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• Use of multiple data sources can enable more complete and informative road injury statistics. • The papers reviewed lack consistency in what was reported and how. • Probabilistic methods are more common when linking administrative data on crash injuries. • Linkage studies can identify topics and case types that warrant more attention in road safety programs, commonly including vulnerable road users. This systematic review examines studies of traffic injury that involved linkage of police crash data and hospital data and were published from 1994 to 2023 worldwide in English. Inclusion and exclusion criteria were the basis for selecting papers from PubMed, Web of Science, and Scopus, and for identifying additional relevant papers using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and supplementary snowballing (n = 60). The selected papers were reviewed in terms of research objectives, data items and sample size included, temporal and spatial coverage, linkage methods and software tools, as well as linkage rates and most significant findings. Many studies found that the number of clinically significant road injury cases was much higher according to hospital data than crash data. Under-estimation of cases in crash data differs by road user type, pedestrian cases commonly being highly under-counted. A limited number of the papers were from low- and middle-income countries. The papers reviewed lack consistency in what was reported and how, which limited comparability. [ABSTRACT FROM AUTHOR]

Objective To describe neurosurgical patient and caregiver perceptions of provider communication, the impact of patient education, and their understanding of information given to them throughout the neurosurgical care trajectory. Methods We organized focus groups composed of patients who had been hospitalized on the neurosurgical service at 5 urban academic tertiary referral hospitals within a large university health system, along with the patients' caregivers. During focus groups, we used semistructured questions to answer the study questions. Content analysis was used to analyze the data. Results Forty-three patients and caregivers took part in 5 focus groups. In total we identified 12 coding categories (or topics) that were associated with patient and family information needs. Despite the fact all patients were receiving care within the same health system, often with the same care team and clinical environments, their experiences often could not have been more different. We found stark variations in how patients and caregivers described the quality of communication and patient education they received that affected their satisfaction. Satisfied patients and caregivers generally felt well informed and reported good understanding of the clinical care plan throughout the perioperative course, whereas dissatisfied patients struggled with unanswered questions, unmet information needs, and a sense of confusion throughout their care experience. Conclusions Our study describes several unmet needs, finds inconsistencies in how information is delivered and a lack of patient-centered and caregiver-centered approaches to communication. Neurosurgery groups should identify unmet needs at their institution and implement strategies and interventions to improve the patient and caregiver experience. [ABSTRACT FROM AUTHOR]

Background Pneumatic tube systems (PTSs) are convenient methods of patient sample transport in medical centers, but excessive acceleration force and time/distance traveled in the PTS have been correlated with increased blood-sample hemolysis. We investigated the utility of smartphones for monitoring of PTS-related variables. Methods Smartphones were sent through the PTS from several hospital locations. Each smartphone used 2 apps as data-loggers to record force of acceleration vs time. To relate the smartphone data to sample integrity, blood samples were collected from 5 volunteers, and hemolysis of the samples was analyzed after they were transported by hand or via 1 of 2 PTS routes. Increased sample hemolysis as measured by plasma lactate dehydrogenase (LD) was also related to the amount of transport in the PTS. Results The smartphones showed higher duration of forceful acceleration during transport through 1 of the 2 PTS routes, and the increased duration correlated with significant increases in hemolysis (H)-index and plasma LD. In addition, plasma LD showed a positive linear relationship with number of shock forces experienced during transport through the PTS. Conclusions Smartphones can monitor PTS variables that cause sample hemolysis. This provides an accessible method for investigating specific PTS routes in medical centers. [ABSTRACT FROM AUTHOR]

Abstract: High quality wind measurements in cities are needed for numerous applications including wind engineering. Such data-sets are rare and measurement platforms may not be optimal for meteorological observations. Two years'' wind data were collected on the BT Tower, London, UK, showing an upward deflection on average for all wind directions. Wind tunnel simulations were performed to investigate flow distortion around two scale models of the Tower. Using a 1:160 scale model it was shown that the Tower causes a small deflection (ca. 0.5°) compared to the lattice on top on which the instruments were placed (ca. 0–4°). These deflections may have been underestimated due to wind tunnel blockage. Using a 1:40 model, the observed flow pattern was consistent with streamwise vortex pairs shed from the upstream lattice edge. Correction factors were derived for different wind directions and reduced deflection in the full-scale data-set by <3°. Instrumental tilt caused a sinusoidal variation in deflection of ca. 2°. The residual deflection (ca. 3°) was attributed to the Tower itself. Correction of the wind-speeds was small (average 1%) therefore it was deduced that flow distortion does not significantly affect the measured wind-speeds and the wind climate statistics are reliable. [Copyright &y& Elsevier]

