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Many studies aggregate prescription opioid misuse (POM) and heroin use into a single phenotype, but emerging evidence suggests that their genetic and environmental influences may be partially distinct.
In total, 7164 individual twins (84.12% complete pairs; 59.81% female; mean age = 30.58 years) from the Australian Twin Registry reported their lifetime misuse of prescription opioids, stimulants, and sedatives, and lifetime use of heroin, cannabis, cocaine/crack, illicit stimulants, hallucinogens, inhalants, solvents, and dissociatives via telephone interview. Independent pathway models (IPMs) and common pathway models (CPMs) partitioned the variance of drug use phenotypes into general and drug-specific genetic (a), common environmental (c), and unique environmental factors (e).
An IPM with one general a and one general e factor and a one-factor CPM provided comparable fit to the data. General factors accounted for 55% (a = 14%, e = 41%) and 79% (a = 64%, e = 15%) of the respective variation in POM and heroin use in the IPM, and 25% (a = 12%, c = 8%, e = 5%) and 80% (a = 38%, c = 27%, e = 15%) of the respective variation in POM and heroin use in the CPM. Across both models, POM emerged with substantial drug-specific genetic influence (26–39% of total phenotypic variance; 69–74% of genetic variance); heroin use did not (0% of total phenotypic variance; 0% of genetic variance in both models). Prescription sedative misuse also demonstrated significant drug-specific genetic variance.
Genetic variation in POM, but not heroin use, is predominantly drug-specific. Misuse of prescription medications that reduce experiences of subjective distress may be partially influenced by sources of genetic variation separate from illicit drug use.
We summarize what we assess as the past year's most important findings within climate change research: limits to adaptation, vulnerability hotspots, new threats coming from the climate–health nexus, climate (im)mobility and security, sustainable practices for land use and finance, losses and damages, inclusive societal climate decisions and ways to overcome structural barriers to accelerate mitigation and limit global warming to below 2°C.
We synthesize 10 topics within climate research where there have been significant advances or emerging scientific consensus since January 2021. The selection of these insights was based on input from an international open call with broad disciplinary scope. Findings concern: (1) new aspects of soft and hard limits to adaptation; (2) the emergence of regional vulnerability hotspots from climate impacts and human vulnerability; (3) new threats on the climate–health horizon – some involving plants and animals; (4) climate (im)mobility and the need for anticipatory action; (5) security and climate; (6) sustainable land management as a prerequisite to land-based solutions; (7) sustainable finance practices in the private sector and the need for political guidance; (8) the urgent planetary imperative for addressing losses and damages; (9) inclusive societal choices for climate-resilient development and (10) how to overcome barriers to accelerate mitigation and limit global warming to below 2°C.
Social media summary
Science has evidence on barriers to mitigation and how to overcome them to avoid limits to adaptation across multiple fields.
Genes associated with educational attainment may be related to or interact with adolescent alcohol, tobacco and cannabis use. Potential gene–environment interplay between educational attainment polygenic scores (EA-PGS) and adolescent alcohol, tobacco, and cannabis use was evaluated with a series of regression models fitted to data from a sample of 1871 adult Australian twins. All models controlled for age, age2, cohort, sex and genetic ancestry as fixed effects, and a genetic relatedness matrix was included as a random effect. Although there was no evidence that adolescent alcohol, tobacco or cannabis use interacted with EA-PGS to influence educational attainment, there was a significant, positive gene–environment correlation with adolescent alcohol use at all PGS thresholds (ps <.02). Higher EA-PGS were associated with an increased likelihood of using alcohol as an adolescent (ΔR2 ranged from 0.5% to 1.1%). The positive gene–environment correlation suggests a complex relationship between educational attainment and alcohol use that is due to common genetic factors.
