Intentional benzodiazepine poisoning in older adults reported to United States Poison Centers.

INTRODUCTION: Despite known contraindications, benzodiazepines are frequently prescribed for older adults. This study utilizes poison control center data on benzodiazepine-involved cases aged 50 and above to compare the characteristics of suspected suicide attempt with other intentional misuse cases. We also examined associations of major medical outcomes (major effect/death) with demographic characteristics and other co-used substances in each group. METHODS: The study employed data from the America's Poison Center National Poison Data System from 2015-2022. Descriptive statistics and binary logistic regression models were used. RESULTS: Of the benzodiazepine-poisoning cases of intentional misuse (n = 93,245), 85 percent were suicide attempts and 15 percent were other intentional misuses. Reports to poisons centers showed a decline from 2019-2022 when compared to 2015-2016. However, the likelihood of a reported suicide attempt, compared to other intentional misuse, was greater in 2019-2022 compared to 2015-2016 and among those who co-used antidepressants, anxiolytics, atypical antipsychotics, other benzodiazepines, other analgesics, anticonvulsants, and alcohol. The odds of major effect/death in both groups were also greater in 2019-2022, with suicide attempt cases in advanced ages showing higher odds. The co-use of antidepressants, prescription opioids, atypical antipsychotics, anticonvulsants, and other analgesics were associated with a higher likelihood of major effect/death in both exposure groups. For instance, adjusted odds ratios for co-used prescription opioids were 2.20 (95 percent confidence intervals: 2.09-2.31) among suicide attempt cases and 3.51 (95 percent confidence intervals: 3.10-3.97) among other intentional misuse cases. DISCUSSION: Healthcare providers need to screen for suicidal ideation among benzodiazepine users, with special attention to an increased risk of suicide attempt among those who co-use antidepressants and opioids and to decreasing adverse outcomes in all misuse cases. Assessments of underlying mental health and substance use problems and medication regimens to minimize polypharmacy and drug interactions are needed to reduce adverse outcomes. CONCLUSIONS: Though the numbers of benzodiazepine-involved suicide attempt and other intentional misuse cases reported to United States poison centers decreased in recent years, the likelihood of major medical effect/death among these cases have increased.

Predictors of Quality of Life Decline in Patients with Oligometastases treated with Stereotactic Ablative Radiotherapy: Analysis of the Population-Based SABR-5 Phase II Trial.

AIMS: Most patients experience stable quality of life (QoL) after stereotactic ablative radiotherapy (SABR) treatment for oligometastases. However, a subset of patients experience clinically relevant declines in QoL on post-treatment follow-up. This study aimed to identify risk factors for QoL decline. MATERIALS AND METHODS: The SABR-5 trial was a population-based single-arm phase II study of SABR to up to five sites of oligometastases. Prospective QoL was measured using treatment site-specific tools at pre-treatment baseline and 3, 6, 9, 12, 15, 18, 21, 24, 30 and 36 months after treatment. The time to persistent QoL decline was calculated as the time from SABR to the first decline in QoL score meeting minimum clinically important difference with no improvement to baseline score on subsequent assessments. Univariable and multivariable logistic regression analyses were carried out to determine factors associated with QoL decline. RESULTS: One hundred and thirty-three patients were included with a median follow-up of 32 months (interquartile range 25-43). Thirty-five patients (26%) experienced a persistent decline in QoL. The median time until persistent QoL decline was not reached. The cumulative incidence of QoL decline at 2 and 3 years were 22% (95% confidence interval 14.0-29.6) and 40% (95% confidence interval 28.0-51.2), respectively. In multivariable analysis, disease progression (odds ratio 5.23, 95% confidence interval 1.59-17.47, P = 0.007) and adrenal metastases (odds ratio 9.70, 95% confidence interval 1.41-66.93, P = 0.021) were associated with a higher risk of QoL decline. Grade 3 or higher (odds ratio 3.88, 95% confidence interval 0.92-16.31, P = 0.064) and grade 2 or higher SABR-associated toxicity (odds ratio 2.24, 95% confidence interval 0.85-5.91, P = 0.10) were associated with an increased risk of QoL decline but did not reach statistical significance. CONCLUSIONS: Disease progression and adrenal lesion site were associated with persistent QoL decline following SABR. The development of grade 3 or higher toxicities was also associated with an increased risk, albeit not statistically significant. Further studies are needed, focusing on the QoL impact of metastasis-directed therapies.

