Real-time ex vivo perfusion of human lymph nodes invaded by cancer (REPLICANT): a feasibility study.

Understanding how breast cancer (BC) grows in axillary lymph nodes (ALNs), and refining how therapies might halt that process, is clinically important. However, modelling the complex ALN microenvironment is difficult, and no human models exist at present. We harvested ALNs from ten BC patients, and perfused them at 37 °C ex vivo for up to 24 h. Controlled autologous testing showed that ALNs remain viable after 24 h of ex vivo perfusion: haematoxylin and eosin-stained histological appearance and proliferation (by Ki67 immunohistochemistry) did not change significantly over time for any perfused ALN compared with a control from time-point zero. Furthermore, targeted gene expression analysis (NanoString PanCancer IO360 panel) showed that only 21/750 genes were differentially expressed between control and perfused ALNs (|log2 FC| > 1 and q < 0.1): none were involved in apoptosis and metabolism, but rather all 21 genes were involved in immune function and angiogenesis. During perfusion, tissue acid-base balance remained stable. Interestingly, the flow rate increased (p < 0.001) in cancer-replaced (i.e. metastasis occupied more than 90% of the surface area on multiple levels) compared to cancer-free nodes (i.e. nodes with no metastasis on multiple sections). CXCL11 transcripts were significantly more abundant in cancer-replaced nodes, while CXCL12 transcripts were significantly more abundant in cancer-free nodes. These cytokines were also detected in the circulating perfusate. Monoclonal antibodies (nivolumab and trastuzumab) were administered into a further three ALNs to confirm perfusion efficacy. These drugs saturated the nodes; nivolumab even induced cancer cell death. Normothermic ALN perfusion is not only feasible but sustains the tumour microenvironment ex vivo for scientific investigation. This model could facilitate the identification of actionable immuno-oncology targets. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

The Effects of Cupping on Hamstring Flexibility in College Soccer Players.

Context: College soccer players suffer from hamstring injuries due to inflexibility and repetitive motions involving intense hamstring lengthening and contraction during sport. Although it is a popular intervention for muscular injury, there exists limited evidence of the effects of therapeutic cupping on hamstring flexibility. Objective: To determine the effect of cupping therapy on hamstring flexibility in college soccer players. Design: Cohort design. Setting: Athletic training clinic. Patients: A total of 25, asymptomatic, National Collegiate Athletic Association Division III soccer players (10 males and 15 females; age = 19.4 [1.30] y, height = 175.1 [8.2] cm, and mass = 69.5 [6.6] kg). Intervention(s): A 7-minute therapeutic cupping treatment was delivered to the treatment group. Four 2-in cups were fixed atop trigger point locations within the hamstring muscle bellies of participants' dominant legs. Control group participants received no intervention between pretest and posttest measurements. Main Outcome Measures: Pretest and posttest measurements of hamstring flexibility, using a passive straight leg raise, were performed on both groups. Passive straight leg raise measurements were conducted by blinded examiners using a digital inclinometer. An independent samples t test was used to analyze changes in hamstring flexibility from pretreatment to posttreatment with P values set a priori at .05. Results: An independent samples t test demonstrated no significant difference in change in hamstring flexibility between participants in the treatment group and those in the control group (t23 = -.961, P = .35). Conclusions: The findings of this study demonstrated no statistically significant changes in hamstring flexibility following a cupping treatment.

Compliance with telephone triage advice among adults aged 45 years and older: an Australian data linkage study.

