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.

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.

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.

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.

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.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. 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.

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.

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.

Two new species of dactylogyrids (Monogenea: Dactylogyridae) infecting the gill filaments of fishes in the southern Peruvian Amazon.

Two new dactylogyrid species were found infecting the gill filaments of two freshwater fishes collected in the Amazon River basin around Madre de Dios, Peru, namely, Demidospermus wilveri n. sp. from Loricaria sp. (Siluriformes: Loricariidae), and Notozothecium agusti n. sp. from Brycon amazonicus (Spix & Agassiz) (Characiformes: Bryconidae). Demidospermus wilveri n. sp. is characterized by having the following combination of characteristics: (1) a male copulatory organ (MCO) with 1½ rings and a spoon-shaped distal end, (2) an accessory piece with expanded distal end, (3) dorsal and ventral bars with broadly V-shaped and expanded ends, and (4) hooks similar in size. Notozothecium agusti n. sp. differs from its ten congeners by the following combination of characteristics: (1) a coiled MCO with 1½ rings and a sinuous accessory piece with kidney-shaped distal end, (2) an rod-shaped and straight dorsal bar, (3) and anchors with robust superficial roots. Demidospermus wilveri n. sp. represents the thirty-second species in the genus, the eighth from Peru and the fifth parasitising a loricariid catfish from the Peruvian Amazon. Notozothecium agusti n. sp. is the second species of the genus described in Peru and the first species infecting a bryconid host.

CYP2D6 Phenotype Influences Pharmacokinetic Parameters of Venlafaxine: Results from a Population Pharmacokinetic Model in Older Adults with Depression.

In this study, we aimed to improve upon a published population pharmacokinetic (PK) model for venlafaxine (VEN) in the treatment of depression in older adults, then investigate whether CYP2D6 metabolizer status affected model-estimated PK parameters of VEN and its active metabolite O-desmethylvenlafaxine. The model included 325 participants from a clinical trial in which older adults with depression were treated with open-label VEN (maximum 300 mg/day) for 12 weeks and plasma levels of VEN and O-desmethylvenlafaxine were assessed at weeks 4 and 12. We fitted a nonlinear mixed-effect PK model using NONMEM to estimate PK parameters for VEN and O-desmethylvenlafaxine adjusted for CYP2D6 metabolizer status and age. At both lower doses (up to 150 mg/day) and higher doses (up to 300 mg/day), CYP2D6 metabolizers impacted PK model-estimated VEN clearance, VEN exposure, and active moiety (VEN + O-desmethylvenlafaxine) exposure. Specifically, compared with CYP2D6 normal metabolizers, (i) CYP2D6 ultra-rapid metabolizers had higher VEN clearance; (ii) CYP2D6 intermediate metabolizers had lower VEN clearance; (iii) CYP2D6 poor metabolizers had lower VEN clearance, higher VEN exposure, and higher active moiety exposure. Overall, our study showed that including a pharmacogenetic factor in a population PK model could increase model fit, and this improved model demonstrated how CYP2D6 metabolizer status affected VEN-related PK parameters, highlighting the importance of genetic factors in personalized medicine.

Correction: Evaluating the Clinical Feasibility of an Artificial Intelligence-Powered, Web-Based Clinical Decision Support System for the Treatment of Depression in Adults: Longitudinal Feasibility Study.

[This corrects the article DOI: 10.2196/31862.].

Physical Artificial Arterial Pulse System for Development and Testing of PPG-Based Sensors.

A physical system to generate a PPG-mimicking signal was designed and validated using everyday low-cost components to aid in medical sensor design. The pulse waveform was created by driving a working fluid into a silicone tube and changing the pressure within it. The corresponding waveform mimics a PPG signal through an artery, is adaptable, and repeatable. The working fluid is interchangeable allowing for change of blood analyte concentrations for development and testing of PPG-based sensors. The system was validated by black ink water compared to water and air compared to water testing to confirm optical transparency of the tube. The produced PPG signal, pulse rate and pressure change were compared to that seen in subjects. Optical transparency for 660 nm - 1550 nm wavelengths of light was validated with the signal, pulse rate and total compliance matching subject data. Thus, the system can mimic arterial pulses, creating a valid PPG signal that can be detected by PPG-based sensors.Clinical Relevance- Provides a low-cost, adaptable, physical PPG signal generator for research and development of optical medical sensor technologies.

