Pilot Testing of the MyCog Assessment: Rapid Detection of Cognitive Impairment in Everyday Clinical Settings.

Cognitive impairment (CI) and dementia can have profound social and emotional effects on older adults. Early detection of CI is imperative both to the identification of potentially treatable conditions and to provide services to minimize the effects of CI in cases of dementia. While primary care settings are ideal for identifying CI, it frequently goes undetected. We tailored a brief, iPad-based, cognitive assessment (MyCog) for primary care settings and piloted it in a sample of older adults. Eighty participants were recruited from an existing cohort study and completed a brief, in-person interview. CI was determined based on a diagnosis of dementia or CI in their medical record or based on a comprehensive cognitive battery performed within the past 18 months. MyCog had a sensitivity of 79% and specificity of 82%, offering a practical, scalable, primary care assessment for the routine case finding of cognitive impairment and dementia.

Disentangling the within- and between-person aspects of implicit alcohol associations on hazardous drinking.

Indirect measures have been used to assess the strength of automatically activated, alcohol-related associations and their relation to hazardous drinking. However, little is known about the longitudinal contributions of between-person and within-person components of implicit alcohol associations (IAAs) to college students' hazardous drinking over time. This study examined how within- and between-person variability in three measures of IAA (drinking identity, alcohol approach, and alcohol excite) are related to hazardous drinking while controlling for their explicit, self-report counterparts. First- and second-year U.S. college students (N = 506; 57% female) completed web-based assessments once every 3 months up to eight assessments, which included IAA measures (Implicit Association Tests), explicit counterparts of the IAAs, and self-reported hazardous drinking (alcohol consumption, problems, and risk of alcohol use disorder). Bayesian generalized multilevel models were used to examine between- and within-person associations among IAA, their explicit counterparts, and hazardous drinking. Results showed that between persons, mean levels of all three IAAs were positively associated with hazardous drinking over time. Once their explicit, self-report counterparts were included, however, only drinking identity IAA remained significant. Within persons, increases in drinking identity IAA were associated with increases in subsequent hazardous drinking risk, even after controlling for its explicit counterpart. These results suggest the importance of disentangling and simultaneously investigating between- and within-person processes in IAAs. Although the between-person component of IAAs may play a larger role in the prediction of hazardous drinking, examining the within-person component of IAA, at least for drinking identity, also appears to be important. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Prediction of cognitive impairment using higher order item response theory and machine learning models.

Timely detection of cognitive impairment (CI) is critical for the wellbeing of elderly individuals. The MyCog assessment employs two validated iPad-based measures from the NIH Toolbox® for Assessment of Neurological and Behavioral Function (NIH Toolbox). These measures assess pivotal cognitive domains: Picture Sequence Memory (PSM) for episodic memory and Dimensional Change Card Sort Test (DCCS) for cognitive flexibility. The study involved 86 patients and explored diverse machine learning models to enhance CI prediction. This encompassed traditional classifiers and neural-network-based methods. After 100 bootstrap replications, the Random Forest model stood out, delivering compelling results: precision at 0.803, recall at 0.758, accuracy at 0.902, F1 at 0.742, and specificity at 0.951. Notably, the model incorporated a composite score derived from a 2-parameter higher order item response theory (HOIRT) model that integrated DCCS and PSM assessments. The study's pivotal finding underscores the inadequacy of relying solely on a fixed composite score cutoff point. Instead, it advocates for machine learning models that incorporate HOIRT-derived scores and encompass relevant features such as age. Such an approach promises more effective predictive models for CI, thus advancing early detection and intervention among the elderly.

Diet-derived metabolites and mucus link the gut microbiome to fever after cytotoxic cancer treatment.

