Synthesis and Functional Evaluation of Synthetic Cannabinoid Receptor Agonists Related to ADB-HEXINACA.

ADB-HEXINACA has been recently reported as a synthetic cannabinoid receptor agonist (SCRA), one of the largest classes of new psychoactive substances (NPSs). This compound marks the entry of the n-hexyl tail group into the SCRA landscape, which has continued in the market with recent, newly detected SCRAs. As such, a proactive characterization campaign was undertaken, including the synthesis, characterization, and pharmacological evaluation of ADB-HEXINACA and a library of 41 closely related analogues. Two in vitro functional assays were employed to assess activity at CB1 and CB2 cannabinoid receptors, measuring Gßγ-coupled agonism through a fluorescence-based membrane potential assay (MPA) and ß-arrestin 2 (ßarr2) recruitment via a live cell-based nanoluciferase complementation reporter assay. ADB-HEXINACA was a potent and efficacious CB1 agonist (CB1 MPA pEC50 = 7.87 ± 0.12 M; Emax = 124 ± 5%; ßarr2 pEC50 = 8.27 ± 0.14 M; Emax = 793 ± 42.5), as were most compounds assessed. Isolation of the heterocyclic core and alkyl tails allowed for the comprehensive characterization of structure-activity relationships in this compound class, which were rationalized in silico via induced fit docking experiments. Overall, most compounds assessed are possibly emerging NPSs.

Examining bias in the award of Veterans Affairs (VA) disability benefits for posttraumatic stress disorder in women veterans: Analysis of evaluation reports and VA decisions.

Studies have raised concerns about possible inequities in the U.S. Department of Veterans Affairs (VA)'s awards of disability for posttraumatic stress disorder (PTSD) to women. However, the diagnoses and opinions made by disability examiners have not been studied. A sample of 270 initial PTSD examination reports and corresponding VA decisions were studied. Compared to men, women veterans were as likely to be diagnosed with a service-related mental disorder, χ2 (1, N = 270) = 2.31, p = .129, odds ratio (OR) = 1.79, 95% CI [0.84, 3.80], and be granted service-connection, χ2 (1, N = 270) = 0.49, p = .483, OR = 1.28, 95% CI [0.65, 2.51]. Women veterans were considered to have more psychiatric symptoms, Z = -2.05, p = .041, r = .16, and more psychiatric impairment, Z = -2.48, p = .013, r = .20, but the percentage of disability awarded by the VA did not differ, χ2 (1, N = 270) = 0.49, p = .483; OR = 1.28, 95% CI [0.65, 2.51]. Secondary analyses implicate the role of military sexual trauma and premilitary trauma in explaining sex differences in symptoms and impairment. The findings indicate that neither opinions by examiners nor corresponding decisions by the VA regarding service connection reflect a negative bias toward women veterans. Results indicate that unbiased examinations lead to equitable VA claims decisions for women veterans. Future studies of the VA PTSD disability program nationally, including examination procedures and VA policies and implementation, will promote equity for women veterans in the PTSD claims process.

Detection of Δ9 -tetrahydrocannabinol (THC) in oral fluid using two point-of-collection testing devices following oral administration of a THC and cannabidiol containing oil.

Point-of-collection testing (POCT) devices are widely used in roadside and workplace drug testing to identify recent cannabis use by measuring the presence of Δ9 -tetrahydrocannabinol (THC) in oral fluid (OF). However, the performance of POCT devices with oral medicinal cannabis products remains poorly described. In a randomised, double-blinded, crossover trial, adults with insomnia disorder (n = 20) received a single (2 mL) oral dose of oil containing 10 mg THC + 200 mg cannabidiol, or placebo, prior to sleep. Participants were tested with the Securetec DrugWipe® 5S (10 ng/mL THC cut-off) and Dräger DrugTest® 5000 (25 ng/mL THC cut-off) POCT devices at baseline (pre-treatment) and then at 0.5, 10, and 18 h post-treatment. An OF sample, taken at each time point, was also analysed using liquid chromatography-tandem mass spectrometry. Large individual variability in OF THC concentrations was observed 0.5 h post-treatment (range: 0-425 ng/mL; mean (SD) 48.7 (107.5) ng/mL). Both the Securetec DrugWipe® 5S and DrugTest® 5000 demonstrated poor sensitivity to THC at 0.5 h post-treatment (25% and 50%, respectively). At 10 and 18 h post-treatment, all participant OF THC concentrations were below screening cut-offs, and all test results were negative. These findings highlight the relatively poor sensitivity of both devices in detecting recent use of an oral medicinal cannabis product. They also suggest a low probability of obtaining a positive THC result the morning after ('one-off') use. Further research is required to establish the probability of obtaining a positive THC result with regular medicinal cannabis use.

