Sex as a predictor of clinical phenotype and determinant of immune response in IgG4-related disease: a retrospective study of patients fulfilling the American College of Rheumatology-European League Against Rheumatism classification criteria.

BACKGROUND: IgG4-related disease is a multiorgan fibroinflammatory disease considered to have an autoimmune origin. Case series describing individual organ involvement have suggested differences in phenotypic expression between males and females. We aimed to characterise differences in IgG4-related disease manifestations between male and female patients in a large single-centre cohort. METHODS: In this retrospective, single-centre cohort study, patients were recruited from the Massachusetts General Hospital Rheumatology Clinic (Boston, MA, USA) and classified according to the American College of Rheumatology-European Alliance of Associations for Rheumatology (ACR-EULAR) classification criteria. Only patients satisfying the ACR-EULAR classification criteria were included in the study. Data on age at diagnosis, organ involvement at baseline, treatment status, and pre-treatment laboratory values were collected. Circulating plasmablasts and B-cell subsets were quantitated by flow cytometry. Active disease was defined by an IgG4-related disease Responder Index score of more than 0. Laboratory values were analysed for patients who were untreated at baseline and had active IgG4-related disease. The main outcomes were assessed in all participants with available data. FINDINGS: Of the 564 participants enrolled in the Massachusetts General Hospital Rheumatology Clinic IgG4-related disease Registry, 328 fulfilled ACR-EULAR classification criteria and were included between January, 2008, and May, 2023. There was a strong male predominance (male:female ratio 2·2:1) with 226 (69%) males and 102 (31%) females, which contrasted markedly with our general rheumatology clinic population (0·4:1; p<0·001). The male predominance increased with each decade of life starting at age 40 years. On average, male patients were 5·5 years older at diagnosis than female patients (63·7 years vs 58·2 years; p=0·0031). We observed male patients to have higher ACR-EULAR classification criteria scores at baseline with a median score of 35·0 (IQR 28·0-46·0), compared with 29·5 (25·0-39·0) for females (p=0·0010). The proportion of male patients with pancreatic and renal involvement was almost double the proportion observed in female patients (50% of the male patients had pancreatic involvement, compared with about 26% of the female patients; p<0·0001). Male patients were more likely to have serological abnormalities at baseline. The distribution of IgG4 values differed significantly between male an female sexes, favouring higher values in males. We found that male patients with IgG4-related disease were more likely to have active B-cell responses in the blood as defined by plasmablast expansions. INTERPRETATION: IgG4-related disease is unusual among autoimmune diseases in that it is more likely to affect males than females and to present with a striking sex-dependent organ distribution and degree of B-cell response. These findings highlight important variation between IgG4-related disease and other conditions generally believed to have an autoimmune basis. Most autoimmune diseases, by contrast to IgG4-related disease, demonstrate pronounced predilections for affecting females more frequently than males. Hypotheses surrounding the cause and pathophysiology of this condition need to consider this unusual sex distribution among patients with IgG4-related disease. FUNDING: National Institutes of Health, National Institute of Allergy and Infectious Diseases, Rheumatology Research Foundation, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Proliferative features of IgG4-related disease.

IgG4-related disease is an immune-mediated disease that can lead to substantial morbidity and organ damage. Capable of affecting nearly any organ system or anatomic site, and showing considerable overlap in clinical presentation with various other diseases, IgG4-related disease often poses a diagnostic challenge for clinicians. Furthermore, there are no diagnostic biomarkers with high specificity for IgG4-related disease, and histopathological examination is nuanced and requires clinical correlation for accurate diagnosis. Therefore, it is crucial for clinicians to recognise the clinical phenotypes of IgG4-related disease. The disease is generally considered to have predominantly fibrotic and proliferative (or inflammatory) manifestations, with distinct clinical, serological and histopathological findings associated with each manifestation. However, the fibrotic and proliferative manifestations of this disease frequently occur together, thereby blurring this dichotomous distinction. In this Series paper, we provide a detailed overview of the clinical manifestations typical of the proliferative features of IgG4-related disease, with an emphasis on the diagnostic evaluation and differential diagnosis of each proliferative disease manifestation. In addition, we summarise the immune mechanisms underlying IgG4-related disease, suggest a framework for how to approach management and monitoring after the diagnosis is established, and highlight current unmet needs for patient care surrounding this disease.

