Participation in Australian drug treatment programs for individuals engaging in high-risk substance use: Data from a nationally representative sample.

INTRODUCTION: Substance use, including drugs, alcohol and smoking have a significant health, social and economic impact. We aim to assess the rate and factors associated with treatment access among individuals with high-risk substance use. METHOD: This study is a cross-sectional analysis of the 2019 Australian National Drug Strategy Household Survey (N = 22,015). Participants were persons with high-risk substance use based on the Alcohol, Smoking and Substance Involvement Screening Test-Lite (ASSIST-Lite) and current smokers. We measured self-reports of past 12-month engagement in a tobacco, alcohol or other drugs treatment program. RESULTS: Overall, 0.4% had high-risk drug use (0.3% cannabis, 0.1% meth/amphetamine or 0.1% opioids), 7.4% had high-risk alcohol use, and 14.0% currently smoked. Among high-risk users, past 12-month treatment access rates were 50.6% [22.3-78.9%] for opioids, 27.1% [8.1-46.1%] for meth/amphetamine, 14.5% [4.3-24.7%] for cannabis, 9.6% [8.1-11.0%] for alcohol and 11.7% [10.6-12.9%] for current smoking. The primary source of treatment support was information and education (12.7% drugs, 4.6% alcohol, 4.0% smoking), followed by counselling (6.7% drugs, 4.5% alcohol, 3.0% smoking). Online or internet support was accessed by 5.9% (drug) and 1.6% (alcohol) people with high-risk use. Psychological distress was associated with treatment access (drugs: odds ratio 3.03 [0.77-11.95], p = 0.111; alcohol: odds ratio 3.16 [2.20-4.56], p ≤ 0.001; smoking: odds ratio 1.95 [1.52-2.49], p ≤ 0.001). DISCUSSION AND CONCLUSIONS: The proportion of people engaging in risky substance use who had used treatment programs remains low, especially for alcohol. Public health strategies to scale up treatment access are warranted.

Add-on Rehmannia-6-Based Chinese Medicine in Type 2 Diabetes and CKD: A Multicenter Randomized Controlled Trial.

BACKGROUND: Diabetes is the leading cause of CKD and kidney failure. We assessed the real-world effectiveness of Rehmannia-6-based Chinese medicine treatment, the most used Chinese medicine formulation, on the change in eGFR and albuminuria in patients with diabetes and CKD with severely increased albuminuria. METHODS: In this randomized, assessor-blind, standard care-controlled, parallel, multicenter trial, 148 adult patients from outpatient clinics with type 2 diabetes, an eGFR of 30-90 ml/min per 1.73 m 2 , and a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g were randomized 1:1 to a 48-week add-on protocolized Chinese medicine treatment program (using Rehmannia-6-based formulations in the granule form taken orally) or standard care alone. Primary outcomes were the slope of change in eGFR and UACR between baseline and end point (48 weeks after randomization) in the intention-to-treat population. Secondary outcomes included safety and the change in biochemistry, biomarkers, and concomitant drug use. RESULTS: The mean age, eGFR, and UACR were 65 years, 56.7 ml/min per 1.73 m 2 , and 753 mg/g, respectively. Ninety-five percent ( n =141) of end point primary outcome measures were retrievable. For eGFR, the estimated slope of change was -2.0 (95% confidence interval [CI], -0.1 to -3.9) and -4.7 (95% CI, -2.9 to -6.5) ml/min per 1.73 m 2 in participants treated with add-on Chinese medicine or standard care alone, resulting in a 2.7 ml/min per 1.73 m 2 per year (95% CI, 0.1 to 5.3; P = 0.04) less decline with Chinese medicine. For UACR, the estimated proportion in the slope of change was 0.88 (95% CI, 0.75 to 1.02) and 0.99 (95% CI, 0.85 to 1.14) in participants treated with add-on Chinese medicine or standard care alone, respectively. The intergroup proportional difference (0.89, 11% slower increment in add-on Chinese medicine, 95% CI, 0.72 to 1.10; P = 0.28) did not reach statistical significance. Eighty-five adverse events were recorded from 50 participants (add-on Chinese medicine versus control: 22 [31%] versus 28 [36%]). CONCLUSIONS: Rehmannia-6-based Chinese medicine treatment stabilized eGFR on top of standard care alone after 48 weeks in patients with type 2 diabetes, stage 2-3 CKD, and severely increased albuminuria. CLINICAL TRIAL REGISTRY: Semi-individualized Chinese Medicine Treatment as an Adjuvant Management for Diabetic Nephropathy (SCHEMATIC), NCT02488252 .

