Energy efficiency and comfort in the workplace: Norwegian cellular and British open plan workplaces

Two office layouts with high and low levels of thermal control were compared, respectively Norwegian cellular and British open plan offices. The Norwegian practice provided every user with control over a window, blinds, door, and the ability to adjust heating and cooling. Occupants were expected to control their thermal environment to find their own comfort, while air conditioning was operating in the background to ensure the indoor air quality. In contrast, in the British office, limited thermal control was provided through openable windows and blinds only for occupants seated around the perimeter of the building. Centrally operated displacement ventilation was the main thermal control system. Users’ perception of thermal environment was recorded through survey questionnaires, empirical building performance through environmental measurements and thermal control through semi-structured interviews. The Norwegian office had 35% higher user satisfaction and 20% higher user comfort compared to the British open plan office. However, the energy consumption in the British practice was within the benchmark and much lower than the Norwegian office. Overall, a balance between thermal comfort and energy efficiency is required, as either extreme poses difficulties for the other

Malignant islet-cell tumors of the pancreas

Although malignant islet-cell tumors are uncommon, they are an important group of pancreatic neoplasms because appropriate treatment can often result in effective palliation even though cure is infrequent. In general, these tumors are relatively slow growing so that a combination of surgical and chemotherapeutic measures may prove very beneficial. In some patients with tumors hypersecreting insulin, gastrin, glucagon, or vasoactive intestinal polypeptide (VIP), the hormonal effects of the neoplasm can be life-threatening. Surgical treatment must, therefore, consider both the functional and malignant characteristics of the individual tumor. In many patients with functional tumors, surgical debulking of the primary tumor may be indicated even when a curative resection cannot be accomplished. Some malignancies may be cured by an appropriate pancreatic resection even when peripancreatic lymph nodes are already involved. Although a Whipple procedure is not indicated when hepatic metastases are present, this procedure may cure tumors localized to the pancreatic head and/or peripancreatic lymph nodes. Because hepatic metastases are usually multiple and involve both lobes, liver resections, other than wedge excisions of peripherally located functional metastases, are not indicated. Malignant nonfunctioning islet-cell tumors are probably best treated with systemic or regional chemotherapy when metastatic. Surgical resections or bypass procedures may be infrequently useful in those cases in which the primary tumor causes either duodenal or bile duct obstruction. The most effective methods used to control hepatic metastases are systemic and hepatic arterial chemotherapy. An alternative is selective hepatic artery embolization. Recently, an implantable hepatic arterial infusion pump has been used with encouraging results in this group of patients. The chemotherapeutic agents that have been most effective in the treatment of hepatic metastases include streptozotocin, DTIC, and fluorouracil . Les tumeurs insulaires malignes sont rares mais elles présentent un grand intérêt car si le traitement entraîne exceptionnellement leur guérison il assure une survie des malades qui en sont porteurs. Ce sont en effet des tumeurs malignes à développement lent, sensibles à l'action de l'association de la chimiothérapie et de la chirurgie. Chez certains sujets les tumeurs secrétant de l'insuline, de la gastrine, du glucagon, du V.I.P. peuvent mettre en jeu la vie du malade sous l'effet de l'hypersecrétion hormonale. Le traitement chirurgical dépend de ce fait, des caractères fonctionnels et du degré de malignité de chaque type de tumeur. En