Growing pains with kratom: experiences discussed in subreddits contrast with satisfaction expressed in surveys.

Background: "Kratom" refers to an array of bioactive products derived from Mitragyna speciosa, a tree indigenous to Southeast Asia. Most kratom consumers report analgesic and stimulatory effects, and common reasons for use are to address mental and physical health needs, manage pain, and to reduce use of other substances. Natural-history studies and survey studies suggest that many kratom consumers perceive benefits from those uses, but such studies are unlikely to capture the full range of kratom-use experiences. Methods: We collected text data from Reddit posts from 2020-2022 to qualitatively examine conceptualizations, motivations, effects, and consequences associated with kratom use among people posting to social media. Reddit posts mentioning kratom were studied using template thematic analysis, which included collecting descriptions of kratom product types and use practices. Network analyses of coded themes was performed to examine independent relationships among themes, and between themes and product types. Results: Codes were applied to 329 of the 370 posts that comprised the final sample; 134 posts contained kratom product descriptions. As Reddit accounts were functionally anonymous, demographic estimates were untenable. Themes included kratom physical dependence (tolerance, withdrawal, or use to avoid withdrawal), perceived addiction (net detrimental effects on functioning), and quitting. Extract products were positively associated with reports of perceived addiction, dependence, and experiences of quitting kratom. Many used kratom for energy and self-treatment of pain, fatigue, and problems associated with opioid and alcohol; they perceived these uses as effective. Consumers expressed frustrations about product inconsistencies and lack of product information. Conclusion: As in previous studies, kratom was deemed helpful for some and a hindrance to others, but we also found evidence of notable negative experiences with kratom products that have not been well documented in surveys. Daily kratom use may produce mild-moderate physical dependence, with greater severity being possibly more common with concentrated extracts; however, there are currently no human laboratory studies of concentrated kratom extracts. Such studies, and detailed kratom product information, are needed to help inform consumer decision-making.

Genetic diversity of 1,845 rhesus macaques improves genetic variation interpretation and identifies disease models.

Understanding and treating human diseases require valid animal models. Leveraging the genetic diversity in rhesus macaque populations across eight primate centers in the United States, we conduct targeted-sequencing on 1845 individuals for 374 genes linked to inherited human retinal and neurodevelopmental diseases. We identify over 47,000 single nucleotide variants, a substantial proportion of which are shared with human populations. By combining rhesus and human allele frequencies with established variant prediction methods, we develop a machine learning-based score that outperforms established methods in predicting missense variant pathogenicity. Remarkably, we find a marked number of loss-of-function variants and putative deleterious variants, which may lead to the development of rhesus disease models. Through phenotyping of macaques carrying a pathogenic OPA1:p.A8S variant, we identify a genetic model of autosomal dominant optic atrophy. Finally, we present a public website housing variant and genotype data from over two thousand rhesus macaques.

Validation of the Approach-Avoidance Temperament Questionnaire in Individuals with Anxiety and Depression.

The Approach-Avoidance Temperament Questionnaire (ATQ) is a well-established measure assessing heightened sensitivity and reactivity to reward/positive stimuli (approach temperament) and to punishment/negative stimuli (avoidance temperament). These basic dimensions of personality are believed to be important for understanding the etiology and maintenance of anxiety and depressive disorders. Despite the ATQ's potential utility in clinical psychology research, its psychometric properties and factor structure have yet to be examined in a psychiatric sample. The aims of the present study were to 1) conduct confirmatory factor analysis to replicate the ATQ's factor structure in individuals diagnosed with an anxiety or depressive disorder (N = 244), 2) assess internal consistency and convergent and divergent validity, and 3) explore differences in approach and avoidance temperaments in individuals with versus without a diagnosis of anxiety or depression. Results confirmed the original two-factor structure of the ATQ in a clinical sample, with approach and avoidance temperaments representing orthogonal dimensions. The measure demonstrated strong internal consistency, convergent and divergent validity, and predictive validity. Individuals with anxiety and depression scored higher on avoidance items and lower on approach items compared to those without clinical diagnoses. This study supports the use of the ATQ in clinical populations.

