Treatment of glioblastoma with re-purposed renin-angiotensin system modulators: Results of a phase I clinical trial.

Glioblastoma is the most common and most aggressive primary brain cancer in adults. Standard treatment of glioblastoma consisting of maximal safe resection, adjuvant radiotherapy and chemotherapy with temozolomide, results in an overall median survival of 14.6 months. The aggressive nature of glioblastoma has been attributed to the presence of glioblastoma stem cells which express components of the renin-angiotensin system (RAS). This phase I clinical trial investigated the tolerability and efficacy of a treatment targeting the RAS and its converging pathways in patients with glioblastoma. Patients who had relapsed following standard treatment of glioblastoma who met the trial criteria were commenced on dose-escalated oral RAS modulators (propranolol, aliskiren, cilazapril, celecoxib, curcumin with piperine, aspirin, and metformin). Of the 17 patients who were enrolled, ten completed full dose-escalation of the treatment. The overall median survival was 19.9 (95% CI:14.1-25.7) months. Serial FET-PET/CTs showed a reduction in both tumor volume and uptake in one patient, an increase in tumor uptake in nine patients with decreased (n = 1), unchanged (n = 1) and increased (n = 7) tumor volume, in the ten patients who had completed full dose-escalation of the treatment. Two patients experienced mild side effects and all patients had preservation of quality of life and performance status during the treatment. There is a trend towards increased survival by 5.3 months although it was not statistically significant. These encouraging results warrant further clinical trials on this potential novel, well-tolerated and cost-effective therapeutic option for patients with glioblastoma.

Embryonic stem cell-like subpopulations are present within Schwannoma.

BACKGROUND: There is accumulating evidence of the presence of embryonic stem cell (ESC)-like cells in benign tumors. AIM: This study aimed to identify ESC-like cells in Schwannoma using the induced-pluripotent stem cell (iPSC) markers OCT4, SOX2, NANOG, KLF4 and c-MYC. METHODS: Immunohistochemical (IHC) staining (n = 20) and RT-qPCR (n = 6) were performed on Schwannoma tissue samples (STS) to investigate protein and mRNA expression of these iPSC markers, respectively. Immunofluorescence (IF) staining was performed to investigate co-localization of the iPSC markers with CD34, α-SMA and CD133. RESULTS: IHC staining and RT-qPCR demonstrated protein and mRNA expression of all five iPSC markers, respectively. IF staining showed expression of SOX2, KLF4 and c-MYC on the tumor cells and the endothelium of the tumor microvessels which also expressed OCT4, while NANOG was exclusively expressed on the endothelium of the tumor microvessels. The OCT4+/CD34+ endothelium expressed CD133. CONCLUSION: We have identified a putative OCT4+/SOX2+/NANOG+/KLF4+/c-MYC+/CD133+ ESC-like subpopulation on the endothelium of tumor microvessels and an OCT4-/SOX2+/NANOG-/KLF4+/c-MYC+/CD133+ ESC-like subpopulation, within Schwannoma.

Cancer Stem Cell Subpopulations Are Present Within Metastatic Head and Neck Cutaneous Squamous Cell Carcinoma.

Cancer stem cells (CSCs) have been identified in many cancer types including primary head and neck cutaneous squamous cell carcinoma (HNcSCC). This study aimed to identify and characterize CSCs in metastatic HNcSCC (mHNcSCC). Immunohistochemical staining performed on mHNcSCC samples from 15 patients demonstrated expression of the induced pluripotent stem cell (iPSC) markers OCT4, SOX2, NANOG, KLF4, and c-MYC in all 15 samples. In situ hybridization and RT-qPCR performed on four of these mHNcSCC tissue samples confirmed transcript expression of all five iPSC markers. Immunofluorescence staining performed on three of these mHNcSCC samples demonstrated expression of c-MYC on cells within the tumor nests (TNs) and the peri-tumoral stroma (PTS) that also expressed KLF4. OCT4 was expressed on the SOX2+/NANOG+/KLF4+ cells within the TNs, and the SOX2+/NANOG+/KLF4+ cells within the PTS. RT-qPCR demonstrated transcript expression of all five iPSC markers in all three mHNcSCC-derived primary cell lines, except for SOX2 in one cell line. Western blotting showed the presence of SOX2, KLF4, and c-MYC but not OCT4 and NANOG in the three mHNcSCC-derived primary cell lines. All three cell lines formed tumorspheres, at the first passage. We demonstrated an OCT4+/NANOG+/SOX2+/KLF4+/c-MYC+ CSC subpopulation and an OCT4+/NANOG-/SOX2+/KLF4+/c-MYC+ subpopulation within the TNs, and an OCT4+/NANOG+/SOX2+/KLF4+/c-MYC+ subpopulation within the PTS of mHNcSCC.