Not all patients with cancer and severe neutropenia develop fever, and the fecal microbiome may play a role. In a single-center study of patients undergoing hematopoietic cell transplant (n = 119), the fecal microbiome was characterized at onset of severe neutropenia. A total of 63 patients (53%) developed a subsequent fever, and their fecal microbiome displayed increased relative abundances of Akkermansia muciniphila, a species of mucin-degrading bacteria (P = 0.006, corrected for multiple comparisons). Two therapies that induce neutropenia, irradiation and melphalan, similarly expanded A. muciniphila and additionally thinned the colonic mucus layer in mice. Caloric restriction of unirradiated mice also expanded A. muciniphila and thinned the colonic mucus layer. Antibiotic treatment to eradicate A. muciniphila before caloric restriction preserved colonic mucus, whereas A. muciniphila reintroduction restored mucus thinning. Caloric restriction of unirradiated mice raised colonic luminal pH and reduced acetate, propionate, and butyrate. Culturing A. muciniphila in vitro with propionate reduced utilization of mucin as well as of fucose. Treating irradiated mice with an antibiotic targeting A. muciniphila or propionate preserved the mucus layer, suppressed translocation of flagellin, reduced inflammatory cytokines in the colon, and improved thermoregulation. These results suggest that diet, metabolites, and colonic mucus link the microbiome to neutropenic fever and may guide future microbiome-based preventive strategies.

An ecological momentary assessment study of outcome expectancies and smoking lapse in daily life.

OBJECTIVE: Outcome expectancies have been identified as key components of behavior change. Expectancies related to affect control are hypothesized to play an important role in smoking cessation, such that smokers may be more likely to lapse if they believe they can control their affect by smoking and less likely if they believe they can control their affect by means other than smoking. However, little is known about whether real-time, real-world changes in affect control expectancies influence smoking lapse during a quit attempt. METHODS: A diverse sample (N = 369) of adult smokers completed ecological momentary assessment of smoking expectancies and lapse for 28 days following a quit attempt. Multilevel logistic regression was used to examine whether the difference score of positive smoking outcome expectancies (the belief that smoking would improve mood) minus positive coping outcome expectancies (the belief that something other than smoking would improve mood) was related to smoking lapse in daily life. RESULTS: There was a significant within-person association between the expectancies difference score and lapse likelihood. When the difference score was 1 unit above a person's typical level, odds of lapse increased by 18.65 % (ß = 0.174, SE = 0.024, p < .0001, OR = 1.189, 95 % CI [1.135, 1.247]). CONCLUSION: Smokers undergoing a quit attempt were more likely to lapse in moments when the difference in the belief that smoking would improve their mood minus the belief that something other than smoking would improve their mood was larger. This work has relevance for tailoring interventions to both cultivate positive coping outcome expectancies and reduce smoking outcome expectancies, and informs theoretical models about the dynamic nature of outcome expectancies.

Alloreactive T cells deficient of the short-chain fatty acid receptor GPR109A induce less graft-versus-host disease.

The intestinal microbiota is essential for the fermentation of dietary fiber into short-chain fatty acids (SCFA) such as butyrate, acetate, and propionate. SCFAs can bind to the G-protein-coupled receptors GPR43 and GPR109A (HCAR2), with varying affinities to promote cellular effects in metabolism or changes in immune function. We explored the role of GPR109A as the main receptor for butyrate in mouse models of allogeneic hematopoietic cell transplantation (allo-HCT) and graft-versus-host disease (GVHD). Deletion of GPR109A in allo-HCT recipients did not affect GVHD, but transplantation of T cells from GPR109A knockout (KO) (Gpr109a-/-) mice into allo-HCT recipient mice significantly reduced GVHD morbidity and mortality compared with recipients of wild-type (WT) T cells. Recipients of Gpr109a-/- T cells exhibited less GVHD-associated target organ pathology and decreased proliferation and homing of alloreactive T cells to target tissues. Although Gpr109a-/- T cells did not exhibit immune deficits at a steady state, following allo-activation, Gpr109a-/- T cells underwent increased apoptosis and were impaired mitochondrial oxidative phosphorylation, which was reversible through antioxidant treatment with N-acetylcysteine (NAC). In conclusion, we found that GPR109A expression by allo-activated T cells is essential for metabolic homeostasis and expansion, which are necessary features to induce GVHD after allo-HCT.

Increasing treatment enrollment among smokers who are not motivated to quit: a randomized clinical trial.

