subgroups. Future work should use prospective designs and more comprehensive risk factor measures to confirm these findings.

Risk for Suicide and Homicide Peaks at Night: Findings From the National Violent Death Reporting System, 35 States, 2003-2017.

Objective: The Mind after Midnight hypothesis proposes that nocturnal wakefulness increases the risk for dysregulated behaviors. Prior studies highlight a greater risk for suicide at night after adjusting for population wakefulness. How this risk varies hour to hour, differs across subgroups, or applies to other behaviors is unknown.Methods: Data on 78,647 suicides and 50,526 homicides from the National Violent Death Reporting System were combined with population wakefulness data for 2003-2017 from the American Time Use Survey. Hourly incident risk ratios (IRRs) were estimated after adjusting for population wakefulness. Two-way analysis of variances identified significant time-by-subgroup interactions that were quantified in post hoc analyses.Results: Suicide counts peaked at 12:00 PM, while homicide counts peaked at 10:00- 11:00 PM. Adjusting for demographics and population wakefulness revealed a 5-fold greater risk for suicide at 3:00 AM (aIRR: 5.20 [4.74-5.70]) and an 8-fold greater risk for homicide at 2:00 AM (aIRR: 8.04 [6.35-10.2]). Hourly risk for suicide varied by age, ethnicity, blood alcohol level, and current partner conflict. Hourly risk for homicide varied by sex and blood alcohol level.Conclusions: Risk for suicide and homicide is greater at night than expected based on the number of people awake at that time. Nighttime risk was greater among young adults and those intoxicated with alcohol, but not among those with a history of suicidal ideation or attempts. Further research should evaluate mechanisms of risk and confirm these findings at an individual level.

CD39 is expressed on functional effector and tissue resident memory CD8+ T cells.

The ecto-ATPase CD39 is expressed on exhausted CD8+ T cells in chronic viral infection and has been proposed as a marker of tumor-specific CD8+ T cells in cancer, but the role of CD39 in an effector and memory T cell response has not been clearly defined. We report that CD39 is expressed on antigen-specific CD8+ short-lived effector cells (SLECs), while it's co-ecto-enzyme, CD73, is found on memory precursor effector cells (MPEC) in vivo . Inhibition of CD39 enzymatic activity during in vitro T cell priming enhances MPEC differentiation in vivo after transfer and infection. The enriched MPEC phenotype is associated with enhanced tissue resident memory (T RM ) establishment in the brain and salivary gland following an acute intranasal viral infection, suggesting that CD39 ATPase activity plays a role in memory CD8+ T cell differentiation. We also show that CD39 is expressed on human and murine T RM across several non-lymphoid tissues and melanoma, while CD73 is expressed on both circulating and resident memory subsets in mice. In contrast to exhausted CD39+ T cells in chronic infection, CD39+ T RM are fully functional when stimulated ex vivo with cognate antigen. This work further expands the identity of CD39 beyond a T cell exhaustion marker.

Implementation of CYP2C19 and CYP2D6 genotyping to guide antidepressant use in a large rural health system.

PURPOSE: We describe the implementation and ongoing maintenance of CYP2C19 and CYP2D6 focused pharmacogenetic (PGx) testing to guide antidepressant and antianxiety medication prescriptions in a large rural, nonprofit health system. SUMMARY: Depression and anxiety are common psychiatric conditions. Sanford Health implemented PGx testing for metabolism of cytochrome P450 (CYP) isozymes 2C19 and 2D6 in 2014 to inform prescribing for multiple medications, including antidepressant and antianxiety therapies. As guidelines, genotype to phenotype translation, panel offerings, and other resources are updated, we adapt our approach. We make educational and informational materials available to providers and patients. Pharmacogenomic clinical pharmacists review PGx results with discrete values and provide guidance documentation in the electronic medical record. A robust clinical decision support system is in place to provide interruptive alerts, noninterruptive alerts, and genomic indicators. A referral-based interdisciplinary clinic is also available to provide in-depth education to patients regarding PGx results and implications. Additionally, partnering with our health plan has expanded access to PGx testing for patients with anxiety or depression. CONCLUSION: The implementation and maintenance of Sanford Health's PGx program to guide antidepressant and antianxiety medication use continues to evolve and requires a multipronged approach relying on both human and informatics-based resources.

Sex differences in plasma proteomic markers in late-life depression.

Previous studies have shown significant sex-specific differences in major depressive disorder (MDD) in multiple biological parameters. Most studies focused on young and middle-aged adults, and there is a paucity of information about sex-specific biological differences in older adults with depression (aka, late-life depression (LLD)). To address this gap, this study aimed to evaluate sex-specific biological abnormalities in a large group of individuals with LLD using an untargeted proteomic analysis. We quantified 344 plasma proteins using a multiplex assay in 430 individuals with LLD and 140 healthy comparisons (HC) (age range between 60 and 85 years old for both groups). Sixty-six signaling proteins were differentially expressed in LLD (both sexes). Thirty-three proteins were uniquely associated with LLD in females, while six proteins were uniquely associated with LLD in males. The main biological processes affected by these proteins in females were related to immunoinflammatory control. In contrast, despite the smaller number of associated proteins, males showed dysregulations in a broader range of biological pathways, including immune regulation pathways, cell cycle control, and metabolic control. Sex has a significant impact on biomarker changes in LLD. Despite some overlap in differentially expressed biomarkers, males and females show different patterns of biomarkers changes, and males with LLD exhibit abnormalities in a larger set of biological processes compared to females. Our findings can provide novel targets for sex-specific interventions in LLD.

Short-lived natural radionuclides as tracers in hydrogeological studies - A review.

Fundamental approaches to the study of groundwater rely on investigating the spatial and temporal distribution of stable and radioactive isotopes and other anthropogenic compounds in natural waterbodies. The most often used tracers for estimating groundwater flow paths and residence times, groundwater/surface water interaction as well as tracing chemical (contamination) sources include stable isotopes of water (δ 18O and δ 2H), radiocarbon (14C; t1/2 = 5730 a), tritium (3H; t1/2 = 12.43 a) as well as unreactive fluorine-containing gases (e.g., chlorofluorocarbons CCl3F or CFC-11; CCl2F3 or CFC-12; C2Cl3F3 or CFC-113; and SF6). While gas tracers are usually referred to as transient tracers and are appropriate for investigating modern flow systems, the isotopic tracers are often used to investigated paleo or regional flow systems. Stable isotopes of water can also be used to investigate groundwater/surface water interactions. Another, thus far been less frequently used group of groundwater tracers, are cosmo- and geo- genic short-lived radioisotopes. These isotopes are uniquely suited for studying a wide range of groundwater problems that have short time scales including high aquifer vulnerability to quantitative and qualitative impacts and groundwater discharge to surface waters. Here, we discuss and compare the applications of radio­sulphur (35S; half-life t1/2 = 87 d), radio­beryllium (7Be; t1/2 = 53 d), radio­phosphorus (32/33P; combined t1/2 = 33 d), natural tritium (3H; t1/2 = 12.43 a), radon (222Rn; t1/2 = 3.8 d) and short-lived radium (224/223Ra; combined t1/2 = 5.2 d). The paper discusses the principles of the individual tracer methods, focusing on the isotopes' input functions or values, on sampling techniques, and on methods of analyses. Case studies that applied a combined use of the tracers are referred to for readers who wish to learn more about the application of the so far underused cosmo- and geo- genic radioisotopes as aquatic tracers.