Clinical reports suggest that the most effective strategies for managing opioid use disorder comprise a comprehensive treatment program of both pharmacological and nonpharmacological approaches. However, the conditions under which these combinations are most effective are not well characterized. This study examined whether the presence of an alternative reinforcer could alter the efficacy of Food and Drug Administration–approved opioid antagonist or agonist medications, as well as the nonopioid flumazenil, in decreasing oxycodone choice self-administration in nonhuman primates. Adult squirrel monkeys (n = 7; four females) responded under concurrent second-order fixed-ratio (FR)-3(FR5:S);TO45s schedules of reinforcement for intravenous oxycodone (0.1 mg/kg) or saline on one lever and 30% sweetened condensed milk or water on the other. Doses of naltrexone (0.00032–1.0 mg/kg), nalbuphine (0.32–10 mg/kg), buprenorphine (0.0032–0.032 mg/kg), methadone (0.32–1.0 mg/kg), or flumazenil (1–3.2 mg/kg) were administered intramuscularly prior to oxycodone self-administration sessions that occurred with either milk or water as the alternative. Naltrexone, a μ-opioid receptor antagonist, was >30-fold more potent when milk was available compared with water and abolished oxycodone intake (injections/session) while concomitantly increasing milk deliveries at the highest dose tested. Pretreatment with the low-efficacy μ-agonist nalbuphine was most effective in the presence of milk compared with water, decreasing oxycodone preference to <50% of control values. The higher efficacy μ-agonists, methadone and buprenorphine, and the benzodiazepine antagonist flumazenil did not appreciably alter the reinforcing potency of oxycodone under either condition. These results suggest that antagonist medications used in combination with alternative reinforcers may be an effective strategy to curtail opioid abuse–related behaviors.

Although acute inflammation serves essential functions in maintaining tissue homeostasis, chronic inflammation is causally linked to many diseases. Macrophages are a major cell type that orchestrates inflammatory processes. During inflammation, macrophages undergo polarization and activation, thereby mobilizing pro-inflammatory and anti-inflammatory transcriptional programs that regulate ensuing macrophage functions. Fatty acid binding protein 5 (FABP5) is a lipid chaperone highly expressed in macrophages. FABP5 deletion is implicated in driving macrophages toward an anti-inflammatory phenotype, yet signaling pathways regulated by macrophage-FABP5 have not been systematically profiled. We leveraged proteomic and phosphoproteomic approaches to characterize pathways modulated by FABP5 in M1 and M2 polarized bone marrow-derived macrophages (BMDMs). Stable isotope labeling by amino acids-based analysis of M1 and M2 polarized wild-type and FABP5 knockout BMDMs revealed numerous differentially regulated proteins and phosphoproteins. FABP5 deletion impacted downstream pathways associated with inflammation, cytokine production, oxidative stress, and kinase activity. Toll-like receptor 2 (TLR2) emerged as a novel target of FABP5 and pharmacological FABP5 inhibition blunted TLR2-mediated activation of downstream pathways, ascribing a novel role for FABP5 in TLR2 signaling. This study represents a comprehensive characterization of the impact of FABP5 deletion on the proteomic and phosphoproteomic landscape of M1 and M2 polarized BMDMs. Loss of FABP5 altered pathways implicated in inflammatory responses, macrophage function, and TLR2 signaling. This work provides a foundation for future studies seeking to investigate the therapeutic potential of FABP5 inhibition in pathophysiological states resulting from dysregulated inflammatory signaling.

Cannabinoid and opioid receptor activities can be modulated by a variety of post-translational mechanisms including the formation of interacting complexes. This study examines the involvement of endogenous and exogenous chaperones in modulating the abundance and activity of cannabinoid CB₁ receptor (CB₁R), opioid receptor (DOR), and CB₁R-DOR interacting complexes. Focusing on endogenous protein chaperones, namely receptor transporter proteins (RTPs), we examined relative mRNA expression in the mouse spinal cord and found RTP4 to be expressed at higher levels compared with other RTPs. Next, we assessed the effect of RTP4 on receptor abundance by manipulating RTP4 expression in cell lines. Overexpression of RTP4 causes an increase and knock-down causes a decrease in the levels of CB₁R, DOR, and CB₁R-DOR interacting complexes; this is accompanied by parallel changes in signaling. The ability of small molecule lipophilic ligands to function as exogenous chaperones was examined using receptor-selective antagonists. Long-term treatment leads to increases in receptor abundance and activity with no changes in mRNA supporting a role as pharmacological chaperones. Finally, the effect of cannabidiol (CBD), a small molecule ligand and a major active component of cannabis, on receptor abundance and activity in mice was examined. We find that CBD administration leads to increases in receptor abundance and activity in mouse spinal cord. Together, these results highlight a role for chaperones (proteins and small molecules) in modulating levels and activity of CB₁R, DOR, and their interacting complexes potentially through mechanisms including receptor maturation and trafficking.

