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Prostate cancer is characterized by considerable geo-ethnic disparity. African ancestry is a significant risk factor, with mortality rates across sub-Saharan Africa of 2.7-fold higher than global averages1. The contributing genetic and non-genetic factors, and associated mutational processes, are unknown2,3. Here, through whole-genome sequencing of treatment-naive prostate cancer samples from 183 ancestrally (African versus European) and globally distinct patients, we generate a large cancer genomics resource for sub-Saharan Africa, identifying around 2 million somatic variants. Significant African-ancestry-specific findings include an elevated tumour mutational burden, increased percentage of genome alteration, a greater number of predicted damaging mutations and a higher total of mutational signatures, and the driver genes NCOA2, STK19, DDX11L1, PCAT1 and SETBP1. Examining all somatic mutational types, we describe a molecular taxonomy for prostate cancer differentiated by ancestry and defined as global mutational subtypes (GMS). By further including Chinese Asian data, we confirm that GMS-B (copy-number gain) and GMS-D (mutationally noisy) are specific to African populations, GMS-A (mutationally quiet) is universal (all ethnicities) and the African–European-restricted subtype GMS-C (copy-number losses) predicts poor clinical outcomes. In addition to the clinical benefit of including individuals of African ancestry, our GMS subtypes reveal different evolutionary trajectories and mutational processes suggesting that both common genetic and environmental factors contribute to the disparity between ethnicities. Analogous to gene–environment interaction—defined here as a different effect of an environmental surrounding in people with different ancestries or vice versa—we anticipate that GMS subtypes act as a proxy for intrinsic and extrinsic mutational processes in cancers, promoting global inclusion in landmark studies.

Objective To determine the sensitivity of dual-energy (DE) virtual non-contrast computed tomography (vNCT), generated from the excretory phase of a CT urogram, compared to true non-contrast CT (tNCT) for the detection of urinary calculi. Methods A search of multiple medical literature databases was performed using predetermined search terms. Inclusion and exclusion criteria were applied, and bias risk was assessed by two independent reviewers using the quality assessment of diagnostic accuracy studies (QUADAS) tool. Collated estimates of sensitivity were generated, and sources of heterogeneity were identified and reviewed. Results Thirteen studies (1760 patients; 1740 urinary calculi) were included for sensitivity assessment. Pooled sensitivity for urinary calculi on vNCT was 78.1% (95% CI: 70.2 to 85.0%); however, heterogeneity between studies was very high (I2 = 92.0%). Sources of heterogeneity between studies were explored through subgroup analysis by categorising studies according to slice thickness (≥ 2 mm and < 2 mm), use of oral hydration, and use of intravenous furosemide. Pooled sensitivity for detection of urinary calculi on vNCT for studies that used oral hydration and < 2 mm slice thickness was 92.2% (95% CI: 89.5 to 94.5%). Pooled specificity was not performed as true negatives were not reported in most studies. Potential sources of bias were identified in included studies. Conclusion vNCT demonstrated a moderate pooled sensitivity compared to tNCT for the detection of urinary calculi in split bolus CT urogram protocols. However, subgroup analysis suggests higher sensitivity when employing oral hydration and < 2 mm slice thickness or increment. Key Points • vNCT demonstrated moderate pooled sensitivity for the detection of urinary calculi in split bolus CT urogram protocols. • Subgroup analysis suggested higher sensitivity with oral hydration and < 2 mm slice thickness or increment.

Global environmental change is identified as a driver of physical transformation of coral reef islands over the past half-century, and next 100 years, posing major adaptation challenges to island nations. Here we resolve whether these recent documented changes in islands are unprecedented compared with the pre-industrial era. We utilise radiometric dating, geological, and remote sensing techniques to document the dynamics of a Maldivian reef island at millennial to decadal timescales. Results show the magnitude of island change over the past half-century (±40 m movement) is not unprecedented compared with paleo-dynamic evidence that reveals large-scale changes in island dimension, shape, beach levels, as well as positional changes of ±200 m since island formation ~1,500 years ago. Results highlight the value of a multi-temporal methodological approach to gain a deeper understanding of the dynamic trajectories of reef islands, to support development of adaptation strategies at timeframes relevant to human security.

