Global real-world experiences with pembrolizumab in advanced urothelial carcinoma after platinum-based chemotherapy: the ARON-2 study.

BACKGROUND: Immune checkpoint inhibitors have changed previous treatment paradigm of advanced urothelial carcinoma (UC). The ARON-2 study (NCT05290038) aimed to assess the real-world effectiveness of pembrolizumab in patients recurred or progressed after platinum-based chemotherapy. PATIENTS AND METHODS: Medical records of patients with documented metastatic UC treated by pembrolizumab as second-line therapy were retrospectively collected from 88 institutions in 23 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). Cox proportional hazards models were adopted to explore the presence of prognostic factors. RESULTS: In total, 836 patients were included: 544 patients (65%) received pembrolizumab after progression to first-line platinum-based chemotherapy in the metastatic setting (cohort A) and 292 (35%) after recurring within < 12 months since the completion of adjuvant or neoadjuvant chemotherapy (cohort B). The median follow-up time was 15.3 months. The median OS and the ORR were 10.5 months and 31% in the overall study population, 9.1 months and 29% in cohort A and 14.6 months and 37% in cohort B. At multivariate analysis, ECOG-PS ≥ 2, bone metastases, liver metastases and pembrolizumab setting (cohort A vs B) proved to be significantly associated with worst OS and PFS. Stratified by the presence of 0, 1-2 or 3-4 prognostic factors, the median OS was 29.4, 12.5 and 4.1 months (p < 0.001), while the median PFS was 12.2, 6.4 and 2.8 months, respectively (p < 0.001). CONCLUSIONS: Our study confirms that pembrolizumab is effective in the advanced UC real-world context, showing outcome differences between patients recurred or progressed after platinum-based chemotherapy.

Real-world effectiveness of pembrolizumab as first-line therapy for cisplatin-ineligible patients with advanced urothelial carcinoma: the ARON-2 study.

BACKGROUND: The advent of immune-checkpoint inhibitors has challenged previous treatment paradigms for advanced urothelial carcinoma (UC) in the post-platinum setting as well as in the first-line setting for cisplatin-ineligible patients. In this study, we investigated the effectiveness of pembrolizumab as first-line treatment for cisplatin-ineligible UC. METHODS: Data from patients aged ≥ 18 years with cisplatin-ineligible UC and receiving first-line pembrolizumab from January 1st 2017 to September 1st 2022 were collected. Cisplatin ineligibility was defined according to the Galsky criteria. Thirty-three Institutions from 18 countries were involved in the ARON-2 study. RESULTS: Our analysis included 162 patients. The median follow-up time was 18.9 months (95%CI 15.3-76.9). In the overall study population, the median OS was 15.8 months (95%CI 11.3-32.4). The median OS was significantly longer in males versus females while no statistically significant differences were observed between patients aged < 65y versus ≥ 65y and between smokers and non-smokers. According to Recist 1.1 criteria, 26 patients (16%) experienced CR, 32 (20%) PR, 39 (24%) SD and 55 (34%) PD. CONCLUSIONS: Our data confirm the role of pembrolizumab as first-line therapy for cisplatin-unfit patients. Further studies investigating the biological and immunological characteristics of UC patients are warranted in order to optimize the outcome of patients receiving immunotherapy in this setting.

Uptake of COVID-19 vaccination among people who inject drugs.