What explains the decline in adolescent binge-drinking in New Zealand?

BACKGROUND: Binge-drinking prevalence among New Zealand adolescents has declined sharply since 2001, as it has in many other high-income countries. Other adolescent risk behaviours (e.g. smoking, cannabis use and precocious sexual activity) have also declined, raising the possibility of common underlying drivers. This study investigates potential contributing factors - both factors that predict risk behaviours in general, and alcohol-specific factors - and the extent to which they account for the decline in binge drinking. METHODS: The study used nationally representative survey data collected in 2001 (N = 6513), 2007 (N = 5934) and 2012 (N = 5489). The outcome measure was prevalence of past month binge drinking (5+ drinks/session). Predictor variables included factors that predict risk behaviours in general (parental monitoring, family attachment, school attachment, having a part-time job, time spent hanging out with friends); alcohol-specific factors (parental alcohol use, adolescent attitude toward alcohol use); and attitude toward and current use of tobacco and cannabis. Likelihood of binge drinking was modelled for each survey year (ref=2001), adjusting for demographic factors. Predictors were added to this base model, with the degree of attenuation of the odds ratio for year indicating the extent to which the included predictor(s) accounted for the trend. RESULTS: Compared with 2001 the odds of binge-drinking in 2012 were 0.33. The strongest independent contributor to the decline was adolescent attitude toward alcohol use, followed by current cannabis use, then current tobacco use. Collectively, general factors in home, school and leisure settings did not significantly contribute to the downward trend in binge drinking. CONCLUSION: Decreasing acceptability of alcohol use among adolescents was the most important identified contributor to adolescent binge-drinking decline. Drinking, smoking and cannabis use trends were empirically linked, yet the decline in binge drinking was not significantly explained by the included predictors common to risk behaviours in general.

New Zealand radiation therapists' perceptions of peer group supervision as a tool to reduce burnout symptoms in the clinical setting.

INTRODUCTION: Research indicates that radiation therapists (RTs) are at risk of burnout and that there is a lack of evidence on effective coping strategies for managing work-related stressors within this workforce. Peer group supervision (PGS) is a useful tool in assisting staff to manage stress in the clinical setting, improve reflective practice and provide support. The aim of this research was to investigate New Zealand (NZ) RTs' perceptions of participating in PGS. METHODS: In-service training on PGS was offered to all RT centres in NZ, and five of the nine centres agreed to partake in PGS. Participants anonymously completed the same online questionnaire, six months apart. The questionnaire consisted of the Clinical Supervision Evaluation Questionnaire (CSEQ), an open-ended question and demographics. The CSEQ asks participants to indicate their agreement with 14 statements related to Purpose, Process and Impact of PGS. RESULTS: Overall, 71 and 48 participants completed the first and second surveys, respectively. In contrast to previous studies, this study found that confidence in practice, team support and group safety were valued by participants. This was supported by the qualitative data that revealed four themes: supportive groups, time out to reflect, organisational barriers and group process issues. RTs with one to five years' experience were more likely to structure their meetings, understand the purpose of the meetings and had clearer expectations of the group process. CONCLUSIONS: PGS may address burnout for RTs with one to five years' experience. This group of RTs feel patient-related matters can be discussed openly during PGS, and PGS appears to be helping to improve their practice and reduce stress. More experienced RTs appear to be using the groups as a 'professional support group', rather than 'peer supervision', as a strategy for managing organisational stressors associated with burnout.

