Revealing uncertainty in the status of biodiversity change.

Biodiversity faces unprecedented threats from rapid global change1. Signals of biodiversity change come from time-series abundance datasets for thousands of species over large geographic and temporal scales. Analyses of these biodiversity datasets have pointed to varied trends in abundance, including increases and decreases. However, these analyses have not fully accounted for spatial, temporal and phylogenetic structures in the data. Here, using a new statistical framework, we show across ten high-profile biodiversity datasets2-11 that increases and decreases under existing approaches vanish once spatial, temporal and phylogenetic structures are accounted for. This is a consequence of existing approaches severely underestimating trend uncertainty and sometimes misestimating the trend direction. Under our revised average abundance trends that appropriately recognize uncertainty, we failed to observe a single increasing or decreasing trend at 95% credible intervals in our ten datasets. This emphasizes how little is known about biodiversity change across vast spatial and taxonomic scales. Despite this uncertainty at vast scales, we reveal improved local-scale prediction accuracy by accounting for spatial, temporal and phylogenetic structures. Improved prediction offers hope of estimating biodiversity change at policy-relevant scales, guiding adaptive conservation responses.

Inverted region in the reaction of the quinone reduction in the A1-site of photosystem I from cyanobacteria.

Photosystem I from the menB strain of Synechocystis sp. PCC 6803 containing foreign quinones in the A1 sites was used for studying the primary steps of electron transfer by pump-probe femtosecond laser spectroscopy. The free energy gap (- ΔG) of electron transfer between the reduced primary acceptor A0 and the quinones bound in the A1 site varied from 0.12 eV for the low-potential 1,2-diamino-anthraquinone to 0.88 eV for the high-potential 2,3-dichloro-1,4-naphthoquinone, compared to 0.5 eV for the native phylloquinone. It was shown that the kinetics of charge separation between the special pair chlorophyll P700 and the primary acceptor A0 was not affected by quinone substitutions, whereas the rate of A0 → A1 electron transfer was sensitive to the redox-potential of quinones: the decrease of - ΔG by 400 meV compared to the native phylloquinone resulted in a ~ fivefold slowing of the reaction The presence of the asymmetric inverted region in the ΔG dependence of the reaction rate indicates that the electron transfer in photosystem I is controlled by nuclear tunneling and should be treated in terms of quantum electron-phonon interactions. A three-mode implementation of the multiphonon model, which includes modes around 240 cm-1 (large-scale protein vibrations), 930 cm-1 (out-of-plane bending of macrocycles and protein backbone vibrations), and 1600 cm-1 (double bonds vibrations) was applied to rationalize the observed dependence. The modes with a frequency of at least 1600 cm-1 make the predominant contribution to the reorganization energy, while the contribution of the "classical" low-frequency modes is only 4%.

Experimental Evidence of Plasmoids in High-ß Magnetic Reconnection.

Magnetic reconnection is a ubiquitous and fundamental process in plasmas by which magnetic fields change their topology and release magnetic energy. Despite decades of research, the physics governing the reconnection process in many parameter regimes remains controversial. Contemporary reconnection theories predict that long, narrow current sheets are susceptible to the tearing instability and split into isolated magnetic islands (or plasmoids), resulting in an enhanced reconnection rate. While several experimental observations of plasmoids in the regime of low-to-intermediate ß (where ß is the ratio of plasma thermal pressure to magnetic pressure) have been made, there is a relative lack of experimental evidence for plasmoids in the high-ß reconnection environments which are typical in many space and astrophysical contexts. Here, we report strong experimental evidence for plasmoid formation in laser-driven high-ß reconnection experiments.

Comparative assessment of radiation therapy-induced vasculitis using [18F]FDG-PET/CT in patients with non-small cell lung cancer treated with proton versus photon radiotherapy.