BACKGROUND: People who inject drugs (PWID) may be at elevated risk of adverse outcomes from SARS-CoV-2 infection; however, data on COVID-19 vaccine uptake among PWID are scarce. This study aimed to determine COVID-19 vaccine uptake among PWID, identify factors associated with sub-optimal uptake, and compare uptake to the general population. METHODS: The Australian Needle Syringe Program Survey is an annual sentinel surveillance project, comprising a self-completed questionnaire and provision of a dried blood sample for HIV and HCV testing. In 2021, respondents provided information on their COVID-19 vaccination status. Multivariate logistic regression models identified correlates of vaccine uptake. RESULTS: Among 1166 respondents, 49% had been vaccinated and in most states and territories, vaccine uptake was significantly lower than among the general population. Independent predictors of vaccine uptake were longer duration of vaccine eligibility (AOR 3.42, 95% CI 2.65, 4.41); prior SARS-CoV-2 diagnostic testing (AOR 2.90, 95% CI 2.22, 3.79); injection of opioids (AOR 1.91, 95% CI 1.20, 3.05); and current opioid agonist therapy (AOR 1.70, 95% CI 1.23, 2.33). Women (AOR 0.70, 95% CI 0.54, 0.92) and those who reported daily or more frequent injection (AOR 0.75, 95% CI 0.57, 1.00) were significantly less likely to be vaccinated. CONCLUSIONS: In most Australian states and territories, uptake of COVID-19 vaccine among PWID lagged uptake among the general population. Increased efforts are required to ensure PWID have equitable access to vaccination. Vaccination programmes within harm reduction services and via outreach, coupled with increased support for peers to act as vaccine champions, are likely to reduce barriers and improve COVID-19 vaccine uptake in this population.

Effects of additional electrical stimulation and pre-rigor conditioning temperature on the ageing potential of hot-boned bovine muscles.

OBJECTIVE: The aim of this study is to characterize the impact of additional electrical stimulation (AES) and various pre-rigor holding temperatures (for 3 h) on the ageing-potential of hot boned bovine M. longissimus lumborum (LL). METHODS: Paired LL loins from 12 bulls were hot-boned within 40 min of slaughter, immediate AES applied and subjected to various holding temperatures (5°C, 15°C, 25°C, and 35°C) for 3 h. RESULTS: AES did not accelerate the rate of rigor attainment, but the 3 h pre-rigor holding temperature did. Shear force values decreased as the pre-rigor holding temperatures increased. AES and holding for 3 h (at 25°C) resulted in higher water-holding capacity. CONCLUSION: Data confirmed that AES did not influence the various meat quality parameters in the present study, but pre-rigor holding temperature (25°C) alone or in combination with AES resulted in superior meat quality.

Genomic evaluation of feed efficiency component traits in Duroc pigs using 80K, 650K and whole-genome sequence variants.

BACKGROUND: Increasing marker density was proposed to have potential to improve the accuracy of genomic prediction for quantitative traits; whole-sequence data is expected to give the best accuracy of prediction, since all causal mutations that underlie a trait are expected to be included. However, in cattle and chicken, this assumption is not supported by empirical studies. Our objective was to compare the accuracy of genomic prediction of feed efficiency component traits in Duroc pigs using single nucleotide polymorphism (SNP) panels of 80K, imputed 650K, and whole-genome sequence variants using GBLUP, BayesB and BayesRC methods, with the ultimate purpose to determine the optimal method to increase genetic gain for feed efficiency in pigs. RESULTS: Phenotypes of average daily feed intake (ADFI), average daily gain (ADG), ultrasound backfat depth (FAT), and loin muscle depth (LMD) were available for 1363 Duroc boars from a commercial breeding program. Genotype imputation accuracies reached 92.1% from 80K to 650K and 85.6% from 650K to whole-genome sequence variants. Average accuracies across methods and marker densities of genomic prediction of ADFI, FAT, LMD and ADG were 0.40, 0.65, 0.30 and 0.15, respectively. For ADFI and FAT, BayesB outperformed GBLUP, but increasing marker density had little advantage for genomic prediction. For ADG and LMD, GBLUP outperformed BayesB, while BayesRC based on whole-genome sequence data gave the best accuracies and reached up to 0.35 for LMD and 0.25 for ADG. CONCLUSIONS: Use of genomic information was beneficial for prediction of ADFI and FAT but not for that of ADG and LMD compared to pedigree-based estimates. BayesB based on 80K SNPs gave the best genomic prediction accuracy for ADFI and FAT, while BayesRC based on whole-genome sequence data performed best for ADG and LMD. We suggest that these differences between traits in the effect of marker density and method on accuracy of genomic prediction are mainly due to the underlying genetic architecture of the traits.

