Preloading with drugs before entry to the nighttime entertainment district: presentation, intoxication rates, and effects of police presence during assessment.

BACKGROUND: Past research has either focused on alcohol or drug preloading before a night out, but not on the interaction between them. With increased risks of harm through interaction effects, we wished to build upon previous research in this area. We sought to determine who drug preloads, why do people engage in this practice, what drug/s are people using, and how inebriated they are as they enter the NED. Additionally, we examined what impact varying levels of police presence has on the collections of sensitive data in this context. METHODS: We captured estimates of drug and alcohol preloading from 4723 people entering nighttime entertainment districts (NEDs) in Queensland, Australia. Data collection occurred under three varying conditions of police presence (i.e., no police present, police present but not engaging with participants, and police engaging with participants). RESULTS: People who admitted to preloading drugs were found to be younger in age than non-drug admitters, more likely to be male than female, use one type of drug (mostly stimulants) rather than multiple (if we exclude alcohol), significantly more intoxicated upon arrival, and more subjectively affected from their use of alcohol and drugs as Breath Approximated Alcohol Concertation levels increased. People were more likely to admit having used drugs in the absence of police, but this had only a small effect. CONCLUSIONS: People who drug preload are a vulnerable subset of the youth population that is susceptible to experiencing harms in this context. As they drink more alcohol, they experience higher affects than those who do not report to also take drugs. Police engagement through service rather than force may mitigate some risks. Further enquiry is needed to better understand those who engage in this practice and to have quick, cheap, objective tests of what drugs these people are using.

Pre-Loading with Drugs before Entering the Nighttime Entertainment District: A Scoping Review.

Background: Nighttime entertainment districts attract many people who pre-load with alcohol and other substances before entering licensed venues. Despite the harms and dangers associated with both alcohol pre-loading and drug use respectively, there is a paucity of research on drug and polysubstance pre-loading. Objectives: The primary objectives of this scoping review are to systematically map out the body of existing literature on drug and polysubstance pre-loading, discuss methodological potentials and pitfalls in field-based research, identify gaps in knowledge, and derive practical implications and opportunities for future research. Methods: Using the PRISMA (ScR) guidelines, we conducted a search of Medline, PsycINFO, Embase, Scopus, CINAHL, Social Services Abstracts, Sociological Abstracts, and Web of Science databases. We followed this up by conducting an author and citation analysis of relevant articles. Results: Of the 632 data sources identified, 338 articles were reviewed after removing duplicates. Overall, only nine articles were included and thematically analyzed. In our review and analysis of the literature, we find people who drug pre-load to be a particularly vulnerable subset of the population. We also posit that the point-of-entry design has greater sensitivity than the commonly used portal-in design. From this, we also draw attention to various time points where field-based researchers can provide intervention. Conclusions: Given the high prevalence of young adults engaging in the behavior, clinicians should consider pre-loading behaviors when assessing for risk and vulnerability. Field-based research would elucidate the full breadth and scope of the growing pre-loading phenomenon and the dangers associated with this practice.

A Proposal for a Taxonomy of Pre-Loading.

Background: Pre-loading of alcohol and other drugs has become a prevalent start to nights out in many countries. Studies into pre-loading have been using different operational definitions and descriptions, leading to confusion and debate in the research literature. Purpose/Objective: We wish to propose a full taxonomy so that research into preloading, of any substances, can be specific and standardized. Methods: We address this problem by analyzing (1) terminology used throughout the literature, (2) the evolving nature of this phenomenon, and (3) the operational components comprising this substance use practice. Additionally, we provide a context and rationale for how we view pre-loading in relation to the broader event-level session. Results: Our results propose a full operational definition and taxonomy of pre-loading to be used, and built upon, by researchers. We also provide a visual representation of pre-loading within an event-level session and provide a method to facilitate consistency across cultures. Conclusions: We propose that this system will lead to greater specificity and higher reliability in the interpretation of research results.

Prediction and monitoring of relapse in stage III melanoma using circulating tumor DNA.