Prospective Longitudinal Assessment of Quality of Life After Stereotactic Ablative Radiotherapy for Oligometastases: Analysis of the Population-based SABR-5 Phase II Trial.

AIMS: To evaluate longitudinal patient-reported quality of life (QoL) in patients treated with stereotactic ablative radiotherapy (SABR) for oligometastases. MATERIALS AND METHODS: The SABR-5 trial was a population-based single-arm phase II study of SABR to up to five sites of oligometastases, conducted in six regional cancer centres in British Columbia, Canada from 2016 to 2020. Prospective QoL was measured using treatment site-specific QoL questionnaires at pre-treatment baseline and at 3, 6, 9, 12, 15, 18, 21, 24, 30 and 36 months after treatment. Patients with bone metastases were assessed with the Brief Pain Inventory (BPI). Patients with liver, adrenal and abdominopelvic lymph node metastases were assessed with the Functional Assessment of Chronic Illness Therapy-Abdominal Discomfort (FACIT-AD). Patients with lung and intrathoracic lymph node metastases were assessed with the Prospective Outcomes and Support Initiative (POSI) lung questionnaire. The two one-sided test procedure was used to assess equivalence between the worst QoL score and the baseline score of individual patients. The mean QoL at all time points was used to determine the trajectory of QoL response after SABR. The proportion of patients with 'stable', 'improved' or 'worsened' QoL was determined for all time points based on standard minimal clinically important differences (MCID; BPI worst pain = 2, BPI functional interference score [FIS] = 0.5, FACIT-AD Trial Outcome Index [TOI] = 8, POSI = 3). RESULTS: All enrolled patients with baseline QoL assessment and at least one follow-up assessment were analysed (n = 133). On equivalence testing, the patients' worst QoL scores were clinically different from baseline scores and met MCID (BPI worst pain mean difference: 1.8, 90% confidence interval 1.19 to 2.42]; BPI FIS mean difference: 1.68, 90% confidence interval 1.15 to 2.21; FACIT-AD TOI mean difference: -8.76, 90% confidence interval -11.29 to -6.24; POSI mean difference: -4.61, 90% confidence interval -6.09 to -3.14). However, the mean FIS transiently worsened at 9, 18 and 21 months but eventually returned to stable levels. The mean FACIT and POSI scores also worsened at 36 months, albeit with a limited number of responses (n = 4 and 8, respectively). Most patients reported stable QoL at all time points (range: BPI worst pain 71-82%, BPI FIS 45-78%, FACIT-AD TOI 50-100%, POSI 25-73%). Clinically significant stability, worsening and improvement were seen in 70%/13%/18% of patients at 3 months, 53%/28%/19% at 18 months and 63%/25%/13% at 36 months. CONCLUSIONS: Transient decreases in QoL that met MCID were seen between patients' worst QoL scores and baseline scores. However, most patients experienced stable QoL relative to pre-treatment levels on long-term follow-up. Further studies are needed to characterise patients at greatest risk for decreased QoL.

Inflammatory biomarker signatures in post-surgical drain fluid may detect anastomotic leaks within 48 hours of colorectal resection.

BACKGROUND: The optimal treatment of colorectal cancer is surgical resection and primary anastomosis. Anastomotic leak can affect up to 20% of patients and creates significant morbidity and mortality. Current diagnosis of a leak is based on clinical suspicion and subsequent radiology. Peritoneal biomarkers have shown diagnostic utility in other conditions and could be useful in providing earlier diagnosis. This pilot study was designed to assess the practical utility of peritoneal biomarkers after abdominal surgery utilising an automated immunoassay system in routine use for quantifying cytokines. METHODS: Patients undergoing an anterior resection for a rectal cancer diagnosis were recruited at University Hospital of Wales, Cardiff between June 2019 and June 2021. A peritoneal drain was placed in the proximity of the anastomosis during surgery, and peritoneal fluid was collected at days 1 to 3 post-operatively, and analysed using the Siemens IMMULITE platform for interleukin (IL)-1ß, IL-6, IL-10, CXCL8, tumour necrosis factor alpha (TNFα) and C-reactive protein (CRP). RESULTS: A total of 42 patients were recruited (22M:20F, median age 65). Anastomotic leak was detected in four patients and a further five patients had other intra-abdominal complications. The IMMULITE platform was able to provide robust and reliable results from the analysis of the peritoneal fluid. A metric based on the combination of peritoneal IL-6 and CRP levels was able to accurately diagnose three anastomotic leaks, whilst correctly classifying all negative control patients including those with other complications. CONCLUSIONS: This pilot study demonstrates that a simple immune signature in surgical drain fluid could accurately diagnose an anastomotic leak at 48 h postoperatively using instrumentation that is already widely available in hospital clinical laboratories.

