A randomised controlled trial of long NY-ESO-1 peptide-pulsed autologous dendritic cells with or without alpha-galactosylceramide in high-risk melanoma.

AIM: We have previously reported that polyfunctional T cell responses can be induced to the cancer testis antigen NY-ESO-1 in melanoma patients injected with mature autologous monocyte-derived dendritic cells (DCs) loaded with long NY-ESO-1-derived peptides together with α-galactosylceramide (α-GalCer), an agonist for type 1 Natural Killer T (NKT) cells. OBJECTIVE: To assess whether inclusion of α-GalCer in autologous NY-ESO-1 long peptide-pulsed DC vaccines (DCV + α-GalCer) improves T cell responses when compared to peptide-pulsed DC vaccines without α-GalCer (DCV). DESIGN, SETTING AND PARTICIPANTS: Single-centre blinded randomised controlled trial in patients ≥ 18 years old with histologically confirmed, fully resected stage II-IV malignant cutaneous melanoma, conducted between July 2015 and June 2018 at the Wellington Blood and Cancer Centre of the Capital and Coast District Health Board. INTERVENTIONS: Stage I. Patients were randomised to two cycles of DCV or DCV + α-GalCer (intravenous dose of 10 × 106 cells, interval of 28 days). Stage II. Patients assigned to DCV + α-GalCer were randomised to two further cycles of DCV + α-GalCer or observation, while patients initially assigned to DCV crossed over to two cycles of DCV + α-GalCer. OUTCOME MEASURES: Primary: Area under the curve (AUC) of mean NY-ESO-1-specific T cell count detected by ex vivo IFN-γ ELISpot in pre- and post-treatment blood samples, compared between treatment arms at Stage I. Secondary: Proportion of responders in each arm at Stage I; NKT cell count in each arm at Stage I; serum cytokine levels at Stage I; adverse events Stage I; T cell count for DCV + α-GalCer versus observation at Stage II, T cell count before versus after cross-over. RESULTS: Thirty-eight patients gave written informed consent; 5 were excluded before randomisation due to progressive disease or incomplete leukapheresis, 17 were assigned to DCV, and 16 to DCV + α-GalCer. The vaccines were well tolerated and associated with increases in mean total T cell count, predominantly CD4+ T cells, but the difference between the treatment arms was not statistically significant (difference - 6.85, 95% confidence interval, - 21.65 to 7.92; P = 0.36). No significant improvements in T cell response were associated with DCV + α-GalCer with increased dosing, or in the cross-over. However, the NKT cell response to α-GalCer-loaded vaccines was limited compared to previous studies, with mean circulating NKT cell levels not significantly increased in the DCV + α-GalCer arm and no significant differences in cytokine response between the treatment arms. CONCLUSIONS: A high population coverage of NY-ESO-1-specific T cell responses was achieved with a good safety profile, but we failed to demonstrate that loading with α-GalCer provided an additional advantage to the T cell response with this cellular vaccine design. CLINICAL TRIAL REGISTRATION: ACTRN12612001101875. Funded by the Health Research Council of New Zealand.

Dual versus single long-acting bronchodilator use could raise acute coronary syndrome risk by over 50%: A population-based nested case-control study.

BACKGROUND: Coronary heart disease occurs more frequently among patients with chronic obstructive pulmonary disease (COPD) compared to those without COPD. While some research suggests that long-acting bronchodilators might confer an additional risk of acute coronary syndrome (ACS), information from real-world clinical practice about the cardiovascular impact of using two versus one long-acting bronchodilator for COPD is limited. We undertook a population-based nested case-control study to estimate the risk of ACS in users of both a long-acting muscarinic antagonist (LAMA) and a long-acting beta2-agonist (LABA) relative to users of a LAMA. METHODS: The study was based on the primary care PREDICT Cardiovascular Disease Cohort and linked data from regional laboratories and the New Zealand Ministry of Health's national data collections. The underlying cohort (n = 29,993) comprised patients aged 45-84 years, who initiated treatment with a LAMA and/or LABA for COPD between 1 February 2006 and 11 October 2016. 1490 ACS cases were matched to 13,550 controls by date of birth, sex, date of cohort entry (first long-acting bronchodilator dispensing), and COPD severity. RESULTS: Relative to current use of LAMA therapy, current use of LAMA and LABA dual therapy was associated with a significantly higher risk of ACS (adjusted OR = 1.72; [95% CI: 1.28-2.31]). CONCLUSION: Dual long-acting bronchodilator therapy, rather than LAMA mono-therapy, could increase the risk of ACS by more than 50%. This has important implications for decisions about the potential benefit/harm ratio of COPD treatment intensification, given the modest benefits of dual therapy.