Aortitis is found in 2-12% of thoracic aortic aneurysm repair/replacement surgeries. Yet little is known about such patients' post-operative outcomes or the role of post-operative corticosteroids. The study was undertaken across three tertiary referral hospitals in Sydney, Australia. Prospectively collected data for all thoracic aortic repair/replacement patients between 2004 and 2018 was accessed from a national surgical registry and analysed. Histopathology records identified cases of inflammatory aortitis which were subclassified as clinically isolated aortitis (CIA), giant cell arteritis (GCA), Takayasu (TAK) or other aortitis. Between-group outcomes were compared utilising logistic and median regression analyses. Between 2004 and 2018, a total of 1119 thoracic aortic surgeries were performed of which 41 (3.7%) were inflammatory aortitis cases (66% CIA, 27% GCA, 5% TAK, 2% other). Eight out of 41 (20%) aortitis patients received post-operative corticosteroids. Compared to non-aortitis patients, the aortitis group was predominantly female (53.7% vs. 28.1%, p 0.05) between aortitis and non-aortitis groups for 30-day mortality (7.3% vs 6.5%), significant morbidity (14.6% vs. 22.4%), or infection (9.8% vs. 6.4%). Outcomes were similar for the non-corticosteroid-treated aortitis subgroup. Histologic evidence of inflammatory thoracic aortitis following surgery did not affect post-operative mortality or morbidity. Withholding corticosteroids did not adversely affect patient outcomes. These findings will assist rheumatologists and surgeons in the post-operative management of aortitis.

There is uncertainty on how multiparametric MRI (mpMRI) and MRI-targeted biopsy (MRI-TB) can be best used to manage low-risk prostate cancer patients on Active Surveillance (AS). We performed a scoping review to evaluate the benefits and harm associated with four different biopsy scenarios in which mpMRI can be implemented in AS. Medline, Embase and Cochrane Library databases (1 January 2013–18 September 2020) were searched. Included studies were on men with low-risk prostate cancer enrolled in AS, who had mpMRI ± MRI-TB and standard prostate biopsy (systematic transrectal ultrasound or transperineal saturation biopsy), at confirmatory or follow-up biopsy. Primary outcomes were the number of Gleason score upgrades and biopsies avoided. Eight confirmatory biopsy studies and three follow-up biopsy studies were included. Compared to the benchmark of using standard biopsy (SB) for all men, the addition of MRI-TB increased the detection of Gleason score upgrades at both confirmatory (6/8 studies) and follow-up biopsy (3/3 studies), with increments of 1.7–11.8 upgrades per 100 men. 6/7 studies suggested that the use of a positive mpMRI to triage men for MRI-TB or SB alone would detect fewer Gleason score upgrades than benchmark at confirmatory biopsy, but the combination of MRI-TB and SB would detect more upgrades than the benchmark. For follow-up biopsy, the evidence on mpMRI triage biopsy scenarios was inconclusive due to the small number of included studies. The addition of MRI-TB to benchmark (SB for all men) maximises the detection of Gleason score upgrades at confirmatory and follow-up biopsy. When the use of mpMRI to triage men for a biopsy is desired, the combination of MRI-TB and SB should be considered for men with positive mpMRI at confirmatory biopsy. The evidence on mpMRI triage scenarios was inconclusive in the follow-up biopsy setting.