PURPOSE: To assess radiation therapy (RT)-induced vasculitis in patients with non-small cell lung cancer (NSCLC) by examining changes in the uptake of 18F-fluoro-D-deoxyglucose ([18F]FDG) by positron emission tomography/computed tomography (PET/CT) images of the ascending aorta (AA), descending aorta (DA), and aortic arch (AoA) before and after proton and photon RT. METHOD: Thirty-five consecutive locally advanced NSCLC patients were definitively treated with proton (n = 27) or photon (n = 8) RT and concurrent chemotherapy. The patients were prospectively enrolled to undergo [18F]FDG-PET/CT imaging before and 3 months after RT. An adaptive contrast-oriented thresholding algorithm was applied to generate mean standardized uptake values (SUVmean) for regions of interest (ROIs) 3 mm outside and 3 mm inside the outer perimeter of the AA, DA, and AoA. These ROIs were employed to exclusively select the aortic wall and remove the influence of blood pool activity. SUVmeans before and after RT were compared using two-tailed paired t-tests. RESULTS: RT treatments were associated with increased SUVmeans in the AA, DA, and AoA-1.9%, 0.3%, and 1.3% for proton and 15.8%, 9.5%, and 15.5% for photon, respectively. There was a statistically significant difference in the ∆SUVmean (post-RT SUVmean - pre-RT SUVmean) in patients treated with photon RT when compared to ∆SUVmean in patients treated with proton RT in the AA (p = 0.043) and AoA (p = 0.015). There was an average increase in SUVmean that was related to dose for photon patients (across structures), but that was not seen for proton patients, although the increase was not statistically significant. CONCLUSION: Our results suggest that patients treated with photon RT for NSCLC may exhibit significantly more RT-induced inflammation (measured as ∆SUVmean) in the AA and AoA when compared to patients who received proton RT. Knowledge gained from further analyses in larger cohorts could aid in treatment planning and help prevent the significant morbidity and mortality associated with RT-induced vascular complications. TRIAL REGISTRATION: NCT02135679.

Replacing the Scalpel With a Computer Mouse: An Evaluation of Time Spent on Electronic Health Record for Plastic Surgery Residents and Its Impact on Resident Training.

BACKGROUND: Following the integration of the electronic health record (EHR) into the healthcare system, concern has grown regarding EHR use on physician well-being. For surgical residents, time spent on the EHR increases the burden of a demanding, hourly restricted schedule and detracts from time spent honing surgical skills. To better characterize these burdens, we sought to describe EHR utilization patterns for plastic surgery residents. METHODS: Integrated plastic surgery resident EHR utilization from March 2019 to March 2020 was extracted via Cerner Analytics at a tertiary academic medical center. Time spent in the EHR on-duty (0600-1759) and off-duty (1800-0559) in the form of chart review, orders, documentation, and patient discovery was analyzed. Statistical analysis was performed in the form of independent t tests and Analysis of Variance (ANOVA). RESULTS: Twelve plastic surgery residents spent a daily average of 94 ± 84 minutes on the EHR, one-third of which was spent off-duty. Juniors (postgraduate years 1-3) spent 123 ± 99 minutes versus seniors (postgraduate years 4-6) who spent 61 ± 49 minutes (P < 0.01). Seniors spent 19% of time on the EHR off-duty, compared with 37% for juniors (P < 0.01). Chart review comprised the majority (42%) of EHR usage, followed by patient discovery (22%), orders (14%), documentation (12%), other (6%), and messaging (1%). Seniors spent more time on patient discovery (25% vs 21%, P < 0.001), while juniors spent more time performing chart review (48% vs 36%, P = 0.19). CONCLUSION: Integrated plastic surgery residents average 1.5 hours on the EHR daily. Junior residents spend 1 hour more per day on the EHR, including more time off-duty and more time performing chart review. These added hours may play a role in duty hour violations and detract from obtaining operative skill sets.

First Probe of Sub-GeV Dark Matter beyond the Cosmological Expectation with the COHERENT CsI Detector at the SNS.

The COHERENT Collaboration searched for scalar dark matter particles produced at the Spallation Neutron Source with masses between 1 and 220 MeV/c^{2} using a CsI[Na] scintillation detector sensitive to nuclear recoils above 9 keV_{nr}. No evidence for dark matter is found and we thus place limits on allowed parameter space. With this low-threshold detector, we are sensitive to coherent elastic scattering between dark matter and nuclei. The cross section for this process is orders of magnitude higher than for other processes historically used for accelerator-based direct-detection searches so that our small, 14.6 kg detector significantly improves on past constraints. At peak sensitivity, we reject the flux consistent with the cosmologically observed dark-matter concentration for all coupling constants α_{D}<0.64, assuming a scalar dark-matter particle. We also calculate the sensitivity of future COHERENT detectors to dark-matter signals which will ambitiously test multiple dark-matter spin scenarios.

