The HIV capsid mimics karyopherin engagement of FG-nucleoporins.

HIV can infect non-dividing cells because the viral capsid can overcome the selective barrier of the nuclear pore complex and deliver the genome directly into the nucleus1,2. Remarkably, the intact HIV capsid is more than 1,000 times larger than the size limit prescribed by the diffusion barrier of the nuclear pore3. This barrier in the central channel of the nuclear pore is composed of intrinsically disordered nucleoporin domains enriched in phenylalanine-glycine (FG) dipeptides. Through multivalent FG interactions, cellular karyopherins and their bound cargoes solubilize in this phase to drive nucleocytoplasmic transport4. By performing an in vitro dissection of the nuclear pore complex, we show that a pocket on the surface of the HIV capsid similarly interacts with FG motifs from multiple nucleoporins and that this interaction licences capsids to penetrate FG-nucleoporin condensates. This karyopherin mimicry model addresses a key conceptual challenge for the role of the HIV capsid in nuclear entry and offers an explanation as to how an exogenous entity much larger than any known cellular cargo may be able to non-destructively breach the nuclear envelope.

Nicotine, THC, and Dolutegravir Modulate E-Cigarette-Induced Changes in Addiction- and Inflammation-Associated Genes in Rat Brains and Astrocytes.

E-cigarette use has been marketed as a safer alternative to traditional cigarettes, as a means of smoking cessation, and are used at a higher rate than the general population in people with HIV (PWH). Early growth receptor 2 (EGR2) and Activity-Regulated Cytoskeleton-Associated Protein (ARC) have a role in addiction, synaptic plasticity, inflammation, and neurodegeneration. This study showed that 10 days of exposure to e-cigarette vapor altered gene expression in the brains of 6-month-old, male, Sprague Dawley rats. Specifically, the e-cigarette solvent vapor propylene glycol (PG) downregulated EGR2 and ARC mRNA expression in frontal cortex, an effect which was reversed by nicotine (NIC) and THC, suggesting that PG could have a protective role against NIC and cannabis dependence. However, in vitro, PG upregulated EGR2 and ARC mRNA expression at 18 h in cultured C6 rat astrocytes suggesting that PG may have neuroinflammatory effects. PG-induced upregulation of EGR2 and ARC mRNA was reversed by NIC but not THC. The HIV antiretroviral DTG reversed the effect NIC had on decreasing PG-induced upregulation of EGR2, which is concerning because EGR2 has been implicated in HIV latency reversal, T-cell apoptosis, and neuroinflammation, a process that underlies the development of HIV-associated neurocognitive disorders.

Adult consequences of repeated nicotine vapor inhalation in adolescent rats.

INTRODUCTION: There has been a resurgence in nicotine inhalation in adolescents due to the popularity and availability of Electronic Nicotine Delivery Systems (ENDS). Almost five times as many US high-school seniors inhale nicotine vapor daily compared with those who smoke tobacco. This study was conducted to determine the impact of repeated adolescent vapor inhalation of nicotine on behavior in adulthood. METHODS: Male and female Sprague-Dawley rats were exposed to 30-minute sessions of ENDS vapor inhalation, twice daily, from Post-Natal Day (PND) 31 to PND 40. Conditions included vapor from the propylene glycol (PG) vehicle or nicotine (30 mg/mL in the PG). Animals were assessed for effects of nicotine on open field (PND 74-105) and wheel activity (PND 126-180) and for volitional exposure to nicotine vapor (PND 285-395). Plasma nicotine and cotinine were assessed in separate groups of male and female Wistar and Sprague-Dawley rats after a single nicotine inhalation session. RESULTS: Group mean plasma nicotine ranged from 39 to 59 ng/mL post-session with minimal strain differences detected. Adolescent nicotine exposure enhanced sensitivity to the locomotor stimulating effects of nicotine (0.1-0.8 mg/kg, s.c.) in an open field in female rats, but didn't change effects of nicotine on wheel activity. Female rats exposed to nicotine (30 mg/mL) vapor as adolescents responded more vigorously than PG exposed females for nicotine vapor in a FR5 challenge. CONCLUSIONS: Repeated adolescent nicotine vapor inhalation leads to enhanced liability for volitional exposure to nicotine vapor in adulthood in female rats, but minimal change in spontaneous locomotor behavior. IMPLICATIONS: These results show that adolescent vaping of nicotine can lead to lasting sensitization to the effects of nicotine in adulthood, including volitional responding for nicotine vapor. Demonstration of this in a controlled animal model establishes causality in a manner not possible from longitudinal evidence in human populations. These findings further highlight the importance of decreasing adolescent nicotine exposure by e-cigarettes to reduce consumption in adulthood.

