Biodistribution of a Mitochondrial Metabolic Tracer, [18F]F-AraG, in Healthy Volunteers.

Purpose: [18F]F-AraG is a radiolabeled nucleoside analog that shows relative specificity for activated T cells. The aim of this study was to investigate the biodistribution of [18F]F-AraG in healthy volunteers and assess the preliminary safety and radiation dosimetry. Methods: Six healthy subjects (three female and three male) between the ages of 24 and 60 participated in the study. Each subject received a bolus venous injection of [18F]F-AraG (dose range: 244.2-329.3 MBq) prior to four consecutive PET/MR whole-body scans. Blood samples were collected at regular intervals and vital signs monitored before and after tracer administration. Regions of interest were delineated for multiple organs, and the area under the time-activity curves was calculated for each organ and used to derive time-integrated activity coefficient (TIAC). TIACs were input for absorbed dose and effective dose calculations using OLINDA. Results: PET/MR examination was well tolerated, and no adverse effects to the administration of [18F]F-AraG were noted by the study participants. The biodistribution was generally reflective of the expression and activity profiles of the enzymes involved in [18F]F-AraG's cellular accumulation, mitochondrial kinase dGK, and SAMHD1. The highest uptake was observed in the kidneys and liver, while the brain, lung, bone marrow, and muscle showed low tracer uptake. The estimated effective dose for [18F]F-AraG was 0.0162 mSv/MBq (0.0167 mSv/MBq for females and 0.0157 mSv/MBq for males). Conclusion: Biodistribution of [18F]F-AraG in healthy volunteers was consistent with its association with mitochondrial metabolism. PET/MR [18F]F-AraG imaging was well tolerated, with a radiation dosimetry profile similar to other commonly used [18F]-labeled tracers. [18F]F-AraG's connection with mitochondrial biogenesis and favorable biodistribution characteristics make it an attractive tracer with a variety of potential applications.

Patient and clinician perspectives of factors that influence the delivery of alcohol brief interventions in Australian primary care: a qualitative descriptive study.

BACKGROUND: Brief interventions (BIs) delivered in primary care can reduce harmful alcohol consumption. Yet, clinicians do not routinely offer BIs to reduce harmful alcohol use. OBJECTIVE: We explored the perspectives of clinicians and patients about the use of alcohol BIs during consultations in Australian primary care. METHODS: Semi-structured interviews and focus groups (face-to-face and virtual) were undertaken with 34 general practitioners, eight practice nurses and 17 patients. Field notes were made from audio-recordings and themes were identified using a descriptive qualitative approach with the field notes as the point of data analysis. RESULTS: Participants identified barriers within the consultation, practice setting and wider healthcare system plus across the community which reduce the delivery of BIs in primary care including: Australian drinking norms; inconsistent public health messaging around alcohol harm; primary care not recognized as a place to go for help; community stigma towards alcohol use; practice team culture towards preventive health, including systems for recording alcohol histories; limitations of clinical software and current patient resources. CONCLUSION: Multiple layers of the healthcare system influence the use of BIs in primary care. Identified facilitators for embedding BIs in primary care included: (i) raising community and clinician awareness of the health harms of alcohol, (ii) reinforcing a primary care culture that promotes prevention and, (iii) supportive resources to facilitate discussion about alcohol use and strategies to reduce intake. Alcohol BIs in primary care could be further supported by community public health messages about alcohol use.

Alcohol is a major source of harm in the community and primary care (including family doctor and general practice settings) can play a role in reducing harmful alcohol use. When clinicians talk to their patients about alcohol use, research has shown they can reduce how much they drink each week. We spoke with general practitioners, nurses and patients in Australia to work out what is getting in the way of conversations about alcohol in primary care. We found that both clinicians and patients think we need to raise community awareness about the health harms of alcohol, that there are health system barriers, and there could be better resources to use in consultations. Low-income patients are particularly disadvantaged by financial costs associated with alcohol and counselling services when they seek help. To increase conversations about alcohol in primary care, it could be more helpful to target the broader community, the health system and primary care.

Safety first: Beliefs of older peers supplying alcohol to underage friends.

