Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal.

Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5' UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor's most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention.

Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal.

The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance.

Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal.

Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases.

Population and contact tracer uptake of New Zealand's QR-code-based digital contact tracing app for COVID-19.

This study aimed to understand the population and contact tracer uptake of the quick response (QR)-code-based function of the New Zealand COVID Tracer App (NZCTA) used for digital contact tracing (DCT). We used a retrospective cohort of all COVID-19 cases between August 2020 and February 2022. Cases of Asian and other ethnicities were 2.6 times (adjusted relative risk (aRR) 2.58, 99 per cent confidence interval (95% CI) 2.18, 3.05) and 1.8 times (aRR 1.81, 95% CI 1.58, 2.06) more likely than Maori cases to generate a token during the Delta period, and this persisted during the Omicron period. Contact tracing organization also influenced location token generation with cases handled by National Case Investigation Service (NCIS) staff being 2.03 (95% CI 1.79, 2.30) times more likely to generate a token than cases managed by clinical staff at local Public Health Units (PHUs). Public uptake and participation in the location-based system independent of contact tracer uptake were estimated at 45%. The positive predictive value (PPV) of the QR code system was estimated to be close to nil for detecting close contacts but close to 100% for detecting casual contacts. Our paper shows that the QR-code-based function of the NZCTA likely made a negligible impact on the COVID-19 response in New Zealand (NZ) in relation to isolating potential close contacts of cases but likely was effective at identifying and notifying casual contacts.

Corrigendum: Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

This corrects the article DOI: 10.1038/nature22364.

Barriers to adopting digital contact tracing for COVID-19: Experiences in New Zealand.

BACKGROUND: Digital contact tracing (DCT) was a central component of the global response to containing COVID-19. Research has raised concerns that DCT could exacerbate inequities, yet the experiences of diverse communities at greater risk from COVID-19 are typically underrepresented. METHODS: The present study aimed to understand the perceived barriers to the adoption of the app amongst Maori, Pasifika, and disabled people. Focus groups and interviews were undertaken with Maori, Pasifika, and disability sector stakeholders and community participants. RESULTS: Participants (n = 34) generally expressed willingness to utilise DCT and support its adoption within the communities. Simultaneously, participants revealed how the app could marginalise community members who struggled with the usability and those distrusting of the government's COVID-19 interventions. CONCLUSIONS: The findings highlight how addressing communication inequality can assist in the development of contact-tracing responses that are both effective and equitable. The study provides insights about the role of information and communication technologies as health resources. PATIENT OR PUBLIC CONTRIBUTION: Consulting with members of the target communities was central throughout the present study, including recommendations for potential participants, participation in interviews and sharing early findings for feedback. This study reports on focus groups and interviews with individuals from Maori and disability sectors.

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.

The potential human health hazard of nitrates in drinking water: a media discourse analysis in a high-income country.

BACKGROUND: Recent studies linking low levels of nitrate in drinking water to colorectal cancer have raised public concerns over nitrate contamination. The aim of this study was to analyze the media discourse on the potential human health hazard of nitrates in drinking water in a high-income country with a large livestock industry: New Zealand (NZ). METHODS: Searches of media sources ("major newspapers") held by the Factiva database for the NZ setting in the five-year period 17 December 2016 to 20 December 2021. RESULTS: The largest number of media items was observed for 2017 (n = 108), the year of a NZ general election, with a notable decrease in 2020 (n = 20) that was likely due to the Covid-19 pandemic, which dominated health media. However, the percentage of these media items with a health focus steadily increased over time, from 11.1% of all articles in 2017 to 51.2% in 2021. The most commonly mentioned health hazard was colorectal cancer, followed by methemoglobinemia. The temporal pattern of media items suggests that the release of scientific studies and scholarly blogs was associated with the publication of subsequent media items. Major stakeholders involved in the discourse included representatives of local and central government, environmental and recreational interest groups, researchers, local residents, agricultural interest groups, and health organizations. Maori (Indigenous New Zealanders) values or perspectives were rarely mentioned. CONCLUSIONS: Analysis of major newspapers for a five-year period indicated that a wide range of expert comment and opinions were made available to the public and policy makers on the issue of nitrates in water. While many different stakeholder views were captured in the media discourse, there is scope for the media to better report the views of Maori on this topic. There is also a need for articles detailing the health issues to also refer to the environmental, recreational, and cultural aspects of protecting water quality to ensure that the public, policy makers, and regulators are aware of co-benefits.