Background: CDI is the single most common cause of nosocomial diarrhea in both adults and children. Available data regarding treatment outcomes in hospitalized children remain limited. CDI recurrence in children has been reported in 20%–30% of cases. Consensus regarding the best testing method for CDI is lacking. The 2018 IDSA guideline recommends a multistep algorithm with detection of glutamate dehydrogenase antigen plus toxin, followed by detection of toxigenic C. difficle with nucleic acid amplification test (NAAT) if results are discordant. Methods: We included patients aged 1–26 years admitted from July 2020 through June 2021 with CDI symptoms and positive toxin or NAAT. Healthcare facility-onset CDI (HO-CDI) was defined as positive specimen collected >3 days after admission. Community-onset CDI (CO-CDI) was defined as positive specimen collected ≤3 days after admission. Community-onset healthcare facility-associated CDI (CO-HCFA-CDI) was defined as positive specimen from a patient who was discharged from the facility ≤4 weeks prior. Recurrence was defined as an episode of CDI occurring within 60 days after onset of a previous infection. Results: Mean age of the 63 patients meeting inclusion criteria was 11.2 years (range, 1–21 years). Most patients (n = 37; 58.7%) were male, tested negative for C. difficile toxins (n = 39; 61.9%), and had mild-to-moderate disease (n = 61; 96.8%). Patients with immunocompromising conditions were common, including malignancy (n = 38; 60.3%), inflammatory bowel disorder (n = 8; 12.7%), and history of solid organ transplant (n = 5; 7.9%). Previously healthy without chronic medical conditions were uncommon (n = 4; 6.3%). CO-CDI was most common (n = 26; 41.3%) followed by HO-CDI (n = 23; 36.5%). Also, 34 patients (53.9%) were exposed to antibiotics within the previous 30 days, 16 (47.0%) of whom received 2 or more antibiotics. Sulfamethoxazole–trimethoprim was the most prescribed agent (13; 38%), most (12; 92.3%) as prophylaxis for Pneumocystis jirovecii pneumonia. Furthermore, 42 patients (66.7%) were receiving gastric acid suppressant agents. Laxatives were given to 14 patients (22.2%) within 72 hours of testing, despite electronic reminders. Most were treated with oral vancomycin (n = 46; 73.0%). In addition, 5 patients (7.9%) did not receive CDI treatment at the discretion of the treating physician; all were toxin negative. CDI was cured in 58 patients (92.1%) with only 5 (7.9%) experiencing recurrence infection. Patients testing positive for C. difficile toxin were more likely to experience infection recurrence compared to those with a negative toxin screen: 4 of 24 (16.7%) versus 1 of 39 (2.6%) (P = .044). Conclusions: Most patients with CDI were treated with oral vancomycin at our institution. We observed significantly lower rate of recurrence than previously reported. Toxin-positive patients experienced higher recurrence rate. Prospective studies are needed to confirm our findings.
Carbapenemase-producing Enterobacterales (CPE) are important globally. In 2017, Ireland declared a national public health emergency to address CPE in acute hospitals. A National Public Health Emergency Team and an expert advisory group (EAG) were established. The EAG has identified key learnings to inform future strategies. First, there is still an opportunity to prevent CPE becoming endemic. Second, damp environmental reservoirs in hospitals are inadequately controlled. Third, antibiotic stewardship remains important in control. Finally, there is no current requirement to extend screening to detect CPE outside of acute hospitals. These conclusions and their implications may also be relevant in other countries.
Strong associations between neural tube defects (NTDs) and monozygotic (MZ) twinning have long been noted, and it has been suggested that NTD cases who do not present as MZ twins may be the survivors of MZ twinning events. We have recently shown that MZ twins carry a strong, distinctive DNA methylation signature and have developed an algorithm based on genomewide DNA methylation array data that distinguishes MZ twins from dizygotic twins and other relatives at well above chance level. We have applied this algorithm to published methylation data from five fetal tissues (placental chorionic villi, kidney, spinal cord, brain and muscle) collected from spina bifida cases (n = 22), anencephalic cases (n = 15) and controls (n = 19). We see no difference in signature between cases and controls, providing no support for a common etiological role of MZ twinning in NTDs. The strong associations therefore continue to await elucidation.
The objectives of this study were to develop and refine EMPOWER (Enhancing and Mobilizing the POtential for Wellness and Resilience), a brief manualized cognitive-behavioral, acceptance-based intervention for surrogate decision-makers of critically ill patients and to evaluate its preliminary feasibility, acceptability, and promise in improving surrogates’ mental health and patient outcomes.
