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Cannabis use has been linked to psychotic disorders but this association has been primarily observed in the Global North. This study investigates patterns of cannabis use and associations with psychoses in three Global South (regions within Latin America, Asia, Africa and Oceania) settings.
Case–control study within the International Programme of Research on Psychotic Disorders (INTREPID) II conducted between May 2018 and September 2020. In each setting, we recruited over 200 individuals with an untreated psychosis and individually-matched controls (Kancheepuram India; Ibadan, Nigeria; northern Trinidad). Controls, with no past or current psychotic disorder, were individually-matched to cases by 5-year age group, sex and neighbourhood. Presence of psychotic disorder assessed using the Schedules for Clinical Assessment in Neuropsychiatry and cannabis exposure measured by the World Health Organisation Alcohol, Smoking and Substance Involvement Screening Test (ASSIST).
Cases reported higher lifetime and frequent cannabis use than controls in each setting. In Trinidad, cannabis use was associated with increased odds of psychotic disorder: lifetime cannabis use (adj. OR 1.58, 95% CI 0.99–2.53); frequent cannabis use (adj. OR 1.99, 95% CI 1.10–3.60); cannabis dependency (as measured by high ASSIST score) (adj. OR 4.70, 95% CI 1.77–12.47), early age of first use (adj. OR 1.83, 95% CI 1.03–3.27). Cannabis use in the other two settings was too rare to examine associations.
In line with previous studies, we found associations between cannabis use and the occurrence and age of onset of psychoses in Trinidad. These findings have implications for strategies for prevention of psychosis.
Extensive evidence indicates that rates of psychotic disorder are elevated in more urban compared with less urban areas, but this evidence largely originates from Northern Europe. It is unclear whether the same association holds globally. This study examined the association between urban residence and rates of psychotic disorder in catchment areas in India (Kancheepuram, Tamil Nadu), Nigeria (Ibadan, Oyo), and Northern Trinidad.
Comprehensive case detection systems were developed based on extensive pilot work to identify individuals aged 18–64 with previously untreated psychotic disorders residing in each catchment area (May 2018–April/May/July 2020). Area of residence and basic demographic details were collected for eligible cases. We compared rates of psychotic disorder in the more v. less urban administrative areas within each catchment area, based on all cases detected, and repeated these analyses while restricting to recent onset cases (<2 years/<5 years).
We found evidence of higher overall rates of psychosis in more urban areas within the Trinidadian catchment area (IRR: 3.24, 95% CI 2.68–3.91), an inverse association in the Nigerian catchment area (IRR: 0.68, 95% CI 0.51–0.91) and no association in the Indian catchment area (IRR: 1.18, 95% CI 0.93–1.52). When restricting to recent onset cases, we found a modest positive association in the Indian catchment area.
This study suggests that urbanicity is associated with higher rates of psychotic disorder in some but not all contexts outside of Northern Europe. Future studies should test candidate mechanisms that may underlie the associations observed, such as exposure to violence.
Artificial illumination is a fundamental human need. Burning wood and other materials usually in hearths and fireplaces extended daylight hours, whilst the use of flammable substances in torches offered light on the move. It is increasingly understood that pottery played a role in light production. In this study, we focus on ceramic oval bowls, made and used primarily by hunter-gatherer-fishers of the circum-Baltic over a c. 2000 year period beginning in the mid-6th millennium cal bc. Oval bowls commonly occur alongside larger (cooking) vessels. Their function as ‘oil lamps’ for illumination has been proposed on many occasions but only limited direct evidence has been secured to test this functional association. This study presents the results of molecular and isotopic analysis of preserved organic residues obtained from 115 oval bowls from 25 archaeological sites representing a wide range of environmental settings. Our findings confirm that the oval bowls of the circum-Baltic were used primarily for burning fats and oils, predominantly for the purposes of illumination. The fats derive from the tissues of marine, freshwater, and terrestrial organisms. Bulk isotope data of charred surface deposits show a consistently different pattern of use when oval bowls are compared to other pottery vessels within the same assemblage. It is suggested that hunter-gatherer-fishers around the 55th parallel commonly deployed material culture for artificial light production but the evidence is restricted to times and places where more durable technologies were employed, including the circum-Baltic.