Investigation of Narrow-band NIR LED Spectral Response Towards a Non-invasive Glucose Sensor.

Spectroscopy is utilised extensively in medical sensing technology. Typically, hand-held spectroscopy equipment uses miniature narrow-band light emitting diodes (LEDs) and photodiodes to emit and detect light, respectively. Photodiodes typically absorb light across a wide spectra so measurements can be corrupted by surrounding light. LEDs in the visible spectrum have a narrower spectral response and can be used in place of a traditional photodiode. However, the absorption characteristics of near infrared (NIR) spectrum LEDs is unknown. A discrete, low-cost spectrophotometer was designed to assess spectral response for 8 narrow band NIR LEDs. The normalised and raw spectral response determined the optimum detector for 1050 nm - 1300 nm is the 1450 nm LED, and the optimum detector for 1450 nm - 1650 nm emissions is the 1650 nm LED.Clinical relevance - Understanding the spectral response of narrow-band LEDs in the NIR spectrum will aid development of NIR hand-held spectroscopy medical devices.

Development and Pilot Testing of the Tremor Retrainer Smartphone Application for the Treatment of Functional Tremor.

Background: Functional tremor is a common and disabling condition with limited treatment options. A prior proof-of-concept pilot study sought to translate entrainment, a key diagnostic feature of functional tremor, into a treatment strategy. Methods: The Tremor Retrainer smartphone application was developed though a collaboration between neurologists and a software engineer. It analyzes data from smartphone accelerometers to measure baseline tremor frequency, then provides auditory cues at a lower frequency for the patient to match with flexion-extension movements at the wrist. The application provides continuous biofeedback on performance via a visual gauge. Patients with functional tremor underwent a one-week treatment protocol with the Tremor Retrainer application and provided feedback on usability and acceptability to guide software programming. Results: Three pediatric patients completed the one-week protocol and their feedback was used to modify the software. All patients felt that the application was easy to use and could be effective in treating functional tremor. Discussion: The Tremor Retrainer smartphone application uses auditory cues and a visual gauge to provide a personalized and widely accessible entrainment-based intervention. Pilot testing in pediatric patients provided key feedback for application design. Highlights: The Tremor Retrainer smartphone application modulates functional tremor frequency by providing pulsed auditory cues for a patient to match with wrist flexion-extension movements while receiving continuous biofeedback via a visual gauge. This adaption of the diagnostic sign of entrainment has potential as an accessible treatment for patients with functional tremor.

Evolution of pharmacogenomic services and implementation of a multi-state pharmacogenomics clinic across a large rural healthcare system.

Introduction: Pharmacogenomics (PGx) aims to maximize drug benefits while minimizing risk of toxicity. Although PGx has proven beneficial in many settings, clinical uptake lags. Lack of clinician confidence and limited availability of PGx testing can deter patients from completing PGx testing. A few novel PGx clinic models have been described as a way to incorporate PGx testing into the standard of care. Background: A PGx clinic was implemented to fill an identified gap in provider availability, confidence, and utilization of PGx across our health system. Through a joint pharmacist and Advanced Practice Provider (APP) collaborative clinic, patients received counseling and PGx medication recommendations both before and after PGx testing. The clinic serves patients both in-person and virtually across four states in the upper Midwest. Results: The majority of patients seen in the PGx clinic during the early months were clinician referred (77%, n = 102) with the remainder being self-referred. Patients were, on average, taking two medications with Clinical Pharmacogenetics Implementation Consortium guidelines. Visits were split almost equally between in-person and virtual visits. Conclusion: Herein, we describe the successful implementation of an interdisciplinary PGx clinic to further enhance our PGx program. Throughout the implementation of the PGx clinic we have learned valuable lessons that may be of interest to other implementors. Clinicians were actively engaged in clinic referrals and early adoption of telemedicine was key to the clinic's early successes.