Kratom addiction per DSM-5 SUD criteria, and kratom physical dependence: Insights from dosing amount versus frequency.

BACKGROUND: Kratom products are widely used in the United States, with inadequate understanding of how dosing amounts/frequencies relate to outcomes. METHODS: Between July-November 2022, we enrolled 395 active US adult kratom consumers into a remote study with a baseline survey. We examined self-reported typical dose amounts and frequencies across people and product types, and their associations with outcomes: multiple regression was used to examine whether amounts and frequencies (doses/day) were associated with acute effects, withdrawal symptoms, scores on the Subjective Opioid Withdrawal Scale (SOWS), and addiction (operationalized as DSM-5-based symptoms of kratom-use disorder, KUD). RESULTS: Participants were 54.9% male, aged 38.1 on average, and 81.3% White. Mean length of kratom use was 5.7 years. Most (95.9%) reported regularly using whole-leaf kratom products; 16 (4.1%) reported regular extract use. SOWS scores were mild to moderate on average (13.5, SD 11.9). KUD symptom counts were mostly in the mild/moderate range (80.7%). Withdrawal and KUD symptoms were more closely associated with dose frequency than dose amount. Men reported more acute effects, withdrawal symptoms with cessation, and KUD symptoms than women. CONCLUSIONS: Greater dose amount and frequency were systematically related to the number of withdrawal symptoms upon cessation and to KUD symptoms; the relationship was stronger for dose frequency than amount. Men may have more acute effects and more withdrawal and KUD symptoms than women. Although kratom may be used nonproblematically by some consumers, physical dependence (tolerance, withdrawal, or use to avoid withdrawal) and KUD become more likely with increasing dose frequency.

The CARD8 inflammasome dictates HIV/SIV pathogenesis and disease progression.

While CD4+ T cell depletion is key to disease progression in people living with HIV and SIV-infected macaques, the mechanisms underlying this depletion remain incompletely understood, with most cell death involving uninfected cells. In contrast, SIV infection of "natural" hosts such as sooty mangabeys does not cause CD4+ depletion and AIDS despite high-level viremia. Here, we report that the CARD8 inflammasome is activated immediately after HIV entry by the viral protease encapsulated in incoming virions. Sensing of HIV protease activity by CARD8 leads to rapid pyroptosis of quiescent cells without productive infection, while T cell activation abolishes CARD8 function and increases permissiveness to infection. In humanized mice reconstituted with CARD8-deficient cells, CD4+ depletion is delayed despite high viremia. Finally, we discovered loss-of-function mutations in CARD8 from "natural hosts," which may explain the peculiarly non-pathogenic nature of these infections. Our study suggests that CARD8 drives CD4+ T cell depletion during pathogenic HIV/SIV infections.

Post-stroke Cognition is Associated with Stroke Survivor Quality of Life and Caregiver Outcomes: A Systematic Review and Meta-analysis.

Disability arising from post-stroke cognitive impairment is a likely contributor to the poor quality of life (QoL) stroke survivors and their carers frequently experience, but this has not been summarily quantified. A systematic literature review and meta-analysis was completed examining the association between general and domain-specific post-stroke cognitive functioning and adult stroke survivor QoL, caregiver QoL, and caregiver burden. Five databases were systematically searched, and eligibility for inclusion, data extraction, and study quality were evaluated by two reviewers using a standardised protocol. Effects sizes (r) were estimated using a random effects model. Thirty-eight studies were identified, generating a sample of 7365 stroke survivors (median age 63.02 years, range 25-93) followed for 3 to 132 months post-stroke. Overall cognition (all domains combined) demonstrated a significant small to medium association with QoL, r = 0.23 (95% CI 0.18-0.28), p < 0.001. The cognitive domains of speed, attention, visuospatial, memory, and executive skills, but not language, also demonstrated a significant relationship with QoL. Regarding caregiver outcomes, 15 studies were identified resulting in a sample of 2421 caregivers (median age 58.12 years, range 18-82) followed for 3 to 84 months post-stroke. Stroke survivor overall cognitive ability again demonstrated a significant small to medium association with caregiver outcomes (QoL and burden combined), r = 0.17 (95% CI 0.10-0.24), p < 0.001. In conclusion, lower post-stroke cognitive performance is associated with significant reductions in stroke survivor QoL and poorer caregiver outcomes. Cognitive assessment is recommended early to identify those at risk and implement timely interventions to support both stroke survivors and their caregivers.