BACKGROUND: Middle-aged and older patients are prominent users of telephone triage services for timely access to health information and appropriate referrals. Non-compliance with advice to seek appropriate care could potentially lead to poorer health outcomes among those patients. It is imperative to assess the extent to which middle-aged and older patients follow triage advice and how this varies according to their socio-demographic, lifestyle and health characteristics as well as features of the call. METHODS: Records of calls to the Australian healthdirect helpline (July 2008-December 2011) were linked to baseline questionnaire data from the 45 and Up Study (participants age ≥ 45 years), records of emergency department (ED) presentations, hospital admissions, and medical consultation claims. Outcomes of the call included compliance with the advice "Attend ED immediately"; "See a doctor (immediately, within 4 hours, or within 24 hours)"; "Self-care"; and self-referral to ED or hospital within 24 h when given a self-care or low-urgency care advice. Multivariable logistic regression was used to investigate associations between call outcomes and patient and call characteristics. RESULTS: This study included 8406 adults (age ≥ 45 years) who were subjects of 11,088 calls to the healthdirect helpline. Rates of compliance with the advices "Attend ED immediately", "See a doctor" and "Self-care" were 68.6%, 64.6% and 77.5% respectively, while self-referral to ED within 24 h followed 7.0% of calls. Compliance with the advice "Attend ED immediately" was higher among patients who had three or more positive lifestyle behaviours, called after-hours, or stated that their original intention was to attend ED, while it was lower among those who lived in rural and remote areas or reported high or very high levels of psychological distress. Compliance with the advice "See a doctor" was higher in patients who were aged ≥65 years, worked full-time, or lived in socio-economically advantaged areas, when another person made the call on the patient's behalf, and when the original intention was to seek care from an ED or a doctor. It was lower among patients in rural and remote areas and those taking five medications or more. Patients aged ≥65 years were less likely to comply with the advice "Self-care". The rates of self-referral to ED within 24 h were greater in patients from disadvantaged areas, among calls made after-hours or by another person, and when the original intention was to attend ED. Patients who were given a self-care or low-urgency care advice, whose calls concerned bleeding, cardiac, gastrointestinal, head and facial injury symptoms, were more likely to self-refer to ED. CONCLUSIONS: Compliance with telephone triage advice among middle-age and older patients varied substantially according to both patient- and call-related factors. Knowledge about the patients who are less likely to comply with telephone triage advice, and about characteristics of calls that may influence compliance, will assist in refining patient triage protocols and referral pathways, training staff and tailoring service design and delivery to achieve optimal patient compliance.

Offending, custody and opioid substitution therapy treatment utilisation among opioid-dependent people in contact with the criminal justice system: comparison of Indigenous and non-Indigenous Australians.

BACKGROUND: Although Indigenous Australians are over-represented among heroin users, there has been no study examining offending, time in custody, and opioid substitution therapy (OST) treatment utilisation among Indigenous opioid-dependent (including heroin) people at the population level, nor comparing these to non-Indigenous opioid-dependent people. The aims of this study were to compare the nature and types of charges, time in custody and OST treatment utilisation between opioid-dependent Indigenous and non-Indigenous Australians in contact with the criminal justice system. METHODS: This was a population-based, retrospective data linkage study using records of OST entrants in New South Wales, Australia (1985-2010), court appearances (1993-2011) and custody episodes (2000-2012). Charge rates per 100 person-years were compared between Indigenous and non-Indigenous Australians by sex, age and calendar year. Statistical comparisons were made for variables describing the cumulative time and percentage of follow-up time spent in custody, as well as characteristics of OST initiation and overall OST treatment utilisation. RESULTS: Of the 34,962 people in the cohort, 6,830 (19.5%) were Indigenous and 28,132 (80.5%) non-Indigenous. Among the 6,830 Indigenous people, 4,615 (67.6%) were male and 2,215 (32.4%) female. The median number of charges per person against Indigenous people (25, IQR 31) was significantly greater than non-Indigenous people (9, IQR 16) (p < 0.001). Overall, Indigenous people were charged with 33.2% of the total number of charges against the cohort and 44.0% of all violent offences. The median percentage of follow-up time that Indigenous males and females spent in custody was twice that of non-Indigenous males (21.7% vs. 10.1%, p < 0.001) and females (6.0% vs. 2.9%, p < 0.001). The percentage of Indigenous people who first commenced OST in prison (30.2%) was three times that of non-Indigenous people (11.2%) (p < 0.001). Indigenous males spent less time in OST compared to non-Indigenous males (median percentage of follow-up time in treatment: 40.5% vs. 43.1%, p < 0.001). CONCLUSIONS: Compared to non-Indigenous opioid-dependent people, Indigenous opioid-dependent people in contact with the criminal justice system are charged with a greater number of offences, spend longer in custody and commonly initiate OST in prison. Hence, contact with the criminal justice system provides an important opportunity to engage Indigenous people in OST.