ISSUE ADDRESSED: Underage drinkers most commonly source alcohol from older peers. However, few studies have examined older peers' supply-related beliefs and motivations. METHODS: A sample of 270 risky drinkers aged 18-19 years were interviewed in Australia where the legal purchase age is 18. They were asked about their provision to underage friends, awareness of secondary supply legislation (intended to prohibit such supply) and 24 psycho-legal beliefs around supply. RESULTS: Half (49%) provided alcohol to a 16- to 17-year-old friend to drink at a party they were both attending at least twice a year. Three-quarters reported provision was okay so long as the recipient(s) were in a safe environment, and 46% reported "everyone gives alcohol to teenagers if they are in a safe environment." There was significantly higher agreement that "my friends would think I was mean if I did not give alcohol to a friend under the age of 18" (37%), compared to "my friends would think I was uncool if I did not give alcohol to a friend under the age of 18" (26%). Two thirds (69%) felt more responsible for an underage friend's safety if they provided the alcohol. A multivariate logistic regression revealed supply was more likely if the supplier: was aged 18 compared to 19 (95% CI OR: 1.57, 4.84), male (1.06, 3.27), of a higher SES quintile (1.08, 1.80) and believed alcohol supply to minors was morally acceptable (1.01, 1.33) and normal (1.04, 1.38). Knowledge of regulatory strategies (68%) designed to prevent supply to minors, and their perceived deterrent value did not significantly impact supply. CONCLUSIONS: Supply of alcohol to underage peers was perceived as morally and socially acceptable in a group of 18- to 19-year-old risky drinkers. SO WHAT?: Opportunities include harm reduction initiatives that prioritise caring responsibilities towards friends, as opposed to relying on external enforcement measures alone.

Frequency and Distribution of Chest Radiographic Findings in Patients Positive for COVID-19.

Background Current coronavirus disease 2019 (COVID-19) radiologic literature is dominated by CT, and a detailed description of chest radiography appearances in relation to the disease time course is lacking. Purpose To describe the time course and severity of findings of COVID-19 at chest radiography and correlate these with real-time reverse transcription polymerase chain reaction (RT-PCR) testing for severe acute respiratory syndrome coronavirus 2, or SARS-CoV-2, nucleic acid. Materials and Methods This is a retrospective study of patients with COVID-19 confirmed by using RT-PCR and chest radiographic examinations who were admitted across four hospitals and evaluated between January and March 2020. Baseline and serial chest radiographs (n = 255) were reviewed with RT-PCR. Correlation with concurrent CT examinations (n = 28) was performed when available. Two radiologists scored each chest radiograph in consensus for consolidation, ground-glass opacity, location, and pleural fluid. A severity index was determined for each lung. The lung scores were summed to produce the final severity score. Results The study was composed of 64 patients (26 men; mean age, 56 years ± 19 [standard deviation]). Of these, 58 patients had initial positive findings with RT-PCR (91%; 95% confidence interval: 81%, 96%), 44 patients had abnormal findings at baseline chest radiography (69%; 95% confidence interval: 56%, 80%), and 38 patients had initial positive findings with RT-PCR testing and abnormal findings at baseline chest radiography (59%; 95% confidence interval: 46%, 71%). Six patients (9%) showed abnormalities at chest radiography before eventually testing positive for COVID-19 with RT-PCR. Sensitivity of initial RT-PCR (91%; 95% confidence interval: 83%, 97%) was higher than that of baseline chest radiography (69%; 95% confidence interval: 56%, 80%) (P = .009). Radiographic recovery (mean, 6 days ± 5) and virologic recovery (mean, 8 days ± 6) were not significantly different (P = .33). Consolidation was the most common finding (30 of 64; 47%) followed by ground-glass opacities (21 of 64; 33%). Abnormalities at chest radiography had a peripheral distribution (26 of 64; 41%) and lower zone distribution (32 of 64; 50%) with bilateral involvement (32 of 64; 50%). Pleural effusion was uncommon (two of 64; 3%). The severity of findings at chest radiography peaked at 10-12 days from the date of symptom onset. Conclusion Findings at chest radiography in patients with coronavirus disease 2019 frequently showed bilateral lower zone consolidation, which peaked at 10-12 days from symptom onset. © RSNA, 2020.

Community pharmacy naloxone supply, before and after rescheduling as an over-the-counter drug: sales and prescriptions data, 2014-2018.