Development of prediction models for one-year brain tumour survival using machine learning: a comparison of accuracy and interpretability.

BACKGROUND AND OBJECTIVE: Prediction of survival in patients diagnosed with a brain tumour is challenging because of heterogeneous tumour behaviours and treatment response. Advances in machine learning have led to the development of clinical prognostic models, but due to the lack of model interpretability, integration into clinical practice is almost non-existent. In this retrospective study, we compare five classification models with varying degrees of interpretability for the prediction of brain tumour survival greater than one year following diagnosis. METHODS: 1028 patients aged ≥16 years with a brain tumour diagnosis between April 2012 and April 2020 were included in our study. Three intrinsically interpretable 'glass box' classifiers (Bayesian Rule Lists [BRL], Explainable Boosting Machine [EBM], and Logistic Regression [LR]), and two 'black box' classifiers (Random Forest [RF] and Support Vector Machine [SVM]) were trained on electronic patients records for the prediction of one-year survival. All models were evaluated using balanced accuracy (BAC), F1-score, sensitivity, specificity, and receiver operating characteristics. Black box model interpretability and misclassified predictions were quantified using SHapley Additive exPlanations (SHAP) values and model feature importance was evaluated by clinical experts. RESULTS: The RF model achieved the highest BAC of 78.9%, closely followed by SVM (77.7%), LR (77.5%) and EBM (77.1%). Across all models, age, diagnosis (tumour type), functional features, and first treatment were top contributors to the prediction of one year survival. We used EBM and SHAP to explain model misclassifications and investigated the role of feature interactions in prognosis. CONCLUSION: Interpretable models are a natural choice for the domain of predictive medicine. Intrinsically interpretable models, such as EBMs, may provide an advantage over traditional clinical assessment of brain tumour prognosis by weighting potential risk factors and their interactions that may be unknown to clinicians. An agreement between model predictions and clinical knowledge is essential for establishing trust in the models decision making process, as well as trust that the model will make accurate predictions when applied to new data.

Comparison of 6 Mortality Risk Scores for Prediction of 1-Year Mortality Risk in Older Adults With Multimorbidity.

Importance: The most appropriate therapy for older adults with multimorbidity may depend on life expectancy (ie, mortality risk), and several scores have been developed to predict 1-year mortality risk. However, often, these mortality risk scores have not been externally validated in large sample sizes, and a head-to-head comparison in a prospective contemporary cohort is lacking. Objective: To prospectively compare the performance of 6 scores in predicting the 1-year mortality risk in hospitalized older adults with multimorbidity. Design, Setting, and Participants: This prognostic study analyzed data of participants in the OPERAM (Optimising Therapy to Prevent Avoidable Hospital Admissions in Multimorbid Older People) trial, which was conducted between December 1, 2016, and October 31, 2018, in surgical and nonsurgical departments of 4 university-based hospitals in Louvain, Belgium; Utrecht, the Netherlands; Cork, Republic of Ireland; and Bern, Switzerland. Eligible participants in the OPERAM trial had multimorbidity (≥3 coexisting chronic diseases), were aged 70 years or older, had polypharmacy (≥5 long-term medications), and were admitted to a participating ward. Data were analyzed from April 1 to September 30, 2020. Main Outcomes and Measures: The outcome of interest was any-cause death occurring in the first year of inclusion in the OPERAM trial. Overall performance, discrimination, and calibration of the following 6 scores were assessed: Burden of Illness Score for Elderly Persons, CARING (Cancer, Admissions ≥2, Residence in a nursing home, Intensive care unit admit with multiorgan failure, ≥2 Noncancer hospice guidelines) Criteria, Charlson Comorbidity Index, Gagné Index, Levine Index, and Walter Index. These scores were assessed using the following measures: Brier score (0 indicates perfect overall performance and 0.25 indicates a noninformative model); C-statistic and 95% CI; Hosmer-Lemeshow goodness-of-fit test and calibration plots; and sensitivity, specificity, and positive and negative predictive values. Results: The 1879 patients in the study had a median (IQR) age of 79 (74-84) years and 835 were women (44.4%). The median (IQR) number of chronic diseases was 11 (8-16). Within 1 year, 375 participants (20.0%) died. Brier scores ranged from 0.16 (Gagné Index) to 0.24 (Burden of Illness Score for Elderly Persons). C-statistic values ranged from 0.62 (95% CI, 0.59-0.65) for Charlson Comorbidity Index to 0.69 (95% CI, 0.66-0.72) for the Walter Index. Calibration was good for the Gagné Index and moderate for other mortality risk scores. Conclusions and Relevance: Results of this prognostic study suggest that all 6 of the 1-year mortality risk scores examined had moderate prognostic performance, discriminatory power, and calibration in a large cohort of hospitalized older adults with multimorbidity. Overall, none of these mortality risk scores outperformed the others, and thus none could be recommended for use in daily clinical practice.