Common adverse events of electronic cigarettes compared with traditional nicotine replacement therapies: A systematic review and meta-analysis.

ISSUES: Established literature suggests that electronic cigarettes (EC) are more effective than traditional nicotine replacement therapies (NRT) as a smoking cessation aid, but the factors that mediate this difference remain poorly understood. We examine how adverse events (AE) associated with EC use relative to NRTs differ, with the view that differences in AEs experienced may drive differences in use and compliance. APPROACH: Papers for inclusion were identified via a three-tiered search strategy. Eligible articles involved healthy participants and compared nicotine ECs to non-nicotine ECs or NRTs and reported frequency of AE as an outcome. Random-effects meta-analyses were conducted to compare the likelihood for each of the AEs between nicotine ECs, non-nicotine placebo ECs and NRTs. KEY FINDINGS: A total of 3756 papers were identified, of which 18 were meta-analysed (10 cross-sectional and 8 randomised controlled trials). Meta-analytic results found no significant difference in the rates of reported AEs (i.e., cough, oral irritation, nausea) between nicotine ECs and NRTs, and between nicotine and non-nicotine placebo ECs. IMPLICATIONS: The variation in the incidence of AEs likely does not explain user preferences of ECs to NRTs. Incidence of common AEs reported because of EC and NRT use did not differ significantly. Future work will need to quantify both the adverse and favourable effects of ECs to understand the experiential mechanisms that drive the high uptake of nicotine ECs relative to established NRTs. CONCLUSIONS: There is inconclusive evidence on the incidence of AEs experience when using ECs compared to NRTs, possibly given the small sample size of studies.

Treatment-seeking behavior and barriers to mental health service utilization for depressive symptoms and hazardous drinking: The role of religious and traditional healers in mental healthcare of Northwest Ethiopia.

Understanding mental healthcare seeking and associated factors is essential for planning mental health services. This study aimed to assess treatment seeking and barriers to care for depressive symptoms and hazardous drinking in a community sample of Northwest Ethiopia. A cross-sectional study was conducted to screen 1,728 participants for depressive symptoms (n = 414) and hazardous drinking (n = 155). Participants were asked whether they had sought mental healthcare. We also assessed the barriers to seeking mental healthcare. Logistic regression was used to identify associated factors. Among people with depressive symptoms, 14.3%, 15.5%, and 19.6% sought treatment from healthcare settings, non-healthcare settings, or any sources, respectively. Religious places (39.5%) were the most helpful treatment sources. People with low levels of internalized stigma (adj OR = 3.00 [1.41, 6.42]) and positive attitudes towards mental illness (adj OR = 2.84 [1.33, 6.07]) were nearly threefold more likely to seek depression treatment. No participants with hazardous drinking sought treatment from healthcare settings, and only 1.3% had sought help from families/friends. Over 97% of participants with depressive symptoms and hazardous drinking reported at least one barrier to treatment-seeking from a healthcare setting. Religious and traditional healers were as important as healthcare settings for treatment-seeking.

Development of the motivational thought frequency scale for alcohol abstinence (MTF-A).

BACKGROUND AND AIMS: For most treatment-seeking patients with severe Alcohol Use Disorder (AUD), abstinence is the clinically indicated goal. Existing AUD motivation scales are non-specific about treatment consumption goals, which limit their effectiveness. Desires and mental imagery are relevant in the motivation for AUD treatment engagement. The Motivational Thought Frequency Scale for an abstinence goal (MTF-A) was adapted from the MTF for controlled drinking (MTF-CD). This study psychometrically evaluated the MTF-A in an alcohol-dependent sample engaged in treatment with a goal of abstinence. To enhance the clinical utility of the scale, a secondary aim was to evaluate a psychometrically equivalent short version of the MTF-A. METHOD: A sample N of 329 treatment-seeking patients with AUD (mean age of 44.44 years, SD = 11.89 years, 72% male) who were undertaking a cognitive behavioral treatment (CBT) program for abstinence completed the Motivational Thought Frequency Scale for Abstinence (MTF-A) and the Severity of Alcohol Dependence Questionnaire (SADQ). The MTF-A measured motivation for abstinence through four factors: intensity, self-efficacy imagery, incentives imagery, and availability. Confirmatory factor analyses (CFAs) were conducted to examine factor structure and model fit. Cronbach's alpha assessed internal consistency. Predictive validity was determined by logistic regression predicting first-session treatment non-attendance and alcohol consumption between baseline assessment and commencement of treatment, controlling for potential confounds. RESULTS: A four-factor structure provided the best fit for the MTF-A, compared with one- and three-factor models. A shortened 9-item MTF-A scale (S-MTF-A) provided better fit than the 13-item MTF-A scale. Both MTF-A and S-MTF-A displayed good internal consistency. Although both MTF-A and S-MTF-A successfully predicted first-session treatment non-attendance, neither predicted alcohol consumption between the baseline assessment and commencement of treatment. CONCLUSIONS: The model fit of the four-factor, 9-item S-MTF-A was superior to the original 13-item MTF-A. Both scales were predictive of participation of AUD treatment. Desires and mental imagery play an important role in AUD treatment motivation.