The mediating role of child delay of gratification in the link between early and prolonged poverty exposure and adolescent allostatic load.

Early and prolonged exposure to poverty disrupts biological processes associated with the body's stress response system, leading to long-term negative health outcomes, including obesity, autoimmune disorders, and cardiovascular disease. Allostatic load (AL), a composite measure of chronic stress on the body, is a robust predictor of subsequent health outcomes. However, developmental research examining the associations of early poverty exposure with AL in adolescence, as well as the underlying mechanisms of influence is limited. Early poverty exposure also impedes healthy development of child self-regulation, which may increase risk for high AL in adolescence, but this mechanistic pathway has not yet been tested. We used data from the national Study of Early Child Care and Youth Development (SECCYD) to examine the longitudinal associations between prolonged poverty exposure in early childhood (0-3 years) and AL in adolescence (age 15). We also tested the mediating role of child delay of gratification, a behavioral measure of self-regulation (at age 54 months), in the potential association between early poverty exposure and adolescent AL. Accounting for model covariates (i.e., child biological sex and race-ethnicity) and individual differences in child delay of gratification, early and prolonged poverty exposure was significantly associated with higher AL at age 15. The indirect effect through child delay of gratification was not significant, but the individual pathways of the indirect effect were significant, and the overall direct association of early poverty exposure with adolescent AL was significant. Our findings show that prolonged exposure to poverty in early childhood (0-3 years) can have significant negative associations with both child delay of gratification (at 54 months) and AL (at age 15). Given that the detrimental impacts of poverty exposure can be detected at an early age, targeted prevention efforts (e.g., anti-poverty programs such as cash assistance programs) may be able to offset some of the risks of early poverty exposure on self-regulation and AL.

Optimizing Digital Tools for the Field of Substance Use and Substance Use Disorders: Backcasting Exercise.

BACKGROUND: Substance use trends are complex; they often rapidly evolve and necessitate an intersectional approach in research, service, and policy making. Current and emerging digital tools related to substance use are promising but also create a range of challenges and opportunities. OBJECTIVE: This paper reports on a backcasting exercise aimed at the development of a roadmap that identifies values, challenges, facilitators, and milestones to achieve optimal use of digital tools in the substance use field by 2030. METHODS: A backcasting exercise method was adopted, wherein the core elements are identifying key values, challenges, facilitators, milestones, cornerstones and a current, desired, and future scenario. A structured approach was used by means of (1) an Open Science Framework page as a web-based collaborative working space and (2) key stakeholders' collaborative engagement during the 2022 Lisbon Addiction Conference. RESULTS: The identified key values were digital rights, evidence-based tools, user-friendliness, accessibility and availability, and person-centeredness. The key challenges identified were ethical funding, regulations, commercialization, best practice models, digital literacy, and access or reach. The key facilitators identified were scientific research, interoperable infrastructure and a culture of innovation, expertise, ethical funding, user-friendly designs, and digital rights and regulations. A range of milestones were identified. The overarching identified cornerstones consisted of creating ethical frameworks, increasing access to digital tools, and continuous trend analysis. CONCLUSIONS: The use of digital tools in the field of substance use is linked to a range of risks and opportunities that need to be managed. The current trajectories of the use of such tools are heavily influenced by large multinational for-profit companies with relatively little involvement of key stakeholders such as people who use drugs, service providers, and researchers. The current funding models are problematic and lack the necessary flexibility associated with best practice business approaches such as lean and agile principles to design and execute customer discovery methods. Accessibility and availability, digital rights, user-friendly design, and person-focused approaches should be at the forefront in the further development of digital tools. Global legislative and technical infrastructures by means of a global action plan and strategy are necessary and should include ethical frameworks, accessibility of digital tools for substance use, and continuous trend analysis as cornerstones.