Effects of combined THC and heroin vapor inhalation in rats.

RATIONALE: Opioids are effective medications, but they have several key limitations including the development of tolerance, establishment of dependence, diversion for non-medical use, and the development of addiction. Therefore, any drugs which act in an additive or synergistic fashion with opioids to address medical applications have the potential to reduce opioid-related harms. OBJECTIVES: To determine if heroin and Δ9-tetrahydrocannabinol (THC) interact in an additive or independent manner to alter nociception, body temperature, and spontaneous locomotor activity when inhaled or injected. METHODS: Groups of female and male rats, implanted with radiotelemetry transmitters, were exposed to vapor generated from heroin (50 mg/mL in propylene glycol vehicle; PG), THC (50 mg/mL), or the combination for assessment of effects on temperature and activity. Thermal nociception was assessed with a warm water tail-withdrawal assay. RESULTS: Heroin inhalation increased temperature and activity whereas THC inhalation decreased temperature and activity in both female and male Sprague-Dawley rats. Effects of combined inhalation were in opposition, and additional experiments found the same outcome for the injection of heroin (0.5 mg/kg, s.c.) and THC (10 mg/kg, i.p.) alone and in combination. In contrast, the co-administration of heroin and THC by either inhalation or injection produced additive effects on thermal nociception in both male and female Sprague-Dawley and Wistar rats. CONCLUSIONS: This study shows that additive effects of THC with an opioid on a medical endpoint such as analgesia may not generalize to other behavioral or physiological effects, which may be a positive outcome for unwanted side effects.

Clinical, computed tomographic, surgical findings and outcome in dogs with sublumbar abscessation: 16 cases (2013-2019).

OBJECTIVES: To describe the clinical presentation, CT imaging findings, surgical treatment and long-term outcome in dogs with sublumbar abscessation. MATERIALS AND METHODS: Medical records of dogs treated for sublumbar abscessation between 2013 and 2019 were retrieved. Criteria for inclusion were a diagnosis of sublumbar abscessation, complete patient history, pre-operative CT imaging, blood work, bacteriology results, record of the surgical treatment, post-operative care and outcome. RESULTS: Sixteen dogs were included in this study with a median follow-up period of 36 months (15/16). Clinicals signs included flank or lumbar soft tissue swelling (12/16), lumbar pain (11/16), hyperthermia (8/16), a cutaneous discharging sinus (5/16) and lethargy (5/16). CT findings were: abscesses of varying size localised in the psoas muscles (16/16), spondylitis (12/16), vertebral osteomyelitis (6/16), discospondylitis (2/16) and epidural inflammation (8/16). Thoracic lesions were present in eight of 12 dogs. Exploratory surgery was performed in 16 dogs via a midline celiotomy in 15 of 16 and a lateral approach in one of 16 cases. The surgical approach was selected based on the location of the draining tracts detected on CT imaging. Vertebral body curettage was performed in five of 16 cases with lesions identified on CT. Vegetal foreign material was found in seven of 16 dogs. Of the 15 animals with long-term follow-up, 13 had no signs of recurrence. CLINICAL SIGNIFICANCE: Surgical treatment of sublumbar abscessation resulted in a good long-term outcome when CT was used to guide the surgical approach and to plan the procedure. Our study highlights common vertebral and epidural lesions associated with sublumbar abscesses with a prevalence of 87.5%.