Endocannabinoids, which are present throughout the central nervous system (CNS), can activate cannabinoid receptors 1 and 2 (CB1 and CB2). CB1 and CB2 agonists exhibit broad anti-inflammatory properties, suggesting their potential to treat inflammatory diseases. However, careful evaluation of abuse potential is necessary. This study evaluated the abuse potential of lenabasum, a selective CB2 receptor agonist in participants (n = 56) endorsing recreational cannabis use. Three doses of lenabasum (20, 60, and 120 mg) were compared with placebo and nabilone (3 and 6 mg). The primary endpoint was the peak effect (E_max) on a bipolar Drug Liking visual analog scale (VAS). Secondary VAS and pharmacokinetic (PK) endpoints and adverse events were assessed. Lenabasum was safe and well tolerated. Compared with placebo, a 20-mg dose of lenabasum did not increase ratings of Drug Liking and had no distinguishable effect on other VAS endpoints. Dose-dependent increases in ratings of Drug Liking were observed with 60 and 120 mg lenabasum. Drug Liking and all other VAS outcomes were greatest for nabilone 3 mg and 6 mg, a medication currently approved by the US Food and Drug Administration (FDA). At a target therapeutic dose (20 mg), lenabasum did not elicit subjective ratings of Drug Liking. However, supratherapeutic doses of lenabasum (60 and 120 mg) did elicit subjective ratings of Drug Liking compared with placebo. Although both doses of lenabasum were associated with lower ratings of Drug Liking compared with 3 mg and 6 mg nabilone, lenabasum does have abuse potential and should be used cautiously in clinical settings.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy treatment, routinely manifesting as increased pain sensitivity (allodynia) in distal extremities. Despite its prevalence, effective treatment options are limited. Cannabinoids are increasingly being evaluated for their ability to treat chronic pain conditions, including CIPN. While previous studies have revealed sex differences in cannabinoid-mediated antinociception in acute and chronic pain models, there is a paucity of studies addressing potential sex differences in the response of CIPN to cannabinoid treatment. Therefore, we evaluated the long-term antiallodynic efficacy of cannabinoid receptor type 1 (CB₁)-selective, cannabinoid receptor type 2 (CB₂)-selective, and CB₁/CB₂ mixed agonists in the cisplatin CIPN model, using both male and female mice. CB₁ selective agonism was observed to have sex differences in the development of tolerance to antiallodynic effects, with females developing tolerance more rapidly than males, while the antiallodynic effects of selective CB₂ agonism lacked tolerance development. Compound-specific changes to the female estrous cycle and female plasma estradiol levels were noted, with CB₁ selective agonism decreasing plasma estradiol while CB₂ selective agonism increased plasma estradiol. Chronic administration of a mixed CB₁/CB₂ agonist resulted in increased mRNA expression of proinflammatory cytokines and endocannabinoid regulatory enzymes in female spinal cord tissue. Ovarian tissue was noted to have proinflammatory cytokine mRNA expression following administration of a CB₂ acting compound while selective CB₁ agonism resulted in decreased proinflammatory cytokines and endocannabinoid regulatory enzymes in testes. These results support the need for further investigation into the role of sex and sex hormones signaling in pain and cannabinoid-mediated antinociceptive effects.

Oxidative stress, fibrosis, and inflammasome activation from advanced glycation end product (AGE)–receptor of advanced glycation end product (RAGE) interaction contribute to diabetic cardiomyopathy (DCM) formation and progression. Our study revealed the impact of β-caryophyllene (BCP) on activating cannabinoid type 2 receptors (CB2Rs) against diabetic complication, mainly cardiomyopathy and investigated the underlying cell signaling pathways in mice. The murine model of DCM was developed by feeding a high-fat diet with streptozotocin injections. After the development of diabetes, the animals received a 12-week oral BCP treatment at a dose of 50 mg/kg/body weight. BCP treatment showed significant improvement in glucose tolerance and insulin resistance and enhanced serum insulin levels in diabetic animals. BCP treatment effectively reversed the heart remodeling and restored the phosphorylated troponin I and sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a expression. Ultrastructural examination showed reduced myocardial cell injury in DCM mice treated with BCP. The preserved myocytes were found to be associated with reduced expression of AGE/RAGE in DCM mice hearts. BCP treatment mitigated oxidative stress by inhibiting expression of NADPH oxidase 4 and activating phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor erythroid 2–related factor 2 (Nrf2) signaling. Also, BCP suppressed cardiac fibrosis and endothelial-to-mesenchymal transition in DCM mice by inhibiting transforming growth factor β (TGF-β)/suppressor of mothers against decapentaplegic (Smad) signaling. Further, BCP treatment suppressed nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasome activation in DCM mice and alleviated cellular injury to the pancreatic tissues evidenced by significant elevation of the number of insulin-positive cells. To demonstrate a CB2R-dependent mechanism of BCP, another group of DCM mice were pretreated with AM630, a CB2R antagonist. AM630 was observed to abrogate the beneficial effects of BCP in DCM mice. Taken together, BCP demonstrated the potential to protect the myocardium and pancreas of DCM mice mediating CB2R-dependent mechanisms.

Neuropathic pain is a form of chronic pain that develops because of damage to the nervous system. Treatment of neuropathic pain is often incompletely effective, and most available therapeutics have only moderate efficacy and present side effects that limit their use. Opioids are commonly prescribed for the management of neuropathic pain despite equivocal results in clinical studies and significant abuse potential. Thus, neuropathic pain represents an area of critical unmet medical need, and novel classes of therapeutics with improved efficacy and safety profiles are urgently needed. The cannabidiol structural analog and novel antagonist of GPR55, KLS-13019, was screened in rat models of neuropathic pain. Tactile sensitivity associated with chemotherapy exposure was induced in rats with once-daily 1-mg/kg paclitaxel injections for 4 days or 5 mg/kg oxaliplatin every third day for 1 week. Rats were then administered KLS-13019 or comparator drugs on day 7 in an acute dosing paradigm or days 7–10 in a chronic dosing paradigm, and mechanical or cold allodynia was assessed. Allodynia was reversed in a dose-dependent manner in the rats treated with KLS-13019, with the highest dose reverting the response to prepaclitaxel injection baseline levels with both intraperitoneal and oral administration after acute dosing. In the chronic dosing paradigm, four consecutive doses of KLS-13019 completely reversed allodynia for the duration of the phenotype in control animals. Additionally, coadministration of KLS-13019 with paclitaxel prevented the allodynic phenotype from developing. Together, these data suggest that KLS-13019 represents a potential new drug for the treatment of neuropathic pain.