Objective: To ascertain the feasibility of implementing three decision support tools (DSTs) for people with rectal cancer within the surgical consultation. Methods: Twenty colorectal surgeons participated in a focus group or individual interviews. Colorectal surgeons were also asked to complete a self-administered questionnaire. Results: All surgeons responded encouragingly to the concept of DSTs. However, for every positive statement an accompanying caveat was made and these were either a criticism of each tool or a barrier to their implementation. Surgeons stated DSTs should be used by patients and surgeons together (80%). The majority (70–75%) thought each tool was ‘useful’ or ‘extremely useful’. However, there were strong views that in their current form the DSTs would not feasible to be used within the surgical consultation. Time restraints, personal and clinical characteristics of the patient, the content of each tool, the potential negative impact on the doctor–patient relationship were noted as real barriers to their implementation. Conclusion: Surgeons have identified a number of barriers that may limit implementation of DSTs into routine clinical practice. Practice implications: Feasibility and implementation studies have the potential to provide important information to help guide development, evaluation and implementation of DSTs. [Copyright &y& Elsevier]

[Display omitted] • Theoretical investigation on the electronic states of TiC including recently detected ground & excited states. • The nature of chemical bonding in the ground, low-lying, and excited electronic states are explained. • TiC is held together by a double-π and a half-σ covalent bond in most states with a charge transfer of 0.3–0.5 e- from Ti to C atoms. • No instances of sp hybridization of C were found in the chemical bonding. We present the results of a theoretical investigation of the TiC molecule, detected recently in experiments. Using state averaged multiconfiguration SCF (MCSCF) followed by multireference configuration-interaction (MRCI) methods, we have calculated relative energies and spectroscopic constants for 14 electronic states of the 1,3Σ+, 1,3Π, and 1,3Δ symmetries and analyzed their chemical bonding. Our results are in excellent agreement with the recent experimental findings. Ti and C atoms are held together by 2 1 2 bonds – a double-π and a half-σ, in all the states other than the two 3Π i states and their singlet analogues. Chemical bonding in the latter is attributed to one π and some σ interactions. There was no instance of sp hybridization of C in the bonding of the excited states. The 4s-4p occupation plays a significant role in the dipole moment and bonding of the electronic states. [ABSTRACT FROM AUTHOR]

Abstract: Problem: This study aimed to provide an assessment of the contribution of design to the occurrence of fatal work-related injuries in Australia. Methods: The Australian National Coroners'' Information System was the data source for fatal injuries. Deaths resulting from workplace injuries on or between 1 July 2000 and 30 June 2002 were included. Results: Seventy seven (37%) of the 210 identified workplace fatalities definitely or probably had design-related issues involved. In another 29 (14%), the circumstances were suggestive that design issues were involved. The most common scenarios involved problems with rollover protective structures and/or associated seat belts; inadequate guarding; lack of residual current devices; inadequate fall protection; failed hydraulic lifting systems in vehicles and mobile equipment; and inadequate protection mechanisms on mobile plant and vehicles. Summary: Design is a significant contributor to work-related fatal injury in Australia. There is considerable scope for preventing serious work-related injury through improving design of plant, equipment, and vehicles used for work-related purposes. [Copyright &y& Elsevier]

In this era of shared doctor-patient decision-making, eliciting and incorporating patients' treatment choices is essential to ensure all patients receive the treatment that is right for them. Clinicians and researchers should fully understand the many factors that influence and guide patients in their preferences for treatment. One of these influences is an individual's general risk propensity or willingness to take risks, yet there is little in the literature about methods for measuring risk propensity. A systematic review was undertaken to identify instruments that measure risk propensity and to appraise their validity and relevance for a clinical setting. Of 3546 articles, 139 were potentially relevant. From these, 14 instruments were identified. Eight measured risk propensity, whereas six measured personality traits associated with risk propensity. Most instruments demonstrated good internal reliability but their appropriateness for patients, particularly older adults, remains unclear. While no instrument was specific to or tested in a clinical setting, instruments that directly measured risk propensity were considered to be the most useful for clinical populations. The further adaptation and validation of these instruments among older adults are important avenues for future research. [ABSTRACT FROM AUTHOR]