Effects of kratom on driving: Results from a cross-sectional survey, ecological momentary assessment, and pilot simulated driving Study.

OBJECTIVES: Despite widespread kratom use, there is a lack of knowledge regarding its effects on driving. We evaluated the self-reported driving behaviors of kratom consumers and assessed their simulated-driving performance after self-administering kratom products. METHODS: We present results from: 1) a remote, national study of US adults who regularly use kratom, and 2) an in-person substudy from which we re-recruited participants. In the national study (N = 357), participants completed a detailed survey and a 15-day ecological momentary assessment (EMA) that monitored naturalistic kratom use. For the remote study, outcomes were self-reported general and risky driving behaviors, perceived impairment, and driving confidence following kratom administration. For the in-person substudy, 10 adults consumed their typical kratom products and their driving performance on a high-fidelity driving simulator pre- and post-kratom administration was evaluated. RESULTS: Over 90% of participants surveyed self-reported driving under the influence of kratom. Most reported low rates of risky driving behavior and expressed high confidence in their driving ability after taking kratom. This was consistent with EMA findings: participants reported feeling confident in their driving ability and perceived little impairment within 15-180 min after using kratom. In the in-person substudy, there were no significant changes in simulated driving performance after taking kratom. CONCLUSIONS: Using kratom before driving appears routine, however, self-reported and simulated driving findings suggest kratom effects at self-selected doses among regular kratom consumers do not produce significant changes in subjective and objective measures of driving impairment. Research is needed to objectively characterize kratom's impact on driving in regular and infrequent consumers.

Responses to a "Typical" Morning Dose of Kratom in People Who Use Kratom Regularly: A Direct-Observation Study.

INTRODUCTION: Use of kratom has outpaced systematic study of its effects, with most studies reliant on retrospective self-report. METHODS: We aimed to assess acute effects following kratom use in adults who use regularly, and quantify alkaloids in the products, urine, and plasma. Between July and November 2022, 10 adults came to our clinic and orally self-administered their typical kratom dose; blinding procedures were not used. Physiological measures included blood pressure, respiratory rate, heart rate, pulse oximetry, temperature, and pupil diameter. Subjective outcomes included Subjective Opioid Withdrawal Scale, Addiction Research Center Inventory, and Drug Effects Questionnaire. Psychomotor performance was also assessed. RESULTS: Participants were 6 men and 4 women, mean age 41.2 years. Nine were non-Hispanic White; 1 was biracial. They had used kratom for 6.6 years (SD, 3.8 years) on average (2.0-14.1). Sessions were 190.89 minutes on average (SD, 15.10 minutes). Mean session dose was 5.16 g (median, 4.38 g; range, 1.1-10.9 g) leaf powder. Relative to baseline, physiological changes were minor. However, pupil diameter decreased (right, b = -0.70, P < 0.01; left, b = -0.73, P < 0.01) 40-80 minutes postdose and remained below baseline >160 minutes. Subjective Opioid Withdrawal Scale pre-dosing was mild (5.5 ± 3.3) and decreased postdose (b = [-4.0, -2.9], P < 0.01). Drug Effects Questionnaire "feeling effects" increased to 40/100 (SD, 30.5) within 40 minutes and remained above baseline 80 to 120 minutes (b = 19.0, P = 0.04), peaking at 72.7/100; 6 participants rated euphoria as mild on the Addiction Research Center Inventory Morphine-Benzedrine-scale. Psychomotor performance did not reliably improve or deteriorate postdosing. CONCLUSIONS: Among regular consumers, we found few clinically significant differences pre- and post-kratom dosing. Alkaloidal contents in products were within expected ranges.