Correlation between Multiparametric MR Imaging and Molecular Genetics in Pontine Pediatric High-Grade Glioma.

BACKGROUND AND PURPOSE: Molecular profiling is a crucial feature in the "integrated diagnosis" of CNS tumors. We aimed to determine whether radiomics could distinguish molecular types of pontine pediatric high-grade gliomas that have similar/overlapping phenotypes on conventional anatomic MR images. MATERIALS AND METHODS: Baseline MR images from children with pontine pediatric high-grade gliomas were analyzed. Retrospective imaging studies included standard precontrast and postcontrast sequences and DTI. Imaging analyses included median, mean, mode, skewness, and kurtosis of the ADC histogram of the tumor volume based on T2 FLAIR and enhancement at baseline. Histone H3 mutations were identified through immunohistochemistry and/or Sanger or next-generation DNA sequencing. The log-rank test identified imaging factors prognostic of survival from the time of diagnosis. Wilcoxon rank-sum and Fisher exact tests compared imaging predictors among groups. RESULTS: Eighty-three patients had pretreatment MR imaging and evaluable tissue sampling. The median age was 6 years (range, 0.7-17 years); 50 tumors had a K27M mutation in H3-3A, and 11, in H3C2/3. Seven tumors had histone H3 K27 alteration, but the specific gene was unknown. Fifteen were H3 wild-type. Overall survival was significantly higher in H3C2/3- compared with H3-3A-mutant tumors (P = .003) and in wild-type tumors compared with any histone mutation (P = .001). Lower overall survival was observed in patients with enhancing tumors (P = .02) compared with those without enhancement. H3C2/3-mutant tumors showed higher mean, median, and mode ADC_total values (P < .001) and ADC_enhancement (P < .004), with lower ADC_total skewness and kurtosis (P < .003) relative to H3-3A-mutant tumors. CONCLUSIONS: ADC histogram parameters are correlated with histone H3 mutation status in pontine pediatric high-grade glioma.

Validation of the Prognostic Utility of ESTRO/EORTC Oligometastatic Disease Classification: A Secondary Analysis From the Population-Based Phase II SABR-5 Trial.

PURPOSE: The recently developed European Society for Radiotherapy and Oncology (ESTRO)/European Organization for Research and Treatment of Cancer (EORTC) oligometastatic disease (OMD) classification has not been validated in terms of its prognostic significance. This study stratified patients from the phase II SABR-5 trial based on ESTRO/EORTC criteria and compared progression-free survival (PFS) and overall survival (OS) to determine the prognostic significance of the classification scheme. METHODS AND MATERIALS: The SABR-5 trial was a single arm phase II study conducted at the 6 regional cancer centers across British Columbia (BC), Canada, where SABR for oligometastases was only offered on trial. Patients with up to 5 oligometastases (total or not controlled by prior treatment and including induced OMD) underwent SABR to all lesions. Patients were 18 years of age or older, Eastern Cooperative Oncology Group 0 to 2, and life expectancy ≥6 months. PFS and OS were calculated using the Kaplan-Meier method and differences between OMD groups were assessed with log-rank tests. Univariable and multivariable analyses were performed using Cox regression modeling. RESULTS: Between November 2016 and July 2020, 381 patients underwent SABR on trial. Median follow-up was 27 months (interquartile range, 18-36). The most frequent OMD group was de novo OMD (69%), followed by repeat (16%) and induced (13%). OMD groups differed significantly in PFS (P < .001) but not OS (P = .069). The OMD classification was an independent predictor of both PFS (P = .005) and OS (P = .002). Of the 5 classification factors, only chronicity (synchronous, hazard ratio, 0.52; P = .027) and oligoprogression (hazard ratio, 2.05; P = .004) were independently prognostic for OS. CONCLUSIONS: In this large prospective cohort, the ESTRO/EORTC classification was an independent predictor of PFS and OS and should be used to identify specific patient groups for clinical trials. In this trial population, the prognostic power is largely attributable to chronicity and oligoprogression. Simplification of the framework may be possible in the future and allow for greater ease of use; however, further data on underrepresented OMD groups and histologies will be required.