Polysubstance use in young people accessing residential and day-treatment services for substance use: substance use profiles, psychiatric comorbidity and treatment completion.

BACKGROUND AND AIMS: People with substance use disorders (SUDs) frequently present to treatment with polysubstance use and mental health comorbidities. Different combinations of substance use and mental health problems require different treatment approaches. Our study aimed to: (i) identify the shared substance use classes among young people at treatment admission, (ii) determine which mental health symptoms, quality of life (QoL) and service types were associated with the identified substance use classes, and (iii) prospectively determine which substance use classes and service types were more likely to complete treatment. DESIGN: Cross-sectional and prospective study using service and outcome data. SETTING: Substance use treatment services in Queensland and New South Wales, Australia. PARTICIPANTS: De-identified service and outcome measure data were extracted from the files of 744 clients aged 18-35 years (48% male) admitted into seven residential and four day-treatment programmes. MEASUREMENTS: Substance use and severity among tobacco, alcohol, cannabis, cocaine, amphetamine-type stimulants, opioids, sedatives and inhalants. Other variables included: depression, anxiety, post-traumatic stress and psychotic symptoms, as well as QoL. FINDINGS: Latent class analysis identified three polysubstance use classes: wide-ranging polysubstance users (WRPU; 22.45%), primary amphetamine users (56.45%) and alcohol and cannabis users (21.10%). The WRPU class had higher odds of psychotic symptoms than the alcohol and cannabis use class [odds ratio (OR) = 1.30; 95% confidence interval (CI) = 1.11-1.11]; and double the odds of residential programme enrolment than those in the amphetamine use class (OR = 2.35; 95% CI = 1.50-3.68). No other class differences on mental health or QoL variables were found. Clients enrolled in day-programmes had higher odds of completing treatment. CONCLUSIONS: There appear to be high levels of polysubstance use among young people entering substance use treatment in Australia. Wide-ranging polysubstance users were more likely to report psychotic symptoms and be enrolled into a residential programme than primary amphetamine users and alcohol and cannabis users.

Vitamin D, bone density, and nephrocalcinosis in preterm infants: a prospective study.

BACKGROUND: Vitamin D (VitD) supplementation is recommended by the American Academy of Pediatrics (AAP) for preterm infants to improve bone density. Complications of VitD supplementation include hypercalciuria and nephrocalcinosis (NC). NC has been reported in 7-64% infants < 32 weeks gestational age (GA) or < 1500 g birth weight (BW). The relationships between VitD supplementation, serum 25-hydroxy VitD levels, bone density, hypercalciuria and development of NC in preterm infants are not well established. METHODS: Prospective, observational cohort study of 56 infants with GA ≤ 32 weeks or BW ≤ 1800 g. Demographics, dietary intakes, serum 25-hydroxy VitD levels and weekly urinalyses were collected until 40 weeks corrected GA or discharge. Bone mineral density (BMD) and content (BMC) were assessed using dual-energy X-ray absorptiometry (DEXA) scan. NC was identified by kidney ultrasound. RESULTS: 56 infants received on average 447 IU/day of VitD with average serum 25-hydoxy VitD level 39.6 ng/mL. DEXA scan showed average BMD 0.13 g/cm2 and BMC 35.8 g. 23/56 (41%) infants were diagnosed with NC. Infants with NC had lower GA (p < 0.01) and BW (p < 0.01) and increased presence of calcium oxalate crystals (78% vs. 36%) (p = 0.002). There were no differences in VitD intake, urine calcium/creatinine ratios or BMD and BMC in infants with versus without NC. CONCLUSIONS: VitD supplementation per AAP guidelines resulted in acceptable serum 25-hydroxyVitD levels, but no improvement in BMD or BMC compared to previously reported values. However, infants receiving recommended amounts born at earlier GA and lower BW are at increased risk of NC. VitD supplementation and serum levels should be closely monitored in this high-risk population. A higher resolution version of the Graphical abstract is available as Supplementary information.

PRAgmatic Clinical Trial Design of Integrative MediCinE (PRACTICE): A Focus Group Series and Systematic Review on Trials of Diabetes and Kidney Disease.