OBJECTIVES: To characterise the community pharmacy supply of naloxone by supply type - individual prescription, prescriber bag, and non-dispensed (supplied over the counter or expired) - during 2014-2018; to examine whether the 2016 rescheduling of naloxone as an over-the-counter drug influenced non-dispensed naloxone supply volume. DESIGN, SETTING: Analysis of monthly naloxone prescriptions (Pharmaceutical Benefits Scheme) and sales data (IQVIA), 2014-2018, for Australia and by state and territory; time series analysis of non-dispensed naloxone supply to assess effect of rescheduling on naloxone supply. MAJOR OUTCOMES: Total naloxone supply to community pharmacies; prescribed and non-dispensed naloxone supply. RESULTS: During 2014-2018, 372 351 400 µg units of naloxone were sold to community pharmacies: non-dispensed naloxone accounted for 205 866.5 units (55.3%), prescriber bags for 155 841 units (41.8%), and individual prescriptions for 10 643.5 units (2.9%). Population-adjusted national naloxone sales to community pharmacies increased between 2014 and 2018 (per year: incidence rate ratio [IRR], 1.15; 95% CI, 1.09-2.22). This increase was primarily attributable to increased volumes of prescriber bag naloxone (IRR, 1.63; 95% CI, 1.50-1.78) and, to a lesser extent, increased individual prescription supply (IRR, 2.04; 95% CI, 1.85-2.26). Non-dispensed naloxone supply volume was unchanged at the national level (IRR, 0.93; 95% CI, 0.85-1.01); changes in non-dispensed supply immediately following rescheduling and subsequently were not statistically significant in time series analyses for most jurisdictions. CONCLUSIONS: Total naloxone supply to community pharmacies in Australia increased between 2014 and 2018, but rescheduling that enabled over-the-counter access did not significantly influence the volume of non-dispensed naloxone.

Alcohol supply as a favour for a friend: Scenarios of alcohol supply to younger friends and siblings.

ISSUES ADDRESSED: Adolescents under the legal purchase age primarily source their alcohol through social networks. This study assessed the provision context from the perspective of both underage recipients and their suppliers who were older peers and siblings. METHODS: Interviewer-administered surveys were conducted with 590 risky-drinking (50 g alcohol per session, at least monthly) adolescents. Participants of legal purchase age (18- to 19-year-olds; n = 269) reported their provision to 16- to 17-year-olds under eight scenarios. Those aged 14-17 (n = 321) reported receipt of alcohol under the same scenarios plus two parental supply contexts. RESULTS: Purchase-age participants reported supply: to an underage friend (67%), an acquaintance (44%) or a sibling (16%) to drink at the same party; to a friend (43%) or sibling (20%) to take to another party (20%) and to a stranger near a bottle shop (5%). Supply to a friend at the same party was more likely if money was exchanged (60% vs 40%; P < 0.001). Almost all (98%) 14- to 17-year-olds reported receiving alcohol from an adult (including 36% from a parent for consumption away from the parent), with a similar pattern of receipt scenarios as those reported by the 18- to 19-year-olds. CONCLUSIONS: Provision of alcohol was more frequent with a friend than a sibling or stranger, in close environmental proximity, and if money was exchanged. SO WHAT?: As supply may be sensitive to monetary considerations, the incidence of underage receipt may be affected by community-wide pricing measures. Traditional alcohol availability regulations should be supplemented by strategies relating to the social nature of supply and demand.

Efficacy and safety of ultrasound-guided high-intensity focused ultrasound for uterine fibroids: a preliminary experience.

