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Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.

Item does not contain fulltext, OBJECTIVE: Primary aldosteronism (PA) is one of the most frequent causes of secondary hypertension. Although clinical practice guidelines recommend a diagnostic process, details of the steps remain incompletely standardized. DESIGN: In the present SCOT-PA survey, we have investigated the diversity of approaches utilized for each diagnostic step in different expert centers through a survey using Google questionnaires. A total of 33 centers from 3 continents participated. RESULTS: We demonstrated a prominent diversity in the conditions of blood sampling, assay methods for aldosterone and renin, and the methods and diagnostic cutoff for screening and confirmatory tests. The most standard measures were modification of antihypertensive medication and sitting posture for blood sampling, measurement of plasma aldosterone concentration (PAC) and active renin concentration by chemiluminescence enzyme immunoassay, a combination of aldosterone-to-renin ratio with PAC as an index for screening, and saline infusion test in a seated position for confirmatory testing. The cutoff values for screening and confirmatory testing showed significant variation among centers. CONCLUSIONS: Diversity of the diagnostic steps may lead to an inconsistent diagnosis of PA among centers and limit comparison of evidence for PA between different centers. We expect the impact of this diversity to be most prominent in patients with mild PA. The survey raises 2 issues: the need for standardization of the diagnostic process and revisiting the concept of mild PA. Further standardization of the diagnostic process/criteria will improve the quality of evidence and management of patients with PA.

Item does not contain fulltext, CONTEXT: Diagnosis of primary aldosteronism (PA) for many patients depends on positive results for the saline infusion test (SIT). Plasma aldosterone is often measured by immunoassays, which can return inaccurate results. OBJECTIVE: This study aimed to establish whether differences in aldosterone measurements by immunoassay versus mass spectrometry (MS) might impact confirmatory testing for PA. METHODS: This study, involving 240 patients tested using the SIT at 5 tertiary care centers, assessed discordance between immunoassay and MS-based measurements of plasma aldosterone. RESULTS: Plasma aldosterone measured by Liaison and iSYS immunoassays were respectively 86% and 58% higher than determined by MS. With an immunoassay-based SIT cutoff for aldosterone of 170 pmol/L, 78 and 162 patients had, respectivel, negative and positive results. All former patients had MS-based measurements of aldosterone < 117 pmol/L, below MS-based cutoffs of 162 pmol/L. Among the 162 patients with pathogenic SIT results, MS returned nonpathologic results in 62, including 32 under 117 pmol/L. Repeat measurements by an independent MS method confirmed nonpathogenic results in 53 patients with discordant results. Patients with discordant results showed a higher (P < 0.0001) prevalence of nonlateralized than lateralized adrenal aldosterone production than patients with concordant results (83% vs 28%). Among patients with nonlateralized aldosterone production, 66% had discordant results. Discordance was more prevalent for the Liaison than iSYS immunoassay (32% vs 16%; P = 0.0065) and was eliminated by plasma purification to remove interferents. CONCLUSION: These findings raise concerns about the validity of immunoassay-based diagnosis of PA in over 60% of patients with presumed bilateral disease. We provide a simple solution to minimize immunoassay inaccuracy-associated misdiagnosis of PA.

Item does not contain fulltext, CONTEXT: Sampling of blood in the supine position for diagnosis of pheochromocytoma and paraganglioma (PPGL) results in lower rates of false positives for plasma normetanephrine than seated sampling. It is unclear how inpatient vs outpatient testing and other preanalytical factors impact false positives. OBJECTIVE: We aimed to identify preanalytical precautions to minimize false-positive results for plasma metanephrines. METHODS: Impacts of different blood sampling conditions on plasma metanephrines were evaluated, including outpatient vs inpatient testing, sampling of blood in semi- vs fully recumbent positions, use of cannulae vs direct venipuncture, and differences in outside temperature. A total of 3147 patients at 10 tertiary referral centers were tested for PPGL, including 278 with and 2869 without tumors. Rates of false-positive results were analyzed. RESULTS: Outpatient rather than inpatient sampling resulted in 44% higher plasma concentrations and a 3.4-fold increase in false-positive results for normetanephrine. Low temperature, a semi-recumbent position, and direct venipuncture also resulted in significantly higher plasma concentrations and rates of false-positive results for plasma normetanephrine than alternative sampling conditions, although with less impact than outpatient sampling. Higher concentrations and rates of false-positive results for plasma normetanephrine with low compared with warm temperatures were only apparent for outpatient sampling. Preanalytical factors were without impact on plasma metanephrines in patients with PPGL. CONCLUSION: Although inpatient blood sampling is largely impractical for screening patients with suspected PPGL, other preanalytical precautions (eg, cannulae, warm testing conditions) may be useful. Inpatient sampling may be reserved for follow-up of patients with difficult to distinguish true- from false-positive results.