Vapor exposure to Δ9-tetrahydrocannabinol (THC) slows locomotion of the Maine lobster (Homarus americanus).

RATIONALE: Despite a long history of use in synaptic physiology, the lobster has been a neglected model for behavioral pharmacology. A restaurateur proposed that exposing lobster to cannabis smoke reduces anxiety and pain during the cooking process. It is unknown if lobster gill respiration in air would result in significant Δ9-tetrahydrocannabinol (THC) uptake and whether this would have any detectable behavioral effects. OBJECTIVE: The primary goal was to determine tissue THC levels in the lobster after exposure to THC vapor. Secondary goals were to determine if THC vapor altered locomotor behavior or nociception. METHODS: Tissue samples were collected (including muscle, brain and hemolymph) from Homarus americanus (N = 3 per group) following 30 or 60 min of exposure to vapor generated by an e-cigarette device using THC (100 mg/mL in a propylene glycol vehicle). Separate experiments assessed locomotor behavior and hot water nociceptive responses following THC vapor exposure. RESULTS: THC vapor produced duration-related THC levels in all tissues examined. Locomotor activity was decreased (distance, speed, time-mobile) by 30 min inhalation of THC. Lobsters exhibit a temperature-dependent withdrawal response to immersion of tail, antennae or claws in warm water; this is novel evidence of thermal nociception for this species. THC exposure for 60 min had only marginal effect on nociception under the conditions assessed. CONCLUSIONS: Vapor exposure of lobsters, using an e-cigarette based model, produces dose-dependent THC levels in all tissues and reduces locomotor activity. Hot water nociception was temperature dependent, but only minimal anti-nociceptive effect of THC exposure was confirmed.

Effects of α-pyrrolidino-phenone cathinone stimulants on locomotor behavior in female rats.

The α-pyrrolidino-phenone cathinone stimulants first came to widespread attention because of bizarre behavior consequent to the use of α-pyrrolidinopentiophenone (α-PVP, "flakka") reported in popular press. As with other designer drugs, diversification of cathinones has been driven by desirable subjective effects, but also by attempts to stay ahead of legal controls of specific molecules. The α-pyrrolidinohexiophenone (α-PHP) and α-pyrrolidinopropiophenone (α-PPP) compounds have been relatively under-investigated relative to α-PVP and provide a key opportunity to also investigate structure-activity relationships, i.e., how the extension of the alpha carbon chain may affect potency or efficacy. Female rats were used to contrast the effects of α-PHP and α-PPP with those of α-PVP in altering wheel activity and effects on spontaneous locomotion, temperature and intracranial self-stimulation reward. The α-PPP, α-PHP and α-PVP compounds (5, 10 mg/kg, i.p.) suppressed wheel activity. Inhalation of α-PHP or α-PVP also suppressed wheel activity, but for an abbreviated duration compared with the injection route. Spontaneous activity was increased, and brain reward thresholds decreased, in a dose-dependent manner by all three compounds; only small decrements in body temperature were observed. These data show that all three of the α-pyrrolidino-phenone cathinones exhibit significant stimulant-like activity in female rats. Differences were minor and abuse liability is therefore likely to be equivalent for all three α-pyrrolidino-phenones.

Female rats self-administer heroin by vapor inhalation.

Over the last two decades the United States has experienced a significant increase in the medical and non-medical use of opioid drugs, resulting in record numbers of opioid-related overdoses and deaths. There was an initial increase in non-medical use of prescription opioids around 2002, followed later by increased heroin use and then most recently fentanyl. Inhalation is a common route of administration for opioids, with a documented history spanning back to Mediterranean antiquity and up through modern use with e-cigarette devices. Unfortunately, preclinical studies using inhalation as the route of administration remain relatively few. This study was conducted to determine the efficacy of e-cigarette vapor inhalation of heroin in rats. Non-contingent exposure to heroin or methadone vapor produced anti-nociceptive efficacy in male and female rats. Female rats were trained to self-administer heroin vapor; the most-preferring half of the distribution obtained more vapor reinforcers when the concentration of heroin was reduced in the vapor vehicle and when pre-treated with the opioid receptor antagonist naloxone. The anti-nociceptive effect of heroin self-administered by vapor was identical in magnitude to that produced by intravenous self-administration. Finally, anxiety-like behavior increased 24-48 h after last heroin vapor access, consistent with withdrawal signs observed after intravenous self-administration. In sum, these studies show that rewarding and anti-nociceptive effects of heroin are produced in rats by vapor inhalation using e-cigarette technology. Importantly, self-administration models by this route can be deployed to determine health effects of inhaled heroin or other opioids.