There is a significant research-to-practice gap with respect to reaching underserved populations with evidence-based tobacco cessation treatments. Increasing enrollment in evidence-based treatments is necessary to reduce tobacco use and tobacco-related health inequities. The purpose of the current study was to evaluate whether Motivation And Problem Solving (MAPS), a flexible, holistic counseling/navigation approach delivered via phone, and proactive provision of Nicotine Replacement Therapy (NRT) would improve Quitline enrollment among a sample of low SES smokers who were not motivated to quit. In a 3×2 factorial design, cigarette smokers (N = 603) were randomized to one of six treatment conditions (Standard Treatment, MAPS-6, or MAPS-12 by NRT or no NRT). Results indicated that both MAPS-6 and MAPS-12 increased Quitline enrollment compared to Standard Treatment (ps < .03). There were no differences between MAPS conditions. NRT did not increase Quitline enrollment. MAPS is an effective intervention with the potential to be disseminated and implemented in healthcare and community settings to increase the reach of evidence-based interventions for tobacco cessation.

An intestinal organoid-based platform that recreates susceptibility to T-cell-mediated tissue injury.

A goal in precision medicine is to use patient-derived material to predict disease course and intervention outcomes. Here, we use mechanistic observations in a preclinical animal model to design an ex vivo platform that recreates genetic susceptibility to T-cell-mediated damage. Intestinal graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation. We found that intestinal GVHD in mice deficient in Atg16L1, an autophagy gene that is polymorphic in humans, is reversed by inhibiting necroptosis. We further show that cocultured allogeneic T cells kill Atg16L1-mutant intestinal organoids from mice, which was associated with an aberrant epithelial interferon signature. Using this information, we demonstrate that pharmacologically inhibiting necroptosis or interferon signaling protects human organoids derived from individuals harboring a common ATG16L1 variant from allogeneic T-cell attack. Our study provides a roadmap for applying findings in animal models to individualized therapy that targets affected tissues.

The role of negative affect in the persistence of nicotine dependence among alternative high school students: A latent growth curve analysis.

BACKGROUND: Previous research has demonstrated how negative affect (i.e., depression, anxiety, stress) is often a correlate of and precursor to nicotine dependence. Although recent evidence shows a gradual decline in tobacco use in the United States, subgroups that report higher levels of negative affect may continue to be at risk of becoming dependent on nicotine. One high-risk subgroup is students who attend alternative high schools. The current longitudinal investigation examined the effect of negative affect on nicotine dependence in this youth population. METHODS: 1060 students from 29 alternative high schools in Southern California completed a series of attitudinal and behavioral measures once per year over a three-year period. The main outcome was nicotine dependence i.e., feeling a strong urge to use nicotine products or experiencing withdrawal symptoms after a period of abstinence, measured using a version of the Fagerstrom Tolerance Questionnaire designed for adolescents. A latent growth curve model was utilized to examine the effect of negative affect on nicotine dependence during this timeframe. RESULTS: The analysis revealed that negative affect had both a concurrent and prospective relationship with nicotine dependence. Moreover, the association between negative affect and nicotine dependence in the present was not statistically significant once the influence of negative affect reported one year earlier was accounted for. CONCLUSIONS: Negative affect may play a critical role in the persistence of nicotine dependence among high-risk youth. Providing resources to help manage negative affect may be critical to curtailing nicotine dependence in this population.

Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation.