The prognosis for patients with advanced-stage pancreatic ductal adenocarcinoma (PDAC) remains dismal. It is generally accepted that combination cancer therapies offer the most promise, such as Folforinox, despite their associated high toxicity. This study addresses the issue of chemoresistance by introducing a complementary dual priming approach to attenuate the DNA repair mechanism and to improve the efficacy of a type 1 topoisomerase (Top1) inhibitor. The result is a regimen that integrates drug-repurposing and nanotechnology using 3 clinically relevant FDA-approved agents (1) Top1 inhibitor (irinotecan) at subcytotoxic doses (2) benzoporphyrin derivative (BPD) as a photoactive molecule for photodynamic priming (PDP) to improve the delivery of irinotecan within the cancer cell and (3) minocycline priming (MNP) to modulate DNA repair enzyme Tdp1 (tyrosyl-DNA phosphodiesterase) activity. We demonstrate in heterotypic 3D cancer models that incorporate cancer cells and pancreatic cancer-associated fibroblasts that simultaneous targeting of Tdp1 and Top1 were significantly more effective by employing MNP and photoactivatable multi-inhibitor liposomes encapsulating BPD and irinotecan compared to monotherapies or a cocktail of dual or triple-agents. These data are encouraging and warrant further work in appropriate animal models to evolve improved therapeutic regimens. [Display omitted] • Single-agent therapy does not induce any survival improvement in PDAC patients. • Minocycline effectively targets the DNA repair mechanism. • Photodynamic priming effectively damages efflux transporter proteins and induces the safe delivery of irinotecan. • Minocycline and photodynamic therapy priming is a potent therapy to reduce the toxic dosage of irinotecan. [ABSTRACT FROM AUTHOR]

• First theoretical study of the electronic and geometric structure of the low-lying states of ScNH. • First theoretical study of the 2Π r state of YNH and its relationship to the 2Π i state. • First detailed study and comparison of the bonding in ScNH and YNH. We report the results of multi-reference configuration interaction calculations of the electronic and geometric structures of the X 2Σ+, B 2Σ+, Ã2Π i , Ã2Π r &2Δ states of the transition metal imides, ScNH and YNH, and compare with the available experimental data. The metal is bonded to the NH group by a double bond in the π system for all states. There are 4 π electrons in the X 2Σ+, B 2Σ+, Ã2Π r &2Δ states and 3 in the Ã2Π i. The atomic orbital composition in the 4 π states is remarkably similar, the average being 75 % 2 p π + 21 % d π + 4 % p π while in the 3 π state we have 88 % 2 p π + 10 % d π + 2 % p π . [ABSTRACT FROM AUTHOR]

Abstract: Objective: To determine whether including the study questionnaire with a letter of invitation improves the response rate in a telephone-based survey. Study Design and Setting: This randomized controlled trial was part of a larger study to assess patient preferences for novel and controversial treatments for inflammatory bowel disease at Royal Prince Alfred Hospital, a tertiary referral teaching hospital in Sydney, Australia. Results: Of 270 eligible patients, 124 (46%) were randomized to receive the questionnaire plus invitation whereas 146 (54%) were in the control group receiving a letter of invitation only. The consent rate was 26% for those receiving the questionnaire and 36% for the control group. The odds ratio for consent to participate among those sent the questionnaire to those not sent the questionnaire was 0.63 (95% CI=0.37–1.07). Conclusion: This study found that the advance mailing of a questionnaire to potential participants in a telephone survey reduced the likelihood of their participation. [Copyright &y& Elsevier]

Abstract: The electronic structure of Na2C2 is studied using ab initio electronic structure methods and is compared to the companion molecule Li2C2. Both the linear D ∞h and planar structures are minima on the ground state potential surface with the planar D 2h conformation being the lowest energy form, similar to Li2C2. At the CCSD(t) level the planar form is more stable that the linear by 11.2kcal/mol as compared with 7.34kcal/mol for Li2C2. Both molecules are significantly ionic. The vibrational frequencies, atomization energy at 0K, D 0, and the standard enthalpy of formation, are calculated and compared to those of Li2C2 as well as HCCH, FCCF and ClCCCl. We find D 0 and to be 331.1 and 84.92kcal/mol for Li2C2 and 298.3 and 93.25kcal/mol for Na2C2. We calibrate these by calculating the same quantities for HCCH, FCCF and ClCCCl. [Copyright &y& Elsevier]