On the robustness of latent class models for diagnostic testing with no gold standard.

It is difficult to estimate sensitivity and specificity of diagnostic tests when there is no gold standard. Latent class models have been proposed as a potential solution as they provide estimates without the need for a gold standard. Using a motivating example of the evaluation of point of care tests for leptospirosis in Tanzania, we show how a realistic violation of assumptions underpinning the latent class model can lead directly to substantial bias in the estimates of the parameters of interest. In particular, we consider the robustness of estimates of sensitivity, specificity, and prevalence, to the presence of additional latent states when fitting a two-state latent class model. The violation is minor in the sense that it cannot be routinely detected with goodness-of-fit procedures, but is major with regard to the resulting bias.

Antidepressant dispensing before, during, and after pregnancy in New Zealand, 2005-2014.

BACKGROUND: Depression during pregnancy is associated with a number of negative impacts on maternal and infant health, therefore good control of depression in pregnant women is crucial. There is a lack of population-level information about patterns of antidepressant use during pregnancy in New Zealand. AIM: To describe antidepressant dispensing patterns before, during, and after pregnancy in New Zealand, 2005-2014. MATERIALS AND METHODS: Antidepressant dispensing records from 270 days prior to pregnancy through to 360 days after pregnancy end were linked with 805 990 pregnancies in the New Zealand Pregnancy Cohort. Proportions (and 95% confidence intervals) with at least one dispensing were calculated for the periods before, during, and after pregnancy and compared over time and by maternal characteristics. RESULTS: Dispensing during the first trimester was lower than in the pre-pregnancy and post-pregnancy periods, and dropped further in later trimesters. The proportion of pregnancies during which an antidepressant was dispensed rose from 3.1 to 4.9% over the study years. Around 80% of those with a dispensing received a selective serotonin reuptake inhibitor. Dispensing before, during, and after pregnancy varied by ethnicity, age, smoking status, and body mass index. Among women taking an antidepressant before pregnancy, younger women and those of Maori, Pacific, or Asian ethnicity were less likely to continue therapy during pregnancy. CONCLUSIONS: This study has established a baseline for antidepressant use around pregnancy in New Zealand, documented increasing use over time, and demonstrated that known ethnic differences in antidepressant use are also evident in the pregnant population.

Early Clearance of Mycobacterium tuberculosis: The INFECT Case Contact Cohort Study in Indonesia.

BACKGROUND: Early clearance of Mycobacterium tuberculosis is the eradication of infection before an adaptive immune response develops. We aimed to identify host factors associated with early clearance. METHODS: Indonesian household contacts patients with smear-positive tuberculosis (TB) had an interferon-γ release assay (IGRA) at baseline and 14 weeks later. Early clearance was defined as a persistently negative IGRA. Contact characteristics, exposure, and disease phenotype were assessed for association with a positive IGRA at each time point. RESULTS: Of 1347 contacts of 462 TB cases, 780 (57.9%) were IGRA positive and 490 (36.3%) were IGRA negative. After 14 weeks, 116 of 445 (26.1%) initially negative contacts were IGRA converters; 317 (71.2%) remained persistently negative. BCG vaccination reduced the risk of a positive baseline IGRA (relative risk [RR], 0.89 [95% confidence interval {CI} .83-.97]; P = .01), and strongly reduced the risk of IGRA conversion (RR, 0.56 [95% CI, .40-.77]; P < .001). BCG protection decreased with increasing exposure (P = .05) and increasing age (P = .004). Risk of IGRA conversion was positively associated with hemoglobin concentration (P = .04). CONCLUSIONS: A quarter of household TB case contacts were early clearers. Protection against M. tuberculosis infection was strongly associated with BCG vaccination. Lower protection from BCG with increasing M. tuberculosis exposure and age can inform vaccine development.