This study examines the political and economic determinants of U.S. foreign direct investment (FDI) in Latin America. The analysis focuses on fifteen Latin American and Caribbean countries for the period of 1979 to 1996. Market size, workers' skill levels, and political instability are found to have a statistically significant effect on the investment behavior of U.S. multinational firms. In addition, we find that a poor human rights record and military coups d'etat positively influenced U.S. FDI flows during the time series.
There is evidence of an association between life events and psychosis in Europe, North America and Australasia, but few studies have examined this association in the rest of the world.
To test the association between exposure to life events and psychosis in catchment areas in India, Nigeria, and Trinidad and Tobago.
We conducted a population-based, matched case–control study of 194 participants in India, Nigeria, and Trinidad and Tobago. Cases were recruited through comprehensive population-based, case-finding strategies. The Harvard Trauma Questionnaire was used to measure life events. The Screening Schedule for Psychosis was used to screen for psychotic symptoms. The association between psychosis and having experienced life events (experienced or witnessed) was estimated by conditional logistic regression.
There was no overall evidence of an association between psychosis and having experienced or witnessed life events (adjusted odds ratio 1.19, 95% CI 0.62–2.28). We found evidence of effect modification by site (P = 0.002), with stronger evidence of an association in India (adjusted odds ratio 1.56, 95% CI 1.03–2.34), inconclusive evidence in Nigeria (adjusted odds ratio 1.17, 95% CI 0.95–1.45) and evidence of an inverse association in Trinidad and Tobago (adjusted odds ratio 0.66, 95% CI 0.44–0.97).
This study found no overall evidence of an association between witnessing or experiencing life events and psychotic disorder across three culturally and economically diverse countries. There was preliminary evidence that the association varies between settings.
Research has shown that 20–30% of prisoners meet the diagnostic criteria for attention-deficit hyperactivity disorder (ADHD). Methylphenidate reduces ADHD symptoms, but effects in prisoners are uncertain because of comorbid mental health and substance use disorders.
To estimate the efficacy of an osmotic-release oral system methylphenidate (OROS-methylphenidate) in reducing ADHD symptoms in young adult prisoners with ADHD.
We conducted an 8-week parallel-arm, double-blind, randomised placebo-controlled trial of OROS-methylphenidate versus placebo in male prisoners (aged 16–25 years) meeting the DSM-5 criteria for ADHD. Primary outcome was ADHD symptoms at 8 weeks, using the investigator-rated Connors Adult ADHD Rating Scale (CAARS-O). Thirteen secondary outcomes were measured, including emotional dysregulation, mind wandering, violent attitudes, mental health symptoms, and prison officer and educational staff ratings of behaviour and aggression.
In the OROS-methylphenidate arm, mean CAARS-O score at 8 weeks was estimated to be reduced by 0.57 points relative to the placebo arm (95% CI −2.41 to 3.56), and non-significant. The responder rate, defined as a 20% reduction in CAARS-O score, was 48.3% for the OROS-methylphenidate arm and 47.9% for the placebo arm. No statistically significant trial arm differences were detected for any of the secondary outcomes. Mean final titrated dose was 53.8 mg in the OROS-methylphenidate arm.
ADHD symptoms did not respond to OROS-methylphenidate in young adult prisoners. The findings do not support routine treatment with OROS-methylphenidate in this population. Further research is needed to evaluate effects of higher average dosing and adherence to treatment, multi-modal treatments and preventative interventions in the community.
To describe the cumulative seroprevalence of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) antibodies during the coronavirus disease 2019 (COVID-19) pandemic among employees of a large pediatric healthcare system.
Design, setting, and participants:
Prospective observational cohort study open to adult employees at the Children’s Hospital of Philadelphia, conducted April 20–December 17, 2020.