BACKGROUND: The advent of effective adjuvant therapies for patients with resected melanoma has highlighted the need to stratify patients based on risk of relapse given the cost and toxicities associated with treatment. Here we assessed circulating tumor DNA (ctDNA) to predict and monitor relapse in resected stage III melanoma. PATIENTS AND METHODS: Somatic mutations were identified in 99/133 (74%) patients through tumor tissue sequencing. Personalized droplet digital PCR (ddPCR) assays were used to detect known mutations in 315 prospectively collected plasma samples from mutation-positive patients. External validation was performed in a prospective independent cohort (n = 29). RESULTS: ctDNA was detected in 37 of 99 (37%) individuals. In 81 patients who did not receive adjuvant therapy, 90% of patients with ctDNA detected at baseline and 100% of patients with ctDNA detected at the postoperative timepoint relapsed at a median follow up of 20 months. ctDNA detection predicted patients at high risk of relapse at baseline [relapse-free survival (RFS) hazard ratio (HR) 2.9; 95% confidence interval (CI) 1.5-5.6; P = 0.002] and postoperatively (HR 10; 95% CI 4.3-24; P < 0.001). ctDNA detection at baseline [HR 2.9; 95% CI 1.3-5.7; P = 0.003 and postoperatively (HR 11; 95% CI 4.3-27; P < 0.001] was also associated with inferior distant metastasis-free survival (DMFS). These findings were validated in the independent cohort. ctDNA detection remained an independent predictor of RFS and DMFS in multivariate analyses after adjustment for disease stage and BRAF mutation status. CONCLUSION: Baseline and postoperative ctDNA detection in two independent prospective cohorts identified stage III melanoma patients at highest risk of relapse and has potential to inform adjuvant therapy decisions.

Circulating tumor DNA predicts survival in patients with resected high-risk stage II/III melanoma.

Background: Patients with high-risk stage II/III resected melanoma commonly develop distant metastases. At present, we cannot differentiate between patients who will recur or those who are cured by surgery. We investigated if circulating tumor DNA (ctDNA) can predict relapse and survival in patients with resected melanoma. Patients and methods: We carried out droplet digital polymerase chain reaction to detect BRAF and NRAS mutations in plasma taken after surgery from 161 stage II/III high-risk melanoma patients enrolled in the AVAST-M adjuvant trial. Results: Mutant BRAF or NRAS ctDNA was detected (≥1 copy of mutant ctDNA) in 15/132 (11%) BRAF mutant patient samples and 4/29 (14%) NRAS mutant patient samples. Patients with detectable ctDNA had a decreased disease-free interval [DFI; hazard ratio (HR) 3.12; 95% confidence interval (CI) 1.79-5.47; P < 0.0001] and distant metastasis-free interval (DMFI; HR 3.22; 95% CI 1.80-5.79; P < 0.0001) versus those with undetectable ctDNA. Detectable ctDNA remained a significant predictor after adjustment for performance status and disease stage (DFI: HR 3.26, 95% CI 1.83-5.83, P < 0.0001; DMFI: HR 3.45, 95% CI 1.88-6.34, P < 0.0001). Five-year overall survival rate for patients with detectable ctDNA was 33% (95% CI 14%-55%) versus 65% (95% CI 56%-72%) for those with undetectable ctDNA. Overall survival was significantly worse for patients with detectable ctDNA (HR 2.63; 95% CI 1.40-4.96); P = 0.003) and remained significant after adjustment for performance status (HR 2.50, 95% CI 1.32-4.74, P = 0.005). Conclusion: ctDNA predicts for relapse and survival in high-risk resected melanoma and could aid selection of patients for adjuvant therapy. Clinical trial number: ISRCTN 81261306.

Distinct subclonal tumour responses to therapy revealed by circulating cell-free DNA.