Patients with arthritis report using cannabis for pain management, and the major cannabinoid delta-9-tetrahydrocannabinol (⁹-THC) has anti-inflammatory properties, yet the effects of minor cannabinoids on arthritis are largely unknown. The goal of the present study was to determine the antiarthritic potential of the minor cannabinoid delta-8-tetrahydrocannabinol (⁸-THC) using the collagen-induced arthritis (CIA) mouse model. Adult male DBA/1J mice were immunized and boosted 21 days later with an emulsion of collagen and complete Freund’s adjuvant. Beginning on the day of the booster, mice were administered twice-daily injections of ⁸-THC (3 or 30 mg/kg), the steroid dexamethasone (2 mg/kg), or vehicle for two weeks. Dorsal-ventral paw thickness and qualitative measures of arthritis were recorded daily, and latency to fall from an inverted grid was measured on alternating days, to determine arthritis severity and functional impairment. On the final day of testing, spontaneous wire-climbing behavior and temperature preference in a thermal gradient ring were measured to assess CIA-depressed behavior. The ⁸-THC treatment (30 mg/kg) reduced paw swelling and qualitative signs of arthritis. ⁸-THC also blocked CIA-depressed climbing and CIA-induced preference for a heated floor without producing locomotor effects but did not affect latency to fall from a wire grid. In alignment with the morphologic and behavioral assessments in vivo, histology revealed that ⁸-THC reduced synovial inflammation, proteoglycan loss and cartilage and bone erosion in the foot joints in a dose-dependent manner. Together, these findings suggest that ⁸-THC not only blocked morphologic changes but also prevented functional loss caused by collagen-induced arthritis.

Chronic pain conditions affect nearly 20% of the population in the United States. Current medical interventions, such as opioid drugs, are effective at relieving pain but are accompanied by many undesirable side effects. This is one reason increased numbers of chronic pain patients have been turning to Cannabis for pain management. Cannabis contains many bioactive chemical compounds; however, current research looking into lesser-studied minor cannabinoids in Cannabis lacks uniformity between experimental groups and/or excludes female mice from investigation. This makes it challenging to draw conclusions between experiments done with different minor cannabinoid compounds between laboratories or parse out potential sex differences that could be present. We chose five minor cannabinoids found in lower quantities within Cannabis: cannabinol (CBN), cannabidivarin (CBDV), cannabigerol (CBG), 8-tetrahydrocannabinol (8-THC), and 9-tetrahydrocannabivarin (THCV). These compounds were then tested for their cannabimimetic and pain-relieving behaviors in a cannabinoid tetrad assay and a chemotherapy-induced peripheral neuropathy (CIPN) pain model in male and female CD-1 mice. We found that the minor cannabinoids we tested differed in the cannabimimetic behaviors evoked, as well as the extent. We found that CBN, CBG, and high-dose 8-THC evoked some tetrad behaviors in both sexes, while THCV and low-dose 8-THC exhibited cannabimimetic tetrad behaviors only in females. Only CBN efficaciously relieved CIPN pain, which contrasts with reports from other researchers. Together these findings provide further clarity to the pharmacology of minor cannabinoids and suggest further investigation into their mechanism and therapeutic potential.

There is a growing interest in the use of medicinal plants to treat a variety of diseases, and one of the most commonly used medicinal plants globally is Cannabis sativa. The two most abundant cannabinoids (⁹-tetrahydrocannabinol and cannabidiol) have been governmentally approved to treat selected medical conditions; however, the plant produces over 100 cannabinoids, including cannabichromene (CBC). Although the cannabinoids share a common precursor molecule, cannabigerol, they are structurally and pharmacologically unique. These differences may engender differing therapeutic potentials. In this review, we will examine what is currently known about CBC with regards to pharmacodynamics, pharmacokinetics, and receptor profile. We will also discuss the therapeutic areas that have been examined for this cannabinoid, notably antinociceptive, antibacterial, and anti-seizure activities. Finally, we will discuss areas where new research is needed and potential novel medicinal applications for CBC.

⁹-Tetrahydrocannabinol (THC) is a psychoactive phytocannabinoid found in the Cannabis sativa plant. THC is primarily metabolized into 11-hydroxy-⁹-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-⁹-tetrahydrocannabinol (COOH-THC), which may themselves be psychoactive. There is very little research-based evidence concerning the pharmacokinetics and pharmacodynamics of 11-OH-THC as an individual compound. Male C57BL/6 mice were treated with THC or 11-OH-THC via intraperitoneal injection, tail vein intravenous injection, or oral gavage, and whole-blood compound levels were measured to determine pharmacokinetic parameters [C_max, time to C_max (T_max), elimination half-life, area under the curve, apparent volume of distribution, systemic clearance, terminal rate constant, and absolute bioavailability] while also monitoring changes in catalepsy, body temperature, and nociception. 11-OH-THC achieved a T_max at 30 minutes for all routes of administration. The maximum concentration at 30 minutes was not different between intravenous and intraperitoneal routes, but the oral gavage C_max was significantly lower. THC had a 10-minute time to the maximum concentration, which was the first blood collection time point, for intravenous and intraperitoneal and 60 minutes for oral gavage, with a lower C_max for intraperitoneal and oral gavage compared with intravenous. When accounting for circulating compound levels and ED₅₀ responses, these data suggest that 11-OH-THC was 153% as active as THC in the tail-flick test of nociception and 78% as active as THC for catalepsy. Therefore, 11-OH-THC displayed equal or greater activity than the parent compound THC, even when accounting for pharmacokinetic differences. Thus, the THC metabolite 11-OH-THC likely plays a critical role in the bioactivity of cannabis; understanding its activity when administered directly will aid in the interpretation of future animal and human studies.