Severe Hypercalcemia due to Hypervitaminosis D in a Breastfed Infant.

Vitamin D is one of the most commonly recommended dietary supplements and is often the first medication ever prescribed in infancy. However, with the variety of concentrations available, including many over-the-counter formulations, dosing errors can easily occur. We present a case of a breastfed infant with a calcium level greater than 23 mg/dL (5.75 mmol/L), whose severe hypercalcemia was due to hypervitaminosis D from accidentally overdosed vitamin D supplementation. We consider the differential diagnosis for her presentation and review the interventions required for treatment of her hypercalcemia. Notably, we reinforce the importance of carefully reviewing dosing of vitamin D supplementation with families. We also discuss the management of hypercalcemia, including the role of fluids, diuretics, and glucocorticoids, as well as the long-term sequalae of severe hypercalcemia.

Drug policies' sensitivity towards women, pregnancy, and motherhood: a content analysis of national policy and programs from nine countries and their adherence to international guidelines.

BACKGROUND AND OBJECTIVES: Substance use in women is associated with unique psycho-social and physical vulnerabilities and poses complex challenges during pregnancy and motherhood. Gender-sensitive drug policy which considers the needs of women and their children could address these concerns. The objectives of this study were: (1) to systematically explore national-level drug policies' sensitivity and responsiveness to women, pregnant women, and children; and (2) to examine the adherence of drug policies with international guidelines for gender sensitivity in drug policy. METHODS: The research team was diverse professional backgrounds and nine countries. A summative content analysis of national drug policy documents, action plans, and strategies was performed. Specific documents focusing on women, pregnancy, and children were analysed. Specific themes and how frequently they appeared in the documents were identified. This quantification was an attempt to explore usage indicating the relative focus of the policies. A thematic map was developed to understand how national-level drug policies conceive and address specific concerns related to women who use drugs. We adapted the UNODC checklist for gender mainstreaming to assess policies' adherence to international guidelines. RESULTS: Twenty published documents from nine countries were reviewed. The common themes that emerged for women, pregnancy, and children were needs assessment, prevention, treatment, training, supply reduction, and collaboration and coordination. Custody of children was a unique theme for pregnant women. Specific psycho-social concerns and social reintegration were special themes for women, whereas legislation, harm reduction, research, and resource allocation were children-specific additional themes. For women-specific content analysis, special issues/concerns in women with drug misuse, need assessment, and prevention were the three most frequent themes; for the children-specific policies, prevention, training, and treatment comprised the three most occurring themes. For pregnant women/pregnancy, prevention, treatment, and child custody were the highest occurring themes. According to ratings of the countries' policies, there is limited adherence to international guidelines which ensure activities are in sync with the specific needs of women, pregnant women and their children. CONCLUSION: Our analysis should help policymakers revise, update and adapt national policies to ensure they are gender-responsive and address the needs of women, pregnant women and their children.

Vertebral Compression Fractures in Very Early Onset Inflammatory Bowel Disease.

To describe clinical characteristics and outcomes of 3 patients with very early onset inflammatory bowel disease (VEOIBD) and vertebral compression fractures. Methods: Patients with VEOIBD receiving care at a single tertiary center were prospectively enrolled in a longitudinal data repository. Retrospective chart review was performed to identify clinical characteristics and comorbidities. Those with clinically apparent vertebral compression fractures subsequently underwent an additional chart review focused on bone health. Results: Three out of 216 (1.4%) patients with VEOIBD had symptomatic vertebral compression fractures. Of the 3 patients with vertebral compression fractures, all had Crohn's disease, 2 had monogenic inflammatory bowel disease, and all reported back pain. One patient notably had a normal dual-energy X-ray absorptiometry, highlighting a potential limitation of dual-energy X-ray absorptiometry to identify increased skeletal fragility in this population. Risk factors for suboptimal bone health included chronic inflammation secondary to poorly controlled inflammatory bowel disease, substantial glucocorticoid exposure, chronic use of other medications associated with suboptimal bone health including proton pump inhibitors and granulocyte colony-stimulating factor, and solid organ transplant. Patients treated with bisphosphonates had improved clinical outcomes, with resolution of back pain and increased bone mineral density. Conclusions: Vertebral compression fracture should be considered in the differential diagnosis of patients with VEOIBD and back pain, especially in those with other risk factors for suboptimal bone health. Treatment of compression fractures with bisphosphonates resulted in resolution of back pain and improved bone density.