Predictors of Aggressive Behavior While under the Influence of Illicit Drugs among Young Adult Methamphetamine Users.

BACKGROUND: Prior research indicates that patterns of combined alcohol and methamphetamine use may be associated with experiencing subjective feelings of aggression or hostility during methamphetamine use episodes. OBJECTIVES: This study examines whether subjective effects of methamphetamine use (i.e., aggression or hostility and paranoia) are associated with aggressive behavior while under the influence of any illicit drugs, controlling for combined alcohol and methamphetamine use and a number of other potential predictors. METHODS: Data from a population-based sample of Australian young adult methamphetamine users (n = 101) collected in 2010 was analyzed. A prediction model of aggressive behavior under the influence of illicit drugs was developed using penalized maximum likelihood logistic regression. RESULTS: Over one-third (34.7%) of methamphetamine users had engaged in verbal and/or physical aggression under the influence of illicit drugs in the last 12 months. In the prediction model, recurrent feelings of aggression or hostility attributed to methamphetamine use (≥3 times in the last 12 months) were associated with aggressive behavior (adjusted odds ratio 4.95, 95% confidence interval 1.67, 14.69). This association was independent of methamphetamine-attributed paranoia, combined alcohol and methamphetamine use, methamphetamine, ecstasy, cocaine, and cannabis use patterns, heavy episodic drinking, gender, and age. No association was found for combined alcohol and methamphetamine use. CONCLUSIONS: These findings indicate a link between methamphetamine-related subjective feelings of aggression or hostility and self-reported aggressive behavior while under the influence of illicit drugs. This suggests that subjective feelings of aggression or hostility may distinguish those who are involved in aggression from other methamphetamine users.

Surrogate endpoints in oncology: when are they acceptable for regulatory and clinical decisions, and are they currently overused?

BACKGROUND: Surrogate outcomes are not intrinsically beneficial to patients, but are designed to be easier and faster to measure than clinically meaningful outcomes. The use of surrogates as an endpoint in clinical trials and basis for regulatory approval is common, and frequently exceeds the guidance given by regulatory bodies. DISCUSSION: In this article, we demonstrate that the use of surrogates in oncology is widespread and increasing. At the same time, the strength of association between the surrogates used and clinically meaningful outcomes is often unknown or weak. Attempts to validate surrogates are rarely undertaken. When this is done, validation relies on only a fraction of available data, and often concludes that the surrogate is poor. Post-marketing studies, designed to ensure drugs have meaningful benefits, are often not performed. Alternatively, if a drug fails to improve quality of life or overall survival, market authorization is rarely revoked. We suggest this reliance on surrogates, and the imprecision surrounding their acceptable use, means that numerous drugs are now approved based on small yet statistically significant increases in surrogates of questionable reliability. In turn, this means the benefits of many approved drugs are uncertain. This is an unacceptable situation for patients and professionals, as prior experience has shown that such uncertainty can be associated with significant harm. CONCLUSION: The use of surrogate outcomes should be limited to situations where a surrogate has demonstrated robust ability to predict meaningful benefits, or where cases are dire, rare or with few treatment options. In both cases, surrogates must be used only when continuing studies examining hard endpoints have been fully recruited.

Genetic and genomic basis of antibody response to porcine reproductive and respiratory syndrome (PRRS) in gilts and sows.