The consumption of ⁹-tetrahydrocannabinol (THC)- or cannabis-containing edibles has increased in recent years; however, the behavioral and neural circuit effects of such consumption remain unknown, especially in the context of ingestion of higher doses resulting in cannabis intoxication. We examined the neural and behavioral effects of acute high-dose edible cannabis consumption (AHDECC). Sprague-Dawley rats (six males, seven females) were implanted with electrodes in the prefrontal cortex (PFC), dorsal hippocampus (dHipp), cingulate cortex (Cg), and nucleus accumbens (NAc). Rats were provided access to a mixture of Nutella (6 g/kg) and THC-containing cannabis oil (20 mg/kg) for 10 minutes, during which they voluntarily consumed all of the provided Nutella and THC mixture. Cannabis tetrad and neural oscillations were examined 2, 4, 8, and 24 hours after exposure. In another cohort (16 males, 15 females), we examined the effects of AHDECC on learning and prepulse inhibition and serum and brain THC and 11-hydroxy-THC concentrations. AHDECC resulted in higher brain and serum THC and 11-hydroxy-THC levels in female rats over 24 hours. AHDECC also produced: 1) Cg, dHipp, and NAc gamma power suppression, with the suppression being greater in female rats, in a time-dependent manner; 2) hypolocomotion, hypothermia, and antinociception in a time-dependent manner; and 3) learning and prepulse inhibition impairments. Additionally, most neural activity and behavior changes appear 2 hours after ingestion, suggesting that interventions around this time might be effective in reversing/reducing the effects of AHDECC.

People with sickle cell disease (SCD) often experience chronic pain as well as unpredictable episodes of acute pain, which significantly affects their quality of life and life expectancy. Current treatment strategies for SCD-associated pain primarily rely on opioid analgesics, which have limited efficacy and cause serious adverse effects. Cannabis has emerged as a potential alternative, yet its efficacy remains uncertain. In this study, we investigated the antinociceptive effects of ⁹-tetrahydrocannabinol (THC), cannabis’ intoxicating constituent, in male HbSS mice, which express >99% human sickle hemoglobin, and male HbAA mice, which express normal human hemoglobin A, as a control. Acute THC administration (0.1–3 mg/kg^–1, i.p.) dose-dependently reduced mechanical and cold hypersensitivity in human sickle hemoglobin (HbSS) but not human normal hemoglobin A (HbAA) mice. In the tail-flick assay, THC (1 and 3 mg/kg^–1, i.p.) produced substantial antinociceptive effects in HbSS mice. By contrast, THC (1 mg/kg^–1, i.p.) did not alter anxiety-like behavior (elevated plus maze) or long-term memory (24-hour novel object recognition). Subchronic THC treatment (1 and 3 mg/kg^–1, i.p.) provided sustained relief of mechanical hypersensitivity but led to tolerance in cold hypersensitivity in HbSS mice. Together, the findings identify THC as a possible therapeutic option for the management of chronic pain in SCD. Further research is warranted to elucidate its mechanism of action and possible interaction with other cannabis constituents.

Targeting the endocannabinoid (eCB) signaling system for pain relief is an important treatment option that is only now beginning to be mechanistically explored. In this review, we focus on two recently appreciated cannabinoid-based targeting strategies, treatments with cannabidiol (CBD) and α/β-hydrolase domain containing 6 (ABHD6) inhibitors, which have the exciting potential to produce pain relief through distinct mechanisms of action and without intoxication. We review evidence on plant-derived cannabinoids for pain, with an emphasis on CBD and its multiple molecular targets expressed in pain pathways. We also discuss the function of eCB signaling in regulating pain responses and the therapeutic promises of inhibitors targeting ABHD6, a 2-arachidonoylglycerol (2-AG)-hydrolyzing enzyme. Finally, we discuss how the novel cannabinoid biosensor GRAB_eCB2.0 may be leveraged to enable the discovery of targets modulated by cannabinoids at a circuit-specific level.

The National Center for Complementary and Integrative Health (NCCIH), which is part of the US National Institutes of Health (NIH), has a broad interest in studying the biologic activities of natural products, especially those for which compelling evidence from preclinical research suggests biologic activities that may be beneficial to health or have a potential role in disease treatment, as well as products used extensively by the American public. As of 2023, use of cannabis for medical purposes is legal in 38 states and Washington, D.C. Such use continues to climb generally without sufficient knowledge regarding risks and benefits. In keeping with NCCIH’s natural product research priorities and recognizing this gap in knowledge, NCCIH formally launched a research program in 2019 to expand research on the possible benefits for pain management of certain substances found in cannabis: minor cannabinoids and terpenes. This Viewpoint provides additional details and the rationale for this research priority at NCCIH. In addition, NCCIH’s efforts and initiatives to facilitate and coordinate an NIH research agenda focused on cannabis and cannabinoid research are described.