The nature and extent of outdoor alcohol marketing in Wellington, New Zealand: a longitudinal audit and spatio-temporal analysis of outdoor alcohol marketing.

AIM: exposure to alcohol marketing is associated with increased consumption. We aimed to (i) measure the nature and extent of outdoor alcohol marketing within a high-density urban neighbourhood and (ii) examine temporal and spatial trends in alcohol marketing. METHODS: this study used a longitudinal design to monitor paid advertising in public spaces over two 10-week periods in Wellington, New Zealand (Nov-Jan 2020-2021, Nov-Jan 2021-2022). The data were collected on-foot following an established route once a week using a phone camera, which also recorded gps data of ad locations. Temporal and spatial trends in alcohol ad prevalence were assessed. RESULTS: over the study period, 13% (n = 1619) of all ads (n = 12,472) were for alcohol. Alcohol ads were predominately for spirits (29%), ready-to-drink (27%) and beer (23%). Almost half of all alcohol ads (49%) did not contain a responsible consumption message, while those with a message were de-emphasized relative to promotional features. A temporal trend was observed in 2020, whereby alcohol marketing decreased over the summer, but this trend was not reflected in 2021. Alcohol ads were more likely than non-alcohol ads to be placed in premium positions on roads of high pedestrian and motor vehicle traffic. CONCLUSION: alcohol marketing is common in urban centres. Local and central government policy could substantially reduce the levels of alcohol marketing exposure via outdoor marketing.

Pilot of a digital contact tracing card in a hospital setting in New Zealand, 2020.

Countries are rapidly developing digital contact tracing solutions to augment manual contact tracing. There is limited empirical evidence evaluating these tools. We conducted a feasibility study of a Bluetooth-enabled card with hospital staff in New Zealand (n = 42). We compared the card data against self-report contact surveys and a stronger Bluetooth device. The cards detected substantially more contacts than self-report contact surveys, while the concordance between Bluetooth devices was high, suggesting that the cards detected clinically relevant close contacts. There was high acceptability among participants, suggesting that their integration would be accepted by healthcare staff. As the pandemic shifts, there is a need to rapidly contact trace and conduct informed risk management, particularly in critical settings such as healthcare.

Nitrate contamination in drinking water and colorectal cancer: Exposure assessment and estimated health burden in New Zealand.

BACKGROUND: Epidemiological evidence in multiple jurisdictions has shown an association between nitrate exposure in drinking water and an increased risk of colorectal cancer (CRC). OBJECTIVE: We aimed to review the extent of nitrate contamination in New Zealand drinking water and estimate the health and financial burden of nitrate-attributable CRC. METHODS: We collated data on nitrate concentrations in drinking water for an estimated 85% of the New Zealand population (∼4 million people) who were on registered supplies. We estimated nitrate levels for the remaining population (∼600,000 people) based on samples from 371 unregistered (private) supplies. We used the effective rate ratio from previous epidemiological studies to estimate CRC cases and deaths attributable to nitrate in drinking water. RESULTS: Three-quarters of New Zealanders are on water supplies with less than 1 mg/L NO3-N. The population weighted average for nitrate exposure for people on registered supplies was 0.49 mg/L NO3-N with 1.91% (95%CI 0.49, 3.30) of CRC cases attributable to nitrates. This correlates to 49.7 cases per year (95%CI 14.9, 101.5) at a cost of 21.3 million USD (95% 6.4, 43.5 million USD). When combining registered and unregistered supplies, we estimated 3.26% (95%CI 0.84, 5.57) of CRC cases were attributable to nitrates, resulting in 100 cases (95%CI 25.7, 171.3) and 41 deaths (95%CI 10.5, 69.7) at a cost of 43.2 million USD (95%CI 10.9, 73.4). CONCLUSION: A substantial minority of New Zealanders are exposed to high or unknown levels of nitrates in their drinking water. Given the international epidemiological studies showing an association between cancer and nitrate ingestion from drinking water, this exposure may cause an important burden of preventable CRC cases, deaths, and economic costs. We consider there is sufficient evidence to justify a review of drinking water standards. Protecting public health adds to the strong environmental arguments to improve water management in New Zealand.

Expert insights on digital contact tracing: interviews with contact tracing policy professionals in New Zealand.

