Lysophosphatidylcholine Regulates Sexual Stage Differentiation in the Human Malaria Parasite Plasmodium falciparum.

Transmission represents a population bottleneck in the Plasmodium life cycle and a key intervention target of ongoing efforts to eradicate malaria. Sexual differentiation is essential for this process, as only sexual parasites, called gametocytes, are infective to the mosquito vector. Gametocyte production rates vary depending on environmental conditions, but external stimuli remain obscure. Here, we show that the host-derived lipid lysophosphatidylcholine (LysoPC) controls P. falciparum cell fate by repressing parasite sexual differentiation. We demonstrate that exogenous LysoPC drives biosynthesis of the essential membrane component phosphatidylcholine. LysoPC restriction induces a compensatory response, linking parasite metabolism to the activation of sexual-stage-specific transcription and gametocyte formation. Our results reveal that malaria parasites can sense and process host-derived physiological signals to regulate differentiation. These data close a critical knowledge gap in parasite biology and introduce a major component of the sexual differentiation pathway in Plasmodium that may provide new approaches for blocking malaria transmission.

Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy.

RAS oncogenes (collectively NRAS, HRAS and especially KRAS) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 and 611. Small molecule inhibitors of the KRAS(G12C) oncoprotein have demonstrated clinical efficacy in patients with multiple cancer types and have led to regulatory approvals for the treatment of non-small cell lung cancer2,3. Nevertheless, KRASG12C mutations account for only around 15% of KRAS-mutated cancers4,5, and there are no approved KRAS inhibitors for the majority of patients with tumours containing other common KRAS mutations. Here we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad-spectrum activity for the active state of both mutant and wild-type KRAS, NRAS and HRAS variants (a RAS(ON) multi-selective inhibitor). Preclinically, RMC-7977 demonstrated potent activity against RAS-addicted tumours carrying various RAS genotypes, particularly against cancer models with KRAS codon 12 mutations (KRASG12X). Treatment with RMC-7977 led to tumour regression and was well tolerated in diverse RAS-addicted preclinical cancer models. Additionally, RMC-7977 inhibited the growth of KRASG12C cancer models that are resistant to KRAS(G12C) inhibitors owing to restoration of RAS pathway signalling. Thus, RAS(ON) multi-selective inhibitors can target multiple oncogenic and wild-type RAS isoforms and have the potential to treat a wide range of RAS-addicted cancers with high unmet clinical need. A related RAS(ON) multi-selective inhibitor, RMC-6236, is currently under clinical evaluation in patients with KRAS-mutant solid tumours (ClinicalTrials.gov identifier: NCT05379985).

Variant Library Annotation Tool (VaLiAnT): an oligonucleotide library design and annotation tool for saturation genome editing and other deep mutational scanning experiments.

MOTIVATION: CRISPR/Cas9-based technology allows for the functional analysis of genetic variants at single nucleotide resolution whilst maintaining genomic context. This approach, known as saturation genome editing (SGE), a form of deep mutational scanning, systematically alters each position in a target region to explore its function. SGE experiments require the design and synthesis of oligonucleotide variant libraries which are introduced into the genome. This technology is applicable to diverse fields such as disease variant identification, drug development, structure-function studies, synthetic biology, evolutionary genetics and host-pathogen interactions. Here, we present the Variant Library Annotation Tool (VaLiAnT) which can be used to generate variant libraries from user-defined genomic coordinates and standard input files. The software can accommodate user-specified species, reference sequences and transcript annotations. RESULTS: Coordinates for a genomic range are provided by the user to retrieve a corresponding oligonucleotide reference sequence. A user-specified range within this sequence is then subject to systematic, nucleotide and/or amino acid saturating mutator functions. VaLiAnT provides a novel way to retrieve, mutate and annotate genomic sequences for oligonucleotide library generation. Specific features for SGE library generation can be employed. In addition, VaLiAnT is configurable, allowing for cDNA and prime editing saturation library generation, with other diverse applications possible. AVAILABILITY AND IMPLEMENTATION: VaLiAnT is a command line tool written in Python. Source code, testing data, example input and output files and executables are available (https://github.com/cancerit/VaLiAnT) in addition to a detailed user manual (https://github.com/cancerit/VaLiAnT/wiki). VaLiAnT is licensed under AGPLv3. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Association between burnout and insomnia in U.S. Air Force Pararescue personnel: A cross-sectional study.