Cannabis use may attenuate neurocognitive performance deficits resulting from methamphetamine use disorder.

OBJECTIVE: Methamphetamine and cannabis are two widely used, and frequently co-used, substances with possibly opposing effects on the central nervous system. Evidence of neurocognitive deficits related to use is robust for methamphetamine and mixed for cannabis. Findings regarding their combined use are inconclusive. We aimed to compare neurocognitive performance in people with lifetime cannabis or methamphetamine use disorder diagnoses, or both, relative to people without substance use disorders. METHOD: 423 (71.9% male, aged 44.6 ± 14.2 years) participants, stratified by presence or absence of lifetime methamphetamine (M-/M+) and/or cannabis (C-/C+) DSM-IV abuse/dependence, completed a comprehensive neuropsychological, substance use, and psychiatric assessment. Neurocognitive domain T-scores and impairment rates were examined using multiple linear and binomial regression, respectively, controlling for covariates that may impact cognition. RESULTS: Globally, M+C+ performed worse than M-C- but better than M+C-. M+C+ outperformed M+C- on measures of verbal fluency, information processing speed, learning, memory, and working memory. M-C+ did not display lower performance than M-C- globally or on any domain measures, and M-C+ even performed better than M-C- on measures of learning, memory, and working memory. CONCLUSIONS: Our findings are consistent with prior work showing that methamphetamine use confers risk for worse neurocognitive outcomes, and that cannabis use does not appear to exacerbate and may even reduce this risk. People with a history of cannabis use disorders performed similarly to our nonsubstance using comparison group and outperformed them in some domains. These findings warrant further investigation as to whether cannabis use may ameliorate methamphetamine neurotoxicity.

Novel methods for the remote investigation of emerging substances: Application to kratom.

The botanical product commonly called "kratom" is still relatively novel to the United States. Like other natural products marketed as supplements, kratom is highly variable, both in terms of the alkaloids naturally occurring in kratom leaves and in terms of processing and formulation. Kratom products sold in the United States are not well-characterized, nor are daily use patterns among regular users. Surveys and case reports have comprised most of the literature on kratom use among humans. To advance our understanding of real-world kratom use, we developed a protocol for the remote study of regular kratom-using adults in the United States. Our study had three aspects implemented in one pool of participants nationwide: an in-depth online survey, 15 days of ecological momentary assessment (EMA) via smartphone app, and the collection and assay of the kratom products used by participants during EMA. Here, we describe these methods, which can be used to investigate myriad drugs or supplements. Recruiting, screening, and data collection occurred between July 20, 2022 and October 18, 2022. During this time, we demonstrated that these methods, while challenging from a logistical and staffing standpoint, are feasible and can produce high-quality data. The study achieved high rates of enrollment, compliance, and completion. Substances that are emerging or novel, but still largely legal, can be productively studied via nationwide EMA combined with assays of shipped product samples from participants. We discuss challenges and lessons learned so other investigators can adapt these methods. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Activity space during treatment with medication for opioid use disorder: Relationships with personality, mood, and drug use.

INTRODUCTION: Activity space in people with substance use disorders (SUDs) has been assessed for theoretical reasons and for detection/prevention of relapse. In this observational study, we relate passively obtained activity space measures to mental states and behaviors relevant to the success of treatment for opioid use disorder. Our long-term goal is to use such data to assess risk in real time and to recognize when SUD patients might benefit from a just-in-time intervention. METHODS: We used GPS data from 238 urban residents in the first 16 weeks of stabilization on medication for opioid use disorder to test preregistered hypotheses about activity space (distance traveled, number of locations, time spent moving, and psychosocial-hazard levels of neighborhoods where participants spent time) in relation to certain static variables (personality, mood propensities) and time-varying treatment-relevant behaviors such as craving and use of opioids and cocaine. RESULTS: The most consistent findings were that 1) mobility decreased over the course of the study; 2) neuroticism was associated with overall lower mobility; 3) trait-like positive mood (averaged from momentary ratings) was associated with higher mobility; 4) participants who used cocaine more frequently had lower mobility; 5) early in treatment, participants spent less time moving (i.e., were more sedentary) on days when they were craving. Some of these findings were in the expected direction (i.e., the ones involving neuroticism and positive mood), and some were opposite to the expected direction (i.e., we expected cocaine use to be associated with higher mobility); others (e.g., changes in mobility over time or in relation to craving) involved nondirectional hypotheses. CONCLUSIONS: Real-time information that patients actively provide is valuable for assessing their current state, but providing this information can be burdensome. The current results indicate that certain static or passively obtained data (personality variables and GPS-derived mobility information) are relevant to time-varying, treatment-relevant mental states and drug-related behavior, and therefore might be useful when incorporated into algorithms for detecting need for intervention in real time. Further research should assess how population-specific these relationships are, and how these passive measures can best be combined with low temporal-density, actively-provided data to obtain valid, reliable assessments with minimal burden.