Polypharmacy and Healthcare Service Use Among Prescription Opioid Poisoning Cases Age 50.

Objectives: To examine relationships between polypharmacy and level of healthcare service use among prescription opioid poisoning cases age 50 and older. Methods: Data came from the American Association of Poison Control Center's National Poison Data System, 2015-2020. We used multinomial logistic regression to examine the study questions. Results: Of the 77 946 cases with prescription opioid exposures, 64.5% were managed at a healthcare facility (HCF). Of HCF-managed cases, 41.2% were treated/evaluated and released and 21.3% and 37.5% were admitted for noncritical care and critical care, respectively. Medications for cardiovascular disease, benzodiazepines, other types of sedatives/hypnotics, antipsychotics, muscle relaxants, acetaminophen, and gabapentin were associated with increased risk of admission to both noncritical and critical care compared to treatment/evaluation and release. Acetaminophen use had the highest relative risk ratios (RRRs) for noncritical care (1.70, 95% CI = 1.51-1.91) and critical care (1.56, 95% CI = 1.39-1.76). Each additional medication/substance used was associated with 1.14 (95% CI = 1.11-1.17) and 1.19 (95% CI = 1.16-1.22) greater risk of noncritical and critical care admissions, respectively. Conclusions: Among older-adult poison control center cases for prescription opioid exposures, co-use of several commonly prescribed/used medicines was associated with increased risk of admissions to both noncritical and critical care units. Careful monitoring of medication use among older adults who use prescription opioids may reduce the risk of unintentional and intentional opioid poisoning.

Patients undergoing colorectal surgery at a Veterans Affairs Hospital do not experience racial disparity in length of stay either before or after implementing an enhanced recovery pathway.

BACKGROUND: Enhanced Recovery Pathways (ERP) have been shown to reduce racial disparities following surgery. The objective of this study is to determine whether ERP implementation mitigates racial disparities at a Veterans Affairs Hospital. METHODS: A retrospective cohort study was conducted using data obtained from the Veterans Affairs Surgical Quality Improvement Program. All patients undergoing elective colorectal surgery following ERP implementation were included. Current procedural terminology (CPT) codes were used to identify patients who underwent similar procedures prior to ERP implementation. RESULTS: Our study included 417 patients (314 pre-ERP vs. 103 ERP), 97.1% of which were male, with an average age of 62.32 (interquartile range (IQR): 25-90). ERP patients overall had a significantly shorter post-operative length of stay (pLOS) vs. pre-ERP patients (median 4 days (IQR: 3-6.5) vs. 6 days (IQR: 4-9) days (p < 0.001)). Within the pre-ERP group, median pLOS for both races was 6 days (IQR: 4-6; p < 0.976) and both groups experienced a decrease in median pLOS (4 vs. 6 days; p < 0.009 and p < 0.001) following ERP implementation. CONCLUSIONS: Racial disparities did not exist in patients undergoing elective surgery at a single VA Medical Center. Implementation of an ERP significantly reduced pLOS for black and white patients.

FGFR Pathway Inhibition in Gastric Cancer: The Golden Era of an Old Target?

Gastric cancer (GC) is the third leading cause of cancer-associated death worldwide. The majority of patients are diagnosed at an advanced/metastatic stage of disease due to a lack of specific symptoms and lack of screening programs, especially in Western countries. Thus, despite the improvement in GC therapeutic opportunities, the survival is disappointing, and the definition of the optimal treatment is still an unmet need. Novel diagnostic techniques were developed in clinical trials in order to characterize the genetic profile of GCs and new potential molecular pathways, such as the Fibroblast Growth Factor Receptor (FGFR) pathway, were identified in order to improve patient's survival by using target therapies. The aim of this review is to summarize the role and the impact of FGFR signaling in GC and to provide an overview regarding the potential effectiveness of anti-FGFR agents in GC treatment in the context of precision medicine.

The effects of pazopanib on doxorubicin pharmacokinetics in children and adults with non-rhabdomyosarcoma soft tissue sarcoma: a report from Children's Oncology Group and NRG Oncology study ARST1321.