MHCII restriction demonstrates B cells have very limited capacity to activate tumour-specific CD4+ T cells in vivo.

There has been growing interest in the role of B cells in antitumour immunity and potential use in adoptive cellular therapies. To date, the success of such therapies is limited. The intrinsic capacity of B cells to specifically activate tumour-specific CD4+ T cells in vivo via TCR-dependent interactions remains poorly defined. We have developed an in vivo tumour model that utilizes MHCII I-E restriction which limits antigen presentation to tumour-specific CD4 T cells to either tumour-specific B cells or host myeloid antigen presenting cells (APCs) in lymphopenic RAG-/-mice. We have previously shown that these naive tumour-specific CD4+ T cells can successfully eradicate established tumours in this model when activated by host APCs. When naïve tumour-specific B cells are the only source of I-E+ APC, very limited proliferation of naïve CD4+ T cells is observed, whereas host I-E+ APCs are potent T cell activators. B cells pre-activated with an anti-CD40 agonistic antibody in vivo support increased T cell proliferation, although far less than host APCs. CD4+ T cells that have already differentiated to an effector/central memory phenotype proliferate more readily in response to naïve B cells, although still 100-fold less than in response to host APCs. This study demonstrates that even in a significantly lymphopenic environment, myeloid APCs are the dominant primary activators of tumour-specific T cells, in contrast to the very limited capacity of tumour-specific B cells. This suggests that future anti-tumour therapies that incorporate activated B cells should also include mechanisms that activate host APCs.

Expansion of CD4+ cytotoxic T lymphocytes with specific gene expression patterns may contribute to suppression of tumor immunity in oral squamous cell carcinoma: single-cell analysis and in vitro experiments.

Background: Cancer immunotherapy targeting CD8+ T cells has made remarkable progress, even for oral squamous cell carcinoma (OSCC), a heterogeneous epithelial tumor without a substantial increase in the overall survival rate over the past decade. However, the therapeutic effects remain limited due to therapy resistance. Thus, a more comprehensive understanding of the roles of CD4+ T cells and B cells is crucial for more robust development of cancer immunotherapy. Methods: In this study, we examined immune responses and effector functions of CD4+ T cells, CD8+ T cells and B cells infiltrating in OSCC lesions using single-cell RNA sequencing analysis, T cell receptor (TCR) and B cell receptor (BCR) repertoire sequencing analysis, and multi-color immunofluorescence staining. Finally, two Kaplan-Meier curves and several Cox proportional hazards models were constructed for the survival analysis. Results: We observed expansion of CD4+ cytotoxic T lymphocytes (CTLs) expressing granzymes, which are reported to induce cell apoptosis, with a unique gene expression patterns. CD4+ CTLs also expressed CXCL13, which is a B cell chemoattractant. Cell-cell communication analysis and multi-color immunofluorescence staining demonstrated potential interactions between CD4+ CTLs and B cells, particularly IgD- CD27- double negative (DN) B cells. Expansion of CD4+ CTLs, DN B cells, and their contacts has been reported in T and B cell-activated diseases, including IgG4-related disease and COVID-19. Notably, we observed upregulation of several inhibitory receptor genes including CTLA-4 in CD4+ CTLs, which possibly dampened T and B cell activity. We next demonstrated comprehensive delineation of the potential for CD8+ T cell differentiation towards dysfunctional states. Furthermore, prognostic analysis revealed unfavorable outcomes of patients with a high proportion of CD4+ CTLs in OSCC lesions. Conclusion: Our study provides a dynamic landscape of lymphocytes and demonstrates a systemic investigation of CD4+ CTL effects infiltrating into OSCC lesions, which may share some pathogenesis reported in severe T and B cell-activated diseases such as autoimmune and infectious diseases.

