The opioid crisis remains a major public health issue in the US and beyond. Despite rapid rises in fentanyl-related mortality nationally, little is known about the role of fentanyl in the occurrence ...of non-fatal overdose among people who use drugs. We examined the prevalence of non-fatal overdose and perceived fentanyl exposure among syringe services program (SSP) clients and modeled the correlates of non-fatal overdose.
Data were drawn from a cross-sectional survey of 203 SSP clients in Baltimore, MD recruited in 2016. Logistic regression models were used to identify the correlates of experiencing non-fatal overdose in the past 12 months.
The majority (65%) was male, 52% were black, 41% were white, and 37% were homeless. Almost all (97%) used heroin, 64% injected heroin with cocaine (i.e., speedball), and many used other types of drugs. Half (53%) perceived fentanyl presence in their drugs either half, most or all of the time. Lifetime and past 12 month prevalence of non-fatal overdose were 58 and 31%, respectively. Independent correlates of non-fatal overdose in the past 12 months were perceiving fentanyl in drugs more than half the time (aOR = 2.79; 95% CI = 1.00-4.68), speedball injection (aOR = 2.80, 95% CI = 1.26-6.23), non-prescription buprenorphine use (aOR = 6.37; 95% CI = 2.86-14.17), and homelessness (aOR = 3.07; 95% CI = 1.28-7.39).
These data demonstrate that SSP clients are at high-risk of overdose, some of which is likely attributable to fentanyl exposure. Addressing the rising fentanyl epidemic will require comprehensive and innovative strategies that attend to drug use patterns and structural factors such as homelessness.
Information on healthcare costs in low-and-middle-income countries is limited. This study presents a framework to perform healthcare cost estimates for each province in China.
This study has two ...aims. Using cervical cancer as an example, the first aim is to use data (including micro-costing data) from one province to derive estimates for other provinces in China. This used provincial and national Chinese-language statistical reports and considered levels of service delivery, hospital-seeking behaviour, and the urban/rural population distribution. The second aim is to characterise the relationship between the reference costs estimated using the method mentioned above and two sets of cost estimates derived using simplified cost-scaling method with per capita Gross Domestic Product (GDP), and the Human Development Index (HDI). For simplified methods, regression modelling characterised the relationship between province-specific healthcare costs and macro-economic indicators, then we used the exponential fit to extrapolate costs.
Using the reference method, the estimated costs were found to vary substantially by urban/rural regions and between provinces; the ratios of highest to lowest provincial costs were 3.5 for visual inspection with acetic acid (VIA), 4.4 for cold knife conisation (CKC) and 4.6 for stage II cancer treatment. The HDI-based scaling method generally resulted in a better fit to reference costs than the GDP method.
These reference costs for cervical cancer can inform cost-effectiveness evaluation of cervical screening and HPV vaccination in China. HDI-based methods for cost-scaling-based on social, as well as purely economic, factors-have potential to provide more accurate estimates.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This study followed up ADHD/autistic symptoms and attentional performance in children/adolescents with ASD and typically developing ones (TD) over 5–7 years. The participants were stratified by age ...at baseline into child (< 12 years) and adolescent (12–19 years) groups. ADHD symptoms, especially hyperactivity, and attentional functions significantly improved during follow-up, more in children than in adolescents, in both ASD and TD. Significantly more omission errors and perseverations were noted in ASD than TD through the follow-up. Children with ASD had more improvement in reaction time while adolescents with ASD had less improvement in commission errors and detectability than TD. No correlation of attentional functions and ADHD symptoms in ASD implied different neural mechanisms of ADHD symptoms between ASD and ADHD.
The abscopal effect could theoretically be potentiated when combined with immunomodulating drugs through increased antigen production. The optimal dosing and schedule of radiotherapy with ...immunotherapy are unknown, although they are actively investigated in laboratory and clinical models. Clinical data in patients treated for metastatic disease with both modalities may guide future studies.
This is a single-institution retrospective review of all patients treated with stereotactic body radiotherapy (SBRT)/stereotactic radiosurgery (SRS) and immunomodulating therapy within 6 months before or after SBRT/SRS for metastatic cancer. Clinical and tumor characteristics were recorded, as well as SBRT/SRS details, immunotherapy details, and survival. Log-rank tests on Kaplan-Meier curves for overall survival (OS) that were calculated from the end of SBRT/SRS were used in univariate analysis and Cox proportional hazards regression for multivariate analysis.