BACKGROUND: Our recent research showed that antibody response to porcine reproductive and respiratory syndrome (PRRS), measured as sample-to-positive (S/P) ratio, is highly heritable and has a high genetic correlation with reproductive performance during a PRRS outbreak. Two major quantitative trait loci (QTL) on Sus scrofa chromosome 7 (SSC7; QTLMHC and QTL130) accounted for ~40 % of the genetic variance for S/P. Objectives of this study were to estimate genetic parameters for PRRS S/P in gilts during acclimation, identify regions associated with S/P, and evaluate the accuracy of genomic prediction of S/P across populations with different prevalences of PRRS and using different single nucleotide polymorphism (SNP) sets. METHODS: Phenotypes and high-density SNP genotypes of female pigs from two datasets were used. The outbreak dataset included 607 animals from one multiplier herd, whereas the gilt acclimation (GA) dataset included data on 2364 replacement gilts from seven breeding companies placed on health-challenged farms. Genomic prediction was evaluated using GA for training and validation, and using GA for training and outbreak for validation. Predictions were based on SNPs across the genome (SNPAll), SNPs in one (SNPMHC and SNP130) or both (SNPSSC7) QTL, or SNPs outside the QTL (SNPRest). RESULTS: Heritability of S/P in the GA dataset increased with the proportion of PRRS-positive animals in the herd (from 0.28 to 0.47). Genomic prediction accuracies ranged from low to moderate. Average accuracies were highest when using only the 269 SNPs in both QTL regions (SNPSSC7, with accuracies of 0.39 and 0.31 for outbreak and GA validation datasets, respectively. Average accuracies for SNPALL, SNPMHC, SNP130, and SNPRest were, respectively, 0.26, 0.39, 0.21, and 0.05 for the outbreak, and 0.28, 0.25, 0.22, and 0.12, for the GA validation datasets. CONCLUSIONS: Moderate genomic prediction accuracies can be obtained for PRRS antibody response using SNPs located within two major QTL on SSC7, while the rest of the genome showed limited predictive ability. Results were obtained using data from multiple genetic sources and farms, which further strengthens these findings. Further research is needed to validate the use of S/P ratio as an indicator trait for reproductive performance during PRRS outbreaks.

Burden of asthma with elevated blood eosinophil levels.

BACKGROUND: Asthma is a common chronic condition with an economic burden of almost $56 billion annually in the US. Biologic markers like blood eosinophils, that help predict the risk of exacerbation could help guide more optimal treatment plans and reduce cost. The purpose of this study was to determine whether healthcare resource use and expenditures vary by eosinophil level among patients with asthma. METHODS: Patients with a diagnosis of asthma defined by ICD-9-CM code 493.xx between January 2004 and July 2011 were extracted from EMRClaims + database (eMAX Health, White Plains NY). Patients were classified as mild, moderate, or severe by medication use following diagnosis, based on recommendations of National Institutes of Health Expert Panel Report 3. Patients were classified as those with elevated eosinophils (≥400 cells/µL) and normal eosinophil level (<400 cells/µL). Patients were followed for resource use, defined as hospitalizations, ER visits and outpatient visit and associated costs were calculated to assess whether an economic difference exists between eosinophil groups. Non-parametric tests were used to compare resource use and associated cost between elevated and normal eosinophil groups. Multivariate modeling was performed to assess the contribution of eosinophil level on the likelihood of study outcomes among patients with severe asthma. RESULTS: Among the 2,164 patients meeting eligibility criteria, 1,144 had severity designations. Of these, 179(16 %) of patients had severe asthma of which 20 % (n = 35) had elevated eosinophils. Seventeen percent of patients with elevated eosinophils were admitted to the hospital during the follow-up period, significantly greater than patients with normal eosinophil levels (12 %; p = 0.011). Overall, compared to patients with normal eosinophil levels (n = 1734), patients with elevated eosinophil levels (n = 430) had significantly greater mean annual hospital admissions (0.51 vs. 0.21/year, p = 0.006) and hospital costs (2,536 vs. $1,091, p = 0.011). Logistic regressions showed that elevated eosinophil level was associated with 5.14 times increased odds of all cause admissions (95 % CI:1.76-14.99, p = 0.003) and 4.07 times increased odds of asthma related admissions (95 % CI: 1.26-13.12, p = 0.019). CONCLUSION: Eosinophil elevation was associated with greater healthcare resource use in patients with asthma.

Value of peripheral blood eosinophil markers to predict severity of asthma.