PURPOSE: The use of tyrosine kinase inhibitors for the treatment for soft tissue sarcomas is increasing given promising signals of activity in a variety of tumor types. The recently completed study in non-rhabdomyosarcoma soft tissue sarcomas, ARST1321, demonstrated that the addition of pazopanib to neoadjuvant ifosfamide, doxorubicin, and radiation improved the pathological near complete response rate compared with chemoradiotherapy alone. Pharmacokinetic (PK) evaluation of doxorubicin with pazopanib has not been previously reported. As an exploratory aim, doxorubicin PK data were collected during the dose-finding phase of the study in patients receiving chemotherapy and pazopanib to assess the effect of pazopanib on doxorubicin PK parameters. METHODS: Blood samples were collected during cycle 2 (week 4) of chemotherapy at the following time points from doxorubicin administration: predose, 5, 30, and 60 min, and 2, 4, 8, 24 ± 3, and 48 ± 3 h after dosing. The population pharmacokinetic and individual post hoc estimates of doxorubicin and doxorubicinol were determined by nonlinear mixed-effects modeling. RESULTS: There were 52 doxorubicin and doxorubicinol samples from 7 individuals in this study (median age: 17 years; range 14-23). The doxorubicin clearance was 26.9 (16.1, 36.4, and 33.9) L/h/m2 (post hoc median and range) and 25.8 (23.3%) L/h/m2 [population estimate and IIV (CV%)]. The doxorubicinol apparent clearance was 67.5 (18.2, 1701) L/h/m2 (post hoc median and range) and 58.7 (63.7%) L/h/m2 [population estimate and IIV (CV%)]. CONCLUSION: The PK data of seven patients treated on ARST1321 is consistent with previously reported population and post hoc doxorubicin clearance and doxorubicinol apparent clearance estimates, showing that the addition of pazopanib does not significantly alter doxorubicin pharmacokinetics. These data support the safety of administration of pazopanib with doxorubicin-containing chemotherapy.

Decision Making from the Experience of Orthognathic Surgery Patients: A Grounded Theory Approach.

INTRODUCTION: Patients' decisions to undergo major surgery such as orthognathic treatment are not just about how the decision is made but what influences the decision. OBJECTIVES: The primary objective of the study was to identify the key processes involved in patients' experience of decision making for orthognathic treatment. METHODS: This study reports some of the findings of a larger grounded theory study. Data were collected through face-to-face interviews of patients who were seen for orthognathic treatment at a teaching hospital in the United Kingdom. Twenty-two participants were recruited (age range 18-66 y), of whom 12 (male = 2, female = 10) were 6 to 8 wk postsurgery, 6 (male = 2, female = 4) were in the decision-making stage, and 4 (male = 0, female = 4) were 1 to 2 y postsurgery. Additional data were also collected from online blogs and forums on jaw surgery. The data analysis stages of grounded theory methodology were undertaken, including open and selective coding. RESULTS: The study identified the central role of dental care professionals (DCPs) in several underlying processes associated with decision making, including legitimating, mediating, scheduling, projecting, and supporting patients' decisions. Six categories were related to key aspects of decision making. These were awareness about their underlying dentofacial problems and treatment options available, the information available about the treatment, the temporality of when surgery would be undertaken, the motivations and expectation of patients, social support, and fear of the surgery, hospitalization, and potentially disliking their new face. CONCLUSION: The decision-making process for orthognathic treatment is complex, multifactorial, and heavily influenced by the role of DCPs in patient care. Understanding the magnitude of this role will enable DCPs to more clearly participate in improving patients' decision-making process. The findings of this study can inform future quantitative studies. KNOWLEDGE TRANSFER STATEMENT: The results of this study can be used both for informing clinical practice around enabling decision making for orthognathic treatment and also for designing future research. The findings can better inform clinicians about the importance of their role in the patients' decision-making process for orthognathic treatment and the means to improve the patient experience. It is suggested that further research could be conducted to measure some of the key constructs identified within our grounded theory and assess how these change during the treatment process.

Management site and level of health care for cannabis- and synthetic cannabinoid-related poison control center cases involving older adults, 2016-2019.