The emerging relationship between metabolism and DNA repair.

The DNA damage response (DDR) consists of multiple specialized pathways that recognize different insults sustained by DNA and repairs them where possible to avoid the accumulation of mutations. While loss of activity of genes in the DDR has been extensively associated with cancer predisposition and progression, in recent years it has become evident that there is a relationship between the DDR and cellular metabolism. The activity of the metabolic pathways can influence the DDR by regulating the availability of substrates required for the repair process and the function of its players. Additionally, proteins of the DDR can regulate the metabolic flux through the major pathways such as glycolysis, tricarboxylic acid cycle (TCA) and pentose phosphate pathway (PPP) and the production of reactive oxygen species (ROS). This newly discovered connection bears great importance in the biology of cancer and represents a new therapeutic opportunity. Here we describe the nature of the relationship between DDR and metabolism and its potential application in the treatment of cancer. Keywords: DNA repair, metabolism, mitochondria.

3D Functional Genomics Screens Identify CREBBP as a Targetable Driver in Aggressive Triple-Negative Breast Cancer.

Triple-negative breast cancers (TNBC) are resistant to standard-of-care chemotherapy and lack known targetable driver gene alterations. Identification of novel drivers could aid the discovery of new treatment strategies for this hard-to-treat patient population, yet studies using high-throughput and accurate models to define the functions of driver genes in TNBC to date have been limited. Here, we employed unbiased functional genomics screening of the 200 most frequently mutated genes in breast cancer, using spheroid cultures to model in vivo-like conditions, and identified the histone acetyltransferase CREBBP as a novel tumor suppressor in TNBC. CREBBP protein expression in patient tumor samples was absent in 8% of TNBCs and at a high frequency in other tumors, including squamous lung cancer, where CREBBP-inactivating mutations are common. In TNBC, CREBBP alterations were associated with higher genomic heterogeneity and poorer patient survival and resulted in upregulation and dependency on a FOXM1 proliferative program. Targeting FOXM1-driven proliferation indirectly with clinical CDK4/6 inhibitors (CDK4/6i) selectively impaired growth in spheroids, cell line xenografts, and patient-derived models from multiple tumor types with CREBBP mutations or loss of protein expression. In conclusion, we have identified CREBBP as a novel driver in aggressive TNBC and identified an associated genetic vulnerability in tumor cells with alterations in CREBBP and provide a preclinical rationale for assessing CREBBP alterations as a biomarker of CDK4/6i response in a new patient population. SIGNIFICANCE: This study demonstrates that CREBBP genomic alterations drive aggressive TNBC, lung cancer, and lymphomas and may be selectively treated with clinical CDK4/6 inhibitors.

Non-Time-Loss and Time-Loss Softball Injuries in Secondary School Athletes: A Report From the National Athletic Treatment, Injury and Outcomes Network (NATION).

CONTEXT: Most studies of injury trends associated with softball focus on injuries requiring at least 24 hours of missed participation time (time-loss [TL] injuries), with little focus on those that do not (non-time-loss [NTL] injuries). A better understanding of injury trends associated with softball will improve athlete care. OBJECTIVE: To describe NTL and TL injuries experienced by secondary school girls' softball players. DESIGN: Descriptive epidemiology study. SETTING: Secondary school athletic training clinics. PATIENTS OR OTHER PARTICIPANTS: Secondary school girls' softball players. MAIN OUTCOME MEASURE(S): Aggregate data were collected from schools participating in the National Athletic Treatment, Injury, and Outcomes Network surveillance program during the 2011-2012 through 2013-2014 academic years. Frequencies and rates of injuries (NTL and TL) according to time of season, event type, body part injured, and diagnosis were analyzed. RESULTS: In total, 1059 injuries were reported during 140 073 athlete-exposures (AEs): overall injury rate = 7.56/1000 AEs. Of these injuries, 885 (83.6%) were NTL (NTL rate = 6.32/1000 AEs) and 174 (16.4%) were TL (TL rate = 1.24/1000 AEs). Of the NTL and TL injuries, the largest numbers occurred during the regular season (NTL: n = 443 [50.1%]; TL: n = 131 [75.3%]). Injuries sustained during practices accounted for the majority of NTL and TL injuries (NTL: n = 631 [71.3%]; TL: n = 104 [59.8%]). The NTL injuries occurred most often at the shoulder (n = 134 [15.1%]) and hand/fingers (n = 109 [12.3%]) and were diagnosed as contusions (n = 316 [35.7%]), strains (n = 157 [17.7%]), and abrasions (n = 151 [17.1%]). The largest numbers of TL injuries were to the head/face (n = 71 [40.8%]) and diagnosed as concussions (n = 50 [28.7%]) and strains (n = 28 [16.1%]). CONCLUSIONS: Secondary school softball players sustained a larger proportion of NTL injuries than TL injuries. Although NTL injuries may be less severe, they are numerous. Efforts are needed to ensure that injury-prevention programs are incorporated into the care of softball athletes to promote health and reduce injury occurrence.

