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.

More than an Amide Bioisostere: Discovery of 1,2,4-Triazole-containing Pyrazolo[1,5-a]pyrimidine Host CSNK2 Inhibitors for Combatting ß-Coronavirus Replication.

The pyrazolo[1,5-a]pyrimidine scaffold is a promising scaffold to develop potent and selective CSNK2 inhibitors with antiviral activity against ß-coronaviruses. Herein, we describe the discovery of a 1,2,4-triazole group to substitute a key amide group for CSNK2 binding present in many potent pyrazolo[1,5-a]pyrimidine inhibitors. Crystallographic evidence demonstrates that the 1,2,4-triazole replaces the amide in forming key hydrogen bonds with Lys68 and a water molecule buried in the ATP-binding pocket. This isosteric replacement improves potency and metabolic stability at a cost of solubility. Optimization for potency, solubility, and metabolic stability led to the discovery of the potent and selective CSNK2 inhibitor 53. Despite excellent in vitro metabolic stability, rapid decline in plasma concentration of 53 in vivo was observed and may be attributed to lung accumulation, although in vivo pharmacological effect was not observed. Further optimization of this novel chemotype may validate CSNK2 as an antiviral target in vivo.

Are older adults more prosocial than younger adults? A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Prosociality refers to voluntary behaviors that intend to benefit others. Most of the existing literature suggests that older adults tend to act more prosocially compared to younger adults, while some studies show that older adults might not be that prosocial under certain conditions. The current study aimed to summarize the mixed findings and quantify the age difference in prosociality by conducting a qualitative systematic review and a quantitative meta-analysis. RESEARCH DESIGN AND METHODS: Literature search was conducted based on five databases. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed and this review was registered at PROSPERO (CRD42022333373). RESULTS: Based on the qualitative synthesis of 51 studies, older adults (n = 109,911) were more prosocial than younger adults (n = 68,501). The meta-analysis of 46 studies further supported this age effect (Hedges' g = 0.31, 95% confidence interval [0.24, 0.37]), and this age effect might be moderated by the types of prosociality. We discovered a moderate age effect in sharing (Hedges' g = 0.53), but a non-significant age effect in helping (Hedges' g = 0.11), comforting (Hedges' g = -0.20), or mixed prosociality (Hedges' g = 0.15). Additionally, the age effect was only significant when older adults had higher socioeconomic status than younger adults. DISCUSSION AND IMPLICATIONS: Future research should develop more comprehensive measures of prosociality, examine more variables that influence aging and prosociality, and investigate the neural mechanism(s) of prosociality to achieve a thorough understanding of the age difference in prosociality.

Retinal cells derived from patients with DRAM2-dependent CORD21 dystrophy exhibit key lysosomal enzyme deficiency and lysosomal content accumulation.

Biallelic mutations in DRAM2 lead to an autosomal recessive cone-rod dystrophy known as CORD21, which typically presents between the third and sixth decades of life. Although DRAM2 localizes to the lysosomes of photoreceptor and retinal pigment epithelium (RPE) cells, its specific role in retinal degeneration has not been fully elucidated. In this study, we generated and characterized retinal organoids (ROs) and RPE cells from induced pluripotent stem cells (iPSCs) derived from two CORD21 patients. Our investigation revealed that CORD21-ROs and RPE cells exhibit abnormalities in lipid metabolism, defects in autophagic flux, accumulation of aberrant lysosomal content, and reduced lysosomal enzyme activity. We identified potential interactions of DRAM2 with vesicular trafficking proteins, suggesting its involvement in this cellular process. These findings collectively suggest that DRAM2 plays a crucial role in maintaining the integrity of photoreceptors and RPE cells by regulating lysosomal function, autophagy, and potentially vesicular trafficking.

Rejection resistant CD30.CAR-modified Epstein-Barr virus-specific T cells as an off-the-shelf platform for CD30+ lymphoma.