Measurement of Electron-Neutrino Charged-Current Cross Sections on

Using an 185-kg NaI[Tl] array, COHERENT has measured the inclusive electron-neutrino charged-current cross section on ^{127}I with pion decay-at-rest neutrinos produced by the Spallation Neutron Source at Oak Ridge National Laboratory. Iodine is one the heaviest targets for which low-energy (≤50 MeV) inelastic neutrino-nucleus processes have been measured, and this is the first measurement of its inclusive cross section. After a five-year detector exposure, COHERENT reports a flux-averaged cross section for electron neutrinos of 9.2_{-1.8}^{+2.1}×10^{-40} cm^{2}. This corresponds to a value that is ∼41% lower than predicted using the MARLEY event generator with a measured Gamow-Teller strength distribution. In addition, the observed visible spectrum from charged-current scattering on ^{127}I has been measured between 10 and 55 MeV, and the exclusive zero-neutron and one-or-more-neutron emission cross sections are measured to be 5.2_{-3.1}^{+3.4}×10^{-40} and 2.2_{-0.5}^{+0.4}×10^{-40} cm^{2}, respectively.

CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response.

Inhibition of the chemokine receptor CXCR4 in combination with blockade of the PD-1/PD-L1 T cell checkpoint induces T cell infiltration and anticancer responses in murine and human pancreatic cancer. Here we elucidate the mechanism by which CXCR4 inhibition affects the tumor immune microenvironment. In human immune cell-based chemotaxis assays, we find that CXCL12-stimulated CXCR4 inhibits the directed migration mediated by CXCR1, CXCR3, CXCR5, CXCR6, and CCR2, respectively, chemokine receptors expressed by all of the immune cell types that participate in an integrated immune response. Inhibiting CXCR4 in an experimental cancer medicine study by 1-wk continuous infusion of the small-molecule inhibitor AMD3100 (plerixafor) induces an integrated immune response that is detected by transcriptional analysis of paired biopsies of metastases from patients with microsatellite stable colorectal and pancreatic cancer. This integrated immune response occurs in three other examples of immune-mediated damage to noninfected tissues: Rejecting renal allografts, melanomas clinically responding to anti-PD1 antibody therapy, and microsatellite instable colorectal cancers. Thus, signaling by CXCR4 causes immune suppression in human pancreatic ductal adenocarcinoma and colorectal cancer by impairing the function of the chemokine receptors that mediate the intratumoral accumulation of immune cells.

Identification of candidate novel production variants on the Bos taurus chromosome X.

Chromosome X is often excluded from bovine genetic studies due to complications caused by the sex specific nature of the chromosome. As chromosome X is the second largest cattle chromosome and makes up approximately 6% of the female genome, finding ways to include chromosome X in dairy genetic studies is important. Using female animals and treating chromosome X as an autosome, we performed X chromosome inclusive genome-wide association studies in the selective breeding environment of the New Zealand dairy industry, aiming to identify chromosome X variants associated with milk production traits. We report on the findings of these genome-wide association studies and their potential effect within the dairy industry. We identify missense mutations in the MOSPD1 and CCDC160 genes that are associated with decreased milk volume and protein production and increased fat production. Both of these mutations are exonic SNP that are more prevalent in the Jersey breed than in Holstein-Friesians. Of the 2 candidates proposed it is likely that only one is causal, though we have not been able to identify which is more likely.

Measurement of the Coherent Elastic Neutrino-Nucleus Scattering Cross Section on CsI by COHERENT.

We measured the cross section of coherent elastic neutrino-nucleus scattering (CEvNS) using a CsI[Na] scintillating crystal in a high flux of neutrinos produced at the Spallation Neutron Source at Oak Ridge National Laboratory. New data collected before detector decommissioning have more than doubled the dataset since the first observation of CEvNS, achieved with this detector. Systematic uncertainties have also been reduced with an updated quenching model, allowing for improved precision. With these analysis improvements, the COHERENT Collaboration determined the cross section to be (165_{-25}^{+30})×10^{-40} cm^{2}, consistent with the standard model, giving the most precise measurement of CEvNS yet. The timing structure of the neutrino beam has been exploited to compare the CEvNS cross section from scattering of different neutrino flavors. This result places leading constraints on neutrino nonstandard interactions while testing lepton flavor universality and measures the weak mixing angle as sin^{2}θ_{W}=0.220_{-0.026}^{+0.028} at Q^{2}≈(50 MeV)^{2}.