Long-term Vaccine Impact on Invasive Pneumococcal Disease Among Children With Significant Comorbidities in a Large Australian Birth Cohort.

BACKGROUND: Little is known about long-term invasive pneumococcal disease (IPD) incidence in children with risk factors (RFs) in populations with high coverage pneumococcal conjugate vaccine (PCV) programs. We measured IPD burden and changes with PCV use in children by RF status. METHODS: A retrospective cohort of all live births in 2001-2012 in New South Wales, Australia was linked to IPD, hospitalization and death data. RFs were identified from International Classification of Diseases codes in linked hospitalizations. For each RF adjusted hazard ratios (aHRs, using Cox models), population attributable fractions (PAFs) and changes post-PCV relative to baseline for IPD were calculated. RESULTS: One-thousand two-hundred fifty-one IPD cases occurred in ~1.1 million children in 12-year study cohort. The 75,404 children (6.8% of cohort) with RFs accounted for 255 (20.4%) IPD cases [rate (per 100,000 person-years) of 61 compared with 14 in no RFs]. Asthma was most common RF (n = 41,074; 3.6%) but highest IPD risk was in 2452 children (0.2%) with immunosuppression, splenic dysfunction or breach in cerebrospinal fluid barrier (aHR~20; PAF 0.7-1.8%) versus asthma (aHR 5.3; PAF 14.8%). Compared with 2001-2004 birth cohort (baseline), IPD incidence in PCV-eligible 2009-2012 birth cohort was 78% (95% confidence interval: -72% to -82%) less in children without RFs. IPD declined nonsignificantly (13%; 95% confidence interval: -70% to +138%) in highest IPD risk group, but by 67% (-43% to -82%) in children with other RFs. CONCLUSIONS: By 8 years of universal PCV, IPD incidence reduced significantly in all children except in the 0.2% at highest risk, for whom antibiotic prophylaxis and additional vaccine doses are recommended but compliance and effectiveness remain uncertain.

Exposure to opioid maintenance treatment reduces long-term mortality.

AIMS: To (i) examine the predictors of mortality in a randomized study of methadone versus buprenorphine maintenance treatment; (ii) compare the survival experience of the randomized subject groups; and (iii) describe the causes of death. DESIGN: Ten-year longitudinal follow-up of mortality among participants in a randomized trial of methadone versus buprenorphine maintenance treatment. SETTING: Recruitment through three clinics for a randomized trial of buprenorphine versus methadone maintenance. PARTICIPANTS: A total of 405 heroin-dependent (DSM-IV) participants aged 18 years and above who consented to participate in original study. MEASUREMENTS: Baseline data from original randomized study; dates and causes of death through data linkage with Births, Deaths and Marriages registries; and longitudinal treatment exposure via State health departments. Predictors of mortality examined through survival analysis. FINDINGS: There was an overall mortality rate of 8.84 deaths per 1000 person-years of follow-up and causes of death were comparable with the literature. Increased exposure to episodes of opioid treatment longer than 7 days reduced the risk of mortality; there was no differential mortality among methadone versus buprenorphine participants. More dependent, heavier users of heroin at baseline had a lower risk of death, and also higher exposure to opioid treatment. Older participants randomized to buprenorphine treatment had significantly improved survival. Aboriginal or Torres Strait Islander participants had a higher risk of death. CONCLUSIONS: Increased exposure to opioid maintenance treatment reduces the risk of death in opioid-dependent people. There was no differential reduction between buprenorphine and methadone. Previous studies suggesting differential effects may have been affected by biases in patient selection.