Studies have examined burnout and its impact on health, to include its influence on sleep. While many studies report a significant relationship between burnout and insomnia in civilian populations, no studies have examined this relationship in a military population. The United States Air Force (USAF) Pararescue personnel are an elite combat force who are specially trained to conduct both first-line combat and full spectrum personnel recovery and may be at high risk of burnout and insomnia. The current study investigated the association between dimensions of burnout and insomnia, and also examined potential moderators of the associations. A cross-sectional survey was administered to 203 Pararescue personnel (Mean Age = 32.1 years; 100% Male; 90.1% Caucasian) recruited from six US bases. The survey included measures of three dimensions of burnout (emotional exhaustion, depersonalization, personal achievement), insomnia, psychological flexibility, and social support. Emotional exhaustion was significantly associated with insomnia with a moderate to large effect size, when controlling for covariates. Depersonalization, but not personal achievement, was also significantly associated with insomnia. There was no evidence that associations between burnout and insomnia were moderated by psychological flexibility or social support. These findings help to identify individuals at risk of insomnia and may ultimately be useful in developing interventions for insomnia in this population.

Zygote morphogenesis but not the establishment of cell polarity in Plasmodium berghei is controlled by the small GTPase, RAB11A.

Plasmodium species are apicomplexan parasites whose zoites are polarized cells with a marked apical organisation where the organelles associated with host cell invasion and colonization reside. Plasmodium gametes mate in the mosquito midgut to form the spherical and presumed apolar zygote that morphs during the following 24 hours into a polarized, elongated and motile zoite form, the ookinete. Endocytosis-mediated protein transport is generally necessary for the establishment and maintenance of polarity in epithelial cells and neurons, and the small GTPase RAB11A is an important regulator of protein transport via recycling endosomes. PbRAB11A is essential in blood stage asexual of Plasmodium. Therefore, a promoter swap strategy was employed to down-regulate PbRAB11A expression in gametocytes and zygotes of the rodent malaria parasite, Plasmodium berghei which demonstrated the essential role of RAB11A in ookinete development. The approach revealed that lack of PbRAB11A had no effect on gamete production and fertility rates however, the zygote to ookinete transition was almost totally inhibited and transmission through the mosquito was prevented. Lack of PbRAB11A did not prevent meiosis and mitosis, nor the establishment of polarity as indicated by the correct formation and positioning of the Inner Membrane Complex (IMC) and apical complex. However, morphological maturation was prevented and parasites remained spherical and immotile and furthermore, they were impaired in the secretion and distribution of microneme cargo. The data are consistent with the previously proposed model of RAB11A endosome mediated delivery of plasma membrane in Toxoplasma gondii if not its role in IMC formation and implicate it in microneme function.

Current status of experimental models for the study of malaria.

Infection by malaria parasites (Plasmodium spp.) remains one of the leading causes of morbidity and mortality, especially in tropical regions of the world. Despite the availability of malaria control tools such as integrated vector management and effective therapeutics, these measures have been continuously undermined by the emergence of vector resistance to insecticides or parasite resistance to frontline antimalarial drugs. Whilst the recent pilot implementation of the RTS,S malaria vaccine is indeed a remarkable feat, highly effective vaccines against malaria remain elusive. The barriers to effective vaccines result from the complexity of both the malaria parasite lifecycle and the parasite as an organism itself with consequent major gaps in our understanding of their biology. Historically and due to the practical and ethical difficulties of working with human malaria infections, research into malaria parasite biology has been extensively facilitated by animal models. Animals have been used to study disease pathogenesis, host immune responses and their (dys)regulation and further disease processes such as transmission. Moreover, animal models remain at the forefront of pre-clinical evaluations of antimalarial drugs (drug efficacy, mode of action, mode of resistance) and vaccines. In this review, we discuss commonly used animal models of malaria, the parasite species used and their advantages and limitations which hinder their extrapolation to actual human disease. We also place into this context the most recent developments such as organoid technologies and humanized mice.