Part 1 involved obtaining qualitative stakeholder feedback from 5 bereaved surrogates and 10 critical care and mental health clinicians. Stakeholders were provided with the manual and prompted for feedback on its content, format, and language. Feedback was organized and incorporated into the manual, which was then re-circulated until consensus. In Part 2, surrogates of critically ill patients admitted to an intensive care unit (ICU) reporting moderate anxiety or close attachment were enrolled in an open trial of EMPOWER. Surrogates completed six, 15–20 min modules, totaling 1.5–2 h. Surrogates were administered measures of peritraumatic distress, experiential avoidance, prolonged grief, distress tolerance, anxiety, and depression at pre-intervention, post-intervention, and at 1-month and 3-month follow-up assessments.
Part 1 resulted in changes to the EMPOWER manual, including reducing jargon, improving navigability, making EMPOWER applicable for a range of illness scenarios, rearranging the modules, and adding further instructions and psychoeducation. Part 2 findings suggested that EMPOWER is feasible, with 100% of participants completing all modules. The acceptability of EMPOWER appeared strong, with high ratings of effectiveness and helpfulness (M = 8/10). Results showed immediate post-intervention improvements in anxiety (d = −0.41), peritraumatic distress (d = −0.24), and experiential avoidance (d = −0.23). At the 3-month follow-up assessments, surrogates exhibited improvements in prolonged grief symptoms (d = −0.94), depression (d = −0.23), anxiety (d = −0.29), and experiential avoidance (d = −0.30).
Significance of results
Preliminary data suggest that EMPOWER is feasible, acceptable, and associated with notable improvements in psychological symptoms among surrogates. Future research should examine EMPOWER with a larger sample in a randomized controlled trial.
This chapter studies the literary representation of dancers, particularly child dancers, in Harlem Renaissance fiction, arguing that this focus can help explore anxieties about generational conflict, gender, sexuality, tradition, and urban life. Attending to representations of children provides a fresh perspective from which to examine the significance of dance both in relation to questions of cultural identity (including black modernists’ engagement with the legacies of minstrelsy) and the emotional cultural politics of the Harlem Renaissance. Against the backdrop of a broader preoccupation with black childhood among social scientists, educators, and political activists, representations of child dancers were freighted with contradictory emotions that complicated discourses of racial uplift. This chapter engages with a range of texts, including Zora Neale Hurston’s “Drenched in Light” and Dorothy West’s “An Unimportant man,” to argue that dancing children sometimes embody new possibilities for the future and resistant aesthetics that defy categorization, but they make for anxious, loaded imagery that flickers between embarrassment and pride, pleasure and unease.
Drug classes are grouped based on their chemical and pharmacological properties, but prescription and illicit drugs differ in other important ways. Potential differences in genetic and environmental influences on the (mis)use of prescription and illicit drugs that are subsumed under the same class should be examined. Opioid and stimulant classes contain prescription and illicit forms differentially associated with salient risk factors (common route of administration, legality), making them useful comparators for addressing this etiological issue.
A total of 2410 individual Australian twins [Mage = 31.77 (s.d. = 2.48); 67% women] were interviewed about prescription misuse and illicit use of opioids and stimulants. Univariate and bivariate biometric models partitioned variances and covariances into additive genetic, shared environmental, and unique environmental influences across drug types.
Variation in the propensity to misuse prescription opioids was attributable to genes (41%) and unique environment (59%). Illicit opioid use was attributable to shared (71%) and unique (29%) environment. Prescription stimulant misuse was attributable to genes (79%) and unique environment (21%). Illicit stimulant use was attributable to genes (48%), shared environment (29%), and unique environment (23%). There was evidence for genetic influence common to both stimulant types, but limited evidence for genetic influence common to both opioid types. Bivariate correlations suggested that prescription opioid use may be more genetically similar to prescription stimulant use than to illicit opioid use.
Prescription opioid misuse may share little genetic influence with illicit opioid use. Future research may consider avoiding unitary drug classifications, particularly when examining genetic influences.
Despite abundant research on the potential causal influence of childhood maltreatment (CM) on psychological maladaptation in adulthood, almost none has implemented the discordant twin design as a means of examining the role of such experiences in later disordered gambling (DG) while accounting for genetic and family environmental confounds. The present study implemented such an approach to disentangle the potential causal and familial factors that may account for the association between CM and DG.