Emergency Department Attendance after Telephone Triage: A Population-Based Data Linkage Study.

OBJECTIVE: To investigate compliance with telephone helpline advice to attend an emergency department (ED) and the acuity of patients who presented to ED following a call. DATA SOURCES/COLLECTION METHODS: In New South Wales (NSW), Australia, 2009-2012, all (1.04 million) calls to a telephone triage service, ED presentations, hospital admissions and death registrations, linked using probabilistic data linkage. STUDY DESIGN: Population-based, observational cohort study measuring ED presentations within 24 hours of a call in patients (1) with dispositions to attend ED (compliance) and (2) low-urgency dispositions (self-referral), triage categories on ED presentation. PRINCIPAL FINDINGS: A total of 66.5 percent of patients were compliant with dispositions to attend an ED. A total of 6.2 percent of patients with low-urgency dispositions self-referred to the ED within 24 hours. After age adjustment, healthdirect compliant patients were significantly less likely (7.8 percent) to receive the least urgent ED triage category compared to the general NSW ED population (16.9 percent). CONCLUSIONS: This large population-based data linkage study provides precise estimates of ED attendance following calls to a telephone triage service and details the predictors of ED attendance. Patients who attend an ED compliant with a healthdirect helpline disposition are significantly less likely than the general ED population to receive the lowest urgency triage category on arrival.

Mortality related to pharmacotherapies for opioid dependence: a comparative analysis of coronial records.

INTRODUCTION AND AIMS: The aim of this study was to compare the mortality associated with oral naltrexone, methadone and buprenorphine in opioid dependence treatment, employing a retrospective data analysis using coronial and prescription data. DESIGN AND METHODS: The number of deaths were identified through national coronial data and number of treatment recipients were estimated from 2000 to 2003 prescriptions and restricted medications data. Mortality rates were expressed as deaths per number of treatment episodes and per person-years at high and low risk of fatal opioid overdose. RESULTS: Thirty-two oral naltrexone, one buprenorphine and 282 methadone-related deaths were identified. Mortality rates in the highest risk period in deaths per 100 person-years were 22.1 (14.6 - 32.2) for oral naltrexone following treatment cessation and 3.0 (2.3 - 3.9) for methadone during treatment induction. Rates in the lowest risk period in deaths per 100 person-years were 1.0 (0.3 - 2.2) during oral naltrexone treatment and 0.34 (0.3 - 0.4) during post-induction methadone treatment. The relative risk of death for oral naltrexone subjects was 7.4 times (high-risk period, p < 0.0001) or 2.8 times (low-risk period, p = 0.055) that of methadone subjects. DISCUSSION AND CONCLUSIONS: This is the first comparison of mortality associated with these three pharmacotherapies for opioid dependence. The risk of death related to oral naltrexone appears higher than that related to methadone treatment.

Follow-up difficulty: correlates and relationship with outcome in heroin dependence treatment in the NEPOD study.

Data collected from 317 heroin users who participated in four studies that were included in the Australian National Evaluation of Pharmacotherapies for Opioid Dependence were analysed to examine predictors of follow-up difficulty and whether follow-up difficulty was related to heroin use outcomes. Participants who were no longer receiving treatment were more difficult to contact and more likely to be lost to follow-up. Participants treated in general practice settings were also more difficult to contact and more likely to be lost to follow-up than participants treated at specialist clinics. Contact difficulty among followed-up participants (either in or out of treatment) was unrelated to heroin use outcomes. The 21% of participants who were followed-up with just one contact attempt reported 20.0 heroin-free days in the previous month, increasing only slightly to 20.9 based on the 70% of participants eventually contacted after up to 20 attempts. The study examined three methods for imputing missing heroin use outcome data and concluded that imputation of missing outcome data by inserting corresponding baseline data may be too conservative.