Early Clearance of Mycobacterium tuberculosis Is Associated With Increased Innate Immune Responses.

BACKGROUND: A proportion of tuberculosis (TB) case contacts do not become infected, even when heavily exposed. We studied the innate immune responses of TB case contacts to understand their role in protection against infection with Mycobacterium tuberculosis, termed "early clearance." METHODS: Indonesian household contacts of TB cases were tested for interferon-γ release assay (IGRA) conversion between baseline and 14 weeks post recruitment. Blood cell populations and ex vivo innate whole blood cytokine responses were measured at baseline and, in a subgroup, flow cytometry was performed at weeks 2 and 14. Immunological characteristics were measured for early clearers, defined as a persistently negative IGRA at 3 months, and converters, whose IGRA converted from negative to positive. RESULTS: Among 1347 case contacts, 317 were early clearers and 116 were converters. Flow cytometry showed a resolving innate cellular response from 2 to 14 weeks in persistently IGRA-negative contacts but not converters. There were no differences in cytokine responses to mycobacterial stimuli, but compared to converters, persistently IGRA-negative contacts produced more proinflammatory cytokines following heterologous stimulation with Escherichia coli and Streptococcus pneumoniae. CONCLUSIONS: Early clearance of M. tuberculosis is associated with enhanced heterologous innate immune responses similar to those activated during induction of trained immunity.

A case-control study to assess the ability of the thymine challenge test to predict patients with severe to life threatening fluoropyrimidine-induced gastrointestinal toxicity.

AIMS: A previous study suggested that a thymine (THY) challenge dose could detect aberrant pharmacokinetics in known cases of fluoropyrimidine toxicity compared with healthy volunteers. The preliminary data suggested that urine sampling also could detect this aberrant disposition. The aim of this case-control study was to assess the ability of the urinary THY challenge test to discriminate cases of severe gastrointestinal toxicity in a cohort of patients treated with 5-fluorouracil or capecitabine. METHODS: Patients (n = 37) received a 250 mg (per os) dose of THY and a cumulative urine sample was collected for 0-4 h. The urinary amounts of THY and metabolite dihydrothymine (DHT) were determined by liquid chromatography/mass spectrometry. Genomic DNA was analysed for DPYD gene variants. Renal function was estimated from blood creatinine levels. Cases (n = 9) and noncases (n = 23) of severe (grade ≥ 3) gastrointestinal toxicity were defined based on Common Terminology Criteria for Adverse Events. RESULTS: The median THY/DHT ratios were 6.2 (interquartile range 2.9-6.4) in cases, including the 2 patients who were DPYD heterozygous carriers. However, this was not significantly different (P = .07) from the THY/DHT in noncases (median 2.6, interquartile range 2.8-4.2). Although creatinine clearance was lower (P = .001) in cases, renal function could not discriminate cases from noncases. However, logistic regression analysis using both of these explanatory variables could discriminate most cases (receiver operating characteristic area 0.8792, 95% confidence interval 0.72-1.00). CONCLUSIONS: The THY challenge test combined with a patient's renal function may be useful as a phenotypic diagnostic test to detect risk of life-threatening fluoropyrimidine gastrointestinal toxicity.

Prescription medicines with potential for foetal harm: dispensing before and during pregnancy in New Zealand, 2005-2015.

PURPOSE: This study describes dispensing of potentially teratogenic prescription medicines before and during pregnancy in New Zealand over the period 2005-2015. METHODS: Records in a national dispensing database were linked with the members of the New Zealand Pregnancy Cohort to determine the proportion of pregnancies with at least one dispensing of a Category D or X medicine, using the Australian pregnancy risk categorisation system. Exposure was examined from 270 days prior to conception through to the end of pregnancy. Pregnancy outcomes of D/X-exposed pregnancies were reviewed. RESULTS: In the study, 874,884 pregnancies were included. Overall, Category D and X medicines were dispensed during 4.3% and 0.058% of pregnancies, respectively. After excluding misoprostol, X exposure decreased to 0.035%. Generally, dispensing declined through the 270-day pre-pregnancy period and continued to decline throughout pregnancy. Dispensing of X medicines increased over the study timeframe, whereas dispensing of D medicines increased from 2005 to 2011 then declined slightly. Smokers were more likely than non-smokers to have been dispensed a D/X medicine, and compared with European women, Maori and Pacific women were less likely to have been dispensed a D/X medicine. Excluding misoprostol, pregnancies exposed to an X medicine were more likely than D/X-unexposed pregnancies to have ended in termination. CONCLUSION: Dispensing of potentially harmful medicines in pregnancy in New Zealand was low, particularly for Category X medicines. However, exposure did increase over the study timeframe. The inclusion of pregnancies that did not progress past early pregnancy better reflects population-level pregnancy exposure to potentially teratogenic medicines.