Sleep in New Zealand children aged 7-9: associations with ethnicity, socioeconomic status, and achievement in reading and mathematics.

STUDY OBJECTIVES: The aims were (1) to investigate differences by ethnicity and socioeconomic status (SES) in objective measures of sleep in children aged 7-9 years and (2) determine whether measures of sleep predict child achievement in reading or mathematics after controlling for ethnicity and SES. METHODS: Four groups of parent-child dyads were recruited: Maori, low-SES schools (n = 18); Maori, high-SES schools (n = 17); New Zealand European, low-SES schools (n = 18); New Zealand European, high-SES schools (n = 17). Child sleep was measured by actigraphy. Parents and teachers reported child daytime sleepiness and behavior, and children completed a self-report of anxiety symptoms. Teachers also reported on child achievement in reading and mathematics. RESULTS: Children from low-SES schools went to bed later on school nights (F[1,68] = 12.150, P = .001) and woke later (F[1,68] = 15.978, P < .001) than children from high-SES schools but had similar sleep duration. There were no differences related to ethnicity. Children from low-SES schools were almost 3 times more likely to be below national standards for mathematics. Children not meeting academic standards in mathematics had a later sleep start time, lower sleep period efficiency, and a decreased total sleep time. However, when SES and sleep period efficiency were modeled together neither were found to significantly influence achievement in mathematics. CONCLUSIONS: In this study, SES influenced sleep timing but not the quality and quantity of sleep in 7- to 9-year-old children, and a significant independent effect of sleep efficiency on learning could not be demonstrated.

Identification of Cancer Stem Cell Subpopulations in Head and Neck Metastatic Malignant Melanoma.

Cancer stem cells (CSCs) have been identified in many cancer types. This study identified and characterized CSCs in head and neck metastatic malignant melanoma (HNmMM) to regional lymph nodes using induced pluripotent stem cell (iPSC) markers. Immunohistochemical (IHC) staining performed on 20 HNmMM tissue samples demonstrated expression of iPSC markers OCT4, SOX2, KLF4, and c-MYC in all samples, while NANOG was expressed at low levels in two samples. Immunofluorescence (IF) staining demonstrated an OCT4+/SOX2+/KLF4+/c-MYC+ CSC subpopulation within the tumor nests (TNs) and another within the peritumoral stroma (PTS) of HNmMM tissues. IF also showed expression of NANOG by some OCT4+/SOX2+/KLF4+/c-MYC+ cells within the TNs in an HNmMM tissue sample that expressed NANOG on IHC staining. In situ hybridization (n = 6) and reverse-transcription quantitative polymerase chain reaction (n = 5) on the HNmMM samples confirmed expression of all five iPSC markers. Western blotting of primary cell lines derived from four of the 20 HNmMM tissue samples showed expression of SOX2, KLF4, and c-MYC but not OCT4 and NANOG, and three of these cell lines formed tumorspheres in vitro. We demonstrate the presence of two putative CSC subpopulations within HNmMM, which may be a novel therapeutic target in the treatment of this aggressive cancer.

Safety and acceptability of clozapine and risperidone in progressive multiple sclerosis: a phase I, randomised, blinded, placebo-controlled trial.