The objective of this prospective cohort study was to evaluate the therapeutic efficacy and safety of ultrasound-guided high-intensity focussed ultrasound (HIFU) in the treatment of uterine fibroids. Twenty premenopausal women with symptomatic fibroids underwent ultrasound-guided HIFU therapy. Twenty-two fibroids with a median baseline volume of 127.0 cm3 (range 18.5-481.2 cm3) were treated. The percentages fibroid volume reduction were 46.9 (range -8.8-73.1) at 1-month, 57.4 (-51.5-95.2) at 3-month, 60.1 (-18.9-97.8) at 6-month and 75.9 (-33.7-99.3) at 12-month, after treatment. The modified Uterine Fibroid Symptom and Quality of Life (UFS-QOL) scores were reduced by 40.7% (0-59.3%) at 3-month, 45.5% (0-70.4%) at 6-month and 44.9% (0-71.4%) at 12-month after treatment. Three patients required subsequent surgical interventions. No significant complications were encountered. Ultrasound-guided HIFU appears to be effective and safe for the treatment of symptomatic uterine fibroids in selected patients. Impact statement What is already known on this subject? Ultrasound-guided high-intensity focussed ultrasound (HIFU) is a relatively new uterine-sparing treatment for fibroids. Most clinical reports are from China, which suggest that this treatment is a safe and effective modality. However, in many other countries, HIFU treatment for fibroids, especially using ultrasound as image guidance, is still considered novel with limited clinical experience. What do the results of this study add? This preliminary report adds to our limited local experience on HIFU and provides reassurance on our continual utilisation of this treatment modality for fibroids. With the increasing demand of uterine-sparing alternatives, experiences shared among different countries are important to make this treatment modality generalisable and universally acceptable. What are the implications of these findings for clinical practice and/or further research?Ultrasound-guided HIFU (USgHIFU) can potential be offered as an alternative treatment modality for women with fibroids.

Alcohol marketing on YouTube: exploratory analysis of content adaptation to enhance user engagement in different national contexts.

BACKGROUND: We know little about how social media alcohol marketing is utilized for alcohol promotion in different national contexts. There does not appear to be any academic work on online exposure to alcohol marketing via social media in India, and most of the limited research in Australia has focused on Facebook. Hence, the present study extends previous research by investigating alcohol promotion conducted on an under-researched form of social media (YouTube) in two contrasting geographic contexts. This study examines and compares the types of strategies used by marketers on Indian and Australian alcohol brands with the greatest YouTube presence, and the extent to which users engage with these strategies. METHODS: The 10 alcohol brands per country with the greatest YouTube presence were identified based on the number of 'subscriptions'. The number of videos, views per video, and the type of content within the videos were collected for each brand. The data were analyzed using an inductive coding approach, using NVivo 10. RESULTS: The targeted brands had gathered 98,881 subscriptions (Indian brands: n = 13,868; Australian brands: n = 85,013). The type of marketing strategies utilized by brands were a mix of those that differed by country (e.g. sexually suggestive content in India and posts related to the brand's tradition or heritage in Australia) and generic approaches (e.g. encouraging time- and event-specific drinking; demonstrations of food/cocktail recipes; camaraderie; competitions and prize draws; and brand sponsorship at music, sports, and fashion events). CONCLUSIONS: This cross-national comparison demonstrates that YouTube provides alcohol marketers with an advertising platform where they utilize tailored marketing approaches to cater to specific national contexts and develop content on the cultural meanings users invoke in their interactions with these strategies. Those exposed to alcohol marketing on YouTube are likely to include those under the legal drinking age.

The association between exposure to social media alcohol marketing and youth alcohol use behaviors in India and Australia.

BACKGROUND: Alcohol marketing on social networking sites (SNS) is associated with alcohol use among young people. Alcohol companies adapt their online marketing content to specific national contexts and responses to such content differ by national settings. However, there exists very little academic work comparing the association between alcohol marketing on SNS and alcohol use among young people in different national settings and across different SNS. Therefore, we aimed to extend the limited existing work by investigating and comparing the association between self-reported exposure to alcohol marketing on three leading SNS (Facebook, YouTube, and Twitter) and alcohol use among young people in diverse national contexts (India and Australia). METHODS: Cross-sectional, self-report data were obtained from a convenience sample of 631 respondents (330 in India; 301 in Australia) aged 13-25 years via online surveys. Respondents answered questions on their drinking behaviors and involvement with alcohol marketing on SNS. RESULTS: Many respondents from both countries reported interacting with alcohol content online, predominantly on Facebook, followed by YouTube and then Twitter. The interaction was primarily in the forms of posting/liking/sharing/commenting on items posted on alcohol companies' social media accounts, viewing the event page/attending the event advertised by an alcohol company via social media, and/or accessing an alcohol website. Multivariate analyses demonstrated significant associations between respondents' interaction with alcohol content and drinking levels, with effects differing by SNS, demographic group, and country. For example, having friends who shared alcohol-related content was an important predictor of usual alcohol consumption for Indian respondents (p < .001), whereas posting alcohol-related information themselves was a stronger predictor among Australians (p < .001). CONCLUSIONS: The results suggest that interaction with alcohol-related content on SNS is associated with young people's alcohol use behaviors and that these behaviors vary by national settings. This study extends previous work by demonstrating this connection across varying social media platforms and national contexts. The results highlight the need to formulate and implement strategies to effectively regulate the SNS alcohol marketing, especially among younger SNS users.