Background: Innate lymphoid cells type 2 (ILC2s) play critical homeostatic functions in peripheral tissues. ILC2s reside in perivascular niches and limit atherosclerosis development.Objectives: ILC2s also reside in the pericardium but their role in postischemic injury is unknown.Methods: We examined the role of ILC2 in a mouse model of myocardial infarction (MI), and compared mice with or without genetic deletion of ILC2. We determined infarct size using histology and heart function using echocardiography. We assessed cardiac ILC2 using flow cytometry and RNA sequencing. Based on these data, we devised a therapeutic strategy to activate ILC2 in mice with acute MI, using exogenous interleukin (IL)-2. We also assessed the ability of low-dose IL-2 to activate ILC2 in a double-blind randomized clinical trial of patients with acute coronary syndromes (ACS).Results: We found that ILC2 levels were increased in pericardial adipose tissue after experimental MI, and genetic ablation of ILC2 impeded the recovery of heart function. RNA sequencing revealed distinct transcript signatures in ILC2, and pointed to IL-2 axis as a major upstream regulator. Treatment of T-cell-deficient mice with IL-2 (to activate ILC2) significantly improved the recovery of heart function post-MI. Administration of low-dose IL-2 to patients with ACS led to activation of circulating ILC2, with significant increase in circulating IL-5, a prototypic ILC2-derived cytokine.Conclusions: ILC2s promote cardiac healing and improve the recovery of heart function after MI in mice. Activation of ILC2 using low-dose IL-2 could be a novel therapeutic strategy to promote a reparative response after MI. [ABSTRACT FROM AUTHOR]

Objective. To quantify segmental mobility of the lumbar spine during a posterior to anterior spinal mobilization procedure.Design. Descriptive study using dynamic magnetic resonance imaging.Background. The posterior to anterior spinal mobilization procedure is frequently used in the assessment and management of spinal dysfunction. How this procedure influences segmental spinal motion however, is not known.Methods. Eleven asymptomatic subjects were positioned prone within a vertically open double donut design magnetic resonance imaging system. An anteriorly directed force was applied manually at each lumbar spinous process while magnetic resonance images were obtained continuously in the sagittal plane. The intervertebral angle was used to quantify segmental motion.Results. The direction of motion at the tested segment was always extension, with values ranging from 1.2 (SD 2.2) at L2 to 3.0 (SD 2.3) degrees at L5. When the force was applied at L3, L4 and L5, the non-tested (adjacent) segments also were observed to move into extension. However, when the posterior to anterior force was applied at L1 and L2 the three caudal segments moved into flexion.Conclusions. Posterior to anterior spinal mobilization consistently caused extension at the tested segment, while the motion of the collective lumbar spine was either an increase or decrease in lordosis depending on the segment at which the force was applied.Relevance Passive movement techniques are commonly used to identify the symptomatic lumbar segment(s) and can be used as a treatment aimed at increasing mobility and/or decreasing pain. Knowledge of how this procedure influences segmental motion of healthy spines is important in understanding how altered mobility is related to symptoms. [Copyright &y& Elsevier]

The coronavirus disease 2019 (COVID-19) pandemic has highlighted the need for health care providers skilled in rapid and flexible decision making, effective and anticipatory leadership, and in dealing with trauma and moral distress. Palliative care (PC) workers have been an essential part of the COVID-19 response in advising on goals of care, symptom management and difficult decision making, and in supporting distressed health care workers, patients, and families. We describe Global Palliative Education Collaborative (GPEC), a training partnership between Harvard, University of California San Francisco, and Tulane medical schools in the U.S.; and two international PC programs in Uganda and India. GPEC offers U.S.-based PC fellows participation in an international elective to learn about resource-limited PC provision, gain perspective on global challenges to caring for patients at the end of life, and cultivate resiliency. International PC colleagues have much to teach about practicing compassionate PC amidst resource constraints and humanitarian crisis. We also describe a novel educational project that our GPEC faculty and fellows are participating in-the Resilience Inspiration Storytelling Empathy Project-and discuss positive outcomes of the project. [ABSTRACT FROM AUTHOR]