OBJECTIVE: Because clozapine and risperidone have been shown to reduce neuroinflammation in humans and mice, the Clozapine and Risperidone in Progressive Multiple Sclerosis (CRISP) trial was conducted to determine whether clozapine and risperidone are suitable for progressive multiple sclerosis (pMS). METHODS: The CRISP trial (ACTRN12616000178448) was a blinded, randomised, placebo-controlled trial with three parallel arms (n=12/arm). Participants with pMS were randomised to clozapine (100-150 mg/day), risperidone (2.0-3.5 mg/day) or placebo for 6 months. The primary outcome measures were safety (adverse events (AEs)/serious adverse events (SAE)) and acceptability (Treatment Satisfaction Questionnaire for Medication-9). RESULTS: An interim analysis (n=9) revealed significant differences in the time-on-trial between treatment groups and placebo (p=0.030 and 0.025, clozapine and risperidone, respectively) with all participants receiving clozapine being withdrawn during the titration period (mean dose=35±15 mg/day). Participants receiving clozapine or risperidone reported a significantly higher rate of AEs than placebo (p=0.00001) but not SAEs. Specifically, low doses of clozapine appeared to cause an acute and dose-related intoxicant effect in patients with pMS who had fairly severe chronic spastic ataxic gait and worsening over all mobility, which resolved on drug cessation. INTERPRETATION: The CRISP trial results suggest that patients with pMS may experience increased sensitivity to clozapine and risperidone and indicate that the dose and/or titration schedule developed for schizophrenia may not be suitable for pMS. While these findings do not negate the potential of these drugs to reduce multiple sclerosis-associated neuroinflammation, they highlight the need for further research to understand the pharmacodynamic profile and effect of clozapine and risperidone in patients with pMS. TRIAL REGISTRATION NUMBER: ACTRN12616000178448.

Systematic Exploration of Countertransference Phenomena in the Treatment of Patients at Risk for Suicide.

Despite its critical role in clinical suicidology, empirical evidence on the nature of countertransference (CT) to patients at risk for suicide (PRS) is lacking. This study aimed to provide a systematic description of CT phenomena to PRS. Psychiatrists, psychologists, and psychotherapists completed the Therapist Response Questionnaire (TRQ) online, with reference to a PRS. Factor analysis (n = 267) yielded a 7-factor structure, including 1) entrapped/rejecting, 2) fulfilled/engaging, 3) aroused/reacting, 4) informal/boundary crossing, 5) protective/overinvolvement, 6) ambivalent/inconsistent, and 7) mistreated/controlling. On average, clinicians reported that CT dimensions tended to not apply to them, except for the positively connoted factor. Our findings suggest that patients at risk for suicide elicit specific dimensions of CT. We offer two alternative interpretations of clinicians' CT endorsement patterns.

Association Between Women's Use of Long-Acting Reversible Contraception and Declining Abortion Rates in New Zealand.

Background: To investigate the hypothesis that increased uptake of long-acting reversible contraception (LARC) by women played a role in the declining abortion rates observed in New Zealand between 2008 and 2014. Materials and Methods: This quantitative ecological study analyzed routinely collected national data pertaining to abortion numbers, contraceptive prescriptions, and census population estimates for the period 2004-2014. Annual prescription and prevalence rates (per 1000 women) were calculated for short- and long-acting methods to investigate changes over time. Poisson's regression was used to (1) test whether the abortion rate changed by year; (2) whether 2010 (when the contraceptive implant became subsidized) was a significant point of change; and (3) test the relationship between declining abortions and patterns of contraceptive use. Results: Estimated LARC prevalence increased from 2009 to 2014, with a corresponding decrease observed in prescription of short-acting methods. The declining abortion rate accelerated each year from 2008 to 2014 (with a faster decline from 2010 to 2014), but 2010 was not a significant point of change. Three factors had statistically significant associations with declining abortion rates (p < 0.01): year (acting as a surrogate for all social changes), women's use of the levonorgestrel (LNG)-implant, and the combined model: use of the LNG-implant and copper intrauterine device (CuIUD) had the best fit (using Akaike's Information Criterion), indicating that this variable explained more of the year-to-year variability in abortion rates. Conclusions: The shift toward women's increased use of the two publically funded LARC methods (LNG-implants and CuIUD) was significantly associated with the declining abortion rates in New Zealand.

Eosinophilic esophagitis incidence in New Zealand: high but not increasing.