Explication of CB1 receptor contributions to the hypothermic effects of Δ9-tetrahydrocannabinol (THC) when delivered by vapor inhalation or parenteral injection in rats.

The use of Δ9-tetrahydrocannabinol (THC) by inhalation using e-cigarette technology grows increasingly popular for medical and recreational purposes. This has led to development of e-cigarette based techniques to study the delivery of THC by inhalation in laboratory rodents. Inhaled THC reliably produces hypothermic and antinociceptive effects in rats, similar to effects of parenteral injection of THC. This study was conducted to determine the extent to which the hypothermic response depends on interactions with the CB1 receptor, using pharmacological antagonist (SR141716, AM-251) approaches. Groups of rats were implanted with radiotelemetry devices capable of reporting activity and body temperature, which were assessed after THC inhalation or injection. SR141716 (4 mg/kg, i.p.) blocked or attenuated antinociceptive effects of acute THC inhalation in male and female rats. SR141716 was unable to block the initial hypothermia caused by THC inhalation, but temperature was restored to normal more quickly. Alterations in antagonist pre-treatment time, dose and the use of a rat strain with less sensitivity to THC-induced hypothermia did not change this pattern. Pre-treatment with SR141716 (4 mg/kg, i.p.) blocked hypothermia induced by i.v. THC and reversed hypothermia when administered 45 or 90 min after THC (i.p.). SR141716 and AM-251 (4 mg/kg, i.p.) sped recovery from, but did not block, hypothermia caused by vapor THC in female rats made tolerant by prior repeated THC vapor inhalation. The CB2 antagonist AM-630, had no effect. These results suggest that hypothermia consequent to THC inhalation is induced by other mechanisms in addition to CB1 receptor activation.

Lasting effects of repeated ∆9 -tetrahydrocannabinol vapour inhalation during adolescence in male and female rats.

BACKGROUND AND PURPOSE: Adolescents are regularly exposed to ∆9 -tetrahydrocannabinol (THC) via smoking and, more recently, vaping cannabis extracts. Growing legalization of cannabis for medical and recreational purposes, combined with decreasing perceptions of harm, makes it increasingly important to determine the consequences of frequent adolescent exposure for motivated behaviour and lasting tolerance in response to THC. EXPERIMENTAL APPROACHES: Male and female rats inhaled THC vapour, or that from the propylene glycol (PG) vehicle, twice daily for 30 min from postnatal day (PND) 35-39 and PND 42-46 using an e-cigarette system. Thermoregulatory responses to vapour inhalation were assessed by radio-telemetry during adolescence and from PND 86-94. Chow intake was assessed in adulthood. Blood samples were obtained from additional adolescent groups following initial THC inhalation and after 4 days of twice daily exposure. Additional groups exposed repeatedly to THC or PG during adolescence were evaluated for intravenous self-administration of oxycodone as adults. KEY RESULTS: Female, not male, adolescents developed tolerance to the hypothermic effects of THC inhalation in the first week of repeated exposure despite similar plasma THC levels. Each sex exhibited tolerance to THC hypothermia in adulthood after repeated adolescent THC. However, enhanced potency was found in females. Repeated THC male rats consumed more food than their PG-treated control group, without significant bodyweight differences. Adolescent THC did not alter oxycodone self-administration in either sex but increased fentanyl self-administration in females. CONCLUSIONS AND IMPLICATIONS: Repeated THC vapour inhalation in adolescent rats has lasting consequences observable in adulthood.

Δ9-tetrahydrocannabinol attenuates oxycodone self-administration under extended access conditions.