Cannabis and its products have been used for centuries for both medicinal and recreational purposes. The recent widespread legalization of cannabis has vastly expanded its use in the United States across all demographics except for adolescents. Meanwhile, decades of research have advanced our knowledge of cannabis pharmacology and particularly of the endocannabinoid system with which the components of cannabis interact. This research has revealed multiple targets and approaches for manipulating the system for therapeutic use and to ameliorate cannabis toxicity or cannabis use disorder. Research has also led to new questions that underscore the potential risks of its widespread use, particularly the enduring consequences of exposure during critical windows of brain development or for consumption of large daily doses of cannabis with high content ⁹-tetrahydrocannabinol. This article highlights current neuroscience research on cannabis that has shed light on therapeutic opportunities and potential adverse consequences of misuse and points to gaps in knowledge that can guide future research.

Low-efficacy mu opioid receptor (MOR) agonists may serve as novel candidate analgesics with improved safety relative to high-efficacy opioids. This study used a recently validated assay of pain-depressed behavior in mice to evaluate a novel series of MOR-selective C9-substituted phenylmorphan opioids with graded MOR efficacies. Intraperitoneal injection of dilute lactic acid (IP acid) served as a noxious stimulus to depress locomotor activity by mice in an activity chamber composed of two compartments connected by an obstructed door. Behavioral measures included (1) crosses between compartments (vertical activity over the obstruction) and (2) movement counts quantified as photobeam breaks summed across compartments (horizontal activity). Each drug was tested alone and as a pretreatment to IP acid. A charcoal-meal test and whole-body-plethysmography assessment of breathing in 5% CO₂ were also used to assess gastrointestinal (GI) inhibition and respiratory depression, respectively. IP acid produced a concentration-dependent depression in crosses and movement that was optimally alleviated by intermediate- to low-efficacy phenylmorphans with sufficient efficacy to produce analgesia with minimal locomotor disruption. Follow-up studies with two low-efficacy phenylmorphans (JL-2-39 and DC-1-76.1) indicated that both drugs produced naltrexone-reversible antinociception with a rapid onset and a duration of ~1 h. Potency of both drugs increased when behavior was depressed by a lower IP-acid concentration, and neither drug alleviated behavioral depression by a non-pain stimulus (IP lithium chloride). Both drugs produced weaker GI inhibition and respiratory depression than fentanyl and attenuated fentanyl-induced GI inhibition and respiratory depression. Results support further consideration of selective, low-efficacy MOR agonists as candidate analgesics.

BACKGROUND AND PURPOSE:

Intracranial epidermoids temporal bone cholesteatomas, and head and neck epidermal inclusion cysts are typically slow-growing, benign conditions arising from ectodermal tissue. They exhibit increased signal on DWI. While much of the imaging literature describes these lesions as showing diffusion restriction, we investigated these qualitative signal intensities and interpretations of restricted diffusion with respect to normal brain structures. This study aimed to quantitatively evaluate the ADC values and histogram features of these lesions.

BackgroundDuring the COVID-19 pandemic, global trends of reduced healthcare-seeking behaviour were observed. This raises concerns about the consequences of healthcare avoidance for population health.AimTo determine the association between healthcare avoidance during the early stages of the COVID-19 pandemic and all-cause mortality.Design and settingThis was a 32-month follow-up within the population-based Rotterdam Study, after sending a COVID-19 questionnaire at the onset of the pandemic in April 2020 to all communty dwelling participants (n = 6241/8732, response rate 71.5%).MethodCox proportional hazards models assessed the risk of all-cause mortality among respondents who avoided health care because of the COVID-19 pandemic. Mortality status was collected through municipality registries and medical records.ResultsOf 5656 respondents, one-fifth avoided health care because of the COVID-19 pandemic (n = 1143). Compared with non-avoiders, those who avoided health care more often reported symptoms of depression (n = 357, 31.2% versus n = 554, 12.3%) and anxiety (n = 340, 29.7% versus n = 549, 12.2%), and more often rated their health as poor to fair (n = 336, 29.4% versus n = 457, 10.1%) . Those who avoided health care had an increased adjusted risk of all-cause mortality (hazard ratio [HR] 1.30, 95% confidence interval [CI] = 1.01 to 1.67), which remained nearly identical after adjustment for history of any non-communicable disease (HR 1.20, 95% CI = 0.93 to 1.54). However, this association attenuated after additional adjustment for mental and physical self-perceived health factors (HR 0.93, 95% CI = 0.71 to 1.20).ConclusionThis study found an increased risk of all-cause mortality among individuals who avoided health care during COVID-19. These individuals were characterised by poor mental and physical self-perceived health. Therefore, interventions should be targeted to these vulnerable individuals to safeguard their access to primary and specialist care to limit health disparities, inside and beyond healthcare crises.

The usual challenges of conducting primary care research, including randomized trials, have been exacerbated, and new ones identified, during the COVID-19 pandemic. HOMER (Home versus Office for Medication Enhanced Recovery; subsequently, Comparing Home, Office, and Telehealth Induction for Medication Enhanced Recovery) is a pragmatic, comparative-effectiveness research trial that aims to answer a key question from patients and clinicians: What is the best setting in which to start treatment with buprenorphine for opioid use disorder for this patient at this time? In this article, we describe the difficult journey to find the answer. The HOMER study began as a randomized trial comparing treatment outcomes in patients starting treatment with buprenorphine via induction at home (unobserved) vs in the office (observed, synchronous). The study aimed to enroll 1,000 participants from 100 diverse primary care practices associated with the State Networks of Colorado Ambulatory Practices and Partners and the American Academy of Family Physicians National Research Network. The research team faced unexpected challenges related to the COVID-19 pandemic and dramatic changes in the opioid epidemic. These challenges required changes to the study design, protocol, recruitment intensity, and funding conversations, as well as patience. As this is a participatory research study, we sought, documented, and responded to practice and patient requests for adaptations. Changes included adding a third study arm using telehealth induction (observed via telephone or video, synchronous) and switching to a comprehensive cohort design to answer meaningful patient-centered research questions. Using a narrative approach based on the Greek myth of Homer, we describe here the challenges and adaptations that have provided the opportunity for HOMER to thrive and find the way home. These clinical trial strategies may apply to other studies faced with similar cultural and extreme circumstances.