The instrumental record reveals that tropical cyclone activity is sensitive to oceanic and atmospheric variability on inter-annual and decadal scales. However, our understanding of the influence of climate on tropical cyclone behaviour is restricted by the short historical record and the sparseness of prehistorical reconstructions, particularly in the western North Pacific, where coastal communities suffer loss of life and livelihood from typhoons annually. Here, to explore past regional typhoon dynamics, we reconstruct three millennia of deep tropical North Pacific cyclogenesis. Combined with existing records, our reconstruction demonstrates that low-baseline typhoon activity prior to 1350 ce was followed by an interval of frequent storms during the Little Ice Age. This pattern, concurrent with hydroclimate proxy variability, suggests a centennial-scale link between Pacific hydroclimate and tropical cyclone climatology. An ensemble of global climate models demonstrates a migration of the Pacific Walker circulation and variability in two Pacific climate modes during the Little Ice Age, which probably contributed to enhanced tropical cyclone activity in the tropical western North Pacific. In the next century, projected changes to the Pacific Walker circulation and expansion of the tropics will invert these Little Ice Age hydroclimate trends, potentially reducing typhoon activity in the deep tropical Pacific. Atmospheric circulation shifts during the Little Ice Age led to greater typhoon generation in the tropical North Pacific according to a comparison of sediment proxy records of past storm activity and outputs of general circulation models.

Sea-level reconstructions over the past two millennia provide a pre-industrial context to assess whether the magnitude and rate of modern sea-level change is unprecedented. Sea-level records from the Indian Ocean over the past 2,000 years are sparse, while records from the Atlantic and Pacific Oceans show variations less than 0.25 m and no significant negative excursions. Here, we present evidence of two low sea-level phases in the Maldives, Indian Ocean, based on fossil coral microatolls. Microatoll growth is constrained by low water levels and, consequently, they are robust recorders of past sea level. U–Th dating of the Maldivian corals identified lowstands at ad 234–605 and ad 1481–1807 when sea level fell to maximum depths of −0.88 m and −0.89 m respectively. These lowstands are synchronous with reductions in radiative forcing and sea surface temperature associated with the Late Antiquity Little Ice Age and the Little Ice Age. Our results provide high-fidelity observations of lower sea levels during these cool periods and show rates of change of up to 4.24 mm yr−1. Our data also confirm the acceleration of relative sea-level rise over the past two centuries and suggest that the current magnitude and rate of sea-level rise is not unprecedented. National Research Foundation (NRF) Accepted version We thank LaMer Group and the Small Island Research Centre, Fares-Maathodaa, Huvadhoo atoll for logistical support, Government of the Maldives for research permission and A. Vila-Concejo, E. Beetham and T. Turner for field assistance. X.W. acknowledges funding support from the National Research Foundation of Singapore (grant nos. NRF2017NRF-NSFC001-047 and NRF-NRFF2011-08) and the Earth Observatory of Singapore.

Background After radical prostatectomy (RP) for prostate cancer (PC), p53 alterations predict biochemical relapse (BCR), however, recent evidence suggests that metastatic relapse (MR) not BCR is a surrogate for PC specific mortality (PCSM). This updated analysis of a previously published study investigated the association between p53 aberrations, MR and PCSM in men with localised PC. Methods Two hundred and seventy-one men with localised PC treated with RP were included. RP specimens stained for p53 by immunohistochemistry were scored as (a) percentage of p53-positive tumour nuclei; and (b) clustering, where ≥12 p53-positive cells within a ×200 power field was deemed ‘cluster positive’. Associations between p53 status and clinical outcomes (BCR, MR and PCSM) were evaluated. Results Increasing percentage of p53-positive nuclei was significantly associated with shorter time to BCR, MR and PCSM (All p

The International Collaboration on Cancer Reporting (ICCR) was formed in 2011 to harmonise the datasets, protocols and checklists for pathological reporting of various cancers and develop internationally agreed upon, evidence-based datasets. A dataset for prostate cancer in radical prostatectomy specimens was developed in 2011-2012 as part of a pilot project; however, it required substantial revision following the ISUP Consensus Conference on Gleason Grading in 2014, the publication of the World Health Organisation (WHO) Classification of Tumours of the Urinary System and Male Genital Organs in 2016, and the 8th edition of the Tumour-Node-Metastasis (TNM) staging system in late 2016. This article presents the up-to-date, evidence-based ICCR dataset and associated commentary for reporting prostate cancer in radical prostatectomy specimens. PubMed and Google search engines were used to review the published literature on the subject, and the dataset was developed in line with the previously published ICCR framework for the development of cancer datasets. Substantial changes have been incorporated into the second edition of the ICCR prostate cancer (radical prostatectomy) dataset. These include revisions to prostate cancer grading, reporting of intraductal carcinoma of prostate and surgical margins, among others. Up-to-date cancer datasets underpin structured reporting and facilitate the production of consistent and accurate pathological data for patient care as well as comparisons between different cohorts and populations internationally.