Lack of adequate floral resources is a key driver of bee population declines and honey bee colony loss, particularly in agricultural landscapes. Most studies evaluating floral resource use and land management consequences in honey bees focus on the period after new colony founding from reproductive swarms (spring-fall). Few studies have investigated nutrition in the late-winter/early-spring (LWES) period, the critical time when colonies break their winter dormancy and increase their colony populations in preparation for swarming. Growth during this timeframe influences beekeepers' ability to produce new colonies and predicts colony productivity for the remainder of the active season. In agricultural areas growing summer annual crops, many fields are fallow during LWES and anecdotally grow large quantities of early blooming winter annual herbaceous "weeds". The value of these resources to honey bee colony health is unknown. In this study, conducted in central Kentucky, we characterized blooming winter annual plant abundance across different land cover types. We placed colonies on sites with varying quantities of blooming winter annual plants and assessed colony growth and individual worker immune system function over LWES. We found that blooming winter annual plants are most abundant on croplands and limited on forested sites and sites dominated by grasses (including lawns and pastures). Colonies on sites with the lowest quantities of blooming winter annual plants showed reduced LWES growth and patterns of individual worker gene expression consistent with nutritional stress relative to colonies on sites with greater abundances of blooming winter annuals. We used the National Land Cover Database to show that proximity to crop fields at larger spatial scales also had positive impacts on colony growth during LWES. Taken together, these results suggest blooming winter annual plants, and, more generally, croplands, may provide critical floral resources for honey bees during the critical pre-swarm growth period following winter dormancy. • Floral resources during late-winter/early-spring are essential for honey bee growth. • Fallow croplands are abundant with bee-attractive blooming winter annual plants. • Honey bee colonies isolated from winter annuals show reduced pre-swarm growth. • Cropland cover at a 1 km spatial scale is correlated with enhanced colony growth. • Fallow fields may be beneficial to honey bees during their critical growth period. [ABSTRACT FROM AUTHOR]

Purpose The aim of this study was to evaluate the cost-effectiveness of nivolumab versus ipilimumab for the treatment of previously untreated patients with BRAF-advanced melanoma (BRAF-AM) from an Australian health system perspective. Methods A state-transition Markov model was constructed to simulate the progress of Australian patients with BRAF-AM. The model had a 10-year time horizon with outcomes discounted at 5% annually. For the nivolumab group, risks of progression and death were based on those observed in the nivolumab arm of a phase III trial (nivolumab vs. dacarbazine). Progression-free survival and overall survival were extrapolated using parametric survival modeling with a log-logistic distribution. In the absence of head-to-head evidence, overall survival and progression-free survival for ipilimumab were estimated on the basis of an indirect comparison using published data. Costs of managing AM were estimated from a survey of Australian clinicians. The cost of ipilimumab was based on the reimbursement price in Australia. The cost of nivolumab was based on expected reimbursement prices in Australia. Quality-of-life data were obtained within the trial using the EuroQol five-dimensional questionnaire. Results Compared with ipilimumab, nivolumab therapy over 10 years was estimated to yield 1.58 life-years and 1.30 quality-adjusted life-years per person, at a (discounted) net cost of US $39,039 per person. The incremental cost-effectiveness ratios for nivolumab compared with ipilimumab were US $25,101 per year of life saved and $30,475 per quality-adjusted life-year saved. Conclusions Nivolumab is a cost-effective means of preventing downstream mortality and morbidity in patients with AM compared with ipilimumab in the Australian setting. [ABSTRACT FROM AUTHOR]