BACKGROUND: Relationships between microbiota composition and clinical outcomes after allogeneic hematopoietic-cell transplantation have been described in single-center studies. Geographic variations in the composition of human microbial communities and differences in clinical practices across institutions raise the question of whether these associations are generalizable. METHODS: The microbiota composition of fecal samples obtained from patients who were undergoing allogeneic hematopoietic-cell transplantation at four centers was profiled by means of 16S ribosomal RNA gene sequencing. In an observational study, we examined associations between microbiota diversity and mortality using Cox proportional-hazards analysis. For stratification of the cohorts into higher- and lower-diversity groups, the median diversity value that was observed at the study center in New York was used. In the analysis of independent cohorts, the New York center was cohort 1, and three centers in Germany, Japan, and North Carolina composed cohort 2. Cohort 1 and subgroups within it were analyzed for additional outcomes, including transplantation-related death. RESULTS: We profiled 8767 fecal samples obtained from 1362 patients undergoing allogeneic hematopoietic-cell transplantation at the four centers. We observed patterns of microbiota disruption characterized by loss of diversity and domination by single taxa. Higher diversity of intestinal microbiota was associated with a lower risk of death in independent cohorts (cohort 1: 104 deaths among 354 patients in the higher-diversity group vs. 136 deaths among 350 patients in the lower-diversity group; adjusted hazard ratio, 0.71; 95% confidence interval [CI], 0.55 to 0.92; cohort 2: 18 deaths among 87 patients in the higher-diversity group vs. 35 deaths among 92 patients in the lower-diversity group; adjusted hazard ratio, 0.49; 95% CI, 0.27 to 0.90). Subgroup analyses identified an association between lower intestinal diversity and higher risks of transplantation-related death and death attributable to graft-versus-host disease. Baseline samples obtained before transplantation already showed evidence of microbiome disruption, and lower diversity before transplantation was associated with poor survival. CONCLUSIONS: Patterns of microbiota disruption during allogeneic hematopoietic-cell transplantation were similar across transplantation centers and geographic locations; patterns were characterized by loss of diversity and domination by single taxa. Higher diversity of intestinal microbiota at the time of neutrophil engraftment was associated with lower mortality. (Funded by the National Cancer Institute and others.).

Retail outlets prompt associative memories linked to the repeated use of nicotine and tobacco products among alternative high school students in California.

Numerous studies have examined how youth are influenced by the presence of tobacco retail outlets that use point-of-sale marketing tactics to promote nicotine and tobacco products. The current investigation extends this research by assessing whether tobacco retail outlets function as environmental cues that prompt associative memories linked to the repeated use of cigarettes, electronic cigarettes, and cigars. Students (N = 1060) from 29 alternative high schools in California were recruited into a three-year cohort study. A repeated measures latent profile analysis was conducted to identify latent subgroups of students. Analyses suggested the presence of one subgroup of students that did not use nicotine and tobacco products and five subgroups of students that used multiple products. A multinomial logistic regression revealed that images of gas stations, convenience stores, and liquor stores presented in the first year of the study prompted spontaneous associations in memory that increased the odds a student would belong to one of the five subgroups that repeatedly used nicotine and tobacco products over a three-year period. These findings suggest that tobacco retail outlets may act as environmental cues that prompt the use of addictive products among at-risk youth. Policymakers should consider implementing strategies that reduce the potency and prevalence of these cues.

Translation of basic research in cognitive science to HIV-risk: a randomized controlled trial.

Many people enrolled in drug diversion programs are not receiving evidence-based prevention for HIV or hepatitis. This study translated basic research from cognitive science to increase screening for infection and condom use in this population. A parallel three-condition randomized trial was conducted in a drug diversion sample (N = 358), comparing a memory practice condition with two active control conditions. Outcomes were condom use frequency and testing for infection (hepatitis B/C, HIV). At 3-month follow-up, participants in the memory practice condition were at least twice as likely (OR = 2.10 or greater, p < .01) to self-report testing compared to those in the control conditions and also reported more frequent condom use compared to a health education condition [B = .37, t(1) = 2.02, p = .02]. Basic research on memory can be effectively translated to brief interventions on infection screening and risk prevention in existing drug diversion programs.

Nrf2 regulates CD4+ T cell-induced acute graft-versus-host disease in mice.