Employees were recruited starting with high-risk exposure groups, utilizing e-mails, flyers, and announcements at virtual town hall meetings. At baseline, 1 month, 2 months, and 6 months, participants reported occupational and community exposures and gave a blood sample for SARS-CoV-2 antibody measurement by enzyme-linked immunosorbent assays (ELISAs). A post hoc Cox proportional hazards regression model was performed to identify factors associated with increased risk for seropositivity.
In total, 1,740 employees were enrolled. At 6 months, the cumulative seroprevalence was 5.3%, which was below estimated community point seroprevalence. Seroprevalence was 5.8% among employees who provided direct care and was 3.4% among employees who did not perform direct patient care. Most participants who were seropositive at baseline remained positive at follow-up assessments. In a post hoc analysis, direct patient care (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.03–3.68), Black race (HR, 2.70; 95% CI, 1.24–5.87), and exposure to a confirmed case in a nonhealthcare setting (HR, 4.32; 95% CI, 2.71–6.88) were associated with statistically significant increased risk for seropositivity.
Employee SARS-CoV-2 seroprevalence rates remained below the point-prevalence rates of the surrounding community. Provision of direct patient care, Black race, and exposure to a confirmed case in a nonhealthcare setting conferred increased risk. These data can inform occupational protection measures to maximize protection of employees within the workplace during future COVID-19 waves or other epidemics.
Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
Ancient DNA from Yersinia pestis has been identified in skeletons at four urban burial grounds in Cambridge, England, and at a nearby rural cemetery. Dating to between ad 1349 and 1561, these represent individuals who died of plague during the second pandemic. Most come from normative individual burials, rather than mass graves. This pattern represents a major advance in archaeological knowledge, shifting focus away from a few exceptional discoveries of mass burials to what was normal practice in most medieval contexts. Detailed consideration of context allows the authors to identify a range of burial responses to the second pandemic within a single town and its hinterland. This permits the creation of a richer and more varied narrative than has previously been possible.
ABSTRACT IMPACT: This work will help to understand a novel therapeutic approach to a common type of acute myeloid leukemia. OBJECTIVES/GOALS: FMS-like tyrosine kinase 3 (or FLT3) mutations occur in ˜30% of acute myeloid leukemia (AML) cases. FLT3 tyrosine kinase domain (TKD) mutations are particularly important in relapsed/refractory FLT3 mutant AML, which portends poor prognosis. This study describes a therapeutic approach to overcoming resistance conferred by FLT3-TKD mutations. METHODS/STUDY POPULATION: To understand the efficacy of a novel type 1 FLT3 inhibitor (NCGC1481), as a monotherapy and combination therapy, several assays were utilized to interrogate functionality of these therapies. Cell lines and patient samples containing aspartate 835 to tyrosine mutations (D835Y, the most common TKD alteration) and phenylalanine 691 to leucine (F691L) were utilized to examine the effects of NCGC1481 with and without other targeted therapies like MEK inhibitors. Specifically, assays measuring viability, cell death using flow cytometry, in vitro clonogenicity, cellular signaling, and xenograft survival were examined in these FLT3-TKD AML models. Synergy was also measured using well described methods, which also allowed for appropriate dose finding for drug combination experiments. RESULTS/ANTICIPATED RESULTS: Our novel type 1 FLT3 inhibitor (NCGC1481) was particularly effective in the most common FLT3 TKD mutant, D835Y. NCGC1481 reduced viability and cell signaling, while also inducing cell death and prolonging xenograft survival in the FLT3-D835Y model system. In contrast, clinically approved FLT3 inhibitors were less effective at suppressing AML cells expressing FLT3-D835Y. In the case of FLT3-F691L, most of the FLT3 inhibitors tested, including NCGC1481, suppressed canonical FLT3 signaling, but did not significantly reduce viability or leukemic clonogenicity. However, when NCGC1481 was combined with other targeted agents like MEK inhibitors, at synergistic doses, eradication of the FLT3-F691L AML clone was substantially increased. DISCUSSION/SIGNIFICANCE OF FINDINGS: In AML, response to FLT3 inhibitor therapy is often short-lived, with resistance sometimes occurring via FLT3-TKD mutations. Given the dismal prognosis of relapsed FLT3 mutant AML, novel therapies are necessary. This study describes efficacy of a novel FLT3 inhibitor, along with its synergistic activity when combined with other targeted agents.