A total of 125 patients were identified who met the inclusion criteria; 70 received SBRT, and 57 received SRS. Eighty-three patients were treated for non-small cell lung cancer, 7 patients for small cell lung cancer, and 35 patients for other cancers, with the most common one being melanoma. Fifty-three percent of patients received nivolumab, 29% pembrolizumab, 13% atezolizumab, 5% other. Twenty percent received immunotherapy before SBRT/SRS, 39% during SBRT/SRS, 41% after. Eighty-six patients had died by the time of the analysis; the median OS for the whole cohort was 9.7 months. Patients who had completed immunotherapy prior to SBRT/SRS had worse OS than those who received concurrent therapy or immunotherapy after SBRT/SRS, with a difference in median OS of 3.6 months vs. 13.0 months (p = 0.010) that was retained on multivariate analysis (p = 0.011). There was no significant difference in OS between patients receiving SRS vs. SBRT (p = 0.20), sex (p = 0.53), age >62 years (p = 0.76), or lung primary vs. others (p = 0.73) on univariate or multivariate analysis. When comparing before/concurrent to after/concurrent administration, there is a difference in survival with after/concurrent survival of 8.181 months and before survival of 13.010 months, but this was not significant (p = 0.25).
OS appears to be worse in patients who complete immunotherapy prior to SBRT/SRS compared to those receiving it concurrently or after. The design of this retrospective review may be prone to lead time bias, although the difference in median survival is longer than the 6-month window before SBRT/SRS and could only account for part of this difference. Further analysis into causes of death and toxicity and prospective studies are needed to confirm the results of this analysis.
This research conducts a quantitative analysis on the macrotexture of asphalt concrete pavement based on three-dimensional (3D) point cloud data. A binocular stereovision-based 3D point cloud data ...collection system is developed. The system is composed of a packaged component that includes a lighting source and two cameras, a dark shading cloth, and the computer control side with the configuration of the operation interface. Meanwhile, specimens of both asphalt concrete and open graded friction course (OGFC) are prepared as the test specimens. Next, 3D point cloud data of the specimens are collected using the proposed system. The macrotexture information is then extracted using the robust Gaussian method. The macrotextures of the pavement surface are characterized by 10 indicators; profile arithmetic average deviation, profile root mean square difference, mean texture depth, profile skewness value, profile steepness, profile unevenness distance, profile peak distance, profile root mean square slope, profile root mean square wavelength, and surface roughness area ratio. At the same time, the friction coefficients of these specimens are measured by British Pendulum Number. Finally, the correlations between each indicator and the friction conditions of different specimens are assessed. Results demonstrate that the proposed macrotexture indicators are reliable for evaluating the friction conditions because significant correlations have been observed. Meanwhile, the correlations for the OGFC gradations are always higher than the asphalt concrete gradations. All the findings prove that the proposed quantitative indicators are effective for the characterization of the macrotexture of asphalt concrete pavement.
The importance of neuropeptide Y (NPY) and Y2 receptors in the regulation of bone and energy homeostasis has recently been demonstrated. However, the contributions of the other Y receptors are less ...clear. Here we show that Y1 receptors are expressed on osteoblastic cells. Moreover, bone and adipose tissue mass are elevated in Y1-/- mice with a generalized increase in bone formation on cortical and cancellous surfaces. Importantly, the inhibitory effects of NPY on bone marrow stromal cells in vitro are absent in cells derived from Y1-/- mice, indicating a direct action of NPY on bone cells via this Y receptor. Interestingly, in contrast to Y2 receptor or germ line Y1 receptor deletion, conditional deletion of hypothalamic Y1 receptors in adult mice did not alter bone homeostasis, food intake, or adiposity. Furthermore, deletion of both Y1 and Y2 receptors did not produce additive effects in bone or adiposity. Thus Y1 receptor pathways act powerfully to inhibit bone production and adiposity by nonhypothalamic pathways, with potentially direct effects on bone tissue through a single pathway with Y2 receptors.