Use of electronic cigarettes in the United States service member and Veteran populations: A narrative review (2019).

Electronic Nicotine Delivery Systems (ENDS) are an increasingly popular form of a nicotine delivery device, particularly among young adults and adolescents. The health consequences of long-term ENDS use are not known. Two populations that warrant special consideration are members of the United States Military (service members) and US Veterans. In this narrative review of literature before December 2019, research on ENDS use in these two populations is described in relation to four themes relevant to ENDS use: Prevalence of ENDS use; perceptions of ENDS; correlates of ENDS use; and use of ENDS for smoking cessation. This narrative review summarized research findings in each of these four areas and identified areas for future research.

Experimentally Engineered Mutations in a Ubiquitin Hydrolase, UBP-1, Modulate In Vivo Susceptibility to Artemisinin and Chloroquine in Plasmodium berghei.

As resistance to artemisinins (current frontline drugs in malaria treatment) emerges in Southeast Asia, there is an urgent need to identify the genetic determinants and understand the molecular mechanisms underpinning such resistance. Such insights could lead to prospective interventions to contain resistance and prevent the eventual spread to other regions where malaria is endemic. Reduced susceptibility to artemisinin in Southeast Asia has been primarily linked to mutations in the Plasmodium falciparum Kelch-13 gene, which is currently widely recognized as a molecular marker of artemisinin resistance. However, two mutations in a ubiquitin hydrolase, UBP-1, have been previously associated with reduced artemisinin susceptibility in a rodent model of malaria, and some cases of UBP-1 mutation variants associated with artemisinin treatment failure have been reported in Africa and SEA. In this study, we employed CRISPR-Cas9 genome editing and preemptive drug pressures to test these artemisinin susceptibility-associated mutations in UBP-1 in Plasmodium berghei sensitive lines in vivo Using these approaches, we show that the V2721F UBP-1 mutation results in reduced artemisinin susceptibility, while the V2752F mutation results in resistance to chloroquine (CQ) and moderately impacts tolerance to artemisinins. Genetic reversal of the V2752F mutation restored chloroquine sensitivity in these mutant lines, whereas simultaneous introduction of both mutations could not be achieved and appears to be lethal. Interestingly, these mutations carry a detrimental growth defect, which would possibly explain their lack of expansion in natural infection settings. Our work provides independent experimental evidence on the role of UBP-1 in modulating parasite responses to artemisinin and chloroquine under in vivo conditions.

Non-Invasive Cardiac Output Monitoring in Cardiogenic Shock: The NICOM Study.

BACKGROUND: The bioreactance technique is a relatively new, totally noninvasive technique that is used to measure cardiac output (CO) and is easy to use. The Non-Invasive Cardiac Output Monitor (NICOM) is 1 such system. Although approved by the Food and Drug Administration for measurement of stroke volume, there is a paucity of literature validating this technology in decompensated heart failure and cardiogenic shock. METHODS AND RESULTS: Fifty patients admitted to our cardiac intensive care unit for cardiogenic shock and Swan-Ganz catheter-guided therapy were prospectively enrolled in the study after informed consent. Simultaneous measurements of CO were obtained using NICOM, indirect Fick and bolus thermodilution. The intraclass correlation coefficient (ICC) was used to assess the precision of NICOM for CO using the 3 repeated measurements of CO over the pooled data. The agreement of the NICOM device in the defined clinical population, compared to indirect Fick and thermodilution, was evaluated by comparing the Pearson correlation coefficient, the Bland-Altman plot and the Lin concordance correlation coefficient. The ICC for cardiac output measured by NICOM showed excellent repeatability (ICC = 0.93, 95% CI = 0.92-0.94, n = 262) in the pooled data. The Pearson correlation coefficient for cardiac output measured by NICOM was poor when compared to indirect Fick (n = 263, r = 0.132, P = 0.033) and TD (n = 258, r = 0.275, P < 0.001). CONCLUSIONS: NICOM technology is not a reliable method of measuring CO in patients with decompensated heart failure and cardiogenic shock.

A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium.