Digital contact tracing (DCT) is the application of digital tools to assist with identifying and informing close contacts of a COVID-19 case. DCT is a potential solution to capacity constraints of current manual contact tracing processes. Expert opinion from contact tracing professionals rarely informs public discourse on the benefits and limitations of DCT solutions. Three focus groups were undertaken in New Zealand to understand benefits and limitations of DCT solutions from contact tracing professionals. One was with the National Investigation and Tracing Centre (NITC) and two were with Public Health Units (PHUs). Participants highlighted four key themes including: (i) equity, (ii) privacy, (iii) communication and public perception and (iv) the operational model. Participants were concerned DCT solutions could exacerbate existing health inequities due to lack of access to, or familiarity with, technology. Poor communication and public understanding of DCT were seen as a major threat to both the efficacy of DCT solutions and the wider COVID-19 response. Most importantly, end-users were cautious of the operational model for DCT data that might: (i) attempt to replace manual processes that cannot or should not be automated by technology (case investigations, follow-ups); (ii) place undue burden on citizens and (iii) increase the workload for the current system beyond its capacity, for unproven or limited benefit. To be effective, contact tracing professionals believed DCT technologies must have strong privacy safeguards, a clear and simple communication strategy, interoperability with the existing contact tracing system and a foundation of health equity.

Where do the children play? An objective analysis of children's use of green space.

Green space is important for health, yet, objective research on children's use of green space is sparse. This study aimed to objectively assess children's use of green space in both public and private settings during their summer leisure time, using wearable cameras. Images from cameras worn by 74 children were analysed for green space use over 4 days. Children spent an average of ∼1/10 h of leisure time in green space in the summer months, were physically active 68%, and with others 85%, of the time. Green spaces are important places for children's health because they are places they frequent and places where they are physically active and socialize. Wearable cameras provide an effective method for objective assessment of green space use.

Tracking the Evolution of Non-Small-Cell Lung Cancer.

BACKGROUND: Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC. METHODS: In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence-free survival. RESULTS: We observed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy-number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy-number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P=4.4×10-4), which remained significant in multivariate analysis. CONCLUSIONS: Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601 .).

Alcohol Sponsorship and Esports: Reinforcing the Need for Legislative Restrictions on Alcohol Sponsorship.

Alcohol sponsorship in esports is on the rise. Many esports athletes and viewers are children and young people. Alcohol sponsorship of esports places millions of children and young people at risk of alcohol-related harm. Action on alcohol sponsorship in esports may provide policy makers an opportunity for greater restrictions on all alcohol sports sponsorship.

Space-time analysis of unhealthy food advertising: New Zealand children's exposure and health policy options.

Reducing children's exposure to unhealthy food advertising is an accepted strategy to end childhood obesity. This study aimed to (i) measure children's space-time exposures to unhealthy food advertising in public outdoor spaces, using GPS and wearable cameras; and (ii) test effectiveness of banning options. We compiled data (collected July 2014-June 2015) on 138 12-year-old children in Wellington, New Zealand, using wearable cameras and GPS devices worn over 4 days. In 2017-18, we linked 59 150 images taken in public outdoor spaces to GPS data. Of these, 1631 contained unhealthy food advertising exposures, defined as ≥50% of an advertisement observed in each image. We examined spatial patterns using kernel density mapping and graphed space-time trends. We interpolated a kriged exposure rate across Wellington to estimate exposure reductions for potential bans. Children were exposed to 7.4 (95% CI 7.0-7.8) unhealthy food advertisements/hour spent in outdoor public spaces. Exposures occurred in shopping centres, residential areas and sports facilities, commonly involving fast food, sugary drinks and ice cream. Peak exposure times were weekend afternoons/evenings and weekdays before/after school. In Wellington, we estimated that banning such advertising within 400 m of playgrounds would yield a 33% reduction in exposure, followed by in residential areas (27%), within 400 m of schools (25%), and 50% for a ban combining all above. This work documents the extent of children's exposure to unhealthy food advertising and the potential impact of bans. Given the ubiquity of advertising in public spaces, this New Zealand research offers innovative methods and findings likely relevant in other jurisdictions.

An objective methodology capturing online commodity marketing and other harms.

Increasingly life is lived online, yet little is known about the actual nature and extent of online content that people view due to the difficulty of recording real time exposure. This includes people's exposure to harmful commodity marketing. This study aimed to develop a methodology to assess the nature and extent of exposure to, and engagement with, unhealthy commodity marketing and other public health harms online, particularly children's exposure. A convenience sample of 16 young adult participants (aged 21-29) recorded their device usage for 2 days using Zoom software. Data were coded and analysed to assess the nature and extent of marketing for alcohol, gambling, junk food and smoking products. Four focus groups were conducted with participants to explore their data collection and coding experiences, and results assessed using thematic analysis. The study found that, with some modifications, this method was feasible for gathering real-time objective data from the online world that can be analysed for a range of public health harms, including marketing of unhealthy commodities. Larger studies are recommended to build global evidence for public health action in the online world.

