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Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry1. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10−8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2–5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

Objective: To examine the risk of bias in chiropractic mixed methods research. Methods: We performed a secondary analysis of a meta-epidemiological review of chiropractic mixed methods studies. We assessed risk of bias with the Mixed Methods Appraisal Tool (MMAT) and used generalized estimating equations to explore factors associated with risk of bias. Results: Among 55 eligible studies, a mean of 62% (6.8 [2.3]/11) of MMAT items were fulfilled. In our adjusted analysis, studies published since 2010 versus pre-2010 (adjusted odds ratio [aOR] = 2.26; 95% confidence interval [CI], 1.39 to 3.68) and those published in journals with an impact factor versus no impact factor (aOR = 2.21; 95% CI, 1.33 to 3.68) were associated with lower risk of bias. Conclusion: Our findings suggest opportunities for improvement in the quality of conduct among published chiropractic mixed methods studies. Author compliance with the MMAT criteria may reduce methodological bias in future mixed methods research.

185Background: The FOLFIRI regimen (5-fluorouracil, leucovorin and irinotecan) is a predominant treatment regimen for metastatic colorectal cancer. To optimize the benefit for the patients, it would be desirable to increase the efficacy of irinotecan by increasing the exposure of SN-38 (the active metabolite of irinotecan) to the cancer cells, while maintaining a good safety profile. The oral drug SCO-101, that is currently being developed by Scandion Oncology A/S, was tested in an early clinical trial (CORIST-trial, ClinicalTrials.gov identifier: NCT04247256). SCO-101 is an inhibitor of ABCG2, UGT1A1 and SRPK1. The CORIST trial was set up to address the safety, tolerability, and efficacy of SCO-101 given orally for 6 days followed by FOLFIRI at varying doses from day 5 to 7, in a biweekly schedule, in patients with metastatic colorectal cancer who have formerly been treated with FOLFIRI and afterwards progressed. The first part of the study was a dose-finding study, where the impact of SCO-101 on the pharmacokinetics (PK) of SN-38 was studied. Methods: 12 patients from the dose-finding part of the CORIST study received 150 mg SCO-101 for 6 days and 45 ? 80% of the recommended dose of FOLFIRI. 6 of the patients had RAS wild-type tumors and these patients are the subject of the current analysis. Blood for PK analysis was sampled from the patients at 1, 2, 4, 8, 24, 48, and 96 hours after treatment with FOLFIRI and SCO-101. The blood samples were analyzed for Cmax, T½ and AUC (0-24h) of SCO-101, irinotecan and SN-38. Results: The PK of SN-38 from the patients in the study, normalized to a dose of irinotecan of 90 mg/m2 showed a T½ day 5 of 19 hours (SD 5,7) a Cmax of 60 ng/ml (SD 20,6) and an AUC_0-24h of 1415 hxng/ml (SD: 670). The results were compared to SN-38 data from treatment with irinotecan at 180 mg/m2, which is used in standard doses of FOLFIRI and the data is presented in the table. The data analysis showed an increased T½, increased Cmax and increased AUC of SN-38 when combining SCO-101 with 90 mg/m2 irinotecan, compared to SN-38 PK data from standard irinotecan treatment of 180 mg/m2. The toxicity profile of the patients treated with 90 mg irinotecan/m2 (50% FOLFIRI) showed only grade 1 and 2 adverse events. Conclusions: SCO-101 in combination with FOLFIRI has demonstrated the ability to modulate the PK profile of SN-38 in mCRC patients with RAS wild-type tumors, by significantly increasing the half-life, the peak plasma concentration, and area under the curve of SN-38. The combined treatment was well tolerated, and the drug is now being tested for efficacy in the CORIST trial.Comparison of SN-38 PK data between standard irinotecan and data from CORIST study.Dose irinotecan/m2T½ hours (SD)Cmax ng/ml (SD)AUC_0-24 hxng/ml (SD)SN-38 Standard180 mg11,7 (4,3)40 (11,6)385 (115)SN-38 CORIST90 mg19 (5,7)60 (20,6)1415 (670)Fold increase (CORIST vs Standard)0,51,61,53,7

Convolutional neural networks have enabled significant improvements in medical image-based diagnosis. It is, however, increasingly clear that these models are susceptible to performance degradation when facing spurious correlations and dataset shift, leading, e.g., to underperformance on underrepresented patient groups. In this paper, we compare two classification schemes on the ADNI MRI dataset: a simple logistic regression model using manually selected volumetric features, and a convolutional neural network trained on 3D MRI data. We assess the robustness of the trained models in the face of varying dataset splits, training set sex composition, and stage of disease. In contrast to earlier work in other imaging modalities, we do not observe a clear pattern of improved model performance for the majority group in the training dataset. Instead, while logistic regression is fully robust to dataset composition, we find that CNN performance is generally improved for both male and female subjects when including more female subjects in the training dataset. We hypothesize that this might be due to inherent differences in the pathology of the two sexes. Moreover, in our analysis, the logistic regression model outperforms the 3D CNN, emphasizing the utility of manual feature specification based on prior knowledge, and the need for more robust automatic feature selection.

SummaryNeuroimaging offers a wide range of opportunities to obtain information about neuronal activity, brain inflammation, blood–brain barrier alterations, and various molecular alterations during epileptogenesis or for the prediction of pharmacoresponsiveness as well as postoperative outcome. Imaging biomarkers were examined during the XIII Workshop on Neurobiology of Epilepsy (XIII WONOEP) organized in 2015 by the Neurobiology Commission of the International League Against Epilepsy (ILAE). Here we present an extended summary of the discussed issues and provide an overview of the current state of knowledge regarding the biomarker potential of different neuroimaging approaches for epilepsy.

Background: Cannabinoids induce biphasic effects on memory depending on stress levels. We previously demonstrated that different stress intensities, experienced soon after encoding, impaired rat short-term recognition memory in a time-of-day-dependent manner, and that boosting endocannabinoid anandamide (AEA) levels restored memory performance. Here, we examined if two different stress intensities and time-of-day alter hippocampal endocannabinoid tone, and whether these changes modulate short-term memory. Methods: Male Sprague-Dawley rats were subjected to an object recognition task and exposed, at two different times of the day (i.e., morning or afternoon), to low or high stress conditions, immediately after encoding. Memory retention was assessed 1 hr later. Hippocampal AEA and 2-arachidonoyl glycerol (2-AG) content and the activity of their primary degrading enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), were measured soon after testing. Results: Consistent with our previous findings, low stress impaired 1-hr memory performance only in the morning, whereas exposure to high stress impaired memory independently of testing time. Stress exposure decreased AEA levels independently of memory alterations. Interestingly, exposure to high stress decreased 2-AG content and, accordingly, increased MAGL activity, selectively in the afternoon. Thus, to further evaluate 2-AG's role in the modulation of short-term recognition memory, rats were given bilateral intra-hippocampal injections of the 2-AG hydrolysis inhibitor KML29 immediately after training, then subjected to low or high stress conditions and tested 1 hr later. Conclusions: KML29 abolished the time-of-day-dependent impairing effects of stress on short-term memory, ameliorating short-term recognition memory performance.