Commitment to and completion of sexual development are essential for malaria parasites (protists of the genus Plasmodium) to be transmitted through mosquitoes. The molecular mechanism(s) responsible for commitment have been hitherto unknown. Here we show that PbAP2-G, a conserved member of the apicomplexan AP2 (ApiAP2) family of DNA-binding proteins, is essential for the commitment of asexually replicating forms to sexual development in Plasmodium berghei, a malaria parasite of rodents. PbAP2-G was identified from mutations in its encoding gene, PBANKA_143750, which account for the loss of sexual development frequently observed in parasites transmitted artificially by blood passage. Systematic gene deletion of conserved ApiAP2 genes in Plasmodium confirmed the role of PbAP2-G and revealed a second ApiAP2 member (PBANKA_103430, here termed PbAP2-G2) that significantly modulates but does not abolish gametocytogenesis, indicating that a cascade of ApiAP2 proteins are involved in commitment to the production and maturation of gametocytes. The data suggest a mechanism of commitment to gametocytogenesis in Plasmodium consistent with a positive feedback loop involving PbAP2-G that could be exploited to prevent the transmission of this pernicious parasite.

The effect of linguistic modification on English as a second language (ESL) nursing student retention.

English-as-a-second-language (ESL) nursing students fail out of nursing programs at a far higher rate than native English speakers. There are many reasons for this trend, however academic failure related to poor performance on multiple-choice (MC) exams, is the most common. Objective The purpose of this interventional comparative research study was to determine the effect of linguistic modification (LM) of MC exam questions on score and timing of ESL compared to native English-speaking nursing students. Method Two-factor analysis of variance and a mixed-effects regression were applied to the data from 69 participants. Results Statistical significance was noted as related to time. All students took significantly less time to complete the LM questions in comparison to the standard questions. Conclusion LM is a process that should be used by nursing faculty to create fair evaluation instruments for all nursing students.

Stage-Specific Changes in Plasmodium Metabolism Required for Differentiation and Adaptation to Different Host and Vector Environments.

Malaria parasites (Plasmodium spp.) encounter markedly different (nutritional) environments during their complex life cycles in the mosquito and human hosts. Adaptation to these different host niches is associated with a dramatic rewiring of metabolism, from a highly glycolytic metabolism in the asexual blood stages to increased dependence on tricarboxylic acid (TCA) metabolism in mosquito stages. Here we have used stable isotope labelling, targeted metabolomics and reverse genetics to map stage-specific changes in Plasmodium berghei carbon metabolism and determine the functional significance of these changes on parasite survival in the blood and mosquito stages. We show that glutamine serves as the predominant input into TCA metabolism in both asexual and sexual blood stages and is important for complete male gametogenesis. Glutamine catabolism, as well as key reactions in intermediary metabolism and CoA synthesis are also essential for ookinete to oocyst transition in the mosquito. These data extend our knowledge of Plasmodium metabolism and point towards possible targets for transmission-blocking intervention strategies. Furthermore, they highlight significant metabolic differences between Plasmodium species which are not easily anticipated based on genomics or transcriptomics studies and underline the importance of integration of metabolomics data with other platforms in order to better inform drug discovery and design.

Enhancing Smoking Risk Communications: The Influence of Health Literacy and Message Content.

Background: Efforts are needed to ensure that smokers with lower health literacy are provided with understandable and impactful information about the health consequences of smoking and benefits of quitting. Purpose: To test the influence of health literacy on smokers' responses to health risk messages manipulated on framing (gain vs. loss) and emotionality (factual vs. emotional). Methods: Participants (N = 402) were randomized to evaluate one of four sets of smoking risk messages (factual gain-framed, factual loss-framed, emotional gain-framed, or emotional loss-framed). Multiple linear regressions examined main effects of health literacy, message emotionality, and message framing on: (a) risk perceptions, (b) behavioral expectations (i.e. cut down, limit, quit), and (c) risk knowledge. Two-way interactions of health literacy with emotionality and framing were examined for these outcomes. Analyses were based on theory-driven, a priori hypotheses. Results: As hypothesized, main effects emerged such that smokers with higher health literacy reported stronger risk perceptions and knowledge retention regardless of message type. Additionally, emotional (vs. factual) and gain- (vs. loss-) framed messages were associated with certain lower risk perceptions regardless of health literacy level. Consistent with hypotheses, two-way crossover interactions emerged between health literacy and emotionality. Among smokers with higher health literacy, factual messages produced higher perceived risk and stronger expectations for quitting. Among smokers with lower health literacy, emotional messages produced higher perceived risk and stronger expectations for quitting. Conclusions: Health literacy plays an important role in influencing how smokers respond to different risk messages. One's health literacy should be considered when determining whether risk communications emphasize factual or emotional content.