Children's healthy and unhealthy beverage availability, purchase and consumption: A wearable camera study.

Children's sugar-sweetened beverages (SSBs) consumption presents significant risks for obesity, type 2 diabetes and dental health. But there is a lack of objective data on beverages in children's overall environments. This study aimed to determine the nature and extent of children's beverage availability, purchase and consumption, throughout their day, using wearable cameras for data collection. Data were sourced from 'Kids'Cam NZ', a study in which randomly-selected New Zealand children (n = 168; 11-14y, mean 12.6y) wore cameras for four days (Thursday-Sunday), automatically taking a photo every 7s. Using content analysis, Thursday and Saturday images (n = 700,201) were systematically analysed. On average, 18.9 (95% CI 16.8, 21.4) drinks/day were available to the children (n = 158), of which 7.5 (95% CI 5.8, 9.7; 39.7%) were non-core drinks, including 6.4 (95% CI 5.0, 8.3; 33.9%) SSBs. At school and home, core drinks (water and unflavoured milk) were the most available. In all other locations in which children spent time (e.g., recreation venues and food retail outlets) non-core drinks dominated, at rates 1.5-5 times that of core drinks availability. Almost all drinks (n = 17; 10.8%) the children purchased were non-core. On average, children (n = 111; 70.3%) consumed a drink 2.6 (95% CI 2.1, 3.1) times/day, including one (95% CI 0.7, 1.3) SSB. At school and home core drinks predominated. SSBs were available to most children in all locations in which they spent time, and dominated their drinks purchases and consumption. SSBs appear to be a typical feature of children's everyday environments, almost certainly making it difficult for children's beverage intakes to align with guidelines. The findings support calls for governments to urgently enact the SSB-related actions in the WHO Commission's Ending Childhood Obesity implementation plan and, in turn, improve child health.

Studying third-parties and environments: New Zealand sun-safety research.

Wearable cameras have been used to study health behaviours, but their utility in assessing third-party behaviours and the built environment is uncertain. This paper reports on the feasibility of using wearable cameras for this purpose in a study of sun-protective behaviours and shade availability during school lunch-breaks. The Kids'Cam study provided 168 children (aged 11-13 years), recruited from 16 randomly selected schools in the Wellington region of New Zealand, with wearable cameras. The devices automatically captured images every 7 s from the child's perspective. Images captured during school lunch-breaks by a random sample of 15 children who took part during terms 4 and 1 (October 2014-April 2015) were selected and assessed for usability. The feasibility of studying third-party sun-protective behaviours and school shade availability was assessed for a subset of 320 images. Of the 3492 eligible lunch-break images, 96.4% were useable; the remainders were excluded due to obstruction, blurriness or unsuitable camera position. Overall, 1278 children and 108 shade structures were observed in the sample images. The use of shade, hats, sleeves, collars and sunglasses could be determined for 97.0%, 77.2%, 74.4%, 47.6% and 54.9% of children, respectively. All shade structures could be classified according to type, and canopy composition could be assessed for 95.4% of structures. Wearable cameras are a feasible tool for assessing sun-safety, particularly shade availability, hat wearing and shade use. This methodology could be used to objectively study other third-party health-related behaviours, and other features of the built environment.

Are children smoke-free at home? Using wearable cameras to study children's exposure to smoking and smoking paraphernalia in private spaces.

BACKGROUND: There is limited evidence available on the nature of children's exposure to smoking and smoking paraphernalia in private spaces (homes and cars). We aimed to evaluate the extent and nature of children's exposure to smoking in these settings using image data captured by wearable cameras. METHODS: One-hundred and sixty-eight children wore wearable cameras for 4 days that automatically took pictures every 7 s. Images captured in private spaces (n = 140,818) by children living in households with a smoker (n = 34) were screened for instances of smoking and smoking paraphernalia. RESULTS: A total of 37 incidents of smoking-four indoor, 21 outdoor, and two in-vehicles-and 62 incidents of smoking paraphernalia were observed. Most smoking incidents in homes (21 of 33) took place outdoors. CONCLUSIONS: The findings support health promotion efforts to make smokers more aware that smoking paraphernalia may normalize smoking for children. The methodology (wearable cameras) appears to have high utility for studying health behaviours in private spaces.