The impact of illicit drug market changes on health agency operations in Sydney, Australia.

At the end of 2000, in Sydney, Australia, there was a dramatic reduction in heroin availability. This study examines how health agencies treating clients for drug and alcohol related issues were able to respond to the changes that took place in their clients and their treatment needs. Key informant interviews were conducted with 48 staff from a wide range of health services in Sydney to provide the data for a thematic analysis. Changes experienced by health agencies included changed patterns of drug use in their clients, increased aggressive incidents, changed numbers of clients accessing treatment services, and a need for more assistance from outside agencies. A strong evidence base for a range of drug treatment options, support of staff development in aggression management skills, and development of good interagency links between mental health, drug and alcohol, and law enforcement services would make health services better prepared for future changes in the drug use of their clients.

A longitudinal comparison of retention in buprenorphine and methadone treatment for opioid dependence in New South Wales, Australia.

BACKGROUND AND AIMS: To examine characteristics of first-time methadone and buprenorphine clients and factors associated with risk of leaving first treatment in New South Wales (NSW), Australia. DESIGN: Retrospective linkage study of opioid substitution therapy (OST) treatment, court, custody and mortality data. SETTING: NSW, Australia. PARTICIPANTS: First-time OST entrants (August 2001-December 2010). MEASUREMENTS: Characteristics of clients were examined. Time-dependent Cox models examined factors associated with the risk of leaving first treatment, with demographic, criminographic and treatment variables jointly considered. Interactions between medication and other variables upon risk of leaving treatment were examined. FINDINGS: There were 15 600 treatment entrants: 7183 (46%) commenced buprenorphine, 8417 (54%) commenced methadone; the proportion entering buprenorphine increased over time. Those starting buprenorphine switched medications more frequently and had more subsequent treatment episodes. Buprenorphine retention was also poorer. On average, 44% spent 3+ months in treatment compared with 70% of those commencing methadone; however, buprenorphine retention for first-time entrants improved over time, whereas methadone retention did not. Multivariable Cox models indicated that in addition to sex, age, treatment setting and criminographic variables, the risk of leaving a first treatment episode was greater on any given day for those receiving buprenorphine, and was dependent on the year treatment was initiated. There was no interaction between any demographic variables and medication received, suggesting no clear evidence of any particular groups for whom each medication might be better suited in terms of improving retention. CONCLUSIONS: Although retention rates for buprenorphine treatment have improved in New South Wales, Australia, individuals starting methadone treatment still show higher retention rates.

A pilot study of buprenorphine-naloxone combination tablet (Suboxone) in treatment of opioid dependence.

In Australia, maintenance treatment for opioid dependence involves supervised daily administration of a dose of methadone or buprenorphine. A sublingual tablet combining buprenorphine and naloxone in a 4:1 ratio (Suboxone) has been developed, designed to deter diversion and intravenous misuse, and may be suitable for unsupervised administration. The aim of this study was to investigate the tolerability of Suboxone, and investigate whether unsupervised administration can be effective in stabilized patients. Employed patients on buprenorphine maintenance, who had ceased heroin use, were switched to Suboxone and provided with weekly supplies of medication to take without supervised administration. Subjects were monitored closely with weekly clinical reviews, and research interviews at baseline, 3 and 6 months. Only 11% of people receiving buprenorphine met eligibility criteria. Seventeen subjects were recruited. Fifteen were retained for the full 6 months. No subject appeared destabilized by unsupervised dosing. Suboxone was well tolerated. The current trial demonstrated that unsupervised administration with regular clinical monitoring can be effective in selected patients. However, using access to unsupervised dosing to promote abstinence from heroin probably limits the potential benefits of unsupervised administration to a very small proportion of patients.

A comparative study of opioid substitution therapy utilisation among opioid-dependent men and women.