BACKGROUND: Asthma represents a significant clinical and economic burden to the US healthcare system. Along with other clinical manifestations of the disease, elevated sputum and blood eosinophil levels are observed in patients experiencing asthma exacerbations. The aim of this study was to evaluate the association between blood eosinophil levels and asthma severity defined using Expert Panel Report 3 guidelines. METHODS: Patients with asthma diagnosis between 2004 and 2011 were extracted from the EMRClaims+ database (eMAX Health, White Plains, NY) containing electronic medical records linked to insurance claims for over 675,000 patients. The date of first asthma diagnosis was defined as the 'index date'. Patients were required to have at least 1 peripheral eosinophil test (elevated defined as ≥ 400 cells/µL) in the 12 month 'assessment' period following the index date. We classified patients as those with mild asthma and moderate-to-severe asthma based on the pattern of medication use, as recommended by the 2007 National Institutes of Health Expert Panel Report. Logistic regression models were used to determine if patients with moderate-to-severe asthma had increased likelihood of an elevated peripheral eosinophil count, after accounting for demographics and comorbidities. RESULTS: Among 1,144 patients with an asthma diagnosis, 60 % were classified as having moderate-to-severe asthma. Twenty four percent of patients with moderate-to-severe asthma and 19 % of patients with mild asthma had an elevated peripheral eosinophil count (p = 0.053). Logistic regression showed that moderate-to-severe asthma was associated with 38 % increased odds of elevated eosinophil level (OR 1.38, 95 % CI: 1.02 to 1.86, p = 0.04). CONCLUSION: Patients with moderate-severe asthma are significantly more likely to have an elevated peripheral eosinophil count than patients with mild asthma.

Genome-wide association studies (GWAS) identify a QTL close to PRKAG3 affecting meat pH and colour in crossbred commercial pigs.

BACKGROUND: Improving meat quality is a high priority for the pork industry to satisfy consumers' preferences. GWAS have become a state-of-the-art approach to genetically improve economically important traits. However, GWAS focused on pork quality are still relatively rare. RESULTS: Six genomic regions were shown to affect loin pH and Minolta colour a* and b* on both loin and ham through GWAS in 1943 crossbred commercial pigs. Five of them, located on Sus scrofa chromosome (SSC) 1, SSC5, SSC9, SSC16 and SSCX, were associated with meat colour. However, the most promising region was detected on SSC15 spanning 133-134 Mb which explained 3.51% - 17.06% of genetic variance for five measurements of pH and colour. Three SNPs (ASGA0070625, MARC0083357 and MARC0039273) in very strong LD were considered most likely to account for the effects in this region. ASGA0070625 is located in intron 2 of ZNF142, and the other two markers are close to PRKAG3, STK36, TTLL7 and CDK5R2. After fitting MARC0083357 (the closest SNP to PRKAG3) as a fixed factor, six SNPs still remained significant for at least one trait. Four of them are intragenic with ARPC2, TMBIM1, NRAMP1 and VIL1, while the remaining two are close to RUFY4 and CDK5R2. The gene network constructed demonstrated strong connections of these genes with two major hubs of PRKAG3 and UBC in the super-pathways of cell-to-cell signaling and interaction, cellular function and maintenance. All these pathways play important roles in maintaining the integral architecture and functionality of muscle cells facing the dramatic changes that occur after exsanguination, which is in agreement with the GWAS results found in this study. CONCLUSIONS: There may be other markers and/or genes in this region besides PRKAG3 that have an important effect on pH and colour. The potential markers and their interactions with PRKAG3 require further investigation.

Psychological Distress and Drug Use Patterns of Young Adult Ecstasy Users: A Complementary Analysis of Australian Datasets.

We examine psychological distress (PD) in young adult Ecstasy users in relation to age of initiation and frequency of use of Ecstasy, cannabis, alcohol, and tobacco. Using two Australian community samples, we assess whether different sampling methods produce comparable estimates of these associations. The Natural History Study of Drug Use (NHSDU; N = 339) in 2009 used population sampling and the 2009 Ecstasy and Related Drug Reporting System (EDRS; N = 359) used purposive sampling. Participants, aged 19-23 years, were recurrent Ecstasy users. PD was assessed using Kessler 10 in the EDRS and Hospital Anxiety Depression Scale in the NHSDU. In both samples, PD was associated with daily tobacco use and early drug initiation, but not frequent Ecstasy use. One-third smoke tobacco daily. Study limitations and implications are noted.