Background: A penicillin allergy guidance document containing an algorithm for challenging penicillin allergic patients with β-lactams was developed by the antimicrobial stewardship program (ASP). As part of this algorithm, a “graded challenge” order set was created containing antimicrobial orders and safety medications along with monitoring instructions. The process is designed to challenge patients at low risk of reaction with infusions of 1% of the target dose, then 10%, and finally the full dose, each 30 minutes apart. We evaluated outcomes from the order set. Methods: Orders of the graded challenge over 17 months (March 2018 through July 2019) were reviewed retrospectively. Data were collected on ordering and outcomes of the challenges and allergy documentation. Use was evaluated based on ASP-recommended indications: history of IgE-mediated or unknown reaction plus (1) no previous β-lactam tolerance and the reaction occurred >10 years ago, or (2) previous β-lactam tolerance, now requiring a different β-lactam for treatment. Only administered challenges were included and descriptive statistics were utilized. Results: Of 67 orders, 57 graded challenges were administered to 56 patients. The most common allergies were penicillins (87.7%) and cephalosporins (38.6%), with the most common reactions being unknown (41.7%) or hives (22%). The most common antibiotics challenged were ceftriaxone (43.9%), cefepime (21.1%), and cefazolin (5.3%). Antibiotics given prior to challenge included vancomycin (48.2%), fluoroquinolones (35.7%), carbapenems (21.4%), aztreonam (19.6%), and clindamycin (12.5%). The median duration of challenged antibiotic was 6 days. The infectious diseases service was consulted on 59.6% of challenges and 75.4% of challenges were administered in non-ICU settings. There was 1 reaction (1.8%) involving a rash with the second infusion, which was treated with oral diphenhydramine and had no lasting effects. Based on indications, 80.7% of challenges were aligned with ASP guidance criteria. The most common use outside of these criteria was in patients without IgE-mediated reactions (10.5%). Most of these had minor rashes and could have received a full dose of a cephalosporin. Allergy information was updated in the electronic health record after 91.2% of challenges. Conclusions: We demonstrated the utility of a graded challenge process at our academic medical center. It was well tolerated, ordered frequently by noninfectious diseases clinicians, administered primarily in non-ICU settings, and regularly resulted in updated allergy information in the medical record. With many patients initially receiving broad-spectrum antibiotics with high costs or increased rates of adverse effects, graded challenges can potentially prevent the use of suboptimal therapies with minimal time and resource investment.
Disclosures: Scott Bergman reports a research grant from Merck.
To assess the utility of an automated, statistically-based outbreak detection system to identify clusters of hospital-acquired microorganisms.
Multicenter retrospective cohort study.
The study included 43 hospitals using a common infection prevention surveillance system.
A space–time permutation scan statistic was applied to hospital microbiology, admission, discharge, and transfer data to identify clustering of microorganisms within hospital locations and services. Infection preventionists were asked to rate the importance of each cluster. A convenience sample of 10 hospitals also provided information about clusters previously identified through their usual surveillance methods.
We identified 230 clusters in 43 hospitals involving Gram-positive and -negative bacteria and fungi. Half of the clusters progressed after initial detection, suggesting that early detection could trigger interventions to curtail further spread. Infection preventionists reported that they would have wanted to be alerted about 81% of these clusters. Factors associated with clusters judged to be moderately or highly concerning included high statistical significance, large size, and clusters involving Clostridioides difficile or multidrug-resistant organisms. Based on comparison data provided by the convenience sample of hospitals, only 9 (18%) of 51 clusters detected by usual surveillance met statistical significance, and of the 70 clusters not previously detected, 58 (83%) involved organisms not routinely targeted by the hospitals’ surveillance programs. All infection prevention programs felt that an automated outbreak detection tool would improve their ability to detect outbreaks and streamline their work.