Off-the-shelf (OTS) adoptive T cell therapies have many benefits such as immediate availability, improved access and reduced cost, but face the major challenges of graft-vs-host disease (GVHD) and graft rejection, mediated by alloreactive T cells present in the graft and host, respectively. We have developed a platform for OTS T cell therapies by using Epstein-Bar virus (EBV)-specific T cells (EBVSTs) expressing a chimeric antigen receptor (CAR) targeting CD30. Allogeneic EBVSTs have not caused GVHD in several clinical trials, while the CD30.CAR, that is effective for the treatment of lymphoma, can also target alloreactive T cells that upregulate CD30 on activation. Although EBVSTs express high levels of CD30, they were protected from fratricide in cis, by the CD30.CAR. Hence, they could proliferate extensively and maintained function both through their native EBV-specific T cell receptor and the CD30.CAR. The CD30.CAR enabled EBVSTs to persist in co-cultures with naive and primed alloreactive T cells and eliminate activated natural killer cells that can also be alloreactive. In conclusion, we show that CD30.CAR EBVSTs have the potential to be an effective OTS therapy against CD30+ tumors and, if successful, could then be used as a platform to target other tumor antigens.

Does sleep link child maltreatment to depressive symptoms among incoming first-year college students?

Study Objectives: We examined whether sleep (i.e. quality, regularity, and duration) mediated associations between child maltreatment (CM) and depressive symptoms among emerging adults undergoing the major life transition of starting college. Methods: Students (N = 1400; 44% male; 48% non-Hispanic white, 20% non-Hispanic Asian, 15% Hispanic all races, 7% non-Hispanic black, and 10% non-Hispanic other races) completed daily sleep diaries for 9 weeks, followed by the Childhood Trauma Questionnaire-Short Form, Pittsburgh Sleep Quality Index, and the Center for Epidemiologic Studies Depression Scale (CES-D). DSD data were used to compute participants' Sleep Regularity Index and average 24-hour total sleep time. We used a nonparametric structural equation modeling bootstrap approach and full information maximum likelihood to account for missing data. In model 1, we controlled for sex and race and ethnicity. In model 2, we further adjusted for baseline CES-D scores. Results: The prevalence of self-reported moderate-to-severe CM was 22%. Small but significant indirect effects of CM on greater depressive symptoms through worse sleep quality (ß = 0.06, 95% CI = 0.04, 0.09) and lower sleep regularity (ß = 0.02, 95% CI = 0.005, 0.03) were observed in model 1. In model 2, only the indirect effect of sleep quality remained significant (ß = 0.03, 95% CI = 0.01, 0.06). Conclusions: Poorer sleep quality may partially account for associations between CM and depressive symptoms during the first semester of college. Including sleep as a target in student health interventions on college campuses may not only help buffer against poor mental health outcomes for students with CM, but also poor academic and socioeconomic outcomes long-term.

Association of Surgeon Self-Reported Gender and Surgical Outcomes in Current U.S. Practice.

OBJECTIVE: This study aimed to evaluate the association of surgeon self-reported gender on clinical outcomes in contemporary U.S. surgical practice. SUMMARY BACKGROUND DATA: Previous research has suggested that there are potentially improved surgical outcomes for female surgeons, yet the underlying causal path for this association remains unclear. METHODS: Using the Vizient® Clinical Database(2016-2021), 39 operations categorized by the CDC's National Healthcare Safety Network were analyzed. Surgeon self-reported gender was the primary exposure. The primary outcome was a composite of in-hospital death, complications, and/or 30-day readmission. Multivariable logistic regression and propensity score matching was used for risk adjustment. RESULTS: The analysis included 4,882,784 patients operated on by 11,955 female surgeons(33% of surgeons, performing 21% of procedures) and 23,799 male surgeons(67% of surgeons, performing 79% of procedures). Female surgeons were younger(45±9 vs. males-53±11 y;P<0.0001) and had lower operative volumes. Unadjusted incidence of the primary outcome was 13.6%(10.7%-female surgeons, 14.3%-male surgeons;P<0.0001). After propensity matching, the primary outcome occurred in 13.0% of patients(12.9%-female, 13.0%-male; OR[M vs. F]=1.02, 95%CI 1.01-1.03;P=.001), with female surgeons having small statistical associations with lower mortality and complication rates but not readmissions. Procedure-specific analyses revealed inconsistent or no surgeon-gender associations. CONCLUSIONS: In the largest analysis to date, surgeon self-reported gender had a small statistical, clinically marginal correlation with postoperative outcomes. The variation across surgical specialties and procedures suggests that the association with surgeon gender is unlikely causal for the observed differences in outcomes. Patients should be reassured that surgeon gender alone does not have a clinically meaningful impact on their outcome.