HIV Care Initiation: A Teachable Moment for Smoking Cessation?

Introduction: Tobacco use among persons living with HIV represents an important risk factor for poor treatment outcomes, morbidity, and mortality. Thus, efforts designed to inform the development of appropriate smoking cessation programs for this population remains a public health priority. To address this need, a study was conducted to longitudinally assess the relationship between intention to quit smoking and cessation over the 12-month period following initiation of HIV care. Methods: Patients initiating HIV care at a large inner city safety net clinic were enrolled (n = 378) in a 12-month prospective study. Audio computer-assisted self-interviews were conducted at baseline, and at 3, 6, 9, and 12 months post-enrollment, and HIV-related clinical data were collected from participants' electronic medical records. Variables of interest included intention to quit smoking, 7-day point prevalence smoking abstinence (biochemically verified), and stage of HIV. Data were collected in Houston, Texas from 2009 to 2015. Results: The sample was 75% male and 62% Black. Findings indicated that intention to quit smoking increased between baseline and 3 months, and subsequently trended downward from 3 to 12 months. Results from linear and generalized linear mixed models indicated that participants with advanced HIV disease (vs. not advanced) reported significantly (p < .05) higher intention to quit smoking at 3, 6, and 12 months post-study enrollment. A similar though nonsignificant pattern was observed in the smoking abstinence outcome. Conclusions: HIV treatment initiation appears to be associated with increases in intention to quit smoking thus serves as a potential teachable moment for smoking cessation intervention. Implications: This study documents significant increases in intention to quit smoking in the 3-month period following HIV care initiation. Moreover, quit intention trended downward following the 3-month follow-up until the 12-month follow-up. In addition, a marked effect for HIV disease stage was observed, whereby participants with advanced HIV disease (vs. those without) experienced a greater increase in intention to quit. HIV treatment initiation appears to be associated with increases in intention to quit smoking, thus serves as a crucial teachable moment for smoking cessation intervention for people living with HIV.

Effects of galantamine on smoking behavior and cognitive performance in treatment-seeking smokers prior to a quit attempt.

OBJECTIVE: Drugs that enhance cholinergic transmission have demonstrated promise treating addictive disorders. Galantamine, an acetylcholinesterase inhibitor, may reduce cigarette smoking in otherwise healthy treatment-seeking smokers. METHODS: The current study is a double-blind, placebo-controlled, study that randomized daily smokers (n = 60) to receive one of two doses of galantamine extended release (8 or 16 mg/day), or a placebo treatment. Participants completed a smoking choice task as well as study measures and cognitive tasks in the laboratory and daily life using ecological momentary assessment. Analysis focused on smoking behavior and satisfaction, cognitive performance, and decision to smoke prior to a quit attempt. RESULTS: Linear mixed models demonstrated that, compared with placebo, both doses of galantamine reduced smoking in a laboratory choice task (p = 0.006) and decreased urine cotinine levels, but not self-reported cigarettes, during the pre-quit period (p = 0.007). Treatment had minimal effect on smoking satisfaction or cognitive performance. CONCLUSIONS: The results suggest that galantamine reduces nicotine intake but it is unlikely that galantamine improves cognitive performance in otherwise healthy, treatment-seeking smokers. Larger randomized clinical trials can determine if galantamine adjunctive to addiction treatment can improve smoking treatment outcomes.

A systematic review of attentional biases in disorders involving binge eating.