A progressively wetter climate in southern East Africa over the past 1.3 million years.

African climate is generally considered to have evolved towards progressively drier conditions over the past few million years, with increased variability as glacial-interglacial change intensified worldwide. Palaeoclimate records derived mainly from northern Africa exhibit a 100,000-year (eccentricity) cycle overprinted on a pronounced 20,000-year (precession) beat, driven by orbital forcing of summer insolation, global ice volume and long-lived atmospheric greenhouse gases. Here we present a 1.3-million-year-long climate history from the Lake Malawi basin (10°-14° S in eastern Africa), which displays strong 100,000-year (eccentricity) cycles of temperature and rainfall following the Mid-Pleistocene Transition around 900,000 years ago. Interglacial periods were relatively warm and moist, while ice ages were cool and dry. The Malawi record shows limited evidence for precessional variability, which we attribute to the opposing effects of austral summer insolation and the temporal/spatial pattern of sea surface temperature in the Indian Ocean. The temperature history of the Malawi basin, at least for the past 500,000 years, strongly resembles past changes in atmospheric carbon dioxide and terrigenous dust flux in the tropical Pacific Ocean, but not in global ice volume. Climate in this sector of eastern Africa (unlike northern Africa) evolved from a predominantly arid environment with high-frequency variability to generally wetter conditions with more prolonged wet and dry intervals.

Computed tomography-derived fractional flow reserve (FFRCT) has no additional clinical impact over the anatomical Coronary Artery Disease - Reporting and Data System (CAD-RADS) in real-world elective healthcare of coronary artery disease.

AIM: To evaluate the impact of computed tomography-derived fractional flow reserve (FFRCT) compared to the anatomical Coronary Artery Disease - Reporting and Data System (CAD-RADS) in the elective assessment of coronary artery disease in real-world cardiology practise. MATERIALS AND METHODS: A retrospective review was undertaken of 1,239 coronary CT examinations from August 2018 to December 2019 with a minimum follow-up period of 1 year. Coronary disease was classified according to the CAD-RADS system. A non-occlusive ≥30% maximum diameter stenosis was considered eligible for FFRCT. Lesion-specific FFRCT and FFR were considered positive if ≤ 0.80. The patients were followed up using the hospital radiology information system and the electronic patient record. A positive outcome was defined by a subsequent invasive angiogram (ICA) showing disease requiring revascularisation or FFR ≤0.80 or a positive stress test or medical therapy for angina in CAD-RADS 4. RESULTS: Of the 1,145 analysable studies (mean follow up 618 ± 153 days) the incidence of a positive result was 7% with a 5.4% elective revascularisation rate. Two hundred and forty-five patients (CAD-RADS 2-4) had FFRCT. FFRCT reduced the accuracy of the CAD-RADS grade from 91% to 78.4% (p<0.001). In CAD-RADS 2, the accuracy is reduced from 99% to 90.7% (p=0.005), and in CAD-RADS 3 from 93.9% to 67.7% (p<0.001). In CAD-RADS 4, FFRCT increases accuracy from 69.4% to 75.5% (p=0.025), but 89.8% of FFRCT are positive and specificity is low (26.7%). CONCLUSION: In the present "real-world" practise, FFRCT does not improve standard radiological assessment of coronary disease graded by the CAD-RADS alone.

Loss of MeCP2 in immature neurons leads to impaired network integration.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations or deletions in Methyl-CpG-binding Protein 2 (MeCP2), a brain-enriched transcriptional regulator. MeCP2 is highly expressed during neuronal maturation and its deficiency results in impaired dendritic morphogenesis and reduced dendritic spine numbers in developing neurons. However, whether MeCP2 deficiency impacts the integration of new neurons has not been directly assessed. In this study, we developed a modified rabies virus-mediated monosynaptic retrograde tracing method to interrogate presynaptic integration of MeCP2-deficient new neurons born in the adult hippocampus, a region with lifelong neurogenesis and plasticity. We found that selective deletion of MeCP2 in adult-born new neurons impaired their long-range connectivity to the cortex, whereas their connectivity within the local hippocampal circuits or with subcortical regions was not significantly affected. We further showed that knockdown of MeCP2 in primary hippocampal neurons also resulted in reduced network integration. Interestingly, (1-3) insulin-like growth factor-1 (IGF-1), a small peptide under clinical trial testing for RTT, rescued neuronal integration deficits of MeCP2-deficient neurons in vitro but not in vivo. In addition, (1-3) IGF-1 treatment corrected aberrant excitability and network synchrony of MeCP2-deficient hippocampal neurons. Our results indicate that MeCP2 is essential for immature neurons to establish appropriate network connectivity.