Effects of Implantable Cardioverter-Defibrillator Leads on the Tricuspid Valve and Right Ventricle: A Randomized Trial.

BACKGROUND: There are no randomized data to inform the extent to which transvenous cardiac leads cause tricuspid regurgitation (TR). OBJECTIVES: This study sought to determine the effect of a transvenous implantable cardioverter-defibrillator (TV-ICD) on TR severity, and secondarily, on right ventricular (RV) size and function. METHODS: We evaluated TR severity before and 6 months after implantable cardioverter-defibrillator insertion in a post hoc analysis of adults randomized to receive a transvenous (n = 252) or subcutaneous implantable cardioverter-defibrillator (S-ICD) (n = 251) device. TR and RV size and systolic function were assessed by echocardiographic images analyzed in a core laboratory. RESULTS: At baseline, at least mild TR was present in 30% of individuals. At 6 months, the proportion of participants with any TR in the TV-ICD group was 42% vs 19% in the S-ICD group (P < 0.001). The proportion with moderate or severe TR was 7% in the TV-ICD group vs 2% in the S-ICD group (P = 0.021). At 6 months, the OR of at least 1 grade worsening of TR in the TV-ICD group as compared with the S-ICD group was 7.2 (95% CI: 3.3-15.8; P < 0.001). There were no differences between groups with respect to RV size or systolic function. CONCLUSIONS: Six months following TV-ICD insertion, there was a 7-fold increase in the risk of at least 1 grade worsening of TR, with 7% of individuals having TR that was moderate or severe. There was no detectable difference in RV size or function; however, longer follow-up is needed.

The Glymphatic System and Subarachnoid Lymphatic-Like Membrane: Recent Developments in Cerebrospinal Fluid Research.

INTRODUCTION: Cerebrospinal fluid (CSF) circulates throughout the ventricles, cranial and spinal subarachnoid spaces, and central spinal cord canal. CSF protects the central nervous system through mechanical cushioning, regulation of intracranial pressure, regulation of metabolic homeostasis, and provision of nutrients. Recently, investigators have characterized the glial-lymphatic (glymphatic) system, the analog of the lymphatic system in the CNS, and described a fourth meningeal layer; the subarachnoid lymphatic-like membrane relevant to the CSF. METHODS: A narrative review was conducted. RESULTS: In this review, we summarize these advances. We describe the development of the original model, controversies, a revised model, and a new conceptual framework. We characterize the biological functions, influence of sleep-wake cycles, and effect of aging with relevance to the glymphatic system. We highlight the role of the glymphatic system in Alzheimer's disease, idiopathic normal pressure hydrocephalus, ischemic stroke, subarachnoid hemorrhage, and traumatic brain injury. Next, we characterize the structure and role of the subarachnoid lymphatic-like membrane. Finally, we explore the relevance of the glymphatic system and subarachnoid lymphatic-like membrane to neurosurgery. CONCLUSION: This manuscript will inform clinicians and scientists regarding preclinical and translational advances in the understanding of the structure, dynamics, and function of the CSF.

Utility of Diffusion Tensor Imaging (DTI) for Prognosis and Management of Cervical Spondylotic Myelopathy: a PRISMA Review.

OBJECTIVE: As advances are made in quantitative magnetic resonance imaging, specifically diffusion tensor imaging, researchers have investigated its potential to serve as a biomarker of disease or prognosticator for post-operative recovery in the management of cervical spondylotic myelopathy. Here, we narratively review the current state of the emerging literature, describing areas of consensus and disagreement. METHODS: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, we queried two large databases for original manuscripts published in English and systematically produced a narrative review of the use of diffusion tensor imaging in the management of cervical spondylotic myelopathy. RESULTS: Of the 437 manuscripts initially returned in our query, 29 met the final inclusion criteria, and data were extracted regarding diffusion tensor imaging indices and their relationships with clinical outcomes following surgery. Preoperative fractional anisotropy was most commonly found to correlate closely with post-surgical clinical outcomes, though results were mixed. CONCLUSION: Preoperative fractional anisotropy most frequently and best correlates with functional outcomes following surgery for cervical spondylotic myelopathy, according to a review of the current literature. The findings were not universal and at times contradictory, highlighting the need for high-quality future investigations to better define the utility of diffusion tensor imaging in spinal disease.