Using population screening for recruitment of young adults engaged in illicit drug use: methodological issues and sampling outcomes.

Social stigma, legal sanctions and the associated lack of sampling frames create barriers to the probabilistic sampling of those engaged in a variety of behaviour, including illicit drug use. We used a novel sampling approach to recruit respondents into a longitudinal study examining amphetamine-type stimulant use. A young adult population was screened for lifetime drug use to create a sampling frame of amphetamine-type stimulant users and non-users. We posted 12,118 screening questionnaires to a random selection of young adults listed on the electoral roll for Brisbane and the Gold Coast, Australia (N=107,275). Using a small pre-paid incentive and intensive telephone and postal reminders we attained a screening response rate of 49.9%. Eligible amphetamine-type stimulant users (used ecstasy or methamphetamine⩾3 times in past 12 months) and non-users (never used ecstasy or methamphetamine) were identified by screening responses. About two-thirds of each selected group took part in the longitudinal study. Comparisons with large-scale population survey data suggest the sample was broadly representative of young adult amphetamine-type stimulant users in Australia.

Epicardial adipose tissue thickness as a predictor of impaired microvascular function in patients with non-obstructive coronary artery disease.

OBJECTIVE: To determine if increased epicardial adipose tissue (EAT) measured by cardiac CT could be associated with impaired myocardial flow reserve (MFR) in patients with non-obstructive coronary artery disease (CAD). BACKGROUND: Studies have shown that EAT volume is related to epicardial obstructive CAD, myocardial ischemia and major adverse cardiac events. However, the association between EAT with coronary microvascular dysfunction and impaired MFR has not been well clarified. METHODS: Consecutive patients who underwent Rb-82 positron emission tomography (PET), coronary artery calcium (CAC) scoring and non-invasive coronary computed tomography angiography (CCTA) were screened. PET scans were analysed for standard myocardial perfusion (MPI) and MFR. CCTA results were analysed and only patients with non-obstructive CAD (<50% luminal diameter stenosis) were included. EAT thickness and volumes were measured from CT scans. RESULTS: Of 137 patients without obstructive CAD by CCTA and with normal Rb-82 PET relative MPI, 26 (19.0%) patients had impaired MFR < 2 and 87 (64%) patients had CAC. EAT(thickness), EAT(volume) and CAC values were higher in patients with impaired MFR < 2 than those with normal MFR ≥ 2 (6.7 ± 1.6 mm vs 4.4 ± 1.0 mm, P < .0001; 119.0 ± 25.3 cm(3) vs 105.8 ± 30.5 cm(3), P < .04 and 508.9 ± 554.3 vs 167.8 ± 253.9, P < .0001, respectively). However, EAT(thickness) had a stronger negative correlation with MFR than EAT(volume) and CAC (r = -0.78 vs r = -0.25 and ρ = -0.32, P < .0001). With multivariable logistic regression analysis, only EAT(thickness) was independently associated with impaired MFR (OR 20.7, 95% CI 4.9-87.9, P < .0001). Importantly, the receiver-operator characteristic (ROC) curves demonstrated a superior performance of EAT(thickness) vs EAT(volume) and EAT(thickness) vs CAC in detecting impaired MFR (AUC: 0.945 vs 0.625, difference between AUC: 0.319, P < .0001; AUC: 0.945 vs 0.710, difference between AUC: 0.235, P < .0006, respectively). On ROC curve analysis, an EAT(thickness) cut-off value > 5.6 mm was optimal in detecting impaired MFR with a sensitivity and specificity of 81% and 92%, respectively. CONCLUSIONS: Increased EAT appears to be associated with impaired MFR. This parameter may help improve detection of patients at risk of microvascular dysfunction.

Quality of life of people who inject drugs: characteristics and comparisons with other population samples.