Automated, statistically-based outbreak detection can increase the consistency, scope, and comprehensiveness of detecting hospital-associated transmission.
Opioid antagonists may mitigate medication-associated weight gain and/or metabolic dysregulation. ENLIGHTEN-2 evaluated a combination of olanzapine and the opioid antagonist samidorphan (OLZ/SAM) vs olanzapine for effects on weight gain and metabolic parameters over 24 weeks in adults with stable schizophrenia.
This phase 3, double-blind study (ClinicalTrials.gov: NCT02694328) enrolled adults 18–55 yo with stable schizophrenia, randomized 1:1 to once-daily OLZ/SAM or olanzapine. Co-primary endpoints were percent change from baseline in body weight and proportion of patients with ≥10% weight gain at week 24. Waist circumference and fasting metabolic parameters were also measured. Completers could enter a 52-week open-label safety extension.
561 patients were randomized: 550 were dosed, 538 had ≥1 post-baseline weight assessment, and 352 (64%) completed; 10.9% discontinued due to AEs. At week 24, least squares mean (SE) percent weight change from baseline was 4.21 (0.68)% with OLZ/SAM and 6.59 (0.67)% with olanzapine (difference, −2.38 [0.76]%; P=0.003). Fewer patients treated with OLZ/SAM (17.8%) had ≥10% weight gain vs olanzapine (29.8%; odds ratio=0.50; P=0.003). The change from baseline in waist circumference was significantly smaller with OLZ/SAM (P<0.001). Common AEs (≥10%) with OLZ/SAM and olanzapine were weight increased (24.8%, 36.2%), somnolence (21.2%, 18.1%), dry mouth (12.8%, 8.0%), and increased appetite (10.9%, 12.3%), respectively. Metabolic parameter changes were generally small and remained stable with long-term OLZ/SAM treatment.
OLZ/SAM treatment limited weight gain associated with olanzapine. Metabolic parameter changes were generally small, similar between groups over 24 weeks, and remained stable over an additional 52 weeks of open-label OLZ/SAM treatment.
We describe an ultra-wide-bandwidth, low-frequency receiver recently installed on the Parkes radio telescope. The receiver system provides continuous frequency coverage from 704 to 4032 MHz. For much of the band (
), the system temperature is approximately 22 K and the receiver system remains in a linear regime even in the presence of strong mobile phone transmissions. We discuss the scientific and technical aspects of the new receiver, including its astronomical objectives, as well as the feed, receiver, digitiser, and signal processor design. We describe the pipeline routines that form the archive-ready data products and how those data files can be accessed from the archives. The system performance is quantified, including the system noise and linearity, beam shape, antenna efficiency, polarisation calibration, and timing stability.
This paper presents the results of the work of the new field initiative launched by the British Museum at the Darband-i Rania pass in the Kurdistan Region of Iraq. The pass is located at the northeastern corner of Lake Dokan, where, though now subsumed into the lake, the Lower Zab flows from the Peshdar into the Rania Plain. It is a strategic location on a major route from Mesopotamia into Iran, and control of both the road and the river must always have been important. The aim of the work, which commenced in autumn of 2016, is to explore a cluster of sites that commanded the pass, with a particular focus on the first millennium b.c. Excavation is being carried out principally at two sites: Qalatga Darband, a large fortified site at the western end of the pass, and Usu Aska, a fort inside the pass itself. The occupations of these two sites are predominantly Parthian and Assyrian respectively. Smaller operations have also been carried out at Murad Rasu, a multi-period site situated on a headland across the waters on the southern shore of Lake Dokan. The results have included the discovery at Qalatga Darband of a monumental complex built of stone and roofed with terracotta roof tiles containing the smashed remains of Hellenistic statuary. Other features indicative of Hellenistic material culture are Mediterranean-type oil-presses and Corinthian column bases and capitals. At Usu Aska remains are being uncovered of an Assyrian fortification of massive proportions.