Female sex workers (FSW) are a marginalized and vulnerable population at high risk of gender-based violence within and outside of their occupation. However, FSW remain underrepresented in the trauma ...and mental health literature. The aims of this study were to (a) characterize exposure to violence among street-based FSW, including violence type, patterns over the life course, and key perpetrator groups, and (b) examine the multivariate associations between posttraumatic stress disorder (PTSD) symptom severity and two constructs (revictimization across life stages and cumulative violence). Data were drawn from the Sex Workers and Police Promoting Health in Risky Environments (SAPPHIRE) study, an observational community-based cohort of street-based FSW recruited through targeted sampling across Baltimore, Maryland (USA) in 2016 to 2017. PTSD symptom severity was measured using the PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders–Fifth Edition (PCL-5). At baseline, 61% of FSW screened positive for PTSD symptoms. The mean PCL-5 score was 38.6. We documented extensive histories of sexual and physical violence (lifetime: 81.8%; childhood and adult revictimization: 15.0% for sexual and 37.7% for physical). The vast majority of perpetrators were male and included paying clients, police officers, family members, and intimate partners. Exposure to childhood and adult sexual violence were independently associated with higher PTSD severity (p < .05), with marginal associations observed for physical violence. Data supported a cumulative violence model of PTSD severity (p < .05). Binge drinking also appeared to be a contributing factor (p < .05). The levels of PTSD observed among our sample were comparable with that reported among treatment-seeking war veterans. Our findings underscore the urgent need for tailored trauma-informed interventions and policies to address violence among urban street-based FSW, a population experiencing extremely high levels of violence, PTSD, and substance use.
Summary
Purpose
We investigated the combination of the MEK inhibitor, cobimetinib, and the pan-PI3K inhibitor, pictilisib, in an open-label, phase Ib study.
Experimental Design
Patients with advanced ...solid tumors were enrolled in 3 dose escalation schedules: (1) both agents once-daily for 21-days-on 7-days-off (“21/7”); (2) intermittent cobimetinib and 21/7 pictilisib (“intermittent”); or (3) both agents once-daily for 7-days-on 7-days-off (“7/7”). Starting doses for the 21/7, intermittent, and 7/7 schedules were 20/80, 100/130, and 40/130 mg of cobimetinib/pictilisib, respectively. Nine indication-specific expansion cohorts interrogated the recommended phase II dose and schedule.
Results
Of 178 enrollees (dose escalation:
n
= 98), 177 patients were dosed. The maximum tolerated doses for cobimetinib/pictilisib (mg) were 40/100, 125/180, and not reached, for the 21/7, intermittent, and 7/7 schedules, respectively. Six dose-limiting toxicities included grade 3 (G3) elevated lipase, G4 elevated creatine phosphokinase, and G3 events including fatigue concurrent with a serious adverse event (SAE) of diarrhea, decreased appetite, and SAEs of hypersensitivity and dehydration. Common drug-related adverse events included nausea, fatigue, vomiting, decreased appetite, dysgeusia, rash, and stomatitis. Pharmacokinetic parameters of the drugs used in combination were unaltered compared to monotherapy exposures. Confirmed partial responses were observed in patients with
BRAF
-mutant melanoma (
n
= 1) and
KRAS
-mutant endometrioid adenocarcinoma (
n
= 1). Eighteen patients remained on study ≥6 months. Biomarker data established successful blockade of MAP kinase (MAPK) and PI3K pathways. The metabolic response rate documented by FDG-PET was similar to that observed with cobimetinib monotherapy.
Conclusions
Cobimetinib and pictilisib combination therapy in patients with solid tumors had limited tolerability and efficacy.
A series of σ2R compounds containing benzimidazolone and diazacycloalkane cores was synthesized and evaluated in radioligand binding assays. Replacing the piperazine moiety in a lead compound with ...diazaspiroalkanes and the fused octahydropyrrolo3,4-b pyrrole ring system resulted in a loss in affinity for the σ2R. On the other hand, the bridged 2,5-diazabicyclo2.2.1heptane, 1,4-diazepine, and a 3-aminoazetidine analog possessed nanomolar affinities for the σ2R. Computational chemistry studies were also conducted with the recently published crystal structure of the σ2R/TMEM97 and revealed that hydrogen bond interactions with ASP29 and π-stacking interactions with TYR150 were largely responsible for the high binding affinity of small molecules to this protein.
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