NSI-189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats.

Enhancing neurogenesis may be a powerful stroke therapy. Here, we tested in a rat model of ischemic stroke the beneficial effects of NSI-189, an orally active, new molecular entity (mol. wt. 366) with enhanced neurogenic activity, and indicated as an anti-depressant drug in a clinical trial (Fava et al., , Molecular Psychiatry, DOI: 10.1038/mp.2015.178) and being tested in a Phase 2 efficacy trial (ClinicalTrials.gov, , ClinicalTrials.gov Identifier: NCT02695472) for treatment of major depression. Oral administration of NSI-189 in adult Sprague-Dawley rats starting at 6 hr after middle cerebral artery occlusion, and daily thereafter over the next 12 weeks resulted in significant amelioration of stroke-induced motor and neurological deficits, which was maintained up to 24 weeks post-stroke. Histopathological assessment of stroke brains from NSI-189-treated animals revealed significant increments in neurite outgrowth as evidenced by MAP2 immunoreactivity that was prominently detected in the hippocampus and partially in the cortex. These results suggest NSI-189 actively stimulated remodeling of the stroke brain. Parallel in vitro studies further probed this remodeling process and demonstrated that oxygen glucose deprivation and reperfusion (OGD/R) initiated typical cell death processes, which were reversed by NSI-189 treatment characterized by significant attenuation of OGD/R-mediated hippocampal cell death and increased Ki67 and MAP2 expression, coupled with upregulation of neurogenic factors such as BDNF and SCF. These findings support the use of oral NSI-189 as a therapeutic agent well beyond the initial 6-hr time window to accelerate and enhance the overall functional improvement in the initial 6 months post stroke.

Magnetic resonance fingerprinting based on realistic vasculature in mice.

Magnetic resonance fingerprinting (MRF) was recently proposed as a novel strategy for MR data acquisition and analysis. A variant of MRF called vascular MRF (vMRF) followed, that extracted maps of three parameters of physiological importance: cerebral oxygen saturation (SatO2), mean vessel radius and cerebral blood volume (CBV). However, this estimation was based on idealized 2-dimensional simulations of vascular networks using random cylinders and the empirical Bloch equations convolved with a diffusion kernel. Here we focus on studying the vascular MR fingerprint using real mouse angiograms and physiological values as the substrate for the MR simulations. The MR signal is calculated ab initio with a Monte Carlo approximation, by tracking the accumulated phase from a large number of protons diffusing within the angiogram. We first study the identifiability of parameters in simulations, showing that parameters are fully estimable at realistically high signal-to-noise ratios (SNR) when the same angiogram is used for dictionary generation and parameter estimation, but that large biases in the estimates persist when the angiograms are different. Despite these biases, simulations show that differences in parameters remain estimable. We then applied this methodology to data acquired using the GESFIDE sequence with SPIONs injected into 9 young wild type and 9 old atherosclerotic mice. Both the pre injection signal and the ratio of post-to-pre injection signals were modeled, using 5-dimensional dictionaries. The vMRF methodology extracted significant differences in SatO2, mean vessel radius and CBV between the two groups, consistent across brain regions and dictionaries. Further validation work is essential before vMRF can gain wider application.

In Vivo PET Imaging of the Activated Immune Environment in a Small Animal Model of Inflammatory Arthritis.