Background: Pragmatic trials inform clinical decision with better generalizability and can bridge different streams of medicine. This study collated the expectations regarding pragmatic trial design of integrative medicine (IM) for diabetes and kidney diseases among patients and physicians. Dissonance between users' perspective and existing pragmatic trial design was identified. The association between risk of bias and pragmatism of study design was assessed. Method: A 10-group semi-structured focus group interview series [21 patients, 14 conventional medicine (ConM) and 15 Chinese medicine (CM) physicians] were purposively sampled from private and public clinics in Hong Kong. Perspectives were qualitatively analyzed by constant comparative method. A systematic search of four databases was performed to identify existing IM pragmatic clinical trials in diabetes or kidney disease. Primary outcomes were the pragmatism, risk of bias, and rationale of the study design. Risk of bias and pragmatism were assessed based on Cochrane risk-of-bias tool and PRECIS-2, respectively. The correlation between risk of bias and pragmatism was assessed by regression models with sensitivity analyses. Results: The subtheme on the motivation to seek IM service was analyzed, covering the perceived limitation of ConM effect, perceived benefits of IM service, and assessment of IM effectiveness. Patients expected IM service to retard disease progression, stabilize concomitant drug dosage, and reduce potential side effects associated with ConM. In the systematic review, 25 studies from six countries were included covering CM, Korean medicine, Ayurvedic medicine, and western herbal medicine. Existing study designs did not include a detailed assessment of concomitant drug change and adverse events. Majority of studies either recruited a non-representative proportion of patients as traditional, complementary, and integrative medicine (TCIM) diagnosis was used as inclusion criteria, or not reflecting the real-world practice of TCIM by completely dropping TCIM diagnosis in the trial design. Consultation follow-up frequency is the least pragmatic domain. Increase in pragmatism did not associate with a higher risk of bias. Conclusion: Existing IM pragmatic trial design does not match the patients' expectation in the analysis of incident concomitant drug change and adverse events. A two-layer design incorporating TCIM diagnosis as a stratification factor maximizes the generalizability of evidence and real-world translation of both ConM and TCIM.

Efficacy, safety and response predictors of adjuvant astragalus for diabetic kidney disease (READY): study protocol of an add-on, assessor-blind, parallel, pragmatic randomised controlled trial.

INTRODUCTION: Diabetic kidney disease (DKD) is a prevalent and costly complication of diabetes with limited therapeutic options, being the leading cause of end-stage kidney disease in most developed regions. Recent big data studies showed that add-on Chinese medicine (CM) led to a reduced risk of end-stage kidney disease and mortality among patients with chronic kidney disease (CKD) and diabetes. Astragalus, commonly known as huang-qi, is the most prescribed CM or used dietary herb in China for diabetes and DKD. In vivo and in vitro studies showed that astragalus ameliorated podocyte apoptosis, foot process effacement, mesangial expansion, glomerulosclerosis and interstitial fibrosis. Nevertheless, the clinical effect of astragalus remains uncharacterised. This pragmatic clinical trial aims to evaluate the effectiveness of add-on astragalus in patients with type 2 diabetes, stage 2-3 CKD and macroalbuminuria, and to identify related response predictors. METHODS AND ANALYSIS: This is an add-on, assessor-blind, parallel, pragmatic randomised controlled clinical trial. 118 patients diagnosed with DKD will be recruited and randomised 1:1 to receive 48 weeks of add-on astragalus or standard medical care. Primary endpoints are the changes in estimated glomerular filtration rate and urine albumin-to-creatinine ratio between baseline and treatment endpoint. Secondary endpoints include adverse events, fasting blood glucose, glycated haemoglobin, lipids and other biomarkers. Adverse events are monitored through self-complete questionnaire and clinical visits. Outcomes will be analysed by regression models. Subgroup and sensitivity analyses will be conducted for different epidemiological subgroups and statistical analyses. Enrolment started in July 2018. ETHICS AND DISSEMINATION: This study was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West/East/Kowloon Central clusters (UW 16-553/HKEC-2019-026/REC (KC/KE)-19-0049/ER-4). We will report the findings in medical journals and conferences. The dataset will be available on reasonable request. TRIAL REGISTRATION NUMBER: NCT03535935.

Patients' and clinicians' expectations on integrative medicine Services for Diabetes: a focus group study.