BACKGROUND: The application of precision medicine in oncology requires in-depth characterisation of a patient's tumours and the dynamics of their responses to treatment. PATIENTS AND METHODS: We used next-generation sequencing of circulating cell-free DNA (cfDNA) to monitor the response of a KIT p.L576P-mutant metastatic vaginal mucosal melanoma to sequential targeted, immuno- and chemotherapy. RESULTS: Despite a KIT mutation, the response to imatinib was mixed. Unfortunately, tumours were not accessible for molecular analysis. To study the mechanism underlying the mixed clinical response, we carried out whole-exome sequencing and targeted longitudinal analysis of cfDNA. This revealed two tumour subclones; one with a KIT mutation that responded to imatinib and a second KIT-wild-type subclone that did not respond to imatinib. Notably, the subclones also responded differently to immunotherapy. However, both subclones responded to carboplatin/paclitaxel, and although the KIT-wild-type subclone progressed after chemotherapy, it responded to subsequent re-administration of paclitaxel. CONCLUSION: We show that cfDNA can reveal tumour evolution and subclonal responses to therapy even when biopsies are not available.

Impact of muffle furnace preparation on the results of crystalline silica analysis.

A prior report demonstrated an unacceptably low level of accuracy in silica analytical testing, with a general negative bias (i.e., underreporting) although other inaccuracies included false-positive results when analyzing blank filters. The possible bias may have been due to the loss of sample during shipping and or sample preparation. We report on a follow-up study that was designed to mimic the original study, but in which sources of variability were evaluated. We found no effect on silica recoveries due to shipping and confirmed the prior study results that the muffle furnace ashing process led to low overall recoveries (49-104%), depending on the adherence to the recommended preparation method. Plasma ashing recoveries ranged from 89 to 108%. Our results suggest that muffle-furnace ashing using a crucible should be restricted. More broadly, however, muffle-furnace ashing is only one source of analytical error that contributes to the relatively poor overall performance revealed by Cox et al. Whatever the case, OSHA should ensure that its proposed requirements to improve laboratory performance will actually lead to the discovery and correction of all major sources of error by participating laboratories. This is particularly important in light of OSHA's proposed reduction in the PEL and action level proposed by OSHA.

How reliable are crystalline silica dust concentration measurements?

To determine how reliably commercial laboratories measure crystalline silica concentrations corresponding to OSHA's proposed limits, 105 filters were prepared with known masses of 20, 40, and 80 µg of respirable quartz corresponding to airborne silica concentrations of 25, 50, and 100 µg/m(3) and were submitted, in a blind test, to qualified commercial laboratories over a nine month period. Under these test conditions, the reported results indicated a lack of accuracy and precision needed to reliably inform regulatory compliance decisions. This was true even for filters containing only silica, without an interfering matrix. For 36 filters loaded with 20 or more micrograms of silica, the laboratories reported non-detected levels of silica. Inter-laboratory variability in this performance test program was so high that the reported results could not be used to reliably discriminate among filters prepared to reflect 8-h exposures to respirable quartz concentrations of 25, 50 and 100 µg/m(3). Moreover, even in intra-laboratory performance, there was so much variability in the reported results that 2-fold variations in exposure concentrations could not be reliably distinguished. Part of the variability and underreporting may result from the sample preparation process. The results of this study suggest that current laboratory methods and practices cannot necessarily be depended on, with high confidence, to support proposed regulatory standards with reliable data.

Relating the bivalve shellfish harvesting area classification criteria in the United States and European Union programmes.

Estimation of the level of risk of faecal contamination of shellfish harvesting areas is undertaken by monitoring faecal indicator bacteria in seawater samples under the United States programme and shellfish flesh samples under the European Union (EU) programme. Determining the relationship between the two approaches is important for assessing the relative level of public health protection and regulating international trade. The relationship was investigated using both statistical modelling and simple compliance assessment on large international data sets of paired seawater and shellfish samples. The two approaches yielded the same conclusions: EU class A is more stringent than the US Approved category for all species; the US Restrictive standard is more restrictive than EU class B for some bivalve species. Therefore, the classifications under the two programmes are not exactly equivalent.

Evaluation of take-home exposure and risk associated with the handling of clothing contaminated with chrysotile asbestos.