PURPOSE: To assess the quality of life (QOL) of persons who inject drugs. METHODS: Some 483 current injecting drug users visiting a large NSP over a 2-week period in October 2009 were interviewed using a structured questionnaire. QOL was measured using the WHOQOL-BREF. Data were collected on age, gender, injecting patterns, current drug treatment status and hepatitis C status. Participant QOL profiles were compared to published domain scores for a range of other population groups. RESULTS: People who inject drugs (PWID) experience a very poor QOL irrespective of socio-demographic characteristics, injecting patterns, hepatitis C sero-status and drug treatment status. Sample participants (PWID) experience a QOL below that experienced by many population groups in the community affected by disabling chronic illnesses. CONCLUSIONS: Injecting drug use is associated with a poor QOL. Some PWID may be self-medicating for chronic non-malignant pain, and it is likely that these people had a low QOL prior to the decision to inject. Despite this caveat, it remains likely that injecting drug use does little to enhance the QOL of the user.

Social contacts and Ecstasy offers: findings of a population-based study.

Ecstasy (MDMA) use is relatively common among young adults in many developed countries. However, little is known about how young non-users are first introduced to Ecstasy, including the relative contribution of peer networks and individual risk factors. We assess the role of social contact with Ecstasy-using peers in regard to young adults' exposure to offers of Ecstasy, using data from the Natural History Study, a population-based study conducted in Australia. Population screening of young adults (19- to 23-year-olds) identified a sample of young Ecstasy users (N = 315) and a comparison group of Ecstasy-naïve participants (N = 199). Two outcomes are considered: being exposed to any Ecstasy offers and being exposed to > 3 offers. Extensive social contact with Ecstasy users was defined as knowing > 10 Ecstasy users. Of the Ecstasy-naïve young adults, > 40% had ever received Ecstasy offers. Extensive social contact with Ecstasy users independently predicted exposure to multiple (> 3) Ecstasy offers for Ecstasy-naïve young adults. These findings indicate that Ecstasy offers are widespread among users and non-users of Ecstasy. For non-users, exposure to Ecstasy offers occurs through social contact with drug-using peers independently of individual risk factors. The pervasiveness of Ecstasy offers suggests that universal education concerning Ecstasy use is required.

Enhanced surveillance of notifications of hepatitis C to Queensland Health up to 19 years previously.

In this study we aimed to assess the utility of following up historical hepatitis C notifications for enhanced surveillance and linking cases to further testing and treatment. Queensland hepatitis C notifications from June 2018, 2013, 2008 and 2003 who were not incarcerated at the time of testing were followed up. The most recent identified clinicians for cases were contacted by telephone. When no information about a current clinician was available, the case was contacted via a letter or text message. Clinicians and cases were encouraged to pursue further testing and treatment and provide information about management. Following notification but prior to this study's follow-up, a majority of cases (309/532; 58%) had a negative polymerase chain reaction (PCR) test or underwent treatment.Clinician follow-up was successful in 21% of eligible cases, with the proportion decreasing with increasing time since notification. In conclusion, contacting clinicians to link notified cases to further testing and treatment may increase testing and treatment in a small proportion of cases notified up to nine years post-notification. From our experience, the follow-up of notifications before this time is unlikely to result in improved outcomes.

Using notifications data to increase hepatitis C testing and treatment rates in Queensland.

Australia's goal of eliminating hepatitis C by 2030 requires increases in uptake of and access to testing and treatment. As hepatitis C is a notifiable condition, health departments have access to information about people exposed to the hepatitis C virus (HCV), including the details of notifying clinicians who ordered their diagnostic pathology tests. Hepatitis C RNA testing confirms active infection that requires treatment, whereas a positive antibody test result only indicates prior exposure to the virus. We undertook a pilot project in Queensland to follow up hepatitis C notifications with clinicians, aiming to increase HCV-RNA testing and treatment uptake. For all individuals with a first-time hepatitis C notification in Queensland between 3 November 2020 and 28 May 2021, we sought information regarding hepatitis C RNA testing from laboratories, excluding those cases diagnosed in prisons. Cases who did not have RNA testing identified as part of or after their initial diagnostic tests were followed up via their notifying clinician. Interviews with selected clinicians were undertaken to improve our understanding of the follow-up process. There were 769 new hepatitis C notifications during our study period: 244 had no subsequent RNA test identified and were followed up for this study. Of these, 134 cases were lost to follow-up; 26 were already being effectively case managed; 22 reported previous treatment and no further risk; and 62 were eligible for HCV-RNA testing. Twenty-six cases subsequently started hepatitis C treatment. Thirty-four percent of notifications that required follow-up resulted from testing initially requested in hospital settings. Following up hepatitis C notifications can result in increased treatment rates; however, the process was resource-intensive and often failed to result in further contact between clinicians and patients. Our findings also highlight the importance of supporting better continuity of care between hospitals and community settings.