Low Pretreatment CD4+:CD8+ T Cell Ratios and CD39+CD73+CD19+ B Cell Proportions Are Associated with Improved Relapse-Free Survival in Head and Neck Squamous Cell Carcinoma.

The ectonucleotidases CD39 and CD73 are present on immune cells and play important roles in cancer progression by suppressing antitumour immunity. As such, CD39 and CD73 on peripheral blood mononuclear cells (PBMCs) are emerging as potential biomarkers to predict disease outcomes and treatment responses in cancer patients. This study aimed to examine T and B cells, including CD39 and CD73 expressing subsets, by flow cytometry in PBMCs from 28 patients with head and neck squamous cell carcinoma (HNSCC) and to assess the correlation with the treatment modality, human papillomavirus (HPV) status, and relapse-free survival (RFS). The PBMCs were examined pre-, mid-, and post-radiotherapy with concurrent cisplatin chemotherapy or anti-epidermal growth factor receptor antibody (cetuximab) therapy. Combination radiotherapy caused changes to T and B cell populations, including CD39 and CD73 expressing subsets, but no such differences were observed between concurrent chemotherapy and cetuximab. Pretreatment PBMCs from HPV+ patients contained increased proportions of CD39-CD73-CD4+ T cells and reduced proportions of CD39-/+CD73+CD4+ T cells compared to the equivalent cells from HPV- patients. Notably, the pretreatment CD4+:CD8+ T cell ratios and CD39+CD73+CD19+ B cell proportions below the respective cohort medians corresponded with an improved RFS. Collectively, this study supports the notion that CD39 and CD73 may contribute to disease outcomes in HNSCC patients and may assist as biomarkers, either alone or as part of immune signatures, in HNSCC. Further studies of CD39 and CD73 on PBMCs from larger cohorts of HNSCC patients are warranted.

Ultrasonic scalpel versus electrocautery for internal mammary artery harvesting: a meta-analysis.

OBJECTIVE: Although an ultrasonic harmonic scalpel (HS) has been used to harvest the internal mammary artery (IMA) for coronary artery bypass grafting, the benefits and risks compared to conventional electrocautery (EC) are not clear. We aimed to compare the outcomes of HS versus EC for IMA harvesting. METHODS: An electronic search was performed to identify all relevant studies. Baseline characteristics, perioperative variables, and clinical outcomes were extracted and pooled for meta-analysis. RESULTS: This meta-analysis included 12 studies. Pooled analyses demonstrated that both groups had comparable preoperative baseline characteristics including age, gender, and left ventricular ejection fraction. HS included more diabetic patients [33% (95% CI 30, 35) vs. 27% (23, 31), p = 0.01]. Harvest time for unilateral IMA was significantly longer with HS than EC [39 (31, 47) minutes vs. 25 (17, 33) minutes, p < 0.01]. However, the rate of pedicled unilateral IMA was significantly higher for EC compared with HS [20% (17, 24) vs. 8% (7, 9), p < 0.01]. The rate of intact endothelium was significantly higher with HS than EC [95% (88, 98) vs. 81% (68, 89), p < 0.01). There was no significant difference in postoperative outcomes including bleeding [3% (2, 4)], sternal infection [3% (2, 4)], and operative/30-day mortality [3% (2, 4)]. CONCLUSIONS: HS required longer IMA harvest times which could be partially attributed to a higher skeletonization rate in this category. HS may cause less endothelial injury than EC; however, no significant differences in postoperative outcomes were seen between the groups.

"Age could not wither her " because of her cytotoxic CD4+ T cells?

Cytotoxic CD4+ T cells specific for CMV cull senescent skin fibroblasts.