OBJECTIVE: Attentional bias (AB) may be one mechanism contributing to the development and/or maintenance of disordered eating. AB has traditionally been measured using reaction time in response to a stimulus. Novel methods for AB measurement include eye tracking to measure visual fixation on a stimulus, and electroencephalography to measure brain activation in response to a stimulus. This systematic review summarizes, critiques, and integrates data on AB gathered using the above-mentioned methods in those with binge eating behaviors, including binge eating, loss of control eating, and bulimia nervosa. METHOD: Literature searches on PubMed and PsycInfo were conducted using combinations of terms related to binge eating and biobehavioral AB paradigms. Studies using AB paradigms with three categories of stimuli were included: food, weight/shape, and threat. For studies reporting means and standard deviations of group bias scores, Hedges' g effect sizes for group differences in AB were calculated. RESULTS: Fifty articles met inclusion criteria and were reviewed. Individuals who binge eat in the absence of compensatory behaviors show an increased AB to food cues, but few studies have examined such individuals' AB toward weight/shape and threatening stimuli. Individuals with bulimia nervosa consistently show an increased AB to shape/weight cues and socially threatening stimuli, but findings for AB to food cues are mixed. DISCUSSION: While there are important research gaps, preliminary evidence suggests that the combination of AB to disorder-specific cues (i.e., food and weight/shape) and AB toward threat may be a potent contributor to binge eating. This conclusion underscores previous findings on the interaction between negative affect and AB to disorder-specific cues. Recommendations for future research are provided.

Host reticulocytes provide metabolic reservoirs that can be exploited by malaria parasites.

Human malaria parasites proliferate in different erythroid cell types during infection. Whilst Plasmodium vivax exhibits a strong preference for immature reticulocytes, the more pathogenic P. falciparum primarily infects mature erythrocytes. In order to assess if these two cell types offer different growth conditions and relate them to parasite preference, we compared the metabolomes of human and rodent reticulocytes with those of their mature erythrocyte counterparts. Reticulocytes were found to have a more complex, enriched metabolic profile than mature erythrocytes and a higher level of metabolic overlap between reticulocyte resident parasite stages and their host cell. This redundancy was assessed by generating a panel of mutants of the rodent malaria parasite P. berghei with defects in intermediary carbon metabolism (ICM) and pyrimidine biosynthesis known to be important for P. falciparum growth and survival in vitro in mature erythrocytes. P. berghei ICM mutants (pbpepc-, phosphoenolpyruvate carboxylase and pbmdh-, malate dehydrogenase) multiplied in reticulocytes and committed to sexual development like wild type parasites. However, P. berghei pyrimidine biosynthesis mutants (pboprt-, orotate phosphoribosyltransferase and pbompdc-, orotidine 5'-monophosphate decarboxylase) were restricted to growth in the youngest forms of reticulocytes and had a severe slow growth phenotype in part resulting from reduced merozoite production. The pbpepc-, pboprt- and pbompdc- mutants retained virulence in mice implying that malaria parasites can partially salvage pyrimidines but failed to complete differentiation to various stages in mosquitoes. These findings suggest that species-specific differences in Plasmodium host cell tropism result in marked differences in the necessity for parasite intrinsic metabolism. These data have implications for drug design when targeting mature erythrocyte or reticulocyte resident parasites.

ZHOUPI controls embryonic cuticle formation via a signalling pathway involving the subtilisin protease ABNORMAL LEAF-SHAPE1 and the receptor kinases GASSHO1 and GASSHO2.

Seed production in angiosperms requires tight coordination of the development of the embryo and the endosperm. The endosperm-specific transcription factor ZHOUPI has previously been shown to play a key role in this process, by regulating both endosperm breakdown and the formation of the embryonic cuticle. To what extent these processes are functionally linked is, however, unclear. In order to address this issue we have concentrated on the subtilisin-like serine protease encoding gene ABNORMAL LEAF-SHAPE1. Expression of ABNORMAL LEAF-SHAPE1 is endosperm specific, and dramatically decreased in zhoupi mutants. We show that, although ABNORMAL LEAF-SHAPE1 is required for normal embryonic cuticle formation, it plays no role in regulating endosperm breakdown. Furthermore, we show that re-introducing ABNORMAL LEAF-SHAPE1 expression in the endosperm of zhoupi mutants partially rescues embryonic cuticle formation without rescuing their persistent endosperm phenotype. Thus, we conclude that ALE1 can normalize cuticle formation in the absence of endosperm breakdown, and that ZHOUPI thus controls two genetically separable developmental processes. Finally, our genetic study shows that ZHOUPI and ABNORMAL LEAF-SHAPE1 promotes formation of embryonic cuticle via a pathway involving embryonically expressed receptor kinases GASSHO1 and GASSHO2. We therefore provide a molecular framework of inter-tissue communication for embryo-specific cuticle formation during embryogenesis.