Comparison of in vivo and in situ detection of hippocampal metabolites in mouse brain using 1 H-MRS.

The study of cerebral metabolites relies heavily on detection methods and sample preparation. Animal experiments in vivo require anesthetic agents that can alter brain metabolism, whereas ex vivo experiments demand appropriate fixation methods to preserve the tissue from rapid postmortem degradation. In this study, the metabolic profiles of mouse hippocampi using proton magnetic resonance spectroscopy (1 H-MRS) were compared in vivo and in situ with or without focused beam microwave irradiation (FBMI) fixation. Ten major brain metabolites, including lactate (Lac), N-acetylaspartate (NAA), total choline (tCho), myo-inositol (mIns), glutamine (Gln), glutamate (Glu), aminobutyric acid (GABA), glutathione (GSH), total creatine (tCr) and taurine (Tau), were analyzed using LCModel. After FBMI fixation, the concentrations of Lac, tCho and mIns were comparable with those obtained in vivo under isoflurane, whereas other metabolites were significantly lower. Except for a decrease in NAA and an increase in Tau, all the other metabolites remained stable over 41 hours in FBMI-fixed brains. Without FBMI, the concentrations of mIns (before 2 hours), tCho and GABA were close to those measured in vivo. However, higher Lac (P < .01) and lower NAA, Gln, Glu, GSH, tCr and Tau were observed (P < .01). NAA, Gln, Glu, GSH, tCr and Tau exhibited good temporal stability for at least 20 hours in the unfixed brain, whereas a linear increase of tCho, mIns and GABA was observed. Possible mechanisms of postmortem degradation are discussed. Our results indicate that a proper fixation method is required for in situ detection depending on the targeted metabolites of specific interests in the brain.

First Measurement of Coherent Elastic Neutrino-Nucleus Scattering on Argon.

We report the first measurement of coherent elastic neutrino-nucleus scattering (CEvNS) on argon using a liquid argon detector at the Oak Ridge National Laboratory Spallation Neutron Source. Two independent analyses prefer CEvNS over the background-only null hypothesis with greater than 3σ significance. The measured cross section, averaged over the incident neutrino flux, is (2.2±0.7)×10^{-39} cm^{2}-consistent with the standard model prediction. The neutron-number dependence of this result, together with that from our previous measurement on CsI, confirms the existence of the CEvNS process and provides improved constraints on nonstandard neutrino interactions.

In-situ measurement of pyrolysis and combustion gases from biomass burning using swept wavelength external cavity quantum cascade lasers.

Broadband high-speed absorption spectroscopy using swept-wavelength external cavity quantum cascade lasers (ECQCLs) is applied to measure multiple pyrolysis and combustion gases in biomass burning experiments. Two broadly-tunable swept-ECQCL systems were used, with the first tuned over a range of 2089-2262 cm-1 (4.42-4.79 µm) to measure spectra of CO2, H2O, and CO. The second was tuned over a range of 920-1150 cm-1 (8.70-10.9 µm) to measure spectra of ammonia (NH3), ethene (C2H4), and methanol (MeOH). Absorption spectra were measured continuously at a 100 Hz rate throughout the burn process, including inhomogeneous flame regions, and analyzed to determine time-resolved gas concentrations and temperature. The results provide in-situ, dynamic information regarding gas-phase species as they are generated, close to the biomass fuel source.

Enhanced Electron-Phonon Coupling for Charge-Density-Wave Formation in La_{1.8-x}Eu_{0.2}Sr_{x}CuO_{4+δ}.

Charge density wave (CDW) correlations are prevalent in all copper-oxide superconductors. While CDWs in conventional metals are driven by coupling between lattice vibrations and electrons, the role of the electron-phonon coupling (EPC) in cuprate CDWs is strongly debated. Using Cu L_{3} edge resonant inelastic x-ray scattering, we study the CDW and Cu-O bond-stretching phonons in the stripe-ordered cuprate La_{1.8-x}Eu_{0.2}Sr_{x}CuO_{4+δ}. We investigate the interplay between charge order and EPC as a function of doping and temperature and find that the EPC is enhanced in a narrow momentum region around the CDW ordering vector. By detuning the incident photon energy from the absorption resonance, we extract an EPC matrix element at the CDW ordering vector of M≃0.36 eV, which decreases to M≃0.30 eV at high temperature in the absence of the CDW. Our results suggest a feedback mechanism in which the CDW enhances the EPC which, in turn, further stabilizes the CDW.