Participants were 3750 twins from the Australian Twin Registry [Mage = 37.60 (s.d. = 2.31); 58% female]. CM and DG were assessed separately via two semi-structured telephone interviews. Random-intercept generalized linear mixed models were fit to the data; zygosity, sex, educational attainment, childhood psychiatric disorder, adult antisocial behavior, and alcohol use disorder (AUD) were included as covariates.
Neither quasi-causal nor familial effects of CM predicted DG after adjusting for covariates. Educational attainment appeared to reduce the risk of DG while AUD appeared to increase risk; evidence also emerged for familial effects of antisocial behavior on DG. Post-hoc analyses revealed a familial effect of CM on antisocial behavior, indicating that the association between CM and DG identified in unadjusted models and in prior studies may be accounted for by genetic and shared family environmental effects of antisociality.
These findings add to the meager literature showing that CM does not exert a causal effect on DG, and present novel evidence that familial effects of antisocial behavior may account for the association between CM and DG identified in extant non-twin research.
To investigate the association between energy drink (ED) use and sleep-related disturbances in a population-based sample of young adults from the Raine Study.
Analysis of cross-sectional data obtained from self-administered questionnaires to assess ED use and sleep disturbance (Epworth Sleepiness Scale, Functional Outcomes of Sleep Questionnaire (FOSQ-10) and the Pittsburgh Sleep Symptoms Questionnaire–Insomnia (PSSQ-I)). Regression modelling was used to estimate the effect of ED use on sleep disturbances. All models adjusted for various potential confounders.
Males and females, aged 22 years, from Raine Study Gen2–22 year follow-up.
Of the 1115 participants, 66 % were never/rare users (i.e. <once/month) of ED, 17·0 % were occasional users (i.e. >once/month to <once/week) and 17 % were frequent users (≥once/week). Compared with females, a greater proportion of males used ED occasionally (19 % v. 15 %) or frequently (24 % v. 11 %). Among females, frequent ED users experienced significantly higher symptoms of daytime sleepiness (FOSQ-10: β = 0·93, 95 % CI 0·32, 1·54, P = 0·003) and were five times more likely to experience insomnia (PSSQ-I: OR = 5·10, 95 % CI 1·81, 14·35, P = 0·002) compared with never/rare users. No significant associations were observed in males for any sleep outcomes.
We found a positive association between ED use and sleep disturbances in young adult females. Given the importance of sleep for overall health, and ever-increasing ED use, intervention strategies are needed to curb ED use in young adults, particularly females. Further research is needed to determine causation and elucidate reasons for gender-specific findings.
To evaluate the feasibility and acceptability of the Takeaway Masterclass, a three-hour training session delivered to staff of independent takeaway food outlets that promoted healthy cooking practices and menu options.
A mixed-methods study design. All participating food outlets provided progress feedback at 6 weeks post-intervention. Baseline and 6-week post-intervention observational and self-reported data were collected in half of participating takeaway food outlets.
North East England.
Independent takeaway food outlet owners and managers.
Staff from eighteen (10 % of invited) takeaway food outlets attended the training; attendance did not appear to be associated with the level of deprivation of food outlet location. Changes made by staff that required minimal effort or cost to the business were the most likely to be implemented and sustained. Less popular changes included using products that are difficult (or expensive) to source from suppliers, or changes perceived to be unpopular with customers.
The Takeaway Masterclass appears to be a feasible and acceptable intervention for improving cooking practices and menu options in takeaway food outlets for those who attended the training. Further work is required to increase participation and retention and explore effectiveness, paying particular attention to minimising adverse inequality effects.
Gambling disorder (GD), recognized in Diagnostic and Statistical Manual of Mental Disorders, Version 5 (DSM-5) as a behavioral addiction, is associated with a range of adverse outcomes. However, there has been little research on the genetic and environmental influences on the development of this disorder. This study reports results from the largest twin study of GD conducted to date.
Replication and combined analyses were based on samples of 3292 (mean age 31.8, born 1972–79) and 4764 (mean age 37.7, born 1964–71) male, female, and unlike-sex twin pairs from the Australian Twin Registry. Univariate biometric twin models estimated the proportion of variation in the latent GD liability that could be attributed to genetic, shared environmental, and unique environmental factors, and whether these differed quantitatively or qualitatively for men and women.