Underuse of beta-blockers by patients with COPD and co-morbid acute coronary syndrome: A nationwide follow-up study in New Zealand.

BACKGROUND AND OBJECTIVE: Clinical guidelines recommend the use of beta-blockers and other cardiovascular prevention drugs in patients with acute coronary syndrome (ACS). Studies in several countries have found that beta-blockers are underused in patients with chronic obstructive pulmonary disease (COPD) and co-morbid heart disease, although most have only examined use in subgroups of patients. We undertook a nationwide follow-up study in New Zealand to describe the use of beta-blockers and other cardiovascular prevention drugs in patients with COPD and ACS. METHODS: National health and pharmaceutical dispensing data were used to derive the study cohort, identify patients who were admitted to hospital with ACS and/or heart failure before cohort entry and during follow-up, and ascertain drug use. RESULTS: The study cohort included 83 435 patients aged ≥45 years, with 290 400 person-years of follow-up. Among 2637 patients with ≥1 ACS admission during follow-up, only 56.6% received a beta-blocker in the 6 months following the first admission, while 87.7% and 81%, respectively, received aspirin and a statin. Patients with higher COPD severity were less likely to receive a beta-blocker than those with lower severity, as were those with no history of previous ACS and/or heart failure. CONCLUSION: Use of beta-blockers following an ACS admission was much lower than expected based on the findings of general audits of ACS management in New Zealand. Along with the higher proportions using aspirin and statins, and the differences in beta-blocker dispensing by COPD severity, this suggests a particular reluctance to prescribe beta-blockers to patients with COPD.

Child undernutrition in households with microbiologically safer drinking water and 'improved water' in Tanna, Vanuatu.

The Sustainable Development Goal drinking water indicators include microbiological safety measures, whereas the Millennium Development Goal indicator 'improved water' may be microbiologically unsafe. In rural Vanuatu, we undertook household surveys, child anthropometry, and tested stored drinking water, to investigate relationships between water and undernutrition. Using Escherichia coli most probable number, we categorized results according to Compartment Bag Test drinking water cutoffs: <1/100 mL (safe), 1-10/100 mL (intermediate risk), >10-100/100 mL (high risk), and >100/100 mL (very high risk). Of 201 households, 191 (95%) had microbiologically unsafe drinking water, regardless of 'improved' status. We investigated cross-sectional associations between households with microbiologically safer drinking water (≤10 E. coli/100 mL) versus 'improved water' and undernutrition among children. Of children under 5, 145 (48.8%, 95% CI: 42.8, 54.8) were stunted and 59 (19.1%, 95% CI: 14.4, 23.8) were underweight. Among households with 'improved water', the adjusted prevalence ratio (95% CI) of stunting was 0.61 (0.46, 0.80) and underweight was 0.46 (0.29, 0.73) compared with 'unimproved water'. However, we found no association between having drinking water with ≤10 E. coli/100 mL at one point in time and undernutrition. Longer-term variations in water quality and unmeasured conditions beyond water may have contributed to these associations.

Latent tuberculosis infection in healthcare workers in low- and middle-income countries: an updated systematic review.