Effective alcohol policies are associated with reduced consumption among demographic groups who drink heavily.

BACKGROUND: Alcohol policies stand out among other noncommunicable disease-relevant policies for the lack of uptake. Composite indicators have been developed to measure the effects of alcohol control policy. We investigated whether drinking patterns among demographic groups from general population samples of drinkers from diverse countries are associated with alcohol control policy as measured by the International Alcohol Control (IAC) Policy Index. METHODS: Representative samples of adult drinkers from 10 countries (five high-income and five middle-income) were surveyed about alcohol consumption, using beverage and location-specific questions. MEASUREMENTS: The IAC Policy Index was analyzed with frequency, typical occasion quantity, and volume consumed. Analyses used mixed models that included interactions between country IAC Policy Index score and age group, gender, and education level. FINDINGS: Each increase in IAC policy index score (reflecting more effective alcohol policy) was associated with a 13.9% decrease in drinking frequency (p = 0.006) and a 16.5% decrease in volume (p = 0.001). With each increase in IAC Policy Index score, both genders decreased for all three measures, but men less so than women. Women decreased their typical occasion quantity by 1.2% (p = 0.006), frequency by 3.1% (p < 0.001), and total volume by 4.2% (p < 0.001) compared to men. Low and mid-education groups decreased their typical occasion quantity by 2.6% (p < 0.001) and 1.6% (p = 0.001), respectively, compared to high education, while for drinking frequency the low education group increased by 7.0% (p < 0.001). There was an overall effect of age (F = 19.27, p < 0.0001), with 18-19 and 20-24-year-olds showing the largest decreases in typical occasion quantity with increasing IAC policy index score. CONCLUSIONS: The IAC Policy Index, reflecting four effective policies, was associated with volume and frequency of drinking across 10 diverse countries. Each increase in the IAC Policy Index was associated with lower typical quantities consumed among groups reporting heavy drinking: young adults and less well-educated. There is value in implementing such alcohol policies and a need to accelerate their uptake globally.

Effective alcohol policies and lifetime abstinence: An analysis of the International Alcohol Control policy index.

INTRODUCTION: Alcohol abstinence remains common among adults globally, although low and middle-income countries are experiencing declines in abstention. The effect of alcohol policies on lifetime abstinence is poorly understood. The International Alcohol Control (IAC) policy index was developed to benchmark and monitor the uptake of effective alcohol policies and has shown strong associations with alcohol per capita consumption and drinking patterns. Uniquely, the index incorporates both policy 'stringency' and 'impact', reflecting policy implementation and enforcement, across effective policies. Here we assessed the association of the IAC policy index with lifetime abstinence in a diverse sample of jurisdictions. METHODS: We conducted a cross-sectional analysis of the relationship between the IAC policy index score, and its components, and lifetime abstinence among adults (15+ years) in 13 high and middle-income jurisdictions. We examined the correlations for each component of the index and stringency and impact separately. RESULTS: Overall, the total IAC policy index scores were positively correlated with lifetime abstinence (r = 0.76), as were both the stringency (r = 0.62) and impact (r = 0.82) scores. Marketing restrictions showed higher correlations with lifetime abstinence than other policy domains (r = 0.80), including restrictions on physical availability, pricing policies and drink-driving prevention. DISCUSSION AND CONCLUSION: Our findings suggest that restricting alcohol marketing could be an important policy for the protection of alcohol abstention. The IAC policy index may be a useful tool to benchmark the performance of alcohol policy in supporting alcohol abstention in high and middle-income countries.

An alternate approach: Percutaneous axillary cannulation for minimally invasive cardiac surgery.