BACKGROUND: Difference of perspective between patients and physicians over integrative medicine (IM) research and service provision remains unclear despite significant use worldwide. We observed an exceptionally low utilisation of IM and potential underreporting in diabetes. We aimed to explore the barriers and recommendations regarding service delivery and research of IM service among diabetes patients and physicians. METHODS: A 10-group, 50-participant semi-structured focus group interview series was conducted. Twenty-one patients with diverse severity of disease, comorbidities and education levels; and 29 physicians (14 conventional medicine (ConM) and 15 Chinese medicine (CM)) with diverse clinical experience, academic background and affiliation were purposively sampled from private and public clinics. Their perspectives were qualitatively analysed by constant comparative method. RESULTS: Seven subthemes regarding barriers towards IM service were identified including finance, service access, advice from medical professionals, uncertainty of service quality, uncertainty of CM effect, difficulty in understanding CM epistemology and access to medical records. Patients underreported the use of CM due to the concern over neutrality of medical advice among physicians. Inconvenience of service access, frequent follow-up, use of decoction and long-term financial burden were identified as key obstacles among patients. Regarding research design, ConM physicians emphasised standardisation and reproducibility while CM physicians emphasised personalisation. Some CM-related outcome measurements were suggested as non-communicable. Both physicians acknowledged the discordance in epistemology should be addressed by pragmatic approach. CONCLUSION: Key obstacles of CAM clinical utilisation are different between patients. Further assessment on IM should be pragmatic to balance between standardisation, reproducibility and real-world practice. Evidence-based IM programs and research should merge with existing infrastructure.

Non-medical prescription stimulant use to improve academic performance among Australian university students: prevalence and correlates of use.

BACKGROUND: Some university students consume pharmaceutical stimulants without a medical prescription with the goal of improving their academic performance. The prevalence of this practice has been well documented in the US, but less so in other countries. The potential harms of using prescription stimulants require a better understanding of the prevalence of this practice within Australian universities. METHODS: An internet survey of 1136 Australian students was conducted in 2015 in three large Australian universities. Students were asked about their personal use of prescription stimulants, attitudes and experiences with prescription stimulants. They were also asked about their use of caffeine, energy drinks and illicit drugs to enhance their academic performance. RESULTS: Lifetime self-reported use of stimulant medication to improve academic performance was 6.5, and 4.4% in the past year. Students were far more likely to report using coffee and energy drinks (41.4 and 23.6% respectively, lifetime use) than prescription stimulants to help them study and complete university assessments. Non-medical use of prescription stimulants was strongly associated with a history of illicit drug use. CONCLUSION: The prevalence of nonmedical prescription stimulant use to improve academic performance is low among university students in Australia, especially when compared with their use of coffee and energy drinks.

Effect of cannabis use in people with chronic non-cancer pain prescribed opioids: findings from a 4-year prospective cohort study.

BACKGROUND: Interest in the use of cannabis and cannabinoids to treat chronic non-cancer pain is increasing, because of their potential to reduce opioid dose requirements. We aimed to investigate cannabis use in people living with chronic non-cancer pain who had been prescribed opioids, including their reasons for use and perceived effectiveness of cannabis; associations between amount of cannabis use and pain, mental health, and opioid use; the effect of cannabis use on pain severity and interference over time; and potential opioid-sparing effects of cannabis. METHODS: The Pain and Opioids IN Treatment study is a prospective, national, observational cohort of people with chronic non-cancer pain prescribed opioids. Participants were recruited through community pharmacies across Australia, completed baseline interviews, and were followed up with phone interviews or self-complete questionnaires yearly for 4 years. Recruitment took place from August 13, 2012, to April 8, 2014. Participants were asked about lifetime and past year chronic pain conditions, duration of chronic non-cancer pain, pain self-efficacy, whether pain was neuropathic, lifetime and past 12-month cannabis use, number of days cannabis was used in the past month, and current depression and generalised anxiety disorder. We also estimated daily oral morphine equivalent doses of opioids. We used logistic regression to investigate cross-sectional associations with frequency of cannabis use, and lagged mixed-effects models to examine temporal associations between cannabis use and outcomes. FINDINGS: 1514 participants completed the baseline interview and were included in the study from Aug 20, 2012, to April 14, 2014. Cannabis use was common, and by 4-year follow-up, 295 (24%) participants had used cannabis for pain. Interest in using cannabis for pain increased from 364 (33%) participants (at baseline) to 723 (60%) participants (at 4 years). At 4-year follow-up, compared with people with no cannabis use, we found that participants who used cannabis had a greater pain severity score (risk ratio 1·14, 95% CI 1·01-1·29, for less frequent cannabis use; and 1·17, 1·03-1·32, for daily or near-daily cannabis use), greater pain interference score (1·21, 1·09-1·35; and 1·14, 1·03-1·26), lower pain self-efficacy scores (0·97, 0·96-1·00; and 0·98, 0·96-1·00), and greater generalised anxiety disorder severity scores (1·07, 1·03-1·12; and 1·10, 1·06-1·15). We found no evidence of a temporal relationship between cannabis use and pain severity or pain interference, and no evidence that cannabis use reduced prescribed opioid use or increased rates of opioid discontinuation. INTERPRETATION: Cannabis use was common in people with chronic non-cancer pain who had been prescribed opioids, but we found no evidence that cannabis use improved patient outcomes. People who used cannabis had greater pain and lower self-efficacy in managing pain, and there was no evidence that cannabis use reduced pain severity or interference or exerted an opioid-sparing effect. As cannabis use for medicinal purposes increases globally, it is important that large well designed clinical trials, which include people with complex comorbidities, are conducted to determine the efficacy of cannabis for chronic non-cancer pain. FUNDING: National Health and Medical Research Council and the Australian Government.