Whole Genome Analysis of SNV and Indel Polymorphism in Common Marmosets (Callithrix jacchus).

The common marmoset (Callithrix jacchus) is one of the most widely used nonhuman primate models of human disease. Owing to limitations in sequencing technology, early genome assemblies of this species using short-read sequencing suffered from gaps. In addition, the genetic diversity of the species has not yet been adequately explored. Using long-read genome sequencing and expert annotation, we generated a high-quality genome resource creating a 2.898 Gb marmoset genome in which most of the euchromatin portion is assembled contiguously (contig N50 = 25.23 Mbp, scaffold N50 = 98.2 Mbp). We then performed whole genome sequencing on 84 marmosets sampling the genetic diversity from several marmoset research centers. We identified a total of 19.1 million single nucleotide variants (SNVs), of which 11.9 million can be reliably mapped to orthologous locations in the human genome. We also observed 2.8 million small insertion/deletion variants. This dataset includes an average of 5.4 million SNVs per marmoset individual and a total of 74,088 missense variants in protein-coding genes. Of the 4956 variants orthologous to human ClinVar SNVs (present in the same annotated gene and with the same functional consequence in marmoset and human), 27 have a clinical significance of pathogenic and/or likely pathogenic. This important marmoset genomic resource will help guide genetic analyses of natural variation, the discovery of spontaneous functional variation relevant to human disease models, and the development of genetically engineered marmoset disease models.

Combined Cognitive and Psychological Interventions Improve Meaningful Outcomes after Acquired Brain Injury: A Systematic Review and Meta-Analysis.

Interventions addressing cognitive and emotional difficulties after acquired brain injury (ABI) often focus on specific impairments in cognition or mood. These interventions can be effective at addressing their specific target, but do not routinely translate to improved activity and participation outcomes. Approaches that combine cognitive and psychological rehabilitation are increasingly popular; however, to date, there have been no systematic evaluations of their efficacy. We conducted a systematic review of five databases, searching for randomised controlled trials of adults with diagnoses of non-progressive ABI at least 1-month post injury, in receipt of interventions that combined cognitive and psychological components compared to any control. Screening and data extraction were evaluated by two independent reviewers using a standardised protocol. Effect sizes were calculated using Hedge's g and estimated using a random-effects model. Risk of bias was assessed using the PEDro-P rating system, and quality of evidence evaluated using the grading of recommendation, assessment, development and evaluation (GRADE) approach. Thirteen studies were included in the meta-analysis (n = 684). There was an overall small-to-medium effect (g = 0.42) for combined interventions compared with controls, with gains maintained at 6-month follow-up. Improvements were observed at the level of impairment, activity, participation and quality of life. GRADE ratings and analyses investigating sensitivity, heterogeneity and publication bias indicated that these effects were robust. No a priori variables moderated these effects. Overall, this review provides strong evidence that combined cognitive and psychological interventions create meaningful change in the lives of people with ABI.

Complex Evolutionary History With Extensive Ancestral Gene Flow in an African Primate Radiation.