BACKGROUND AND AIM: Eosinophilic esophagitis (EoE) is an immune-mediated inflammatory condition of the esophagus. Recent literature has shown an increasing incidence of the disease. However, no epidemiological data exist regarding New Zealand rates of EoE. The disease is associated with atopy, and New Zealand's high rate of atopic disease means the disease may be important in our population. We carried out a retrospective study to describe the incidence of EoE in the Wellington region of New Zealand, as well as key histological and clinical factors associated with the disease. METHOD: A search was made of laboratory and endoscopic databases in the Wellington region to identify all diagnosed cases in the five years between January 1, 2011, and December 31, 2015. Case notes were examined to determine the key demographic and clinical parameters in the cases. Incidence rates were calculated for each year, and the effects of age group and sex on the incidence rates were analyzed. RESULT: We found 152 cases of EoE in the Wellington region with an annual incidence of 6.95 per 100,000 person/years. We found no evidence of a significant difference in incidence rates by year in our study population. There was a significantly lower incidence rate in those aged <16 compared to those aged ≥16 (RR=0.26). Males had a higher incidence rate than females with an estimated rate ratio of 2.45 (p<0.05). CONCLUSION: Our results are in contrast to previous reports of increasing incidence rates and may reflect a leveling off of incidence. Further research is needed to determine whether the low incidence in our pediatric age group is due to ascertainment bias or due to a real difference in the epidemiology of EoE in NZ compared to other countries.

Declining adolescent cannabis use occurred across all demographic groups and was accompanied by declining use of other psychoactive drugs, New Zealand, 2001-2012.

AIM: Cannabis use declined in New Zealand adolescents between 2001 and 2012. We investigated i) whether changes in adolescent cannabis use occurred across all demographic groups, and ii) whether declining cannabis use was accompanied by increasing use of other psychoactive drugs. METHOD: We conducted secondary analysis of repeat cross-sectional data from nationally representative surveys of secondary school students (2001, 2007, 2012) to determine trends in never-use of cannabis and other psychoactive drugs by age, sex, ethnicity, deprivation, school decile and urban/rural locale. Logistic regression was used to test whether changes in cannabis non-use over time varied between demographic groups. RESULTS: Never-use of cannabis and of other psychoactive substances increased between 2001 and 2012 in all included age, ethnic, sex and socioeconomic groups. Maori, younger students and those in low decile schools demonstrated the greatest reductions in cannabis use over the study period. CONCLUSION: The decline in adolescent cannabis use between 2001 and 2012 occurred across all main demographic groups and was not accompanied by a rise in the use of other psychoactive drugs. Ethnic and socioeconomic inequities in adolescent cannabis use decreased over the study period.

Treat-to-target in rheumatoid arthritis: Evaluating the patient perspective using the Patient Opinion Real-Time Anonymous Liaison system: The RA T2T PORTAL study.

OBJECTIVES: To determine the level of agreement among patients with rheumatoid arthritis (RA) with the principles and recommendations of the treat-to-target (T2T) initiative in New Zealand (NZ) and to further explore specific patient opinions via online iterative surveys. METHODS: Participants with RA were recruited from rheumatology clinics in NZ and invited to receive and reply to surveys administered via the Patient Opinion Real-Time Anonymous Liaison (PORTAL) system. An enrolment survey recorded demographics, disease duration and treatment and then RA T2T surveys were administered weekly. A Likert scale 1-5 measured agreement with the principles and recommendations and further surveys explored responses of interest identified by investigators from each prior survey. RESULTS: One hundred and ninety patients consented to participate in PORTAL and 132 in the RA T2T surveys. Level of agreement with RA T2T principles was: 93.3% to 99.3% and to the recommendations: 77.3%-100%. The lowest level of agreement 77.3% was with recommendation 8, 3 monthly treatment adjustment, and the highest was 100% agreement with recommendation 10, shared decision-making. Patients agreed less with low disease activity as the target compared with remission (91.4% and 98%). Despite high-level agreement for the use of a disease activity score (95.7%), 23% did not feel the individual components reflected their disease control. Patients rated difficulty coping, erosions on imaging, health-related quality of life and pain all significantly higher than C-reactive protein as indicators of worsening arthritis. CONCLUSIONS: Despite a high level of patient agreement with RA T2T this study highlights the importance of patient engagement in the RA T2T process to individualize therapy adjustments, make shared decisions and decide on targets that accurately reflect disease control according to patients.

Addressing Ethnic Disparities in Adolescent Smoking: Is Reducing Exposure to Smoking in the Home a Key?