Semi-individualised Chinese medicine treatment as an adjuvant management for diabetic nephropathy: a pilot add-on, randomised, controlled, multicentre, open-label pragmatic clinical trial.

INTRODUCTION: Diabetes mellitus and diabetic nephropathy (DN) are prevalent and costly to manage. DN is the leading cause of end-stage kidney disease. Conventional therapy blocking the renin-angiotensin system has only achieved limited effect in preserving renal function. Recent observational data show that the use of Chinese medicine (CM), a major form of traditional medicine used extensively in Asia, could reduce the risk of end-stage kidney disease. However, existing clinical practice guidelines are weakly evidence-based and the effect of CM remains unclear. This trial explores the effect of an existing integrative Chinese-Western medicine protocol for the management of DN. OBJECTIVE: To optimise parameters and assess the feasibility for a subsequent phase III randomised controlled trial through preliminary evaluation on the effect of an adjuvant semi-individualised CM treatment protocol on patients with type 2 diabetes with stages 2-3 chronic kidney disease and macroalbuminuria. METHODS AND ANALYSIS: This is an assessor-blind, add-on, randomised, controlled, parallel, multicentre, open-label pilot pragmatic clinical trial. 148 patients diagnosed with DN will be recruited and randomised 1:1 to a 48-week additional semi-individualised CM treatment programme or standard medical care. Primary end points are the changes in estimated glomerular filtration rate and spot urine albumin-to-creatinine ratio between baseline and treatment end point. Secondary end points include fasting blood glucose, glycated haemoglobin, brain natriuretic peptide, fasting insulin, C peptide, fibroblast growth factor 23, urinary monocyte chemotactic protein-1, cystatin C, nephrin, transforming growth factor-ß1 and vascular endothelial growth factor. Adverse events are monitored through self-completed questionnaire and clinical visits. Outcomes will be analysed by regression models. Enrolment started in July 2015. ETHICS AND REGISTRATION: This protocol is approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (reference number UW 14-301). TRIAL REGISTRATION NUMBER: NCT02488252.

Differences in polysubstance use patterns and drug-related outcomes between people who inject drugs receiving and not receiving opioid substitution therapies.

AIMS: To test if polysubstance use profiles and drug-related outcomes differ between those receiving and not receiving opioid substitution therapies (OST) among people who inject drugs (PWID). DESIGN: An annual cross-sectional, sentinel sample of PWID across Australia. SETTING: Data came from 3 years (2011-13) of the Illicit Drug Reporting System (IDRS). PARTICIPANTS: A total of 2673 participants who injected drugs from the combined national IDRS samples of 2011 (n = 868), 2012 (n = 922) and 2013 (n = 883). MEASUREMENTS: Latent class analysis (LCA) was used to summarize participants' self-reported use of 18 types of substances, with the resulting polysubstance use profiles then associated with participant experience of a number of drug-related outcomes. FINDINGS: Polysubstance use profiles exhibiting a broad range of substance use were generally at increased risk of negative drug-related outcomes, whether or not participants were receiving OST, including thrombosis among OST receivers [odds ratio (OR) = 2.13, 95% confidence intervals (CI) = 1.09-4.17], injecting with used needles among OST receivers and non-receivers, respectively (OR = 2.78, 95% CI = 1.50-5.13; OR = 2.15, 95% CI = 1.34-3.45) and violent criminal offences among OST receivers and non-receivers, respectively (OR =2.30, 95% CI = 1.16-4.58; OR = 1.87, 95% CI = 1.14-3.07). An important exception was non-fatal overdose which was related specifically to a class of PWID who were not receiving OST and used morphine frequently (OR = 1.83, 95% CI = 1.06-3.17) CONCLUSION: Regardless of opioid substitution therapies usage, people who inject drugs who use a broad-range of substances experience greater levels of injecting-related injuries and poorer health outcomes and are more likely to engage in criminal activity than other groups of people who inject drugs.