Increasing numbers of older adults use cannabis and cannabis-derived products that can have adverse effects. This study examined management site and level of healthcare services for older adult poison control center cases involving cannabis products. Using the American Association of Poison Control Centers' (PCC) National Poison Data System, 2016-2019, we extracted the 3109 cases aged 50+ for which cannabis was the only or primary substance. Multinomial logistic regression models were fit to examine associations between specific cannabis forms and management/care site (on site [mostly at home], at a healthcare facility [HCF], or no follow-up due to referral refusal or leaving against medical advice) and level of healthcare services for cases managed at a HCF. The results show that between 2016 and 2019, PCC cannabis cases involving older adults increased twofold, largely due to cases of cannabidiol, edibles, and concentrated extracts. Plant form and synthetic cannabinoid cases declined substantially. Compared to plant forms, synthetic cannabinoid cases had 4.22 (95% CI = 2.59-6.89) greater odds of being managed at, rather than outside, a HCF and 2.17 (1.42-3.31) greater odds of critical care unit admission. Although e-cigarette cases, compared to plant form cases, had lower odds of being managed at a HCF, HCF-managed e-cigarette cases had 3.43 greater odds (95% CI = 1.08-10.88) of critical care unit admission. Synthetic cannabinoid cases also had 1.86 (95% CI = 1.03-3.35) greater odds of no follow-up, and the presence of a secondary substance was also a significant factor. Stricter regulations for listing chemical ingredients and providing safety guidelines are needed for cannabis-derived products.

Neutrophils can promote clotting via FXI and impact clot structure via neutrophil extracellular traps in a distinctive manner in vitro.

Neutrophils and neutrophil extracellular traps (NETs) have been shown to be involved in coagulation. However, the interactions between neutrophils or NETs and fibrin(ogen) in clots, and the mechanisms behind these interactions are not yet fully understood. In this in vitro study, the role of neutrophils or NETs on clot structure, formation and dissolution was studied with a combination of confocal microscopy, turbidity and permeation experiments. Factor (F)XII, FXI and FVII-deficient plasmas were used to investigate which factors may be involved in the procoagulant effects. We found both neutrophils and NETs promote clotting in plasma without the addition of other coagulation triggers, but not in purified fibrinogen, indicating that other factors mediate the interaction. The procoagulant effects of neutrophils and NETs were also observed in FXII- and FVII-deficient plasma. In FXI-deficient plasma, only the procoagulant effects of NETs were observed, but not of neutrophils. NETs increased the density of clots, particularly in the vicinity of the NETs, while neutrophils-induced clots were less stable and more porous. In conclusion, NETs accelerate clotting and contribute to the formation of a denser, more lysis resistant clot architecture. Neutrophils, or their released mediators, may induce clotting in a different manner to NETs, mediated by FXI.

Cannabis and synthetic cannabinoid poison control center cases among adults aged 50+, 2009-2019.

OBJECTIVES: Older (aged 50+) cannabis users are growing in numbers, but research on poison control center (PCC) cases has not focused on them. In this study, we examined: (1) changing trends in cannabis forms reported in PCC cases; (2) demographic and clinical factors associated with different cannabis forms; and (3) associations between cannabis forms and medical outcomes. METHODS: We used the American Association of Poison Control Centers' National Poison Data System (NPDS), January 1, 2009-December 31, 2019, to examine the 5201 cases aged 50+ in which cannabis was the only or primary substance. Following descriptive analyses, multinomial logistic regression was fit to examine associations of three cannabis forms (dried/undried plant, other preparations, and synthetic cannabinoids/e-cigarettes for cannabis delivery) with cases' demographic and clinical characteristics, and binary logistic regression was fit to examine associations of medical outcomes (major/potentially major vs. nonmajor) with cannabis forms. RESULTS: Cannabis-related cases involving older adults increased 18-fold (from 61 to 1074) between 2009 and 2019. Compared to plant forms, other preparations had 51.24 times greater odds of appearing in 2018-2019 than in 2009-2011 (95% CI = 27.74-94.67), and synthetic cannabinoids/e-cigarettes had 2.19 times greater odds of appearing in 2014-2015 (95% CI = 1.64-2.93) but lower odds of appearing in 2016-2017 (RRR = 0.67, 95% CI = 0.50-0.89). Other preparations were positively associated with older age, adverse reactions, and suicide attempts but negatively associated with medical cannabis legal states. Synthetic cannabinoids/e-cigarettes were positively associated with being male, intentional misuse/abuse, and chronic use. Compared to plant forms, major medical outcomes/death were less likely among those who used other preparations (OR = 0.75, 95% CI = 0.56-0.99) but more likely among those who used synthetic cannabinoids/e-cigarettes (OR = 2.07, 95% CI = 1.60-2.66). CONCLUSIONS: Although PCC cannabis cases involving older adults are relatively few, cases of other cannabis preparations than plant forms increased rapidly in recent years while cases of synthetic cannabinoids decreased. The rate of major medical outcomes also appears to be high.