Background

In an evolving landscape of practices and policies, reviewing and incorporating the latest scientific evidence is necessary to ensure optimal clinical management for people with opioid use disorder. We provide a synopsis of the 2024 update of the 2018 National Guideline for the Clinical Management of Opioid Use Disorder, from the Canadian Research Initiative in Substance Matters.

There is conflicting evidence regarding the use of steroids in severe community-acquired pneumonia (CAP), with previous randomised controlled trials limited by small sample sizes. ESCAPe and CAPE COD are two recently published large trials on steroids in severe CAP. ESCAPe assessed the initiation of methylprednisolone within 72–96 h of hospital admission, while CAPE COD studied the use of hydrocortisone within 24 h of the development of severe CAP. ESCAPe did not show any differences in all-cause 60-day mortality or any of its secondary outcomes. CAPE COD showed that hydrocortisone improved all-cause 28-day mortality and reduced the risk of intubation or vasopressor-dependent shock. Important differences between the trials included the steroid regimens used, timing of steroid administration and baseline characteristics, with more diabetic patients included in ESCAPe. The results of CAPE COD support the initiation of hydrocortisone within 24 h of developing severe CAP, but more research is needed to evaluate long-term outcomes and optimum dosing regimens for steroids in severe CAP.

The Pokémon series is no stranger to mobile games, being responsible for one of the most successful ever (Pokémon Go), as well as many others with different takes on the massive franchise, but this time it’s a Pokémon card game - a tradition nearly as old as the original games - that has taken the spotlight in Pokémon TCG Pocket.

For the physical version of Pokémon TCG, the collecting has always been as big or bigger than the battling, and right off the bat we can see that TCG Pocket has made plenty of room for both these aspects in its design. In fact, the battling isn’t even available until you level up a few times, which, while a bit limiting, is a fine way for players to get their bearing and collect a few cards before they start competing. The game does suffer from just a tad bit too much forced tutorialization in the early stages, particularly when getting to the battles, but it’s still hardly the worst sinner among mobile titles in this regard.

The collecting all starts with the opening of packs, an infamously addictive part of any card game, and they’ve done a good job of making the process quite satisfying TCG Pocket. More importantly, the number of packs given for free is quite generous - at least two packs a day by default - meaning the game is perfectly playable without spending money, regardless of whether you’re in it for the collecting or battling aspect. Whenever you obtain new cards, they also get filled out in a sort of card Pokédex, which adds to the fun of collecting new ones.

A lot of what makes the collecting in TCG Pocket enjoyable, however, is quite simply the excellent card art. This is, of course, borrowed mostly from the game’s physical counterpart, and strengthened by little touches like being able to being able to zoom in and tilt the cards, with a slight holographic on the rarer ones. Whether they’re cute or cool, the Pokémon themselves are at the heart of this franchise and with the generally splendid art the game does a great job of bringing them to life, in some ways doing them more justice than recent mainline entries with low-detailed 3D models.

As for the other part of aesthetics, namely sound design, the game is also passable in this area but nothing special with slightly boring battle music. It's not the biggest issue perhaps, as most are likely to play mobile games with sound disabled, but with all the cosmetic unlockables (which we shall get to) it   seems like a wasted opportunity not to have unlockable battle themes when the Pokémon series has so many great ones to draw upon from its legacy.

Looking for a moment at the less positive side, while Pokémon TCG Pocket is fairly generous to free-to-play players, it does still suffer from some of the pitfalls that are typical of that type of mobile game; namely, the amount of noise that comes with too many currencies, constant quests and rewards, and perhaps a few more types of cosmetics than is necessary. Again, I wouldn't describe Pokémon TCG Pocket as the worst sinner of this type of issue, mostly just that it can be a bit overwhelming at first, and of course knowing that it’s intended to add to the addictiveness of the game can be a bit iffy, but ultimately it isn’t too hard to ignore aspects you don’t care about and simply enjoy the ones you do.

It might be high time to touch on the battles themselves, which to many players might be their first encounter ever with the actual rules of these pretty collectible cards. While it might not be simplest card game ever invented, I’m happy to say the TCG Pocket variant is still intuitive, fun, and quite strategic once you get the hang of it. To summarize it in very brief: you play and evolve Pokémon from your hand onto the field and charge them up with energy types to allow them to attack. Just like in the RPGs, only one Pokémon is active at a time and can use one move per turn, while you can assign others to your “bench”, where they await their turn in the spotlight. Unlike in the RPGs, switching Pokémon won’t cost you your turn (only some energy), meaning benched Pokémon can potentially step into action immediately - if you have the energy necessary. Rather than any form of life-points, you win the battle by defeating three of your opponents' Pokémon, which each award one point.