Abstract: Corticotropin-releasing factor (CRF) plays a major role in controlling the body’s response to stress. Because painful conditions are inherently stressful, we hypothesize that CRF may act via CRF-1 receptors to contribute to the pain experience. Studies were designed to investigate whether blocking CRF-1 receptors with selective antagonists or reducing their expression with CRF-Saporin, would attenuate ulcer, inflammatory- and neuropathic-like pain. Five experimental designs were undertaken. In experiment 1, ulcer pain was induced in mice following oral administration of indomethacin, while in experiments 2 and 3, inflammatory pain was induced in rats with either carrageenan or FCA, respectively. For these studies, animals were dosed with CP-154,526 (3, 10, 30 mg/kg) and NBI 27914 (1–30 mg/kg) 1 h prior to the assessment of tactile, thermal or mechanical hypersensitivity, respectively. In experiment 4, neuropathic pain was induced. Twenty-one days following spinal nerve ligation (SNL), animals received CRF-Saporin or control. Three weeks later tactile allodynia was assessed. Similarly, in experiment 5, a separate set of rats received CRF-Saporin or control. Twenty-one days later, mechanical hyperalgesia was assessed following intraplantar carrageenan. Results from the antagonist studies showed that CP-154,526 and NBI 27914 either fully or partially reversed the referred ulcer pain with minimal effective doses (MED) equal to 3 and 10 mg/kg, respectively. Similarly, both NBI 27914 and CP-154,526 reversed the thermal and mechanical hypersensitivity elicited by carrageenan and FCA with MEDs ≤ 5 and 10 mg/kg, respectively. Findings from the two CRF-Saporin studies determined that pre-treatment with this toxin significantly attenuated SNL- and carrageenan-induced tactile hypersensitivity. Together, these findings suggest that CRF-1 receptors mediate pain and implicate CRF in this regard. [Copyright &y& Elsevier]

Abstract: Validation of gait analysis has the potential to bridge the gap between data from animal pain models and clinical observations. The goal of these studies was to compare alterations in gait due to inflammation or nerve injury to traditional pain measurements in animals. Pharmacological experiments determined whether gait alterations were related to enhanced nociception, edema, or motor nerve dysfunction. Gait was analyzed using an automated system (DigiGait) after injection of an inflammatory agent (carrageenan; CARR or FCA; Freund''s complete adjuvant) or nerve injury (axotomy; AXO, partial sciatic nerve ligation; PSNL, spinal nerve ligation; SNL or chronic constriction injury; CCI). All models caused significant alterations in gait and thermal (inflammatory) or mechanical (nerve injury) hyperalgesia. Both indomethacin and morphine were able to block or reverse thermal hyperalgesia and normalize gait in the CARR model. Indomethacin partially blocked and did not reverse paw edema, suggesting that gait alterations must be primarily driven by enhanced nociception. In nerve injury models, AXO, PSNL, CCI, and SNL caused changes to the largest number of gait indices with the rank order being AXO>PSNL=CCI >> SNL. Gabapentin and duloxetine reversed mechanical hyperalgesia but did not normalize gait in any nerve injury model. Collectively, these data suggest that pain is the primary driver of abnormal gait in models of inflammatory but not nerve injury-related pain and suggests that, in the latter, disruption in gait is due to perturbation to the motor system. Gait may therefore constitute an alternative and potentially clinically relevant measure of pain due to inflammation. [Copyright &y& Elsevier]

Abstract: Several recent reports have demonstrated a role for selective cannabinoid CB2 receptor agonists in pain modulation, showing both analgesic and antihyperalgesic activities. While the mechanism of action is poorly understood, it has been postulated that these effects may be indirect, involving release of endogenous opioids. We have previously reported that administration of the selective cannabinoid CB2 receptor agonist GW405833 (2,3-dichloro-phenyl)-[5-methoxy-2-methyl-3-(2-morpholin-4-yl-ethyl)-indol-1-yl]-methanone) to rats elicits potent and efficacious antihyperalgesic effects against neuropathic and inflammatory pain and, at high dose (100 mg/kg), is analgesic and ataxic [Valenzano, K.J., Tafesse, L., Lee, G., Harrison, J.E., Boulet, J., Gottshall, S.L., Mark, L., Pearson, M.S., Miller, W., Shan, S., Rabadi, L., Rotstheyn, Y., Chaffer, S.M., Turchin, P.I., Elsemore, D.A., Toth, M., Koetzner, L., Whiteside, G.T., 2005. Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. Neuropharmacology 48, 658–672]. In the current study, we confirm these properties using mouse models and investigate the role of cannabinoid CB2 receptors using knockout animals. Furthermore, we provide evidence that the antinociceptive properties of GW405833 are opioid independent. GW405833 elicited robust antihyperalgesic effects in mouse models of inflammatory (Freund''s complete adjuvant) and neuropathic (Seltzer) pain. In contrast, GW405833 showed no antihyperalgesic activity against Freund''s complete adjuvant-mediated inflammatory pain in cannabinoid CB2 receptor knockout mice. As in rats, high-dose GW405833 (100 mg/kg) showed both analgesic and sedative activities in wild-type mice, activities that were also apparent in cannabinoid CB2 receptor knockout mice. In rats, neither the antihyperalgesic effect in the Freund''s complete adjuvant model nor the analgesic effects in tail flick and hot plate assays were inhibited by pre-treatment with the non-selective opioid receptor antagonist, naltrexone. These data demonstrate that the antihyperalgesic effects of GW405833 are mediated via the cannabinoid CB2 receptor, whereas the analgesic and sedative effects are not. Furthermore, these data suggest that the mechanism of action for GW405833 does not depend on the release of endogenous opioids. [Copyright &y& Elsevier]