BACKGROUND: Percutaneous axillary artery cannulation for cardiopulmonary bypass (CPB) offers a novel alternate approach to mechanical circulatory support for patients with contraindications to femoral perfusion. To our knowledge, this has not yet been reported in minimally invasive cardiac surgery (MICS). AIM: We aim to highlight our experience using percutaneous axillary artery cannulation to safely facilitate CPB for minimally invasive cardiac surgery MICS. METHODS: Four patients who underwent robotic cardiac surgery utilizing the axillary artery for percutaneous cannulation between November 2019 and August 2021 at a single center were identified and included in the analysis. Preoperative, intraoperative, and postoperative data were collected and analyzed to support this case series. RESULTS: There were no perioperative hematomas, brachial plexus injuries, or neurovascular injuries. Within 30-days postoperatively there was no mortality, vessel injury, stroke, new onset atrial fibrillation, or other life-threatening bleeding. CONCLUSION: Percutaneous cannulation of the axillary artery is a novel and promising CPB modality for robotic cardiac surgery in patients with extensive peripheral and aortic atherosclerotic disease.

Benchmarking alcohol policy based on stringency and impact: The International Alcohol Control (IAC) policy index.

This study developed a measurement tool to assess stringency and 'on-the-ground' impact of four key alcohol policy domains to create an alcohol policy index suitable for benchmarking alcohol policy and assessing change over time in middle- and high-income countries. It involved a collaboration between researchers in 12 diverse countries: New Zealand; Australia; England; Scotland; Netherlands; Vietnam; Thailand; South Africa; Turkey; Chile; Saint Kitts and Nevis and Mongolia. Data on the four most effective alcohol policy domains (availability, pricing policy, alcohol marketing, drink driving) were used to create an alcohol policy index based on their association with alcohol per capita consumption (APC) of commercial (recorded) alcohol. An innovation was the inclusion of measures of impact along with the stringency of the legislation or regulation. The resulting International Alcohol Control (IAC) Policy Index showed a very high negative correlation (-0.91) with recorded APC. Greater affordability of alcohol, an impact measure taking into account prices paid and countries' Gross Domestic Product, was predictive of higher APC (-0.80). Countries in which more modes of alcohol marketing are legally allowed and used had higher APC. Legislation on outlet density and drink driving predicted APC whereas trading hours did not. While stringency and impact measures varied between domains in terms of relationship with APC, overall, there was a strong correlation between impact and stringency (0.77). The IAC Policy Index, which includes measures of policy stringency and 'on-the-ground' impacts in relation to four key policy areas, was found to be strongly associated with commercial alcohol consumed in a number of diverse country settings. It showed a larger relationship than previous indices that include more policy dimensions. The index provides a relatively simple tool for benchmarking and communication with policy makers to encourage a strong focus on uptake of these four most effective alcohol policies.

Predictors of medicinal cannabis users' willingness to utilise a new prescription Medicinal Cannabis Scheme in New Zealand.

AIM: To investigate medicinal cannabis users' intentions to transition to the new prescription Medicinal Cannabis Scheme (MCS) in New Zealand. METHOD: An online survey of 3,634 past-year medicinal cannabis users completed prior to implementation of the MCS in New Zealand in April 2020. Logistic regression models were fitted to identify predictors of intended future engagement with the MCS. RESULTS: Seventy-eight percent of respondents were aware of the new MCS and 66% intended to use it. Higher income (OR=1.57), younger age (OR=1.02) and smoking cannabis (v. vaping (OR=2.0) or oral ingestion in edible form (OR=2.22)) predicted intention to engage with the MCS. Conversely, Maori (OR=0.63) and those who grew their own cannabis (OR=0.52) were less likely to intend to engage with the new prescription MCS. CONCLUSION: The lower intended engagement with the MCS by Maori, lower income groups and those who home-grow cannabis may reflect their perceptions of the MCS as restrictive and expensive.

Regulation of photosynthetic electron flow on dark to light transition by ferredoxin:NADP(H) oxidoreductase interactions.