BACKGROUND: Evolving immune-mediated therapeutic strategies for rheumatoid arthritis (RA) may benefit from an improved understanding of the complex role that T-cell activation plays in RA. This study assessed the potential of fluorine-18-labeled 9-ß-d-arabinofuranosylguanine ([18F]F-AraG) positron emission tomography (PET) imaging to report immune activation in vivo in an adjuvant-induced arthritis (AIA) small animal model. METHODS: Using positron emission tomography-computed tomography imaging, uptake of [18F]F-AraG in the paws of mice affected by arthritis at 6 (acute) and 20 (chronic) days following AIA induction in a single paw was assessed and compared to uptake in contralateral control paws. Fractions of T cells and B cells demonstrating markers of activation at the 2 time points were determined by flow cytometry. RESULTS: Differential uptake of [18F]F-AraG was demonstrated on imaging of the affected joint when compared to control at both acute and chronic time points with corresponding changes in markers of T-cell activation observed on flow cytometry. CONCLUSION: [18F]F-AraG may serve as an imaging biomarker of T-cell activation in inflammatory arthritis. Further development of this technique is warranted and could offer a tool to explore the temporal link between activated T cells and RA as well as to monitor immune-mediated therapies for RA in clinical trials.

Substance use outcomes following treatment: Findings from the Australian Patient Pathways Study.

BACKGROUND AND AIMS: Our understanding of patient pathways through specialist Alcohol and Other Drug treatment and broader health/welfare systems in Australia remains limited. This study examines how treatment outcomes are influenced by continuity in specialist Alcohol and Other Drug treatment, engagement with community services and mutual aid, and explores differences between clients who present with a primary alcohol problem relative to those presenting with a primary drug issue. METHOD: In a prospective, multi-site treatment outcome study, 796 clients from 21 Alcohol and Other Drug services in Victoria and Western Australia completed a baseline interview between January 2012 and January 2013. A total of 555 (70%) completed a follow-up assessment of subsequent service use and Alcohol and Other Drug use outcomes 12-months later. RESULTS: Just over half of the participants (52.0%) showed reliable reductions in use of, or abstinence from, their primary drug of concern. This was highest among clients with meth/amphetamine (66%) as their primary drug of concern and lowest among clients with alcohol as their primary drug of concern (47%), with 31% achieving abstinence from all drugs of concern. Continuity of specialist Alcohol and Other Drug care was associated with higher rates of abstinence than fragmented Alcohol and Other Drug care. Different predictors of treatment success emerged for clients with a primary drug problem as compared to those with a primary alcohol problem; mutual aid attendance (odds ratio = 2.5) and community service engagement (odds ratio = 2.0) for clients with alcohol as the primary drug of concern, and completion of the index treatment (odds ratio = 2.8) and continuity in Alcohol and Other Drug care (odds ratio = 1.8) when drugs were the primary drugs of concern. CONCLUSION: This is the first multi-site Australian study to include treatment outcomes for alcohol and cannabis users, who represent 70% of treatment seekers in Alcohol and Other Drug services. Results suggest a substantial proportion of clients respond positively to treatment, but that clients with alcohol as their primary drug problem may require different treatment pathways, compared to those with illicit drug issues, to maximise outcomes.

Translocation of botulinum neurotoxin serotype A and associated proteins across the intestinal epithelia.

Botulinum neurotoxins (BoNTs) are some of the most poisonous natural toxins. Botulinum neurotoxins associate with neurotoxin-associated proteins (NAPs) forming large complexes that are protected from the harsh environment of the gastrointestinal tract. However, it is still unclear how BoNT complexes as large as 900 kDa traverse the epithelial barrier and what role NAPs play in toxin translocation. In this study, we examined the transit of BoNT serotype A (BoNT/A) holotoxin, complex and recombinantly purified NAP complex through cultured and polarized Caco-2 cells and, for the first time, in the small mouse intestine. Botulinum neurotoxin serotype A and NAPs in the toxin complex were detectable inside intestinal cells beginning at 2 h post intoxication. Appearance of the BoNT/A holotoxin signal was slower, with detection starting at 4-6 h. This indicated that the holotoxin alone was sufficient for entry but the presence of NAPs enhanced the rate of entry. Botulinum neurotoxin serotype A detection peaked at approximately 6 and 8 h for complex and holotoxin, respectively, and thereafter began to disperse with some toxin remaining in the epithelia after 24 h. Purified HA complexes alone were also internalized and followed a similar time course to that of BoNT/A complex internalization. However, recombinant HA complexes did not enhance BoNT/A holotoxin entry in the absence of a physical link with BoNT/A. We propose a model for BoNT/A toxin complex translocation whereby toxin complex entry is facilitated by NAPs in a receptor-mediated mechanism. Understanding the intestinal uptake of BoNT complexes will aid the development of new measures to prevent or treat oral intoxications.