The potential for para-occupational (or take-home) exposures from contaminated clothing has been recognized for the past 60 years. To better characterize the take-home asbestos exposure pathway, a study was performed to measure the relationship between airborne chrysotile concentrations in the workplace, the contamination of work clothing, and take-home exposures and risks. The study included air sampling during two activities: (1) contamination of work clothing by airborne chrysotile (i.e., loading the clothing), and (2) handling and shaking out of the clothes. The clothes were contaminated at three different target airborne chrysotile concentrations (0-0.1 fibers per cubic centimeter [f/cc], 1-2 f/cc, and 2-4 f/cc; two events each for 31-43 minutes; six events total). Arithmetic mean concentrations for the three target loading levels were 0.01 f/cc, 1.65 f/cc, and 2.84 f/cc (National Institute of Occupational Health and Safety [NIOSH] 7402). Following the loading events, six matched 30-minute clothes-handling and shake-out events were conducted, each including 15 minutes of active handling (15-minute means; 0.014-0.097 f/cc) and 15 additional minutes of no handling (30-minute means; 0.006-0.063 f/cc). Percentages of personal clothes-handling TWAs relative to clothes-loading TWAs were calculated for event pairs to characterize exposure potential during daily versus weekly clothes-handling activity. Airborne concentrations for the clothes handler were 0.2-1.4% (eight-hour TWA or daily ratio) and 0.03-0.27% (40-hour TWA or weekly ratio) of loading TWAs. Cumulative chrysotile doses for clothes handling at airborne concentrations tested were estimated to be consistent with lifetime cumulative chrysotile doses associated with ambient air exposure (range for take-home or ambient doses: 0.00044-0.105 f/cc year).

Prevention of tea-induced extrinsic tooth stain.

OBJECTIVES: The objectives of this study were to determine whether the addition of milk to tea reduces the ability of tea to stain extracted human teeth and, if so, to ascertain the component of milk that is responsible for milk's stain reducing properties. METHODS: Extracted human teeth were immersed in a tea solution, with the addition of 2% milk, 5.26% lactose, 2.7% casein or 10% fat-free milk for 24 h at 37°C. A dental spectrophotometer (VITA Easyshade Compact) was used to evaluate the colour of the teeth both before and after immersion in the tea solutions. Commission internationale de l'éclairage (CIE) L*a*b* colour space values were recorded, and the change in colour (ΔE*) was calculated. A two-tailed t-test or one-way analysis of variance (anova) was used to determine whether there were statistical differences between groups. RESULTS: Milk significantly reduces the ability of tea to stain teeth (P = 0.0225), specifically in the L* and a* dimensions (P = 0.0182 and P = 0.0124, respectively) of the colour sphere. Casein, which makes up 80% of the protein content in bovine milk, is the component of milk that is responsible for significantly reducing tea's ability to stain teeth (P < 0.0001). CONCLUSIONS: The addition of milk to tea significantly reduces the tea's ability to stain teeth. Casein was determined to be the component of milk that is responsible for preventing tea-induced staining of teeth to a similar order of magnitude that can be obtained by vital bleaching treatments.

Penile cancer: current therapy and future directions.

Background Penile cancer (PC) is a rare cancer in western countries, but is more common in parts of the developing world. Due to its rarity and the consequent lack of randomized trials, current therapy is based on retrospective studies and small prospective trials. Design Studies of PC therapy were searched in PubMed and abstracts at major conferences. Results PC is generally an aggressive malignancy characterized by early locoregional lymph node (LN) spread and later metastases in distant sites. Given the strong predictive value of LN involvement for overall survival, evaluating regional LNs is critical. Advanced LN involvement is increasingly being treated with multimodality therapy incorporating chemotherapy and/or radiation. A single superior cisplatin-based regimen has not been defined. Further advances may occur with a better collaboration on an international scale and comprehensive understanding of tumor biology. To this end, the preventive role of circumcision and understanding of the oncogenic roles of Human Papilloma Virus-16, and smoking may yield advances. Preliminary data suggest a role for agents targeting epidermal growth factor receptor and angiogenesis. Conclusion Advances in therapy for PC will require efficient trial designs, synergistic collaboration, incentives to industry and the efforts of patient advocacy groups and venture philanthropists.