In the replication study, when using a lower GD threshold, there was evidence for significant genetic (60%; 95% confidence interval (CI) 45–76%) and unique environmental (40%; 95% CI 24–56%), but not shared environmental contributions (0%; 95% CI 0–0%) to GD liability; this did not significantly differ from the original study. In the combined analysis, higher GD thresholds (such as one consistent with DSM-5 GD) and a multiple threshold definitions of GD yielded similar results. There was no evidence for quantitative or qualitative sex differences in the liability for GD.
Twin studies of GD are few in number but they tell a remarkably similar story: substantial genetic and unique environmental influences, with no evidence for shared environmental contributions or sex differences in GD liability.
Like other Western societies, the UK is undergoing important social and demographic changes, most notably the continued ‘ageing’ of the population and the increasing ethnic diversity of the older population. In the UK ethnicity is defined on the basis of self-identification from a standard list of categories included in routine administrative data collection, social surveys and the decennial census. This approach recognises that ethnicity is a multidimensional concept that embraces a constellation of characteristics including country of birth, skin colour, language(s) spoken, nationality, culture and religion, and which represents an individual/group identity that is grounded in shared origins or social background; shared culture and traditions that are distinctive and maintained between generations; and a common language and/or religious tradition. Fundamental to the concept of ethnicity is that it represents an individual's self-assessment of their status and, consequently, may change over time and is not externally attributed or imposed by others. In terms of diversity, the 2011 Census data report that 16 per cent of the population of England and Wales self-define themselves as non-White compared with 5 per cent in 1991, with approximately 4 per cent self-defining as Black/African-Caribbean and 5 per cent as South Asian (2.5 per cent Indian, 2 per cent Pakistani and 0.8 per cent Bangladeshi).
These two demographic trends noted above intersect with the ageing of the communities of migrants who came to the UK from the Caribbean and India in the 1950s, from Pakistan in the 1970s, with the Bangladeshi group arriving in the late 1970s and early 1980s. For these groups migration was for a range of reasons including economic opportunities, family reunification or because of expulsion from their country of residence in the case of the Ugandan Asians. Eighteen per cent of the White population of England and Wales are aged over 65 compared with 14 per cent of the African Caribbean group, 8 per cent of the Indian community and 4 per cent each for the Pakistani and Bangladeshi populations (Lievesley, 2010). A key feature of these ageing members of our minority populations is that they are almost exclusively comprised of first-generation migrants (Herbert, 2008; Qureshi, 1988).
OBJECTIVES/SPECIFIC AIMS: Unlike the high cure rates (90%) of children with acute lymphoblastic leukemia (ALL), that of adults is still lagging behind and better therapies are needed. Maternal embryonic leucine-zipper kinase (MELK) is aberrantly upregulated in cancer, and implicated in cancer stem cell survival. A recent study has identified FOXM1, a MELK substrate, as a therapeutic target in B cell ALL (B-ALL). Thus, we hypothesized that MELK may act as a therapeutic target in ALL via targeting FOXM1 activity. METHODS/STUDY POPULATION: Western blot and qPCR were used to assess MELK expression in 14 ALL cell lines. Knock-down and kinase inhibition approaches targeting MELK expression and function, followed by CCK-8 and Annexin V (flow cytometry) assays to measure cell viability and apoptosis, respectively. RESULTS/ANTICIPATED RESULTS: MELK was significantly upregulated in patients with ALL (oncomine data analysis). MELK was also significantly higher in B-ALL and T-ALL cell lines compared with that in blood cells of healthy donors. MELK knock-down significantly decreased cell viability (40%–70%, p<0.05, Fig. 1) in ALL cells, and induced apoptosis (~40%). OTS167, a potent MELK inhibitor exhibited cytotoxic activities in both B and T-ALL cells. The IC50 of OTS167 ranged from 20 to 60 nM; we also found a significant increase in apoptosis (p<0.05). Mechanistically, MELK inhibition resulted in decrease of FOXM1 protein levels 3 hours post-treatment. DISCUSSION/SIGNIFICANCE OF IMPACT: MELK is highly expressed in ALL and represents a novel therapeutic target likely via modulating FOXM1 activity. Functional and mechanistic studies will complement and ensure the success of the undergoing Phase I/II clinical trial of OTS167 in patients with refractory or relapsed AML, ALL, and other advanced hematologic malignancies.