Slowly-Conducting Pyramidal Tract Neurons in Macaque and Rat.

Anatomical studies report a large proportion of fine myelinated fibers in the primate pyramidal tract (PT), while very few PT neurons (PTNs) with slow conduction velocities (CV) (<~10 m/s) are reported electrophysiologically. This discrepancy might reflect recording bias toward fast PTNs or prevention of antidromic invasion by recurrent inhibition (RI) of slow PTNs from faster axons. We investigated these factors in recordings made with a polyprobe (32 closely-spaced contacts) from motor cortex of anesthetized rats (n = 2) and macaques (n = 3), concentrating our search on PTNs with long antidromic latencies (ADLs). We identified 21 rat PTNs with ADLs >2.6 ms and estimated CV 3-8 m/s, and 67 macaque PTNs (>3.9 ms, CV 6-12 m/s). Spikes of most slow PTNs were small and present on only some recording contacts, while spikes from simultaneously recorded fast-conducting PTNs were large and appeared on all contacts. Antidromic thresholds were similar for fast and slow PTNS, while spike duration was considerably longer in slow PTNs. Most slow PTNs showed no signs of failure to respond antidromically. A number of tests, including intracortical microinjection of bicuculline (GABAA antagonist), failed to provide any evidence that RI prevented antidromic invasion of slow PTNs. Our results suggest that recording bias is the main reason why previous studies were dominated by fast PTNs.

Cosmic-ray antinuclei as messengers of new physics: status and outlook for the new decade.

The precise measurement of cosmic-ray antinuclei serves as an important means for identifying the nature of dark matter and other new astrophysical phenomena, and could be used with other cosmic-ray species to understand cosmic-ray production and propagation in the Galaxy. For instance, low-energy antideuterons would provide a "smoking gun" signature of dark matter annihilation or decay, essentially free of astrophysical background. Studies in recent years have emphasized that models for cosmic-ray antideuterons must be considered together with the abundant cosmic antiprotons and any potential observation of antihelium. Therefore, a second dedicated Antideuteron Workshop was organized at UCLA in March 2019, bringing together a community of theorists and experimentalists to review the status of current observations of cosmic-ray antinuclei, the theoretical work towards understanding these signatures, and the potential of upcoming measurements to illuminate ongoing controversies. This review aims to synthesize this recent work and present implications for the upcoming decade of antinuclei observations and searches. This includes discussion of a possible dark matter signature in the AMS-02 antiproton spectrum, the most recent limits from BESS Polar-II on the cosmic antideuteron flux, and reports of candidate antihelium events by AMS-02; recent collider and cosmic-ray measurements relevant for antinuclei production models; the state of cosmic-ray transport models in light of AMS-02 and Voyager data; and the prospects for upcoming experiments, such as GAPS. This provides a roadmap for progress on cosmic antinuclei signatures of dark matter in the coming years.

Invited Review: Emerging functions of histone H3 mutations in paediatric diffuse high-grade gliomas.

Paediatric diffuse high-grade gliomas (pHGG) are rare, but deadly tumours. The discovery of recurrent mutations in the tail of histone H3, changing lysine 27 to methionine, or glycine 34 to arginine or valine, has illuminated a critical role for epigenetic dysregulation in the aetiology of childhood gliomas and opened new avenues of exploration that have resulted in numerous advances for the field. In this review, we describe the current models of H3K27M mutant cancer that are available to the research community and the insights they have provided on tumour biology and the epigenetic and transcriptional effects of histone mutations. We also review the current understanding of the H3G34R/V mutation and the therapeutic outlook for the treatment of pHGG.

Immune response and reactogenicity of an unadjuvanted intradermally delivered human papillomavirus vaccine using a first generation Nanopatch™ in rhesus macaques: An exploratory, pre-clinical feasibility assessment.