Sources of variation of Escherichia coli concentrations in bivalve molluscs.

Bivalve molluscs can concentrate contaminants, including pathogenic microorganisms, from the water column during their normal filter-feeding activity. In the European Union, the risk of human and animal faecal contamination in bivalves is estimated by determining the concentration of Escherichia coli in time-series samples from production areas. A structured field study was undertaken to determine the extent to which such concentrations varied between sites, sampling occasions and shellfish species and to determine the residual variability of the method. E. coli was enumerated in three species of bivalve mollusc (Crassostrea gigas, Mytilus spp. and Pecten maximus) co-located in each of three geographically separate commercial shellfisheries. The data were subjected to analysis of variance (ANOVA). This showed that the effects of site, sampling occasion, species and site/sampling occasion interaction were all significant. The proportion of variation due to site was markedly greater than that due to other factors. Post-ANOVA analysis showed that the concentration of E. coli in P. maximus was significantly higher than in the other two species. Mytilus spp. and C. gigas exhibited comparable levels of E. coli. The observed standard deviation of the most probable number method in the study was 0.33 log(10).

This is the rhythm of the night: Examining the phases of a night-out on preloading motivations and intentions to backload.

BACKGROUND: Field research into the preloading phenomena has rarely examined how patrons move and transition into target events. We conceptualised three phases of the night (PotN) - entering, within and leaving - which a patron can be intercepted by a research group. Our research tested the differences between the PotN on preloading, preloading motivations and alcohol consuming behaviours in a popular night-time entertainment district (NED). METHODS: The sample comprised 1,585 young-adult patrons (934 Men, 651 Women; ages 18-27 years) collected in a cross-sectional design over three PotN. We measured the patron's preloading motivations, current alcohol intoxication and backloading intentions between three different phases of a night-out on Thursday, Friday and Saturday nights, from 9:00p.m. - 4:00 a.m. in Brisbane NEDs (Queensland, Australia). RESULTS: The phases contributed to a difference in preloading rates - one that decreased over the night (p <.001). Between the phases, the motivation of 'saving money' (≈45%) decreased as a reason for preloading and to 'socialise' (≈20%) increased. Enhancement-based preloading motivations (i.e., 'enjoy the feeling' and 'get drunk') were related to increased alcohol intoxication and backloading intentions at different PotN. However, 'saving money' motivations were also associated with a decrease in alcohol intoxication and backloading intentions (i.e., planning to return home to continue alcohol consumption). CONCLUSIONS: Preloading is valued highly by patrons when proximal to the actual preloading. There is a difference between the PotN on preloading rates, preloading motivations, intentions to backload and drinking outcomes as patrons shift from preloading, to entering the NED, to eventually leaving.

Multicenter phase II study of trabectedin in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: This multicenter phase II trial evaluated the efficacy and safety of trabectedin in metastatic castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: Two schedules were evaluated in three cohorts: weekly as 3-h i.v. infusion at 0.58 mg/m(2) for 3 out of 4 weeks (Cohort A, n = 33), and every 3 weeks (q3wk) as 24-h infusion at 1.5 mg/m(2) (Cohort B1, n = 5) and 1.2 mg/m(2) (Cohort B2, n = 20). The primary end point was prostate-specific antigen (PSA) response; secondary end points included safety, tolerability and time to progression (TTP). RESULTS: Trabectedin resulted in PSA declines ≥ 50% in 12.5% (Cohort A) and 10.5% (Cohort B2) of patients. Among men pretreated with taxane-based chemotherapy, PSA response was 13.6% (Cohort A) and 15.4% (Cohort B2). PSA responses lasted 4.1-8.6 months, and median TTP was 1.5 months (Cohort A) and 1.9 months (Cohort B2). The dose of 1.5 mg/m(2) (approved for soft tissue sarcoma) given as 24-h infusion q3wk was not tolerable in these patients. At 1.2 mg/m(2) q3wk and 0.58 mg/m(2) weekly, the most common adverse events were nausea, fatigue and transient neutropenia and transaminase increase. CONCLUSIONS: Two different trabectedin schedules showed modest activity in metastatic CRPC. Further studies may require identification of predictive factors of response in prostate cancer.