Selective peptide inhibitors of antiapoptotic cellular and viral Bcl-2 proteins lead to cytochrome c release during latent Kaposi's sarcoma-associated herpesvirus infection.

Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with B-cell lymphomas including primary effusion lymphoma and multicentric Castleman's disease. KSHV establishes latency within B cells by modulating or mimicking the antiapoptotic Bcl-2 family of proteins to promote cell survival. Our previous BH3 profiling analysis, a functional assay that assesses the contribution of Bcl-2 proteins towards cellular survival, identified two Bcl-2 proteins, cellular Mcl-1 and viral KsBcl-2, as potential regulators of mitochondria polarization within a latently infected B-cell line, Bcbl-1. In this study, we used two novel peptide inhibitors identified in a peptide library screen that selectively bind KsBcl-2 (KL6-7_Y4eK) or KsBcl-2 and Mcl-1 (MS1) in order to decipher the relative contribution of Mcl-1 and KsBcl-2 in maintaining mitochondrial membrane potential. We found treatment with KL6-7_Y4eK and MS1 stimulated a similar amount of cytochrome c release from mitochondria isolated from Bcbl-1 cells, indicating that inhibition of KsBcl-2 alone is sufficient for mitochondrial outer membrane permiabilzation (MOMP) and thus apoptosis during a latent B cell infection. In turn, this study also identified and provides a proof-of-concept for the further development of novel KsBcl-2 inhibitors for the treatment of KSHV-associated B-cell lymphomas via the targeting of latently infected B cells.

Growth and Tolerance of Preterm Infants Fed a New Extensively Hydrolyzed Liquid Human Milk Fortifier.

OBJECTIVES: This study was a comparison of growth and tolerance in premature infants fed either standard powdered human milk fortifier (HMF) or a newly formulated concentrated liquid that contained extensively hydrolyzed protein. METHODS: This was an unblinded randomized controlled multicenter noninferiority study on preterm infants receiving human milk (HM) supplemented with 2 randomly assigned HMFs, either concentrated liquid HMF containing extensively hydrolyzed protein (LE-HMF) or a powdered intact protein HMF (PI-HMF) as the control. The study population consisted of preterm infants ≤33 weeks who were enterally fed HM. Infants were studied from the first day of HM fortification until day 29 or hospital discharge, whichever came first. RESULTS: A total of 147 preterm infants were enrolled. Noninferiority was observed in weight gain reported in the intent-to-treat (ITT) analysis was 18.2 and 17.5 g · kg(-1) · day(-1) for the LE-HMF and PI-HMF groups, respectively. In an a priori defined subgroup of strict protocol followers (n = 75), the infants fed LE-HMF achieved greater weight over time than those fed PI-HMF (P = 0.036). The LE-HMF group achieved greater linear growth over time compared to the PI-HMF (P = 0.029). The protein intake from fortified HM was significantly higher in the LE-HMF group compared with the PI-HMF group (3.9 vs 3.3 g · kg(-1) · day(-1), P < 0.0001). Both fortifiers were well tolerated with no significant differences in overall morbidity. CONCLUSIONS: Both fortifiers showed excellent weight gain (grams per kilograms per day), tolerance, and low incidence of morbidity outcomes with the infants who were strict protocol followers fed LE-HMF having improved growth during the study. These data point to the safety and suitability of this new concentrated liquid HMF (LE-HMF) in preterm infants. Growth with this fortifier closely matches the recent recommendations for a weight gain of >18 g · kg(-1) · day(-1).

Polysubstance use in cannabis users referred for treatment: drug use profiles, psychiatric comorbidity and cannabis-related beliefs.

BACKGROUND: Population-based surveys demonstrate cannabis users are more likely to use both illicit and licit substances, compared with non-cannabis users. Few studies have examined the substance use profiles of cannabis users referred for treatment. Co-existing mental health symptoms and underlying cannabis-related beliefs associated with these profiles remains unexplored. METHODS: Comprehensive drug use and dependence severity (Severity of Dependence Scale-Cannabis) data were collected on a sample of 826 cannabis users referred for treatment. Patients completed the General Health Questionnaire, Cannabis Expectancy Questionnaire, Cannabis Refusal Self-Efficacy Questionnaire, and Positive Symptoms and Manic-Excitement subscales of the Brief Psychiatric Rating Scale. Latent class analysis was performed on last month use of drugs to identify patterns of multiple drug use. Mental health comorbidity and cannabis beliefs were examined by identified drug use pattern. RESULTS: A three-class solution provided the best fit to the data: (1) cannabis and tobacco users (n = 176), (2) cannabis, tobacco, and alcohol users (n = 498), and (3) wide-ranging substance users (n = 132). Wide-ranging substance users (3) reported higher levels of cannabis dependence severity, negative cannabis expectancies, lower opportunistic, and emotional relief self-efficacy, higher levels of depression and anxiety and higher manic-excitement and positive psychotic symptoms. CONCLUSION: In a sample of cannabis users referred for treatment, wide-ranging substance use was associated with elevated risk on measures of cannabis dependence, co-morbid psychopathology, and dysfunctional cannabis cognitions. These findings have implications for cognitive-behavioral assessment and treatment.