Healthcare workers (HCWs) are at increased risk of latent tuberculosis (TB) infection (LTBI) and TB disease.We conducted an updated systematic review of the prevalence and incidence of LTBI in HCWs in low- and middle-income countries (LMICs), associated factors, and infection control practices. We searched MEDLINE, Embase and Web of Science (January 1, 2005-June 20, 2017) for studies published in any language. We obtained pooled estimates using random effects methods and investigated heterogeneity using meta-regression.85 studies (32 630 subjects) were included from 26 LMICs. Prevalence of a positive tuberculin skin test (TST) was 14-98% (mean 49%); prevalence of a positive interferon-γ release assay (IGRA) was 9-86% (mean 39%). Countries with TB incidence ≥300 per 100 000 had the highest prevalence (TST: pooled estimate 55%, 95% CI 41-69%; IGRA: pooled estimate 56%, 95% CI 39-73%). Annual incidence estimated from the TST was 1-38% (mean 17%); annual incidence estimated from the IGRA was 10-30% (mean 18%). The prevalence and incidence of a positive test was associated with years of work, work location, TB contact and job category. Only 15 studies reported on infection control measures in healthcare facilities, with limited implementation.HCWs in LMICs in high TB incidence settings remain at increased risk of acquiring LTBI. There is an urgent need for robust implementation of infection control measures.

A phase I vaccination study with dendritic cells loaded with NY-ESO-1 and α-galactosylceramide: induction of polyfunctional T cells in high-risk melanoma patients.

Vaccines that elicit targeted tumor antigen-specific T-cell responses have the potential to be used as adjuvant therapy in patients with high risk of relapse. However, the responses induced by vaccines in cancer patients have generally been disappointing. To improve vaccine function, we investigated the possibility of exploiting the immunostimulatory capacity of type 1 Natural killer T (NKT) cells, a cell type enriched in lymphoid tissues that can trigger improved antigen-presenting function in dendritic cells (DCs). In this phase I dose escalation study, we treated eight patients with high-risk surgically resected stage II-IV melanoma with intravenous autologous monocyte-derived DCs loaded with the NKT cell agonist α-GalCer and peptides derived from the cancer testis antigen NY-ESO-1. Two synthetic long peptides spanning defined immunogenic regions of the NY-ESO-1 sequence were used. This therapy proved to be safe and immunologically effective, inducing increases in circulating NY-ESO-1-specific T cells that could be detected directly ex vivo in seven out of eight patients. These responses were achieved using as few as 5 × 105 peptide-loaded cells per dose. Analysis after in vitro restimulation showed increases in polyfunctional CD4+ and CD8+ T cells that were capable of manufacturing two or more cytokines simultaneously. Evidence of NKT cell proliferation and/or NKT cell-associated cytokine secretion was seen in most patients. In light of these strong responses, the concept of including NKT cell agonists in vaccine design requires further investigation.

Generation of a pregnancy cohort for medicine utilisation and medicine safety studies in New Zealand.

PURPOSE: The aim of this study was to use national health databases to assemble a pregnancy cohort for undertaking medicine utilisation and safety studies in New Zealand. METHOD: Pregnancies conceived between January 2005 and March 2015 were identified in the National Maternity Collection, the National Minimum Dataset, the Mortality Collection, and the Laboratory Claims Collection. Pregnancy start and end dates were calculated and used in conjunction with the National Health Index number to merge the records from the four collections to create the New Zealand Pregnancy Cohort. Records of live born and stillborn infants identified in the National Maternity Collection and the Mortality Collection that were linkable with a cohort member formed the baby cohort. RESULTS: The cohort consists of 941 468 pregnancies to 491 272 women. One-third of the pregnancies, predominantly early pregnancy losses and terminations, were not found in the National Maternity Collection. Records of 632 090 live born or stillborn infants are linked with 623 099 pregnancies. CONCLUSIONS: The New Zealand Pregnancy Cohort is a comprehensive collection of virtually all pregnancies which ended in a live or stillbirth and many, though not all, which ended as early pregnancy losses or terminations in New Zealand over the past decade, and better represents the pregnant population than a cohort generated from the National Maternity Collection alone would do. This cohort will be valuable for investigating patterns of medicine use during pregnancy in New Zealand and developing a fuller understanding of potential impacts of foetal exposure in early pregnancy.

Patterns of use of long-acting bronchodilators in patients with COPD: A nationwide follow-up study of new users in New Zealand.