Surface engineering of SPIONs: role of phosphonate ligand multivalency in tailoring their efficacy.

We report the design of scaffolds containing mono-, bis-, and tris-phosphonate coordinating groups, and a polyethylene glycol chain, for stabilizing superparamagnetic iron oxide nanoparticles (SPIONs), using simple and versatile chemistry. We demonstrate that the number of anchoring phosphonate sites on the ligand influence the colloidal stability, magnetic and biological properties of SPIONs, and the latter do not solely depend on attaching moieties that can enhance their aqueous dispersion. These parameters can be tailored by the number of conjugation sites on the ligand, as evidenced from dynamic light scattering at various salt concentrations, magnetic relaxivities and cell viability studies.

Characteristics of individuals presenting to treatment for primary alcohol problems versus other drug problems in the Australian patient pathways study.

BACKGROUND: People seeking treatment for substance use disorders often have additional health and social issues. Although individuals presenting with alcohol as the primary drug of concern (PDOC) account for nearly half of all treatment episodes to the Australian alcohol and other drug (AOD) service system, previous treatment cohort studies have focused only on the profile of Australian heroin or methamphetamine users. While studies overseas indicate that clients seeking treatment primarily for their drinking are less likely to experience social and economic marginalisation than those seeking treatment primarily for illicit or pharmaceutical drug use, very little research has directly compared individuals presenting with alcohol as the PDOC to those primarily presenting with other drugs as their PDOC. METHODS: Seven hundred and ninety-six participants were recruited at entry to specialist AOD treatment in Victoria and Western Australia, and completed measures of demographic and social factors, substance use, quality of life, service use, and criminal justice involvement. We compared those with alcohol as their PDOC to those with other drugs as their PDOC using Pearson chi-square and Mann-Whitney U tests. RESULTS: Rates of social disadvantage, poor quality of life, high severity of substance dependence, and past-year AOD, mental health, acute health, and social service use were high in all groups. However, participants with alcohol as the PDOC were older; more likely to have an educational qualification; less likely to report criminal justice involvement, housing/homelessness service use, tobacco smoking, or problems with multiple substances; and reported better environmental quality of life; but were more likely to have used ambulance services, than those with other drugs as their PDOC. CONCLUSIONS: While those seeking treatment primarily for alcohol problems appear less likely to suffer some forms of social and economic disadvantage or to use multiple substances than those with a primary drug problem, they experience similarly high levels of substance dependence severity and mental health and AOD service use. These findings reinforce the need for AOD services to integrate or coordinate care with programs that address the many complexities clients frequently present with, while also acknowledging differences between those seeking treatment for alcohol versus other drug problems.

A Systematic Review of the Impact of Exposure to Internet-Based Alcohol-Related Content on Young People's Alcohol Use Behaviours.

AIMS: To conduct a systematic review of studies exploring the relationship between exposure to Internet-based alcohol-related content and alcohol use among young people. METHODS: Searches of electronic databases and reference lists of relevant articles were conducted to retrieve studies of relevance up until December 2015. Full texts of the studies that met the inclusion criteria were read, appraised for quality using the Kmet forms and guidelines, and included in this review. RESULTS: Fifteen relevant studies were identified. The included studies were a mix of cross-sectional, longitudinal, experimental and qualitative studies conducted in the USA, the UK, Australia and New Zealand. The age range of the participants involved in these studies was 12-25 years. Included studies employed a variety of study designs and a range of different exposure variables and outcome measures. Studies demonstrated significant associations between exposure to Internet-based alcohol-related content and intentions to drink and positive attitudes towards alcohol drinking among young people. CONCLUSION: Exposure to alcohol-related content on the Internet might predispose young people to patterns of alcohol use by promoting alcohol as a natural and vital part of life. However, the research exploring the influence of this novel form of advertising on young people's alcohol use is emergent, and comprised primarily of cross-sectional studies. To evaluate the direction of the association between exposure to online alcohol-related content and alcohol use, we call for further research based on longitudinal designs. SHORT SUMMARY: From 15 relevant studies identified, this review reports significant associations between exposure to Internet-based alcohol-related content and intentions to drink and positive attitudes towards alcohol drinking among young people, with different influences found at different stages of alcohol use.