INTRODUCTION: Smoking among New Zealand (NZ) adolescents has declined since 2000, but ethnic disparities remain pronounced. To inform prevention efforts, we investigated exposure to and relative importance of known predictors of adolescent smoking and how these have changed over time, for Maori (NZ's indigenous population) and adolescents overall. METHODS: We used repeat cross-sectional data, 2003-2015, from a national survey of 14- to 15-year olds (N = 20 443-31 696 per year). For the overall sample and for Maori and non-Maori, we calculated adjusted odds ratios (aORs) to assess the association between regular smoking and risk factors each year: one or more parents smoke, best friend smokes, older sibling(s) smoke, and past week exposure to smoking in the home. We calculated population attributable risk (PAR) for risk factors in 2003 and 2015. RESULTS: Between 2003 and 2015, aORs for exposure to smoking in the home increased from 1.7 (95% CI 1.6% to 1.8%) to 2.6 (2.1% to 3.1%) overall and from 1.8 (1.6% to 2.1%) to 3.4 (2.5% to 4.5%) for Maori; aORs for "best friend smokes" also increased, while aORs for sibling smoking and parental smoking did not change meaningfully. PAR for exposure to smoking in the home increased from 17% to 31% overall and from 28% to 57% for Maori, while PARs for other risk factors decreased. CONCLUSIONS: Exposure to smoking in the home has become more strongly associated with adolescent smoking over time and is an increasingly important risk factor at the population level (independent of parental smoking), particularly for Maori. IMPLICATIONS: Our findings have implications for reducing smoking uptake and ethnic disparities in NZ, and potentially elsewhere, given the similarity in risk factors and trends for adolescent smoking internationally. Our findings suggest that reducing second-hand smoke exposure in homes will likely reduce uptake of smoking. Because Maori children are both more exposed and appear to be more strongly influenced by exposure to smoking in the home, interventions to reduce indoor smoking could have differentially positive effects for Maori. Greater research and policy attention to reducing smoking in homes is warranted.

Agreement of triage decisions between gastroenterologists and nurses in a hospital endoscopy unit.

INTRODUCTION: Efficient and accurate triage of endoscopy referrals is essential. Many of the decisions made are based on national and local triage criteria. Standardizing this approach for nurse use could maintain quality, address clinical risk and significantly improve resource utilization. AIMS: This study aimed to compare gastroenterologist and nurse triage of unselected gastroenterology referrals in order to evaluate the proportion of referrals felt able to be triaged to endoscopy and the inter-rater agreement between a triage gastroenterologist and endoscopy nurses for clinical triage decisions regarding the urgency of gastroscopy and colonoscopy. METHODS: The proportion of referrals triaged to endoscopy by a consultant gastroenterologist performing triage as a part of normal practice and two endoscopy nurses using a decision algorithm was measured. The inter-rater agreement for the triage category decision (urgency of referral) between the three triage clinicians was assessed. An adjudication panel provided a consensus decision triage category decision in cases where there was not complete agreement between the three triage clinicians. RESULTS: Each clinician assessed 105 referrals. Nurse A was able to triage 54 (51%) referrals to a triage category and Nurse B 44 (42%) referrals. Cohen's κ was run to determine if there was agreement between clinicians for the triage categories allocated. The agreement between the two nurses was substantial (k=0.645, P<0.0005). Between the gastroenterologist and each nurse, moderate agreement was seen (Nurse A, k=0.589, P<0.0005; Nurse B, k=0.437, P<0.0005). Moderate agreement was seen between the nurses and an adjudication panel (Nurse A, k=0.423, P<0.0005; Nurse B, k=0.464, P<0.0005). However, there was only slight agreement between the adjudication panel and the gastroenterologist (k=0.099, P=0.010). CONCLUSION: Nurse triage using a decision algorithm is feasible, and inter-rater agreement is substantial between nurses and moderate to substantial between the nurses and a gastroenterologist. An adjudication panel demonstrated moderate agreement with the nurses but only slight agreement with the triage gastroenterologist. This suggests that nurse triage using a decision algorithm can approximate decision making by an experienced gastroenterologist.