Interrelationships between maternal carotenoid status and newborn infant macular pigment optical density and carotenoid status.

PURPOSE: Deposition of the macular pigment carotenoids lutein and zeaxanthin in the human retina occurs early in life. In this study, we examined the interrelationships of maternal carotenoid status and newborn infant macular pigment levels and systemic carotenoid status. As a secondary measure, we also evaluated the effects of intrauterine growth restriction (IUGR) on carotenoid status in term newborn infants. METHODS: We measured mother and infant skin carotenoids using resonance Raman spectroscopy (RRS), serum carotenoids by HPLC, and mother breast milk carotenoids by HPLC. We measured infant macular pigment levels using noninvasive blue light reflectometry. RESULTS: We enrolled 30 healthy term infants, their mothers, and 10 IUGR infants and their mothers. A subset of 16 infants was imaged for macular pigment optical density (MPOD). Infant serum zeaxanthin levels correlated with MPOD (r = 0.68, P = 0.007). Mother serum zeaxanthin levels correlated with infant MPOD (r = 0.59, P = 0.032). Infant and mother serum lutein did not correlate with MPOD. Mother-infant correlations were found for total serum carotenoids (r = 0.42, P = 0.020) and skin carotenoids (r = 0.48, P = 0.001). No difference was seen between IUGR infants and controls in total serum or skin carotenoids. Mothers of IUGR infants had lower total serum carotenoids (P = 0.019) and breast milk carotenoids than controls (P = 0.006). CONCLUSIONS: Our findings suggest that maternal zeaxanthin status may play a more important role than lutein status in macular pigment deposition in utero. Controlled trials are needed to determine whether maternal zeaxanthin prenatal supplementation can raise infant macular pigment levels and/or improve ocular function.

Resonance Raman spectroscopy and the preterm infant carotenoid status.

OBJECTIVE: The aim of the study was to validate the noninvasive resonance Raman spectroscopy (RRS) method in infants in comparison with the high-performance liquid chromatography (HPLC) method, and to evaluate the carotenoid status in preterm infants fed with mother's milk or formula. METHODS: In the first phase of the study, resonance Raman measurements were made on male term infants' skin and correlated with tissue harvested at the time of circumcision. Each baby's foreskin was weighed, enzymatically digested, and the total carotenoids were extracted and quantitated by the HPLC. Next, to evaluate the carotenoid status of preterm infants (BW <1500 g), the skin and serum carotenoids in infants fed with either human milk or preterm formula were studied from the start of feedings and every 2 weeks until hospital discharge. Skin carotenoids were measured by RRS and the serum total carotenoids by HPLC. RESULTS: Foreskin carotenoid levels measured by RRS correlated with HPLC measurements of total serum carotenoids (R = 0.52, P < 0.01, n = 16). Forty preterm infants were studied for their carotenoid status. Thirty-two infants were fed mother's milk, whereas 8 were fed a preterm infant formula that was not enriched with carotenoids. The gestation and birth weight of the 2 feeding groups were similar. The infants fed human milk had a higher serum total carotenoid concentration and skin Raman counts than formula-fed infants. The skin Raman counts and total serum carotenoid correlated (R = 0.44, P = 0.01). The human milk-fed infants' serum total carotenoid concentrations and Raman values did not change during the study period; however, the formula-fed group's total serum and skin carotenoid decreased significantly during the study. CONCLUSIONS: RRS of infant's skin reliably assesses total carotenoid status noninvasively. Human milk-fed preterm infants have higher serum and skin carotenoids than formula-fed infants suggesting that formula-fed infants may benefit from carotenoid supplementation.

Nutritional therapy for burns in children and adults.

Burns are a serious injury that requires optimal nutritional support. This review discusses the nutritional care for adults and children with major burns. A burned patient's metabolism is greatly accelerated with increased requirements for energy, carbohydrates, proteins, fats, vitamins, minerals, and antioxidants. Early nutrition by parenteral and enteral feedings is vital. Careful assessment of the nutritional state of the burn patient is also important to reduce infection, recovery time, and long-term sequelae.