Growing nonmedical use of prescription opioids is a global problem, motivating research on ways to reduce use and combat addiction. Medical cannabis ("medical marijuana") legalization has been associated epidemiologically with reduced opioid harms and cannabinoids have been shown to modulate effects of opioids in animal models. This study was conducted to determine if Δ9-tetrahydrocannabinol (THC) enhances the behavioral effects of oxycodone. Male rats were trained to intravenously self-administer (IVSA) oxycodone (0.15 mg/kg/infusion) during 1 h, 4 h or 8 h sessions. Following acquisition rats were exposed to THC by vapor inhalation (1 h and 8 h groups) or injection (0-10 mg/kg, i.p.; all groups) prior to IVSA sessions. Fewer oxycodone infusions were obtained by rats following vaporized or injected THC compared with vehicle treatment prior to the session. Follow-up studies demonstrated parallel dose-dependent effects of THC, i.p., on self-administration of different per-infusion doses of oxycodone and a preserved loading dose early in the session. These patterns are inconsistent with behavioral suppression. Additional groups of male and female Wistar rats were assessed for nociception following inhalation of vaporized THC (50 mg/mL), oxycodone (100 mg/mL) or the combination. Tail withdrawal latency was increased more by the THC/oxycodone combination compared to either drug alone. Similar additive antinociceptive effects were produced by injection of THC (5.0 mg/kg, i.p.) and oxycodone (2.0 mg/kg, s.c.). Together these data demonstrate additive effects of THC and oxycodone and suggest the potential use of THC to enhance therapeutic efficacy, and to reduce the abuse, of opioids.

Tolerance to hypothermic and antinoceptive effects of ∆9-tetrahydrocannabinol (THC) vapor inhalation in rats.

RATIONALE: A reduced effect of a given dose of ∆9-tetrahydrocannabinol (THC) emerges with repeated exposure to the drug. This tolerance can vary depending on THC dose, exposure chronicity and the behavioral or physiological measure of interest. A novel THC inhalation system based on e-cigarette technology has been recently shown to produce the hypothermic and antinociceptive effects of THC in rats. OBJECTIVE: To determine if tolerance to these effects can be produced with repeated vapor inhalation. METHODS: Groups of male and female Wistar rats were exposed to 30 min of inhalation of the propylene glycol (PG) vehicle or THC (200 mg/mL in PG) two or three times per day for four days. Rectal temperature changes and nociception were assessed after the first exposure on the first and fourth days of repeated inhalation. RESULTS: Female, but not male, rats developed tolerance to the hypothermic and antinociceptive effects of THC after four days of twice-daily THC vapor inhalation. Thrice daily inhalation for four days resulted in tolerance in both male and female rats. The plasma THC levels reached after a 30 min inhalation session did not differ between the male and female rats. CONCLUSIONS: Repeated daily THC inhalation induces tolerance in female and male rats, providing further validation of the vapor inhalation method for preclinical studies.

Effects of Δ9-THC and cannabidiol vapor inhalation in male and female rats.

RATIONALE: Previous studies report sex differences in some, but not all, responses to cannabinoids in rats. The majority of studies use parenteral injection; however, most human use is via smoke inhalation and, increasingly, vapor inhalation. OBJECTIVES: To compare thermoregulatory and locomotor responses to inhaled ∆9-tetrahydrocannabinol (THC), cannabidiol (CBD), and their combination using an e-cigarette-based model in male and female rats METHODS: Male and female Wistar rats were implanted with radiotelemetry devices for the assessment of body temperature and locomotor activity. Animals were then exposed to THC or CBD vapor using a propylene glycol (PG) vehicle. THC dose was adjusted via the concentration in the vehicle (12.5-200 mg/mL) and the CBD (100, 400 mg/mL) dose was also adjusted by varying the inhalation duration (10-40 min). Anti-nociception was evaluated using a tail-withdrawal assay following vapor inhalation. Plasma samples obtained following inhalation in different groups of rats were compared for THC content. RESULTS: THC inhalation reduced body temperature and increased tail-withdrawal latency in both sexes equivalently and in a concentration-dependent manner. Female temperature, activity, and tail-withdrawal responses to THC did not differ between estrus and diestrus. CBD inhalation alone induced modest hypothermia and suppressed locomotor activity in both males and females. Co-administration of THC with CBD, in a 1:4 ratio, significantly decreased temperature and activity in an approximately additive manner and to similar extent in each sex. Plasma THC varied with the concentration in the PG vehicle but did not differ across rat sex. CONCLUSION: In summary, the inhalation of THC or CBD, alone and in combination, produces approximately equivalent effects in male and female rats. This confirms the efficacy of the e-cigarette-based method of THC delivery in female rats.