During photosynthesis, electron transport is necessary for carbon assimilation and must be regulated to minimize free radical damage. There is a longstanding controversy over the role of a critical enzyme in this process (ferredoxin:NADP(H) oxidoreductase, or FNR), and in particular its location within chloroplasts. Here we use immunogold labelling to prove that FNR previously assigned as soluble is in fact membrane associated. We combined this technique with a genetic approach in the model plant Arabidopsis to show that the distribution of this enzyme between different membrane regions depends on its interaction with specific tether proteins. We further demonstrate a correlation between the interaction of FNR with different proteins and the activity of alternative photosynthetic electron transport pathways. This supports a role for FNR location in regulating photosynthetic electron flow during the transition from dark to light.

Effects of storage time and temperature on highly multiparametric flow analysis of peripheral blood samples; implications for clinical trial samples.

We sought to determine the effect of time and temperature of blood sample storage before preparation of human peripheral blood mononuclear cells (PBMCs) by Ficoll-hypaque density gradient centrifugation. Blood samples from healthy donors were stored at room temperature (RT) or refrigerated at 4°C before preparation of PBMCs. Cell yield and viability, and proportions of major cell populations within PBMCs, as determined by fluorescence flow cytometry, were assessed for both fresh and cryopreserved samples. Highly multiparametric mass cytometry was performed on cryopreserved PBMCs. We found that refrigeration had marked negative effects on subsequent PBMC yield. Storage at RT led to co-purification of low density neutrophils with PBMCs, but had no detectable effects on the proportions of multiple cell subsets including, but not limited to, monocytes, NK cells, B cells, Treg cells, and naïve, central memory and effector memory CD4+ and CD8+ T cells and CD45RA-positive terminal effector CD8+ T cells. Expression of a number of cell surface receptors, including CXCR5, CCR6, CXCR3 and TIGIT, but not CD247 was reduced after RT storage before PBMC preparation, and this effect correlated with the degree of low density neutrophil contamination. As such, when PBMC preparation cannot be undertaken immediately after blood draw, storage at RT is far superior to refrigeration. RT storage leads to neutrophil activation, but does not compromise measurement of PBMC subset distribution. However caution must be applied to interpretation of cytometric measurements of surface molecules such as chemokine receptors.

Bacterial antigen is directly delivered to the draining lymph nodes and activates CD8+ T cells during Staphylococcus aureus skin infection.

Staphylococcus aureus is one of the most common causes of community- and hospital-acquired bacterial infection worldwide. While neutrophils play an important role in anti-S. aureus immune defense, the role of adaptive immunity is less clear. In this study, we generated a model antigen-expressing S. aureus strain to investigate the dynamics and magnitude of T cell immune responses against this pathogen. We demonstrate that S. aureus is delivered to the draining lymph nodes (LNs) by lymphatic flow immediately after intradermal inoculation. There, the bacterium initiates CD8+ cytotoxic T lymphocyte (CTL) proliferation via activating LN-resident dendritic cells. Large numbers of neutrophils are recruited to the draining LNs to engulf bacteria; however, neutrophil depletion did not impact on CTL proliferation, despite increasing bacterial burden. Tissue-resident memory T cells were formed in the skin at bacteria-inoculated sites. Yet, blood and tissue-resident memory T cells failed to prevent secondary cutaneous S. aureus infection. Our study defines the delivery kinetics of S. aureus from the skin and suggests that CTLs are dispensable for protection against skin infections.

Comparison of peripheral blood mononuclear cell isolation techniques and the impact of cryopreservation on human lymphocytes expressing CD39 and CD73.