Understanding the drivers of speciation is fundamental in evolutionary biology, and recent studies highlight hybridization as an important evolutionary force. Using whole-genome sequencing data from 22 species of guenons (tribe Cercopithecini), one of the world's largest primate radiations, we show that rampant gene flow characterizes their evolutionary history and identify ancient hybridization across deeply divergent lineages that differ in ecology, morphology, and karyotypes. Some hybridization events resulted in mitochondrial introgression between distant lineages, likely facilitated by cointrogression of coadapted nuclear variants. Although the genomic landscapes of introgression were largely lineage specific, we found that genes with immune functions were overrepresented in introgressing regions, in line with adaptive introgression, whereas genes involved in pigmentation and morphology may contribute to reproductive isolation. In line with reports from other systems that hybridization might facilitate diversification, we find that some of the most species-rich guenon clades are of admixed origin. This study provides important insights into the prevalence, role, and outcomes of ancestral hybridization in a large mammalian radiation.

Artificial intelligence-enhanced epileptic seizure detection by wearables.

OBJECTIVE: Wrist- or ankle-worn devices are less intrusive than the widely used electroencephalographic (EEG) systems for monitoring epileptic seizures. Using custom-developed deep-learning seizure detection models, we demonstrate the detection of a broad range of seizure types by wearable signals. METHODS: Patients admitted to the epilepsy monitoring unit were enrolled and asked to wear wearable sensors on either wrists or ankles. We collected patients' electrodermal activity, accelerometry (ACC), and photoplethysmography, from which blood volume pulse (BVP) is derived. Board-certified epileptologists determined seizure onset, offset, and types using video and EEG recordings per the International League Against Epilepsy 2017 classification. We applied three neural network models-a convolutional neural network (CNN) and a CNN-long short-term memory (LSTM)-based generalized detection model and an autoencoder-based personalized detection model-to the raw time-series sensor data to detect seizures and utilized performance measures, including sensitivity, false positive rate (the number of false alarms divided by the total number of nonseizure segments), number of false alarms per day, and detection delay. We applied a 10-fold patientwise cross-validation scheme to the multisignal biosensor data and evaluated model performance on 28 seizure types. RESULTS: We analyzed 166 patients (47.6% female, median age = 10.0 years) and 900 seizures (13 254 h of sensor data) for 28 seizure types. With a CNN-LSTM-based seizure detection model, ACC, BVP, and their fusion performed better than chance; ACC and BVP data fusion reached the best detection performance of 83.9% sensitivity and 35.3% false positive rate. Nineteen of 28 seizure types could be detected by at least one data modality with area under receiver operating characteristic curve > .8 performance. SIGNIFICANCE: Results from this in-hospital study contribute to a paradigm shift in epilepsy care that entails noninvasive seizure detection, provides time-sensitive and accurate data on additional clinical seizure types, and proposes a novel combination of an out-of-the-box monitoring algorithm with an individualized person-oriented seizure detection approach.

Reply to Augello, P.A.; Wu, J. Comment on "Rogers et al. The Combined Effects of Cannabis, Methamphetamine, and HIV on Neurocognition. Viruses 2023, 15, 674".

We thank Augello and Wu [...].

Cognitive and Motor Therapy After Stroke Is Not Superior to Motor and Cognitive Therapy Alone to Improve Cognitive and Motor Outcomes: New Insights From a Meta-analysis.