Abstract: This paper investigates the relationship between suicide rates and prevalence of mental disorder and suicide attempts, across socio-economic status (SES) groups based on area of residence. Australian suicide data (1996–1998) were analysed in conjunction with area-based prevalences of mental disorder derived from the National Survey of Mental Health and Well-Being (1997). Poisson regression models of suicide risk included age, quintile of area-based SES, urban–rural residence, and country of birth (COB), with males and females analysed separately. Analysis focussed on the association between suicide and prevalences of (ICD-10) affective disorders, anxiety disorders, substance use disorders and suicide attempts by SES group. Prevalences of other psychiatric symptomatology, substance use problems, health service utilisation, stressful life-events and personality were also investigated. Significant increasing gradients were evident from high to low SES groups for prevalences of affective disorders, anxiety disorders (females only), and substance use disorders (males only); sub-threshold drug and alcohol problems and depression; and suicide attempts and suicide (males only). Prevalences of mental disorder, other sub-threshold mental health items and suicide attempts were significantly associated with suicide, but in most cases associations were reduced in magnitude and became statistically non-significant after adjustment for COB, urban–rural residence, and SES. For male suicide the relative risk (RR) in the lowest SES group compared to the highest was 1.40 (95% CI 1.29–1.52, ) for all ages, and 1.46 (95% CI 1.27–1.67, ) for male youth (20–34 years). This relationship was not substantially modified in males when regression models included prevalences of affective disorders, and other selected mental health variables and demographic factors. From a population perspective, SES remained significantly associated with suicide after controlling for the prevalence of mental disorders and other psychiatric symptomatology. Mental conditions and previous suicidal behaviour may play an intermediary role between SES and suicide, but this study suggests that an independent relationship between suicide and SES also exists. [Copyright &y& Elsevier]

Abstract: To date, two cannabinoid receptors have been identified, CB1 and CB2. Activation of these receptors with non-selective cannabinoid receptor agonists reduces pain sensitivity in animals and humans. However, activation of CB1 receptors is also associated with central side effects, including ataxia and catalepsy. More recently, a role for selective CB2 agonists in pain modification has been demonstrated. GW405833, a selective CB2 agonist, was recently reported to partially reverse the inflammation and hyperalgesia in a rat model of acute inflammation. In the current report, we extend the characterization and therapeutic potential of this compound. For the first time, we show that GW405833 selectively binds both rat and human CB2 receptors with high affinity, where it acts as a partial agonist (∼50% reduction of forskolin-mediated cAMP production compared to the full cannabinoid agonist, CP55,940). We also report for the first time that intraperitoneal administration of GW405833 (0.3–100mg/kg) to rats shows linear, dose-dependent increases in plasma levels and substantial penetration into the central nervous system. In addition, GW405833 (up to 30mg/kg) elicits potent and efficacious antihyperalgesic effects in rodent models of neuropathic, incisional and chronic inflammatory pain, the first description of this compound in these models. In contrast, analgesia, sedation and catalepsy were not observed in this dose range, but were apparent at 100mg/kg. Additionally, GW405833 was not antihyperalgesic against chronic inflammatory pain in CB2 knockout mice. These data support the tenet that selective CB2 receptor agonists have the potential to treat pain without eliciting the centrally-mediated side effects associated with non-selective cannabinoid agonists, and highlight the utility of GW405833 for the investigation of CB2 physiology. [Copyright &y& Elsevier]