CD39 and CD73 are ecto-nucleotidases present on human peripheral blood mononuclear cells (PBMCs) and are emerging biomarkers on these cells in various disorders including cancer. Many factors influence PBMC quality, so it is essential to validate sample processing methods prior to incorporation in clinical studies. This study examined the impact of both PBMC cryopreservation and PBMC isolation using SepMate density gradient centrifugation on CD39 and CD73 expressing subsets. First, PBMCs were isolated from the peripheral blood of 11 healthy donors by routine Ficoll-Paque density gradient centrifugation, cryopreserved and compared with freshly isolated PBMCs by flow cytometry. The proportions of T and B cells expressing combinations of CD39 and CD73 were relatively stable over 6-month cryopreservation, although some T cell combinations revealed small but significant changes. Second, peripheral blood was collected from six healthy donors to compare PBMCs isolated by SepMate or Ficoll-Paque density gradient centrifugation. Compared with Ficoll-Paque, the more rapid SepMate method yielded 9.1% less PBMCs but did not alter cell viability or proportions of T and B cells expressing combinations of CD39 and CD73. The present study reveals that cryopreservation is suitable for studying T and B cells expressing combinations of CD39 and CD73. However, caution should be exercised when observing small differences in these cryopreserved subsets between different cohorts. Further, SepMate and Ficoll-Paque methods of PBMC isolation show similar results for T and B cell subset analysis; however, SepMate is a faster and easier approach.

Exploring medicinal use of cannabis in a time of policy change in New Zealand.

AIMS: To explore patterns of medicinal cannabis use prior to implementation of the new Medicinal Cannabis Scheme (MCS) in New Zealand. METHODS: An anonymous online convenience survey of 3,634 last-year medicinal users of cannabis promoted via Facebook™ from May to August 2019. RESULTS: Fifty percent of the sample were female, 18% were Maori and the median age was 38 years. The medical conditions for which cannabis was most often used were pain (81%), sleep (66%) and mental health conditions (64%). Respondents perceived cannabis to be an effective therapy and reported reducing use of other pharmaceutical medicines. Fifty-two percent reported side effects from cannabis use, including increased appetite (29%), drowsiness (12%), eye irritation (11%), dependency (10%), memory impairment (10%) and lack of energy (9%). Smoking was the dominant route of administration. Nearly half (47%) had discussed their use of cannabis with a medical professional in the previous year, while 14% had requested a prescription and 5% accessed a prescribed cannabis-based product (mostly oral CBD). CONCLUSION: Respondents self-medicated with cannabis to treat a wide range of health complaints. Only half discussed medicinal cannabis use with their medical professional, and a minority requested a prescription and used a prescribed cannabis-based product.

Determinants of the retail price of illegal drugs in New Zealand.

INTRODUCTION: New Zealand has a number of unusual geographical features that may influence the price of illegal drugs including international isolation, numerous rural communities, and two separate islands (North and South Islands). AIMS: (1) Collect data on the prices of different drug types from all regions of New Zealand; (2) Identify independent predictors of the reported prices. METHOD: An online drug survey was promoted via a targeted Facebook™ campaign. A total of 6331 respondents completed the survey. Normal regression models were constructed to identify predictors of the reported price of an ounce of cannabis, gram of methamphetamine, pill of ecstasy and tab of LSD using demographics, drug use frequency, drug market indicators, region, community size, type of seller, and location of purchase as predictor variables. RESULTS: Higher availability was a predicator of lower prices for cannabis (-3% per higher availability category), methamphetamine (-4%) and ecstasy (-5%). Those living in the North Island (-26%) and buying from gangs (-5%) paid lower prices for methamphetamine. Those living in rural communities reported higher prices for methamphetamine (+5%) but lower prices for cannabis (-3%). Daily cannabis users (+4%) and those on social welfare (+2%) paid higher prices for cannabis. CONCLUSION: Lower prices for methamphetamine in the North Island may reflect the concentration of methamphetamine manufacture there. The fact that gangs offer lower prices for methamphetamine suggests they do not have monopoly control of this market. Gangs may be able to offer lower prices for methamphetamine due to scale of production/trafficking and lower risk of victimisation. Higher prices for methamphetamine in rural areas may reflect less competitive markets. Lower prices for cannabis in rural communities may be due to proximity to growing locations. Daily cannabis users and those on social welfare may be less able to delay their cannabis purchases to low price harvest months.