Estimates of the past thermal state of the land surface are crucial to assess the magnitude of current anthropogenic climate change as well as to assess the ability of Earth System Models (ESMs) to forecast the evolution of the climate near the ground, which is not included in standard meteorological records. Subsurface temperature reacts to long-term changes in surface energy balance – from decadal to millennial time scales – thus constituting an important record of the dynamics of the climate system that contributes, with low-frequency information, to proxy-based paleoclimatic reconstructions. Broadly used techniques to retrieve past temperature and heat flux histories from subsurface temperature profiles based on a singular value decomposition (SVD) algorithm were able to provide robust global estimates for the last millennium, but the approaches used to derive the corresponding 95 % confidence interval were wrong from a statistical point of view in addition to being difficult to interpret. To alleviate the lack of a meaningful framework for estimating uncertainties in past temperature and heat flux histories at regional and global scales, we combine a new bootstrapping sampling strategy with the broadly used SVD algorithm and assess its performance against the original SVD technique and another technique based on generating perturbed parameter ensembles of inversions. The new bootstrap approach is able to reproduce the prescribed surface temperature series used to derive an artificial profile. Bootstrap results are also in agreement with the global mean surface temperature history and the global mean heat flux history retrieved in previous studies. Furthermore, the new bootstrap technique provides a meaningful uncertainty range for the inversion of large sets of subsurface temperature profiles. We suggest the use of this new approach particularly for aggregating results from a number of individual profiles, and to this end, we release the programs used to derive

For decades, conservation tillage has been promoted as a measure to increase carbon stocks in arable soils. Since organic farming improves soil quality and soil carbon storage, reduced tillage under organic farming conditions may further enhance this potential. Therefore, we assessed soil organic carbon (SOC) stocks of reduced tillage compared with mouldboard ploughing in nine organic farming field trials in France, Germany, the Netherlands, and Switzerland with the same sampling and analytical protocol. We sampled soil cores until a depth of 100 cm to determine soil carbon stocks that are relevant for climate change mitigation but are often overlooked in tillage studies with shallow sampling depths. The studied field experiments were between 8 and 21 years old and comprised different soil types with clay contents ranging from 10% to 50%. SOC stocks increased with increasing clay-to-silt ratio, precipitation and organic fertiliser input. Across sites, reduced tillage in comparison with ploughing increased SOC stocks in the surface layer (0–10/15 cm) by 20.8% or 3.8 Mg ha 1, depleted SOC stocks in the intermediate soil layers to 50 cm soil depth with a maximum depletion of 6.6% or 1.6 Mg ha 1 in 15/ 20–30 cm and increased SOC stocks in the deepest (70–100 cm) soil layer by 14.4% or 2.5 Mg ha 1. The subsoil SOC stock increase may be linked to the inherent soil heterogeneity. Cumulative SOC stocks increased by 1.7% or 1.5 Mg ha1 (0–50 cm, n = 9) and 3.6% or 4.0 Mg ha 1 (0–100 cm, n = 7) by reduced tillage compared with ploughing with estimated mean C sequestration rates of 0.09 and 0.27 Mg ha 1 yr 1, respectively. There was no effect of field trial duration on tillage induced cumulative SOC stocks differences. Under reduced tillage, biomass production was 8% lower resulting in a decrease of crop C input by 6%. However, this reduction may have been outbalanced by increased C inputs from weed biomass resulting from a higher weed incidence in reduced tillage, which warran