Sex Differences in Systemic and Coronary Arterial Hemodynamics in Heart Failure With Preserved Ejection Fraction.

Heart failure (HF) with preserved ejection fraction (HFpEF) predominantly affects females. Systemic and coronary arterial abnormalities are present in HFpEF and may contribute to HFpEF in females. We performed a cross-sectional study of 32 participants with HFpEF and 26 controls. Arterial hemodynamics were noninvasively assessed by combining arterial tonometry with echocardiography. Coronary microvascular function was assessed by rubidium-82 positron emission tomography as the myocardial flow reserve. Coronary vascular resistance (CVR) at rest and vasodilator stress were calculated using positron emission tomography. CVR reserve was calculated as stress - rest CVR. Multivariable linear regression assessed the associations of female sex with arterial hemodynamics in participants with and without HF, and the association of HF with arterial hemodynamics within each sex stratum. Demographics and left ventricular systolic and diastolic function were similar between males and females. Among those with HFpEF, females had a higher steady and pulsatile arterial load and more impaired (less negative) CVR reserve than males. Conversely, in controls, females had similar hemodynamics to males. We then divided the sample based on sex. Femaleswith HFpEF had a higher pulsatile arterial load and higher stress CVR than control females. Among males, arterial hemodynamics were similar, regardless of HFpEF status. The measures of early pulsatile arterial load were independently associated with higher E/e' and lower myocardial flow reserve in females only. In conclusion, despite similar left ventricular function between sexes, older females with HFpEF are characterized by additional systemic and coronary arterial hemodynamic abnormalities compared with males with HFpEF and similarly aged females without HFpEF.

Bone targeting agents, but not radiation therapy, improves survival in patients with bone metastases from advanced urothelial carcinoma receiving pembrolizumab: results from the ARON-2 study.

The ARON-2 study (NCT05290038) aimed to assess the real-world efficacy of pembrolizumab in patients recurred or progressed after platinum-based chemotherapy. This retrospective analysis reports the outcomes of urothelial carcinoma (UC) patients with bone metastases (BM). Medical records of patients with documented metastatic UC treated by pembrolizumab as second-line therapy were reviewed from60 institutions in 20 countries. Patients were assessed for Overall Response Rate (ORR), Progression-Free Survival (PFS), and Overall Survival (OS). Univariate and multivariate analyses were used to explore the association of variables of interest with OS and PFS. 881 patients were included; of them, 263 (30%) presented BM. Median follow-up time was 22.7 months. Patients with BM showed both shorter median OS (5.9 months vs 13.1 months, p < 0.001) and PFS (3.5 months, vs 7.3 months, p < 0.001) compared to patients without BM. Patients who received bone targeted agents (BTAs) showed a significantly longer median OS (8.5 months vs 4.6 months, p = 0.003) and PFS (6.1 months vs 3.2 months, p = 0.003), while no survival benefits were observed among patients who received radiation therapy for BM during pembrolizumab treatment compared to those who did not. In multivariate analysis, performance status, concomitant liver metastases, and the lack of use of BTAs were significantly associated with worse OS and PFS. Bone involvement in UC patients treated with pembrolizumab predicts inferior survival. Poor performance status and liver metastases may further worsen outcomes, while the use of BTAs is associated with improved outcomes.