Risk Factors and Patterns of Potentially Avoidable Readmission in Patients With Cancer.

PURPOSE: Patients with cancer are particularly at risk for readmission within 30-days after discharge. To identify the patients who might benefit from more-intensive discharge interventions, we identified the risk factors associated with 30-day potentially avoidable readmissions. METHODS AND MATERIALS: We included all consecutive discharges from the oncology division of an academic tertiary medical center in Boston, Massachusetts, between July 1, 2009, and June 30, 2010. Potentially avoidable 30-day readmissions to the index hospital and two other hospitals within its network were identified. We performed a multivariable logistic regression in which the final model included variables found in bivariable testing to be significantly associated with the outcome. RESULTS: Among the 2,916 patients discharged during the study period, 1,086 (37.3%) were readmitted within 30 days. Of these, 341 (31.4% of all readmissions, 11.7% of all discharges) were identified as potentially avoidable. In the multivariable analysis, the following patient factors were associated with a significantly higher risk of a potentially avoidable readmission: total number of medications at discharge, liver disease, last sodium level, and last hemoglobin level before discharge. In addition, potentially avoidable readmissions occurred significantly earlier than unavoidable readmissions (median, 10 v 13 days; P < .001). CONCLUSION: Almost 40% of patients with cancer had a 30-day readmission, and almost one third of these were deemed potentially avoidable, and several risk factors for this were identified. Interventions at discharge may be prioritized to patients with these risk factors.

Inhaled delivery of Δ(9)-tetrahydrocannabinol (THC) to rats by e-cigarette vapor technology.

Most human Δ(9)-tetrahydrocannabinol (THC) use is via inhalation, and yet few animal studies of inhalation exposure are available. Popularization of non-combusted methods for the inhalation of psychoactive drugs (Volcano(®), e-cigarettes) further stimulates a need for rodent models of this route of administration. This study was designed to develop and validate a rodent chamber suitable for controlled exposure to vaporized THC in a propylene glycol vehicle, using an e-cigarette delivery system adapted to standard size, sealed rat housing chambers. The in vivo efficacy of inhaled THC was validated using radiotelemetry to assess body temperature and locomotor responses, a tail-flick assay for nociception and plasma analysis to verify exposure levels. Hypothermic responses to inhaled THC in male rats depended on the duration of exposure and the concentration of THC in the vehicle. The temperature nadir was reached after ∼40 min of exposure, was of comparable magnitude (∼3 °Celsius) to that produced by 20 mg/kg THC, i.p. and resolved within 3 h (compared with a 6 h time course following i.p. THC). Female rats were more sensitive to hypothermic effects of 30 min of lower-dose THC inhalation. Male rat tail-flick latency was increased by THC vapor inhalation; this effect was blocked by SR141716 pretreatment. The plasma THC concentration after 30 min of inhalation was similar to that produced by 10 mg/kg THC i.p. This approach is flexible, robust and effective for use in laboratory rats and will be of increasing utility as users continue to adopt "vaping" for the administration of cannabis.

Locomotor Stimulant and Rewarding Effects of Inhaling Methamphetamine, MDPV, and Mephedrone via Electronic Cigarette-Type Technology.

Although inhaled exposure to drugs is a prevalent route of administration for human substance abusers, preclinical models that incorporate inhaled exposure to psychomotor stimulants are not commonly available. Using a novel method that incorporates electronic cigarette-type technology to facilitate inhalation, male Wistar rats were exposed to vaporized methamphetamine (MA), 3,4-methylenedioxypyrovalerone (MDPV), and mephedrone (4-methylmethcathinone) in propylene glycol vehicle using concentrations ranging from 12.5 to 200 mg/ml. Rats exhibited increases in spontaneous locomotor activity, measured by implanted radiotelemetry, following exposure to methamphetamine (12.5 and 100 mg/ml), MDPV (25, 50, and 100 mg/ml), and mephedrone (200 mg/ml). Locomotor effects were blocked by pretreatment with the dopamine D1-like receptor antagonist SCH23390 (10 µg/kg, intraperitoneal (i.p.)). MA and MDPV vapor inhalation also altered activity on a running wheel in a biphasic manner. An additional group of rats was trained on a discrete trial intracranial self-stimulation (ICSS) procedure interpreted to assess brain reward status. ICSS-trained rats that received vaporized MA, MDPV, or mephedrone exhibited a significant reduction in threshold of ICSS reward compared with vehicle. The effect of vapor inhalation of the stimulants was found comparable to the locomotor and ICSS threshold-reducing effects of i.p. injection of mephedrone (5.0 mg/kg), MA (0.5-1.0 mg/kg), or MDPV (0.5-1.0 mg/kg). These data provide robust validation of e-cigarette-type technology as a model for inhaled delivery of vaporized psychostimulants. Finally, these studies demonstrate the potential for human use of e-cigarettes to facilitate covert use of a range of psychoactive stimulants. Thus, these devices pose health risks beyond their intended application for the delivery of nicotine.