Discovery of Uncommon Tryptophan-Containing Diketopiperazines from Aspergillus homomorphus CBS 101889 Using an Aspergillus nidulans Heterologous Expression System.

Fungal secondary metabolite (SM) biosynthetic gene clusters (BGCs) containing dimethylallyltryptophan synthases (DMATSs) produce structurally diverse prenylated indole alkaloids with wide-ranging activities that have vast potential as human therapeutics. To discover new natural products produced by DMATSs, we mined the Department of Energy Joint Genome Institute's MycoCosm database for DMATS-containing BGCs. We found a DMATS BGC in Aspergillus homomorphus CBS 101889, which also contains a nonribosomal peptide synthetase (NRPS). This BGC appeared to have a previously unreported combination of genes, which suggested the cluster might make novel SMs. We refactored this BGC with highly inducible promoters into the model fungus Aspergillus nidulans. The expression of this refactored BGC in A. nidulans resulted in the production of eight tryptophan-containing diketopiperazines, six of which are new to science. We have named them homomorphins A-F (2, 4-8). Perhaps even more intriguingly, to our knowledge, this is the first discovery of C4-prenylated tryptophan-containing diketopiperazines and their derivatives. In addition, the NRPS from this BGC is the first described that has the ability to promiscuously combine tryptophan with either of two different amino acids, in this case, l-valine or l-allo-isoleucine.

Changes in Hip Isometric Strength of Female College Soccer Players After High-Workload Training Session.

CONTEXT: The hip adductor and abductor muscles play vital roles as stabilizers in the lower-extremity. Their activation during soccer-specific actions is essential, but local muscular fatigue can hinder athletic performance and increase the risk of injury. DESIGN: This study aimed to observe the variations in frontal plane hip strength in female college soccer players before and after a high-workload soccer-specific training session. Furthermore, the study sought to compare the relative changes in hip strength with the internal and external load measures obtained during that session. METHODS: Twenty female college soccer players participated in a retrospective observational study. Isometric hip adductor and abductor strength were measured before and after a training session in the college spring season. Measurements were taken with a handheld dynamometer (MicroFET 2) while the players were supine. Global positioning system sensors (Catapult Vector S7), commonly worn by players during training sessions and competitive matches, were used to measure external and internal loads. Statistical analyses were performed using paired samples t test to assess hip adductor and abductor strength changes before and after the training session. Spearman rank was used to identify correlation coefficients between global positioning system data and isometric hip strength. RESULTS: The findings revealed significant decreases in the strength of the right hip adduction (P = .012, -7% relative change), right abduction (P = .009, -7.6% relative change), and left abduction (P = .016, -4.9% relative change) after the training session. Furthermore, relative decreases in hip isometric adduction and abduction strength are related to the distance covered at high speeds. CONCLUSION: The results of this study highlight that hip isometric adduction and abduction strength tend to decrease after exposure to high workloads during soccer-specific training.

Increased BMI associated with decreased breastfeeding initiation in Million Veteran Program participants.

Background: Breastfeeding has been associated with maternal and infant health benefits but has been inversely associated with body mass index (BMI) prepartum. Breastfeeding and BMI are both linked to socioeconomic factors. Methods: Data from parous female participants with available breastfeeding information from the Million Veteran Program cohort was included. BMI at enrollment and earliest BMI available were extracted, and polygenic scores (PGS) for BMI were calculated. We modeled breastfeeding for one month or more as a function of BMI at enrollment; earliest BMI where available pre-pregnancy; and PGS for BMI. We conducted Mendelian randomization for breastfeeding initiation using PGS as an instrumental variable. Results: A higher BMI predicted a lower likelihood of breastfeeding for one month or more in all analyses. A +5 kg/m 2 BMI pre-pregnancy was associated with a 24% reduced odds of breastfeeding, and a +5 kg/m 2 genetically predicted BMI was associated with a 17% reduced odds of breastfeeding. Conclusions: BMI predicts a lower likelihood of breastfeeding for one month or longer. Given the high success of breastfeeding initiation regardless of BMI in supportive environments as well as potential health benefits, patients with elevated BMI may benefit from additional postpartum breastfeeding support.

Lower Locus Coeruleus Integrity Signals Elevated Entorhinal Tau and Clinical Progression in Asymptomatic Older Individuals.