Impact of online learning on sense of belonging among first year clinical health students during COVID-19: student and academic perspectives.

BACKGROUND: The need to belong is a fundamental human desire that provides the basis for relationships and community; it provides a sense of security that enables growth and development. This sense of belonging is pivotal to new University students, indeed, without it, students are at greater risk of failing or withdrawing from their studies. Yet developing a sense of belonging within a new cohort is complex and multi-faceted and further complicated by a sudden shift away from in-person to online learning. Using the situated-learning framework, our study explores first year clinical health students' sense of belonging in the context of the rapid transition to online learning because of the COVID-19 pandemic. METHODS: We utilised a current mixed-method approach including a survey incorporating previously validated tools, demographic and open-ended qualitative questions. Data was also gathered from three focus groups: two dedicated student groups and one academic focus group. Qualitative data was subjected to thematic analysis whilst descriptive statistics were used to describe the quantitative data. RESULTS: 179 first year students complete the survey and four students, and five academics were involved in the focus groups. All participants were from clinical health science courses at an Australian university. Our qualitative results indicated a global theme of: Navigating belonging during the COVID-19 crisis: a shared responsibility; with four organising themes describing (1) dimensions of belonging, (2) individual experiences and challenges, (3) reconceptualising teaching and learning, and (4) relationships are central to belonging. CONCLUSION: While the rapid transition to online learning did not greatly impact knowledge acquisition of first-year students in this cohort, the lack of sense of belonging highlights the need for further research into development of this essential aspect of learning in the online domain. Although contextualised in the COVID-19 pandemic, it became clear that the findings will remain relevant beyond the current situation, as a student's need to belong will always be present in the face of challenges or change.

Childhood Cancer Information-Seeking: Findings from the National Cancer Institute's Cancer Information Service.

The benefits of cancer information-seeking may be particularly salient to individuals impacted by childhood cancer, including patients, caregivers, health professionals, and advocates. The purpose of this study was to explore information-seeking patterns for childhood cancer through the National Cancer Institute's Cancer Information Service (CIS), a multi-channel, bilingual resource for cancer information. The study team conducted descriptive analyses on secondary data characterizing 1820 caregivers, health professionals, organizations, and members of the general public who contacted the CIS about childhood cancer between September 2018 and June 2022. Almost 80% of inquiries about childhood cancer were initiated by caregivers, followed by the public, health professionals, and organizations. Although English was the primary language used by individuals to reach the CIS when discussing childhood cancer, there were variations in points of access (i.e., telephone, instant messaging, email, social media) across the four user groups. Most childhood cancer inquiries were about staging and treatment, and the primary cancer sites discussed by CIS users were neurologic or brain, hematologic, and musculoskeletal cancers. Discussion topics included managing and coping with cancer, clinical trials, and treatment side effects. Just over half (54%) of CIS contacts about childhood cancer resulted in a health professional referral. Findings provide direction for the CIS and other public health organizations to deliver, prioritize, and tailor their services to support the information needs of childhood cancer survivors and their families-as well as those who care and advocate for them-who may have a significant need for credible cancer information.

Zooarchaeology of the Modern Era: An Introduction.

The last 500 years is characterized by immense socioeconomic and environmental transformations on a global scale. Animals were significantly affected by these processes but were also central to many of the transformations that shaped the modern world. While there has been a growing number of researchers investigating animal bones from archaeological sites from this period, the "Zooarchaeology of the Modern Era" working group provides the first dedicated forum for these scholars to meet. This paper introduces a special collection of studies which resulted from the first meeting of this research group and explores how these investigations help us understand our modern world.

Tetrahydrocannabinol and Cannabidiol in Tourette Syndrome.