Physiological sex steroid replacement in premature ovarian failure: randomized crossover trial of effect on uterine volume, endometrial thickness and blood flow, compared with a standard regimen.

BACKGROUND: Premature ovarian failure (POF) is currently managed by non-physiological sex steroid regimens which are inadequate at optimizing uterine characteristics. Previous short-term studies have demonstrated some benefits of a sex steroid replacement (SSR) regimen devised to replicate the physiological cycle. This study aimed to directly compare the effects of longer-term administration of physiological SSR (pSSR) and standard SSR (sSSR) regimens on the uterine volume, blood flow and endometrial thickness (ET) in women with POF. METHODS: In a controlled crossover trial, 34 women with POF were randomized to receive 12 months of 4-week cycles of transdermal estradiol and vaginal progesterone (pSSR) followed by 12 months of 4-week cycles of oral ethinylestradiol and norethisterone (sSSR), or vice versa. Each treatment period was preceded by a 2-month washout period. At 0, 3, 6 and 12 months of each treatment period, transvaginal ultrasound examined the uterine volume and ET, as primary end-points, and uterine artery resistance (UARI) and pulsatility indices (UAPI), as secondary end-points. Serum estradiol, progesterone and gonadotrophins were also measured. RESULTS: Of the 29 women eligible for the uterine analysis, 17 completed the entire study protocol, but 25 women contributed data to statistical analysis of treatment effect. There was a greater estimated mean ET with the use of pSSR (4.8 mm) compared to that with standard therapy (3.0 mm), with an estimated difference of 1.8 mm [95% confidence interval (CI), 0.7 to 2.8, P=0.002]. The estimated mean uterine volume was also greater during physiological treatment (24.8 cm(3)) than during standard treatment (20.6 cm(3)), but the estimated difference of 4.2 cm(3) (95% CI -0.4 to 8.7) was not statitsically significant, P=0.070. The small differences between the two treatments in the mean UARI and mean UAPI were not statistically significant. The estimated treatment differences were fairly constant across the treatment periods, suggesting that prolonged treatment does not increase response. CONCLUSIONS: pSSR has a greater beneficial effect upon ET in women with POF in comparison with standard therapy. A similar trend was seen for uterine volume. Further studies are required to optimize treatment and to assess pregnancy rate and outcome. Trial Registration www.ClinicalTrials.gov, NCR00732693.

Context-dependent judgments of color that might allow color constancy in scenes with multiple regions of illumination.

For a color-constant observer, a change in the spectral composition of the illumination is accompanied by a corresponding change in the chromaticity associated with an achromatic percept. However, maintaining color constancy for different regions of illumination within a scene implies the maintenance of multiple perceptual references. We investigated the features of a scene that enable the maintenance of separate perceptual references for two displaced but overlapping chromaticity distributions. The time-averaged, retinotopically localized stimulus was the primary determinant of color appearance judgments. However, spatial separation of test samples additionally served as a symbolic cue that allowed observers to maintain two separate perceptual references.

Accuracy of mandibular proximal segment position using virtual surgical planning and custom osteosynthesis plates.

The purpose of this study was to determine whether the use of custom osteosynthesis plates increased the accuracy of proximal segment position following bilateral sagittal split osteotomy in a cohort of 30 patients when compared to a control group of 25 patients who had surgery with conventional plates. Surgery was performed by a single surgeon between October 2015 and December 2017. Post-surgical cone beam computed tomography scans were segmented using Mimics Innovation Suite (Materialise NV), and surface-based superimposition was achieved using ProPlan CMF (Materialise NV). However, there was a tendency for the rotational error to be smaller in the custom group than in the control group. The root mean square error in both groups and for all variables fell within clinical parameters of 2 mm and 4°. In conclusion, the results of this study indicate that customized mandibular fixation plates do not necessarily improve the accuracy of the proximal segments post-surgically; however they may be of benefit in individual patients.