Efficient removal of bacteria from aqueous media with kaolinite and diatomaceous earth products.

AIMS: To understand the relationships between physical and chemical parameters of kaolinite and diatomaceous earth, and their capacities to remove bacteria from aqueous media. To determine the optimal aqueous media parameters for use of these products in water disinfection processes. METHODS AND RESULTS: Seven kaolinite and three diatomaceous earth products were evaluated. Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus megaterium were used as proxy for bacterial pathogens. Fully calcined kaolin and amorphous diatomaceous earth demonstrated the highest extent and consistency in removing all the bacteria. The removal depended on ionic strength and pH of aqueous media with 100 mmol l-1 pH 5 potassium hydrogen phthalate buffer revealing the highest (2 log per gram) extent of the removal. Al3+ cations enhanced sorption up to 4 log per gram. CONCLUSIONS: Calcined kaolin and amorphous diatomaceous earth are excellent sorbents for bacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: Fully calcined kaolin and amorphous diatomaceous earth are perspective tools for wastewater and water disinfection against waterborne bacterial pathogens.

Salvage procedure for chronic periprosthetic knee infection: the application of DAIR results in better remission rates and infection-free survivorship when used with topical degradable calcium-based antibiotics.

PURPOSE: Debridement, systemic antibiotics and implant retention (DAIR) is very successful for early periprosthetic joint infection (PJI), but can fail in late-onset cases. We selected patients with PJI who were unsuitable for two-stage exchange total knee arthroplasty (TKA) and compared the outcomes of DAIR with or without degradable calcium-based antibiotics. METHODS: All patients fulfilled the criteria for late-onset PJI of TKA, as defined by an International Consensus Meeting in 2013, but were unsuitable for multistage procedures and TKA exchange due to operative risk. Fifty-six patients (mean age: 70.6 years, SD ± 10.8), in two historical collectives, were treated using a single-stage algorithm consisting of DAIR without antibiotics (control group, n = 33, 2012-2014), or by DAIR following the implantation of degradable antibiotics as indicated by an antibiogram (intervention group, n = 23, 2014-2017). OSTEOSET® (admixed vancomycin/tobramycin), and HERAFILL-gentamicin® were used as carrier systems. The primary endpoint was re-infection or surgical intervention after DAIR. RESULTS: There were no significant differences between the two groups in terms of mean age, Charlson comorbidity index or the rate of mixed infections. Overall, 65.2% of patients achieved remission in the intervention group compared with only 18.2% in the control group (p < 0.001); 50% of re-infections in the intervention group even occurred after 36 months. Kaplan-Meier analysis showed that, compared with controls, the intervention group experienced significantly longer 3-year infection-free survival. CONCLUSION: DAIR shows poor efficacy in difficult-to-treat cases, as demonstrated in our control group, which had a re-infection rate of 81.8%. In contrast, a DAIR group receiving topical calcium-based antibiotics showed significantly higher 3-year infection-free survival. Therefore, the combination of DAIR and degradable antibiogram-based local antibiotics is a reasonable salvage procedure for this body of patients. This is important as the number of severely sick patients who are too old for appropriate PJI treatment is estimated to increase significantly due to demographic change.

Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma.

Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values <0.05 considered significant. K3326X and I157T were associated with increased risk of developing sporadic PDAC (odds ratio (ORdom ) = 1.78, 95% confidence interval (CI) = 1.26-2.52, p = 1.19 × 10-3 and ORdom = 1.74, 95% CI = 1.15-2.63, p = 8.57 × 10-3 , respectively). Neither mutation was significantly associated with risk of developing early-onset PDAC. This retrospective study demonstrates novel risk estimates of K3326X and I157T in sporadic PDAC which suggest that upon validation and in combination with other established genetic and non-genetic risk factors, these mutations may be used to improve pancreatic cancer risk assessment in European populations. Identification of carriers of these risk alleles as high-risk groups may also facilitate screening or prevention strategies for such individuals, regardless of family history.