BACKGROUND AND OBJECTIVE: While several studies have found that prescribing practices do not conform to chronic obstructive pulmonary disease (COPD) treatment guidelines, none have examined longitudinal patterns of use of long-acting beta2 -agonist (LABA) and long-acting muscarinic antagonist (LAMA) therapy across an entire country. We undertook a nationwide follow-up study to describe treatment patterns in new users of long-acting bronchodilators. METHODS: National health and pharmaceutical dispensing data were used to identify patients aged ≥45 years who initiated LABA and/or LAMA therapy for COPD between 1 February 2006 and 31 December 2013. Dispensings of LABAs, LAMAs and inhaled corticosteroids (ICSs) were aggregated into episodes of use of therapeutic regimens. Kaplan-Meier curves, sunburst plots and sequence index plots were generated to summarize, respectively, the duration of the first regimen, the sequences in which unique regimens were used and the patterns of use and non-use during follow-up. RESULTS: The study cohort included 83 435 patients with 290 400 person-years of follow-up. The most commonly initiated regimen was a LABA with an ICS. ICS use was inconsistent with international guidelines: over- and under-treatment occurred in patients with infrequent and frequent exacerbations, respectively, and ICS monotherapy was common. The median duration of the first regimen was 46 days. Many patients used multiple regimens over time and periods of non-use were common. CONCLUSION: In this nationwide study, patterns of use of LABAs, LAMAs and ICSs were complex and often did not comply with treatment guidelines. Further work is required to address the discrepancy between guidelines and prescribing practices.

Media reporting of health interventions in New Zealand: a retrospective analysis.

AIM: To evaluate New Zealand media articles on their coverage of key issues regarding health interventions and whether it is consistent with available evidence. METHODS: A retrospective analysis was carried out of all articles published in five New Zealand media sources over a 6-week period between 15 October and 26 November 2014. Articles were included if their primary focus was on health interventions involving medications, devices or in-hospital procedures. Articles were assessed for coverage of key issues using previously validated 10-point criteria. A literature review was performed to compare content with scientific evidence. RESULTS: We identified 30 articles for review. Only 4 of 30 articles covered indications, benefits and risks, and of these, two were consistent with available evidence (7%, 95% CI 1%-22%). For articles that discussed at least one of indications, benefits or risks, and there was corresponding evidence available, there was a high level of consistency with the evidence (89%, 95% CI 77%-95%). The overall mean value of coverage from the 10-point criteria was 51% (95% CI 45%-58%). Single questions regarding the potential harm, costs associated with the intervention and the availability of alternative options were particularly poorly covered. They were rated as 'satisfactory' in 13%, 23% and 33% of the 30 articles respectively. CONCLUSION: New Zealand news articles covering medical treatments and interventions are largely consistent with available evidence but are incomplete. Vital information is being consistently missed, especially around the potential harms and costs of medical interventions.

Outcomes for women without conventional treatment for stage 1A (microinvasive) carcinoma of the cervix.

BACKGROUND: An unethical clinical study that entailed withholding treatment from women diagnosed with cervical intraepithelial neoplasia 3 (CIN3) was conducted at National Women's Hospital, Auckland, New Zealand. Women with microinvasive carcinoma of the cervix also had treatment withheld. AIMS: To describe the management and outcomes for women with microinvasive carcinoma for many of whom conventional treatment was withheld. MATERIALS AND METHODS: Retrospective cohort study of women with a diagnosis of stage 1A cervical carcinoma at National Women's Hospital. Medical records, cytology and histopathology were reviewed and data linked with cancer and death registries up to December 2000. RESULTS: Between 1955 and 1976, 62 women were initially diagnosed with stage 1A cervical cancer and 20 were diagnosed during follow up (to 1995). Sixty of the 82 women had initial management characterised as 'probably non-curative'; 20 of these received only a small diagnostic excision. Women in the latter group were more likely to: (i) subsequently have positive cytology (P < 0.0005), (ii) have untreated positive cytology (P = 0.02), and (iii) undergo multiple biopsies after initial management (P = 0.001). Of the women who received only a small diagnostic excision, eight of 20 developed invasive carcinoma of the cervix (≥ stage 1B) or vaginal vault, compared to two of 22 women who received initial treatment characterised as 'probably curative'. CONCLUSIONS: Women with microinvasive carcinoma were included in a natural history study of CIN3; they underwent numerous procedures designed to observe rather than treat their condition, and had a substantial risk of invasive cancer.