Tetrahydrocannabinol and Cannabidiol in Tourette SyndromeThis randomized controlled crossover trial examined the use of oral tetrahydrocannabinol (THC) with cannabidiol (CBD) to reduce tics in patients with severe Tourette syndrome. Treatment with THC and CBD for 6 weeks led to a significant reduction in tics as measured by the total tic score on the Yale Global Tic Severity Scale, without major adverse effects.

"Doctor, Can I Drink an Alcohol-Free Beer?" Low-Alcohol and Alcohol-Free Drinks in People with Heavy Drinking or Alcohol Use Disorders: Systematic Review of the Literature.

No- and low-alcohol drinks (NoLo) have been proposed as a potential way forward for the reduction in the alcohol burden of disease. So far, there is scarce synthesized evidence on the effects of these products on people with alcohol use disorder (AUD), or with a heavy or high-risk drinking pattern. The aim of the present study is to systematically review the evidence of the use of NoLo drinks in these populations. A total of 4045 records were screened and 10 studies were included in the review. Craving and desire to drink have been found to increase after the consumption of NoLo drinks in patients with AUD. The increase in craving correlates with the severity of alcohol dependence. In addition, in this population, alcohol-related cues might trigger physiological responses similar to those experienced when using alcohol. Furthermore, as mentioned, in some of the studies, consumption was shown to increase as the %ABV or verbal descriptors indicate lower alcohol. Last, according to the epidemiological data, heavy drinkers tend to use NoLo drinks on top of their usual alcohol consumption rather than as part of regular drinking patterns. Further studies should be conducted in people with AUD or people with a high-risk drinking pattern to provide new insight to guide clinicians, patients, and other stakeholders to make evidence-based informed decisions.

A Bifunctional Chemical Reporter for in Situ Analysis of Cell Envelope Glycan Recycling in Mycobacteria.

In mycobacteria, the glucose-based disaccharide trehalose cycles between the cytoplasm, where it is a stress protectant and carbon source, and the cell envelope, where it is released as a byproduct of outer mycomembrane glycan biosynthesis and turnover. Trehalose recycling via the LpqY-SugABC transporter promotes virulence, antibiotic recalcitrance, and efficient adaptation to nutrient deprivation. The source(s) of trehalose and the regulation of recycling under these and other stressors are unclear. A key technical gap in addressing these questions has been the inability to trace trehalose recycling in situ, directly from its site of liberation from the cell envelope. Here we describe a bifunctional chemical reporter that simultaneously marks mycomembrane biosynthesis and subsequent trehalose recycling with alkyne and azide groups. Using this probe, we discovered that the recycling efficiency for trehalose increases upon carbon starvation, concomitant with an increase in LpqY-SugABC expression. The ability of the bifunctional reporter to probe multiple, linked steps provides a more nuanced understanding of mycobacterial cell envelope metabolism and its plasticity under stress.

Government responses to gender-based violence during COVID-19.

Gender-based violence (GBV) significantly and substantially threatens women's health. The COVID-19 pandemic has exacerbated existing risks and patterns of GBV. The impact of COVID-19 on GBV is not inevitable, however, and can be mediated by the policies of governments. In this study we developed the Government GBV Response Index to systematically examine how countries (N = 60) performed in response to the pandemic with respect to the government 1) enacting specific national-level GBV policy; 2) making dedicated COVID-19 specific funding available; and 3) adapting existing GBV responses to COVID-19 related restrictions and challenges. Most countries (N = 33) delivered fewer than two policy responses. We also performed rapid case study analyses to investigate what might contribute to countries having more comprehensive government policy. We find that civil society organizations played a key role in facilitating GBV policy during the pandemic, especially if they are well-funded and well-connected to the government, and if the country has a high-level government official responsible for gender issues.

Bone marrow adiposity in pediatric Crohn's disease.