Nuclear factor erythroid-derived 2-like 2 (Nrf2) is a ubiquitously expressed transcription factor that is well known for its role in regulating the cellular redox pathway. Although there is mounting evidence suggesting a critical role for Nrf2 in hematopoietic stem cells and innate leukocytes, little is known about its involvement in T-cell biology. In this study, we identified a novel role for Nrf2 in regulating alloreactive T-cell function during allogeneic hematopoietic cell transplantation (allo-HCT). We observed increased expression and nuclear translocation of Nrf2 upon T-cell activation in vitro, especially in CD4+ donor T cells after allo-HCT. Allo-HCT recipients of Nrf2 -/- donor T cells had significantly less acute graft-versus-host disease (GVHD)-induced mortality, morbidity, and pathology. This reduction in GVHD was associated with the persistence of Helios+ donor regulatory T cells in the allograft, as well as defective upregulation of the gut-homing receptor LPAM-1 on alloreactive CD8+ T cells. Additionally, Nrf2 -/- donor CD8+ T cells demonstrated intact cytotoxicity against allogeneic target cells. Tumor-bearing allo-HCT recipients of Nrf2 -/- donor T cells had overall improved survival as a result of preserved graft-versus-tumor activity and reduced GVHD activity. Our findings characterized a previously unrecognized role for Nrf2 in T-cell function, as well as revealed a novel therapeutic target to improve the outcomes of allo-HCT.

The Rutgers Alcohol Problem Index for Adolescent Alcohol and Drug Problems: A Comprehensive Modern Psychometric Study.

OBJECTIVE: The Rutgers Alcohol Problem Index (RAPI) has been used extensively as a measure of alcohol-related problems experienced by adolescents and young adults. The present study aimed to comprehensively examine the psychometric profile and criterion-related validity of an 18-item RAPI adapted to measure negative consequences resulting from alcohol and other drug use in an at-risk adolescent population. METHOD: Categorical confirmatory factor analysis and the graded response model were used for evaluations of the latent factor structure, item properties, test information, and item invariance across gender, age groups (middle vs. late adolescence), and drug use profiles (readily available drugs vs. other illicit drugs), as well as computation of the item response theory scale scores for each of 617 alternative high school students (44% female). RESULTS: A reduced set of 16 RAPI items provided plausible evidence of unidimensionality and good measurement precision at a relatively wide range of the latent trait continuum. All but two items were invariant across the drug use profiles. The other illicit drug group had higher levels of the latent substance-related problems than the readily available drug group. Criterion-related validity was supported using a measure of past-year polysubstance use. CONCLUSIONS: The RAPI can be effectively modified to measure negative consequences resulting from alcohol and other drug use and reflects a sufficiently wide range of the latent continuum of problem use.

Corrigendum: Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury.

This corrects the article DOI: 10.1038/nm.4470.

Trajectories of cannabis-related associative memory among vulnerable adolescents: Psychometric and longitudinal evaluations.

Indirect tests of memory associations relevant to cannabis have been shown to be useful in explaining and predicting adolescent cannabis use habits. This study sought to increase the understanding of adolescent cannabis-related associative memory and cannabis use behavior over time. A longitudinal sample of alternative high school students (N = 775) was assessed yearly for 3 years. The study first conducted extensive longitudinal measurement analyses of the cannabis-related word association test (WAT) applying contemporary psychometric models. Second, the study examined the longitudinal trajectories of cannabis-related associative memory and cannabis use and their contemporaneous and longitudinal relationships. Results showed that the cannabis-related WAT provided strong evidence of sound psychometric properties. Longitudinal change in cannabis-related associative memory was best described by modeling either a linearly decreasing trajectory or two separate trajectories: During middle adolescence, levels of cannabis-related associative memory were highest and stable but then gradually decreased toward late adolescence. Moreover, cannabis-related associative memory was contemporaneously predictive of cannabis use within ages 15 to 19 while controlling for the underlying growth process of cannabis use and time-invariant covariates (TICs) of gender and lifetime concurrent use of alcohol and cigarettes. Partial support of longitudinal prediction of cannabis use was also obtained from age 17 to 18 and age 19 to 20 while adjusting for growth in cannabis use and the TICs. These results demonstrated that predictive effects of cannabis-related memory associations on cannabis use were detected within some of the 1-year age spans and were consistent within ages across adolescent years. (PsycINFO Database Record

Nutritional Support from the Intestinal Microbiota Improves Hematopoietic Reconstitution after Bone Marrow Transplantation in Mice.