INTRODUCTION AND AIMS: Few population-based studies have examined differences in opioid substitution therapy (OST) treatment utilisation between men and women. Using a population of opioid-dependent people in New South Wales, Australia, first-episode and long-term OST treatment utilisation profiles were compared between men and women, differentiating between treatment initiation in the community and in custody. DESIGN AND METHODS: Retrospective data linkage study using records of new OST entrants (2001-2010) and custody episodes (2000-2012). First OST treatment episode and overall treatment utilisation characteristics were compared between men and women initiating treatment in the community or in custody. Treatment retention was evaluated at 3, 6, 9 and 12 months after first commencing OST and overall, as the median proportion of follow-up time spent in treatment. RESULTS: There were 15,600 new OST entrants in the cohort--10,930 were men (70.1%) and 4670 women (29.9%); 12,584 (80.7%) initiated treatment in the community and 3016 (19.3%) in custody. More men initiated OST in custody (24.0% vs. 8.3%, P < 0.001) and only received OST in custody (57.5% vs. 41.8%, P < 0.001). Women were retained longer in their first OST treatment episode at all four time points in both treatment settings and in treatment overall (community: 46.6% vs. 39.1%, P < 0.001; custody: 41.3% vs. 30.8%, P < 0.001). DISCUSSION AND CONCLUSIONS: There are a number of key differences in OST treatment utilisation profiles between men and women. Whereas men commonly initiate and only receive OST in custody, treatment retention is higher among women, independent of the setting treatment is initiated.

Opioid substitution therapy as a strategy to reduce deaths in prison: retrospective cohort study.

OBJECTIVES: To describe deaths in prison among opioid-dependent people, and examine associations between receipt of opioid substitution therapy (OST) and risk of death in prison. DESIGN: Retrospective cohort study. SETTING: Adult prisons in New South Wales (NSW), Australia. PARTICIPANTS: 16 715 opioid-dependent people who were received to prison between 2000 and 2012. INTERVENTIONS: Opioid substitution therapy. PRIMARY OUTCOME MEASURES: Natural and unnatural (suicide, drug-induced, violent and other injury) deaths in prison. RESULTS: Cohort members were in prison for 30 998 person-years (PY), during which time there were 51 deaths. The all-cause crude mortality rate (CMR) in prison was 1.6/1000 PY (95% CI 1.2 to 2.2/1000 PY), and the unnatural death CMR was 1.1/1000 PY (95% CI 0.8 to 1.6/1000 PY). Compared to time out of OST, the hazard of all-cause death was 74% lower while in OST (adjusted HR (AHR): 0.26; 95% CI 0.13 to 0.50), and the hazard of unnatural death was 87% lower while in OST (AHR: 0.13; 95% CI 0.05 to 0.35). The all-cause and unnatural death CMRs during the first 4 weeks of incarceration were 6.6/1000 PY (95% CI 3.8 to 10.6/1000 PY) and 5.5/1000 PY (95% CI 2.9 to 9.4/1000 PY), respectively. Compared to periods not in OST, the hazard of all-cause death during the first 4 weeks of incarceration was 94% lower while in OST (AHR: 0.06; 95% CI 0.01 to 0.48), and the hazard of unnatural death was 93% lower while in OST (AHR: 0.07; 95% CI 0.01 to 0.53). CONCLUSIONS: Mortality of opioid-dependent prisoners was significantly lower while in receipt of OST.

The impact of opioid substitution therapy on mortality post-release from prison: retrospective data linkage study.

AIMS: Release from prison is a high-risk period for mortality. We examined the impact of opioid substitution therapy (OST), for opioid dependence during and after incarceration, upon mortality post-release. DESIGN: A cohort was formed of all opioid-dependent people who entered OST between 1985 and 2010 and who, following first OST entry, were released from prison at least once between 2000 and 2012. We linked data on OST history, court and prison records and deaths. SETTING: New South Wales (NSW), Australia. PARTICIPANTS: A total of 16,453 people released from prison 60,161 times. MEASUREMENTS: Crude mortality rates (CMRs) were calculated according to OST retention; multivariable Cox regressions for post-release periods were undertaken to examine the association between OST exposure (a time-dependent variable) and mortality post-release, for which covariates were updated per-release. FINDINGS: There were 100,978 person-years (PY) post-release; 1050 deaths occurred. Most received OST while incarcerated (76.5%); individuals were receiving OST in 51% of releases. Lowest post-release mortality was among those continuously retained in OST post-release CMR 4 weeks post-release = 6.4 per 1000 PY; 95% confidence interval (CI) = 5.2, 7.8, highest among those with no OST (CMR = 36.7 per 1000 PY; 95% CI = 28.8, 45.9). Multi-factorial models showed OST exposure in the 4 weeks post-release reduced hazard of death by 75% (adjusted hazard ratio 0.25; 95% CI = 0.12, 0.53); OST receipt in prison had a short-term protective effect that decayed quickly across time. CONCLUSION: In New South Wales, Australia, opioid substitution therapy in prison and post-release appears to reduce mortality risk in the immediate post-release period.