To identify sociodemographic characteristics associated with frequency of consuming home-cooked meals and meals from out-of-home sources.
Cross-sectional analysis of a population-based cohort study. Frequency of consuming home-cooked meals, ready meals, takeaways and meals out were derived from a participant questionnaire. Sociodemographic characteristics regarding sex, age, ethnicity, working overtime and socio-economic status (SES; measured by household income, educational attainment, occupational status and employment status) were self-reported. Sociodemographic differences in higher v. lower meal consumption frequency were explored using logistic regression, adjusted for other key sociodemographic variables.
Fenland Study participants (n 11 326), aged 29–64 years at baseline.
Eating home-cooked meals more frequently was associated with being female, older, of higher SES (measured by greater educational attainment and household income) and not working overtime. Being male was associated with a higher frequency of consumption for all out-of-home meal types. Consuming takeaways more frequently was associated with lower SES (measured by lower educational attainment and household income), whereas eating out more frequently was associated with higher SES (measured by greater educational attainment and household income) and working overtime.
Sociodemographic characteristics associated with frequency of eating meals from different out-of-home sources varied according to meal source. Findings may be used to target public health policies and interventions for promoting healthier diets and dietary-related health towards people consuming home-cooked meals less frequently, such as men, those with lower educational attainment and household income, and overtime workers.
Whether monozygotic (MZ) and dizygotic (DZ) twins differ from each other in a variety of phenotypes is important for genetic twin modeling and for inferences made from twin studies in general. We analyzed whether there were differences in individual, maternal and paternal education between MZ and DZ twins in a large pooled dataset. Information was gathered on individual education for 218,362 adult twins from 27 twin cohorts (53% females; 39% MZ twins), and on maternal and paternal education for 147,315 and 143,056 twins respectively, from 28 twin cohorts (52% females; 38% MZ twins). Together, we had information on individual or parental education from 42 twin cohorts representing 19 countries. The original education classifications were transformed to education years and analyzed using linear regression models. Overall, MZ males had 0.26 (95% CI [0.21, 0.31]) years and MZ females 0.17 (95% CI [0.12, 0.21]) years longer education than DZ twins. The zygosity difference became smaller in more recent birth cohorts for both males and females. Parental education was somewhat longer for fathers of DZ twins in cohorts born in 1990–1999 (0.16 years, 95% CI [0.08, 0.25]) and 2000 or later (0.11 years, 95% CI [0.00, 0.22]), compared with fathers of MZ twins. The results show that the years of both individual and parental education are largely similar in MZ and DZ twins. We suggest that the socio-economic differences between MZ and DZ twins are so small that inferences based upon genetic modeling of twin data are not affected.
The current study examined a stage-based alcohol use trajectory model to test for potential causal effects of earlier drinking milestones on later drinking milestones in a combined sample of two cohorts of Australian monozygotic and same-sex dizygotic twins (N = 7,398, age M = 30.46, SD = 2.61, 61% male, 56% monozygotic twins). Ages of drinking, drunkenness, regular drinking, tolerance, first nontolerance alcohol use disorder symptom, and alcohol use disorder symptom onsets were assessed retrospectively. Ages of milestone attainment (i.e., age-of-onset) and time between milestones (i.e., time-to-event) were examined via frailty models within a multilevel discordant twin design. For age-of-onset models, earlier ages of onset of antecedent drinking milestones increased hazards for earlier ages of onset for more proximal subsequent drinking milestones. For the time-to-event models, however, earlier ages of onset for the “starting” milestone decreased risk for a shorter time period between the starting and the “ending” milestone. Earlier age of onset of intermediate milestones between starting and ending drinking milestones had the opposite effect, increasing risk for a shorter time period between the starting and ending milestones. These results are consistent with a causal effect of an earlier age of drinking milestone onset on temporally proximal subsequent drinking milestones.