Bone marrow transplantation (BMT) offers curative potential for patients with high-risk hematologic malignancies, but the post-transplantation period is characterized by profound immunodeficiency. Recent studies indicate that the intestinal microbiota not only regulates mucosal immunity, but can also contribute to systemic immunity and hematopoiesis. Using antibiotic-mediated microbiota depletion in a syngeneic BMT mouse model, here we describe a role for the intestinal flora in hematopoietic recovery after BMT. Depletion of the intestinal microbiota resulted in impaired recovery of lymphocyte and neutrophil counts, while recovery of the hematopoietic stem and progenitor compartments and the erythroid lineage were largely unaffected. Depletion of the intestinal microbiota also reduced dietary energy uptake and visceral fat stores. Caloric supplementation through sucrose in the drinking water improved post-BMT hematopoietic recovery in mice with a depleted intestinal flora. Taken together, we show that the intestinal microbiota contribute to post-BMT hematopoietic reconstitution in mice through improved dietary energy uptake.

Gut microbiota injury in allogeneic haematopoietic stem cell transplantation.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is considered to be the strongest curative immunotherapy for various malignancies (primarily, but not limited to, haematologic malignancies). However, application of allo-HSCT is limited owing to its life-threatening major complications, such as graft-versus-host disease (GVHD), relapse and infections. Recent advances in large-scale DNA sequencing technology have facilitated rapid identification of the microorganisms that make up the microbiota and evaluation of their interactions with host immunity in various diseases, including cancer. This has resulted in renewed interest regarding the role of the intestinal flora in patients with haematopoietic malignancies who have received an allo-HSCT and in whether the microbiota affects clinical outcomes, including GVHD, relapse, infections and transplant-related mortality. In this Review, we discuss the potential role of intestinal microbiota in these major complications after allo-HSCT, summarize clinical trials evaluating the microbiota in patients who have received allo-HSCT and discuss how further studies of the microbiota could inform the development of strategies that improve outcomes of allo-HSCT.

Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration.

The thymus is not only extremely sensitive to damage but also has a remarkable ability to repair itself. However, the mechanisms underlying this endogenous regeneration remain poorly understood, and this capacity diminishes considerably with age. We show that thymic endothelial cells (ECs) comprise a critical pathway of regeneration via their production of bone morphogenetic protein 4 (BMP4) ECs increased their production of BMP4 after thymic damage, and abrogating BMP4 signaling or production by either pharmacologic or genetic inhibition impaired thymic repair. EC-derived BMP4 acted on thymic epithelial cells (TECs) to increase their expression of Foxn1, a key transcription factor involved in TEC development, maintenance, and regeneration, and its downstream targets such as Dll4, a key mediator of thymocyte development and regeneration. These studies demonstrate the importance of the BMP4 pathway in endogenous tissue regeneration and offer a potential clinical approach to enhance T cell immunity.

Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury.

There is a substantial unmet clinical need for new strategies to protect the hematopoietic stem cell (HSC) pool and regenerate hematopoiesis after radiation injury from either cancer therapy or accidental exposure. Increasing evidence suggests that sex hormones, beyond their role in promoting sexual dimorphism, regulate HSC self-renewal, differentiation, and proliferation. We and others have previously reported that sex-steroid ablation promotes bone marrow (BM) lymphopoiesis and HSC recovery in aged and immunodepleted mice. Here we found that a luteinizing hormone (LH)-releasing hormone antagonist (LHRH-Ant), currently in wide clinical use for sex-steroid inhibition, promoted hematopoietic recovery and mouse survival when administered 24 h after an otherwise-lethal dose of total-body irradiation (L-TBI). Unexpectedly, this protective effect was independent of sex steroids and instead relied on suppression of LH levels. Human and mouse long-term self-renewing HSCs (LT-HSCs) expressed high levels of the LH/choriogonadotropin receptor (LHCGR) and expanded ex vivo when stimulated with LH. In contrast, the suppression of LH after L-TBI inhibited entry of HSCs into the cell cycle, thus promoting HSC quiescence and protecting the cells from exhaustion. These findings reveal a role of LH in regulating HSC function and offer a new therapeutic approach for hematopoietic regeneration after hematopoietic injury.