Patients with Crohn's disease often have low bone mineral density and an increased risk of osteoporosis. Although decreased bone formation can be seen at diagnosis, the underlying pathophysiology of suboptimal bone accrual remains poorly understood. We sought to evaluate a novel mechanism affecting osteogenesis in patients with Crohn's disease. In this case series, we evaluated bone marrow composition at the distal femur and proximal tibia of the left knee measured via magnetic resonance (MR) spectroscopy and relaxometry in five adolescents with the diagnosis of Crohn's disease. The subjects were enrolled prospectively between 2011 and 2013 at Boston Children's Hospital. Additional clinical information, including DXA scans to evaluate bone mineral density and body composition, and Crohn's disease history, such as glucocorticoid use and disease duration, were assessed. Healthy adolescents have persistent hematopoietic marrow with only 40 to 50 % fat in the long bone metaphyses. The current participants with Crohn's disease had increased marrow adiposity, with a mean fat fraction of 67.8 %. There appeared to be a trend towards higher fat fraction with shorter disease duration, while participants with the longest disease duration had the lowest fat fraction. Participants also had decreased bone density, increased fat mass, and lower lean mass, as assessed by DXA and compared to pediatric reference data. Our MRI results demonstrate increased marrow adiposity in children with Crohn's disease, especially early in the course of the disease. DXA may better demonstrate longer-term effects on bone. Additional studies are needed to evaluate bone marrow composition in these patients and to elucidate further the inverse relationship between marrow adipocytes and osteogenesis, as well as the relationship between bone marrow adiposity and body composition.

Primary Hyperparathyroidism From Ectopic Parathyroid Adenoma in a 12-Year-Old With Slipped Capital Femoral Epiphysis.

Primary hyperparathyroidism has been reported in pediatric patients presenting with slipped capital femoral epiphysis (SCFE), but never in patients with ectopic parathyroid adenoma. A 12-year-old boy with obesity and autism spectrum disorder presented with a limp and was found to have bilateral SCFE. Calcium was elevated to 12.3 mg/dL with parathyroid hormone (PTH) of 1191 pg/mL. Neck ultrasound revealed no parathyroid adenoma. He was discharged following bilateral surgical pinning with plans for outpatient workup. Repeat labs 5 days later demonstrated calcium had risen to 16.7 mg/dL. Technetium-99m sestamibi scintigraphy and a computed tomography scan revealed a 2.7 × 1.6 × 1.9 cm intrathymic mediastinal lesion. He underwent a thoracoscopic resection of the mass, and intraoperative PTH levels fell appropriately. Pathology revealed a parathyroid adenoma. Postoperatively, the patient developed hungry bone syndrome followed by normocalcemic secondary hyperparathyroidism which resolved with high-dose vitamin D supplementation. Primary hyperparathyroidism presenting as SCFE in a pediatric patient has been reported in 13 previous cases. This is the first reported case of bilateral SCFE arising from an ectopic parathyroid adenoma. Thoracoscopic resection is a relatively new approach in pediatrics. Primary hyperparathyroidism can be associated with SCFE, especially bilateral, and should be considered in patients with traditional risk factors for SCFE. Pediatric patients with primary hyperparathyroidism and negative neck imaging should be further evaluated for ectopic parathyroid adenomas with nuclear medicine or cross-sectional imaging that includes the head, neck, and mediastinum. Thoracoscopic resection can be considered in pediatric patients with mediastinal ectopic parathyroid adenoma.

Automaticity and Executive Abilities in Developmental Dyslexia: A Theoretical Review.

Cognitive difficulties are well documented in developmental dyslexia but they present a challenge to dyslexia theory. In this paper, the Model of the Control of Action is proposed as a theoretical explanation of how and why deficits in both automaticity and executive abilities are apparent in the cognitive profiles of dyslexia and how these deficits might relate to literacy difficulties. This theoretical perspective is used to consider evidence from different cognitive domains. The neuroanatomical underpinnings of automaticity and executive abilities are then discussed in relation to the understanding of dyslexia. Links between reading, writing, and executive function are considered. The reviewed evidence suggests that dyslexia theory should consider an interaction between procedural learned behaviour (automaticity) and higher-order (executive) abilities. The capacity to handle environmental interference, develop and engage adaptive strategies accordingly, and plan actions all require interactions between the cerebellum and the prefrontal cortex (PFC). Difficulties in these areas might explain both impairments in the cumulative development of literacy skills in childhood and general task management in everyday life in adulthood. It is suggested that improved measures are required to assess this cerebellar-PFC interaction and to allow early identification of future literacy difficulties, allowing implementation of timely interventions and reasonable adjustments.