This bench system and charging up of your Pokémon before they can take action might in some regards make the game slower compared to other card games, but it also adds a strategic element, since you can generally see what moves you and your opponent have available in the immediate future and can only really be caught by surprise by item or support cards (which can be quite useful but rarely complete game changers). It’s not the type of game where you perform crazy one-turn game-winning combos, but it’s fun for the strategic aspect and of course the satisfaction that comes from evolving your Pokémon throughout the battle - and sometimes pulling off an impressive comeback.

Adding to this are the EX-cards, extra powerful cards that come with the added risk of rewarding the opponent two points if defeated rather than one. I’ve seen complaints that this risk is too big in a game when it only takes three points to win (unlike the physical version of the game where you need six points), but when the card is extra strong and you have the option of switching it out it seems justified, plus you still have that golden window of playing it when your opponent already has two points, at which point the extra risk is nullified.

Ultimately there is one distinct issue with the battle system, however, which is how type weaknesses are handled. Pokémon TCG, whether physical or digital, has condensed Pokémon down to nearly half as many types (a tad too few in my opinion, though all 18 would definitely have been overwhelming), while the weaknesses and resistances are reduced to one type per card, and in TCG Pocket resistances are removed so you only have the weaknesses. This, for example, means that (most) Water types are weak to Lightning   but not Grass, while Fire types are weak to Water but not Ground (which has been combined with Fighting). The issue however is not so much the differences from the RPGs as it is simply having these basic and pretty consistent weaknesses in a game that, unfortunately, strongly encourages mono-type   decks in its design (or one type + colorless), since you’ll be needing specific energy types to charge your Pokémon and receive them at random if your deck uses multiple types.

While there is something to be said for having to commit to certain types, it’s a bit unfortunate that it’s taken to the degree where dual-type decks can feel awkward and triple-type decks, while allowed, require very specific cards or a lot of luck to pull off. The result is that when most players play with only one type and all types have one weakness, online matches will often either play out without weaknesses playing any role or with one player having an advantage before the first card is even played. One can always hope that this is somehow redesigned a bit in the future, but for now it’s an unfortunate though not game-breaking issue, as the weaknesses are at least a bit milder here, adding only a flat amount of damage rather than a multiplier.

Lastly it wouldn't review this game without mentioning the nostalgic aspect, which to many a player might add an extra appeal to the experience. Even as someone who hasn't dabbled in Pokémon cards for nearly 20 years, I can still recognize many that I’ve owned myself at some point, and it’s also great to revisit the first generation, which has smartly put front and center for now (with a small mix from other generations on top). I consider it a good call to start off with a single set of a manageable size for now - one that doesn’t seem too daunting - while leaving plenty of room to grow in the future.

All in all, Creatures Inc. and Dena Co. have done a great job adapting the Pokémon card game to mobile in a way that can appeal to both old and new players, and to those who want to collect and those who want to battle. It brings Pokémon to life with great card art and, contrary to unfortunate trends, the game is also fairly generous to its free-to-play players (and certainly a cheaper alternative to collecting the physical cards). While it does suffer from a few design issues and some classic pitfalls, it’s overall one of the better mobile games out there at the moment and certainly worth checking out for those who have nostalgia for the Pokémon TCG or old school Pokémon in general.

Full Article - https://www.vgchartz.com/article/463039/pokemon-tcg-pocket-android/

You remember Lucas Pope, right? He who casually dropped two of the most influential puzzle games ever then got distracted by yellow cranks for six years, occasionally popping up to drop a demake of Papers Please? Well, Pope has ceased hogging that crank, for now at least, and just released Haloween-y adventure game Moida Mansion. It’s on Itch here, and it’s completely free to play in your browser.

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Like a plague doctor delicately administering another handful of leeches, Ice Pick Lodge have shared a bit more about the recently announced Pathologic 3, explaining how their plans for the cult epidemic-battling series have progressed since the release of Pathologic 2.

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Ganymede, the largest moon in the solar system, has signs of an enormous ancient impact that would have redistributed its mass, changing its orientation in relation to Jupiter

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Cracks running through samples of asteroid Ryugu were probably formed by the repeated thawing and freezing of water inside it, which could have helped asteroids like this carry the building blocks of life to early Earth

The European Space Agency is sending a probe to get a closer look at the asteroid Dimorphos, which had its orbit altered by NASA’s DART mission in 2022

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From nuclear strikes to giant spikes, discover the systems in place to prevent a collision and test your decision-making to see if you could avoid a catastrophic impact

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In the 1960s and 1970s, NASA spent a lot of time thinking about whether toroidal (donut-shaped) fuel tanks were the way to go with its spacecraft. Toroidal tanks have a bunch of potential advantages over conventional spherical fuel tanks. For example, you can fit nearly 40% more volume within a toroidal tank than if you were using multiple spherical tanks within the same space. And perhaps most interestingly, you can shove stuff (like the back of an engine) through the middle of a toroidal tank, which could lead to some substantial efficiency gains if the tanks could also handle structural loads.

Because of their relatively complex shape, toroidal tanks are much more difficult to make than spherical tanks. Even though these tanks can perform better, NASA simply doesn’t have the expertise to manufacture them anymore, since each one has to be hand-built by highly skilled humans. But a company called Machina Labs thinks that they can do this with robots instead. And their vision is to completely change how we make things out of metal.

The fundamental problem that Machina Labs is trying to solve is that if you want to build parts out of metal efficiently at scale, it’s a slow process. Large metal parts need their own custom dies, which are very expensive one-offs that are about as inflexible as it’s possible to get, and then entire factories are built around these parts. It’s a huge investment, which means that it doesn’t matter if you find some new geometry or technique or material or market, because you have to justify that enormous up-front cost by making as much of the original thing as you possibly can, stifling the potential for rapid and flexible innovation.