Why has adolescent smoking declined dramatically? Trend analysis using repeat cross-sectional data from New Zealand 2002-2015.

OBJECTIVES: Adolescent smoking has declined in New Zealand and in many other countries since the late 1990s, yet the reasons for the decline are not well understood. We investigated the extent to which established risk factors for adolescent smoking (parental, sibling and peer smoking, and exposure to smoking in the home) explained the downward trend. DESIGN: Trend analysis of repeat cross-sectional data from an annual nationally representative survey. SETTING: New Zealand. PARTICIPANTS: Secondary school students aged 14-15 (n=398 221). OUTCOME MEASURE: Regular (at least monthly) smoking. METHODS: For each risk factor (parental smoking, best friend smoking, older sibling smoking and past week exposure to smoking in the home) we plotted prevalence of exposure, 2002-2015. Next, using multivariable logistic regression, we modelled the trend in regular smoking (expressed as an OR for year) adjusting for age, sex, ethnicity and socioeconomic position. The risk factors were added to the model-individually and collectively-to test whether they attenuated the OR for year. RESULTS: Exposure to all risk factors except 'past week exposure to smoking in the home' decreased between 2002 and 2015. We observed a strong downward trend in regular smoking among adolescents (OR=0.88 per year, 95% CI 0.88 to 0.88, p<0.001). 'Best friend smoking' was the only risk factor that significantly attenuated the trend. However, due to circularity, this factor provides an unsatisfactory explanation for population level smoking decline. CONCLUSIONS: The established risk factors that we explored do not appear to have contributed to the remarkable decline in adolescent smoking in New Zealand between 2003 and 2015. Further research is needed to assess the possible contribution of factors outside our model, such as changes in the policy context, the social meaning of smoking and broader social and economic conditions.

Bacterial bioclusters relate to hydrochemistry in New Zealand groundwater.

Groundwater is a major source of New Zealand's water supply and supports base flows in rivers. Microbial communities in groundwater ecosystems mediate biogeochemical processes, and it is therefore crucial to understand microbial diversity in these ecosystems. We analysed bacterial assemblages from 35 New Zealand groundwater monitoring sites with varying hydrogeochemical conditions across the country. Proteobacteria was the most abundant phylum, and Variovorax represented the most common taxon. Pseudomonas, Burkholderia, Acidovorax, Janthinobacterium, Polaromonas and Caulobacter were the other common taxa. There was no Operational Taxonomic Unit (OTU) that was found in every one of the 35 samples. Here, we introduce a framework that has potential utility for groundwater ecosystem management, where the samples with similar microbial communities are grouped together into 'bioclusters'. Metabolic inferences derived from the taxonomic data were used to predict the oxygen requirements, metabolic potential and bacterial energy sources of each biocluster. Groundwater chemistry explains 59% of the variation in the relative abundance of all OTUs, with NO3-N, pH, DO, NH4-N, Fe, Br and SO4 displaying the strongest relationships to bioclusters. We propose that the biocluster framework, coupled with metabolic inferences derived from the taxonomic data, may have application outside New Zealand for on-going monitoring of the health of groundwater ecosystems.

He Tamariki Kokoti Tau-Tackling Preterm: a data-linkage methodology to explore the clinical care pathway in preterm deliveries.

BACKGROUND: Significant health inequities exist around maternal and infant health for Maori, the indigenous people of Aotearoa New Zealand - and in particular around a premature (preterm) delivery. Maori babies are more likely to be born preterm (8.1%, compared to an overall rate of 7.4%) and they are more likely to have a preterm death. An essential part of redressing these disparities is to examine the clinical care pathway and outcomes associated with preterm deliveries. This paper describes a protocol utilising national and local health collections to enable such a study. DESIGN: This is a retrospective cohort study comprising 5 years data pertaining to preterm deliveries from 2010 to 2014. These data are generated from linked national administrative and local health information collections to explore a range of neonatal outcomes and infant mortality in relation to the antenatal care pathway and known risk factors for preterm delivery. This study is being conducted within a Kaupapa Maori paradigm that dismisses victim blaming and seeks to intervene at structural levels to improve the health and wellbeing of Maori whanau (family). SIGNIFICANCE OF THE STUDY: Our data-linkage methodology optimises the utility of New Zealand health collections to address a significant health issue. Our findings will fill the information gaps around the burden of preterm delivery by quantifying the incidence of preterm delivery and adverse neonatal and infant outcomes in Aotearoa New Zealand. It will explore access to evidenced based care including use of steroids before birth, and appropriate place of delivery. The results from this study will inform maternity care services to improve management of preterm deliveries - both locally and internationally. This in turn will improve the preterm sequela by reducing the long-term health burden and health inequities.