Effect of Brief Mindfulness Practice on Self-Reported Affect, Craving, and Smoking: A Pilot Randomized Controlled Trial Using Ecological Momentary Assessment.

INTRODUCTION: Despite efficacious pharmacological and behavioral treatments, most smokers attempt to quit without assistance and fail to quit. Mindfulness practice may be useful in smoking cessation. METHODS: This ecological momentary assessment (EMA) study was a pilot parallel group randomized controlled trial of a brief mindfulness practice (Brief-MP) intervention on self-reported smoking behavior delivered to smokers on a Personal Digital Assistant (PDA) in the field. Adult community smokers (N = 44) were randomly assigned to a Brief-MP (n = 24) or Control (sham meditation; n = 20) group. Participants were instructed to smoke as much or as little as they liked. Participants carried a PDA for 2 weeks and were instructed to initiate 20 minutes of meditation (or control) training on the PDA daily, completing an assessment of cognitive and affective processes immediately afterwards. Additionally, they completed assessments at random times up to four times per day. Primary outcome variables were negative affect, craving, and cigarettes smoked per day, all self-reported. RESULTS: Thirty-seven participants provided EMA data totaling 1874 assessments. Linear Mixed Model analyses on EMA data revealed that Brief-MP (vs. Control) reduced overall negative affect, F(1, 1798) = 13.8, P = .0002; reduced craving immediately post-meditation, (Group × Assessment Type interaction, F(2, 1796) = 12.3, P = .0001); and reduced cigarettes smoked per day over time (Group × Day interaction, F(1, 436) = 5.50, P = .01). CONCLUSIONS: Brief-MP administered in the field reduced negative affect, craving, and cigarette use, suggesting it may be a useful treatment.

Cognitive Function as a Transdiagnostic Treatment Target in Stimulant Use Disorders.

Stimulant use disorder is an important public health problem, with an estimated 2.1 million current users in the United States alone. No pharmacological treatments are approved by the U.S. Food and Drug Administration for stimulant use disorder and behavioral treatments have variable efficacy and limited availability. Most individuals with stimulant use disorder have other comorbidities, most with overlapping symptoms and cognitive impairments. The goal of this article is to present a rationale for cognition as a treatment target in stimulant use disorder and to outline potential treatment approaches. Rates of lifetime comorbid psychiatric disorders among people with stimulant use disorders are estimated at 65% to 73%, with the most common being mood disorders (13% to 64%) and anxiety disorders (21% to 50%), as well as non-substance-induced psychotic disorders (<10%). There are several models of addictive behavior, but the dual process model particularly highlights the relevance of cognitive impairments and biases to the development and maintenance of addiction. This model explains addictive behavior as a balance between automatic processes and executive control, which in turn are related to individual (genetics, comorbid disorders, psychosocial factors) and other (craving, triggers, drug use) factors. Certain cognitive impairments, such as attentional bias and approach bias, are most relevant to automatic processes, while sustained attention, response inhibition, and working memory are primarily related to executive control. These cognitive impairments and biases are also common in disorders frequently comorbid with stimulant use disorder and predict poor treatment retention and clinical outcomes. As such, they may serve as feasible transdiagnostic treatment targets. There are promising pharmacological, cognitive, and behavioral approaches that aim to enhance cognitive function. Pharmacotherapies target cognitive impairments associated with executive control and include cholinesterase inhibitors (e.g., galantamine, rivastigmine) and monoamine transporter inhibitors (e.g., modafinil, methylphenidate). Cognitive behavioral therapy and cognitive rehabilitation also enhance executive control, while cognitive bias modification targets impairments associated with automatic processes. Cognitive enhancement to improve treatment outcomes is a novel and promising strategy, but its clinical value for the treatment of stimulant use disorder, with or without other psychiatric comorbidities, remains to be determined in future studies.