The contributions of viral hepatitis and alcohol to liver-related deaths in opioid-dependent people.

BACKGROUND: Mortality rates are elevated among heroin-dependent populations compared to the general population. Liver disease is emerging as an important contributor to mortality as the heroin-dependent population ages. Two major risk factors for liver disease are hepatitis C virus infection and chronic heavy alcohol use. Both of these are highly prevalent among heroin dependent people, but their relative contribution to liver-related mortality is poorly understood. METHODS: Data recording all prescriptions of opioid substitution treatment in New South Wales, Australia, 1997-2005, were linked to the National Death Index. Crude and standardised mortality rates and standardised mortality ratios were calculated for liver-related and other major causes of death. Frequency counts were obtained for viral hepatitis and alcohol mentions in underlying liver deaths. RESULTS: There were 208 underlying liver deaths for a CMR of 72.4 per 100,000 py (95% CI 62.9, 82.9), and liver deaths occurred at 9.8 times the general population rate (95% CI 8.5, 11.2). There were increases in liver-related mortality over time. Viral hepatitis was mentioned in three-quarters (n=156, 76%), and alcohol in 43% (n=90) of underlying liver deaths. CONCLUSIONS: Liver-related deaths were shown to be increasing in this heroin-dependent population, and the majority of these deaths involved chronic viral hepatitis infection. Increased uptake of treatment for hepatitis C virus infection is crucial to reducing the burden of liver-related mortality in this population. Hepatitis B vaccination, and screening of OST patients for alcohol use disorders and delivery of brief interventions as clinically indicated may also be of benefit.

The increasing mortality burden of liver disease among opioid-dependent people: cohort study.

AIMS: Hepatitis C (HCV) infection is highly prevalent among injection drug users (IDUs) and likely to cause significant mortality over time, but little research attention has focused upon the magnitude of this risk, particularly among ageing users. This study examined trends over time in mortality attributed to liver disease, and in particular contrasting this with other more commonly studied causes of death [acquired immune deficiency syndrome (AIDS), suicide and overdose] among an ageing cohort of heroin-dependent people in Australia. DESIGN: Data linkage study of methadone treatment entrants with the National Deaths Index. SETTING: A cohort entering methadone treatment for heroin dependence in New South Wales, Australia, 1980-85. PARTICIPANTS: A total of 2489 people entering methadone treatment for heroin dependence and 54,847 person-years (PY) of follow-up. MEASUREMENTS: Linkage of data on all methadone entrants between 1980 and 1985 with data from the Australian National Deaths Index, linked using probabilistic record linkage software. FINDINGS: There were 8.2 deaths per 1000 PY [95% confidence interval (CI) 7.5-9.0], with standardized mortality ratios (SMRs) of 4.6 (95% CI 4.2-5.0). Almost one in five (17%) of deaths were from underlying liver-related causes, most commonly viral hepatitis. The overall mortality rate for any liver cause was 1.4 deaths per 1000 PY (95% CI 1.1-1.7), 17 times higher than to the general population (95% CI 13.4-21.3), with relative elevations more marked for females (SMR 27.9; 95% CI 17.7-41.9) than males (SMR 14.5; 95% CI 10.8-19.0). Liver mortality increased over time, becoming the most common cause of death by the end of follow-up. CONCLUSIONS: Liver disease has become the most common cause of mortality among ageing opioid-dependent people in an ageing Australian cohort. There is an imperative to reduce the long-term risks of HCV and other risks to the liver, including alcohol consumption, which are typically not the major clinical focus for this group.