On the other end of the spectrum you have the also very slow and expensive process of making metal parts one at a time by hand. A few hundred years ago, this was the only way of making metal parts: skilled metalworkers using hand tools for months to make things like armor and weapons. The nice thing about an expert metalworker is that they can use their skills and experience to make anything at all, which is where Machina Labs’ vision comes from, explains CEO Edward Mehr who co-founded Machina Labs after spending time at SpaceX followed by leading the 3D printing team at Relativity Space.

“Craftsmen can pick up different tools and apply them creatively to metal to do all kinds of different things. One day they can pick up a hammer and form a shield out of a sheet of metal,” says Mehr. “Next, they pick up the same hammer, and create a sword out of a metal rod. They’re very flexible.”

The technique that a human metalworker uses to shape metal is called forging, which preserves the grain flow of the metal as it’s worked. Casting, stamping, or milling metal (which are all ways of automating metal part production) are simply not as strong or as durable as parts that are forged, which can be an important differentiator for (say) things that have to go into space. But more on that in a bit.

The problem with human metalworkers is that the throughput is bad—humans are slow, and highly skilled humans in particular don’t scale well. For Mehr and Machina Labs, this is where the robots come in.

“We want to automate and scale using a platform called the ‘robotic craftsman.’ Our core enablers are robots that give us the kinematics of a human craftsman, and artificial intelligence that gives us control over the process,” Mehr says. “The concept is that we can do any process that a human craftsman can do, and actually some that humans can’t do because we can apply more force with better accuracy.”

This flexibility that robot metalworkers offer also enables the crafting of bespoke parts that would be impractical to make in any other way. These include toroidal (donut-shaped) fuel tanks that NASA has had its eye on for the last half century or so.

Machina Labs’ CEO Edward Mehr (on right) stands behind a 15 foot toroidal fuel tank.Machina Labs

“The main challenge of these tanks is that the geometry is complex,” Mehr says. “Sixty years ago, NASA was bump-forming them with very skilled craftspeople, but a lot of them aren’t around anymore.” Mehr explains that the only other way to get that geometry is with dies, but for NASA, getting a die made for a fuel tank that’s necessarily been customized for one single spacecraft would be pretty much impossible to justify. “So one of the main reasons we’re not using toroidal tanks is because it’s just hard to make them.”

Machina Labs is now making toroidal tanks for NASA. For the moment, the robots are just doing the shaping, which is the tough part. Humans then weld the pieces together. But there’s no reason why the robots couldn’t do the entire process end-to-end and even more efficiently. Currently, they’re doing it the “human” way based on existing plans from NASA. “In the future,” Mehr tells us, “we can actually form these tanks in one or two pieces. That’s the next area that we’re exploring with NASA—how can we do things differently now that we don’t need to design around human ergonomics?”

Machina Labs’ ‘robotic craftsmen’ work in pairs to shape sheet metal, with one robot on each side of the sheet. The robots align their tools slightly offset from each other with the metal between them such that as the robots move across the sheet, it bends between the tools. Machina Labs

The video above shows Machina’s robots working on a tank that’s 4.572 m (15 feet) in diameter, likely destined for the Moon. “The main application is for lunar landers,” says Mehr. “The toroidal tanks bring the center of gravity of the vehicle lower than what you would have with spherical or pill-shaped tanks.”

Training these robots to work metal like this is done primarily through physics-based simulations that Machina developed in house (existing software being too slow), followed by human-guided iterations based on the resulting real-world data. The way that metal moves under pressure can be simulated pretty well, and although there’s certainly still a sim-to-real gap (simulating how the robot’s tool adheres to the surface of the material is particularly tricky), the robots are collecting so much empirical data that Machina is making substantial progress towards full autonomy, and even finding ways to improve the process.

An example of the kind of complex metal parts that Machina’s robots are able to make.Machina Labs

Ultimately, Machina wants to use robots to produce all kinds of metal parts. On the commercial side, they’re exploring things like car body panels, offering the option to change how your car looks in geometry rather than just color. The requirement for a couple of beefy robots to make this work means that roboforming is unlikely to become as pervasive as 3D printing, but the broader concept is the same: making physical objects a software problem rather than a hardware problem to enable customization at scale.

The Federal Emergency Management Agency supervisor who was fired after she told her staff to skip hurricane-damaged homes with Trump signs in their yards says it wasn't an isolated incident and is a "colossal event."

An updated Android trojan called FakeCall hijacks bank calls. Tech expert Kurt “CyberGuy" Knutsson says Android phone manufacturers and Google need to step up their game on security.

Shameless scammers trick veterans into giving personal info or cash. Tech expert Kurt “CyberGuy" Knutsson explores five common scams.

Voice assistants may cause confusion across devices. Tech expert Kurt “CyberGuy" Knutsson offers some solutions to fix it.

If rumours are true and this one should be, I started it, we have a special edition of the Weekend show where we talk about the evolution of the role of the CIO with two incredible CIOs as the CIO Association of Canada turns 20. Don’t miss it.  MUSIC UP Can HP make you love […]

The asteroid that wiped out dinosaurs after slamming into the Earth 66 million years ago is believed to have come from beyond Jupiter, a new study says.

A stadium-sized asteroid is passing relatively close to Earth on Tuesday, NASA announced. Its distance from Earth and its massive size makes it a "potentially hazardous object."