Long-term outcomes from large cohorts are not yet available upon which to base recommended follow-up protocols after prostate focal therapy. This is an updated summary of a 2015 SIU-ICUD review of the best available current evidence and expert consensus on guidelines for surveillance after prostate focal therapy. We performed a systematic search of the PubMed, Cochrane and Embase databases to identify studies where primary prostate focal therapy was performed to treat prostate cancer. Multiparametric magnetic resonance imaging (mpMRI) should be performed at 3–6 months, 12–24 months and at 5 years after focal therapy. Targeted biopsy of the treated zone should be performed at 3–6 months and fusion biopsy of any suspicious lesion seen on mpMRI. Additionally, a systematic biopsy should be performed at 12–24 months and again at 5 years. In histological diagnosis, characteristic changes of each treatment modality should be noted and in indeterminate situations various immunohistochemical molecular markers can be helpful. Small volume 3 + 3 (Prognostic grade group [PGG] 1) or very small volume (

Low-lying coral reef islands are considered highly vulnerable to climate change, necessitating an improved understanding of when and why they form, and how the timing of formation varies within and among regions. Several testable models have been proposed that explain inter-regional variability as a function of sea-level history and, more recently, a reef platform size model has been proposed from the Maldives (central Indian Ocean) to explain intra-regional (intra-atoll) variability. Here we present chronostratigraphic data from Pipon Island, northern Great Barrier Reef (GBR), enabling us to test the applicability of existing regional island evolution models, and the platform size control hypothesis in a Pacific context. We show that reef platform infilling occurred rapidly (~4–5 mm yr−1) under a “bucket-fill” type scenario. Unusually, this infilling was dominated by terrigenous sedimentation, with platform filling and subsequent reef flat formation complete by ~5000 calibrated years BP (cal BP). Reef flat exposure as sea levels slowly fell post highstand facilitated a shift towards intertidal and subaerial-dominated sedimentation. Our data suggest, however, a lag of ~1500 yr before island initiation (at ~3200 cal BP), i.e. later than that reported from smaller and more evolutionarily mature reef platforms in the region. Our data thus support: (1) the hypothesis that platform size acts to influence the timing of platform filling and subsequent island development at intra-regional scales; and (2) the hypothesis that the low wooded islands of the northern GBR conform to a model of island formation above an elevated reef flat under falling sea levels.

Wave-driven flooding is a serious hazard on coral reef-fringed coastlines that will be exacerbated by global sea-level rise. Despite the global awareness of atoll island vulnerability, little is known about the physical processes that control wave induced flooding on reef environments. To resolve the primary controls on wave-driven flooding at present and future sea levels, we present a globally applicable method for calculating wave overtopping thresholds on reef coastlines. A unique dataset of 60,000 fully nonlinear wave transformation simulations representing a wide range of wave energy, morphology and sea levels conditions was analysed to develop a tool for exploring the future trajectory of atoll island vulnerability to sea-level rise. The proposed reef-island overtopping threshold (RIOT) provides a widely applicable first-order assessment of reef-coast vulnerability to wave hazards with sea-level. Future overtopping thresholds identified for different atoll islands reveal marked spatial variability and highlight distinct morphological characteristics that enhance coastal resilience., Sea-level rise will exacerbate wave overtopping on low-lying coral reef islands. Here the authors present a novel method that quantifies wave overtopping thresholds and associated reef-island vulnerability trajectories based on differences in local wave climate, reef morphology and island height.