International Validity of the HOSPITAL Score to Predict 30-Day Potentially Avoidable Hospital Readmissions.

IMPORTANCE: Identification of patients at a high risk of potentially avoidable readmission allows hospitals to efficiently direct additional care transitions services to the patients most likely to benefit. OBJECTIVE: To externally validate the HOSPITAL score in an international multicenter study to assess its generalizability. DESIGN, SETTING, AND PARTICIPANTS: International retrospective cohort study of 117 065 adult patients consecutively discharged alive from the medical department of 9 large hospitals across 4 different countries between January 2011 and December 2011. Patients transferred to another acute care facility were excluded. EXPOSURES: The HOSPITAL score includes the following predictors at discharge: hemoglobin, discharge from an oncology service, sodium level, procedure during the index admission, index type of admission (urgent), number of admissions during the last 12 months, and length of stay. MAIN OUTCOMES AND MEASURES: 30-day potentially avoidable readmission to the index hospital using the SQLape algorithm. RESULTS: Overall, 117 065 adults consecutively discharged alive from a medical department between January 2011 and December 2011 were studied. Of all medical discharges, 16 992 of 117 065 (14.5%) were followed by a 30-day readmission, and 11 307 (9.7%) were followed by a 30-day potentially avoidable readmission. The discriminatory power of the HOSPITAL score to predict potentially avoidable readmission was good, with a C statistic of 0.72 (95% CI, 0.72-0.72). As in the derivation study, patients were classified into 3 risk categories: low (n = 73 031 [62.4%]), intermediate (n = 27 612 [23.6%]), and high risk (n = 16 422 [14.0%]). The estimated proportions of potentially avoidable readmission for each risk category matched the observed proportion, resulting in an excellent calibration (Pearson χ2 test P = .89). CONCLUSIONS AND RELEVANCE: The HOSPITAL score identified patients at high risk of 30-day potentially avoidable readmission with moderately high discrimination and excellent calibration when applied to a large international multicenter cohort of medical patients. This score has the potential to easily identify patients in need of more intensive transitional care interventions to prevent avoidable hospital readmissions.

Full-genome analyses of a Potato Virus Y (PVY) isolate infecting pepper (Capsicum annuum L.) in the Republic of South Africa.

Potato Virus Y (PVY) is a pathogen of economic importance in pepper and other major crop species in the family Solanaceae. Three major PVY strain groups: O, C, and N, have been distinguished on the basis of genome sequencing. In this study, the first full-genome sequence of a PVY isolate (JVW-186) infecting pepper from the province of KwaZulu-Natal, Republic of South Africa is reported. The complete genome sequence of JVW-186 was assembled from overlapping RT-PCR clones using MEGA 5 software. Two ORFs were identified at position 186 and 2915 of the sequence encoding the viral polyprotein and the frameshift translated protein P3N-PIPO, respectively. RDP4 software confirmed three recombination breakpoints at position 343, 1365, and 9308 of the sequence. At each recombination event, a 1,021-bp fragment at the 5' end in the region of the P1/HC-Pro protein and a 392-bp fragment in the region of the coat protein shared a high sequence similarity of 91.8 and 98.89 % to the potato borne PVY(C) isolate PRI-509 and the PVY(O) isolate SASA-110, respectively. The non-recombinant fragment 1 (342-bp) clustered within the C clade of PVY isolates; however, the large 7,942-bp fragment 3 did not cluster within any of the clades. This suggests the possibility of a PVY isolate that has evolved due to the dynamics of selection pressure or the likelihood of an ancestral PVY strain.