Increasing rates of people identifying as transgender presenting to Endocrine Services in the Wellington region.

AIMS: Overseas clinics specialising in management of transgender people have noted a marked increase in the numbers of people requesting therapy in the last few years. No data has been presented for New Zealand. We therefore reviewed the number of transgender people seen in the Wellington Endocrine Service to assess if the pattern was similar and assess any potential problems for service delivery. METHODS: Using hospital records, we reviewed the new appointments of people who were referred for advice on gender reassignment and seen in the Wellington Endocrine Service from 1990 to 2016. RESULTS: In total, 438 people who identified as transgender attended the clinic at least once in this period. There has been a progressive increase in number of people identifying as transgender presenting to the clinic, particularly since 2010. In addition to increasing overall numbers, there has been in particular increase in referrals for people under age 30, as well as an increasing proportion of people requesting female-to-male (FtM) therapy so that it is now approaching the number of people requesting male-to-female therapy (MtF). CONCLUSION: The pattern observed is comparable to changes reported overseas. These changes have practical consequences for the delivery of both secondary and primary level healthcare, requiring an increased focus on clinical coordination between the relevant medical services and their links to the primary services sector.

Evaluation of neurological changes in secondary progressive multiple sclerosis patients treated with immune modulator MIS416: results from a feasibility study.

BACKGROUND: While disease progression can be readily monitored in early stage relapsing multiple sclerosis (MS), it is more challenging for secondary progressive multiple sclerosis (SPMS). This advanced stage of disease has distinct pathophysiology due to compartmentalization of neuroinflammatory activity within the central nervous system, resulting in increased incidence and severity of cognitive dysfunction. The shift in the dominant disease pathways is underscored by the failure of relapsing therapies to benefit SPMS patients, highlighting the need for novel treatment strategies and clinical trial endpoints that are well-aligned with potential benefits. The Expanded Disability Status Scale (EDSS) is widely used but is weighted towards ambulatory ability, lacking sensitivity to other aspects of neurological impairment experienced in more severely disabled SPMS patients, so may not effectively capture their clinical status.To investigate the feasibility of an alternative clinical trial endpoint model for a phase 2B trial of an immune modulator for SPMS, the potential for treatment efficacy-based patient-centered outcomes was assessed within the context of a before and after, 12-week clinical trial of safety and tolerability. METHODS: Patients treated with MIS416 for 12 weeks were evaluated for clinical status at baseline and end of dosing, using the established Multiple Sclerosis Functional Composite, Short Form Health Survey, and Expanded Disability Status Scale. Responder status was determined for eight outcome measures based on minimally important change, defined using published studies. To evaluate the patients' immune response to MIS416, blood plasma samples collected at baseline and pre- and 24-h post doses 1-4 were analyzed using multiplex cytokine quantification assays. RESULTS: Using a combination of patient-centered outcomes, MIS416 treatment was associated with improved clinical status for 10/11 patients: eight patients showed improvement on two to five outcome measures, five of which also showed improvement by EDSS. Multi-dimensional scaling analysis of MIS416-induced factors quantified in individual patients, revealed immune response patterns which had a strong concordance with the extent of the patients' clinical response. CONCLUSIONS: The data support the feasibility of using patient-centered outcomes as additional clinical trial endpoints, for determining the efficacy of disease-modifying therapies, in secondary progressive multiple sclerosis patients. TRIAL REGISTRATION: ClinicalTrial.gov, NCT01191996.