Sea-level rise (SLR) is predicted to elevate water depths above coral reefs and to increase coastal wave exposure as ecological degradation limits vertical reef growth, but projections lack data on interactions between local rates of reef growth and sea level rise. Here we calculate the vertical growth potential of more than 200 tropical western Atlantic and Indian Ocean reefs, and compare these against recent and projected rates of SLR under different Representative Concentration Pathway (RCP) scenarios. Although many reefs retain accretion rates close to recent SLR trends, few will have the capacity to track SLR projections under RCP4.5 scenarios without sustained ecological recovery, and under RCP8.5 scenarios most reefs are predicted to experience mean water depth increases of more than 0.5 m by 2100. Coral cover strongly predicts reef capacity to track SLR, but threshold cover levels that will be necessary to prevent submergence are well above those observed on most reefs. Urgent action is thus needed to mitigate climate, sea-level and future ecological changes in order to limit the magnitude of future reef submergence.

background: Adjuvant chemotherapy improves survival for patients with resected pancreatic cancer. Elderly patients are under-represented in Phase III clinical trials, and as a consequence the efficacy of adjuvant therapy in older patients with pancreatic cancer is not clear. We aimed to assess the use and efficacy of adjuvant chemotherapy in older patients with pancreatic cancer.\ud methods: We assessed a community cohort of 439 patients with a diagnosis of pancreatic ductal adenocarcinoma who underwent operative resection in centres associated with the Australian Pancreatic Cancer Genome Initiative.\ud results: The median age of the cohort was 67 years. Overall only 47% of all patients received adjuvant therapy. Patients who received adjuvant chemotherapy were predominantly younger, had later stage disease, more lymph node involvement and more evidence of perineural invasion than the group that did not receive adjuvant treatment. Overall, adjuvant chemotherapy was associated with prolonged survival (median 22.1 vs 15.8 months; P\ud conclusion: Patients aged greater than or equal to70 are less likely to receive adjuvant therapy although it is associated with improved outcome. Increased use of adjuvant therapy in older individuals is encouraged as they constitute a large proportion of patients with pancreatic cancer.

Deterioration of coral health and associated change in the coral holobiont’s bacterial community are often a result of different environmental stressors acting synergistically. There is evidence that water flow is important for a coral’s resistance to elevated seawater temperature, but there is no information on how water flow affects the coral-associated bacterial community under these conditions. In a laboratory cross-design experiment, Acropora muricata nubbins were subjected to interactive effects of seawater temperature (27 °C to 31 °C) and water flow (0.20 m s−1 and 0.03 m s−1). In an in situ experiment, water flow manipulation was conducted with three colonies of A. muricata during the winter and summer, by partially enclosing each colony in a clear plastic mesh box. 16S rRNA amplicon pyrosequencing showed an increase in the relative abundance of Flavobacteriales and Rhodobacterales in the laboratory experiment, and Vibrio spp. in the in situ experiment when corals were exposed to elevated temperature and slow water flow. In contrast, corals that were exposed to faster water flow under laboratory and in situ conditions had a stable bacterial community. These findings indicate that water flow plays an important role in the maintenance of specific coral-bacteria associations during times of elevated thermal stress.

This study measured reading workstation monitors and the viewing environment currently available within BreastScreen New South Wales (BSNSW) centres to determine levels of adherence to national and international guidelines. Thirteen workstations from four BSNSW service centres were assessed using the American Association of Physicists in Medicine Task Group 18 Quality Control test pattern. Reading workstation monitor performance and ambient light levels when interpreting screening mammographic images were assessed using spectroradiometer CS-2000 and chroma meter CL-200. Overall, radiologic monitors within BSNSW were operating at good acceptable levels. Some non-adherence to published guidelines included the percentage difference in maximum luminance between pairs of primary monitors at individual workstations (61.5 % or 30.8 % of workstations depending on specific guidelines), maximum luminance (23.1 % of workstations), luminance non-uniformity (11.5 % of workstations) and minimum luminance (3.8 % of workstations). A number of ambient light measurements did not comply with the only available evidence-based guideline relevant to the methodology used in this study. Larger ambient light variations across sites are shown when monitors were switched off, suggesting that differences in ambient lighting between sites can be masked when a standard mammogram is displayed for photometric measurements. Overall, BSNSW demonstrated good adherence to available guidelines, although some non-compliance has been shown. Recently updated United Kingdom and Australian guidelines should help reduce confusion generated by the plethora and sometimes dated nature of currently available recommendations.