présence de lésions hypersecrétantes l'exérèse de la tumeur primitive doit être envisagée alors même que la possibilité d'obtenir une guérison définitive ne peut être escomptée. Il est aussi à noter que certaines lésions malignes ont été traitées avec succès alors que les ganglions lymphatiques correspondants étaient déjà envahis. Si l'opération est contre-indiquée en présence de métastases hépatiques la duodénopancréatectomie céphalique s'applique aux tumeurs insulaires céphaliques qu'elles s'accompagnent ou non d'un envahissement des ganglions juxta-pancréatiques. Du fait que les métastases hépatiques sont souvent multiples et qu'elles intéressent les deux lobes l'action sur le foie se limite à l'éxérèse des métastases accessibles à la résection hépatique segmentaire. Les tumeurs insulaires malignes qui ne sont pas hypersecrétantes relèvent de la chimiothérapie par voie générale ou de la chimiothérapie régionale dès lors qu'elles s'accompagnent de métastases. C'est seulement lorsque ces lésions entraînent une obstruction de la voie biliaire principale ou du duodénum que la résection ou les anastomoses de dérivation sont indiquées. La chimiothérapie par voie générale ou par la voie de l'artère hépatique ou encore l'embolisation de cette dernière représentent les meilleures méthodes de traitement des métastases hépatiques. L'emploi récent de pompes à infusion de l'artère hépatique a donné des résultats intéressants chez ces malades. Les agents chimiques les plus efficaces sont la streptozotocine, le DTIC et le Fluorouracil. Aunque los tumores malignos de células insulares del páncreas son raros, éstos constituyen un grupo importante entre las neoplasias pancreáticas por cuanto el tratamiento apropiado con frecuencia resulta en una paliación efectiva a pesar de que la curación sea poco frecuente. En general estos tumores son de crecimiento lento y la combinación de la cirugía con quimioterapia puede llegar a ser beneficiosa. En algunos pacientes con tumores que hipersecretan insulina, gastrina, glucagón o VIP (polipéptido vasoactivo intestinal), los efectos hormonales del neoplasma pueden poner en peligro la vida. Por ello el tratamiento quirúrgico debe considerar tanto las caracteristicas funcionales como las de malignidad de cada tumor en particular. En muchos pacientes con neoplasmas funcionantes, el debultamiento quirúrgico del tumor primario puede estar indicado cuando la resección curativa no es realizable. Algunas neoplasias malignas pueden ser curadas mediante una resección pancreática adecuada a pesar de que los ganglios linfáticos peripancreáticos ya se hallen afectados. Aún cuando el procedimiento de Whipple no esta indicado en presencia de metástasis hepáticas, esta operación puede curar tumores localizados en la cabeza del páncreas y/o en los ganglios linfáticos peripancreáticos. Debido a que las metástasis hepáticas generalmente son múlitples y afectan a ambos lóbulos, las resecciones hepáticas, diferentes de las resecciones en cuña para lesiones funcionantes localizadas en la periferie del higado no están indicadas. Los tumores malignos no funcionantes de células insulares probablemente deben ser tratadas con quimioterapia sistémica o regional cuando se encuentren en fase metastásica. Las resecciones quirúrgicas o los procedimientos derivativos infrecuentemente son de utilidad en aquellos casos en los cuales el tumor primario causa obstrucción duodenal o del conducto biliar. Los métodos de mayor efectividad en el control de las metéstasis hepáticas son los de quimioterapia sistémica y arterial hepática. Una alternativa es la embolización selectiva de la arteria hepática. Recientemente ha venido a ser utilizada una bomba implantable de infusión arterial heptica con resultados halagadores en este grupo de pacientes. Los agentes quimioterapéuticos que han probado ser de mayor efectividad en el tratamiento de las metástasis hepáticas incluyen la estreptozotocina, la dimetiltrizenoimidazol carboxamida (DTIC) y el Fluorouracilo.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41316/1/268_2005_Article_BF01656036.pd

Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus.

BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. CONCLUSION: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.UK funding includes Cancer Research UK and NIH.This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s13058-016-0718-

Fine-Scale Mapping of the 5q11.2 Breast Cancer Locus Reveals at Least Three Independent Risk Variants Regulating MAP3K1

Peer reviewe

No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing.

BACKGROUND: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. METHODS: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. RESULTS: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). CONCLUSIONS: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.The COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 - HEALTH-F2-2009-223175). BCAC is funded by Cancer Research UK [C1287/A10118, C1287/A12014] and by the European Community´s Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 16 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defense (W81XWH-10-1- 0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. This study made use of data generated by the Wellcome Trust Case Control consortium. Funding for the project was provided by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by The Cancer Genome Atlas Project established by the National Cancer Institute and National Human Genome Research Institute.This is the author accepted manuscript. The final version is available from BMJ Group at http://dx.doi.org/10.1136/jmedgenet-2015-103529

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Impact of individual level uncertainty of lung cancer polygenic risk score (PRS) on risk stratification

Background Although polygenic risk score (PRS) has emerged as a promising tool for predicting cancer risk from genome-wide association studies (GWAS), the individual-level accuracy of lung cancer PRS and the extent to which its impact on subsequent clinical applications remains largely unexplored. Methods Lung cancer PRSs and confidence/credible interval (CI) were constructed using two statistical approaches for each individual: (1) the weighted sum of 16 GWAS-derived significant SNP loci and the CI through the bootstrapping method (PRS-16-CV) and (2) LDpred2 and the CI through posteriors sampling (PRS-Bayes), among 17,166 lung cancer cases and 12,894 controls with European ancestry from the International Lung Cancer Consortium. Individuals were classified into different genetic risk subgroups based on the relationship between their own PRS mean/PRS CI and the population level threshold. Results Considerable variances in PRS point estimates at the individual level were observed for both methods, with an average standard deviation (s.d.) of 0.12 for PRS-16-CV and a much larger s.d. of 0.88 for PRS-Bayes. Using PRS-16-CV, only 25.0% of individuals with PRS point estimates in the lowest decile of PRS and 16.8% in the highest decile have their entire 95% CI fully contained in the lowest and highest decile, respectively, while PRS-Bayes was unable to find any eligible individuals. Only 19% of the individuals were concordantly identified as having high genetic risk (> 90th percentile) using the two PRS estimators. An increased relative risk of lung cancer comparing the highest PRS percentile to the lowest was observed when taking the CI into account (OR = 2.73, 95% CI: 2.12–3.50, P-value = 4.13 × 10−15) compared to using PRS-16-CV mean (OR = 2.23, 95% CI: 1.99–2.49, P-value = 5.70 × 10−46). Improved risk prediction performance with higher AUC was consistently observed in individuals identified by PRS-16-CV CI, and the best performance was achieved by incorporating age, gender, and detailed smoking pack-years (AUC: 0.73, 95% CI = 0.72–0.74). Conclusions Lung cancer PRS estimates using different methods have modest correlations at the individual level, highlighting the importance of considering individual-level uncertainty when evaluating the practical utility of PRS

AD51B in Familial Breast Cancer

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C&gt;T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11–1.19, P = 8.88 x 10−16) and among familial cases (OR: 1.24, 95% CI: 1.16–1.32, P = 6.19 x 10−11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk

Iam hiQ—a novel pair of accuracy indices for imputed genotypes

Background Imputation of untyped markers is a standard tool in genome-wide association studies to close the gap between directly genotyped and other known DNA variants. However, high accuracy with which genotypes are imputed is fundamental. Several accuracy measures have been proposed and some are implemented in imputation software, unfortunately diversely across platforms. In the present paper, we introduce Iam hiQ, an independent pair of accuracy measures that can be applied to dosage files, the output of all imputation software. Iam (imputation accuracy measure) quantifies the average amount of individual-specific versus population-specific genotype information in a linear manner. hiQ (heterogeneity in quantities of dosages) addresses the inter-individual heterogeneity between dosages of a marker across the sample at hand. Results Applying both measures to a large case–control sample of the International Lung Cancer Consortium (ILCCO), comprising 27,065 individuals, we found meaningful thresholds for Iam and hiQ suitable to classify markers of poor accuracy. We demonstrate how Manhattan-like plots and moving averages of Iam and hiQ can be useful to identify regions enriched with less accurate imputed markers, whereas these regions would by missed when applying the accuracy measure info (implemented in IMPUTE2). Conclusion We recommend using Iam hiQ additional to other accuracy scores for variant filtering before stepping into the analysis of imputed GWAS data

Measurement of the View the tt production cross-section using eμ events with b-tagged jets in pp collisions at √s = 13 TeV with the ATLAS detector

This paper describes a measurement of the inclusive top quark pair production cross-section (σtt¯) with a data sample of 3.2 fb−1 of proton–proton collisions at a centre-of-mass energy of √s = 13 TeV, collected in 2015 by the ATLAS detector at the LHC. This measurement uses events with an opposite-charge electron–muon pair in the final state. Jets containing b-quarks are tagged using an algorithm based on track impact parameters and reconstructed secondary vertices. The numbers of events with exactly one and exactly two b-tagged jets are counted and used to determine simultaneously σtt¯ and the efficiency to reconstruct and b-tag a jet from a top quark decay, thereby minimising the associated systematic uncertainties. The cross-section is measured to be: σtt¯ = 818 ± 8 (stat) ± 27 (syst) ± 19 (lumi) ± 12 (beam) pb, where the four uncertainties arise from data statistics, experimental and theoretical systematic effects, the integrated luminosity and the LHC beam energy, giving a total relative uncertainty of 4.4%. The result is consistent with theoretical QCD calculations at next-to-next-to-leading order. A fiducial measurement corresponding to the experimental acceptance of the leptons is also presented