The human papillomavirus (HPV) 9-valent, recombinant vaccine (Gardasil™9) helps protect young adults (males and females) against anogenital cancers and genital warts caused by certain HPV genotypes (ref. Gardasil™9 insert). This vaccine is administered intramuscularly (IM). The aim of this study was to determine preclinically whether intradermal (ID) vaccination with an unadjuvanted 9-valent recombinant HPV vaccine using a first-generation ID delivery device, the Nanopatch™, could enhance vaccine immunogenicity compared with the traditional ID route (Mantoux technique). IM injection of HPV VLPs formulated with Merck & Co., Inc., Kenilworth, NJ, USA Alum Adjuvant (MAA) were included in the rhesus study for comparison. The Nanopatch™ prototype contains a high-density array comprised of 10,000 microprojections/cm2, each 250 µm long. It was hypothesized the higher density array with shallower ID delivery may be superior to the Mantoux technique. To test this hypothesis, HPV VLPs without adjuvant were coated on the Nanopatch™, stability of the Nanopatch™ with unadjuvanted HPV VLPs were evaluated under accelerated conditions, skin delivery was verified using radiolabelled VLPs or FluoSpheres®, and the immune response and skin site reaction with the Nanopatch™ was evaluated in rhesus macaques. The immune response induced by Nanopatch™ administration, measured as HPV-specific binding antibodies, was similar to that induced using the Mantoux technique. It was also observed that a lower dose of unadjuvanted HPV VLPs delivered with the first-generation Nanopatch™ and applicator or Mantoux technique resulted in an immune response that was significantly lower compared to a higher-dose of alum adjuvanted HPV VLPs delivered IM in rhesus macaques. The study also indicated unadjuvanted HPV VLPs could be delivered with the first-generation Nanopatch™ and applicator to the skin in 15 s with a transfer efficiency of approximately 20%. This study is the first demonstration of patch administration in non-human primates with a vaccine composed of HPV VLPs.

A bias for action in cancer screening?

Research that has explored public enthusiasm for cancer screening has suggested that the public may be overly enthusiastic about being screened with certain tests, and this has been attributed, in part, to lack of knowledge about the risks and benefits. In this article the authors considered the possibility that some people may be enthusiastic about screening even when they are informed and also accept that the test unquestionably does not save lives. Two studies were conducted, one that involved a nationally representative U.S. sample and another that involved an online convenience sample. All participants were asked whether they would want to receive a hypothetical screening test for breast (women) or prostate (men) cancer that does not reduce the chance of cancer death or extend the length of life. Over half of participants wanted to receive the described screening test. Many people did not believe that cancer screening might not save lives, yet screening preferences were not due to disbelief alone. Results further suggested that cancer worry, reassurance, and a desire for health information explained variance in preferences for unbeneficial screening, adjusting for beliefs about screening benefits, perceptions of screening risks, family history, perceptions of cancer risk, and demographics. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Rates of cannabis use in patients with cancer.

Background: A comprehensive assessment of cannabis use by patients with cancer has not previously been reported. In this study, we aimed to characterize patient perspectives about cannabis and its use. Methods: An anonymous survey about cannabis use was offered to patients 18 years of age and older attending 2 comprehensive and 2 community cancer centres, comprising an entire provincial health care jurisdiction in Canada (ethics id: hreba-17011). Results: Of 3138 surveys distributed, 2040 surveys were returned (65%), with 1987 being sufficiently complete for analysis (response rate: 63%). Of the respondents, 812 (41%) were less than 60 years of age; 45% identified as male, and 55% as female; and 44% had completed college or higher education.Of respondents overall, 43% reported any lifetime cannabis use. That finding was independent of age, sex, education level, and cancer histology. Cannabis was acquired through friends (80%), regulated medical dispensaries (10%), and other means (6%). Of patients with any use, 81% had used dried leaves.Of the 356 patients who reported cannabis use within the 6 months preceding the survey (18% of respondents with sufficiently complete surveys), 36% were new users. Their reasons for use included cancer-related pain (46%), nausea (34%), other cancer symptoms (31%), and non-cancer-related reasons (56%). Conclusions: The survey demonstrated that prior cannabis use was widespread among patients with cancer (43%). One in eight respondents identified at least 1 cancer-related symptom for which they were using cannabis.