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

Chronic hepatitis C (CHC) infection is associated with insulin resistance and with oxidative stress, but the relationship between the two has not been thoroughly examined. To evaluate the association between insulin resistance and oxidative stress in CHC patients. In 115 CHC patients (68 with genotype 1 and 47 with genotype 3), the relationship between the serum concentration of malondialdehyde (MDA), a marker of oxidative stress and insulin resistance as defined by the homeostasis model (HOMA-IR) was examined. There was no significant difference in MDA levels between genotype 1- and genotype 3-infected subjects (12.882 vs. 12.426 ng/mL, p = 0.2). By univariate analysis, factors associated with HOMA-IR in both genotypes were oxidative stress as measured by MDA (p = 0.002), body mass index (BMI), portal activity, and fibrosis. Genotype-specific differences in HOMA-IR association were steatosis and triglycerides (TG) for genotype 1, and age and glutathione (GSH) for genotype 3. In a stepwise multiple linear regression analysis in both genotypes, MDA was a significant and independent predictor of HOMA-IR (p = 0.04). As expected, BMI and fibrosis were likewise independently correlated to HOMA-IR. In addition, MDA levels were higher (p

Deregulation of microRNA (miRNA) expression can have a critical role in carcinogenesis. Here we show in prostate cancer that miRNA-205 (miR-205) transcription is commonly repressed and the MIR-205 locus is hypermethylated. LOC642587, the MIR-205 host gene of unknown function, is also concordantly inactivated. We show that miR-205 targets mediator 1 (MED1, also called TRAP220 and PPARBP) for transcriptional silencing in normal prostate cells, leading to reduction in MED1 mRNA levels, and in total and active phospho-MED1 protein. Overexpression of miR-205 in prostate cancer cells negatively affects cell viability, consistent with a tumor suppressor function. We found that hypermethylation of the MIR-205 locus was strongly related with a decrease in miR-205 expression and an increase in MED1 expression in primary tumor samples (n=14), when compared with matched normal prostate (n=7). An expanded patient cohort (tumor n=149, matched normal n=30) also showed significant MIR-205 DNA methylation in tumors compared with normal, and MIR-205 hypermethylation is significantly associated with biochemical recurrence (hazard ratio=2.005, 95% confidence interval (1.109, 3.625), P=0.02), in patients with low preoperative prostate specific antigen. In summary, these results suggest that miR-205 is an epigenetically regulated tumor suppressor that targets MED1 and may provide a potential biomarker in prostate cancer management.

Census-based approaches can provide important measures of the ecological processes controlling reef carbonate production states. Here, we describe a rapid, non-destructive approach to carbonate budget assessments, termed ReefBudget that is census-based and which focuses on quantifying the relative contributions made by different biological carbonate producer/eroder groups to net reef framework carbonate production. The methodology is presently designed only for Caribbean sites, but has potential to be adapted for use in other regions. Rates are calculated using data on organism cover and abundance, combined with annual extension or production rate measures. Set against this are estimates of the rates at which bioeroding species of fish, urchins and internal substrate borers erode reef framework. Resultant data provide a measure of net rates of biologically driven carbonate production (kg CaCO3 m−2 year−1). These data have potential to be integrated into ecological assessments of reef state, to aid monitoring of temporal (same-site) changes in rates of biological carbonate production and to provide insights into the key ecological drivers of reef growth or erosion as a function of environmental change. Individual aspects of the budget methodology can also be used alongside other census approaches if deemed appropriate for specific study aims. Furthermore, the methodology spreadsheets are user-changeable, allowing local or new process/rate data to be integrated into calculations. Application of the methodology is considered at sites around Bonaire. Highest net rates of carbonate production, +9.52 to +2.30 kg CaCO3 m−2 year−1, were calculated at leeward sites, whilst lower rates, +0.98 to −0.98 kg CaCO3 m−2 year−1, were calculated at windward sites. Data are within the ranges calculated in previous budget studies and provide confidence in the production estimates the methodology generates.