OBJECTIVE: Elevated entorhinal cortex (EC) tau in low beta-amyloid individuals can predict accumulation of pathology and cognitive decline. We compared the accuracy of magnetic resonance imaging (MRI)-derived locus coeruleus integrity, neocortical beta-amyloid burden by positron emission tomography (PET), and hippocampal volume in identifying elevated entorhinal tau signal in asymptomatic individuals who are considered beta-amyloid PET-negative. METHODS: We included 188 asymptomatic individuals (70.78 ± 11.51 years, 58% female) who underwent 3T-MRI of the locus coeruleus, Pittsburgh compound-B (PiB), and Flortaucipir (FTP) PET. Associations between elevated EC tau and neocortical PiB, hippocampal volume, or locus coeruleus integrity were evaluated and compared using logistic regression and receiver operating characteristic analyses in the PiB- sample with a clinical dementia rating (CDR) of 0. Associations with clinical progression (CDR-sum-of-boxes) over a time span of 6 years were evaluated with Cox proportional hazard models. RESULTS: We identified 26 (21%) individuals with high EC FTP in the CDR = 0/PiB- sample. Locus coeruleus integrity was a significantly more sensitive and specific predictor of elevated EC FTP (area under the curve [AUC] = 85%) compared with PiB (AUC = 77%) or hippocampal volume (AUC = 76%). Based on the Youden-index, locus coeruleus integrity obtained a sensitivity of 77% and 85% specificity. Using the resulting locus coeruleus Youden cut-off, lower locus coeruleus integrity was associated with a two-fold increase in clinical progression, including mild cognitive impairment. INTERPRETATION: Locus coeruleus integrity has promise as a low-cost, non-invasive screening instrument to detect early cortical tau deposition and associated clinical progression in asymptomatic, low beta-amyloid individuals. ANN NEUROL 2024.

DHODH inhibition enhances the efficacy of immune checkpoint blockade by increasing cancer cell antigen presentation.

Pyrimidine nucleotide biosynthesis is a druggable metabolic dependency of cancer cells, and chemotherapy agents targeting pyrimidine metabolism are the backbone of treatment for many cancers. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine biosynthesis pathway that can be targeted by clinically approved inhibitors. However, despite robust preclinical anticancer efficacy, DHODH inhibitors have shown limited single-agent activity in phase 1 and 2 clinical trials. Therefore, novel combination therapy strategies are necessary to realize the potential of these drugs. To search for therapeutic vulnerabilities induced by DHODH inhibition, we examined gene expression changes in cancer cells treated with the potent and selective DHODH inhibitor brequinar (BQ). This revealed that BQ treatment causes upregulation of antigen presentation pathway genes and cell surface MHC class I expression. Mechanistic studies showed that this effect is (1) strictly dependent on pyrimidine nucleotide depletion, (2) independent of canonical antigen presentation pathway transcriptional regulators, and (3) mediated by RNA polymerase II elongation control by positive transcription elongation factor B (P-TEFb). Furthermore, BQ showed impressive single-agent efficacy in the immunocompetent B16F10 melanoma model, and combination treatment with BQ and dual immune checkpoint blockade (anti-CTLA-4 plus anti-PD-1) significantly prolonged mouse survival compared to either therapy alone. Our results have important implications for the clinical development of DHODH inhibitors and provide a rationale for combination therapy with BQ and immune checkpoint blockade.

Rocky Mountain spotted fever is a neglected tropical disease in Latin America.

Rocky Mountain spotted fever (RMSF), a severe and extraordinarily lethal infectious disease, has emerged as a widespread public health crisis among predominantly vulnerable populations in several countries of Latin America, particularly evident in northern Mexico. Historically, RMSF has gained less attention than many other tropical infectious diseases, resulting in insufficient allocations of resources and development of capabilities for its prevention and control in endemic regions. We argue that RMSF fulfills accepted criteria for a neglected tropical disease (NTD). The relative neglect of RMSF in most Latin American countries contributes to disparities in morbidity and mortality witnessed in this region. By recognizing RMSF as an NTD, an increased public policy interest, equitable and more appropriate allocation of resources, scientific interest, and social participation can ameliorate the impact of this potentially treatable disease, particularly in vulnerable populations.