OBJECTIVE: To evaluate whether cognitive and motor therapy (CMT) is more effective than no therapy, motor therapy, or cognitive therapy on motor and/or cognitive outcomes after stroke. Additionally, this study evaluates whether effects are lasting and which CMT approach is most effective. DATA SOURCES: AMED, EMBASE, MEDLINE/PubMed, and PsycINFO databases were searched in October 2022. STUDY SELECTION: Twenty-six studies fulfilled the inclusion criteria: randomized controlled trials published in peer-reviewed journals since 2010 that investigated adults with stroke, delivered CMT, and included at least 1 motor, cognitive, or cognitive-motor outcome. Two CMT approaches exist: CMT dual-task ("classical" dual-task where the secondary cognitive task has a distinct goal) and CMT integrated (where cognitive components of the task are integrated into the motor task). DATA EXTRACTION: Data on study design, participant characteristics, interventions, outcome measures (cognitive/motor/cognitive-motor), results and statistical analysis were extracted. Multilevel random effects meta-analysis was conducted. DATA SYNTHESIS: CMT demonstrated positive effects compared with no therapy on motor outcomes (g=0.49; 95% confidence interval [CI], 0.10, 0.88) and cognitive-motor outcomes (g=0.29; 95% CI, 0.03, 0.54). CMT showed no significant effects compared with motor therapy on motor, cognitive, and cognitive-motor outcomes. A small positive effect of CMT compared with cognitive therapy on cognitive outcomes (g=0.18; 95% CI, 0.01, 0.36) was found. CMT demonstrated no follow-up effect compared with motor therapy (g=0.07; 95% CI, -0.04, 0.18). Comparison of CMT dual-task and integrated revealed no significant difference for motor (F1,141=0.80; P=.371) or cognitive outcomes (F1,72=0.61, P=.439). CONCLUSIONS: CMT was not superior to monotherapies in improved outcomes after stroke. CMT approaches were equally effective, suggesting that training that enlists a cognitive load per se may benefit outcomes.

Kratom's Emergence and Persistence Within the US Polydrug Epidemic.

Purpose of Review: Use of "kratom" products, derived from the bioactive botanical Mitragyna speciosa have increased amidst US polydrug use epidemics. Kratom alkaloids interact with opioid, serotonergic, adrenergic, and other receptors and regular users have described experiencing a wide range of effects. Some with polydrug use histories have reported using kratom as a substitute for other drugs or to nonmedically self-manage substance use disorder (SUD) symptoms. Data describing this remain scare and come from self-report. We review this literature describing kratom use as a drug substitute, or as a nonmedical "self-treatment" for attenuating dependence or SUD symptoms. Recent Findings: Kratom products have been documented as being used as a licit and illicit opioid substitute. Use to reduce alcohol or stimulant consumption is less well documented. Although prior and current polydrug use appear common among a some kratom users, it is unclear if co-use is contemporaneous or concomitant. Temporal order of use initiation is typically undocumented. Use for energy and recreation are also increasingly reported. Summary: Data on kratom consumption come primarily from self-report with significant limitations. Until controlled human laboratory studies have been conducted, we can presently only describe what is known about human kratom use based on self-report. Such data describe real-world kratom use, leaving unaddressed human abuse liability or therapeutic potential of kratom alkaloids. Clinicians should be mindful of use motivations among people with SUD histories, sensitively assessing use. The paucity of data highlights the urgent need to increase funding and research for understanding kratom's effects in humans.

Rare penetrant mutations confer severe risk of common diseases.

We examined 454,712 exomes for genes associated with a wide spectrum of complex traits and common diseases and observed that rare, penetrant mutations in genes implicated by genome-wide association studies confer ~10-fold larger effects than common variants in the same genes. Consequently, an individual at the phenotypic extreme and at the greatest risk for severe, early-onset disease is better identified by a few rare penetrant variants than by the collective action of many common variants with weak effects. By combining rare variants across phenotype-associated genes into a unified genetic risk model, we demonstrate superior portability across diverse global populations compared with common-variant polygenic risk scores, greatly improving the clinical utility of genetic-based risk prediction.

Genome-wide coancestry reveals details of ancient and recent male-driven reticulation in baboons.

Baboons (genus Papio) are a morphologically and behaviorally diverse clade of catarrhine monkeys that have experienced hybridization between phenotypically and genetically distinct phylogenetic species. We used high-coverage whole-genome sequences from 225 wild baboons representing 19 geographic localities to investigate population genomics and interspecies gene flow. Our analyses provide an expanded picture of evolutionary reticulation among species and reveal patterns of population structure within and among species, including differential admixture among conspecific populations. We describe the first example of a baboon population with a genetic composition that is derived from three distinct lineages. The results reveal processes, both ancient and recent, that produced the observed mismatch between phylogenetic relationships based on matrilineal, patrilineal, and biparental inheritance. We also identified several candidate genes that may contribute to species-specific phenotypes.