Ovarian Reserve After Ultrasound-Guided High-Intensity Focused Ultrasound for Uterine Fibroids: Preliminary Experience.

OBJECTIVE: To determine the effect on ovarian reserve of ultrasound-guided high-intensity focused ultrasound (HIFU) in the treatment of uterine fibroids. METHODS: We performed a mid-study analysis of markers of ovarian reserve using data from a prospective cohort study evaluating the safety of ultrasound-guided HIFU for uterine fibroids. Blood samples obtained from 12 women with uterine fibroids less than one week before treatment were used for measurement of serum anti-Mullerian hormone (AMH), and this testing was repeated in the first, third, sixth, and 12th month after ultrasound-guided HIFU treatment. RESULTS: Fourteen fibroids from 12 patients were treated using ultrasound-guided HIFU. The median baseline fibroid volume was 101.2 cm(3) (range 18.5 to 349.2 cm(3)). The median treatment time was 140.5 minutes (46 to 192 minutes), and median sonication time was 1449 seconds (range 541 to 2445 seconds). The median energy delivered was 575 521.5 joules (range 216 400 to 898 273 joules). The median AMH levels (ng/mL) before treatment and at one, three, six, and 12 months after treatment were 0.3 (range 0.01 to 1.94), 0.47 (0.01 to 1.43), 0.205 (0.01 to 1.81), 0.26 (0 to 2.37), and 0.06 (0.02 to 1.04), respectively. There was no significant difference between the AMH levels before and at any time after treatment. No patient became amenorrheic or reported symptoms suggestive of menopause after treatment. CONCLUSION: Our preliminary experience suggests that ovarian reserve does not seem to be affected by ultrasound-guided HIFU in the treatment of uterine fibroids.

Intracellular pH reduction prevents excitotoxic and ischemic neuronal death by inhibiting NADPH oxidase.

Sustained activation of N-methyl-d-aspartate (NMDA) -type glutamate receptors leads to excitotoxic neuronal death in stroke, brain trauma, and neurodegenerative disorders. Superoxide production by NADPH oxidase is a requisite event in the process leading from NMDA receptor activation to excitotoxic death. NADPH oxidase generates intracellular H(+) along with extracellular superoxide, and the intracellular H(+) must be released or neutralized to permit continued NADPH oxidase function. In cultured neurons, NMDA-induced superoxide production and neuronal death were prevented by intracellular acidification by as little as 0.2 pH units, induced by either lowered medium pH or by inhibiting Na(+)/H(+) exchange. In mouse brain, superoxide production induced by NMDA injections or ischemia-reperfusion was likewise prevented by inhibiting Na(+)/H(+) exchange and by reduced expression of the Na(+)/H(+) exchanger-1 (NHE1). Neuronal intracellular pH and neuronal Na(+)/H(+) exchange are thus potent regulators of excitotoxic superoxide production. These findings identify a mechanism by which cell metabolism can influence coupling between NMDA receptor activation and superoxide production.

Pre-Drinking Behavior of Young Heavy Drinkers.

BACKGROUND: Pre-drinking has been linked to subsequent heavy drinking and the engagement in multiple risky behaviors. OBJECTIVES: The present study examined a group of adolescents who recently had a "big night out" to determine whether there were differences in their pre-drinking behavior based on age, gender, geographic location, and social setting. METHODS: Participants (n = 351, aged 16-19) representing the heaviest 20-25% of drinkers in their age group were recruited using nonrandom sampling from metropolitan (Melbourne, Sydney, Perth) or regional (Bunbury) locations across Australia and administered a survey by a trained interviewer. RESULTS: Almost half the sample pre-drank (n = 149), most commonly at a friend's house. Those aged 18-19 were more likely to pre-drink, and did so at higher quantities compared to their younger counterparts. Males and females reported similar pre-drinking duration, quantity and amount spent on alcohol. Compared to those in cities, regional participants consumed greater quantities over longer periods of time. Two-thirds of participants consumed alcohol in excess of national guidelines during their pre-drinking session. These participants were more likely to nominate price as a motivation to pre-drink and were less likely to report that someone else provided them alcohol. CONCLUSIONS: This study sheds light on the pre-drinking habits of a population of young risky drinkers, and highlights the need for policy makers to address this form of drinking to reduce alcohol-related harm among young people.